Download Aunt Cathy`s Guide to Nutrition

MeritCare Medical Center
Aunt Cathy’s
Some Ideas for Trying to
Eat More of Those Terrific
Antioxidant Phytochemicals
. . . and Liking It.
Cathy Breedon PhD, RD, CSP, FADA
Clinical Nutrition Specialist
MeritCare Health Systems, Fargo, ND
and UND School of Medicine
Recipe 1: Cranberry-Raspberry-Orange-Jello Thing-y.
This one is originally out of the Better Homes and gardens cookbook . . . probably an
older one (1950s - the red and white plaid one) or one that was a re-issue. It is called
something like "Cranberry Raspberry Ring" or something close. It is in the salad section.
Here's my version:
1. Cut up an orange and remove the seeds and stem area. Put it into a food processor (rind
and all) with a little orange juice (a splash or so) to blenderize it into mass of orange pulp.
2. Take a fresh or frozen bag of cranberries and pick out any bad ones (there are usually a
few - they often float up if you put them into some water to wash them off.) Pour the rest
of the bag into the food processor and blend it up with the orange. You can process it to
bigger chunks of cranberry or down to tiny, as you prefer. As a rule, frozen ones mush up
faster than fresh but the fresh ones are the best tasting if they are available.
3. Boil some water and pour 1-1/2 cups boiling water into a large bowl that can take
changes in heat and cold. Stir in a packet of Jello (or whatever brand) lemon gelatin and a
packet of raspberry gelatin. Stir while sprinkling it in so it dissolves well without globbing
up into gelatinous strangely chewy masses. You can use regular or sugar free. I use sugar
free because I don't need the calories and one of my Thanksgiving guests has diabetes.
Using sugar free means she gets to have a lot more of it.
4. Stir in the cranberry/orange mixture. Pour in a bag of frozen raspberries (the kind that
are frozen without any added sugar.) The cold berries will gel it up pretty quickly. At this
point, I just stick the bowl into the fridge with some saran wrap on top and it is ready to
eat in literally just a few minutes. Just scoop some out and put it in a bowl or on a plate.
Replace saran wrap on the remainder.
The original recipe has two additional steps:
1. After it is partially gelled, gently stir in 6 oz of a diet or regular lemon-lime soda.
(Chug the rest . . . you have to stay hydrated while slaving over a hot stove.) The soda
idea is to trap the carbonation, which gives it a little fizzy kick. I usually don't bother with
that part. I forgot once and barely noticed, and since it was so much more work . . .
2. They have you put it into a ring mold or bundt pan so you can serve it in an attractive
way, flipped over and very home-ec looking. I have done this but it is pretty messy and
really only looks nice for about 3.5 minutes, or until people start taking some. If it gets a
bit warm in the room it can experience some melting. What a mess! So, I just keep it in
the mixing bowl itself in the fridge for normal use, or pour it all into a nice serving bowl
and put it into the fridge so it can go to the table later.
Bottom line: It tastes great. Calories are low: cranberries are very low kcal, the sugar
free version adds no additional calories. So really, it is just the berries, and they are not
high. However, both cranberries and raspberries are full of those terrific red/blue
anthocyanin antioxidant pigments. It also keeps a person regular if consumed in large
volumes daily. My mother likes it a little sweeter so she sprinkles some splenda or
nutrasweet on hers and mixes it in. I like it with a bit more bite. It is a nice healthy and
yummy snack. My mother also puts it on ice cream. Mothers are very wise.
Variation: My husband likes it even better if I use a bag of the frozen triple berry
mixture (frozen raspberries, blueberries and blackberries or boysenberries) instead of
raspberries alone. He loves blueberries and since all those berries are great antioxidant
phytochemicals, we try different combos.
Recipe 2: Spinach and Raspberry Salad.
Get a bag of ready-to-use spinach (preferably minus the e-coli) and put some on a plate.
Get a bag of frozen raspberries (the same kind as above, frozen separately initially and
without syrup) and pour some onto the spinach. You can pour a little or a lot. I pour a lot.
Put it into the fridge ahead of time and the berries will melt a bit and some juices will be
on the spinach leaves. You can also have the berries already thawed, or whatever. The
juices of the raspberries (from a bit of smashing) is all I use as a dressing. My husband
likes to put on a bit of raspberry vinaigrette dressing. For special deluxe salads (that is . . .
company) we sprinkle it with slivered almonds and fresh sliced pears. The pears should
be added just before serving so they don't get brown, or use some fruit fresh. The
raspberries usually go on top of the pears, and then the nuts on top of it all. Really
yummy and industrial strength phytochemicals and magnesium!
I once fed this to my niece’s third grade class along with several other brightly colored
fruits and vegetables that were likely to be regarded as new and exotic (and therefore
perceived to be icky.) If the kids tasted everything they were rewarded (bribed) with cool
glitter pens. Afterward they voted and in general they liked a lot of the foods, but the
spinach raspberry salad was the food they elected as the clear favorite. (SPINACH??!!)
My niece asked me if I would make this for her for her birthday. I said yes.
Recipe 3: Pretty Darn Good Broccoli
I learned about this in a Russian restaurant in St. Paul. They served what looked like just
a ton of plain steamed broccoli as a side dish and I was preparing to be brave and eat it
because a bunch of nutrition people were there with me that I did not know. I remember
thinking "Ratz! I'm going to have to eat that!" :-)
I love broccoli if there is enough hollandaise sauce, but plain can taste kind of bitter to
me, especially raw broccoli. But when I tasted it I discovered that it was really good!
(Not just “I can eat this” good . . . it was “I WANT to eat this” good.)
I asked them what the secret was. Just before the chef served it, he just sprinkled it with a
little warm water into which a small amount of honey had been dissolved. Plain sugar
would likely work well, too. The point of that one is that for many people who can taste
some bitter substances in vegetables like broccoli or kale (like a lot of little kids and
immature people like me,) a touch of sweet can cut the bitterness quite a lot.
But since foods like broccoli and kale are real nutrition giants (tons of nutrients and
friendly phytochemicals, fiber and extremely low calories . . . as in, practically none,) if
the little bit of sugar used makes them palatable enough for the "I-hate-broccoli" set to eat
them and enjoy them, it is a very good trade-off.
Recipe 4: Stealth Vegetables
Take any kind of left-over fruits or vegetables from a meal and put them into a freezer
bag and pop them into the freezer (using appropriately safe food handling techniques,
etc., of course.) Do this for several days, weeks or months. When the volume of these
little freezer treats reaches critical mass, put all of them into a food processor and blend
the heck out of them.
Put the pureed vegie/fruit/whatever combo into an ice cube tray and freeze it. When
frozen, pop out the cubes and put them into a freezer bag. Keep them handy there in the
freezer section where they are visible, easy to grab and easy to remember that you have
them. If they are out of sight or you have to dig for them . . . well, you know.
Anyway, whenever you make something with a lot of flavor (chili, spaghetti sauce,
soups, curry, meatloaf, etc.) toss a cube or two or six into the mix. Depending what you
put in there, you can add a dollop of a nice variety of beneficial phytochemicals, vitamins
and minerals and hardly any calories.
Now, here’s an important thing to remember: You must be sure to blenderize the
stuff sufficiently so there are no recognizable chunks of vegetable carcass remaining.
That’s the stealth part.
Enjoy! Cathy B.
MeritCare Medical Center and
Roger Maris Cancer Center
Aunt Cathy’s
Guide to Nutrition:
Nutrition and
Breast Cancer
(This is the shorter little-or no-references version;
a version with more references cited is also available)
5/2010
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Clinical and Metabolic Nutrition Specialist
MeritCare Medical Center, Fargo, ND,
UND School of Medicine Dept. of Pediatrics
and Breast Cancer Survivor
(Roger Maris Cancer Center Class of ’98)
This is a quick summary of some things in the nutrition news related to breast
cancer. Although very few references are provided in this brief version, all the
suggestions are based on reports in the legitimate scientific literature and the references
are available on my more thorough papers that are also on MeritCare Medical Center’s
website. My recommendations are not based on goofy things found on the Internet.
When “researching” a topic on the internet, it is important to consider the
reliability of the source. After all, there is no law against fiction in America! People can
pretty much print anything. For example, websites that end in .edu (colleges and
universities) tend to be more reliable than sites designed primarily to sell you something.
We are learning a lot of new things every day, so the information here is subject
to change at any moment! ☺ (That’s why there is always a date on my papers.) And of
course, none of the following suggestions are intended to take the place of the advice of
your health care provider.
Outline:
page
1. A Plant-Based Diet
2
2. Soybeans … a Special Kind of Plant
6
3. Bundles of Joy: “Baby Plants” (Nuts, Seeds, Beans and the Germ of Grains)
8
4. Amounts and Types of Fats
9
5. Vitamin and Mineral Antioxidants
12
6. Intake of Other Vitamins and Minerals
14
7. Other Plant Chemicals
19
8. “Conditionally Essential” Nutrients
20
9. Miscellaneous
21
10. Quick Summary of My Best Guess for Reducing Risk of Breast Cancer
22
1
1. A PLANT-BASED DIET
Increasing the proportion of fruits, vegetables and whole grains in the diet
reduces risk of many cancers. They provide an amazing assortment of cancer-fighters,
including vitamins and certain “phytochemicals” (plant chemicals), some of which are
potent protective substances called “antioxidants.”
Although the word phytochemicals just means chemicals found in plants, and the
term does not indicate whether certain ones are good, bad or neutral, there is another
clear benefit of a primarily plant-based diet: it also decreases meat intake, a source of
saturated fat. Additionally, it has been found that curing or grilling meats or cooking meat
to a “well done” state can produce some substances that can increase risk of cancer,
including cancer of the breast. [Note: Under-cooking meat is not safe either because of
the risk of bacterial food-borne illness, so that won’t help.]
Research reports can be very confusing with different conclusions reached based on
different study designs. Additionally, the studies brought to our attention via media soundbytes tend to be those perceived to be newsworthy because they are in disagreement with a
lot of other studies. [As a rule of thumb, one study reporting a contradictory finding does
not negate the findings of hundreds of other studies showing the opposite … it just makes
for better headlines.]
One thing that makes things so confusing is that in nature nothing occurrs in a
vacuum. But research studies often try to study an issue by looking to see what happens
when everything is kept constant except for one particular variable, like, say, “hot dog
consumption.” But since these food qualities can interact with other circumstances, the
results may be only applicable under certain specific conditions. For example, a generous
antioxidant intake like eating brightly colored fruits and vegetables with the hot dog (or
even putting ketchup on it) decreases some of the negative effects of some components of
cured meats.
An example of one of these potentially cancer-causing substances is called “sodium
nitrite” which is used in curing meats to protect against certain bacteria and to preserve
the red/pink quality of the meat. In the stomach nitrites can be converted to nitrosamines
… which are the substances that appear to increase risk of cancer. However, eating foods
at the same time that provide generous antioxidants can prevent the formation of
nitrosamines. Some cured meats actually have some vitamin C (an antioxidant vitamin)
added to prevent nitrosamine production.
In any case, we Americans tend to eat quite a lot of meat … some estimates are that
we on average eat 3 times the suggested amount. And processed meats are usually very
high in sodium. So simply filling up on more veggies and fruits can help cut back on the
sheer volume of meats consumed. The fruits and veggies are the source of some of the
most potent beneficial antioxidant phytochemicals.
2
Many of the beneficial plant chemical substances happen to be the brightly
colored pigments that give fruits and vegetables their color. These pigments are very
promising as agents of reducing risk of cancers and many other threats to health (such as
the complications of diabetes or blindness due to macular degeneration.) As an example
of how powerful these pigments are, consider that lycopene, the red color in tomatoes,
ketchup and tomato sauce, has 200 times the protective antioxidant capacity of the
same amount of vitamin E, a well-known antioxidant vitamin.
The research questions now are about figuring out
HOW, WHEN and WHY
various plant substances appear to be protective,
not IF there is a role for any of them.
3
So, a good rule-of-thumb is to eat all the
brightly colored fruits and vegetables
you can get your hands on!
They are low in fat and calories, and they have lots of other important
substances like vitamins, minerals and fiber. Foods like these that have lots of
goodies relative to calories are called “nutrient dense” foods, which is the opposite of
much less desirable “empty calorie” foods, which have lots of calories but few
nutrients or other health benefits.
Here are a few of the specific substances in the news
that have been studied the most and which
(in addition to their vitamin and mineral content)
clearly have something special to offer in decreasing risk of cancer:
“Cruciferous” vegetables like cauliflower, Brussels sprouts, cabbage, and broccoli
contain many anti-cancer substances, including one called sulforaphane.
Dark green plants have lutein that is a potent antioxidant that also has a special role in
eye health.
Green plants like broccoli, spinach and asparagus also often have hidden orange
pigment like the beta carotene that can be seen in orange-colored plant foods
like carrots, peaches, cantaloupe and yams.
Green and black tea have polyphenols.
Limes have limonene
Blue/red colored fruits and vegetables like red grapes, blueberries, strawberries, beets,
egg plant, cherries, raspberries, pomegranates, and cranberries have anthocyanins.
4
Yellow corn and squash have zeaxanthin, which also appears to be especially important
in eye health.
Tomatoes and watermelon have lycopene, one of the phytochemical pig,ents that has
been studied the most so far.
Tea, apples, onion, grapes, and green vegetables have a beneficial “flavonoid” called
Quercetin.
Garlic has Allicin and SAC; they do not give it color but they certainly give it a smell.
(I have also heard that it repels vampires. ☺)
Wine has several polyphenols and a very interesting substance called resveratrol.
The best thing about these phytochemicals is that they are being found to be
beneficial in a broad range of health conditions, so eating these fruits and vegetables
decreases our risk of much more than cancer. Many of these plant substances are not
destroyed by heat, so fresh, frozen and canned fruits and vegetables all have something to
offer. There are MANY others … literally thousands more in plant foods. Most have
not even been studied yet.
So although claims are sometimes made for taking certain ones of these
substances as supplements to reduce risk of cancer, (especially by people selling them)
it is clear that it would be naïve to think that the few we have researched so far are
“The Ones,” or that supplementing large amounts of one or a few of them would likely
substantially decrease risk of cancer for an individual.
Supplements of lutein and lycopene are common, and they have not been shown
to be injurious. They may or may not be helpful, but they are fairly expensive and each
provides only that one useful substance, so they are not as likely to be as beneficial
as eating a wide variety of actual fruits and vegetables that provides so many more. This
is in part because many of these substances are known to act most effectively together.
Fruits, vegetables and whole grains are also much less expensive than exotic
supplements. They provide lots of other important nutrients, they more filling and they
taste good, too! What’s not to like?
If you don’t like certain ones there are bound to be plenty of others that you
WILL like. Preparing them in many different ways can help too. You can even make
what I call “stealth vegetables” to sneak some into your family’s meals.
[See my handout on line called “Some Ideas for Trying to Eat More
of Those Terrific Antioxidant Phytochemicals . . . and Liking It.”]
5
The complex composition of fruits and vegetables make it hard to tease out the
substances of special importance. In addition, it is not just what one eats, but the
relative balance of many diet elements. For example, one could follow a completely
“vegetarian” diet but still eat way too much nutrient-poor (empty calorie) food. After all,
french fries, soda, candy and beer are “vegetarian.” In America, in fact, the french
fry is THE most commonly eaten vegetable!
The ratio of vegetables-to-meat consumption and the ratio of the amount of
calories-from-vegetables to calories-from-animal-products have been used
successfully to evaluate dietary patterns related to cancer risk. Research into these
beneficial “phytochemicals” is absolutely spilling over with new exciting findings.
2. Soybeans … a Special Kind of Plant
Soybeans are in a class of plantfoods called “legumes” that includes dried beans
(like kidney beans, black beans, navy beans, etc.,) peanuts, lentils and peas. Foods made
from soybeans, like soy milks, soy nuts, tofu and soy sauce, provide a number of
phytochemicals called isoflavones including one called genestein that may lower risk of
many cancers. They have other health benefits as well. These substances are often
described as “plant estrogens” and they are chemically and functionally similar to human
hormones. One definition of a hormone is that it is a substance that causes your body to
DO something, so hormones in general (plant or animal-based) are more likely to cause
problems if they are not in balance than other food substances are.
Think about all the things your very own estrogen can give you: acne, cramps,
babies, etc. ☺ Pretty important stuff. And it is well known that hormones have a lot of
importance in breast cancer in particular, although the details are far from clear. However,
is it reasonable to assume that a plant-based estrogen supplement in a generous dose is
desirable or even safe? Recent studies have not found consistent relationships in the use
of these products relative to breast cancer. Much of the data comes from animal research
that tends to look at just the effect of varying one diet component at a time, which is not as
easy to generalize to real people eating a varied diet. Large human studies are underway,
and some have also reported conflicting results.
For example, it appears that there are certain personal genetic factors that affect
whether soy intake has a role in various cancers. It was first found to be of potential
benefit several years ago when it was noted that the incidence of breast and prostate
cancer is about six times lower in some parts of the world where soy is a regular part
of the diet. However, there are a great many other differences in the diets and lifestyles
and genetic patterns of those population groups besides just the average soy intake.
That kind of large epidemiologic (population-wide) study is useful to stimulate
questions and to guide further research, but it can never show that when two things are
often found together, one of the things is the cause of another. For example, it is true that,
overall, taller children have more math skills than short ones. Is that because being tall
6
makes you smart? No … it’s actually because older children in higher grades at school
have been taught more math … and they happen to also be taller than younger children.
(But that doesn’t keep me from trying to get taller to help me do better at math! ☺)
“Soy nuts” provide the most soy isoflavones found naturally in a small serving of
food in the US. However, many other substances besides isoflavones in soybeans appear
to be important as well, including fiber, protein, vitamins, and minerals. One of the most
recently identified players on this team is the mineral magnesium. Large national studies
indicate that the majority of Americans take in at less than 2/3 of the recommended
amount of magnesium. Recently published studies of over 35,000 women in Iowa suggest
that there is an inverse association of dietary magnesium intake with incidence of
colorectal cancer. That is, the highest intakes of magnesium were associated with the
lowest incidence of colon cancer.
Colon cancer risk factors have often been found to be risk factors for breast
cancer and prostate cancer as well. So, paying attention to research in those areas
also helps us learn how we might decrease risk of breast cancer. And, hey – we all
have a colon, so reducing both kinds of cancer risk at once sounds like a smart idea!
It is recognized that soy foods are fine, certainly nutritious, and possibly helpful in
decreasing risk of cancer. But it is not clear that taking concentrated isoflavone
supplements (instead of just eating soy foods) is safe. In fact, some research suggests that
taking one type of concentrated soy isoflavone (daidzein) may enhance the cancerpreventive properties of the drug tamoxifen, but another (genestein) may actually interfere
with the protective effects of tamoxifen. Oh, fine!
It is interesting that people seem to perceive concentrated soy isoflavone products
as being “natural” and therefore automatically safe and more effective. However, high
concentrations of isolated plant chemicals (natural or not) put into pills and then taken out
of a little bottle is a long way from nature. And of course, just because something is a
plant, it is natural, and God made it does not mean it is safe or that it works to solve a
particular problem. There are a million examples of this … poison ivy, cocaine and
foxglove come right to mind. God may have made them all, but He does not want you to
eat them.
At this time the best advice is to include soy FOODS as desired, but to avoid
supplements that feature concentrated isoflavones until these issues are sorted out.
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2. Bundles of Joy: “Baby Plants”
Nuts, Seeds, Legumes/Beans and the Germ of Grains
Because improving magnesium intake has the potential to improve cardiovascular
health, diabetes incidence and management, and neurologic health, and it has many more
benefits, there is clearly no reason NOT to be sure that you get the recommended amount.
The very best sources include the parts of the plants that will turn into the baby
plant. That is … seeds, nuts, beans and the “germ” of grains. Those are by far the best
sources of magnesium and quite a lot of other critical nutrients.
“Refined” grains like “enriched white flour” are missing the highly nutritious
germ part of the grain, and most of the lost nutrients are not added back when the flour
is “enriched.”
That process only adds back three B
vitamins (thiamin, riboflavin and niacin) and
iron. That is why there is so much interest
now in helping people choose “whole grain”
products instead of refined grains. Any whole
grains will do … it does not have to be
wheat.
To have a good amount of whole
grains, the first or second ingredient on the
list should have the word “whole” in it.
Just calling a product “wheat bread”
does not mean that it is WHOLE wheat
bread. Similarly, “12-Grain” bread has
12 different grains in it, but the name doesn’t
tell you if any of them are WHOLE grains.
If the word “whole” comes much later on the list than the first or second ingredient, it
essentially means: “a whole grain walked by when we were making this.”
To give you an example of the amount of some “baby plant” foods one might eat to
obtain some benefit, consider that in large studies, for several health conditions measured,
differences were shown between a pattern of eating about an ounce of nuts or peanuts four
8
times a week or more, or never or rarely eating these foods. The measurably better health
outcomes were associated with eating those foods four or more times a week, and the
worst health outcomes were associated with the pattern of rarely eating them.
If you are allergic to a lot of these “baby plant” foods or simply do not like to eat
them, you should check into supplementing magnesium. These really are the richest
sources of magnesium (and several other minerals,) and most multivitamins with minerals
provide only about 10-25% of the recommended amount of magnesium. That may be
enough if your diet is just a bit low, but some folks will definitely benefit from an
additional supplement. But before you cross ALL these baby plant foods off your list,
remember that cocoa powder comes from cocoa beans --- another baby plant!--- (see
picture below) … and that means that chocolate covered peanuts might be considered a
“health food” in certain circumstances. ☺
[Please see my Magnesium handout for all the details and specific
recommendations about suggested forms and amounts.]
3. AMOUNTS AND TYPES OF FATS
Reducing total dietary fat is less important than previously believed, but lowering
the proportion of omega-6 fats and increasing the proportion of omega-3 fats and
monounsaturated fats appears to decrease risk of breast cancer.
Omega-6 fats are predominant in cornoil, safflower oil and many other cooking oils.
Omega-3 fats are most generous in flaxseed, canola oil, walnuts, fish and fish oils.
Monounsaturated fats are in nuts and legumes and in peanut oil and olive oil.
That’s another benefit of eating nuts and peanuts: the fat tends to be “happy fat.” That
is, it has the same calories of other fat, but it does not increase your risk of heart disease
or cancer. I like to think of them as “dangerous to your butt but not to your heart!”
The fish-oil omega-3 fats (EPA and DHA) have important anti-cancer
properties that are not available from the vegetable sources, especially among people
who have been found to be less able to convert the plant-forms to these longer forms. The
finding that some folks are more dependent on a ready-to-go source of EPA and DHA is
9
a fairly new discovery and it is often unrecognized at present. Inability to produce your
own EPA and DHA from plant oils is a serious (and not uncommon) problem.
This is why flax oil and fish oil are not equally helpful to all people. Although
both are omega-3 fats, some folks cannot convert the oil (linolenic acid) in flax and other
plants to EPA and DHA, the omega-3 fats so important in humans and other animals.
However, the flax seeds themselves have some substances besides the omega-3rich oil that may be useful in decreasing risk of cancer. First, because they are seeds
(baby plants) they are very nutrient dense and good sources of magnesium. Second, they
contain substances called “lignins” that may specifically reduce risk of breast cancer.
This combination makes the flax seeds, but not flax oil capsules, a particularly good food
to incorporate into the diet. Be creative … add ground flax to your meatloaf!
[Also, flax is a North Dakota product, so be sure to buy a lot! ☺]
Both EPA and DHA appear to be beneficial, and they also have benefits in a wide
variety of health concerns from heart disease to MS, diabetes, arthritis, depression and
dementia, so this seems like a prudent direction to go. [EPA stands for the molecular
description of this fat (EicosaPentaenoic Acid), but I always think of it as standing for
“Environmental Protection Agency” because it helps protect our internal environment!]
Fish oil is the source of both EPA and DHA, and the American Heart Association and
others encourage most people to take 1000 mg fish oil capsule daily, in part because we
can’t readily tell who the individuals are who cannot make their own.
Omega-3 fatty acids also may increase the effectiveness of certain cancer
treatments. Certain types of chemotherapy seem to work better when additional omega-3
fatty acids are provided in the diet.
Increasing the ratio of omega-3 fatty acids relative to omega-6 fatty acids in
the diet has additional benefit in dealing with cardiovascular disease, diabetes and in
autoimmune disorders like MS and arthritis. Most Americans eat a diet that provides 10
or more grams of omega-6 fat for every gram of omega-3 fat --- that is, a 10-to-1 ratio.
For most people it is recommended that we try to change the ratio to be closer to
4-to-1, which is the ratio typically found in the “Mediterranean Diet” … a pattern
associated with decreased risk of cancer and heart disease.
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If a person has an inflammatory disease like multiple sclerosis, diabetes or
arthritis, a ratio of 2-to-1 might be even better. [Please see my handout on line for more
detail about oils and fats and omega-6:omega-3 ratios, and also my papers on nutrition
for people with diabetes or MS for more information on this topic, including many
references.]
“Monounsaturated” fats are a type of fat
that also seems to be protective against cancer.
They are mostly found in olive oil, peanut oil, nuts
and avocados. Some of the protection is related to
beneficial phytochemicals found in those foods.
For example, olive oil is recognized as a source
Of additional cancer-fighting phytochemicals.
That is not a surprise, since these oils are also made
from foods that are “baby plants!”
Using monounsaturated fats also can displace
some of the less desirable omega-6 fats (like corn oil),
saturated fats or trans fat in our diet.
Trans Fats
It appears to be beneficial to decrease intake of certain types of saturated fat (animal
fat, coconut oil) and especially trans-fats (found in many types of shortening, margarine and
commercial baked goods.) Trans fats are accidentally formed by the traditional process used to
make vegetable oils into soft spreadable solids. The process is called “partial hydrogenation.”
It turns out that trans fats are particularly not healthy to eat. Trans fats in foods are
beginning to be banned in some places, such as in all New York City restaurants. Manufacturers
are developing ways to get it out of our food supply, but for now we still need to check labels.
11
Since 2006, trans-fats in foods
have to be listed on the food labels, but
looking for the words “partially
hydrogenated” in the ingredient list is
the best indication of whether a food
actually contains any trans fat.
This is useful because by law
amounts under 1 gram “per serving”
(like a teaspoon of margarine) can be
reported as “zero trans fat” on the label.
Their idea of what constitutes a
“serving” and those of consumers are
often quite different.
Many foods now being advertised that they are “trans free” and they actually are
because they have not used the partial-hydrogenation process to solidify them into a
spreadable texture.
Although most nutrition advice suggests limiting intake of amimal fat in
general, it may be that dairy fat may be less cancer-promoting than some other
animal fats. This is possibly because it contains a special form of fat called conjugated
linoleic acid. High-fat dairy food and conjugated linoleic acid intakes were found to be
associated with a lower incidence of colorectal cancer in Swedish men and women. As
noted earlier, often the cancer risk factors associated with colon cancer and prostate
cancer in particular are very similar to those in breast cancer.
Conjugated linoleic acid is currently receiving a lot of attention as a possible
anti-cancer substance but no conclusions are available yet. As always, the factors
associated with the “dairy fat” piece, like the calcium intake piece and the vitamin D
piece, are very hard to separate in studies with humans. But it appears that all three of
these substances may contribute to decreased risk. (More on vitamin D later.)
5. Vitamin and Mineral Antioxidants
In general, generous amounts of antioxidants automatically accompany a diet rich in fruits
and vegetables. That diet pattern also has been shown to have benefits in decreasing breast cancer
risk. As discussed earlier, the antioxidant strength of the phytochemical pigments far exceeds that
of the antioxidant vitamins and minerals. However, most vitamins and minerals have many other
important roles to play in metabolism.
As discussed earlier, it appears that many dietary antioxidants work in conjunction with
each other, so studies that examine the effects of a substance in isolation are less likely to
12
demonstrate any effect that might potentially be present. Effects observed of vitamins C and E
and selenium are likely related in part to their antioxidant properties. A very low-fat diet may
actually provide inadequate vitamin E because the major natural food source is polyunsaturated
oil. (Saturated fats like fat in meat or milk are not very good sources of vitamin E.) Other minerals
like zinc and copper are involved in antioxidant activity as one of many important functions.
The mineral selenium has several roles in the body as an antioxidant and in the function
of energy metabolism and in the immune system. Inadequacy causes serious health problems.
Selenium inadequacy is more common in America than vitamin C or E deficiency, so it will get a
closer look here. There is a large amount of promising research into the role of assuring selenium
adequacy in several types of cancer. There is also data that suggests that assuring selenium
adequacy may help in the effectiveness of certain chemotherapy medications.
Some recommendations for decreasing cancer risk suggest aiming for at least 200 iu
vitamin E, about 500 mg vitamin C and 60 mcg selenium daily as safe and appropriate intake
levels, along with a diet rich in fruits, vegetables and whole grains. For comparison, the
RDA-type recommendations for most healthy people sets the level of vitamin E at 30 iu, vitamin C
at 90 mg and selenium at 60 mcg. Notice that the suggested levels here for vitamins E and C are
more generous than the usual recommended amount, but the selenium level is at the usually
recommended amount. This is because assuring normal adequacy of selenium is likely important
in protecting against the development of several cancers, but taking more provides no additional
benefit, and high doses can be unsafe.
The toxic level of selenium has been shown to be about 800 mcg/day over a long period of
time, and experts have suggested an upper limit of safety to be 600 mcg/day. The selenium content
of foods varies with where the food was grown, so it is hard to assess the amount in a particular
person’s diet. However, a supplemental amount of 50-70 mcg is safe. Even if a person lives in a
“high selenium” region, that amount is unlikely to contribute significantly to toxicity problems.
The amount in supplements varies from none to about 200 mcg, so check the label. Your State
Extension Service Agent can tell you about the selenium level in the soil where you live.
Recently some confusion about the role of selenium in cancer risk was raised by a
large study called the Selenium and Vitamin E Cancer Prevention Trial [SELECT] that
involved 35,533 “healthy” men. They gave some of the men 200 mcg/day of selenium
and/or 400 iu of vitamin E and after five-seven years they found no difference in the
incidence of prostate cancer in the group given extra selenium compared with the men who
received no extra selenium (the “placebo” treatment.)
The fact that this regimen did not have an effect on the incidence of developing
cancer, however, was very likely due to the fact that none of the men in the study were ever
selenium deficient. Other research studies showing benefit from providing additional
selenium have involved correcting deficiency and assuring adequacy. In other words, if
one’s selenium intake is fine, throwing more into the mix does not provide further
protection. But this study tells us nothing at all about whether correcting selenium
inadequacy might have decreased the incidence of developing cancer.
13
Inadequacy of any nutrient can cause all kinds of problems,
so it is always wise to assure an adequate intake of all of them.
6. INTAKE OF OTHER VITAMINS AND MINERALS
The body's defenses against cancer depend on adequacy of all the tools needed by
the immune system. That is just what many vitamins and minerals are … the tools you need
to run your body. Many nutrients have been shown to be important for fighting cancer in
particular. For example, as described earlier, assuring adequacy of the mineral magnesium
has been found to reduce risk of colon cancer. Several B-vitamins are looking like they are
important as well.
For example, in one report, older women with the lowest vitamin B-12
levels were at greatest risk of breast cancer. Many people become less able to
absorb vitamin B12 from food as they age. When vitamin B12 status has been most
carefully assessed, it has been shown that about 1/3 of the elderly are actually vitamin
B12 deficient. Taking acid-blocking medications for gastro-esophageal reflux (heartburn)
can also cause this problem regardless of age. In both situations, the form of vitamin B-12
found in vitamin pills can bypass the problem and prevent deficiency.
Vitamin B-12 is also important for nerve health, and prevention of anemia and
hearing loss. There are some genetic conditions that result in vitamin B12 deficiency for
other reasons that require other methods to correct. [Please see my “Vitamin B12” paper on
MeritCare’s website for more information about this issue.]
Adequacy of vitamin B6 and folic acid has long been found to be important
in lowering the risk of breast and/or colon cancer, especially among women who drink
alcohol regularly. Interestingly, regular alcohol use or chronic antibiotic use specifically
impairs absorption of folic acid in the intestine. A collection of genetic patterns and health
conditions also affect absorption or utilization of folates at the tissue level. That makes for a
lot of unaccounted-for variability in trying to see large over-riding patterns about intake and
breast cancer risk.
For a look at the complexity involved with trying to figure out the role of
any nutritional factor in health, cancer prevention and treatments,
lets look a bit closer just at the folic acid research:
•
Some studies show that inadequacy of folic acid increases risk of breast cancer.
•
Some suggest that high intakes might increase the rate of breast cancer.
14
•
At the same time, others are showing that generous folic acid may increase
protection agains breast cancer.
•
Then there are others noting that the effects of folate in foods or folic acid as a
supplement or additive may affect people’s risk of breast cancer differently
depending on several well-recognized genetic differences in folate metabolism, and
things like hormone status, age and status relative to menopause. An example of this
is the well-recognized MTHFR gene most commonly seen in some people of Irish
heritage … and there are quite a lot of us Irish (or part-Irish) people out there. Other
ethnic groups have also been found to have similar genetic problems with folic acid.
[This gene pattern affects one’s ability to utilize certain food forms of folates,
and the problem is invisible without special testing. Luckily, the answer is not to
get yourself tested for possible Irish gene patterns … simply taking a standard
multivitamin will solve the problem whether you have that genetic pattern or
not. The form in the multivitamin is able to bypass the whole difficulty
with the food forms of folate.]
•
In nature, folic acid often works together with vitamin B12. That means that the
consistent finding of poor vitamin B12 status in many people can affect the outcome
of studies exploring folate intake in cancer prevention or treatment. However, in
most studies, the vitamin B12 status of the people being studied is not evaluated.
•
Food folates are also associated closely with consumption of certain vegetables and
fruits. [That’s where the word “folate” comes from … the Latin name for “foliage.”]
So, how can we tell whether it is the folate or the other things in the food like other
nutrients, phytochemicals or even pesticides that are related to cancer risk?
•
Then, we know that some food forms of folate are just naturally much less available
to be absorbed than others by everyone, so it matters a lot which ones were actually
used by the people in the studies. But of course, that is generally not actually
evaluated in any of these studies.
•
There is also a raft of information looking at applications of folates (from foods or
supplements) in various forms as adjuncts (helpers) to make chemotherapy more
effective or to decrease certain bad side effects of the treatments. In some cases, it
has been shown to make it possible for a patient to tolerate a higher dose of
chemotherapy and to increase effectiveness of treatment. This was something my
oncologist and I utilized in my own cancer treatments over ten years ago with great
success. But these effects are very specific to the particular chemotherapy regimen,
so there is no universal one-size-fits-all recommendation in this area. I wish there
were.
Bottom line on Folic Acid / Folate and Breast Cancer: This research is much too
complicated to come up with a definitive statement that addresses all these issues.
15
However, with the usual caveat that the information provided here is not intended
to take the place of the advice of your heath care professional nor is it intended to
provide personal specific nutrition guidance for any particular individual, here’s
my current best guess about folic acid and breast cancer (subject to change at any
moment. ☺):
•
Eat lots of fruits and vegetables, some of which will contain absorbable folates
(along with a lot of good other stuff.) Interestingly, in some studies that
questioned a slightly increased risk of breast cancer in postmenopausal women
only, the increased risk was only related to food folate intake, but not to
supplemental folates or to total folates, and no “dose-response” was observed.
That means that there was no pattern apparent among the people in each group
related to how much folate they took in. Hmmm … that makes it kind of hard to
assume that it’s the folate causing whatever effect they found. [Am J Clin Nutr. 2009
Feb;89(2):624-33. Folate and one-carbon metabolism nutrients from supplements and diet in relation to
breast cancer risk.]
•
Eat plenty of whole grains that are less “processed/refined” for many
reasons. Of the processed grains you eat, folic acid has been added in a wellabsorbed form since 1998, but that is not the reason for using more whole grains
and less refined grains. … it’s the other good stuff in the germ of the grains.
Many studies show no effect on increased rates of various cancers since
fortification began, but since 1998 the folic acid fortification of grain products in
the US has hugely decreased birth defects and certain types of stroke. [An example
of the kind of reports out there: J Clin Pharmacol. 2010 May 10. Pediatric Cancer Rates After
Universal Folic Acid Flour Fortification in Ontario. “…These data may also provide some
reassurance that universal flour fortification does not heighten the risk of pediatric cancer.”]
•
Taking a multivitamin supplement that includes folic acid (e.g. 400 mcg, the
RDA) is not scary, and it can also improve intake of absorbable vitamin B12,
vitamin D and some magnesium … plus other good things. It also helps you
out if you are secretly part Irish. [Am J Clin Nutr. 2010 Apr 21. Folate and other onecarbon metabolism-related nutrients and risk of postmenopausal breast cancer in the Cancer
Prevention Study II Nutrition Cohort. “CONCLUSIONS: Our study of predominantly supplement
users suggests that high intakes of folate averaged over 10 y do not increase breast cancer risk, but
may be protective, particularly against ER- breast cancers.”]
•
If you are being treated for cancer, ask your health care provider before
using any supplements. In terms of eating lots of good nutritious FOOD, I
am willing to bet that he/she will think that is a fine idea.
16
Vitamin D
Vitamin D adequacy is known to reduce the risk of breast cancer, colon cancer,
prostate cancer, pancreatic cancer and more recently lung cancer, cervical cancer, stomach
cancer, and ovarian cancer. New research is published very regularly now associating vitamin D
adequacy with lower risk of cancer in yet another body part. It is now quite reasonable (and very
important) to urge people to assure adequacy and not to simply assume it. This strategy is not
scary … what is scary about “assuring adequacy?” What is scary is inadequacy!
The World Health Organization estimates that 40-50% of the world’s population is vitamin
D deficient (based on results of many studies in which vitamin D status is actually assessed.)
Traditionally, it rarely has been evaluated. Leading medical journals have described the situation
as an unrecognized epidemic of deficiency in the north especially but truly an epidemic / pandemic
all over the world because of variable sun exposure due to clothing, skin color, sun screen use, fear
of melanoma and the lure of air conditioning. Factors like aging skin also result in significantly
reduced production of vitamin D even with generous sun exposure.
Some people are covered up always because of modesty or religious beliefs, some because
they live in the desert and only long robes will protect from the heat. I am just covered up as a
public service. ☺ The point is … lots of people are now known to be deficient regardless of where
they live because now we are beginning to actually check. Vitamin D is the number one assay
requested in America at present, but most people are still not having their deficiency recognized
and corrected. The consequences are severe in terms of a multitude of health problems, including
cancer, heart disease, osteoporosis, diabetes, MS and a variety of autoimmune diseases, falls,
frailty and depression. Nobody needs vitamin D deficiency but lots of folks have it.
Vitamin D has also been shown to be helpful as an adjunct to chemotherapy. In its role as
an “antiproliferative” agent, vitamin D helps to control inappropriate cell growth and it makes
some treatments work better. Additionally, it has been shown to be a factor in managing the side
effects of discomfort, pain and weakness associated with various chemotherapy treatments.
For example, a recent study was reported of women taking an aromatase inhibitor as
part of their breast cancer treatment. They were asked to rate the discomfort/pain they were
experiencing. Afterward, vitamin D levels were checked and those who had described the most
pain were found to be the ones who also had the lowest vitamin D levels. Low vitamin D levels
were then corrected in the deficient women and when they rated their pain again they described it
as much less severe. At the time of the study, neither the women nor the researchers were aware of
any particular woman’s vitamin D level, her reported pain level, nor whether a vitamin D
correction was made.
In most cases, assuring adequacy has been found to require an intake significantly higher
than the RDA level, which was long ago set at 400 iu daily. Most recent research is showing that
the maintenance (not therapeutic) intake level for many people is 1000-4000 iu/day. This is a level
that is impossible to get just from food. Supplementation is required to provide that much.
17
Luckily, vitamin D supplements in that range (1000-4000 iu/day) are safe, inexpensive,
easily available, tiny and easy to swallow. The treatment dose to correct deficiency varies but it is
often 50,000 iu vitamin D per week for eight weeks. [Note that that amount is PER WEEK – NOT
PER DAY.]
Many oncologists will check a person’s vitamin D level at the beginning of treatment to
determine whether a corrective dose of vitamin D is needed or if just a maintenance level of 2,000
iu or so will keep them in the optimal range of around 40-50 ng/dL. The earlier level of 25
ng/dL that was thought to be “normal” is now recognized as not being an adequate blood level to
promote optimal health. Around the country, some laboratory print-outs still have the old “25”
level shown as normal, so it is a good idea to ask what the actual number is and not just rely on a
report of “normal.”
Vitamin K
As always, assuring adequacy of all essential nutrients supports our ability to prevent
or fight cancer. We learn more about this every day. For example, recent research found that
vitamin K inadequacy increased risk of colon cancer and liver cancer, along with many other
serious health problems like heart disease, osteoporosis and kidney problems. It was also found
that, as has been the case with vitamin D, we very rarely check it and just assume that it is fine.
However, it has now been shown that inadequacy of vitamin K is fairly common. It is also
easy, cheap and safe to fix.
The best food sources are dark green leafy vegetables. Interestingly, no upper level of
safety has ever been established for vitamin K because overdose has never been seen. I know this
is a big relief to all you fans of the dark-leafy-green veggies out there. Nobody has ever overdosed
on spinach!
[Only people taking a particular medication called Coumadin need to be sure to eat a
consistent amount of vitamin K daily to regulate the effectiveness of the drug. Nobody benefits
from vitamin K deficiency … including people on this medication. Vitamin K inadequacy
actually makes the drug more dangerous to use. If you use this medication please see my separate
handout on line about vitamin K before making any changes to your vitamin K intake. Your health
care provider will want to see the new research on this before making any changes.]
At this time, many multivitamins do not even contain vitamin K --- until recently no
one knew it was a problem! This omission is in the slow process of being fixed, but one can take
vitamin K separately if there is a reason why those terrific leafy green vegetables are not an option.
The details about vitamin D and vitamin K (lots of ‘em!) are in my “Top Five
Recommendations” handout and in the separate “Vitamin K” handout, which (like all the others)
you can get for free by Googling “Cathy Breedon Handouts” or typing my name in the search box
at www.meritcare.com. Please feel free to share any of my papers you find there with others.
Health care providers can also contact me for a special paper addressing the specific issues of
vitamin K nutrition for patients using the drug Coumadin.
18
7. WHAT ABOUT OTHER PHYTOCHEMICALS?
Besides all the phytochemical research with the pigment antioxidants and soy
products described earlier, there is a great deal of interest in literally thousands of other
plant substances in the prevention and treatment of cancer of all types. Some of these
substances have anti-cancer properties, and some appear to be able to minimize side
effects of chemotherapy or help it work better. On the other hand, some are not safe to
take in amounts beyond what one would get from eating the plants that contain them
for dinner. And some are not safe at all … remember poison ivy and cocaine? Actually,
most of our current pharmaceutical products are derived from phytochemicals.
Most of this kind of phytochemical research is just in the discovery and
initial confirmation phase, where many current well-established medications once
started out. Most of these substances have not yet been studied in the large carefully
controlled clinical trials needed to show that they are both effective and safe, even though
they may be described as having been used somewhere in the world for some purpose for
many years. Some have only been shown to be potentially useful in test tubes and labs
and they have not yet been tested in animals or people. Some have turned out to help with
cancer but cause some other type of serious problem. An example of the opposite
problem is the use of chaparral tea, a beverage traditionally used as a relaxing agent. It is
now banned because it was discovered to also be a potent cause of liver cancer. [Herbal
interactions with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem.
2010;17(16):1635-78]
So it is much too premature to recommend that people should seek to take in
abnormally high amounts of these plant substances in an effort to prevent or treat cancer.
When we isolate and concentrate a plant chemical because it has some particular
chemical activity, we move out of the world of nutrition and into the world of
pharmacy. In other words, a much better description of the use of concentrated herbal
substances would be “herbal pharmacy” and not “herbal nutrition.”
The reason that the terms “herbal nutrition” or “food supplement” are used is not
because the substance is actually a nutrient or a food. It is because there is a loop-hole in
the FDA’s laws governing the sale of drugs. The law does not require safety testing or
even testing to show effectiveness of a product if the manufacturer simply labels it as a
food or nutritional supplement. If the same substance were marketed as a pharmaceutical
product or drug, such (expensive and time-consuming) testing would be required. In other
words, we are essentially not at all protected from scams nor from harm when we use
these products.
Although this labeling seems confusing, usually one can quickly tell the difference
between what is an actual nutrition function and what is truly a pharmacy function. Just
ask yourself whether the substance under discussion is being taken in a concentrated
amount to cause some chemical effect on body functions, or if it is just your dinner. An
example is shown on the next page.
19
Sorting it out: Is it a food/nutrient or is it a pharmaceutical product?
Some examples:
Food
Slice of cinnamon toast
Pharmacy
1000 mg powdered cinnamon in a capsule
Piece of licorice candy
1000 mg of the isolated plant flavonoid
“isoliquiritigenin” found in licorice.
Bowl of vegetable curry
flavored with the common
curry spice tumeric
1000 mg isolated curcumin, a phytochemical
found in the common curry
spice turmeric.
There are WAY too many reports of this type to cite here, and the whole herbal
pharmacy issue is outside of my area of expertise … I only know about nutrition. But
interested health care professionals … or anyone at all … can find them easily on line at
www.pubmed.gov (Free Public Medline from the National Library of Medicine,
National Institute of Health.) Just type the words cancer and herb in the search box …
or you can limit your search by specifying a particular substance … like the spice
curcumin … or a particular form of cancer … like breast cancer. This is also how I keep
up with the nutrition and cancer research. (Ain’t technology wonderful?!)
However, it is encouraging to note that there are so many potentially helpful
substances waiting to be discovered and developed in a wide variety of plant foods. And
while we wait for the definitive research on concentrated plant chemicals in the battle
against cancer, it is certainly reasonable to eat lots of fruits, vegetables and whole grains,
and to cook with a variety of commonly used interesting spices that appear to have health
benefits.
8. “Conditionally Essential” Nutrients
Conditionally essential means that usually one makes enough of a necessary
substance, but sometimes we can’t make enough of it. When that happens, that nutrient
becomes “essential” to take in from outside the body, just like well-recognized essential
vitamins and minerals. Three of these substances of interest in breast cancer are CoQ10,
alpha-lipoic acid and carnitine.
Coenzyme Q (CoQ10 – also called ubiquinone) and alpha lipoic acid (also
called thioctic acid) are both potent antioxidant substances that one can normally make
enough of, but in certain medical conditions patients benefit from being provided with a
supplemental amount. They are “conditionally essential.” Both are very safe, but as
supplements they can be pricey. Some applications of alpha lipoic acid (e.g. in diabetic
neuropathy) showed benefit when the dosage was at least 600 mg/day.
20
In the cancer applications, both substances look to be helpful in helping people
physically cope with side effects of chemotherapy and other treatments for cancer that
can result in neuropathy and heart damage. They both have several other roles in normal
metabolism, especially in energy production.
Carnitine is a tiny molecule normally made in the liver and kidney. It is important
for making energy for muscles to work, and that includes the heart muscle. Carnitine also
has a role as an antioxidant. Some people are normally less able to make carnitine as well
as others can. Some medications and treatments also result in inadequate production of
carnitine. This results in considerable fatigue and even heart damage. Some “cancer
fatigue” studies have shown benefit from 4000 mg carnitine daily.
There is evidence that some people fighting cancer may benefit significantly from
receiving supplemental carnitine, CoQ10 and alpha-lipoic acid with their cancer treatments.
All three are very safe and they are available over the counter and also by prescription.
Prescriptions are more likely to be covered by insurance. The only apparent down side is the
cost. As always, be sure to discuss the use of any of these substances with your health care
provider. I have a paper just on carnitine on Meritcare’s website because it has many other
important health applications. Additionally, all three of these supplements are discussed in
more detail in my paper on nutrition for people with diabetes which is also on the website.
9. Miscellaneous
There is plenty of evidence that
exercising, not smoking, maintaining a healthy
weight and breast-feeding one’s infants are
also players on the team to decrease the risk of
breast cancer. I’m going to go out on a limb
here and advocate that we all try to do these
things too. ☺
Also, remember to laugh a lot.
I think finding something to laugh about went
a long way toward helping me cope with
cancer and its treatment. In fact, as the
memories of the tough times recede, it’s the
funny stuff that hangs around … like shaving
my head with duct tape after chemotherapy, or
having a contest at work to help me find the
right look when picking out a wig.
Here’s the picture that won by a
landslide: it’s my husband Dan and I
wearing the 1970s “Sonny and Cher”
look. What do you think?
Don’t let worries about nutrition suck the joy out of life.
At our house we have battled cancer, and we eat lots of wonderfully healthy foods
and dutifully take our appropriate nutrition supplements. But my husband and I also like
21
having a regular ten-o’clock date in the kitchen with the local news on TV and a some
brownies or some other treat. And anyway … most of the time my brownies:
•
•
•
Have lots of walnuts (baby plants!)
Are made with olive oil (monounsaturated fat!)
And they usually even have some of those “stealth vegetables” in there
(like powdered spinach … sounds icky but it isn’t.)
That means that these brownies may actually be “health foods” … kind of like
chocolate-covered peanuts. Consider the terrific nutrient density … the ratio of good-foryou stuff to calories. They just happen to taste good and to impart a certain party
atmosphere to the end of the day! But even if a food has very minimal nutrition value,
whatever you choose to enjoy and share with family and friends can be a “health food” …
especially for mental health. Bon appetite!
10. Quick Summary: My Best Guesses for Breast Cancer Risk Reduction:
•
Eat lots and lots of fruits, vegetables and “baby plants” and aim for most of your overall diet to
be “plant-based”, with less meat than Americans usually eat.
•
If you do eat cured meats or grilled meats, be sure to eat lots of fruits or vegetables with them,
and avoid charring the outside … or the inside, for that matter.
•
Take a standard multivitamin with minerals for many reasons. I use a store brand – it does
NOT have to be expensive. Take it whenever it is convenient for you; I have a bad memory so
I won’t remember to take things through the day. So, I just take everything in the morning and
let it fight it out in there! It doesn’t have to be perfect.
•
Have your vitamin D level checked. Lot’s of folks are deficient and completely unaware of the
problem. Take a 2000 iu vitamin D capsule to maintain a good level. If your level is deficient,
your doctor can help you correct it with a temporary higher dosage.
•
Check to see if your multivitamin contains vitamin K if you do not regularly eat a good amount
of dark leafy greens. If you usually don’t eat those dark leafy greens, either switch to a
multivitamin with about 100 mcg of vitamin K, or add a separate vitamin K supplement.
•
It is a good idea for your multivitamin or some combination of supplements to provide 50-60
mcg of selenium (the advisable intake.) Vitamins C and E can be taken at the advisable intake
of 90 mg C and 30 iu of E, but in general they can be safely taken at 5-10 times that amount.
•
Increase your ratio of omega-3 to omega-6 fats by replacing omega-6 fats (e.g. corn oil) with
monounsaturated oils (olive and peanut). Eat some flax seed or use flax oil if you like it. Take
at least one 1000 mg fish oil capsule daily (one that says EPA and DHA) if you do not eat fatty
fish like salmon or mackerel at least twice a week. (And, no, deep-fried breaded fish does not
count … wrong kind of “fatty.” Darn!).
•
If you do not eat much in the way of baby plants, consider both a magnesium and chromium
supplement, and be sure you are getting a good amount of dietary fiber in some form.
•
Enjoy every day, every friendship, and every meal!
22
Sanford Medical Center
Aunt Cathy’s Guide to Nutrition:
Calcium Odds and Ends:
12-2010
Cathy Breedon PhD, RD, CSP, FADA
Clinical & Metabolic Nutrition Specialist
Sanford Medical Center, Fargo, ND
and UND School of Medicine
Absorption and Where it Ends Up …
Role of Vitamins D and K
--------------------------------------------------------------------------------------------------------------------------
1
------------------------------------------------------------Food Sources of Calcium
(Serving Size and mg of Calcium)
-------------------------------------------------------Dairy
American cheese, processed 1 oz 175
Blue cheese 1 oz 150
Cheddar cheese 1 oz 200
Cottage cheese 1/2 cup 80
Cream cheese 1 oz 25
Ice cream 1 cup 175
Milk (any regular kind) 1 cup 300
Calcium fortified milk 1 cup 500
Parmesan cheese 1 oz 390
Swiss cheese 1 oz 275
Yogurt 1 cup 275-350
Seafood
Clams, raw 3 oz 60
Oysters, raw 1/2 cup 110
Salmon, canned with bones 3 oz 165
Sardines, canned w bones 3 oz 370
Shrimp 3 oz 100
Nuts, Dry Beans and Seeds
Almonds 1/2 cup 150
Beans (cooked) 1/2 cup 45-100
Brazil nuts 1 oz 50
Hazelnuts 1/2 cup 120
Sesame seeds 1 Tblsp 90
Soybeans, roasted “nuts” 1/2 cup 120-230
Fruits / Vegetables
(calcium absorption is mixed; oxalates
decrease absorption of double-starred **
items.)
Apricots, dried 1/2 cup 45
Asparagus 1/2 cup 15
Beans, green ** 1/2 cup 30
Beet greens (cooked) 1/2 cup 75
Broccoli 1/2 cup 70
Cabbage (cooked) 1/2 cup 35
Cabbage, bok choy 1/2 cup 125
2
Carrots 1/2 cup 25
Celery 1/2 cup 25
Collard greens, ** 1/2 cup 180
Dates 1/2 cup 50
Kale (cooked) 1/2 cup 100
Lettuce, iceberg 1/4 head 25
Mustard greens ** 1/2 cup 95
Onions (cooked) 1/2 cup 25
Parsnips (cooked) 1/2 cup 35
Raisins 1/2 cup 25
Rhubarb (cooked) 1/2 cup 100
Spinach (cooked) ** 1/2 cup 85
Squash, summer or winter 1/2 cup 55
Turnip greens (cooked) ** 1/2 cup 125
Calcium-fortified orange juice1/2 cup 150
Food Data Source: Agriculture Handbook
No. 8-4 US Dept. of Agriculture
Science & Education Admin.
Sanford Medical Center
2011
Aunt Cathy’s Guide to Nutrition:
By Request:
A SHORT CARNITINE
DISCUSSION THAT
MIGHT BE HELPFUL
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical and Metabolic Nutrition Specialist
Sanford Medical Center, Dept. of Pediatrics
and Clinical Associate Professor of Pediatrics
UND School of Medicine, Fargo, ND
The role of supplemental carnitine in conditions characterized by excessive
obesity, hunger, lethargy, hypotonia, and poor exercise endurance
Carnitine is a substance normally made in the liver and kidney, and it is also available in
meats. It consists of a molecule of methionine and a molecule of lysine — two essential amino
acids. It plays a critical role in the ability to burn fat for fuel because it is part of the enzyme
system "carnitine palmitoyl transferase" which transfers fat molecules into the mitochondria
to produce ATP. Because muscle (including and especially heart muscle) is very dependent on
fat fuels for aerobic energy production, anything that compromises carnitine's operation can
result in a variety of problems. For example, for people with inborn errors of mitochondria
metabolism, providing additional carnitine can help to prevent extremely serious consequences.
An example is the not uncommon beta-oxidation disorder MCADD (Medium-Chain AcylCoA
Dehydrogenase Deficiency.)
Some drugs impair the production of carnitine so that one is more dependent on an
exogenous source than normal. Valproic acid is an example of this, and relative carnitine
insufficiency can often be a big contributor to the lethargy and certain other side effects reported
with the use of this medication. Additionally, inadequate carnitine also compromises the efficacy
of the valproic acid itself, resulting in break-through seizures and increased risk of liver toxicity.
With this medication, carnitine supplementation appears to decrease liver toxicity
significantly. Valproic acid is the seizure medication most studied in relation to carnitine, but
other seizure medications appear to affect carnitine requirements as well. Certainly if the child is
symptomatic a trial on carnitine is very reasonable.
People on ketogenic diets for seizure control also need extra carnitine because they are
burning fat as almost their only fuel - - they need much more carnitine than they could be relied
upon to make on their own. Additionally, many people on these special diets do continue to need
seizure medications, which may further increase the need for an outside source of carnitine.
People with various liver and kidney conditions are sometimes supplemented with
carnitine because production can be compromised. We also use it with premature infants on
TPN in the NICU because their ability to produce carnitine is compromised by the immaturity of
the liver and kidney.
Carnitine-related problems contribute to difficulty burning
fat for fuel resulting in symptoms that may include:
________________________________________________________________________
1. excessive fat storage
2. low muscle tone
3. excessive appetite due to failure to make the needed amount of ATP
(usable energy) from food consumed
4. very poor tolerance of aerobic activity and endurance-type of exercise
5. abnormally high sense of fatigue or excessive sleeping
6. muscle pain with exertion
7. cardiomyopathy
8. episodes of dangerously low blood sugars that can result in brain damage,
or even death … sometimes labeled a SIDS event.
9. unusual difficulty with control of blood sugar in people with insulindependent diabetes … we should be especially suspicious of carnitine
inadequacy among those with blood sugar volatility who are carefully
following their nutrition plans and medications.
These are among the symptoms that have been corrected by carnitine supplementation in at
least 25 people (not counting premies) that I have worked with personally who turned out to have
had unrecognized metabolic abnormalities. [This also does not count the patients for whom we
automatically initiated carnitine therapy in anticipation of need, thereby preventing the problems
described.] If someone way out here in Fargo, ND has found that many patients with what turned
out to be (previously unrecognized) carnitine-related health problems, the likelihood is good
that there are lots of folks out there whose carnitine problems are simply not being looked
for and therefore not recognized.
There are clearly many people who have some of the symptoms described above for
whom carnitine adequacy/inadequacy is completely unrelated. To determine if carnitine is a
problem, a trial on carnitine will often result in noticeable changes within few weeks …
2
sometimes days. If it is not a factor, supplemental carnitine could be discontinued after a trial of
about a couple months. We would normally continue the trial at least that long before writing it
off because some conditions result in a degree of carnitine depletion so pervasive that it takes a
while to get enough cells operating well enough to see a benefit. [Please see the note on the last
page regarding special carnitine issues to consider for people who are candidates for bariatric
surgery.]
Carnitine used as described is very safe. The only problem with the stuff is that it is
pricey. Insurance will usually cover it (ordered as "Carnitor, or the generic equivalent,") but the
amount of coverage varies. For this reason, we do not do this kind of trial casually. However, as I
mentioned earlier, the metabolic abnormalities in symptomatic patients that I have seen who
benefitted markedly from carnitine supplementation were undetected at the time the trial
was initiated. As you know, what we often think is extremely rare can sometimes be fairly
common but just rarely recognized. The only way to know for sure is a trial on carnitine. I
much prefer a prescription form of carnitine for the trial, as some OTC carnitine products
may not provide the amount of carnitine on the label. [I do not want to miss a potential effect
because the product used in the trial provided the wrong amount. People can use OTC carnitine
after the trial if they wish, but insurance will usually not pay for that form.]
Blood levels can reflect inadequacy when they are low or if the total:free carnitine ratio is
disturbed. However, the blood level apparently does not necessarily reflect the muscle tissue
level, including the level available to the heart muscle. So if a person is symptomatic but labs
are normal, one would still do the trial and watch for changes in symptoms. In other words, there
is probably little reason to get labs except for curiosity or research. Certainly, when labs do
indicate deficiency, we would supplement. But when labs do not reflect a deficiency state, we
would still do a trial of supplemental carnitine in a symptomatic patient. So, the labs are really
not of great use in this situation. As the health effects of carnitine inadequacy (for whatever
reason) are not benign, my prejudice is to do a rule-out trial with symptomatic patients.
So, that is the story in a nutshell. If you decide to do a trial, the usual trial in adults is
about 1 gram three times a day (i.e. 3000 mg/day.) The pills are in a 330 mg size, so 3000 mg can
be adequately approximated by three pills 3 times a day. The pills are spread out (any way that is
comfy for the patient) to avoid an osmotic diarrhea that can result from giving the whole lot of tiny
particles all at once. The pediatric dose (PDR info) is 50-100 mg/kg/day divided into 3 doses, with
a 3000 mg/day the usual upper level. The therapeutic/maintenance amount may be much less than
this, but the higher end of the usual range is often best in a test situation, since the person may be
starting out with a significant deficiency. If we under-shoot with a low dose, there may not be
enough carnitine to see changes during the trial period. I don't want to miss something if it is there.
I have had some very large patients whose symptoms (hypotonia, excessive hunger,
lethargy, excessive weight gain and poor endurance, etc.) have responded very well, but an
amount above the theoretical 3000 mg “top” was sometimes needed to bring the positive changes
about. One very heavy and fatigued adolescent responded beautifully but he required 6000
mg/day to bring about the changes we were looking for. [Happy aside: He is now normal weight
and going to college.] As is usually the case, when one is very far outside the “normal” rage for
body weight, a standard per/kg intake level may no longer directly apply.
3
A number of patients with “familial hypotonia of unknown etiology” have responded
amazingly well to this therapeutic intervention even though as yet no one has identified their
actual metabolic problem. All we know is that something about their genetic pattern causes
problems, some of which may be ameliorated by providing supplemental carnitine.
This picture (hypotonia, excessive hunger, lethargy, excessive weight gain and poor
endurance) is intriguingly like some of the typical symptoms observed in Prader-Willi
Syndrome. The #15 chromosome is missing all or part of a leg, but exactly what disturbance in
metabolism results from the deletion is not well understood, nor is it the same in all people with
PWS. However, as these individuals suffer greatly from their condition, it is reasonable to do a
trial as described above. It will either help or it won’t in any individual, but I do have four
patients with PWS for whom supplementation appears to significantly help control the
symptoms, making their lives and those of their families much better.
The children also have more energy to learn and to engage in play. They also learn better
because they are not as obsessed with accessing food. Prader-Willi Syndrome is currently treated
with growth hormone in some children, so one cannot ascribe all of any observed benefit to
carnitine in children treated with both. However, it is reasonable to do both, as the efficacy of
growth hormone treatment could certainly be compromised if energy metabolism was limited by
a relative problem with carnitine adequacy. Certainly a trial would be in order if the symptoms
described above continue to be observed after growth hormone therapy has been initiated.
When a patient demonstrates that supplemental carnitine is helpful, the level that seems
to be effective needs to progress with growth (i.e. mg/kg body weight). I have seen some
situations in which a child out-grew his prescription because this aspect of his care was not being
monitored and the treatment became less effective the more he grew. With math-competent
parents (and the doctor’s permission, of course) I teach the parents how to increase the dosage as
the child attains certain weights. Other families call me each month with the baby’s weight and I
calculate the level for them,
When initiating treatment, the carnitine dose is generous in an attempt to correct a
possible inadequacy … that is, the bucket may be empty so we need to fill it up as part of our
test. However, once the bucket is appropriately full, the therapeutic level is no longer needed
and a maintenance level should be identified. This will be quite individual. As a marker for
having reached the point of having a “full bucket” I tell parents that an indication of this will be
that the child may “start to smell a bit like a little fish” (reflecting getting rid of unneeded
carnitine.) One mother called me and left this message: “At last! We have achieved fishiness!”
At that point we back off and set about to find the maintenance level for that particular child.
Other conditions can be characterized by the same symptoms (lethargy, weight gain,
hypotonia, etc.) Some of my patients with Down Syndrome or Phenylketonuria have struggled
with the same set of energy-related problems, and in several cases, the carnitine supplementation
has helped tremendously. It has been life-altering. For others, the carnitine was not shown to
alter the situation at all. The only way to know which person with these symptoms will respond
to carnitine supplementation is to do a trial.
4
There are many other applications of supplemental carnitine being studied in
addition to the scenario discussed above. These include (among others): hypertriglyceridemia,
mitochondrial diseases, retinal health and macular degeneration, cardiovascular disease,
metabolic syndrome, diabetes, renal disease, parkinsonism, chemotherapy adjunct to minimize
neurologic damage and fatigue, various chronic conditions characterized by fatigue, prevention
of liver toxicity due to use of certain medications, age-related cognitive impairment and
osteoporosis. (See my Diabetes hand-out, Eye Health hand-out and Prental Nutrition hand-out
for more information about those specific carnitine issues.)
SOME THOUGHTS ABOUT BARIATRIC SURGERY
IN INDIVIDUALS WHO HAVE A
CARNITINE-RELATED WEIGHT PROBLEM
___________________________________________________________________________
I think it would be very reasonable to do a trial on generous carnitine
in severely obese individuals prior to moving to bariatric surgery.
One reason is that people who do respond to carnitine can likely avoid the costs,
pain and complication risks of bariatric surgery. Carnitine use does not interfere with an
individual’s ability to absorb micronutrients the way the surgery does, which avoids the
documented problems of clinically significant vitamin and mineral deficiencies like copper,
vitamin B12, thiamin (vitamin B1) and many others months or years after surgery. These three
nutrients are mentioned specifically because neurologic injury (sometimes irreversible injury)
from deficiency is documented in spite of generous oral intake in some bariatric surgery patients.
Long term follow-up of these micronutrient issues is absent in many bariatric
surgery programs, and often the only outcome of professional interest has been whether or not
weight loss occurred, and whether there were improvements in dyslipidemias or diabetes
management. Failure to establish long-term nutrient adequacy is particularly problematic
because many women of childbearing age do become pregnant after bariatric surgery. That
increases risk of birth defects and other types of poor pregnancy outcome. And now some places
have begun to do bariatric surgery on pediatric patients. They do lose weight post-surgically …
but they are likely to lose much more than weight unless overall nutrition is carefully monitored.
One other reason for doing a trial on carnitine before moving on to surgery is that if
patients do have a carnitine-related weight problem they will continue to have it. The
surgery does not correct the problem. That means they will continue to be unable to burn fat
efficiently, and they will continue to experience significant hunger that may drive them to
overeat in spite of surgery. This may be a factor especially in the number of individuals who
regain their weight after surgery or who undergo a second bariatric surgery. Therefore, a trial on
carnitine would help to identify the people who might fail to do well in terms of maintaining
weight loss after surgery unless carnitine supplementation was a continued part of their regimen.
For those bariatric surgery patients who do need supplemental carnitine, continuing to
provide it can play a role in successfully keeping the weight off.
5
Carnitine: Content of Foods
and Quick Fact Sheet
Foods providing about 100 mg of carnitine
Beef steak
100 g
95 mg
Ground beef
100 g
94 mg
Typical intake from food:
Generally, 20 to 200 mg are ingested per day by those
on an omnivorous diet, while a strict vegetarian diet
may provide only 1 mg/day. The word carnitine
comes from the Latin word for meat but the amount
varies with type of meat.
Also note the high variability in carnitine in
commercial “complete nutrition” products.
Foods providing 10-30 mg of carnitine
Production:
Pork
100 g
28 mg
Bacon
100 g
23 mg
Tempeh
100 g
20 mg
In animals, carnitine is biosynthesized primarily in
the liver and kidneys from the amino acids lysine or
methionine. Vitamin C (ascorbic acid) is essential to
the synthesis of carnitine.
Promote
100 ml
12 mg
Requirements:
Foods providing 1 to 6 mg of carnitine
Cod fish
100 g
5.6 mg
Chicken breast
100 g
3.9 mg
American cheese
100 g
3.7 mg
Ice cream
100 ml
3.7 mg
Whole milk
100 ml
3.3 mg
Avocado
one medium
2.0 mg
PediaSure
100 ml
1.7 mg
Cottage cheese
100 g
1.1 mg
Foods providing less than 1 mg of carnitine
Whole-wheat bread
100 g
0.36 mg
Asparagus
100 g
0.20 mg
White bread
100 g
0.15 mg
Macaroni
100 g
0.13 mg
Foods providing less than 1/10th of a mg of
carnitine
Peanut butter
100 g
0.08 mg
Rice (cooked)
100 g
0.04 mg
Eggs
100 g
0.01 mg
Orange juice
100 ml
0.002 mg
Ensure
100 ml
0 mg
During growth, pregnancy or wound healing
requirements for carnitine can exceed its natural
production. That is, it is conditionally essential
during periods of anabolism, and also in a variety of
other metabolic conditions.
People with liver or kidney problems may have
difficulty producing it. Renal patients may also be
eating a low meat diet, which can result in a diet
low in pre-formed carnitine. It is also lost in
dialysate, so needs of dialyzed patients are greater
than they would otherwise be.
The seizure medication valproic acid impairs
production of carnitine, but needs it to work.
Inadequate carnitine reduces effectiveness and
increases potential for liver toxicity of the drug,
and it accounts for some of the reported side
effects such as lethargy and weight gain.
Beneficial Applications:
Supplemental carnitine has a role in low muscle
tone, managing diabetes, exercise tolerance,
macular degeneration, obesity, heart failure, cancerrelated and HIV-related fatigue, male infertility,
ischemia / reperfusion brain injury, peripheral
neuropathies, dementia, depression and cognitive
impairment associated with various conditions.
6
MeritCare Medical Center
6/2009
Aunt Cathy’s Guide to:
Thinking About
OTHER
Nutrition Issues
in Celiac Disease
Cathy Breedon PhD, RD, CSP, FADA
Clinical Nutrition Specialist
MeritCare Medical Center, Fargo, ND
and UND School of Medicine
1. General Nutrition Adequacy Issues
It is important for individuals avoiding gluten to take a close look at the nutritional
adequacy of the foods remaining in the diet. This may mean getting some help from a Registered
Dietitian, as not all the threats to complete nutrition are obvious. Any diet that eliminates a number
of common foods has the potential to leave some gaps in nutrient intake.
In addition to general nutritional adequacy, there are diet/nutrition factors besides gluten
control that can provide additional benefit to people with celiac disease. Many chronic health
conditions have an inflammatory component. CD, MS, diabetes, rheumatoid arthritis,
inflammatory bowel disease and lupus, for example, all have the potential to result in increased
inflammation. It is now recognized that inflammation is an important contributor to heart disease
as well, so the recommendations included here to decrease inflammation and to protect tissues from
the negative effects of inflammation are of great potential benefit.
2. Omega-3 and Omega-6 Fats in the Diet and the Problem of Inflammation.
One of the most important issues in controlling inflammation is the ratio of two different
families of certain polyunsaturated oils in our diets. The two families are called omega-3 and omega-6
fats, and in America we tend to eat far more omega-6 fats than omega-3 fats - - in fact we eat them in a
ratio of 10-to-1! There is a clear benefit for all of us in moving toward a ratio of 4-to-1 (as in the heart
healthy “Mediterranean Diet.”)
Some researchers believe that for people with inflammatory conditions, a ratio of 2-to-1
may be even more beneficial. This is because certain inflammatory substances (prostaglandins) are
made out of these fats, and the ones made out of omega-6 fats are much more inflammatory than
the ones made out of omega-3 fats. That means that by altering the ratio of these fats in our diet,
we can decrease the degree of inflammation experienced. In brief here is how to change the
ratio:
1
A. Replace corn oil (high in omega-6 and very low in omega-3) in cooking and baking with olive
oil (neutral, so it displaces the high omega-6 oils) or canola oil (an oil with a better ratio of
omega-3 and omega-6 fat.)
B. Incorporate ground flax seed and fatty fish like salmon in the diet. These are terrific sources of
omega-3 fat. Flax oil is a good source of omega-3 fat, but the rest of the flax seed is very nutrient
dense as well, including nutrients that are often low in the diets of Americans, like magnesium
and chromium. Additionally, it has some substances (lignans) that appear to decrease risk of
breast cancer. For that reason, the ground flax has a better benefit-to-cost ratio that buying
flax oil or flax oil capsules.
C. If eating fish is not attractive (or if you are worried about mercury), you should consider taking
fish oil capsules. These are labeled “EPA and DHA” and a Consumer Reports survey showed
that all the brands in the US were safe and equal in quality, with price being the only difference.
The price ranged from 6 cents each to 60 cents each, so check out a local warehouse-type or
discount store for the best buy. The capsules tend to be a bit large for some folks to easily
swallow. Because the benefits of taking fish oil (for nearly everyone,) are being recognized,
more and more products will be available in the near future. Many new forms are already
available, including liquids and pastes that are citrus flavored and not fishy-tasting. You can
find many products on line just by googling fish oil or omega 3.
Although flax is rich in a certain omega-3 fat (linolenic acid --- a vegetable oil,) there is a
special benefit to taking in at least some of the omega-3 fat in the forms found in fish (EPA
and DHA.) Think of EPA as standing for “Environmental Protection Agency” – protecting
your internal environment! Even the American Heart Association (a very conservative
organization) recommends that most people take 1000 mg of fish oil daily. Fish oil is also being
used to decrease risk of cancer and as an adjunct to chemotherapy. The form of fat that is DHA
in fish is also particularly important in brain / neurologic health. Some people have been found to
be unable to make enough EPA and DHA out of the vegetable oil linolenic acid (the one in flax
and canola) so taking some in a ready-to-go form is a wise idea.
3. Fiber Issues.
Unless carefully planned, the gluten-free diet can also be low in dietary fiber, including the
kind that “moves things along” (like cellulose in wheat bran), and the kind that helps to lower
cholesterol. That type is called “water soluble fiber”, and it includes Guar gum, Legumes, Oat bran
and Pectin – which can be remembered by the acronym “GLOP.” Some of the cholesterol eaten and
some that enters the intestinal tract in the form of bile from the liver can be thought of as “getting
stuck in the GLOP” and excreted instead of being absorbed into the body.
People with celiac disease obviously cannot have wheat bran, and the oat bran can be iffy
because of cross contamination, so they need to work a little harder to obtain the many benefits of
foods that contain both kinds of dietary fiber. Legumes are one option … dried beans and peas (like
chili beans, navy beans, pinto beans, split peas, etc.) are great sources of fiber and additionally they
are very nutritious. This is because any plant part that is actually what turns into a baby plant is full
of all the nutrients needed by the new plant. In grains it is the “germ.” The rest of any grain is
2
primarily starch and the fibrous coating. Other foods that are high in both fiber and nutrients like
this are nuts and seeds (like the flaxseed discussed earlier.)
4. Increased “Free Radical” Production and Protection by Antioxidants:
Just running your body produces a certain type of waste product called “free radicals.”
They can cause injury to cells, but normally they are kept from causing injury by substances that
we eat or make collectively called “antioxidants.” They include certain vitamins (like vitamins C
and E), and a substance made with the mineral selenium (glutathione peroxidase.) There is some
new evidence that assuring adequacy of selenium may be a therapeutic tools to prevent both tissue
damage and complication of CD such as autoimmune thyroid diseases (AITD.)
A number of substances in plants (certain phytochemicals) are now known to be terrific
antioxidants, and there is a lot of interest in these plant substances for promoting good health in
general. The plant pigments (coloring agents) especially, such as “lutein” in leafy greens,
“lycopene” in tomatoes and “anthocyanins” in blueberries are examples of some very promising
protective substances. Eating plenty of brightly colored vegetables and fruits is a very good
idea for many reasons for everyone.
Inflammatory conditions result in a much greater production of free radicals than is
usual. For this reason, people with inflammatory conditions like CD and diabetes should aim
for a much more generous intake of antioxidants than usual to minimize the increased risk of
cell damage. In this situation, a reasonable and safe daily amount of vitamin E is 400 iu, vitamin C
500-1000 mg, and selenium 100-200 mcg, plus lots of brightly colored fruits and vegetables. The
vitamin C, E and selenium amounts shown above are higher than the usual Recommended Dietary
Allowance (RDA) amount, because the RDA is designed to meet the needs of folks without a
chronic inflammatory disease. Do not take more than this (especially of selenium) without
consulting your health care provider.
Even more potent antioxidants are the phytochemicals that are pigments (coloring agents)
naturally occurring in plants. For example, lycopene, the red color in tomatoes, is 200 times more
potent as an antioxidant than vitamin E, and it has been shown to help minimize the oxidation
damage from excess free radicals related to CD.
[Neurologic impairment due to vitamin E and copper deficiencies in celiac disease. Neurology 2009 Sept 9; 71(11):860-1. Selenium
deficiency in celiac disease: risk of autoimmune thyroid diseases. Minerva Med. 2008 Dec;99(6):643-53. Lycopene, quercetin and
tyrosol prevent macrophage activation induced by gliadin and IFN-gamma. Eur J Pharmacol. 2007;566(1-3):192-9.]
5. Vitamin K Inadequacy: A Newly Recognized National Problem Needing
Special Attention in Celiac Disease
Eating leafy green vegetables has an additional benefit because it is now recognized that vitamin
K is often inadequate in Americans. Dark leafy greens are broccoli are the very best natural sources.
At the moment, vitamin K is not included in most multivitamins because the serious inadequacy
3
problem is only newly recognized. It has now been discovered that inadequate vitamin K contributes
to osteoporosis, arterial calcinosis (an independent risk factor for cardiovascular disease,) kidney
calcinosis and liver cancer as well as pregnancy problems and bleeding problems, so eating these
foods is very important for everyone. Additionally poorly controlled CD greatly increases the risk of
vitamin K deficiency. For more on this, including issues for people using the blood-thinning
medication Coumadin, please see my handout just on vitamin K.
[Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding. Adv Ther. 2007 Nov-Dec;24(6):1286-9. Coagulopathy due to
celiac disease presenting as intramuscular hemorrhage. J Gen Intern Med. 2007 Nov;22(11):1608-12.]
6. Re-emergence of Iodine Insufficiency in the USA
Another new problem on the horizon for everyone is a re-emergence of iodine deficiency
disease in the United States and the world. In short, the problems are these: Certain regions are
known to have inadequate iodine in the soil and this results in IDD (Iodine Deficiency Disease) if
iodine is not provided in some other way. Iodizing salt has been the traditional approach, but that
intervention was initiated before we advised people to cut way back on salt consumption to help
control high blood pressure. [see iodine map on the last page.]
Additionally, there is a popular fad of using exotic “gourmet” salts from around the world, most of
which are not iodized. “Sea salt” is usually not iodized, but some brands are. Even the common salt
at the grocery store looks pretty similar … iodized vs non-iodized … and folks are no longer being
reminded to pick the iodized version. Most vitamins, (including many prenatal vitamins) contain no
iodine because of the assumption that the iodization of salt program “took care of” the widespread
public health problem of iodine deficiency.
Recently the World Health Organization increased the iodine recommendation for pregnant
women, in part because they found that even in regions where salt was regularly iodized, the amount
was insufficient for the best pregnancy outcome. (Iodine deficiency is actually the number one cause
of preventable mental retardation in the world.) Thyroid function is very reliant on adequacy of both
iodine and selenium. So, in addition to issues in brain development of infants, iodine deficiency can
rob people of energy because of hypothyroidism.
What is the connection to celiac disease? Well, people with celiac disease are not protected from
this deficiency, nor is the issue likely to be in the radar of most health care professionals yet, so I am
bringing it up here. It is not unreasonable to suppose that any person with nutrient absorption
problems would have an increased risk of poor iodine status beyond that of the general public.
Additionally, as described above, there is the suggestion of a possible connection to autoimmune
thyroid disease for selenium deficiency. Selenium and iodine work together for the thyroid to
function. I have not seen any specific celiac/iodine connection in the scientific literature, but the
whole issue is very new. In general, in the US most men tend to get an adequate amount of iodine,
but many women do not … this is probably just a reflection of how much total food one typically eats.
[Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr.
2009 Feb;89(2):668S-72S. Iodine Content of prenatal multivitamins in the United States. NEJM. 2009;360:939-940. Iodine status
of the U.S. population, National Health and Nutrition Examination Survey 2003-2004. Thyroid. 2008 Nov;18(11):1207-14.]
4
7. “Eat Right” AND take a Multivitamin with Minerals
AND take extra vitamin D!
It is now well recognized throughout the scientific community that most people would
benefit from taking a standard multivitamin with minerals. The old advice to “just eat right” has
been found to be extremely unlikely to assure optimal health in most people. The new advice is
“Eat right … and take a multivitamin with minerals … and take additional vitamin D”
References for these audacious claims are in the handouts in great number.
There are many reasons for the recommendation that everyone should take a multivitamin
with minerals even if one does “eat right,” including significant individual variability in absorbing
certain vitamins in the forms found in foods. For example, folic acid and vitamin B-12 are
actually more reliably absorbed in the pill form than in the forms found in foods. There are 1)
genetic reasons, 2) aging-related reasons, 3) drug interaction reasons, and 4) intestinal injury (e.g.
CD) reasons that make it hard for some people to absorb adequate amounts of these vitamins from
the usual food sources. It is wise to simply assure an intake at (at least) the RDA level of these two
vitamins in the form found in vitamin pills because this form bypasses the problem in all of the
above situations except for intestinal injury from poorly controlled CD.
Both of these vitamins have been shown to be critical to cardiovascular health because they
prevent the build-up of a substance called “homocysteine” and other problems that the high
homocysteine level reflects. It is prudent to simply prevent the problem. Inadequate folic acid is a
known risk factor for cancer of the breast, colon and prostate, and for depression and birth defects.
Vitamin B-12 is critical for neurologic health. Assuring adequacy of these vitamins in an easy-toabsorb form has broad benefits. If your CD is not in good control, a much more generous intake is
certainly needed. These nutrients are commonly inadequate in newly diagnosed individuals with
CD … poor control would mimic that situation.
[Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. World J Gastroenterol. 2009 Feb
28;15(8):955-60. Celiac disease and ischemic stroke. Rev Neurol(Paris);2009 Jan 12. Vit A Celiac Disease Presenting as
Xeropthalmic Fundus. Retina;2008 Mar 28(3):525-5. Undiagnosed coeliac disease and nutritional deficiencies in adults screened in
primary health care. Scand J Gastroenterol. 2007 Jan;42(1):60-5; Celiac sprue, hyperhomocysteinemia, and MTHFR gene variants. J
Clin Gastroenterol. 2006 Aug;40(7):596-601; Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at
diagnosis: role of B12, folate, and genetics. Clin Gastroenterol Hepatol. 2005 Jun;3(6):574-80.]
Additionally, inadequate vitamin D intake is now recognized as a serious underdiagnosed and widespread problem with a great many serious health consequences. These
include congestive heart failure, heart attack, MS, diabetes, osteoporosis, muscle/nerve pain,
muscle weakness, rheumatoid arthritis and cancer of the breast, prostate, colon and pancreas,
to name a few. Note the many “autoimmune” conditions listed. It appears that vitamin D
deficiency can be a trigger for the development of many of these conditions in genetically
susceptible people, just as certain viruses can trigger them.
Over 200 tissues in your body have receptors looking for vitamin D in order to operate
correctly. The current RDA is 200-400 iu of vitamin D, and it is now known that in the northern
third of the US especially, this amount is inadequate to maintain appropriate blood levels of
the vitamin. [see map]
5
This is also true in people who are elderly, or have dark skin, or who are covered up or out
of the sun. In these situations, 1000-2000 iu has been shown to be needed in several recent
studies. It is now known that the upper level of safety for vitamin D is actually over 10,000 iu
daily chronically, so this amount is nowhere near a dangerous amount. What is a real and present
danger now is inadequacy.
There are few foods that are naturally good sources of vitamin D-- salmon is the only one
that one might actually eat, so the 400 iu provided by a vitamin pill is a good place to start. Milk is
fortified with vitamin D (it doesn’t have it naturally) and only a few other foods are fortified, such
as some orange juice and some yogurt. So, while milk is one of the very best dietary sources in the
US, one cup has only 100 iu of vitamin D added to it. It is clear that relying on milk to provide the
target amount of vitamin D described is unrealistic without additional vitamin supplements on the
team. If you are in an at-risk group (e.g. dark skin, living up north, etc.) it is necessary to take an
additional vitamin D supplement even if you drink a lot of milk and take a multivitamin. Note that
milk “straight from the cow” does not contain any vitamin D, so some of our farm families get
none and are quite unaware if it.
Here are some examples of 4 ways to obtain
adequate vitamin D (~ 1000-2000 iu):
Plan 1 -- The “I love milk plan”:
1 multivitamin
4 cups milk
1,000 iu vitamin D supplement
400 iu
400 iu
1000 iu
Total = 1800
Plan 2 -- The “I hate milk plan”:
1 multivitamin
0 cups milk
1,000 vitamin D supplement
400 iu
0 iu
1000 iu
Total = 1400
Plan 3 – The “I insist on getting my vitamin D only in the form of fortified foods and
not from pills” plan:
0 vitamin supplements
0 iu
4 oz daily salmon (110 iu/oz)
440 iu
Total = 1440
10 cups of milk (WHATTTT???) 1000 iu
Plan 4 – The “I insist on getting my vitamin D only in the form naturally occurring
in the foods I eat and not from fortification or pills” plan:
0 vitamin supplements
0 iu
0 cups milk
0 iu
14 oz daily salmon (110 iu/oz)
1540 iu
Total = 1540 iu
As you can see, one really cannot realistically get there from here without supplementation.
6
For people who are eliminating wheat, rye, barley and often oats from their diet, and
often dairy foods as well for other reasons, there is great potential for failing to obtain the
best health-promoting level of a number of nutrients. Not all of these will be corrected with the
multivitamin with minerals, but it is certainly a good start. You do not need to buy an expensive
product – the best-known discount and warehouse stores have very good ones that are well
absorbed (contrary to the information provided by people selling more expensive products.)
Another important CD note regarding vitamin D is that the recommended amounts
described are not taking any malabsorption into account. If your CD is in good control, those
levels (1000-2000 iu) could be fine. If your CD is NOT in good control, you could easily have a
seriously inadequate intake. However, having intestinal symptoms of celiac disease is not necessary
for it to result in severe vitamin D deficiency. In some cases the only symptom of celiac a person
had was the pain and bone damage from vitamin D deficiency. Additionally, there was no
difference in some studies of nutrient status between people with partial villous atrophy compared
with those who had severe villous atrophy. So although avoiding gluten is clearly the most
important factor in CD, it appears that generous supplementation of vitamins is a very reasonable
adjunct factor in making CD hurt people less even if they have the gluten–free diet well in place.
Interference with absorption of bone-related nutrients (vitamins A,D, K and the minerals
calcium, phosphorus and magnesium in particular) are all seen commonly in celiac disease. For
example, poor bone density was found in 75% of newly diagnosed children, but it was still very
common (40%) among those who were not newly diagnosed and who were said to be following the
gluten restricted diet.
Assessment 0f bone mineral density in children with celiac disease. Pol Merku Kekarski. 2008 Mar 24(141);219-26.
Severe primary hypothyroidism masked by asymptomatic celiac disease. Endocr. Pract. 2008 Apr 14(3);347-50. Adult celiac
disease with severe or partial villous atrophy: a comparison study. Gastroenterol Clin Biol. 2008 Mar;32(3):236-42. A correlation of
symptoms with vitamin D deficiency and system response to cholecalciferol treatment: a randomized controlled trial. Endocr Pract.
2009 May-Jun;15(3):203-12. Resistance to vitamin D treatment as an indication of celiac disease in a patient with primary
hypoparathyroidism. Clinics(Sao Paulo)2009 Jan;64(3):259-61. Disabling osteomalacia and myopathy as the only presenting feature
of celiac disease: a case report. Cases J 2009 Jan 7;2(1)20. Osteoporosis in celiac disease and in endocrine and reproductive
disorders. World J Gastroenterol. 2008 Jan 28;14(4):498-505;Bone in celiac disease. Osteoporos Int. 2008 Apr 17. Osteomalacic
myopathy associated with coexisting celiac disease and primary biliary cirrhosis. Med Princ Pract 2008; 17(5):428-8.
Because a low vitamin D level is so dangerous, it is a VERY good idea to ask your
health care provider to check your blood vitamin D level at least annually in the winter. Ask
him/her to order a “25-hydroxy cholecalciferol level” --- the form of vitamin D that tells if you
have enough on board.
Please share this handout with him/her as well so that it is clear how important this is.
Interestingly, it is looking like EVERYONE should probably have vitamin D levels checked annually
– not just folks with CD -- because they are finding what has been described as “an unrecognized
epidemic of vitamin D deficiency” in the US and around the world. Because the symptoms are nearly
always invisible, and the problem is very common and very dangerous, the only way to be sure that
any individual is “OK” is to check the blood level. Until fairly recently this has rarely been done.
7
8. New investigations into milk intolerance in CD: Casein and/or Lactose
Many people with CD experience some difficulty drinking milk at all, let alone drinking 10
cups a day. For them, it is useful to remember that there is no reason why one must take their
vitamin D supplement in a form that involves drinking milk. The form in milk is just a supplement
of vitamin D – it is not naturally there. All that is required is that one make sure to get the nutrients
one would expect to get from milk -- i.e. calcium, phosphorus, potassium, vitamins D and B12 and
B2 (riboflavin) – from some other sources. A Registered Dietitian can help figure out lots of ways
to reach a nutrition goal.
The milk-intolerance itself has often been attributed to lactose intolerance – trouble
digesting milk sugar because of intestinal injury. This causes cramps, gas and diarrhea. Certainly
some individuals may be lactose intolerant for reasons unrelated to CD, but that would likely be a
minority of them. So, it has been hard to explain the continued gastro-intestinal distress when the
individual has been controlling the CD diet very well and there is no expectation of intestinal injury
that would lead to lactose intolerance. Now there is a new clue:
It appears that for many people with CD, there is an actual intolerance of the cow’s
milk protein that is similar in many respects to the intolerance of gliadin protein in gluten.
In that situation, it would be especially inappropriate to try to meet one’s vitamin D requirement in the
form of dairy foods. It appears that it is the casein part of the protein that is the problem … that is, the
curds rather than the whey. (The whey part is primarily a protein called lactoglobulin.) That means
that foods made from milk that happen to be very low in lactose could still be a problem for
some people with CD. For example, cheese is very low in lactose, but the protein is almost all casein.
I have included some highlights of a study that looked at this recently:
Mucosal reactivity to cow's milk protein in coeliac disease. Clin Exp Immunol. 2007
Mar;147(3):449-55. Patients with coeliac disease (CD) on a gluten-free diet may still have gastrointestinal
symptoms. On clinical grounds cow's milk (CM) protein sensitivity may be suspected. Here, using rectal protein
challenge, we investigated the local inflammatory reaction to gluten and CM protein in adult patients with CD in
remission. … Casein, in contrast to alpha-lactalbumin, induced an inflammatory response similar to that produced
by Cow’s milk. A mucosal inflammatory response similar to that elicited by gluten was produced by CM
protein in about 50% of the patients with coeliac disease. Casein, in particular, seems to be involved in this
reaction.
One practical suggestion that comes from this research is that people who continue to have
celiac symptoms in spite of careful avoidance of gluten should do a trial of strictly avoiding casein
for a few weeks to see if symptoms improve. If it doesn’t help, then that is not the problem so
dairy foods can be re-introduced. But if it does result in improvement, consider removal of milk
protein from the diet and replacing of the nutrients usually contributed by milk in the American diet
as described earlier. And as emphasized earlier, it is NOT SAFE to simply remove this kind of
food and then not replace the nutrients.
8
9. A Mineral of Special Note: Magnesium
Magnesium is critical for over 300 processes in the body. And yet, according to a large
national survey by the CDC (the NHANES Report), this important mineral is low in the diets of
the majority of Americans. Inadequacy contributes to diabetes, obesity, migraine, muscle spasms,
poor pregnancy outcome, and many other problems, but it is often unrecognized. Because one of
the most important dietary sources is the “germ” part of whole grains, there is a greater likelihood
of poor intake among people avoiding gluten. Other good sources include nuts and legumes, but
many people do not eat much of these foods for a variety of reasons. Most multivitamins with
minerals contain very little magnesium -- often only 10-25% of the recommended amount for
healthy people. For these reasons, some folks will need an additional magnesium supplement of
200-300 mg/day in the form of magnesium oxide or magnesium chloride. Others can do well with
just some diet tinkering. Check out the Magnesium handout on the website for the particulars and
specific recommendations.
10. Iron, Copper and Zinc
These three minerals have all been found to be problematic in celiac disease, especially when
The diet is poorly managed and intestinal damage is present. It is well known that the first recognized
symptom of celiac disease is often anemia. Iron deficiency because of intestinal injury can be a
cause of this. However, newly recognized as a factor in this picture is copper deficiency, which
can result in inability to transport iron well and therefore looks like iron-deficiency anemia. This is
one reason why treatment with supplemental iron alone can often be ineffective. Another is that
chronic inflammation alone can result in an anemic state in spite of iron status.
Additionally, there are many factors that affect both iron and zinc absorption …
enhancing it or impairing it. Both are affected by the same factors, but often only iron status is
measured in the form of hemoglobin or hematocrit measures. A good rule of thumb is to assume
unrecognized zinc inadequacy when one is known to be iron deficient. As zinc is a factor in over
200 enzyme systems in the body, including the immune system, making DNA, growth, and wound
healing (including intestinal injury repair), inadequacy can be globally damaging. If one supplements
zinc, however, it is important to also supplement copper, because supplementation of zinc alone can
interfere with copper absorption.
New reports also suggest that there may be an increased urinary loss of copper in the urine of
women with celiac disease … a factor separate from the question of impaired absorption. And in
addition to the anemia issue, unrecognized copper deficiency can also result in irreversible
muscle/nerve damage.
I have additional information available on line with lots of information about factors that affect
absorption of these nutrients that can be used to help improve the situation: “Nutrition Support of
Iron Deficiency” is on line with other handouts of potential interest as described at the end of this
paper.
[Copper deficiency in celiac disease. J Clin Gastroenterol. 2009 Feb;43(2):162-4. Serum zinc in small children with celiac disease. Acta
Paedoiatr 2009 Feb 98(2); 343-5. Neurologic disorders in adults with celiac disease. Can J Gastroenterol 2008 Nov 22(11);909-11,
.Serum copper, ceruloplasmin and 24-h urine copper evaluations in celiac patients. Dig Dis Sci. 2008 Jun;53(6):1564-72. Copper
9
Deficiency in Celiac Disease: A Report of 5 Cases and a Review of the Literature. J Clin Gastroenterol. 2008 May 15. Anemia of
chronic disease. Haematologia 2008:dec 93(12);1785-91. Neurologic impairment due to vitamin E and copper deficiencies in celiac
disease. Neurology 2008 Sept 9; 71(11):860-1. The soluble transferrin receptor (sTfR)-ferritin index is a potential predictor of celiac
disease in children with refractory iron deficiency anemia. Clin Chem Lab Med. 2005;43(1):38-42.Hematologic manifestation of
childhood celiac disease. Acta Haematol. 2004;111(4):211-4.Refractory iron deficiency anemia as the primary clinical manifestation of
celiac disease. J Pediatr Hematol Oncol. 2003 Feb;25(2):169-72. Efficacy of gluten-free diet alone on recovery from iron deficiency
anemia in adult celiac patients. Am J Gastroenterol. 2001 Jan;96(1):132-7.]
11. A Newer Topic: Carnitine and Celiac Disease
Carnitine (also called L-carnitine) is a substance one produces in the liver and kidneys, but
which is also found in meats. It is important for getting fuel into your muscles, so having an
inadequate amount contributes substantially to fatigue and even to heart muscle problems
(cardiomyopathy.) Normally we hear little about it because most folks take in or produce all they
need. However, in a number of health conditions, adequacy may require an additional supplemental
intake. For several years there has been interest in evaluating the possibility of a relative carnitine
deficiency in people with CD.
[Encephalopathy due to carnitine deficiency in an adult patient with gluten enteropathy. Clin Neurol Neurosurg. 2006
Dec;108(8):794-7. Plasma carnitine ester profile in adult celiac disease patients maintained on long-term gluten free diet.
World J Gastroenterol. 2005 Nov 14;11(42):6671-5. Carnitine deficiency in patients with coeliac disease and idiopathic
dilated cardiomyopathy. Nutr Metab Cardiovasc Dis. 2005 Aug;15(4):279-83. Intestinal permeability in long-term follow-up
of patients with celiac disease on a gluten-free diet. Dig Dis Sci. 2005 Apr;50(4):785-90. Serum carnitine and selenium levels
in children with celiac disease. Indian J Gastroenterol. 2004 May-Jun;23(3):87-8. Plasma L-carnitine levels in children with
celiac disease. Minerva Pediatr. 1992 Sep;44(9):401-5 Serum carnitine and selenium levels in children with celiac disease.
Indian J Gastroenterol. 2004 May-Jun;23(3):87-8.]
A recent prospective investigation looking specifically at carnitine supplementation in
CD patients with fatigue found that they benefitted from supplementation. I have included the
complete abstract of the research study below so that you can share this information with your
health care provider. This benefit in fatigue-reduction is consistent with applications in many other
conditions in which fatigue is a common problem. I listed a few examples of those after the
abstract below.
L-Carnitine in the treatment of fatigue in adult celiac disease patients: a pilot study. Dig
Liver Dis. 2007 Oct;39(10):922-8. BACKGROUND: Fatigue is common in celiac disease. LCarnitine blood levels are low in untreated celiac disease. L-Carnitine therapy was shown to
improve muscular fatigue in several diseases. AIM: To evaluate the effect of L-carnitine
treatment in fatigue in adult celiac patients. METHODS: Randomised double-blind versus
placebo parallel study. Thirty celiac disease patients received 2 g daily, 180 days (L-carnitine
group) and 30 were assigned to the placebo group (P group). The patients underwent clinical
investigation and questionnaires (Scott-Huskisson Visual Analogue Scale for Asthenia, Verbal
Scale for Asthenia, Zung Depression Scale, SF-36 Health Status Survey, EuroQoL). OCTN2
levels, the specific carnitine transporter, were detected in intestinal tissue. RESULTS: Fatigue
measured by Scott-Huskisson Visual Analogue Scale for Asthenia was significantly reduced
in the L-carnitine group compared with the placebo group (p=0.0021). OCTN2 was decreased
in celiac patients when compared to normal subjects (-134.67% in jejunum), and increased
10
after diet in both celiac disease treatments. The other scales used did not show any significant
difference between the two celiac disease treatment groups. CONCLUSION: L-Carnitine
therapy is safe and effective in ameliorating fatigue in celiac disease. Since L-carnitine is
involved in muscle energy production its decreased absorption due to OCTN2 reduction
might explain muscular symptoms in celiac disease patients. The diet-induced OCTN2
increase, improving carnitine absorption, might explain the L-carnitine treatment
efficacy.
A few examples of related elated applications of carnitine in the treatment of fatigue:
Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related
quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006.
Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body
composition, lipid profile and fatigue. Drugs Aging. 2003. Safety, tolerability and symptom
outcomes associated with L-carnitine supplementation in patients with cancer, fatigue, and
carnitine deficiency: a phase I/II study. J Pain Symptom Manage. 2006. Double-blind, multicenter
trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp
Rheumatol. 2007. L-carnitine decreases severity and type of fatigue induced by interferon-alpha in
the treatment of patients with hepatitis C. Neuropsychobiology. 2003.
12. Effects of Gluten Exposure on Absorption of Nutrients in the Intestine
As a recap, poor control of gluten intake results in poor absorption of essentially all
nutrients, whether in food or taken as supplements. Several examples of this were described
earlier, but the poor absorption would affect all nutrients, so your body would not have a “level
playingfield” to do all the things it needs to do. This includes brain function as well. So, as always,
gluten avoidance remains the cornerstone of nutrition for Celiac Disease. All the other issues
described above are just the icing on the (gluten-free) cake.
[Metabolic and nutritional features in adult celiac patients. Dig Dis. 2008;26(2):128-33.Affective and psychiatric disorders in celiac
disease. Dig Dis. 2008;26(2):140-8.]
11
MAPS of INTEREST: VITAMIN D and IODINE
VITAMIN D:
https://www.health.harvard.edu/newsweek/images/latitude-vitaminD.jpg
Except during the summer months, the skin makes little if any vitamin D from the sun at latitudes
above 37 degrees north (in the United States, the shaded region in the map) or below 37 degrees
south of the equator. People who live in these areas are at relatively greater risk for vitamin D
deficiency.
(Actually, that’s where I live … but you can see why it’s a really big deal Up North!”)
IODINE: Map showing spatial correlation between the former "Goiter Belt" in the northern U.S. and
areas where the iodine content of drinking water is naturally low.
www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm
12
For additional information on these and other topics you can go to MeritCare’s website
(www.meritcare.com) and find other articles in the “Aunt Cathy’s Guide to Nutrition” series.
Just type Cathy Breedon in the “search box” and a page comes up where you can click
“Cathy Breedon: Handouts.”
Topics include information and references especially for people interested in:
1. Specific health problems (diabetes, celiac disease, cancer, MS, hemochromatosis, epidermolysis
bullosa, etc.
2. Pregnancy and infant nutrition
3. Summaries providing much more detail about nutrients discussed here, such as magnesium,
vitamin D, vitamin K, vitamin B12, iron, and different kinds of fat and oil.
13
2/2011
Sanford Medical Center
Aunt Cathy’s Guide to:
Choosing
Appropriate
Infant Milks and
Formulas
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
Sanford Medical Center, Dept. of Pediatrics
and Clinical Associate Professor of Pediatrics
UND School of Medicine, Fargo, ND
Part 1: Nutrition Issues in Breastfeeding.
The ideal food for most babies is human milk. Even for this nearly Universal Truth
however, there are exceptions (e.g. infants with the rare inborn metabolic error "galactosemia" may
not have human milk.) Formulas are attempts to provide similar nutrition for healthy babies who
are not breast-fed, or to meet the nutritional requirements of infants with special health problems.
The American Academy of Pediatrics recommends human milk for at least the first year of life.
Although it is less common in America than in other nations, nursing through the second
year (or even longer) is also beneficial and the practice is increasing. [However, it is important to
note that, for reasons described later, it is not recommended to breastfeed the baby exclusively
without the addition of selected other foods after six months, and without vitamin D
supplementation throughout breastfeeding.]
This part of the paper will focus primarily on some evolving issues regarding the
assurance of macronutrient and micronutrient adequacy in human milk. Commercial
formulas and cow’s/goat’s milk issues in infant feeding will follow.
[For a more complete discussion of the many benefits of human milk and a review of the data now
available that demonstrates its clear superiority to any formula for most babies, please see my
separate paper entitled “Some Issues in Breastfeeding.”]
Macronutrients: Protein, Carbohydrate and Lipids
The best infant diets are those which provide adequate but not excessive amounts of
calories, protein, vitamins, minerals and fluid, with a distribution of calories from carbohydrate,
protein and fat in the "desirable range". This is the range within which babies have been seen to
grow well without excessive metabolic stress (Fomon, 1974.) It appears that most babies are fairly
flexible little people and tend to do well within a fairly broad range of feeding practices.
1
Percent of calories from:
CHO
PRO
FAT
_________________________________________________________________________
Desirable range:
35 - 65
7 - 16
30 - 55
_____________________________________________________________
Human milk:
38
7
55
_________________________________________________________________________
Protein
Why is human milk at the lower end of the range in protein?
Human milk has a protein content on the lower end of the range and a fat content on the
upper end. This is acceptable because the forms of protein and fat are so perfectly suited to baby's
immature digestive and metabolic systems that absorption and utilization of these nutrients is
optimal. The protein content of human milk will continue to stay in the appropriate range even
when mothers are protein deficient. This is because protein goes into the milk at mother’s
expense if there is an inadequacy.
No other food has protein that is so well absorbed or well utilized, so it is best to avoid the
extremes of the “desirable range” if something other than human milk is fed. In other words, a
diet that provides only 7% of calories as protein from formula or any other source could be
inadequate for optima growth.
As discussed in a later section, commercial formulas do provide a more generous
percentage of calories as protein for that reason (milk-based formulas provide ~9-11 % of calories
as protein, and soy products provide 11-13%. But both human milk and formula protein
adequacy can be compromised by practices such as adding lots of additional carbohydrate or fat
calories for babies with higher calorie needs, or giving a substantial amount of cereals, fruits or
juices to the diet.
Neither the protein nor calcium content of human milk is greatly affected by current
maternal diet, but that does mean that maternal dietary inadequacies will be compensated for by a
loss from the mother’s stores or tissues. For that reason, a poor intake is certainly not optimal for
mother’s health. Mother and baby should not be in competition for nutrients. There are also
specific examples of the many benefits associated with assuring the adequacy and absorbability of
maternal calcium intake during both pregnancy and breastfeeding.
For example, the adequacy of current calcium intake and absorption has been shown to
decrease the developing baby’s exposure to harmful substances that may be stored in the mother’s
bones. This includes heavy metals like lead. If the mother has to mobilize her bone calcium to
replace blood calcium lost to the fetus or the milk, any lead present in her bones would be freed
and enter the bloodstream along with the calcium. It would therefore reach both mother and baby.
2
Carbohydrate
The carbohydrate of human milk is lactose …a combination of glucose and another
simple sugar (a monosaccharide) called galactose. The lactose is broken apart by lactase enzyme
and the two monosaccharides are then small enough to be absorbed. Failure to break it apart
means the lactose will not be absorbed. If the problem is severe enough this can result in wasted
calories, diarrhea and intestinal gassiness … the classical picture of “lactose intolerance.”
So how common is lactose intolerance in infants? Actually, babies all around the
world are rarely truly “lactose intolerant” even in populations who become less able to digest
lactose as they get older. Babies can be temporarily lactose intolerant due to intestinal damage
due to malnutrition, infection, or certain diseases like unrecognized celiac disease (after gluten
has been introduced.) But even then, the benefits of continuing to provide human milk far
outweigh any potential problem with lactose in most instances.
The popular conception that lactose intolerance is a big problem with infants is very
overblown, and it is primarily a marketing opportunity. As discussed later, many formulas that are
advertised as lactose free also have other changes in their construction that can contribute to baby’s
tolerance.
Lipids: Fats and Sterols
Cholesterol One of the components of human milk that is not in any formula is readymade cholesterol. Cholesterol is actually a very important structural sterol, being a key
component of all cell membranes and the myelin around nerves. Babies need to grow rapidly so
they need to make lots of new cell membranes, and they need to myelinate their nervous system
in utero and in the first two years after delivery. Several hormones and bile are also made out of
cholesterol.
We have always assumed that babies could simply make their own cholesterol from the
other substances in formula. However, if a baby had difficulty making the optimal amount of
cholesterol, no commercial formulas would help him/her out. But human milk would provide
that extra boost.
[There is a rare genetic condition of severe inability to produce cholesterol called SmithLemli-Opitz Syndrome. Impairment of cholesterol production is so severe that even the human
milk pre-formed cholesterol content is insufficient to solve the problems for several reasons.
However, babies having difficulty producing optimal cholesterol temporarily for reasons of
serious illness or prematurity might truly benefit from having some delivered “ready-made.”]
Essential fatty acids The fatty acid distribution depends on the mother’s diet, and in
most instances in America, people take in generous total fat (or other calorie sources,) and
sufficient amounts of linoleic and alpha-linolenic acids from plant oils (the “essential” fatty
acids.) It is not difficult to assure caloric adequacy and adequate amounts of these two essential
fatty acids for the fetus and for human milk.
3
However, it now appears that some other fatty acids may also be “essential” because
the ability of some people to make enough of them on their own is insufficient. Pregnancy
and lactation in particular appear to be periods where some people fail to make an optimal
amount from the two 18-carbon essential vegetable oils.
One example of a potentially essential form of fat is the 22-carbon omega-3 fat called
DHA (DocosaHexaenoic Acid). DHA is critical to brain and retinal development. Our
assumptions have been that this fat can be readily made from alpha-linolenic acid by way of an
intermediate 20-carbon fat called EPA (Eicosapentaenoic Acid.). Now it appears that the
omega-3 fats EPA and DHA, and the 20 carbon omega-6 fat ARA (Arachidonic Acid) are
“conditionally essential.” In other words, some people can make enough on their own and some
people cannot, and they are especially unable to do it during pregnancy and lactation when
providing DHA is so important for brain development.
Milk DHA levels can be quite variable depending on the mother’s current intake and
stores, and worldwide the DHA content of human milk has been found to be decreasing. This is
now seen to be a serious issue during pregnancy as well. Bottom line: It is now recognized
that the ability of most humans to produce DHA from the essential plant fatty acid
linolenic acid via EicosaPentaenoic Acid (EPA) is much less than was presumed.
Long-Chain Omega 3 Fats in Mother’s Milk:
Fetal and Infant Development Issues:
The discussion of omega-3 fats in particular is included here because it is unrelated to the
macronutrient (calorie) function of fat discussed later. Oils rich in omega-3 fatty acids perform
many specific important metabolic functions. They have important implications in pregnancy
and infant nutrition in particular. As described, DHA is a major fat of the brain, and research is
growing that providing some pre-formed DHA is advantageous. Other health benefits continue to
be identified, including the (so far) a possibility of decreased risk of preterm delivery and
decreased risk of allergies.
[There are many additional health benefits identified for other age groups as well, including
maintaining cognition as we age, and issues related to attention and mood. These are described in
some detail in my paper “All Those Lipids: Recommendations for Using Different Types of Fats
and Oils (Omega-3, Omega-6 and Monounsaturated Oils)” That paper also explains the
relationship of the different fatty acids more clearly … and it has pictures!]
Food sources of EPA and DHA: Fish and fish oil provide ready-made EPA and DHA.
Taken during pregnancy they improve the DHA content of the fetal brain, and during lactation it
increases the amount of pre-formed DHA provided to the infant.
The “pre-formed” part is important: it is now recognized that there is considerable
variation in the ability of different individuals to efficiently operate the pathways that make
alpha-linolenic acid into EPA and then into DHA. Alpha-linolenic acid is the form of omega-3
4
fat found in plants. Flax, canola and walnut oil are the most generous sources. Many --- perhaps
even most ---people can use it to make the DHA as needed. But for many people there is a clear
benefit from getting at least some EPA and DHA “ready-made” in fish and fish oil supplements.
This appears to be particularly true during pregnancy and lactation.
That means that many people must rely on an outside source of EPA and DHA to assure
adequacy for their own needs and for the baby. In essence, this means that for some people,
these fats are also “essential” because that term means that a person cannot make enough on
their own.
This discovery of impaired ability to make adequate EPA and DHA from linolenic acid is
well demonstrated now. For example, it is one of the reasons behind the recommendation of the
American Heart Association that people eat fatty fish twice a week or take supplemental fish oil
because that is the ready-made source of both EPA and DHA. So, clearly, we need to look
closer at the adequacy of the mother’s diet and nutritional status in general.
Many health professionals erroneously assume that mother’s milk will have all the
nutrients needed by the baby regardless of mother’s nutrient intake. As noted earlier, it is
the same concept as the old “perfect parasite” theory of a generation or two ago that presumed
that babies simply took whatever they needed from the mother’s body during pregnancy. That
view has been disproved and discarded long ago, but the same old idea continues to be
erroneously applied to the concept of nutritional adequacy in both pregnancy and lactation.
DHA made from an algae source is also available as a supplement, and it is the kind
used in some supplements designed for pregnant women and in some children’s gummi DHA
supplements. This is the same form used to provide pre-formed DHA in infant formulas. It can
be a reasonable source of DHA depending on the dosage or amount of DHA per-gummi. And
comparison shopping shows that gummi-type DHA supplements for often children provide very
little DHA per gummi and they can be quite costly. Additionally, the algae-based products do
NOT contain any EPA … the omega-3 fat between linolenic acid and DHA.
EPA has many metabolic roles in the body involving inflammation, blood clotting,
the immune system and other functions, and a person with an inability to produce DHA will
likely have a difficulty making EPA as well. For that reason, fish oil as a supplement for
pregnant and nursing women has advantages over the products that only provide DHA. Fish oil
supplements are easily available now that are free of mercury and other substances that
would be of concern when eating fish to get these special oils.
Do breast-fed babies need anything else?
A Look at Micronutrients: Vitamins and Minerals
5
Maternal diet/stores CAN be a factor in the amount of several vitamins and
minerals in mother’s milk as well. These include iodine, zinc, selenium, all the B-vitamins
and vitamin C, so attention must be paid to the adequacy of her intake. The fat soluble vitamins
(A, D, E and K) are now being re-evaluated in this regard as well.
This is a surprise to many health professionals because earlier models of prenatal and
infant nutrition were based on assumptions that the fetus was a “perfect parasite” taking
everything it needed, even at mother’s expense. The same assumption carried over to
assumptions about the nutritional content of human milk.
This was all in the absence of being able to confirm things scientifically. However, now
that these issues have been able to be evaluated, it is clear that the presumption of nutritional
adequacy provided to the fetus or breastfed infant needs to be replaced with careful
attention to a number of nutrients in the mother’s diet.
Micronutrient Issues: Vitamins
Vitamin D
An epidemic of vitamin D inadequacy in people of all ages has been the focus of
literally hundreds of recent reports in the scientific literature. For years, vitamin D inadequacy
has been assumed to be a non-issue because most of the time, deficiency lacks the only symptom
that has traditionally led physicians to even look for it: that is, overt bone deformity in children.
It has long been (erroneously) assumed that everybody easily produces generous amounts
of vitamin D from the action of sunlight on skin. Additionally, as vitamin D is found naturally in
very few foods, it has been added to milk and a few other foods more recently in the US.
However, the amount currently added is insufficient to maintain appropriate blood vitamin D
levels in most cases. Vitamin D deficiency is now recognized as very common,
very dangerous, very often unevaluated and rarely corrected. The health
consequences are very serious, but the entire situation is very easy to fix once
the issue is recognized.
Maternal/child vitamin D deficiency issues deserve a close look here.
[The following is an excerpt on specific vitamin D deficiency issues in lactation from my paper “Aunt
Cathy’s Guide: My Current Top Five Ways to Improve Your Family’s Nutrition.”
There is much more on multiple vitamin D issues in that publication, including recommendations for
action. A version is also available with many references from reports in the scientific literature.]
----------------
6
Vitamin D Inadequacy in Breastfeeding Alert
Interestingly, mother’s milk is an amazingly nutritious food and breastfeeding is certainly
encouraged. However, the milk does not contain vitamin D. This is probably because when
people were invented nobody lived in Fargo. As an adaptation to live well up here, we need to
have a furnace, a coat, really good mittens and vitamin D. It is that simple. It is also a possibility
that the milk would provide adequate amounts if the mother herself were not vitamin D deficient.
This question is being studied, but in the meantime, for the health of both mother and baby, it is
best to assume that it provides too little unless it is actually checked.
Because of the finding of serious vitamin D deficiency in many breast-fed babies, in 2003
the American Academy of Pediatrics recommended that breastfed babies be given “at least 200
iu of vitamin D by two months of age.” In 2008 that recommendation was changed to
400 iu/day for ALL infants and they recommended starting it right away because many
babies were actually born with inadequate stores of vitamin D because their mothers were
deficient during pregnancy (in spite of taking prenatal vitamins.)
This recommended change also included formula-fed babies and not just breast-fed
babies because the standard formulas provided 400 iu only when about a quart (32 oz) a day is
consumed. Newborns usually take only about 20 oz, so formula-fed infants would also fail to
obtain 400 iu without supplementation.
This change brings US recommendations in line with those of their Canadian colleagues
who have recommended 400 iu for babies, and at least 800 iu for everyone else up there for
several years now. Here are some details of the kind of research that led to this change in
recommendation:
A recent study in Boston of 380 healthy infants and toddlers who were seen for a routine
health visit evaluated the prevalence of vitamin D inadequacy or overt deficiency. Forty four of
365 children,12%, had levels lower than 20 ng/mL (clearly deficient) and 146 children (40%)
had inadequate vitamin D status based on levels below an accepted optimal threshold (<30
ng/mL.*)
[Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers.
Arch Pediatr Adolesc Med. 2008;162(6):505-512.
Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of
deficiency. J Perinatol. 2007 Sep;27(9):568-71.]
The same Boston authors studied the therapeutic amounts of vitamin D supplementation
needed to correct the low vitamin D status of the children. They concluded that these two
approaches were effective for bringing low vitamin D levels into the range of >30 ng/mL*
within a 6 week treatment period: Daily 2000 IU vitamin D2 or D3, or Weekly 50,000 IU
vitamin D2.
[Treatment of Hypovitaminosis D in Infants and Toddlers.
J Clin Endocrinol Metab. 2008 Apr 15.]
7
*However, note that a report described earlier suggested that the healthiest ranges of serum
vitamin D may in fact be above this “optimal threshold” of >30 ng/mL, and that it might be in
the range of 36-48 ng/mL. [Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes.
Adv Exp Med Biol. 2008;624:55-71.]
Many other approaches to therapeutic supplementation are being investigated as well.
There are concerns about inadequacy of vitamin D in breastmilk (or in any infant feeding
regimen) in MANY areas beyond its relationship to the pattern of overt bone deformity we call
rickets. Most are not visible.
Inadequacy of vitamin D is now known to be an independent risk
factor for an ever-widening range of negative health conditions:
“All-Cause Mortality”
Asthma Diabetes (both Type 1 & Type 2)
Cancer of the Breast, Colon, Prostate, Pancreas
and other types, with roles in both prevention and treatment.
Cardiovascular Disease
both heart attack and especially congestive heart failure
Depression and Dementia
Developmental Problems
End-Stage Renal Disease
Immune System Compromise
Lupus, Fibromyalgia and Scleroderma
Multiple Sclerosis
Osteoarthritis, Osteomalacia and Osteoporosis
Pain in Muscle, Nerve and Bone
Pre-eclampsia in Pregnancy
Rheumatoid Arthritis
Sarcopenia (muscle weakness) and Falls
8
Clearly, assuring the mother’s vitamin D adequacy is very
important to her health as well as the health of her infant, but this is
a topic outside the scope of the present article.
“The recommended adequate intakes for vitamin D are inadequate, and, in the
absence of exposure to sunlight, a minimum of 1000 IU vitamin D is required to
maintain a healthy concentration of 25(OH)D in the blood.”
Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes.
Adv Exp Med Biol. 2008;624:55-71.
Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc
Med. 2008;162(6):505-512. Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin
Endocrinol Metab. 2008 Apr 15.] Prevalence of Vitamin D Deficiency Among Healthy Infants
and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Vitamin D Status: Measurement,
Interpretation, and Clinical Application. Ann Epidemiol. 2008 Mar 8. Sunlight, UV-radiation,
vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15.
Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008
Apr;87(4):1080S-6S. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of
deficiency. J Perinatol. 2007 Sep;27(9):568-71.Am J Clin Nutr. 2004 Mar;79(3):362-71) ]
[See my “Top Five” handout for much more on vitamin D.]
This topic is absolutely mushrooming in the scientific literature and the issue is too big to
describe thoroughly. Note that the references cited above were from 2007 and 2008. Below
are just a few of the 2008-9 references out there I had in one of my other papers, and the 2010
literature has even more Every day another study pops out! I just don’t have time to organize
it all in time for this Feb. 2011 paper to get where it has to go.
However, anyone interested in looking further into this issue can easily go to
www.pubmed.org and enter the search term vitamin D. The response is overwhelming. You
can also limit your search, say, by entering the words vitamin D infant or lactation, or
whatever. “Pubmed” stands for “Public Medline.” It is a free service provided by the National
Library of Medicine at the National Institute of Health in Washington DC)
A Sample of Some of the Many 2007-2009
Vitamin D References in the Scientific Literature
2009
Modern concepts in the diagnosis and treatment ovitamin D deficiency and its clinical consequences. J Environ
Pathol Toxicol Oncol. 2009;28(1):1-4. Vitamin D and aging. J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):7884. Vitamin D and type 2 diabetes Is there a link? Prim Care Diabetes. 2009 Apr 21. Behavioural and physical
characteristics associated with vitamin D status in women. Bone. 2009 Jun;44(6):1085-91 Hypovitaminosis D is
Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus. J
Pediatr. 2009 May 14. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged
and older European men. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):722-9. Sex-specific association of serum
vitamin D levels with physical function in older adults.Osteoporos Int. 2009 May;20(5):751-60. Vitamin D status
and muscle function in post-menarchal adolescent girls. J Clin Endocrinol Metab. 2009 Feb;94(2):559-63. 25.
9
Vitamin D Supplementation and Reduced Risk of Preeclampsiain Nulliparous Women. Epidemiology. 2009 May
15. Association of 25-Hydroxyvitamin D With Blood Pressure in Predominantly 25-Hydroxyvitamin D Deficient
Hispanic and African Americans. Am J Hypertens. 2009 May 14. Effect of vitamin D supplementation in the
institutionalized elderly. J Bone Miner Metab. 2009 May 15. Association between serum 25-hydroxyvitamin D level
and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern
Med. 2009 Feb 23;169(4):384- 90. Nutrition and health: guidelines for dental practitioners.Oral Dis. 2009 May 15.
Circulating calcitriol concentrations and total mortality. Clin Chem. 2009 Jun;55(6):1163-70. Vitamin D and
cardiovascular disease.Pharmacotherapy. 2009 Jun;29(6):691-708.Serum vitamin D, parathyroid hormone levels,
and carotid atherosclerosis. Atherosclerosis. 2009 Jun 6. Prospective Study of Serum 25-Hydroxyvitamin D Level,
Cardiovascular Disease Mortality, and All-Cause Mortality in Older U.S. Adults. J Am Geriatr Soc. 2009 Jun 22
Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After Rosuvastatin Treatment: A Novel
Pleiotropic Effect of Statins? [Crestor] Cardiovasc Drugs Ther. 2009 Jun 20.
2008
Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162
(6):505-512. Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15.
Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.
Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol.
2008;624:1-15. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008
Apr;87(4):1080S-6S.] [Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008
Jan;9(1):107-118. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc
Med. 2008:162(6):505-512 Hypovitaminosis D among healthy children in the United States. .Arch Pediatr Adolesc
Med. 2008:162(6):513-519. ndependent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin
D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008:168(12):1340-1349. Vitamin D and
cardiovascular disease risk. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):7-12. Hypovitaminosis D in obese
children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008
Feb;57(2):183-91. 25- Hydroxyvitamin D and Risk of Myocardial Infarction in Men A Prospective Study Arch
Intern Med. 2008;168(11): 1174-1180. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother.
2008 Jan;9(1):107-118. Vitamin D in Health and Disease. Clin J Am Soc Nephrol. 2008 Jun 4. Monthly ambient
sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-9,
2007
Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007
Sep;27(9):568-71. Dose response to vitamin D supplementation among postmenopausal African American women.
Am J Clin Nutr. 2007 Dec;86(6):1657-62. The urgent need to recommend an intake of vitamin D that is effective.
Am J Clin Nutr. 2007 Mar;85(3):649-50. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid
Biochem Mol Biol. 2007;103(3-5):708-11 Prevalence of Vitamin D Deficiency Among Healthy Infants and
Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Neonatal vitamin D status at birth at latitude 32 degrees
72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71. Macro- and micronutrients in patients with
congestive heart failure, particularly African-Americans. Vasc Health Risk Manag. 2007;3(5):743-7. Vitamin D
supplementation & total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007
10;167:1730-7
Vitamin K
A new focus on a previously unrecognized inadequacy of vitamin K in many Americans
is showing that many people get far too little and that it contributes to serious health problems
such as osteoporosis, kidney damage, calcification of the arteries, pre-eclampsia, diabetes and
cancer of the liver and colon. This is in addition to the long recognized role of vitamin K as a
tool needed when one needs to clot blood.
10
Until fairly recently (starting in about 2005) the blood-clotting function was the only
known role of vitamin K. Another factor recently identified as contributing to inadequacy is our
assumption that generous amounts of vitamin K are provided by intestinal bacteria. Because of
this, little nutrition advice focused on this nutrient, it was not included in many multivitamin
products, and even the MyPyramid.gov website neglected to include it (or vitamin D) in the
sample two-week diet for nutritional adequacy evaluation.
However, it appears that we are all actually much more dependent on an outside source
(dietary or supplement) than was assumed. Vitamin K status was (and still is) rarely evaluated,
so it is still assumed that all is well. Recent research makes it clear that many people are in fact
getting far too little of this nutrient, and it is hurting them.
Concerns about “toxicity” of vitamin K based on the observation that it dissolves in oil
have also been shown to be incorrect. In fact, vitamin K is so non-toxic that there is not an upper
end of safety identified for its intake. No-one has ever demonstrated an overdose. One reason it
is not toxic is that it operatesna s a simple co-factor … a tool that must be present for certain
things to move forward. It does not MAKE you clot your blood … it LET’S you clot your blood
if your body is telling you to do it.
[Aside: People on the anti-coagulation drug Coumadin need to have a very consistent
amount because the drug works by interfering with vitamin K. Inadequacy is dangerous
for them too, however because it increases the volatility of coagulation. It also puts them
at risk for osteoporosis, cardiovascular disease and cancers like everyone else. No one
benefits from a vitamin deficiency situation. The Coumadin issue is a specific
drug/nutrient interaction … not a general nutrition issue. For people NOT on this drug,
vitamin K is not scary … although inadequacy of vitamin K IS scary.
Please see my paper “New Roles for Vitamin K” for all the details and references, and
another paper I have available for health professionals specifically on the Coumadin issue
and the new research that should significantly change how we manage it.]
Some of the new issues being identified have significant implications for pregnancy
and lactation. Women who have insufficient vitamin K are at risk of hemorrhage at
delivery and have an increased risk of pre-eclampsia. Their infants are at risk of
intrauterine hemmorhagic events.
Consider that in America it is common to give infants a vitamin K shot at birth, to
reduce the risk of hemorrhage in newborns who received inadequate vitamin K in utero.
That means that overt consequential deficiency in the newborn was a common enough
occurrence to make vitamin K administration at birth become a standard practice.
I think that means that we should look more closely at maternal vitamin K status (and
everyone’s for that matter.) For one thing, the vitamin K shot at birth does not protect against
hemorrhagic events in either mom or fetus. Studies of newborns have demonstrated that some
11
children are born with evidence of earlier hemorrhagic events that can contribute to
developmental delays.
Additionally, not all babies actually receive the vitamin K shot because of home delivery
options, parents’ right of refusal, etc. Teleologically, it would seem to be an inefficient plan to
design people in such a way that infants all around the world would be born vitamin deficient
and at great risk unless someone is on hand with a syringe full of vitamin K. This is an issue
requiring attention from both the obstetric and pediatric medical experts working together.
In the meantime, mother’s milk can easily be low in vitamin K if mother is low. And
many mothers have been shown to be low. If the baby received the vitamin K shot, the low
vitamin K status of her milk will not be an issue any more for the baby (Although it will still be a
problem for mother.)
But any breastfed baby to whom that shot was not administered really needs to have
vitamin K reliably provided. And again … at the moment it is not standardly in many vitamin
supplement products. Additionally, it would be a good idea to provide that extra vitamin K to a
formula-fed infant as well if the shot was not given … the amount provided in the formula does
not provide a generous enough amount to compensate for a combination of low stores at birth
and no vitamin K shot.
Vitamins B12 and B6
The B vitamins play many critical roles in metabolism and inadequacy can compromise
the growth and development of the baby. In America, serious deficiency of B vitamins is
presumed to be extremely rare, but it is now recognized that some of them need a much closer
look. Most health professionals are aware that alcohol abuse frequently results in dangerous
deficiency of thiamin and folic acid, and of course, perinatal alcohol abuse is even more
problematic. But there are other specific concerns about vitamins B12 and B6 that deserve
some special attention during both pregnancy and breastfeeding.
As described earlier, for some nutrients (e.g. calcium and protein,) a relatively deficient
mother will still provide a good amount to the fetus/baby even at her own body’s expense.
However, all of the water soluble vitamins (B vitamins and vitamin C) will fail to be
provided optimally to the baby if mother is deficient … maternal needs for these nutrients
must be met before she “shares.”
Vitamin B12
Recently, for example, it was found that babies of mothers who had an inadequate
intake of vitamin B12 have deficiency levels even if the mother’s labs show her own vitamin
B12 level to still be in the normal range. Deficiency is extremely injurious to the nervous
system of both mother and baby. The following are three circumstances that put people at special
risk.
12
1. Because vitamin B12 is found naturally only in animal products, vegans are well known
to be at great risk unless they take a vitamin supplement containing vitamin B12. There
are MANY reports in the scientific literature about this problem and the damage to the
infants when it occurs during pregnancy or lactation. But simply assuring that the vegan
mother has been taking a supplement regularly for quite some time is all one needs to do.
But if she has not been taking one, or has only begun to take vitamin B12
during pregnancy, for example, her vitamin B12 status could easily still be too low
for the fetus/baby to receive the needed amount for optimal development. As vitamin
B12 is extremely non-toxic, ideally in this situation a physician or other provider should
consider giving her a therapeutic level to correct a suspected deficiency right away.
2. One of the less-well-recognized emerging risk factors for vitamin B12 deficiency is
among people who have GERD (gastro-esophageal reflux disease) and use PPI
(proton pump inhibitor) medications that prevent gastric acid production. Natural
sources of vitamin B12 require the presence of gastric acid before it can be absorbed.
[This is different from the role of Intrinsic Factor in vitamin B12 absorption.]
People who use these medications cannot absorb vitamin B12 from natural
sources, but they can easily get around this problem by taking a supplement that
contains vitamin B12 … just like vegans but for a different reason. In this case it is
because the crystalline B12 in supplements does not require the presence of acid in order
to become absorbable. But also just like vegans, if she has been taking the medication
for a long time and has only recently begun to take supplemental vitamin B12, there
may be a degree of deficiency sufficient to warrant giving a therapeutic amount.
3. It is becoming increasingly common for women of childbearing age to have undergone
bariatric surgery (gastric bypass for weight loss) prior to becoming pregnant. Longterm vitamin and mineral status in the women is rarely evaluated, but when it IS, there
are several nutrients commonly found to be seriously inadequate even with the use of
prescribed supplements.
Some of these, like copper deficiency (generally extremely rare in the general
public and therefore not monitored) are showing up as causes of serious neurologic
damage. The potential damage to a fetus or breast-fed infant is huge. Additionally,
months/years after the actual surgery many woman stop taking their prescribed
supplements for a variety of reasons. This is even more common among people with
less ability to afford them. Long term follow-up is rarely undertaken for anything
besides weight status and effect on cholesterol or diabetes. By the time micronutrient
inadequacies are recognized it is because they are severe enough to be visible … and
that is often past the point where prevention of injury is an option.
An additional important observation is that a study evaluating the nutritional status of
people considering bariatric surgery found that the majority had significant inadequacy
of a number of nutrients even before having the surgery. This may be because of a
likely history of trying various restrictive or unbalanced diets to lose weight. But it is also
13
a reflection of the fact that many people whose appearance suggests that they are very
“well-fed” are actually not “well-nourished” at all in terms of vitamins and minerals. In
fact, intake of several vitamins and minerals is recognized in large national studies to be
unsatisfactory in a large number of Americans.
[Please see my “Carnitine Explanations” paper for more information about another important
problem issue that may be present in some people undergoing bariatric surgery.]
Deficiency of vitamin B12 is just one of several problems that are of great concern in
the special pregnancy/lactation context. This mother may have several severe nutritional
problems that are very likely to have gone unrecognized. Unfortunately, the simple
multivitamin that solved vitamin B12 problems for vegans and PPI users is unlikely to be an
adequate intervention here. What should be done about it is outside the scope of this paper, but
vitamin B12 shots would likely be a needed. Heightening the awareness of healthcare
professionals about the existence of the problem is a good place to start.
[Please see my “Vitamin B12” handout for more information about problem issues with this nutrient.]
Vitamin B6
Adequacy of vitamin B6 in exclusively breast-fed infants has been found to rely often on
gestationally accumulated stores. For some infants, human milk alone without supplemental
foods may be insufficient to meet vitamin B6 needs after 6 months of age (Pediatr Gastroenterol Nutr
1996 23(1):38-44.) Earlier introduction of meats or the use of a multivitamin drop will correct this
situation. Most infant vitamin drops contain vitamin B6 and they often contain iron, but they do
not contain zinc. Meats are the richest sources of vitamin B6 and well-absorbed iron and zinc
… the three nutrients that have been observed to “drop out” of breastmilk after 6 months.
This argues for reversing our most recent traditional pattern of introduction of solids
by introducing meats by about age 6 months instead of introducing it after 10 months or
later. This problem can also be addressed by using a crushable-type multivitamin with minerals
instead of an infant vitamin drop; it contains all three of the micronutrients (zinc, iron and vitamin
B6) that decrease so precipitously in mother’s milk after 6 months. It can be crushed and added to
baby food.
Micronutrient Issues: Minerals
Iron
The iron in human milk is very well absorbed – the best of them all, with estimates
between 25% and 50% absorption. Compare this with the next best source of iron (meats, at
about 20%) and with the much less absorbable form in plants and pills (which are only about
14
0.25-2% absorbed.) But although iron in human milk is well absorbed, but there is not a great
deal of it.
Most term babies are presumed to have enough iron stored up so they do not "run out"
until about 4 months of age. Since this is the age at which many babies begin to have the
developmental skills to eat from a spoon, providing foods that are good iron sources plus the iron
in mother’s milk may be adequate.
On the other hand, one might argue for providing an additional source of iron (e.g. an
iron drop) to avoid emptying baby's iron reserves before he/she actually “runs out.” Premature
babies often have poorer iron stores because the iron (like zinc, calcium and other minerals) is
stored in the baby's body primarily in the third trimester of pregnancy. They simply get out of
line too soon.
The iron "cost" of growth is high, and inadequacy of iron stores can have serious
consequences. Anemia is associated with decreased ability to learn and to pay attention that can
remain a problem for months after the anemia itself is corrected by treatment. Additionally, the
“presumed iron stores” of the average term baby are just that … “presumed” … not “assessed.”
Historically this approach has not always served us well.
Iron-deficiency anemia has also been found to be associated with increased likelihood of
being identified as having mild or moderate developmental delay in school. This is likely
because iron has many important rolls in all of the cells of the body, including such tasks as
oxygen transport, energy production, protection against environmental toxins, and function of
brain neurotransmitters. For example, some iron-related brain-development functions in utero
are on such a strict time-table that inadequacy of iron during that period can cause irreparable
impairment.
As was the case with calcium, good iron status also decreases the absorption of lead from
the environment, a known agent of severe injury to brain, bone and kidneys, and a contributor to
hypertension. Iron deficiency results in an attempt to increase absorption of iron in the intestine,
and the process accidentally increases the absorption of lead as well.
Reliance on hemoglobin to screen for poor iron status is risky without also having
information about the adequacy of the person’s iron intake. This is because hemoglobin levels
can actually remain normal until iron stores are depleted. A low hemoglobin is a sign of trouble,
but a normal one tells very little about the status of iron stores. Measures of iron stores (like a
“ferritin” level) are rarely used at present in evaluating babies who appear to be healthy. But
asking specific questions about regular iron supplement use and/or meat consumption tells us a
lot about the likelihood of there being an unrecognized compromised iron status in a particular
woman or infant.
There is some concern that providing additional iron to a breast-fed baby may decrease the
effectiveness of one of the substances in human milk that helps to control bacterial growth.
Lactoferrin in human milk binds iron that E. coli bacteria in the gastro-intestinal tract need in
order to reproduce. Giving additional iron would make more free iron available to the bacteria
as well as to the baby.
15
It is not clear that this is a big problem, however, since there are many other bacteriafighting substances in human milk that are not affected by the presence of iron. Also, the fact
that most formula-fed infants thrive while regularly receiving generous dietary iron that is not
bound to lactoferrin suggests that is not a major problem. After all, these babies receive none of
the many other protective substances in breast milk either.
Complicating the picture is the finding that the iron in infant cereal that has traditionally
been used to provide iron in baby's diet may not be as well absorbed as had been believed. Its
ability to provide useable iron to the infant has been questioned, but so far no one has questioned
whether iron provided in the form of fortified cereal increases the risk of E coli infection in
breast-fed (or any) infants.
Two feeding practices can sometimes have an effect on the absorption of iron in infants:
1) Iron supplements given with a (non-human) milk or formula feeding are likely to be less
well absorbed compared with supplements fed with an acidic food or meat. Meat
contains “Meat Protein Factor” which enhances absorption of inorganic iron from other
foods fed with the meat.
2) Although in some cultures it is common to feed tea to infants, the tannins in it greatly
reduce inorganic iron absorption in both infants and adults. This does not appear to be a
problem for organic iron forms such as are found in breastmilk and meats, so feeding tea
to breastfed infants does not induce iron deficiency anemia the way it can in those not
breastfed.
Interestingly, in some world situations the traditional feeding of tea to infants has
actually been of great benefit in terms of child survival for the simple reason that the
water fed to baby has been boiled and germs have been destroyed. Together, protective
elements in mother’s milk and boiling any water fed to baby are a terrific combination
where bacteria and parasites make the water unsafe.
However, there is a risk of iron (and zinc) deficiency in a non-breastfed
infant who is regularly given tea, and people in many cultures do commonly give it.
One way to solve this potential problem (besides encouraging breastfeeding) would be to
advise them to introduce meats earlier, because the generous iron and zinc content is in
a form that is unaffected by the presence of tannins, plus the effects of Meat Protein
Factor can help avoid the problem.
Zinc
Iron often described as the micronutrient most likely to be deficient in Americans.
However, it is useful to remember that iron status is also the only non-electrolyte nutrient we
evaluate in many settings. Status of many other nutrients may be suboptimal, but one that is
particularly likely to be “iffy” in an individual with iron deficiency is zinc.
16
This is because in nature iron and zinc tend to be distributed similarly in foods and they
are also similarly affected by substances that impair or increase intestinal absorption. A person
who is iron deficient may also be zinc deficient, although we rarely evaluate it and therefore do
not recognize it. And if that person is iron deficient in spite of taking iron supplements and eating
iron-fortified foods (which are usually NOT also fortified with zinc,) the odds are even greater
that zinc adequacy may be compromised. The exception would be a person has relative iron
deficiency because of excessive blood loss.
This is not to make a case for checking zinc levels in people’s blood … the point is that
we can regard iron inadequacy as a marker/screening-tool for suspicion of unrecognized
inadequacy of zinc in particular, and many other nutrients as well. In general, people do not
consume a diet that gives them a terrific amount of all the nutrients needed except for just the
only one we check. Think of that low iron measure as the “canary in the coal mine” that tips you
off to an otherwise invisible threat in time to do something about it.
Why is zinc such an issue here?
Zinc is a co-factor in over two hundred metabolic pathways in the body, including making
DNA (the genetic center of every cell and hugely important for growth), making T-cells, and
metabolizing alcohol and other potentially dangerous substances. Inadequacy is known to impair
growth and the function of the immune system. However, zinc has been found to need some
attention in breast-fed infants. The same mineral storage patterns are seen for both iron and zinc,
with the third trimester being the major period of mineral accretion in the fetus. For this reason,
preterm infants are also especially likely to have poor zinc stores.
For term infants, the combination of a well-nourished mother who provided normal fetal
zinc stores and then provides human milk should meet growth needs until about age six months.
After that time, zinc and iron may be inadequate as described earlier. Of course, a history of poor
zinc nutrition of the mother complicates the picture further. Some studies have found that zinc
supplementation of exclusively breastfed infants in these circumstances improves growth or other
parameters of zinc adequacy [e.g. Lancet 2000 Jun 10;355(9220.)]
Supplementing a mother to maintain adequate zinc status does not correct this problem
because the zinc content of the milk begins to drop regardless of her zinc status. As described
earlier, a change in recommended “starter food” patterns has been suggested that includes an
earlier introduction of meats (the most abundant source of bioavailable forms of both iron and
zinc, and also a generous source of vitamin B6) in breast-fed infants [Acta Paediatr 1998;87(6); J
Mammary Gland Biol Neoplasia 1999;4(3)].
Again, note that infant vitamin drops do not provide zinc (or any minerals except iron
and sometimes fluoride) and they contain no folic acid. So if earlier introduction of meats is
undesirable, the best way to assure adequacy of zinc, iron and vitamin B6 would be to give a
crushed chewable children’s multivitamin with minerals.
Nutrient levels will not exceed safe ranges with this dosage, and this approach also
provides baby with the 400 iu of vitamin D recommended for all infants by the American
17
Academy of Pediatrics and the Canadian health groups as well. If texture is an issue, the pill can be
crushed to a fine powder using a small mortar and pestle. These are sold in kitchen stores and
discount stores (often for $10 or less) because they are used to crush fresh spices. The powder can
be mixed into any baby food.
More information about the zinc content and foods, zinc absorption
and some special zinc-related issues in fetal alcohol syndrome, are included in my handouts:
“Nutrition Support of Iron Deficiency” and “Thinking about Prenatal Nutrition and Fetal Alcohol Syndrome (FAS.)”
Iodine
Another nutrient problem that has recently been found to need more attention is
IODINE DEFICIENCY. In many parts of the world (including parts of the US) iodine
deficiency is common, and the traditional international approach to solving it has been to add
iodine to salt. However, it appears that the amount obtained from iodized salt is actually not
sufficient during pregnancy, and that even in areas that have been thought to have corrected
iodine deficiency many women obtain too little.
Iodine Deficiency Disease (IDD) is the number one cause of preventable mental
retardation in the world. The resurgence of the problem of iodine deficiency in the US has
great importance in pregnancy and lactation in particular because of the devastating effects on
the intellectual development of the child. Iodine deficiency can also result in deafness, and a
serious lack of energy in anyone affected because it impairs the function of the thyroid gland.
The World Health Organization is now increasing the recommendation for iodine intake by
25%, especially in pregnancy.
Here is an excerpt from a presentation by UNICEF Deputy Executive Director Kul
Gautam:
“… IDD is the single greatest cause of preventable mental retardation. Severe deficiencies cause
cretinism, stillbirth and miscarriage. But even mild deficiency can significantly affect the
learning ability of populations. Scientific evidence shows alarming effects of IDD. Even a
moderate deficiency, especially in pregnant women and infants, lowers their intelligence by 10 to
15 IQ points, with incalculable damage to social and economic development of nations and
communities. Today over 1 billion people in the world suffer from iodine deficiency, and 38
million babies born every year are not protected from brain damage due to IDD…”
UNICEF Deputy Executive Director Kul Gautam
This quotation comes from the website http://www.saltinstitute.org/Issues-in-focus/Food-salt-health/Iodized-saltother-additives. It has much more information about the problems of (and solutions for) IDD.
[For more detail on the most recent research on this topic in the scientific literature, please see my handout
“New Attention to an Old Problem: Iodine Deficiency in Pregnancy and Lactation”
18
The area of the United States that used to be designated the “goiter belt” because of low
iodine in the soil is shown on the map on the next page. The actual iodine content of foods
depends on where they were grown, and some protection has likely been provided to the lowiodine regions by the fact that at least some produce may have been grown in an iodine-sufficient
region.
This is a new issue to keep in mind as we promote growing one’s own food and buying
from local producers instead of transporting produce from far away. Local food production is
terrific for many reasons, but if one lives in an iodine-poor region, it is important to assure iodine
sufficiency via a demonstrably adequate intake from some form of iodine supplement.
Map showing spatial correlation between the former "Goiter Belt*"
in the northern U.S. and areas where
the iodine content of drinking water is naturally low.
www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm
[*Goiter is an abnormal enlargement of the thyroid gland, often due to iodine deficiency.]
Back home in America, many people under age 50 who live in iodine-poor regions of the
country are quite unaware that they should select “iodized salt.” The public health hoopla that
accompanied the iodizing of salt in the early 1950s (yes, I remember it … I was THERE!)
somehow faded away and the issue went off the radar. Many people of child-bearing age today
have no knowledge that this was once a widespread deficiency disease in the US of critical
19
importance to everyone’s health and especially dangerous to the development of infants
and children … and they don’t know it has come back
Even when one intends to buy the iodized salt, the packaging is often very similar and
they are side-by-side on the shelf at the store. Most specialty salts that are popular now, like sea
salt or exotic salts, are also not iodized. So generally, one should choose iodized salt if one uses
salt at home, and people who use little salt should be sure to find an iodine supplement,
especially if they live in the northern half of the country.
Additionally, we frequently are advised to cut back on salt for other health reasons,
which can further limit iodine intake. Recently some national health recommendations pushed
for an even lower daily sodium intake than before … instead of 3000 mg/day they recommended
1500 mg. I am not arguing against this recommendation … just pointing out the need to make
sure that people who follow this health advice are not accidentally injured by iodine deficiency.
Remember that the choice of salt as the way to supplement dietary iodine was made
well before ideas of sodium restriction were common for health reasons. Other factors have
made an inadequate intake much more likely today. For example, in the 1950s people made
most meals from scratch, so iodized salt would be added whenever salt was used in cooking.
Now most of our sodium intake comes in the form of processed foods, which are high in salt but
the salt is not iodized. Here is an excerpt from a website on this topic:
“…In the United States, from the outset, salt producers cooperated with public health authorities
and made both iodized and plain salt available to consumers at the same price. Even so, the Salt Institute
estimates that only about 70% of the table salt sold in the United States is iodized.
Salt used in processed foods is not iodized. Given that people are cooking less at home and
buying either restaurant or processed foods, iodine intakes in the U.S. have declined from about 250
μg/day to 157 micrograms/day. Public health authorities recommend 150 μg or more and the need is
particularly acute for expectant mothers. Daily Iodine intakes of 1,000 - 1,100 μg are safe for adults and
children over 4 years of age…”
http://www.saltinstitute.org/Uses-benefits/Salt-in-Food/Essential-nutrient/Iodized-salt
Also, because it has long been assumed that the iodine deficiency problem was “solved”
in the US by the iodizing program, at present many vitamin pills contain no iodine at all,
including many prenatal vitamins. So, this is one more nutrient that a person should check for
when they select a multivitamin.
20
The WIC Program recently added
use of a prenatal vitamin without iodine as a
nutrition risk factor for women enrolling in
the program. That means that some low
income women of childbearing age may
soon begin to have this addressed.
At least an awareness of the problem
is developing. However, MOST women
are NOT on the WIC Program so this
problem is unlikely to be readily
recognized. There is great potential for
harm.
There has been a resurgence of goiter development (a marker of iodine deficiency) in
America as well as around the world, and thought to be a problem. Additionally, data it is often
missed because it is no longer shows that average iodine intakes have decreased markedly in the
US. It is also reported that on average iodine intake is sufficient here [Iodine status of the U.S.
population, National Health and Nutrition Examination Survey 2003-2004. Thyroid. 2008 Nov;18(11):1207-14.]
However, when one stratifies the data it becomes clear that a great many women
here (and around the world) do NOT have a sufficient iodine intake even when men
generally do. The risk to fetal and maternal health is substantial, and easy to fix once the
problem is recognized.
Major Point: The problem of iodine deficiency needs
to be put back on our radar; this is a very newly recognized and
extremely important health problem that needs attention.
Please see my paper “Aunt Cathy’s Guide to Nutrition:
New Attention to an Old Problem:
Iodine Deficiency in Pregnancy and Lactation 2011”
for detail on this topic, including an annotated bibliography.
Some newer references are included here since this topic may be quite new to many
readers and I don’t want them to think I am making this stuff up! ☺
Iodine deficiency in infancy - a risk for cognitive development. Dtsch Med Wochenschr. 2010 Aug;135 (3132):1551-6.Parameters of thyroid function throughout and after pregnancy in an iodine-deficient population.
Thyroid. 2010 Sep;20(9):995-1001. Some subgroups of reproductive age women in the United States may be
at risk for iodine deficiency. J Nutr. 2010 Aug;140(8):1489-94. Iodine intake and maternal thyroid function
during pregnancy. Epidemiology. 2010 Jan;21(1):62-9.Georgian Med News. 2010 Jan; (178):65-8.Iodine
deficiency in the prenatal period may form learning ability deficiency in the postnatal period. Epidemiology of
iodine deficiency: Salt iodisation and iodine status. Best Pract Res Clin Endocrinol Metab. 2010 Feb;24(1):111. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. 2010
Feb;24(1):29-38.Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the
offspring: a review. Am J Clin Nutr. 2009 Feb;89(2):668S-72S.
21
Fluoride
Fluoride is low in human milk and whether the mother's fluoride intake affects the amount
in milk is still subject to some debate. The recommendations for using fluoridated water, fluoride
drops, fluoride toothpaste and topical fluoride treatments have changed many, many times over the
years that I have been involved in pediatric nutrition. They are being changed again this year
regarding the recommended amount of fluoride to add to low-fluoride-containing water supplies.
The American Dental Association has a current list of very specific recommendations on
all aspects of the topic of fluoride as it relates to dental issues. It is available at this website:
http://www.ada.org/public/topics/fluoride/infantsformula.asp
22
Sanford Medical Center
I received this excellent question in the
mail, and I think it’s a discussion worth
sharing:
“At our WIC program, we are able to provide
several different formulas if an infant does not
tolerate our contract formulas. Typically, at
the age of 5-6 months we will ask parents to
reintroduce a contract product. We do this on
the basis that as an infant gets older, he or she
may tolerate the formula better than before
(mainly due to the fact that the infant is
tolerating solid foods at this point). This has
been in practice long before my time here and
I’m now looking for evidence/research to back
this up.”
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Regarding “A Trial Back on . . .”
A WIC Nutritionist Question
Reply: The practice of re-trying a baby who did not tolerate a formula back on the original
product was originally based on three things:
1)
For many years, doctors and nutrition people perceived that soy-based products were
inherently significantly lower quality than milk-based products. My formula handout discusses
where we are with that. Basically, unlike some years ago, there is no big nutritional advantage
to switching back to milk-based formulas for non-premature babies or those who are otherwise
healthy.
If the baby's initial intolerance problem was in fact allergy-related (i.e. involving
immunoglobulin E and not just a lactose intolerance type of issue,) such a trial would not be a
great idea because allergy to cow's milk CAN "go away" but not usually in the first year. If it
were a true allergy I would be very hesitant to just switch them back at 6 months (or whenever)
without specific orders for safety reasons. If the baby were to have a severe anaphylactic
reaction, for example, there could be very serious consequences.
An additional feature to consider here is the issue of trust between the nutritionist and the
client. Many parents perceive the insistence on a re-trial of the formerly-problematic formula
as being dangerous and foolhardy. We say, "well, if he still has the problem we can always
switch back." However, the "if he still has the problem" part suggests that we pretty casually
put their baby in what may be jeopardy.
Now, if it were very important to switch back, that is one thing. But if not? Why would
we put them through this kind of anxiety-inducing experience? This is especially a problem
when the parents feel very strongly about staying on the present product. We have the power to
make them switch ("take it or leave it,") but to do it when there is no pressing reason (like a
relative non-issue such as the perceived nutritional value of milk-based vs soy-based) it does
have the potential to harm to our relationships with them.
1
2.
A lot of the "switch back to the old formula" has roots in the use of more pricey
hypoallergenic formulas in place of standard or soy products. In this situation, if the problem is
not of a true allergy nature (rendering the hydrolyzation of the protein unnecessary) then the
family or the WIC program can save some money by moving toward an intact-protein formula.
However, if it is a true allergy, the same caveats apply as above. Example: hypoallergenic
formula might be used for a colicky baby for whom it seemed to be helpful in the first months
of life; however, most babies are not colicky after 6 months and they would likely do fine on
standard or soy formula, saving big bucks. But colic is not an “allergy” and a recurrence is not
potentially life-threatening the way an allergic response can be.
3.
WIC costs have also been players in this drama, as the more costly hypoallergenic
formulas have sometimes not been on a state's rebate formula list. In that case, the WIC people
may be very eager to get back onto any of the “contract” formulas for budgetary reasons.
However, again, in that case the primary urge is financial and not baby health, so we really
have to be cautious about the circumstances in which we “make” the baby switch back.
So, the bottom line is that it is sort of a relic of the past to insist on switching back from
soy-based back to milk-based. In regard to trials of intact protein in place of a hypoallergenic
formula, it would depend on whether or not the reason for the switch initially was because of a
true allergy. If it is an allergy I wouldn't see any big (non-financial) reason to switch back.
Risks to baby health trump thriftiness every time in this situation.
Hope this helps! Cathy B.
2
Aunt Cathy’s “PMS” System for
Decision-Making:
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Whole, 2% or Skim Milk for Ages 1-2.
Sorting out the formulas or questions about when to use whole milk or skim milk can be
complicated by issues unrelated to the science of nutrition. For example, a formula may not be
usable in a situation for which it might be helpful because of costs, contracts with other formula
companies, or confusion because of the way a product is promoted.
Health professionals serving large infant-feeding programs like WIC (“Special
Supplemental Food Program for Women, Infants and Children” of the Dept. of Agriculture) often
find this sort of confusion to be very costly in terms of time, money and frustration. In response
to hearing these concerns raised by many state WIC programs, I devised a way of thinking about a
formula and milk choice issue that attempts to sort out the important aspects from those that are
irrelevant or changeable. The following example examines the question of the need to use whole
milk after the first birthday until a child is two (which remains the current AAP recommendation):
The “Whole Milk Dilemma”
Many health professionals expressed concern that insisting on the use of whole milk for
all of this age group of children may be inappropriate for those with lower than average ability to
expend calories (e.g. children with spina bifida) and those who are already in the overweight /
obese categories. However, they felt obligated to follow the official AAP recommendation.
In some states WIC programs did not allow clients to use whole milk without getting a
physician’s prescription. Much time and money was invested in obtaining documentation that
the child needed a lower-calorie product. Policies and flow-charts had to be established to assure
that these issues were handled correctly. Here’s a great example:
“Proposed Policy Regarding the Use of 2% or Skim Milk by Children under Age Two
Participating in the _____ State WIC Program.
1. For children observed to have three rolls of fat on the thigh, the Nutritionist may call the child’s
physician to request a prescription for skim or 2% milk to be used in place of whole milk.
2. Children under age two who have two or fewer rolls of fat on the thigh are to receive whole milk.
Their fat stores will be monitored at clinic visits. Should they develop a third roll of fat, a
prescription will be requested as described above.”
It sounds pretty silly and unhelpful, but it was real.
This is especially irritating to the client and the MD when have both agreed that the child
is doing very well on 2% or skim milk. So, lets look at the “PMS” of this issue:
1
P = Policy
M = Marketing
S = Science
Policy: “Only whole milk will only be allowed from the end of the first year of life until age two.”
Marketing is not really an issue/problem with this issue (but it sometimes certainly IS.)
Science:
1. The only difference between whole, 2% and skim milk is in the amount of fat and calories per
ounce. Other nutrients are provided in the same amounts.
2. The form of fat in the milk is a very poor source of essential fatty acids, it can be somewhat
constipating, and there is no special property of cow’s milk fat (or goat’s milk fat) that promotes
brain development … babies just need calories for that. None of the formulas contain milk fat so a
formula-fed infant got none in the important first year. Neither did the breastfed
baby because Mother’s milk does not contain cow’s milk fat either. So why would it be so important that
children between ages 1 and 2 be fed a large percentage of their calories in the form of cow’s milk fat, and
why would we insist on it? Answer: I can’t think of one.
3. Babies need adequate calories to grow and to myelinate their brains. Before the WIC Program was
established many poor babies did not get enough calories because skim milk was a few cents cheaper than
whole milk. The reason for the AAofP recommending whole milk was to try to at least provide
enough calories for the baby’s growth and development, and whole milk has twice the calories of
skim. Once the WIC Program was established, no infant should be at risk of obtaining inadequate calories
for growth and development because of poverty. The original reason for the recommendation is gone.
4. Insisting on using high fat milk in this situation may result in excess caloric intake, and if so it
could contribute to obesity, the more common problem these days. However, usually it does
NOT result in over consumption of calories, because the baby self –regulates caloric intake. But
in that case it would certainly decrease the content of vitamins, minerals and protein in the
children’s diets because satiety induced by all those fat calories would cause them to eat less of
other foods.
5. However, in the extreme, such as when a child has very low caloric requirements because of
being able to move very little, this can cause lots of trouble. Similarly, it can cause real problems
if (for example) the child is tube-fed and therefore unable to regulate his/her caloric intake.
Additionally, policies that require waiting until a child is demonstrably overweight or obese
before allowing a lower fat milk to be used are clearly not in children’s best interests. (See my handout
on nutrition for children with special needs for more information.)
Conclusions: In this scenario, it appears that the Science evaluation did not argue against using skim
or 2% milk in children ages 1-2. What remains then is to determine if there is a good reason for continuing
a Policy of requiring WIC nutritionists to provide only whole milk for children of this age group. If so, this
also totally undermines the idea that professional WIC nutritionists are able to evaluate the appropriateness
of a child’s nutrition and to act on it. If no good reasons can be proposed for requiring whole milk at
this age, then CHANGE THE POLICY to use the form of milk or milk substitute judged to be best
by the WIC health care professional who is considering the needs of the individual child in his/her
care.
2
2/2011
Sanford Medical Center
Aunt Cathy’s Guide to:
Choosing
Appropriate
Infant Milks and
Formulas
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
Sanford Medical Center, Dept. of Pediatrics
and Clinical Associate Professor of Pediatrics
UND School of Medicine, Fargo, ND
Part 3: Cow’s/Goat’s Milk and Evaporated Milk Formulas as the
Primary Feeding Product for Infants.
Cow’s milk and goat’s milk are inappropriate for use as the primary feeding product in
place of human milk or commercial formula. They fall outside of the "desirable range" of
carbohydrate, protein and fat, and can present problems for some infants.
This is especially true for very young babies or for those who have special health
problems. In addition, 2% (low fat) and skim milk provide inadequate calories (about 15 and 11
calories per ounce, respectively), so babies tend to drink even more of these products than they
would whole milk, formula or human milk, which all provide about 20 calories per ounce.
Percent of calories from:
CHO
PRO
FAT
__________________________________________________________________________
Desirable range:
35 - 65
7 - 16
30 - 55
______________________________________________________________________
Cow's milk: Whole:
30
20
50
2% :
38
26
36
Skim :
57
40
3
Goat's milk:
27
19
54
Are there any other problems?
At a time when many American infants were being fed skim milk, Fomon et al, (1974)
showed that young infants fed skim milk as their major food drank about 1.5 times the amount
normally taken, in an effort to get adequate calories. As you can see on the chart above, the amount
of protein would be very high, and since so much of the baby's energy would be derived from protein,
1
there would be a large amount of nitrogenous waste produced that must be excreted via the kidney
(i.e., a high "Renal Solute Load.")
This has the potential to result in dehydration because of the obligatory loss of water to
excrete the waste products. Sometimes the loss of fluid can be more than the baby can afford. In
very young infants or in those with special health problems, including those with growth failure,
diarrhea, or fluid limits, a high "Renal Solute Load" can be dangerous.
These milks are also less than ideal because they contain up to 8 times as much sodium as is
in human milk and formula. If skim milk is used as described above, that can mean a sodium intake
of 12 times the amount in human milk, since the baby will drink so much more of it.
In addition, these milks do not provide complete nutrition, because they are poor
sources or iron, vitamins C and B-6, copper, zinc and essential fatty acids. Vitamins A and D are also
low unless they are added in processing.
Most commercial milk has vitamin D added, but milk obtained directly from a dairy farm or
the family barnyard often has none. As a result, severe vitamin D deficiency is not uncommon
among many “farm” children, especially in the north [Rickets in the Dairy State. Wisconsin Medical Journal.
2004;103:84-87. 7.]
In addition to these problems, goat's milk (but not cow’s milk) is also naturally too low
in folic acid (a B-vitamin especially important during periods of rapid growth because of its role in
DNA production), and offers no special advantage over cow's milk. Many commercially canned
goat's milks do have folic acid added. Babies who are allergic to cow's milk protein are often allergic
to goat's milk, too.
I was involved in the care of an infant whose exclusive (“natural”) diet of raw goat’s milk
landed him in the hospital at age 4 months, very near death, with overt scurvy, anemia and neurologic
problems from deficiency of folic acid, vitamins C, B6, D, iron, zinc and several other nutrients.
Fortunately, emergency treatment saved this baby’s life, but there is no way to determine if there will
be any long-term consequences of such severe malnutrition of multiple nutrients during infancy.
These are serious issues.
Unpasteurized milks are not recommended due to the risk of bacterial contamination.
This includes conditions like listeria, brucellosis and salmonella, to mention just a few. Heat
treatment also improves the digestibility of the milk, but the milk fat remains much harder for babies
to digest than the fat in human milk or commercial formulas, and it is a poor source of linoleic and
alpha-linolenic acid, the essential fatty acids.
Some babies appear to have a sensitivity to unheated cow's milk (but usually not to formula)
that causes bleeding from the intestine. The amount of blood loss is often so small as to be
unnoticeable in the stool, but it can result in a serious loss of iron. This blood loss, along with the
poor iron content of cow's milk and its impairment or iron absorption from other sources, can
contribute to the development of anemia.
2
I have seen young children with this kind of “cow’s milk anemia” related to these factors
plus a diet pattern that provided too much of the child’s calories in the form of milk/yogurt/cheese,
etc., and very little other foods. Interestingly, several children had been identified as anemic, but the
solution recommended was just to give a supplement of inorganic iron (e.g. ferrous sulfate.) This is
particularly unlikely to be very helpful because:
1)
milk impairs absorption of inorganic iron and
2)
the basic problem of dietary imbalance is not addressed so multiple other critical (but less likely
to be tested for) nutritional inadequacies remain uncorrected. For example, this dietary pattern
would also lead to relative inadequacy of zinc and copper, both of which can be very serious
inadequacies.
Essential Fatty Acid Deficiency
Of the linoleic acid found in butterfat (the fat in cow’s milk,) it appears that only 50-80% of
the total amount is in the form of linoleic acid that is biologically active (Fomon 93), so the values
shown on the chart on the next page overestimate the actual amount of linoleic acid available for
metabolic uses. This is another clear indication why cow’s milk or goat’s milk should only be used
as a part of a child’s diet and certainly not as the main source of calories.
Other forms of fat need to be included in an infant’s diet, as cow’s milk fat alone can actually
result in essential fatty acid deficiency. I once observed this situation in a child admitted to the
intensive care unit in our hospital with a variety of unusual symptoms. A careful diet assessment
revealed that nearly all of his fat intake was in the form of dairy fat. A laboratory measurement of
the triene:tetraene ratio then confirmed the suspected EFA deficiency.
Note that the table on the next page addressing the relative inadequacy of linoleic acid (the
omega-6 essential fatty acid.) It does not address the additional inadequacy of linolenic acid (the
omega-3 essential fatty acid) discussed earlier as being so important for making subsances such as
EPA and DHA. Further, most vegetable oils are not well-balanced in the ratio of omega-6 to
omega-3 fatty acids. The essential fatty acids in corn oil, for example, are almost all omega-6.
[For additional information on this issue please see
“All Those Lipids: Recommendations for Using Different Types of Vegetable Oils
(Omega-3, Omega-6 and Monounsaturated Oils.)”]
3
Essential Fatty Acids
_________________________________________________________________________________________
Suggested Intake: (FAO/WHO) and regulation level for formulas is 1.2 % of energy as Linoleic Acid.
Goal is to provide 500 mg/day (Foman 93)
________________________________________________________________________________________
Linoleic Acid per 100 kcals &
Linoleic Acid as a
Total PUFAs
Total PUFAs as a
intake per 18 or 24 oz milk/day Percent of Total Fat
mg/oz
Percent of Total Fat
(Fomon 93)
(Worthington Roberts 96)
(Pennington: Bowes & Church 94)
_____________________________________________________________________________________
Cow's milk:
Whole: 1.12 mg/100 kcals
1%
37
4
18 oz = 4.1 mg
24 oz = 5.4 mg
_____________________________________________________________________________________
2% : 0.92 mg/100 kcals
1%
25
4
18 oz = 2.5 mg
24 oz =3.3 mg
_____________________________________________________________________________________
Skim : 0.02mg/100 kcals
1%
18 oz = 0.04 mg
24 oz =0.05 mg
______________________________________________________________________________________
Human milk:
5%
200
14.3
So why do people want to use cow's milk for infants?
Some people have the mistaken notion that unpasteurized cow's milk or goat's milk is
somehow more nutritious or "natural" . . . which it is for baby cows and goats. For human infants it
is significantly less appropriate than human milk or formula, and as already described, it is potentially
dangerous. The major reasons for switching from commercial formula to cow's milk (pasteurized or
not) during the first year are cost and convenience factors.
For young infants or those with health problems, this practice should not be encouraged.
However, if the infant is at least six months old, is a healthy baby, and is eating the equivalent
volume of 2-1/2 to 3 jars of baby food daily, some of the problems with whole cow's milk can be
tempered.
For example, by adding three 4-oz servings of cereal, fruit, or vegetables daily, the
carbohydrate portion of the diet moves into the acceptable range, and the protein percentage
decreases down to the acceptable range. By filling up on other foods, the baby will probably also
drink less milk, which will also decrease the protein and sodium intake. If one selects the other foods
carefully (including meats and a wide variety of other nutrient-dense foods), some of the other
nutritional shortcomings can be remedied as well, such as decreasing the high sodium content and
improving the vitamin /mineral content of the diet.
4
Because of the observations about inadequacy noted above, a few years back (about 30,
actually) when I was first working for the (brand new) WIC Program, the American Academy of
Pediatrics decided that switching from human milk or formula to whole milk would be acceptable
after age six months “for babies who were eating a variety of foods.”
However, studies were done that showed that although it is possible to achieve a balanced diet
this way, most babies who had been put onto whole milk, in fact did not receive a balanced and
appropriate diet. So the recommendation of human milk or formula for the first year of life was reinstituted. The more recent questions about the safety of pasteurized cow's milk products during
infancy (e.g. yogurt, cottage cheese and ice cream) as adjunct foods do not represent a major policy
change. [Interestingly, during the AAP’s “6-months-is-ok” period, WIC held its ground and
continued to provide only iron-fortified formula to non-breastfeeding infants for the entire first year
of life. Way to go, WIC!]
One further caution before switching to cow’s milk or goat’s milk is to be sure that the baby
regularly eats table foods that contain some (especially omega-3 rich) vegetable oils in order to obtain
appropriate levels of essential fatty acids. Most baby foods are extremely low in fat, as are many of
the “starter” table foods like fruit, crackers and cereals. Other dairy foods like cheese, butter or
yogurt provide only the same limited amount as milk does, even when the total fat content is high.
So, especially when the baby is eating commercial baby foods as a major part of the diet and
has switched to milk, extra care must be taken to provide sufficient essential fatty acids. Fortunately,
this can be done quite easily when one is aware that it is an issue. Hydrogenated oils like margarine
and shortening should not be considered as sources of essential fatty acids because the
hydrogenation process significantly decreases the essential fatty acid content of the product.
This is in addition to the well-known concerns about partially hydrogenated oils forming trans fat.
What about evaporated milk formula?
Many people have been raised on home-made evaporated milk formula, although it is rarely
used today. Its major advantage is its lower cost than commercially made formulas, while being
better suited to infants than regular cow's milk. Because it is canned, it has been sterilized and the
heat treatment makes the protein more digestible.
Corn syrup or sugar has traditionally been added to adjust the proportion of carbohydrate, protein
and fat, as shown below. Water is added to adjust the calories to 20 calories per oz, (the same calories
as in human milk, formulas and whole milk). (See the chart on below)
______________________________________________________________________________________
Percent of calories from:
CHO
PRO
FAT
____________________________________________________________________________________________________
Desirable range:
35 - 65
7 - 16
30 - 5
Evaporated Milk Formula made with Corn Syrup:
45
15
40
______________________________________________________________________________________
5
Digestion and absorption are still not as good as is seen with human milk and formula,
because the form of fat is more difficult for babies to digest in addition to being a poor source of
essential fatty acids. Milk fat can be quite constipating for some children, but the corn syrup
usually has an osmotic laxative effect to counter it. (Somehow that arrangement does not sound
optimal!)
In the 1980s a concern was raised about the safety of corn syrup for small infants (J. Food
Protect. 1989:45,1028.) Some samples were found to contain heat-resistant spores of Clostridia
botulinum, a type of bacteria that has been associated with a form of SIDS (Sudden Infant Death
Syndrome). It was estimated that about 5% of SIDS cases at that time may have been due to "infant
botulism" linked to the use of corn syrup or honey in young infants.
For this reason it was suggested that when this type of formula is used, the corn syrup or honey
should be replaced by table sugar. Since then, manufacturing techniques have improved and corn
syrup no longer is regarded as a risk factor for developing infant botulism (J Food Protect. 1991),
although honey should continue to be avoided in the first year of life. [Note: Honey baked into foods
like graham crackers is safe because the high temperature of preparation kills the spores. This
question still comes up often.]
Human milk or commercial infant formulas are still preferred over evaporated milk
formula because of their more complete nutrition and better digestibility. As with any cow's
milk product, evaporated milk formula is naturally low in iron, copper, selenium, zinc, essential fatty
acids, and vitamins C and B-6. Vitamins A and D are usually added, but might not be. This product
should be of historical interest only. It belongs to what I call the “This is white … just feed it to ‘em
School of Nutrition”
Because of the great potential for nutrient inadequacy, a registered dietitian or physician who
is knowledgeable about these issues should look carefully at a baby's whole feeding plan to assess its
adequacy. A supplement should be recommended if other foods are not providing these missing
nutrients. However, my experience has been that nobody looks at this issue at all, so careful
nutrient supplementation in this situation is theoretically possible but practically non-existent.
And, as the babies do not “look funny” their deficiency state usually remains unrecognized.
And finally, I found on the internet a blog from a woman who has discovered the joys of
making one’s own evaporated milk infant formula. The main benefit she cited was that it was
much cheaper than regular formula. [But not as cheap as breastfeeding! ☺] The best part: she is quite
comfortable about using it for her baby because she has “talked to some people over fifty and they
seem to be OK.”
As it happens, I was fed evaporated milk formula with corn syrup in 1950 and I lived to tell
about it. But in those days we were not fed that product exclusively … we were also fed ironfortified cereal practically before we left the hospital, and right away we were regularly fed egg
yolks and liver as well. The yolks were also given “for iron,” since then (as now) that was about the
only nutrient ever evaluated so anemia was actually sometimes recognized as a problem. But it turns
out that the iron was not wonderfully absorbable from either the cereal or the yolks.
6
In retrospect, the yolks turned out to have lots of other good things we didn’t even know
existed, like choline. Choline is looking like a very important nutrient for brain function (as in the
neurotransmitter “acetylcholine”) and providing some ready-made choline to babies looks like a very
good idea.
Pre- and Postnatal Health: Evidence of Increased Choline Needs. JADA August 2010)
And thank heaven for that liver, which provided actually absorbable iron and zinc, plus lots of
choline and vitamins A and D and many other nutrients!
Using the classical (translation: “old”) evaporated milk formula with today’s typical feeding
patterns (e.g. waiting to introduce other foods until 4-6 months) has the potential to do significant
harm to that baby.
And even if some of us over-fifty people are actually “OK,” it is really quite foolish to trust
that precious baby’s health and development to our scientific knowledge base of 60 years ago. We
old folks didn’t have seat belts either and we’re still here. Well … at least, SOME of us are!
7
2/2011
Sanford Medical Center
Aunt Cathy’s Guide to:
Choosing
Appropriate
Infant Milks and
Formulas
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
Sanford Medical Center, Dept. of Pediatrics
and Clinical Associate Professor of Pediatrics
UND School of Medicine, Fargo, ND
Part 4: Thinking about When to Recommend Whole Milk,
Low Fat (2%) Milk or Skim Milk before Age Two
A. What percent of calories is provided by fat in each type of milk?
At a time when many American infants were often being fed skim milk, Fomon et al,
(1974) showed that young infants fed skim milk as their major food drank about 1.5 times the
amount normally taken, in an effort to get adequate calories. This was a concern for several
reasons:
1. The amount of protein would be very high because skim milk provides 40% of calories as
protein. This is much more than in whole milk (20%) or human milk (7%.) Because so much of
the baby's energy would be derived from protein, there would be a large amount of nitrogenous
waste produced that must be excreted via the kidney (i.e., it would contribute to a high "Renal
Solute Load").
In the first months of life, this can result in dehydration because of the obligatory loss of
water to excrete the waste products; sometimes the loss of fluid can be more than the baby can
afford. In very young infants or in those with special health problems, including those with
growth failure, diarrhea, or fluid limits, a high "Renal Solute Load" can be dangerous. It becomes
much less of an issue in an older baby or child who is growing normally.
2. The volume of milk required to achieve a particular caloric intake is about twice as much for
skim milk compared with whole milk or human milk. Some children, as noted above, simply
could not take in enough volume to maintain appropriate fat stores and to grow. I call that
problem “Tiny Tummy Syndrome.” However, they will try hard to take in the calories they need
and so they do increase the volume of milk, resulting in an even higher net protein intake provided
in inadequate calories.
1
3. The essential fatty acid content of cow’s milk was discussed earlier in the infany feeding
section and there is a chart there of EFA levels indifferent types of cow’s milk. The same applies
here. The major point is that NONE of these milks (skim, 2% or whole) have much in the
way of essential fatty acids, so it is not a reason to insist on whole milk for a child.
What About after One Year?
Whole?
2%?
Skim?
After one year, whole cow's milk has been recommended for most children until age two.
This recommendation is being seriously reconsidered at this time. Lower fat milks can also be
appropriate based on a particular child’s caloric requirements and the presence of other sources
of fat in the diet. A complete review of this topic is beyond the scope of this paper, but it is useful
to note that the global “whole-milk-to-age-two” concept is a public health guideline, and it is not
intended to tie the hands of qualified health care professionals who determine that an individual
child would be better served by using 2% or even skim milk. As shown later, there are no magic
qualities of cow’s milk fat that make it an essential component of a child’s diet.
Consider that the breast-fed baby receives no cow’s milk fat at all, nor does the formula-fed
baby because the fat is replaced by vegetable oils. So why, at age one, would a child suddenly
“need” milk fat? And unlike human milk, infant formulas provide no cholesterol (the precursor to
myelin) at all. Interestingly, the milk fat is not the baby’s primary source of cholesterol, so skim
milk is not very different in regard to pre-formed cholesterol content than whole milk. (See chart on
the next page.)
As noted earlier, cow’s milk fat is a poor source of essential fatty acids, including those
leading to production of DHA, a major fat involved in brain development. It is no more beneficial
to the myelinization of a child’s brain than any other source of acetate (the 2-carbon unit that is the
substance from which cholesterol and then myelin are produced.) Acetate can be made from any
calorie source … carbohydrate, protein or fat. Interestingly, the reason I am given most often
by health professionals for insisting on whole milk for a toddler is because “he needs it for
brain development.” Unfortunately, all that milk fat only provides a lot of calories and not
the truly and directly brain-building components DHA or cholesterol.
It is useful to consider that children have a growth schedule to keep, and if for some reason
calories are inadequate, the child will burn fat stores to continue to grow in length and continue
brain-building operations. If calories remain inadequate, linear growth will next be compromised
and available energy will be preferentially used for brain-building. What this means is a child
with inadequate calories will not have to make a judgment like “Gosh! I just can’t decide! Should
I make a brain or a fat bottom?”
Anyway, it means that one could conclude that a child of appropriate/normal weight and
apparent fat stores would have adequate calories for brain-building.
When I see a little “Three-Roller” toddler (related to the number of rolls of fat on thighs) in my
office, I do not worry that he would be at risk of getting inadequate calories “for his brain” if I
switch him to skim milk from whole.
2
Consideration of these issues can allow for safe and intelligent departures from the
“whole milk until two” recommendations, even as we wait for official changes to come from
professional associations.
This is especially true when insisting on feeding a high fat milk is contrary to the
child’s best interests, as is often the case with children with handicaps that decrease mobility,
or overweight children whose caloric intake is clearly already generous.
The negative effect of whole milk on the overall nutritional quality of the diet
Many American toddlers are already consuming a generous amount of calories as fat from
other food sources. The use of whole milk also actually decreases the amount of other foods
that a child with a normal appetite would consume. If our model is that healthy infants will
control their intake of calories to match their caloric requirements (and it is,) then feeding a diet
that is higher in calorie-to-nutrient ratio would certainly decrease the over-all nutrient content.
Here is a simple example:
The calories in 4 oz whole milk is equal to the calories in
4 oz skim milk + 4 oz strained carrots.
They provide the same calories. Which provides more nutrients?
Insisting on using a high fat milk with a chubby toddler is generally not in his/her best
interest. One consideration might be whether this would encourage excessive caloric intake, but
the more likely response of an otherwise healthy child is that he/she will simply eat less food in
general to obtain the appropriate (lower) number of calories, so the nutrient:calorie ratio of the
diet will decline.
This is especially non-helpful if the parent tells you that the child’s usual diet features
foods already high in fat like macaroni and cheese, french fries, potato chips, butter, gravy, peanut
butter and hot dogs [I know … there is a choking issue with these last two especially that is very
real. But the fact is, in real life many babies and toddlers are commonly fed these foods: “I give it
to him because he really likes it.”]
3
If the rest of the child’s diet is described as above, it is already a very generous source
of fat. It would be hard to come up with a logical reason why one would want to increase it
further by insisting that the baby use whole milk simply because he/she is “not yet two.”
Is there a risk of essential fatty acid deficiency if we give skim milk before age
two instead of whole milk?
No, for these reasons:
1. There is the same risk of EFA deficiency whether one uses whole, 2% or skim milk
because, as shown earlier, none of these milks is a good source of essential fatty acids.
2.
For “normal, healthy children” who were either breastfed or fed commercial
formulas for the first year, both feeding products provided generous EFAs and the
child’s fat stores would therefore contain generous amounts. This assumes that the
child has reasonably appropriate “normal healthy” fat stores upon visual inspection; an
emaciated child would of course be at greater risk of EFA deficiency … but that child
is not a member of the “normal, health children” group and a lot of rules will be
different.
3. Ironically, an example of the primary exception to the assumption of good EFA
stores in a child with reasonable fat stores would be one who was switched to milk
(whole, 2% or skim) at age 6 months or so of age. That child will have had 6 months
of EFA-free milk, so his/her fat stores are less trustworthy in this regard. In terms of
stored EFA fat at least, we ARE what we eat!
There is also an historical perspective to consider:
When the “whole milk until age two” recommendation was established,
there was no WIC Program, and many poor children actually
got too few calories to grow and develop well.
Skim milk costs a few cents less per gallon, so the poorest families chose it. The AAP
“whole milk” recommendation was an attempt at that time to remedy that situation to at least
improve the adequacy of calories during this important period of brain development. That is ALL
it addressed.
The WIC Program was established in the late 1970s to encourage breast-feeding by giving
food to low-income nursing mothers, and by funding replacement of cow’s milk (of any kind) for
non-nursing infants with far more nutritious commercial formula. This particular poverty-related
health problem has long ago disappeared … no poor babies in America have to be fed skim milk
4
because of financial need. But the whole milk recommendation remains with us in spite of
considerable evidence that it is really not ideal, and sometimes frankly suboptimal. It takes a long
time for official positions to be changed.
The protein and micronutrient content of skim, 2% and whole milk is quite
comparable. Vitamins A and D are equally fortified in all three. The only real difference is
the calorie content:
Per 8 fluid oz
Protein Calories Cholesterol Calcium
(g)
(Kcals) (mg)
(mg)
Phosphorus
(mg)
Vit. D Vit. A Vit. B2 Potassium
(iu) (iu)
(mg)
(mg)
8.4
86
4
300
300
100
500
0.3
406
2% Low Fat milk 8.1
121
18
297
232
100
500
0.2
399
8.2
159
33
291
228
100
500
0.4
370
Skim milk
Whole milk
(data from Pennington, J. Bowes & Church’s Food Values of Portions Commonly Used 16th Ed. )
Interpretation of the chart above:
The difference in the cholesterol content is not a very significant, especially as we know that
infants fed formula instead of mother’s milk receive no pre-formed cholesterol at all for the first
year. This means that infants apparently can make their own cholesterol to myelinate their brains
and for normal formation of cell membranes. The exceptions are those with a rare metabolic defect
called Smith-Lemli-Opitz Syndrome which interferes with the ability to make cholesterol.
The protein and micronutrient differences are also not significant.
The difference in calories is significant:
A teaspoon pat of butter has about 36 kcals.
The difference between skim and 2% milk is 35 kcals.
The difference between 2% and whole milk is 38 kcals.
So, one could picture their relative caloric and fat value as follows:
Skim milk = 8 oz Skim Milk
2% milk = 8 oz skim milk with a pat of butter floating in it.
Whole milk = 8 oz skim milk with 2 pats of butter floating in it.
5
Comparison of Skim Milk, 2% Low Fat Milk and Whole Milk
Today in the USA, the situation is quite different from the situation in the early 1970s
described above. Because of programs like WIC, more babies are being breastfed, and no nonbreastfed baby has to use skim milk instead of formula to save a few pennies and in the process
receive only half the calories per oz.
It is also interesting to note that there is a priority system among the body’s tissues, and
a child’s calories will be preferentially used for brain development at the potential cost to other
tissues. Therefore, if a child has normal-to-generous fat stores on board one can assume that
calories, at least, are sufficient for brain development. [Think of it this way: A toddler who takes
in too few calories to meet all of his/her needs will NOT choose to have “thunder thighs”(also
called “two-rollers”) instead of a well-made brain.] The misunderstanding of this situation often
leads to inappropriate use of high fat milk out of concern “for his brain.”
See “Aunt Cathy’s PMS System of Baby Formula Decision-Making” on the next page
for a quick example of problem solving that uses the “Whole-2%-or-Skim” issue as an example.
6
Aunt Cathy’s Guide for
Problem Solving:
How Much Should
This Baby Eat?
Troubleshooting in the Front Lines
Cathy Breedon, PhD, RD, CSP, FADA
Perinatal/Pediatric Nutrition Specialist
MeritCare Medical Center and
Clinical Associate Professor of Pediatrics
UND School of Medicine, Fargo, ND
It is well known that healthy, typically developing infants will tend to take the amount of breast
milk, formula and/or food needed to meet their energy (calorie) needs. When lower energy foods are
provided, these babies increase their intake; when higher energy foods are provided, they will eat less.
Of course, this depends on a few major factors:
1.
The food must not be SO LOW in energy that the baby cannot possibly eat the volume of food
required to get enough, or SO HIGH in energy that the amount needed to quench thirst carries
with it exorbitant calories.
2.
The feeder must make the food easily accessible to the baby.
3.
The feeder must not coax, prod or force baby to take more than the amount needed to meet hunger
needs, or fail to feed enough in an effort to prevent having a “fat baby.”
4.
The baby must be able to eat, to keep the food down, and to digest and absorb it adequately.
This article will provide some tools for judging the adequacy and appropriateness of an infant’s or
child’s intake, including checklists to aid in the detective work needed to identify the reason for a
particular growth pattern or reported intake. While these tools can be useful in working with healthy
infants and children, they can be especially helpful in evaluating the nutritional status of those children
with special health care needs and for identifying appropriate nutrition interventions.
A registered dietitian (RD) can evaluate in detail a child’s intake by working together with the
primary care provider (PCP), nurse or other health care professionals. Some RDs are also board
certified as pediatric nutrition specialists. They will have the credential CSP after their names in
addition to the letters RD.
GUIDLEINES FOR EVALUATING
AN INFANT’S INTAKE
Caregivers are often concerned about finding the magic number of ounces or spoons of food
that a baby “should” take. Once a mother’s milk supply is established, a breast-fed baby has much
more control over the amount of food taken than a formula fed infant. The breast-fed infant’s mother
cannot see how much is taken and how much is left. Bottle feeding tends to encourage “empty bottle
syndrome”: making baby take every last drop or bite whether it’s needed or not. (“Come on,
Baby….finish this stuff! It’s too expensive to waste!”) This can teach a child to ignore internal
hunger cues and it also teaches that the best way to make Mom and Dad happy is to eat everything in
sight!
This sort of learning may contribute to later obesity, as suggested by studies assessing the
effects of internal and external clues for eating among normal weight and overweight adults. In some
studies it was found that overweight individuals tended to eat more in response to external cues to eat
(the sight of food, the time of day when one usually eats) rather than in response to an actual sensation
of hunger. Breast-feeding as well as bottle-feeding could contribute to this same pattern if one uses
feeding as a pacifier and cure for all upsets and discomforts.
Many of us have learned to use food as a therapy for stress, depression, boredom or
nervousness. These eating patterns can contribute to weight problems because we are not eating in
response to a physical hunger stimulus, but to meet a psychological need.
If a baby is growing appropriately we do not need to be so over-concerned about the amounts
an individual infant consumes. Since each baby has his/her own pattern and rate of growth, periods of
growth spurts and variable activity levels, it is reasonable to try to let healthy babies set their own
energy intake on a daily basis.
For example: a record of normal intakes at 6 months of age indicated that the average intake
was 37 oz/day of formula or milk, with an additional 9% of calories coming from other foods.1
However, the range of normal intakes (between the 10th and 90th percentiles) at this age was 30 to 50
oz per day. There is no reason to suppose that an individual 6 month old infant should take the
“average” amount of formula, especially when the amount of other food eaten by the baby could be far
less or far greater than 9% of calories.
There is also no pressing scientific reason behind the “rule” that a baby should never be given more
than a quart (32 ounces) of formula a day. This non-helpful guideline probably evolved from four
factors:
1. By the time most babies drink a quart of formula daily they have reached a developmental age
when it is appropriate to begin to take solids. That is, the baby is usually 4-6 months old, so the
rule is a good reminder to begin introducing other foods.
2. A quart (32 oz) of formula provides the RDA for vitamins, minerals and protein, so healthy babies
do not need to take more than that volume to meet those guidelines. At this point, if
developmentally ready, infants can very safely work on learning to eat other foods. The nutrient
balance of baby’s sometimes unpredictable beginning food choices will not be a problem.
3. Because a quart of formula does provide for adequate levels of vitamins, minerals and protein, and
since formula can be quite expensive, it is financially reasonable to use no more than 32 ounces of
formula each day and provide the additional energy baby needs as other foods.
2
4. Some confusion on this point has also arisen from the fact that the WIC Program (Special
Supplemental Food Program for Women, Infants and Children) provides formula for infants in an
amount each month that makes about 26 ounces per day (one can of formula concentrate per day,
or a similar amount mixed from formula powder.) People sometimes fail to realize that WIC is a
supplemental food program, not a program that purports to meet all of the nutritional needs of its
clients.
When infants reach a size when 26 ounces of formula no longer meets their needs, their caregivers
are expected to either purchase some additional formula or, if age-appropriate, other foods can be
offered to the baby. This WIC program limit of formula provided is based on funding limitations.
It is not intended to be used as the upper limit of formula an infant may safely or appropriately
take.
So, although the commonly heard “32 ounce limit” of formula daily may be a useful guide, it is
certainly not a Rule. Consuming over 32 ounces is not harmful or dangerous. Many infants
regularly take over 32 oz/day without any problems. As long as the child is growing appropriately
and being given opportunities to acquire developmentally appropriate eating skills, a formula
intake above 32 oz/day is of no concern.
However, the quantity of human milk or formula consumed can be a limiting factor in the nutrient
quality of an infant’s diet even if the baby’s energy needs are being appropriately met. Babies who
are healthy, growing normally and taking the great majority of their nutrition as a nutritionally
complete or near-complete product (e.g. human milk or commercial formula) will likely be
obtaining the right amount of food and individual nutrients. [Vitamin D needs closer attention, of
course.] With the introduction of other foods however, the complete nutrition product will begin to
be displaced. This is reflected in the average milk or formula intake at age eleven months dropping
to 18-24 oz/day from the peak intake at around 6-7 months of age. Additionally, the content of
iron, zinc and vitamin B6 decreases markedly in human milk after 6 months.
The nutrient quality of the diet then becomes more dependent on the particular foods offered and
consumed. Many infants are fed an appropriate amount of a variety of foods, but it is at this point
that a more careful look at diet proportions is warranted. For example, it is sometimes erroneously
assumed that the baby’s diet will be balanced as long as formula or human milk is provided, even
when the volume consumed is extremely low.
A quick-and-easy estimate of the
“typicalness” of a formula intake volume
for screening healthy infants:
Multiply the ounces taken in by 20 kcal/oz
(this assumes the formula is prepared
following the usual directions ) and divide
by the infant’s weight.
3
In the first year of life, an intake of about 90-120 kcal/kg (kilocalories per kilogram of body
weight) which is the same as 41-50 kcal/lb (kilocalories per pound of body weight) is typical, with the
numbers in the higher end of the range mort often seen in the first half of the year. In the past, 100-120
kcal/kg (45-50 kcal/lb) have been used as guidelines, but more recently it was found that many infants
will grow normally and thrive on the smaller caloric intake levels as well.2
The key of energy (caloric) adequacy will always be :
Look at the baby’s growth, especially weight for length (weight/length) ratio
and apparent body fat stores.
If other food sources are included in the infant’s diet, you can easily calculate the energy
contribution of baby foods using the tables of average values from manufacturers’ product information
or food nutrient tables. New labeling laws also make this much easier than in the past. Additionally, a
simplified system like the old diabetic exchange system can be used for table foods.
Calculating the energy intake and then comparing it with the “typical” range is a useful screening
tool to help identify problems not immediately apparent. Values above or below this range, even in
apparently healthy infants, certainly warrant a closer look since they may be indicators of certain
problems. However, the typical range is not be to used as a feeding rule that a particular child must
conform to on a regular basis.
This method to interpret the appropriateness of a baby’s energy intake for its weight assumes that
the baby is of fairly normal weight for age and length. Remember that very thin or very chubby babies
will not play by the same rules because their unusual weight for length and age significantly changes
the denominator in the ratio:
•
Very thin babies will appear to have a more generous caloric intake than they actually do.
•
Conversely, a high caloric intake in a chubby baby may appear to be within the usual range because
there are so many pounds or kilograms to spread the calories over.
To correct for this effect, it can be helpful to recalculate kcal/kg or kcal/lb
using the average weight for a child of the baby’s length.
(See Case Studies 1 and 2 for examples.)
4
TROUBLESHOOTING ON THE FRONT LINES
Looking for Explanations when Unusual Intake Patterns are Reported
Note: All of the case studies and scenarios presented here have come from
actual experiences with babies for whom these questions and considerations
detected the real cause of inappropriate growth.
Things to Consider in Assessing All Intake Records:
1. How accurate is the intake record?
Is the person describing the intake:
ƒ
Providing first-hand information (e.g. is baby fed by others part of the day?)
ƒ
Guessing?
ƒ
ƒ
Clear about arithmetic and the actual size of the bottle or cup used?
Remembering to count night feedings, all beverages and all snacks?
ƒ
Able to accurately describe formula preparation?
2. How typical is the intake record?
ƒ
Is the record from the weekend at home but baby is fed at a sitter’s house five days a week?
ƒ
Is the child ill or just now recovered from an illness and weight loss?
3. Check that the total day’s intake volume reported is consistent with estimates obtained
through other approaches.
For example, compare a reported estimate of total ounces of formula consumed per day with both
the number of ounces prepared daily and the sum obtained when asking the caregiver to go through
a typical day describing each feeding.
In addition you may ask the number of cans of concentrate used in a day or how many days one
can of powdered formula feeds the baby. This type of cross-checking will pick up errors like
missed night feedings, and it can clarify complex situations like Case Study 3 (a very thin infant
who was reported to take a lot of formula but who never seemed to be satisfied.)
5
Things to Consider in Assessing Specific Patterns of Unusual Intake:
Figure 1 below describes four scenarios that often are seen when evaluating the intake of infants.
Explanations of each of four scenarios follows the figure.
Authors Note: I often use the term “fluffy” instead of obese when discussing a child with caregivers
because it is less judgmental. Our society equates generous adiposity with many negative personal
qualities. In order to optimize the therapeutic relationship it is important for the family to know that
I care about and like their child. Although this term is not scientific or technical, I find that it works
well for me and my clients, and it fits my Aunt Cathy patient-care style.
Figure 1:
Four scenarios to consider when the
reported intake seems to be at odds
with the baby’s appearance
Infant
Appearance
Reported Intake
High
Low
1
3
2
4
Thin
Fluffy
SCENARIO 1:
A very high reported intake, especially for a slim or normally proportioned baby
BABY Problems to Consider
•
Is baby experiencing any malabsorption? Ask about stool patterns.
•
Is baby vomiting excessively or does the baby have reflux?
Ask about the frequency, forcefulness and volume. Note that volume of vomitus is often
overestimated even by health professionals. To better estimate amounts lost, one can pour a small
amount of water on a table surface or cloth and ask the caregiver to compare it with the reported
volume. (“Is it about this much?”) It is surprising how a small amount can appear to be quite a lot.
6
If vomiting is reported to be significant, has pyloric stenosis or gastroesophageal reflux (GER)
been ruled out by the physician? In infants reflux can be related to immaturity of the lower
esophageal sphincter.
•
Does baby vomit consistently or only under certain circumstances, such as:
ƒ
Only when left alone after a feeding, as has been reported in cases of rumination associated with
nonorganic failure to thrive.
ƒ
Only when made to intake more than a certain volume.
ƒ
Only when fed certain foods or when certain water is used to prepare formula.
ƒ
Only when fed in an “infant seat.”
ƒ
Only when a certain person is the feeder.
•
Is the baby much more physically active, irritable and/or jittery than usual?
•
Is baby “hypermetabolic”?
Higher metabolic rates are sometimes seen when babies are working hard to breath, born small for
gestational age, fighting infections, trying to achieve catch-up growth, recovering from an acute
illness and sometimes when they have been exposed to significant mounts of alcohol or other drugs
in utero.
•
Is the baby adequately oxygenated?
Progressing to a state of health in which extra oxygen is no longer needed is seen as highly
desirable by caregivers both as a significant marker of progress for the baby and because it makes
infant care and transportation much easier. For this reason, there can be a tendency for families
and health care professionals to want to get the baby off oxygen as soon as possible.
However, sometimes adequate food intake and growth are only able to be achieved because of
assisted oxygenation. Prematurely removing oxygen support can result in a baby having to use so
much energy to breathe that growth is impaired. Also, exhaustion from the excessive breathing
effort can make a baby stop eating before nutritional needs are met.
Providing oxygen when it is needed assures that the child does not have to choose between eating
and breathing. Helping all concerned understand these concepts is very important.
CAREGIVER Problems to Consider
•
Is the formula mixed incorrectly?
If too much water is added, baby must drink a very large volume to try to get enough calories.
He/she mail fail to get enough to maintain appropriate weight for length.
7
SCENARIO 2:
A very high reported intake, especially “fluffy” baby
BABY Problems to Consider
•
Is baby truly fluffy (having a very high weight/length ratio) or just large for age
(weight/length ratio normal)?
If the weight/length ratio is within normal limits then the baby likely is managing his/her own
intake appropriately. Do not attempt to make baby take less to match some average intake for age.
•
If baby is truly fluffy and also consuming a very high caloric intake, is he able to sense satiety
normally?
Some children with brain injury (such as congenital hydrocephalus) can experience problems with
this even as infants. Other children (such as those with Prader-Willi Syndrome) are more likely to
experience this problem later in childhood.
CAREGIVER Problems to Consider
•
Is food being used as a pacifier?
•
Does the caregiver understand that babies often cry for reasons other than hunger?
•
Does the caregiver believe that baby needs to take in a particular amount regardless of
appetite?
•
Is there pressure from family members or other to:
•
ƒ
Keep that kid quiet!
ƒ
Put some meat on his bones!
ƒ
Giver her a lot of food or formula to make her sleep through the night!
Is formula being prepared correctly?
Failure to add enough water to the formula can contribute to dehydration. Babies may be forced by
thirst to take more formula than they are hungry for (calorically,) creating a vicious cycle.
•
Is baby being kept too warm and sweating a lot, leading to taking extra formula in an effort
to meet fluid needs?
If so, and if the heat situation cannot be adjusted, give guidelines for a reasonable formula intake
and provide additional water in some form as appropriate.
8
SCENARIO 3:
A low reported intake, especially for a slim or normally-proportioned baby
BABY Problems to Consider
•
Is the baby much more physically active, irritable and/or jittery than usual?
Does this behavior use up energy quickly and also interfere with baby’s ability to eat because of
distractibility or exhaustion?
•
Is the baby hypermetabolic?
Higher metabolic rates are sometimes seen when babies are working hard to breathe. Some babies
in this situation are those with heart or lung conditions. Some were born small for gestational age
and they may be trying to achieve catch-up growth.
Babies fighting infections, or recovering from an acute illness may fall into this category.
Sometimes babies who have been exposed to significant amounts of alcohol or other drugs in utero
will have this problem.
•
Is baby adequately oxygenated?
(See Scenario 1)
•
Is there anything physically interfering with the baby’s ability to suck and swallow
adequately?
Poor lip closure, structural tongue or lip problems, and poor coordination of sucking, swallowing
and breathing can all interfere with getting enough in. They can make feeding very time consuming
and also quite unpleasant for the baby. Evaluation and recommendations by a pediatric speech
therapist or occupational therapist can be very helpful in this situation.
•
Is tummy capacity adequate?
If a higher caloric density feeding were used, would the baby continue to take the same volume or
would he/she decrease intake to maintain the same caloric level?
How long does baby take to finish a feeding?
How often does baby eat?
Does baby seem to experience early satiety?
9
•
Does the baby perceive hunger?
Can baby communicate hunger adequately?
Does baby ever cry to be fed or does the caregiver have to initiate the feedings?
Is baby taking any medications that can suppress appetite or cause gastrointestinal distress or
drowsiness?
CAREGIVER Problems to Consider
•
Can the caregiver recognize baby’s signals that he/she wants to eat?
•
Does the caretaker have realistic expectations about baby’s feeding abilities and needs?
•
Does the feeder stop feeding too soon, when baby is only catching his/her breath?
•
Does the feeder engage the baby during feeding? Is there eye contact and cuddling?
•
Are the feeding utensils appropriate?
For example, is the type of nipple appropriate and the nipple hole the right size so baby does not
become exhausted or frustrated, or choke when eating?
•
Does the feeder have an eating disorder?
Does the caretaker eat regularly? Does he/she have extreme views about fitness or about not
wanting to have a fat baby?
•
Is the caregiver very young and/or inexperienced in basic baby care?
•
Are there other children to care for, or other obligations? Who actually feeds this baby?
•
Is the caregiver afraid that frequent feeding or cuddling with “spoil” the baby?
•
Does the caregiver think that snacking between meals is bad and so feeds baby only three
times a day?
•
Is the feeder engaged in a “Food War,” -- a battle of wills -- with an infant that has resulted
in disordered eating (e.g. near total food refusal) on the part of the infant?
•
Is being fed unpleasant for the baby?
A history of having been intubated or forcibly fed can cause a baby to associate oral eating with
unpleasant experiences. Children who have experienced only minimal oral feeding because of
10
health problems can also find the introduction of an oral feeding regimen to be quite unpleasant
and frightening. Those with some degree of dysphagia (“unsafe swallowers”) may experience oral
food intake as a terrifying exercise in trying not to choke and aspirate food into the lungs.
Some babies and children are extremely sensitive to certain textures and oral sensations. Some
have a “hypersensitive gag reflex.” Again, the RD can assist the family as they talk with the PCP
to consider a feeding evaluation by a Pediatric Occupational Therapist and/or Speech Therapist.
Many of them have special programs and experience in overcoming this type of feeding aversion.
SCENARIO 4:
Low reported intake, especially for a very fluffy baby
BABY Problems To Consider
•
Is baby hypotonic or less active than usual?
A baby with low energy requirements will often take less formula than average because of
decreased hunger, especially when fat stores are quite generous. But even so, baby may still get
more calories than are required because of the drive to meet fluid needs. Sometimes only high
calorie fluids are available.
Baby may also be coaxed or forced to take more than he/she would choose because caregivers are
concerned about an unusually low intake volume. Chubby children with Down Syndrome or
certain types of nerve and/or muscle diseases can sometimes present this way
Tube-fed children with minimal energy expenditure are especially vulnerable to overfeeding when
caregivers or health professions set goals based on the usual caloric intake levels observed for the
“average” baby’s age, activity/movement or size. Weight gain goals can sometimes be set at levels
that are that are inappropriate when baby’s body composition is atypical.
CAREGIVER Problems to Consider
•
Is the formula mixed incorrectly?
As noted above, if too little water is added, baby may appear to be taking a relatively low volume
of formula but he/she actually may be getting quite a lot of calories.
•
Is baby receiving substantial amounts of corn syrup (60 kcal/oz) for constipation problems?
•
Is a lot of cereal or other thickener added to the formula in an attempt to prevent spitting up
or gastroesophageal reflux, or because of dysphagia concerns?
11
The caloric contribution of thickeners and corn syrup can be substantial: infant cereals are 9 kcals
per level teaspoon, and corn syrup contributes 10 kcals per teaspoon. These additives can also
seriously alter the ratios of carbohydrate and/or fat to protein, sometimes leading to a relative
inadequacy of protein. The micronutrient content of the diet is also quite likely to be disturbed
unless carefully assessed and adjusted.
CASE STUDY 1:
A “fluffy” baby with a reported intake in the typical kcal/kg range
DATA: At age 3 months, LS is a very fluffy-looking baby. He weighs 6.6 kg (14 lb 8 oz) and is 57
cm long (22.5 in). His weight/length is above the 95th percentile.
He takes about 760 kcal daily, all from formula, which is 115 kcal/kg, and well within the normal
range for his age.
Question: Why is he gaining weight at an excessive rate on this apparently normal intake?
ANSWER: Since his weight/length ratio is not in the normal range; the Rule-of-Thumb kcal/kg range
will not apply directly. It assumes a normal distribution of lean body mass and fat stores.
Children with a disproportionately high amount of fat relative to lean body mass will need fewer
Kcal/kg than average to support themselves. This is because lean body mass is the most metabolically
active tissue, and the caloric requirements to maintain fat stores are much lower.
12
One can use this alternate calculation to get a sense of the energy needed to support his (tentatively
presumed to be normal “non-fat” tissues) plus a more typical amount of fat stores for age.
1. On the weight/length NCHS growth chart above find L.S.’s length along the bottom of the page.
Follow a straight line upward at that point until it intersects the 50th percentile. Then go to the side
to find the average weight for children of that length.
The average weight for this length is _________(a).
2. Recalculate the kcal/kg (kcal/lb) using this weight as the denominator. Is the intake still in the
typical range? Depending on the situation, it may or may not be. This calculation can provide a
clue to help you assess the situation correctly.
760 kcals= kcal/kg average wt for length
(a)
For example, if the intake is now above the usual range, it may be that the child has normal caloric
requirements and he is “fluffy” due to higher than usual caloric intake. In this case continue your
assessment using Scenario 2.
However, if his recalculated intake is still in the typical range, it may be a clue that the child has lower
than normal caloric requirements. This may occur with children who are hypotonic (who have low
musle tone,)those who move less than usual for any reason and in certain forms of muscle disease. In
this case, continue your assessment using Scenario 4.
Which scenario is suggested by L.S.’s history?
(answers on page 16)
If a lower weight/length is desirable (e.g. for a child whose condition results in decreased physical
activity or decreased lean body mass, such as spine bifida or certain neuro-muscular conditions), pick a
percentile that would decrease the risk of overfeeding and of inducing what could be very debilitating
“over-fatness.” These children can be quite overfat but not look especially overweight on the charts.
Depending on the child’s degree of mobility or muscular impairment, a weight-to-length ratio between
the 10th to 25th percentile may actually be optimal for continued independence. Use that weight to
calculate the caloric intake goal.
[Please see my handout “Why Are Children With Chronic Illnesses or Handicapping Conditions at
High Risk of Receiving Suboptimal Nutrition?” for more specific information.]
As always, it is critical to:
•
follow each child’s individual growth pattern since all of these Rules-of-Thumb are just starting
guesses. Assessment of body fat stores is an important adjunct for children with unusual body
composition, in order to assure that fat stores are not depleted or excessive. This may be an
“official” assessment – using a caliper and following skinfold thickness – or sometimes just an
13
educated eye and a “finger pinch” can be just as helpful. Many neurologically-affected children can
have a slim appearance but actually have adequate-to-generous fat stores. In such cases, it is not in
their best interests to push for a somewhat arbitrary weight gain that would only make it harder for
them to move themselves or to be cared for my others.
•
assess the adequacy of protein, vitamins, minerals and fluid especially when low caloric
requirements result in decreased total food intake or when certain food groups must be eliminated
due to allergies or texture problems.
•
consider the potential for altered nutrient requirements. These may accompany a particular
medical condition or therapeutic regimen such as drug nutrient interactions, nutrient malabsorption
or excessive losses.
CASE STUDY 2:
A very thin baby with an intake in the typical kcal/kg range.
DATA: at 7 kg and 72 cm (15 lb 6 oz; 28.3 in), AG is quite thin. Her weight-to-length is below the
5th percentile and yet she appears to take 100 kcal/kg (45.5 kcal/lb), which is a typical intake.
Why does she fail to gain well on what appears to be a normal intake?
ANSWER: As with L.S., this baby has an unusual body composition that makes the Rule-of-Thumb
not apply. She is virtually all lean body mass (with minimal fat,) so her metabolic rate for her length is
higher than would be expected.
1. Use the alternate calculation: Find the average weight for her length. The average weight for
this length is __________ (a). (See Figure 3 on the next page.)
2. Recalculate kcal/kg (or kcal/lb) using this weight as the denominator.
700 kcals = ______ kcals/kg
(a)
Is the intake still in the typical range? If it is, this would be a clue that something else is getting in
her way, so continue your assessment using Scenario 1.
If the intake now looks low, it appears that something is preventing her from taking enough volume to
meet her needs, so continue your assessment using Scenario 3.
Which Scenario is suggested by A.G.’s history?
(answers on page 16)
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14
This alternate calculation can also assist in setting intake goals for children with special medical or
physical problems when it is clinically appropriate to do so.
Example: In Case Study 2, if this child’s nutrition care plan established a caloric and protein intake
based on her actual weight, she would continue to be underfed. Instead, choose a weight denominator
(using the weight/length ratio on the NCHS growth chart) that is more desirable.
If an average weight/length is desirable (e.g. for a child with nutritional needs in the typical range,
but whose intake is controlled by others because all feedings are via a tube), base the energy and
protein recommendations on an average weight for a child of that length. Then follow up by
monitoring growth carefully and adjusting the feeding as needed. For catch-up growth, even higher
intakes may be needed on a temporary basis. It is not uncommon for children to “outgrow” their
feeding unless someone checks this periodically. What was once adequate per kg of body weight
drops to a level that fails to support appropriate growth, so follow-up is crucial. Sometimes caregivers
can be taught to do this calculation and progress the feeding volume themselves as the child grows.
CASE STUDY 3:
A thin infant with a very large reported formula intake volume.
DATA: B.W., a very thin-appearing 6.2 kg baby boy, was reported by his mother to have had a
regular intake for many weeks of five 8 oz bottles of formula daily and no solids (40 oz x 20 kcal/oz =
800 kcal/day; 800 kcal/6.2 kg = 129 kcal/kg) which is a higher intake than usual, especially for such a
thin baby.
15
B.W.’s mother reported that he “seems to want to eat all the time” and is “never satisfied” with a
feeding. This pattern could reflect a serious medical problem and if found to be a true representation
of the situation, it should result in a referral for medical evaluation.
ANSWER: On further questioning however, the mother was asked to describe formula
preparation and feeding in greater detail and from several different angles. She then described
preparing only one can of formula concentrate daily. Formula concentrate contains 40 kcal/oz and
comes in 13 oz cans, providing a maximum of only 84 kcal/kg for a 6.2 kg baby). It was discovered
that mother was not comfortable with arithmetic or measurement, and that the bottles she was using
held only 4 to 5 oz each rather than 8 oz.
B.W.’s mother had been afraid to give the baby more in spite of his evident hunger. She was told by a
person staffing a professional pediatric health phone consultation line at a local clinic that giving him
40 oz (as she had been) was “probably over feeding since 32 ounces was the limit.” The health care
professional indicated that the child’s reported desire for more to eat when his intake was already so
high was “probably just attention-getting behavior.”
If the health care professional had asked about the child’s appearance (very thin), and obtained
a more thorough description of formula preparation, the problem would have been immediately
apparent and easily resolved.
A similar picture might have occurred with the overdilution of the formula, and there is an additional
threat of water intoxication. This mother avoided that measuring problem by using the empty formula
concentrate can as the measuring device for adding water 1:1. Over- and under-dilution of formula are
actually fairly common mistakes. One study found that as up to 5% of people preparing formula
misunderstand the directions and dilute the formula twice; another 5% fail to dilute the formula
concentrate at all. However, only very careful questioning will detect the real problem.
SUMMARY
A good understanding of the underlying assumptions about growth and body composition which
provide the basis for the usual nutritional recommendations for infants and children is very important.
It makes it possible for the health care professional to make “intelligent departures” from the usual
feeding recommendations in order to meet the needs of children with special health problems.
Careful questioning can be of great value in helping to differentiate between the serious health
problems that require medical care, and the problems which are correctable by simple dietary
adjustments. Knowing the right questions to ask can make it easier to be a successful nutrition
detective and an advocate for these young children.
Answers to Case Studies 1 and 2
Case 1
L.S. Intake = 160 kcal/kg (72 kcal/lb)
Scenario 2
Case 2
A.G Intake = 78 kcal/kg (36 kcal/lb)
Scenario 3
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MeritCare Medical Center
2009
Aunt Cathy’s Guide to:
Nutrition Support
of Iron Deficiency
Cathy Breedon PhD, RD, CSP,FADA
Clinical Nutrition Specialist
MeritCare Health Systems and UND School of Medicine
Fargo, ND
Iron deficiency can result in poor ability to deliver oxygen to
the body, loss of energy, poor ability to concentrate,
impaired growth and mental development in children,
impaired carnitine producion, and many other problems.
Iron deficiency can be quite common and it can be caused by a
variety of factors. It may be related to:
1. Diets that provide poor amounts of iron or iron in forms that are poorly
absorbed.
2. Abnormal iron losses, such as hemorrhage, heavy menstrual periods, or
losses related to childbirth or surgery.
3. Conditions that impair iron absorption, such as Cystic Fibrosis, or
intestinal diseases like Crohn’s disease or Inflammatory Bowel
Disease. “Bariatric” surgery for weight loss is also associated with
significant iron deficiency. In many parts of the world, people
commonly have severe iron deficiency because of intestinal parasites.
4. Conditions that increase requirements, (such as rapid growth of tissues
during pregnancy, infancy or childhood,) can result in inadequacy when
the usually adequate intake of iron is not enough to meet all the
increased iron needs.
A Cautionary Note:
Iron deficiency is NOT ALWAYS the cause of anemia.
There are conditions in which iron may only appear to be inadequate
when a person has a low hemoglobin level in his/her blood that is detected
by a laboratory test that measures hemoglobin. A low hemoglobin level can
be related to problems that are quite unrelated to inadequate iron intake.
It is important to determine the likely cause of what may only
look like iron deficiency, because giving more iron will not be helpful
and it may actually be harmful. For example, conditions like Sickle Cell
Anemia and Thalassemia cause red blood cells to break too easily. Their
iron stores may even be generous, but the individual simply can’t make new
red blood cells fast enough to make up for the broken ones.
Chronic diseases like arthritis, celiac disease, and infections can
also result in low hemoglobin measurements that look like iron deficiency
anemia in the laboratory but for which inadequate iron is not the problem.
This is called “the anemia of chronic disease.” Inadequacies of other
nutrients like copper can also cause hemoglobin to be low. Iron deficiency
is a common cause of anemia, but if providing generous absorbable iron
does not correct it, it will not be helpful to just continue to give more
and more iron. [Anemia of chronic disease and defective erythropoietin production in patients with
celiac disease. Haematologica. 2008 Dec;93(12):1785-91.]
Detective work is in order in this case.
Now back to the major focus of this paper:
Solving the problem when iron deficiency IS the problem:
FOODS THAT ARE GENEROUS SOURCES OF
WELL-ABSORBED IRON:
MEATS:
1. “Heme iron” vs “Inorganic iron” issues
Meats of all kinds contain iron in an especially absorbable form called “heme”
iron. This is also called “organic iron.” Absorption of organic iron is not affected by the
presence or absence of certain other substances in foods the way plant iron is. Iron in this
form is about 20% absorbed.
Twenty percent absorption does not sound very high, but “inorganic iron” is much
less well absorbed. Inorganic iron is the kind in plants and in supplements with the
word “ferrous” or “ferric” in them. Ferrous sulfate and ferrous gluconate are examples
you will see on most iron supplement labels. An “organic iron” supplement that
contains the well-absorbed “heme” form of iron is available though less commonly
used. It is called “heme iron polypeptide.” However, if iron deficiency is not corrected
by the usual inorganic iron supplements or diet changes, this can be a very helpful
nutritional supplement. It is well absorbed, it does not compete with other substances for
absorption, and it is better tolerated by many people than the inorganic iron supplements.
The nature of these inorganic iron “tolerance” issues will be discussed below.
2
Like other nutrients, supplemental or dietary iron does no good at all if it is not
absorbed into the bloodstream from the intestines. It just passes right out in the stools.
Ferrous sulfate, a very commonly used iron supplement product, is less than 2%
absorbed. Some plant forms of iron in foods like spinach that naturally contain
“oxalates” are only 0.025% absorbed! Spinach is a terrific food to include in your diet
for many reasons, but it is NOT a terrific iron source.
Often at the higher doses used to treat anemia, inorganic iron supplements like
ferrous sulfate can cause stools to turn a black color and they may also contribute to
constipation. Neither is an unmanageable problem – the color is not a problem, and the
constipation can be addressed a variety of ways with certain helpful foods or by using a
laxative.
However, the reality is that people often discontinue taking this form of
supplement because of these problems. In fact, when you hear about children being
poisoned by iron supplements, it is often because they got into the medicine cabinet and
took a handful of the small but high-dose ferrous sulfate pills that some adult quit taking
for just these reasons! And of course, no iron supplements will solve an iron deficiency
problem if a person doesn’t take them.
2. Meat Protein Factor”
In addition to being a generous source of absorbable iron, meat also has a special
property of causing increased absorption of iron from the inorganic iron sources in
the meal! In other words, the iron in chili beans will be much more easily absorbed if
there is meat in the chili. This is called the “Meat Protein Factor” effect. It is not well
understood how it works, but it clearly does increase absorption of inorganic iron in other
foods and supplements, so it helps to further improve recovery from low iron stores.
3. Meat: Variable AMOUNT of Iron
The total AMOUNT of iron in different kinds of meat varies. Red meat is the
highest in absorbable iron. Poultry and fish have much less iron than red meat, but what
they have is still a much greater amount than what is found in plant foods, and it also
much better absorbed than inorganic iron. Additionally, white meat chicken/turkey has
less iron than dark meat. Think of the iron content of meat as “color-coded” … darkest is
highest and lightest is lowest. But all have the “Meat Protein Factor” effect described
above, and the form of iron is well absorbed.
Of the different types of meat, liver is an extremely generous source of
absorbable iron. This also includes foods made from liver like paté or liverwurst. Not
surprisingly, the iron content of blood is high and it is in an absorbable “heme” form, so
things like Scandinavian/ German “blood sausage,” and “blood pudding” are rich in iron.
This is not a universally popular choice, however.
3
FOODS THAT INCREASE ABSORPTION OF
(INORGANIC) IRON:
Acid
Any acid substance, including vinegar, citric acid and vitamin C (ascorbic acid) can
enhance iron absorption from sources of inorganic iron (the form of iron found in pills or
plants, like ferrous sulfate.) Because of this, people with iron deficiency are often advised
to take their iron supplement or iron fortified cereal with orange juice, or some other
acidic beverage. However, the size of the increase in absorption is not as great as many
people think, so that intervention alone is not likely to be that helpful.
For example, as noted earlier inorganic iron is generally only about 2% (or less)
absorbed, with some forms being much less absorbable than that because of substances in
some foods that interfere with absorption. For that reason, the “take with orange juice”
effect is a much less important factor affecting iron absorption than the highly absorbable
and generous heme iron found in meat (especially red meat.)
As described above, the presence of acid and/or meat will contribute to improved
absorption of inorganic iron. Other food substances can significantly impair absorption
of inorganic iron but they have minimal effect on absorption of organic iron. For
example, the organic iron forms like “heme” iron are about 20% absorbed, which is at
least ten times as well absorbed as any inorganic iron. In addition, the per cent of
absorption of inorganic iron is much more likely to be negatively affected by other
substances in a meal.
FOODS THAT DECREASE ABSORPTION OF
(INORGANIC) IRON:
Dairy foods
Dairy foods are notoriously poor sources of iron that also decrease absorption of
the iron in plants and pills. That means that taking iron supplements with milk, or
putting milk on iron-fortified cereal, or cheese on a sandwich can result in less of the iron
present in the pill, cereal or bread being absorbed. This is one of the issues behind the
phenomenon of iron deficiency anemia in infants and toddlers who have cow or goat milk
in place of mother’s milk or iron fortified formulas. Those who drink quite a lot of milk
will be displacing other foods that are good sources of iron, in addition to actually
impairing iron absorption. Not surprisingly, this effect is most likely seen in children who
do not eat much meat and do not take a multivitamin with minerals. The presence of milk
does not impair absorption of the generous organic iron in meat.
4
Tea
Tea contains “tannins,” a plant substance that binds iron very well in the intestines and
significantly reduces its absorbability. This effect is so marked that tea is the one food
shown to be interfere with iron absorption enough to be helpful for people who have
hemochromatosis, a serious genetic problem of absorbing way too much iron. And, as
seen before, it has the most marked effect in decreasing absorption of inorganic iron.
Tea has many other excellent healthful properties, but for the anemic individual it
is important to remember that improving iron status is not one of them.
Clinical trial on the effect of regular tea drinking on iron accumulation in genetic hemochromatosis.
“A significant reduction in iron absorption was observed when the test meal was accompanied by
drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by
about one third compared with that of the control group.” Gut. 1998;43(5):699-704.
Hemochromatosis is dangerous and it is now known to be much more common
than previously thought. For information on nutrition factors that can be helpful
in this dangerous condition of excessive iron absorption, please see “Nutrition
Support of Hemochromatosis Therapy” at www.meritcare.com. Other nutrition
topics can also be found there. Put my name (Cathy Breedon) in the search box,
press enter, and click the line that says “Cathy Breedon’s Handouts.”
Leafy greens
Many foods like spinach contain “oxalates” that bind up iron in the intestinal tract and
make it too big a molecule to be absorbed well. This is true even though the iron and
vitamin C content are generous. Some green plants like broccoli do not have oxalates and
so their iron is better absorbed. As noted before, these are extremely nutritious foods … it
is just that the oxalate-containing ones should not to be relied on to solve the problem if a
person is iron deficient.
Bran
The bran is the fibrous coating on grains. Bran contains “phytates” which impair iron
absorption as tannins and oxalates do. For that reason, taking a bowl of iron-fortified bran
cereal in milk along with a cup of tea is not the best way to get iron where you want it to
go. Some grains naturally contain less phytate than others, but it is still an issue.
Eggs
Interestingly, although in the 1950s egg yolk used to be fed to infants as an iron
source, the form of iron in eggs has been found to be poorly absorbed. Eggs are an
excellent source of protein (the protein in one egg is like the amount in 1 ounce of meat)
and other nutrients as well. The egg white has most of the protein (6 of the 7 grams) and
essentially none of the iron at all. Nearly all of the iron is in the yolk.
5
Iron-fortified foods and enriched grains
Iron “fortification” involves adding inorganic iron to foods that would not usually
have iron, such as milk-based infant formulas or similar “nutrition beverages” for adults
or children. “Fortified” also can mean that the iron (or another nutrient) was added to
achieve a level higher than would naturally be in the food. Total-type cereals are an
example: it is fortified to provide 18 mg of iron per cup compared with 4.5 mg iron in a
cup of a similar but unfortified whole wheat cereal like regular wheat flakes.
“Enrichment” means that a nutrient was removed by processing but then it was
added back to the level it contained before processing. In America, iron is added back
to refined grains. The available iron naturally in the grains is in the “germ” part of the
grain that is lost when grains are refined. Unfortunately, we do not add back any other
minerals; only iron and three B vitamins are added back (B1, B2 and B3.) That is all …
no magnesium, no chromium, no vitamin E, etc. This is one of the reasons why “whole
grain” products (containing the germ and bran) are nutritionally superior to
enriched grains. In 1998, processed grains products, whole or enriched, began to have
the B vitamin “folic acid” added to improve the folic acid status of Americans. This was
food “fortification”… a nutrient was added that was not there very much naturally.
The iron content of commercial cereals can be quite variable, depending on
the enrichment or fortification of the product. For example, “Quick” iron-fortified
cream-of-wheat has over 15 mg of (inorganic) iron per cup, but unfortified cream-ofwheat or oatmeal only has about 2 mg. Foods that have had iron added will indicate that
they are fortified or enriched with iron if you check the label. The words “ferrous” or
“ferric” in the ingredient list is an indication of iron being added.
The amount of iron contained naturally in some other foods
Legumes like lima beans and peas have 5-6 mg of iron per cup, but vegetables like corn
and carrots have only about 1 mg. Prune juice contains quite a lot of iron (over 9 mg per
cup compared with about 1 mg per cup of other fruit juices) and it naturally contains some
other substances that help one avoid the constipation issues. Absorbability of the iron has
not been well studied, however.
Iron and Zinc Content Chart of Food in General
The chart on the next page shows the iron and zinc content of a number of foods
and some factors described earlier that affect absorption of both minerals. As you can see,
the foods that are highest in absorbable iron tend to also be high in absorbable zinc,
and vice versa. This is important in anemia because inadequate zinc can also impair the
production of red blood cells. Zinc is involved in over 200 processes in the body but it is
harder to evaluate with labs than iron is. Iron deficiency is the most often recognized
nutrient deficiency in the USA, but that is in part because it is the one we actually
look for by checking hemoglobin levels. So unless the person is anemic because of
blood loss, a person who is found to be iron deficient in an “iron fortified/enriched”
world could easily have unrecognized poor zinc status as well.
6
MeritCare Health Systems
Aunt Cathy’s
Guide to Nutrition:
Iron and Zinc in Food
Cathy Breedon PhD, RD, CSP, FADA
Clinical Nutrition Specialist
MeritCare Medical Center
UND School of Medicine Fargo, ND
(Data Source: Agriculture Handbook No. 8-4 US Dept. of Agriculture Science & Education Admin.)
7
MeritCare Health System
Aunt Cathy’s
General Thoughts about
Safely Discontinuing the
Ketogenic Diet
for Seizure Control
Cathy Breedon PhD, RD, CSP, FADA
Clinical & Perinatal/Pediatric Nutrition Specialist
MeritCare Health Systems, Fargo, ND and UND
School of Medicine
Children on the ketogenic diet for seizure control can sometimes go off the diet
and continue to experience good seizure control. Often they will continue to need some
seizure-control medications, but they may need less.
Anytime the family or the child’s physician wants to do a trial off the ketogenic diet
we can easily set up a trial. However, there are some important things about the
process to know about, so this information should be shared with all concerned. That way
everyone will be on the same page regarding how to safely discontinue the ketogenic diet,
and what may need to be done afterward.
What needs to happen before the trial off diet is initiated:
The physician will need to decide if he/she wants to give the
child some additional seizure-control medication ahead of time.
Here is the rationale for this:
1. If the child IS still depending heavily on being in ketosis to control seizures, without
the extra medication protection at the start of the trial, when he/she goes out of ketosis
there would be a risk of an increase in seizure activity.
2. If the child does well after going out of ketosis while on this more generous medication
level, the family and the physician can then set about to wean the medications back
down to see how well seizure control is maintained off diet.
The nature of the ketogenic diet is that it is not the kind of thing from which a person
can be "slowly weaned off." Once carbohydrate is introduced, the person almost
immediately stops producing ketones. In other words you can “walk down” with her
medications, but the diet is either "all or none" so there is no safety net. There is no
gradual change in ketone production ... when carbohydrate comes in, ketones go away.
The trial off diet is easy from a food/nutrition standpoint:
1. For children who eat foods orally, just give the child something to eat with a
generous amount of carbohydrate in it, like a glass of milk or a jelly sandwich … whatever
is age appropriate and that the child might like. In other words, just switch to a typical diet
for age and the carbohydrate normally present there will naturally put a stop to ketone
production. (The nutritionist / dietitian can help figure out what carbohydrate-containing
foods would work if there are any questions.)
2. For the tube-fed child using RCF formula (Ross Carbohydrate Free,) the simplest
solution is to just add carbohydrate to the RCF. According to the manufacturer, 3-1/2 level
tablespoons of table sugar and 12 oz of water per 13 oz can of RCF will make a product
with the average amount of carbohydrate found in standard infant formula (20 calories per
oz.) For this situation, however, it is perfectly fine to just round it off to 4 Tablespoons,
which is ¼ level cup of sugar per can of RCF concentrate. The resultant product will
provide closer to 24 calories per oz, another caloric density commonly used in infants.
So, if it is decided to do a trial off diet, the safe way is as described above. If one then
weans the medications back down and finds that there is good seizure control in spite
of the diet change, here's what should be done next:
1. Get together with the pediatric nutritionist after the child has been off the diet for a
while to take a look at the nutrient intake on the new unrestricted diet. The reason is related
to the fact that the child often has had such an unusual diet for so long, it may take a while
to learn to like a nice variety of food. Maybe he/she will dive right in ...that would be
great! ... but if it doesn't go that way the nutritionist can always figure out some things that
will make sure to provide good nutrition while the child is getting used to the new foods.
2. When children do well with seizure control after they go off the diet, they still may
need some amount of seizure medications. Needing none would be terrific, but it might
turn out that the child still needs to have some. The physician and family will decide this.
Since there are some nutrition issues associated with any kind of seizure medication use,
the nutritionist should look the whole picture over and figure out what, if anything, needs to
be done to adjust for drug/nutrient interactions.
Additionally, some children have other issues that put them at risk of vitamin and mineral
inadequacies that will still need to be addressed. An example of this is a child who moves
very little and therefore has very low calorie requirements. A feeding program that will
meet his/her calorie needs will clearly not meet the requirements for other critical nutrient
requirements without appropriate supplementation. Similarly, for some children restricted
food texture tolerance limits the variety of foods, and nutrient inadequacy is common
unless the overall feeding plan is looked at closely.
For more information on a variety of related subjects, please see my
“Guide to Nutrition for Children with Special Health Care Needs.”
It can be downloaded for free from our website (www.meritcare.com.) Just type my name
in the search box in the upper right corner, and click “Cathy Breedon: Handouts.” A list of
many topics will appear, and this one is about 2/3 of the way down the list.
Sanford Medical Center
Aunt Cathy's Guide To:
The Unsaturated Fat
Families: Mono & Poly
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Clinical/Metabolic Nutrition Specialist
Sanford Medical Center and
UND School of Medicine, Fargo, ND
Omega 3 family
Omega 6 family
“The Fisher Family”
“The Cornelius Family” “The Olivetti Family”
Plant
forms
Polyunsaturated (more
than one double bond)
Polyunsaturated (more
than one double bond)
Monounsaturated (only one
double bond)
18 carbons
Alpha linolenic (18:3)
Linoleic (18:2)
Gamma Linolenic
(18:3)
Oleic, etc. (18:1)
Essential
Essential
Critter
forms
Polyunsaturated (more
than one double bond)
Polyunsaturated (more
than one double bond)
20 carbons
EPA (EicosaPentaenoic
Acid) (20:5)
ARA (20:4)
(Arachidonic Acid)
(May be essential too)
Omega 9 family
(May be essential too)
Important
New Discovery:
22 carbons
DHA (DocosaHexaenoic
Acid) (22:6)
Many people are now
known to be much less able
to do the conversions
) than we thought, so
EPA, DHA and ARA are
also “essential fats” for
them in addition to linoleic
and linolenic acid.
(
(May be essential too)
What does “omega” mean when talking
about fatty acid carbon chains?
It sounds very scientific, but it just means that you start counting the
carbons in the chain from the very end of the fatty acid chain.
“A to Z” = alpha to omega in the Greek alphabet = “beginning and end”
alpha end
omega end
18-carbons-in-a-chain fats:
9 8 7 6 5 4 3 2 1
18 carbons, 1 double bond (monounsaturated) fatty acid starting after 9 carbons from the “omega” (z) end of
the chain, so it is in the “omega 9” family) 18:1 = (18 carbons, one double bond)
6 5 4 3 2 1
Linoleic
18 carbons, 2 double bond (monounsaturated) fatty acid starting after 6 carbons from the “omega” (z) end of
the chain, so it is in the “omega 6” family) 18:2 = (18 carbons, two double bonds)
3 2 1
Linolenic
18 carbons, 3 double bond (monounsaturated) fatty acid starting after 6 carbons from the “omega” (z) end of
the chain, so it is in the “omega 6” family) 18:3 (18 carbons, three double bonds)
“Essential Fatty Acids” Linoleic and alpha-Linolenic
Linoleic
How to keep them sorted out:
Alpha-Linolenic
The only difference is the second n … write it in script and turn it on its side and it is a 3!
=3
(It’s the omega 3 one. The other one isn’t.)
We can add two more carbons and stick in another double bond to make 20 carbon fatty acids,
and then do it again to make 22 carbon fatty acids. These are “critter-level” fatty acids, not plant
fatty acids like linolenic and linoleic acid. [This process is called “enlongation and desaturation”]
20-carbons-in-a-chain fats:
Omega-3 = EPA Eicosapentaenoic Acid
(Eicosa = 20 carbons Penta = 5 enoic = double bonds)
3 2 1
Omega-6 = Arachidonic Acid
(the name is from an old system and so it is not very helpful. If it were named today it would be
ETA Eicosatetraenoic Acid (Eicosa = 20 carbons Tetra= 4 enoic = double bonds)
6 5 4 3 2 1
------------------------------------------------------------------------------------------------------------
22-carbons-in-a-chain fats:
Omega-3 = DHA Docosahexaenoic Acid
(Docosa = 22 carbons Hexaenoic = 6 double bonds)
3 2 1
Why is this important:
Although these fats can be burned as fuel like any fat,
the big deal with these is that
we make several important things out of them
Prostaglandins
Thromboxanes
The 20-carbon fats are the material from which
one makes prostaglandins … inflammatory
messengers. If one makes a prostaglandin out
of ARA (the omega 6 one) the response is
REALLY INFLAMMATORY! But if one
makes a prostaglandin out of EPA (the omega
3 one) instead, the inflammatory response is
MUCH LESS!
The 20-carbon fats are the material from which
one makes thromboxanes … messengers that
tell your blood to clot. If one makes a
thromboxane out of ARA (the omega 6 one)
the coagulation response is REALLY
CLOTTY! But if one makes a thromboxane
out of EPA (the omega 3 one) instead, much
LESS BLOOD CLOTTING results.
Excessive tendencies to clot blood and inflame the arterial walls increase risk of cardiovascular
disease. Both are increased a lot by making these substances from ARA instead of EPA. Both are
also increased by making them from EPA (because that’s what prostaglandins/thromboxanes do)
but the ones made out of EPA cause a much milder response than the ones made from ARA do.
DHA is a critical fat of the brain and retina, and it has roles in development, maintenance of
cognition as we age, mood and attention, and decreasing risk of macular degeneration. As we
now know that many people are not as able to make these very long chain fats, it is a very good
idea to obtain some “ready made.”
Most Americans get adequate ARA (the omega 6 fat) from meat, but the source of ready made
EPA and DHA (the omega 3 fats) is fatty fish like salmon or mackerel, and many Americans eat
very little of these foods. That is why the American Heart Association recommends that
people eat fatty fish twice weekly or take 1000 mg fish oil capsule daily. For certain health
situations, such as having “high triglycerides,” they suggest that 2-4 capsules daily can be helpful
with a physician’s supervision.
This is why I always say you should think of EPA as “Environmental Protection Agency”
since it protects your internal environment from excessive inflammation and blood clotting …
both of which are very important in cardiovascular disease and other serious health concerns.
And it comes pre-packaged with DHA in ready made form.
The typical “American Diet” (whatever THAT is) is described as having
10-20 omega 6 fattyacids for every one omega 3 fatty acid.
That is, a 10:1 ratio up to a 20:1 ratio.
The “Mediterranean Diet” is a heart-healthy eating pattern also associated with
decreased riskof cancer, and one feature of this diet is a ratio of only
4 omega 6 fatty acids for every omega 3 fatty acid.
That is, a 4:1 ratio.
How to remember this stuff: “6 is always bigger than 3”
Omega 6 fats make more clotty (“aggregatory”) thromboxanes than Omega 3 fats do.
Omega 6 fats make more inflammatory prostaglandins than Omega 3 fats do.
In all the ratios described above, the larger number of the two is ALWAYS the omega 6
2009
MeritCare Health System
Aunt Cathy's Guide To:
All Those Lipids
Recommendations for Using
Different Types of Vegetable
Oils (Omega-3, Omega-6 and
Monounsaturated Oils)
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Clinical Nutrition Specialist
MeritCare Health Systems and
UND School Of Medicine
Fargo, ND
Practical Applications: The Bottom Line
(Subject to change at any moment! ☺):
1.
When buying margarine and shortening, look for some brands that are now available
labeled "free of trans fatty acids." Trans fatty acids are formed as a by-product of the
process that produces “partially hydrogenated” vegetable oils – which converts the liquid
oils to a more solid, spreadable texture. The trans fats seem to be as bad (or worse) for the
heart as “saturated” fats like lard and coconut oil in terms of causing a person’s body to
produce more cholesterol. It also is a factor in whether or not the cholesterol in the blood
“sticks” to the inside of arteries and clogs things up. Other health problems are being
identified as well. High consumption of trans fat is associated with increased inflammation
and high “oxidative stress” in humans. This could increase the risk of the development or
acceleration of several diseases, such as cancer, atherosclerosis, and type 2 diabetes, and a
possible increased risk of infertility. (Am J Clin Nutr. 2007 Jan;85(1):231-7. Am J Clin Nutr. 2006 Nov;84(5):981-8.
J Nutr. 2005 Mar;135(3):562-6. )
Some new techniques for making margarine and shortening from vegetable oils do not cause
trans fatty acids to be formed at all, so look for the phrase “no trans fat” on the label.
Starting January 2006, a law went into effect requiring the trans fat content to appear on the
label. This requirement is stimulating research by food producers to explore more ways to
prepare foods without trans fat. Foods produced prior to this date will still be able to have
undisclosed trans fat.
Foods may be labeled “No Trans Fat” if they contain less than a gram per serving, so the
better way to be sure to minimize intake of trans fat is to also look on the ingredient list
for the words “partially hydrogenated.” In addition to trans fats that we might add to our
foods, the ingredient list of many commercially made baked goods and other commercial
foods also need to be looked at. Removing trans fat from our food supply is the goal and it
is a work in progress. Until it is gone we should read ingredient lists carefully.
1
2. Nuts and peanuts are generally friendly in terms of the type of fat they contain, and they
also are great sources of important minerals like magnesium and other goodies. Like other
foods that contain a generous amount of fat, nuts and peanuts are high calorie foods, but the
forms of fat they contain appears to be primarily dangerous to your width and not to your
heart! In other words, the calories they contribute may be a problem for people who are aiming
to take in fewer calories, but the form of fat is not as contributory to health problems as certain
other forms of fat are. It now appears that besides not contributing to the risk of heart disease
and cancer, adding nuts and legumes to the diet can actually be a tool to decrease the risk.
Nuts and legumes tend to have good proportion of the fat as monounsaturated fat, and of the
polyunsaturated fats a reasonable ratio of omega-6 to omega-3 fat. (More on that topic will
follow.) A large Harvard study of women followed for 16 years, eating nuts or peanuts four
or more times a week was associated with a 25% decreased risk of developing diabetes
compared with women who rarely ate them. A recent review of research studies found that nut
consumption can actuallylower bad cholesterol (LDL) more than following a diets that are “low
fat” and nuts can be an excellent food in the fight against what is called “metabolic syndrome.”
[Edible nuts and metabolic health. Curr Opin Lipidol. 2007 Feb;18(1):25-30. Tree nuts and the lipid profile: a review of clinical studies. Br J
Nutr. 2006 Nov;96 Suppl 2:S68-78. Nut and peanut butter consumption and risk of type 2 diabetes in women. JAMA. 2002;288(20):2554-60.
Effect of diets enriched in almonds on insulin action and serum lipids in adults with normal glucose tolerance or type 2 diabetes. Am J Clin
Nutr. 2002;76(5):1000-6. Evidence-based dietary recommendations for patients with type 2 diabetes mellitus. Nutr Clin Care. 2003;6(2):51-61.]
Peanuts were counted separately in the study of likelihood of developing diabetes because they
are really not a nut but a member of the bean (legume) family. However, both had the same
apparent beneficial effect. Note that both nuts and legumes are excellent sources of fiber and
important nutrients like magnesium and chromium, which also are especially important in
diabetes. The fat, protein, fiber, and vitamin/mineral content are all part of that complex puzzle,
but the bottom line is that it is good to include nuts and legumes in one’s diet.
[Role of cellular magnesium in health and human disease. Front Biosci. 2004 Jan 1;9:262-76. Magnesium intake and risk of type 2 diabetes in
men and women.Diabetes Care. 2004 Jan;27(1):134-40. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2
diabetes in women. Diabetes Care. 2004 Jan;27(1):59-65. The association between magnesium intake and fasting insulin concentration in
healthy middle-aged women. J Am Coll Nutr. 2003 Dec;22(6):533-8.Low plasma magnesium in type 2 diabetes. Swiss Med Wkly. 2003 May
17;133(19-20):289-92. Magnesium deficiency in African-Americans: does it contribute to increased cardiovascular risk factors? J Natl Med
Assoc. 2003 Apr;95(4):257-62. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects:
a randomized double-blind controlled trial. Diabetes Care. 2003 Apr;26(4):1147-52. Role of magnesium in insulin action, diabetes and cardiometabolic syndrome X.Mol Aspects Med. 2003 Feb-Jun;24(1-3):39-52.]
(Please see “Aunt Cathy’s Guide to Nutrition: Magnesium and Chromium” and “Aunt Cathy’s
Guide to OTHER Nutrition Issues in Diabetes” if you want details about their role in diabetes.)
3. For cooking and baking, canola oil, olive oil, non-hydrogenated soy oil and walnut oil are
best and they appear to be better for you than corn oil. They all contain the same amount of
calories – about 9 calories per gram, or about 100 per tablespoon. But both have better
proportions of the “friendlier” oils (monounsaturated and omega-3 polyunsaturated fats); corn
oil is almost all the “omega-6” kind of fat. The reason for this is explained more fully below.
4. Adding ground flax to foods is also good for you. It needs to be ground up, though (or
purchased that way -- you can get it at most grocery stores now) because otherwise the intact
flax seeds just pass right on through like a high fiber supplement, and the good stuff inside is
not absorbed into the body. Use a coffee grinder if you want to grind whole flaxseeds at home –
the tiny seeds just jump over the blades in a regular food processor. The generous amount of
2
"friendly" fat in flax is an omega-3 fat called "alpha-linolenic acid." Ground flaxseeds can be
added to hot or cold cereal or granola, or used in muffins, pancakes, meatloaf, etc. Some readyto-eat cereals are now available that have ground flaxseed in them; some have the whole intact
seeds in them so they may be less helpful. Most ground flax products are best stored in the
refrigerator or they can turn rancid.
It appears that the ground flaxseed is more beneficial than taking the flax oil in capsules,
probably because of the micronutrients and the fiber. A fiber-like material in the seeds
called “lignins” appears to have health benefits as well. Soybeans and walnuts will also provide
many additional nutrients besides “friendly” fat.
[Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an
equal amount of soy. Am J Clin Nutr. 2004; 79(2):318-25. Flaxseed and cardiovascular risk. Nutr Rev. 2004;62(1):18-27. Flax facts. A grain for
good health. Diabetes Self Manag. 2003;20(6):18, 20-2. The effect of flax seed cultivars with differing content of alpha-linolenic acid and
lignans on responses to mental stress. J Am Coll Nutr. 2003;22(2):157-64. Dietary flaxseed meal is more protective than soy protein concentrate
against hypertriglyceridemia and steatosis of the liver in an animal model of obesity. J Am Coll Nutr. 2003 ;22(6):494-501.]
5. Eat fish when able (avoiding the swordfish and other big fish known to contain high levels
of mercury), and consider taking a couple of fish oil capsules daily, especially if you do not
eat fish. This has to do with trying to eat more oils from the "omega-3" family and less from the
"omega-6" family. Taking in the forms of omega-3 oils in fish (EPA and DHA) has certain
advantages over only eating the plant/vegetable form (linolenic acid.) There is more on this
topic later. The fish oil supplements are less likely to contribute mercury in part because the
mercury tends to be distributed mostly in the flesh of the fish and not as much in the fat. Also,
various treatments are used to make the capsules safer. There is a table on Page 8 that shows the
amount of omega-3 fat in oils, flax and fish.
[Measurement of organochlorines in commercial over-the-counter fish oil preparations: implications for dietary and therapeutic
recommendations for omega-3 fatty acids and a review of the literature. Arch Pathol Lab Med. 2005 Jan;129(1):74-7. Measurement of mercury
levels in concentrated over-the-counter fish oil preparations: is fish oil healthier than fish? Arch Pathol Lab Med. 2003 Dec;127(12):1603-5.
Mercury, fish, fish oil and the risk of cardiovascular disease]Tidsskr Nor Laegeforen. 2004;124(2):198-200. Bio-accumulation profiles of
chemical contaminants in fish from the lower Willamette River, Portland Harbor, Oregon. Arch Environ Contam Toxicol. 2004;46(1):114-23.
Childhood urine mercury excretion: dental amalgam and fish consumption as exposure factors. Environ Res. 2004;94(3):283-90. Is fish
consumption safe? J La State Med Soc. 2004;156(1):42, 44-9. Mercury and selenium in whole blood and serum in relation to fish consumption
and amalgam fillings in adolescents. J Trace Elem Med Biol. 2003;17 (3):165-70. Ameri-can Society for Circumpolar Health. Comparison of
mercury in selected subsistence foods from western Alas-ka. Int J Circumpolar Health. 2003;62(4):448. Survey of total mercury and
methylmercury levels in edible fish from the Adriatic Sea. Food Addit Contam. 2003;20(12):1114-9. Hazards of heavy metal contamination.Br
Med Bull. 2003;68:167-82.]
Why do we care about the amounts and the ratios of
“Omega-3” to “Omega-6” fat?
The reason for the recommendations in suggestions #3-5 above is that increasing the ratio
of the omega-3 family of oils relative to the omega-6 family is looking very helpful in decreasing
risk of developing a number of serious health conditions. It may also slow the progression
and/or decrease complications of many medical conditions. It also appears to be a factor in having
a healthy pregnancy and in the development of the infant both before and after birth.
There will likely be a lot more fine-tuning of the recommendations coming out for specific
types of fat and not just broad classes of fat. For example, new knowledge about certain special
types of omega-6 fats is looking interesting as well. An example is one called gamma-linolenic
(different from alpha linolenic acid) that appears be quite promising in decreasing nerve damage
3
(neuropathy) related to diabetes, and in decreasing inflammation. It is also being studied in
critically ill patients with very encouraging results, along with other specific types of oil. The best
food sources of gamma linolenic acid include nuts, and some leafy greens (like evening primrose
oil.) Mother’s milk is usually rich in gamma linolenic acid. Although there is still much to learn,
there is a rapidly growing body of research being reported in the scientific literature exploring these
issues. References of a sampling of the most recent research is shown below:
At Low Doses, a {gamma}-Linolenic Acid-Lipoic Acid Conjugate Is More Effective Than Docosahexaenoic Acid-Enriched Phospholipids in
Preventing Neuropathy in Diabetic Rats. J Nutr. 2007 Feb;137(2):368-372. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid.
Curr Pharm Biotechnol. 2006 Dec;7(6):531-4. Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its derivatives.
Curr Pharm Biotechnol. 2006 Dec;7(6):457-66. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in
mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006 Sep;34(9):2325-33.
Additionally, there is a huge amount of research showing that the special forms of omega-3 fats
found in fish and fish-oil supplements (EPA and DHA) have certain very important advantages
for many people. EPA decreases inflammation in a wide range of inflammatory diseases like MS,
cardiovascular disease and arthritis. I think of EPA (whose real name is eicosapentaenoic acid)
should be thought of as “Environmental Protection Agency” instead, because it seems to be very
protective against a number of health problems.
DHA in particular appears to be very important for the development of the brain and the retina of
the eye, so it is critical during pregnancy and infancy. It has also been shown to be helpful in the
continued good operation of the brain (e.g. in possibly helping to ward off age-related problems like
alzheimers and other forms of dementia,) and for decreased risk of, or progression of, depression,
blindness due to macular degeneration, attention deficit disorder and Parkinson’s disease.
More research is ALWAYS needed, of course, but the cumulative results of a great many
studies have been in the same direction. Assuring an adequate intake of these fats looks like a
VERY good idea. Additionally, it is now recognized that for some people it is difficult to
efficiently convert the plant omega-3 oils (like those in canola, flax and walnuts) into the
important EPA and DHA oils that are found ready-made in the fish oil. This may be a factor in
a broad range of inflammatory conditions and critical in pregnancy.
The American Heart Association recommends 1000 mg of fish oil for most people with risk of
heart disease. People at risk include those who smoke, who have disturbed blood lipids (too much
LDL cholesterol or triglycerides, or too little HDL cholesterol,) who are overweight or sedentary, or
who have high blood pressure, diabetes, or a family history of heart disease. Other factors
contribute to heart disease risk as well.
[Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3 Fatty
Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am
J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S.]
Specific Health/Medical Conditions:
AIDS/ HIV Nutritional treatment for acquired immunodeficiency virus infection using an enterotropic peptide-based formula
enriched with n-3 fatty acids: a randomized prospective trial Eur J Clin Nutr. 2001 Dec;55(12):1048-52. Effects of proteinenergy malnutrition and human immunodeficiency virus-1 infection on essential fatty acid metabolism in children. Nutrition.
2000 Jun;16(6):447-53. Effects of fish oil on cytokines and immune functions of mice with murine AIDS. J Lipid Res. 1998
Aug;39(8):1677-87.
4
Alzheimer’s Disease A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged
Alzheimer mouse model. J Neurosci. 2005 Mar 23;25(12):3032-40. Polyunsaturated fatty acids in the central nervous system:
evolution of concepts and nutritional implications throughout life. Reprod Nutr Dev. 2004 Nov-Dec;44(6):509-38. Chronic
administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused
rats. J Nutr. 2005 Mar;135(3):549-55. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse
model.Neuron. 2004 Sep 2;43(5):633-45. Importance of "health foods", EPA and DHA, for preventive medicine. Rinsho Byori.
2004 Mar;52(3):249-53.Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control
study.Br J Nutr. 2003 Apr;89(4):483-9. J Neurosci. 2005 Mar 23;25(12):3032-40. Neuroinflammatory perspectives on the two
faces of Alzheimer's disease. J Neural Transm. 2004;111 (3):281-94. Consumption of fish and n-3 fatty acids and risk of
incident Alzheimer disease. Arch Neurol. 2003;60(7):940-6. Essential fatty acids and the brain. Can J Psychiatry.
2003;48(3):195-203. Omega-6/omega-3 ratio and brain-related functions. World Rev Nutr Diet.2003;92:37-56. J Neural
Transm. 2003;11 (1):95-110. Dietary lipids in the aetiology of Alzheimer's disease: implications for therapy. Drugs Aging.
2003;20(6):399-418. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J
Nutr. 2003;89(4):483-9. The role of diet in cognitive decline. J Neural Transm. 2003;110(1):95-110.
Arthritis Biological basis for the benefit of nutraceutical supplementation in arthritis. Drug Discov Today. 2004 15;9 (4):165-72.
Omega-6/omega-3 fatty acids and arthritis. World Rev Nutr Diet.2003;92:152-68. Dietary fatty acids and immune reactions in
synovial tissue. Eur J Med Res. 2003;8(8):381-7. A biomarker of n-3 compliance in patients taking fish oil for rheumatoid
arthritis. Lipids. 2003;38(4):419-24. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic.
Lipids. 2003;38(4):343-52. Dietary n-3 fats as adjunctive therapy in a prototypic inflamma-tory disease: issues and obstacles for
use in rheumatoid arthritis. Prostaglandins Leukot Essent Fatty Acids.2003;68(6):399-405. The role of fish oils in the treatment
of rheumatoid arthritis. Drugs.2003;63(9):845-53. Nutritional management of rheumatoid arthritis: a review of the evidence. J
Hum Nutr Diet.2003;16(2):97-109. Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the
nervous system? Prostaglandins Leukot Essent Fatty Acids.2003;68(3):219-24. Anti-inflammatory effects of a low arachidonic
acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003;23(1):27-36.
Asthma Eur Respir J. 2000;16(5):861-5. Cochrane Database Syst Rev. 2000;(4):CD001283.
Bone Health
Repletion with (n-3) fatty acids reverses bone structural deficits in (n-3)-deficient rats. J Nutr. 2004
Feb;134(2):388-94.
Cancer Prevention (General) Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its
derivatives. Curr Pharm Biotechnol. 2006 Dec;7(6):457-66.Carcinogenesis. 2003;24(5):919-25. Chin Med J
(Engl).203;116(3):453-8; Eur J Cancer. 2002;11 Suppl 2:S1.
Lung Cancer
Nutr Cancer.203;45-2:106-7; Nutr Cancer.2002;42(1):18-24; J Nutr.2002;132(7):2069-75.
Breast Cancer Nutr Cancer.2003;45(2)211-217. Dietary flaxseed inhibits human breast cancer growth and metastasis and
downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Nutr Cancer. 2002;43(2):187-92.
Int J Cancer. 2003;107(2):276-82; J Nutr.203;133(5):1409-14; J Nutr Biochem. 2002;13(12):711-16; Nutr
Cancer.2002;43(2):187-92. . Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in
human breast cancer xenografts. Cancer Lett. 2002 8;185(1):31-7
Colon Cancer Effect of an omega-3 fatty acid containing lipid emulsion alone and in combination with 5
fluorouracil (5 FU) on growth of the colon cancer cell line Caco-2.Eur J Nutr. 2003;42(6):324-31. Colon Detect
Prev.200327(1):55-6; Cancer Res.203;63(5):972-9; Int Epidemiol.203; 32(2):200 9; Carcinogenesis 2003;4 [Epub
ahead of print]. J Nutr 2002;132(11 Suppl):3508S:3512S.
Prostate Cancer Harv Mens Health Watch.2003;7(10):5; Cancer Epidemiol Biomarkers Prev.2003l;12(1):64-7;
Prostaglandins Leukot Essent Fatty Acids.2002;66(5-6):467-77. Effect of flaxseed supplementation on prostatic carcinoma in
transgenic mice.Urology. 2002 N;60(5):919-24.
Adjunct to Chemotherapy in Cancer Treatment Formation and anti-proliferative effect of prostaglandin
E3 from eicosapentaenoic acid in human lung cancer cells. J Lipid Res. 2004 Mar 1 [Epub ahead of print]Nutr Cancer.
2002;44(2):176-81; J Control Release.2001;74(1-3):233-6; Clin Cancer Res 2001.7(7):2041-9; Anticancer Res.2001;21
(1A):29-38; Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin.
Cancer Chemother Pharmacol. 2001;47(1):34-40. Anticancer Res.1999;19(6C):5583-6.
5
Cardiovascular Disease (Esp. Heart Disease, Hypertriglyceridemia and Stroke)
Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3
Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA,
May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S. Blood omega-3 and trans Fatty acids in middle-aged acute
coronary syndrome patients. Am J Cardiol. 2007 Jan 15;99(2):154-8. Greater fish, fruit, and vegetable intakes are related to
lower incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. Circulation. 2007
Jan 16;115(2):188-95. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic
factors in type 2 diabetes. Diabetologia. 2007 Feb;50(2):250-8. Depression and cardiovascular mortality: a role for n-3 fatty
acids? Am J Clin Nutr. 2006 Dec;84(6):1513-7. Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its
derivatives. Curr Pharm Biotechnol. 2006 Dec;7(6):457-66. NEJM.2004;350(1) :29-37. Nutr Rev. 2004;62(1):18-27. J Nutr.
2005 Mar;135(3):562-6. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial
dysfunction. n-3 fatty acids and the risk of sudden cardiac death. Emphasis on heart rate variability. Dan Med Bull.
2003;50(4):347-67. Dietary fish oil up-regulates cholesterol 7alpha-hydroxylase mRNA in mouse liverleading to an in-crease in
bile acid and cholesterol excretion. FEBS Lett. 2004 cholesterol and paraoxonase levels in patients with familial combined
hyperlipidemia. Metabolism. 2004;53(2):153-8. Fish oil increases antioxidant enzyme activities in macrophages and reduces
atherosclerotic lesions in apoE-knockout mice. Cardiovasc Res. 2004;61(1):169-76. Fish oil interaction with warfarin. Ann
Pharmacother. Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic vegetarians: a randomised
trial. Br J Nutr. 2006 Apr;95(4):779-86.2004;38(1):50- 2. Vitamins, supplements, herbal medicines, and arrhythmias. Cardiol
Rev. 2004;12(2):73-84. Cardiovasc Res. 2004;61(1):169- 76. Flaxseed and cardiovascular risk. Nutr Rev. 2004;62(1):18-27.
Flax facts. A grain for good health. Diabetes Self Manag. 2003;20(6):18, 20-2. Dietary flaxseed meal is more protective than
soy protein concentrate against Hypertriglyceridemia and steatosis of the liver in an animal model of obesity. J Am Coll Nutr.
2003 ;22(6):494-501.Int J Vitam Nutr Res.2003;73(3):163-70; J Throm Haemost.2003;1(4):690-7; J Women’s Health-Larchmt.
2003;12(2):109-14; Int J Clin Pract.2003;57(4):305-14; Circulation.2003;108(7):820-5. Am J Cardiol.2003;91 (7A):1 8E-23E.
Circulation.2002;106:289-91.;559(1-3):125-8.]
Chronic Fatigue Syndrome In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are
related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett. 2005 Dec;26(6):745-51. Determination of
fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome. Nutr Neurosci. 2003 Dec;6(6):389-92.
Treatment of chronic fatigue syndrome by dietary supplementation with omega-3 fatty acids--a good idea? Med Hypotheses.
2002 Mar;58(3):249-50.
Cystic Fibrosis Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic
fibrosis patients: a randomized, controlled study. Nutrition. 2006 Jan;22(1):36-46. Biological effects of a dietary omega-3
polyunsaturated fatty acids supplementation in cystic fibrosis patients: a randomized, crossover placebo-controlled trial. Clin
Nutr. 2006 Jun;25(3):418-27. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med.
2004;350 (6):560-9. JPEN J Parenter Enteral Nutr. 2003;27(1):52-7. Cochrane Database Syst Rev. 2002;(3):CD002201. J Appl
Physiol. 2002;92(5):2169-76. Curr Opin Pulm Med. 2000;6(6):530-2.
Diabetes At Low Doses, a {gamma}-Linolenic Acid-Lipoic Acid Conjugate Is More Effective Than Docosahexaenoic AcidEnriched Phospholipids in Preventing Neuropathy in Diabetic Rats. J Nutr. 2007 Feb;137(2):368-372. Gamma linolenic acid: an
antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006 Dec;7(6):531-4Use of cod liver oil during the first year of life
is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr.
2003;78(6):1128-34. Flax facts. A grain for good health. Diabetes Self Manag. 2003;20(6):18, 20-2. Circulation.2003;107(14:
1852-7; Atherosclerosis. 2003; 166(1):85-93; Circulation.2003.107(14): 1852-7; Exp Clin Endocrinol Diabetes.2003;111(2):60-5;
Exp Clin Endo-crinol Diabetes.2003; 111 (5):239-45. Int J Cardiol.2003(88:2-3):183-90; J Nutr.2003;133(7):2239-43; Diab.
Metab. 2002;28(1):20-Lipids.2000;35(8):927-31. Nutrition. 2003;19(3):213-28. Dietary flax oil reduces renal injury, oxidiz-ed
LDL content, & tissue n-6/n-3 FA ratio in experimental polycystic kidney disease. Lipids.2002;37(11):1059-65.
Epilepsy
Epilepsia.2002;43(1):103-4; Nutr Health.2002;16(1):51-3; Synapse.2000;37(2):90-4.
Eye Health – Macular Degeneration and others Dietary fatty acids and the 5-year incidence of age-related
maculopathy. Arch Ophthalmol. 2006 Jul;124(7):981-6. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and
associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol.
2006 Jul;124(7):995-1001. Improvement of visual functions and fundus alterations in early age-related macular degeneration
treated with a combination of acetyl-L-carnitine, n-3 fatty acids, & coenzyme Q10. Ophthalmologica.2005;219(3);154-66.
Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress.
Brain Pathol. 2005;15(2):159-66. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.
Prog Retin Eye Res. 2005;24(1):87-138. Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma. J Fr
Ophtalmol.2005;28(3):312-6.Effect of docosahexaenoic acid supplementation on retinal function in a patient with autosomal
6
dominant Stargardt-like retinal dystrophy. Br J Ophthalmol. 2004 Feb;88(2):305-6. Biological safety assessment of
docosahexaenoic acid supplementation in a randomized clinical trial for X-linked retinitis pigmentosa. Arch Ophthalmol. 2003
Sep;121(9):1269-78. J Nutr Sci Vitaminol (Tokyo). 2003 Jun;49(3: 210-3. Invest Ophthalmol Vis Sci. 2003;44(5):2252-9; Invest
Ophthalmol Vis Sci. 2003 44(8): 3685-91; Exp Eye Res. 2003;77(2):167-73.
Inflammatory Diseases (general) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases.
Am J Clin Nutr. 2006 Jun;83(6 Suppl):1505S-1519S Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm
Biotechnol. 2006 Dec;7(6):531-4. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006
Jun;83(6 Suppl):1505S-1519S. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Opin Clin Nutr Metab
Care.2003;6(4):413-9l; Prostaglandins Leukot Essent Fatty Acids.2003;68(3):219-24; Prostaglandins Leukot Essent Fatty Acids.
2003;69(1):51-9; J Am Col Nutr. 2002;21(6):495-505; Isr Med Assoc J.2002;4(1):34-8.
Inflammatory Bowel Disease – IBD-- Crohn’s Disease & Chronic Ulcerative Colitis. Nutr
Hosp;2003;18(2):57-64; Lipids.2002;37(10):935-40; Proc Nutr Soc.2002;61(3): 391-5; J Nutr.2002;132(1):11-9.
Kidney Disease. J Am Diet Assoc. 2003;103(9):1174-7. Lipids. 2002;37(11):1059-65. J Am Soc Nephrol. 2003;14(2):389-96.
Pol Arch Med Wewn. 2002;108(2):753-60. JPEN J Parenter Enteral Nutr. 2002;26(6):351-6. Prostaglandins Leukot Essent Fatty
Acids. 2001;65(5-6):265-70. Mol Cell Biochem. 2001;225(1-):109-19.
Lupus
J Clin Immunol.23(1):23-33; J Clin Immunol.2003;22(4):206-19; Lupus.2002.10(3):246-8.
Mental Health:
General: Dietary omega-3 fatty acids for women. Biomed Pharmacother. 2007 Jan 2; Effects of nutrients (in food) on the
structure and function of the nervous system: update on dietary requirements for brain. Part 2 : macronutrients. Omega-3 fatty
acids and mood disorders. Am J Psychiatry. 2006 Jun;163(6):969-78. Omega-3 fatty acids: evidence basis for treatment and future
research in psychiatry. J Clin Psychiatry. 2006 Dec;67(12):1954-67 Current clinical applications of omega-6 and omega-3 fatty
acids. Nutr Clin Pract. 2006 Aug;21(4):323-41. J Nutr Health Aging. 2006 Sep-Oct;10(5):386-99. S-adenosyl Methionine: a
Connection between Nutritional and Genetic Risk Factors for Neurodegeneration in Alzheimer's Disease. J Nutr Health Aging.
2006 Nov-Dec;10(6):541-4. Omega-3 fatty acids upregulate adult neurogenesis. Neurosci Lett. 2007 Jan 7; Selective Deficits in
the Omega-3 Fatty Acid Docosahexaenoic Acid in the Postmortem Orbitofrontal Cortex of Patients with Major Depressive
Disorder Biol Psychiatry. 2006 Dec 2. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of
schizophrenic patients: Gender differences and partial normalization with antipsychotic medications. Schizophr Res. 2007 Jan 18
Lower omega-3 polyunsaturated fatt y acids and lower docosahexaenoic acid in men with pedophilia. Neuro Endocrinol Lett. 2006
Dec;27(6):719-23. Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebocontrolled Pilot Study. Biol Psychiatry. 2006 Aug 22; Polyunsaturated fatty acids: do they have a role in the pathophysiology of
autism? Neuro Endocrinol Lett. 2006 Aug;27(4):465-71. Are neurodegenerative disorder and psychotic manifestations avoidable
brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(3):203-15. Subtle changes in the aging human brain.
Nutr Health. 2006;18(3):217-24. Nutrigenomic approaches to study the effects of n-3 PUFA diet in the central nervous system.
Nutr Health. 2006;18(3):227-32. Docosahexaenoic acid in neural signaling systems. Nutr Health. 2006;18(3):263-76. The impact
of diet and exercise on brain plasticity and disease. Nutr Health. 2006;18(3):277-84. Are neurodegenerative disorder and
psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(3):203-15.
Emerging treatments for depression. Expert Opin Pharmacother. 2006 Dec;7(17):2323-39. Polyunsaturated fatty acids and
neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Omega-3 fatty acids on the forced-swimming test. J
Psychiatr Res. 2006 Oct 30; Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary
requirements for brain. Part 1: micronutrients. J Nutr Health Aging. 2006 Sep-Oct;10(5):377-85. Effects of nutrients (in food) on
the structure and function of the nervous system: update on dietary requirements for brain. Part 2 : macronutrients. J Nutr Health
Aging. 2006 Sep-Oct;10(5):386-99.The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia. Prog
Neuropsychopharmacol Biol Psychiatry. 2006 Dec 19; The protective effects of omega-3 fatty acids against MK-801-induced
neurotoxicity in prefrontal cortex of rat. Neurochem Int. 2007 Jan;50(1):196-202. Omega-3 fatty acids and monoamine
neurotransmission. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):259-69. The effect of childhood malnutrition
on externalizing behavior. Curr Opin Pediatr. 2006 Oct;18(5):565-70. Relationship between omega-3 fatty acids and plasma
neuroactive steroids in alcoholism, depression and controls. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):30914. Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of
psychopathology. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):329-49 Omega-3 fatty acids and antioxidants
in neurological and psychiatric diseases: An overview. Prog Neuropsycho-pharmacol Biol Psychiatry. 2007 Jan 30;31(1):12-26.
Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology
and treatment of recurrent neuro-psychiatric illness. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):237-57.
The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot
Essent Fatty Acids. 2006 Oct-Nov;75(4-5):323-7. Are neurodegenerative disorder and psychotic manifestations avoidable brain
7
dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(2):89-101. Omega-3 fatty acids, energy substrates, and brain
function during aging. Prostaglandins Leukot Essent Fatty Acids. 2006 Sep;75(3):213-20. Omega-3 fatty acids in ADHD and
related neurodevelopmental disorders. Int Rev Psychiatry. 2006 Apr;18(2):155-72. Prevention of oxidative stress-mediated
neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in
schizophrenia. Int Rev Psychiatry. 2006 Apr;18(2):119-31. Omega-3 fatty acid deficiencies in neurodevelopment, aggression and
autonomic dysregulation: opportunities for intervention. Int Rev Psychiatry. 2006 Apr;18(2):107-18. Essential fatty acids and
their role in conditions characterised by impulsivity. Int Rev Psychiatry. 2006 Apr;18(2):99-105. Essential fatty acids and mental
illness. Int Rev Psychiatry. 2006 Apr;18(2):81-4.
Autism: Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo-controlled
Pilot Study. Biol Psychiatry. 2006 Aug 22; Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism?
Neuro Endocrinol Lett. 2006 Aug;27(4):465-71. (More under Mental Health: General)
Depression: . Emerging treatments for depression. Expert Opin Pharmacother. 2006 Dec;7(17):2323-39. Polyunsaturated
fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Omega-3 fatty acids on the forcedswimming test. J Psychiatr Res. 2006 Oct 30; . Relationship between omega-3 fatty acids and plasma neuroactive steroids in
alcoholism, depression and controls. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):309-14. Ethyleicosapentaenoate and dexamethasone resistance in therapy-refractory depression. Int J Neuro-psychopharmacol. 2004;1-9.Eur
Neuropsychopharmacol.2003;13(4):267-71; Tidjschr Diergeneeskd. 2003; 128(6): 191-2; Am J Clin Nutr.2003;78(1):40-6; J
Affect Disorder.1998;48(2-3):145-55. (More under Mental Health: General)
Schizophrenia: . The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia.
Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):323-7. Are neurodegenerative disorder and psychotic
manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(2):89-101. Abnormalities in the
fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: Gender differences and partial
normalization with antipsychotic medications. Schizophr Res. 2007 Jan 18. The n-3 polyunsaturated fatty acid/dopamine
hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 19; Prevention of oxidative stress-mediated
neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in
schizophrenia. Int Rev Psychiatry. 2006 Apr;18(2):119-31. J Neural Transm Suppl.2003;(64):105-17; Cochrane Database Syst
Rev.2003;(2):CD)1257; Psychiatr Clin North Am.2003;26(1)85-102; Biol Psychiatry.2003;53(1):56-64. (More under Mental
Health: General)
Multiple Sclerosis – MS
Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Antioxidants and
polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Low fat dietary intervention with
omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73 (5):
397-404. Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Evid Rep Technol
Assess (Summ). 2005 Feb;(114):1-3.Omega-3 fatty acids in health and disease: part 2--health effects of omega-3 fatty acids in
autoimmune diseases, mental health, and gene expression. J Med Food. 2005 Summer;8(2):133-48. Omega-3 fatty acids in
inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505Pancreatitis J Parenter Enteral Nutr. 2002 NovDec;26(6):351-6. Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. Prostaglandins Leukot
Essent Fatty Acids.2003;68(3):219-24. J Am Coll Nutr. 2002; 21(6):495. 505; Acta Neurol Scand;2000(102-3). Clin Exp
Immunol. 2000;122(3): 445-52; Acta Neurol Scand. 2000;102(3):143-9.
Parenteral Nutrition (Feeding via an I.V.)
Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med. 2006 Apr;34(4):972-9. Omega-3 fatty acidssupplemented parenteral nutrition in the critically ill: another step forward on the "great journey"? Use of fish oil in parenteral
nutrition: Rationale and reality. Proc Nutr Soc. 2006 Aug;65(3):264-77. Fish oil in the critically ill: from experimental to clinical
data. Curr Opin Clin Nutr Metab Care. 2006 Mar;9(2):140-8. Metabolic effects of parenteral nutrition enriched with n-3
polyunsaturated fatty acids in critically ill patients. Clin Nutr. 2006 Aug;25(4):588-95. Effects of enteral feeding with
eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic
shock. Crit Care Med. 2006 Sep;34(9):2325-33. Parenteral fish oil supplementation in patients with abdominal sepsis. Clin Nutr.
2003 Aug;22(S1):S23.Nutr.2003;19(3):275-9.
Polycystic Ovary Disease and Ovarian Function Trans fatty acid intakes and the risk of ovulatory infertility. Am
J Clin Nutr. 2007 Jan;85(1):231-7. J Nutr.2003;133(1):108-6; Lipids. 2002;37(11):1059-65; Srp Arh CelokLek. 2002;130(78):251-7.
8
Pregnancy and Infant Development Issues:
Oils rich in omega-3 fatty acids appear to have important implications in pregnancy and infant
nutrition in particular. DHA (a long-chain omega-3 fatty acid) is a major fat of the brain, and the
research is growing that suggests that providing some pre-formed DHA is advantageous. [Eur J Clin
Nutr. 2004;58(3):429-37. Pediatrics 2003;111(1):e39-44; Arch Dis Child Fetal Neonatal Ed.2003;88(5):F383-F390.] DHA is known to be essential
It has also
been reported that maternal alcohol intake can alter fatty acid transport by the human placenta,
decreasing fetal availability of polyunsaturated fats in general and of DHA especially. (Br J Nutr. 2002;
87(3):247-52.) It may be that this decreased DHA transport is one of the (many) mechanisms of FAS
(Fetal Alcohol Syndrome.)
for retinal development in infants [Invest 44(8):3685-91; Ophthalmol Vis Sci.2003;Invest Ophthalmol Vis Sci.2003;44(8):3685-9.]
Omega-3 fats are also associated with decreased risk of premature delivery. As premature
delivery is the most common cause of low infant birth weight, and infant morbidity and mortality,
this is a very important observation. [J Nutr.2003;133(5 Suppl 2): 1606S-1625S. Exp Biol Med (Maywood). 2001;(226(6):498-506;
BMJ.2002;324(7335):447; Obstet Gynecol Serv.2001;56(5 Suppl 1):S1-S13; Pediatrics. 2001 Aug;108(2):359-71; Obstet Gynecol Surv. 2001;56(5
Suppl 1):S1-13; Pediatr Clin North Am.2001;48(1):173-88; BJOG.2000;107(3):382-95.]
There is growing interest in the potential role of maternal supplementation of antiinflammatory n-3 polyunsaturated fattyacids (n-3 PUFAs) in the prevention of allergic disease.
[J
For more information on this topic please see “Aunt Cathy’s Guide to
Nutrition: A Top Ten Nutrtion Plan for Optimizing Pregnancy.”
Allergy Clin Immunol. 2003 Dec;112(6):1178-84.]
Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev. 2006 May;64(5 Pt 2):S24-33; discussion S72-91. Nutrition and
theory of mind--The role of polyunsaturated fatty acids (PUFA) in the development of theory of mind. Prostaglandins Leukot Essent Fatty Acids.
2006 Jul;75(1):33-41. Omega 6 to omega 3 fatty acid imbalance early in life leads to persistent reductions in DHA levels in glycerophospholipids in
rat hypothalamus even after long-term omega 3 fatty acid repletion. Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic
rat brain. J Nutr. 2006 Jun;136(6):1570-5. Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. Neuroscience.
2006;139(4):1397-403. Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. Neuroscience. 2006;139(4):1397403. Reduced brain DHA content after a single reproductive cycle in female rats fed a diet deficient in N-3 polyunsaturated fatty acids. Biol
Psychiatry. 2006 Nov 1;60(9):987-90. Role of docosahexaenoic acid in neuronal plasma membranes. Sci STKE. 2006 Feb 7;2006(321):pe6.
Docosahexaenoic acid facilitates cell maturation and beta-adrenergic transmission in astrocytes. J Lipid Res. 2006 Mar;47(3):571-81. Overexpression
of dopamine receptor genes and their products in the postnatal rat brain following maternal n-3 fatty acid dietary deficiency. J Neurochem. 2005
Dec;95(6):1550-62. A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy. Obstet Gynecol. 2003
Mar;101(3):469-79
What is a Good Ratio of Omega-3 to Omega-6 Fatty Acids to Aim For?
Most Americans eat about ten grams of omega-6 fat for every one gram of omega-3. That
is, the ratio is ten to one. Some estimates are even higher. We should try to change that ratio to
four-to-one, and if we have an inflammatory disease, two-to-one might even be better. Corn oil
is almost all omega-6, so it is not the best choice. Compared with omega-3 fats, the omega-6 fats
tend to increase inflammatory responses. If you buy a fish oil supplement, look for the words "EPA
and DHA" on the label -- these are the "good guy" omega-3 fats that you are trying to get. (I
remember this by thinking of EPA as "Environmental Protection Agency" since it protects your
personal internal environment.)
A report on EPA-DHA (NOT on cod-liver oil, which is different in a number of ways)
supplements available in the U.S. appeared in Consumer Reports (2003Jul;68(7):30-2.) They evaluated
the safety of products on the market (e.g. related to mercury concerns, etc.), the actual content of
each product, and the price. The good news is that they found all to be safe, and all products
contained what the label said was in there. However the price per 300 mg of supplemental fish oil
ranged from 6 to 60 cents each! Expensive items provided no additional benefit. The cheapest are
9
found at bulk-sales stores like Sam's Club or Costco, etc. (in BIG bottles.) Most pharmacies carry
them in smaller bottles.
Alpha linolenic acid is the form of omega-3 fat found in plants. Flax, canola and walnut oil
are the most generous sources. Usually we can use it to make the EPA and DHA we need, but
many people clearly benefit from getting at least some EPA and DHA “ready-made,” (i.e. in fish
and fish oil supplements.) For example, some people may have difficulty making adequate EPA out
of the omega 3 fats in plants. Another group of people at particular risk of cardiovascular disease
was identified who have a different genetic trait for which providing EPA may be especially
helpful. They have a variant 5-lipoxygenase genotype affecting leukotriene production and
inflammation. (NEJM.2004;350(1):29-37; Nutr Rev. 2004 Jan;62(1):18-27.)
Some guidelines are now available: A qualified health claim for fish oil supplements with
EPA and DHA in capsule form has been approved by the FDA. The supplements should be used
with a physician’s knowledge and approval, as certain aspects of the use of high doses of fish oil
can increase bleeding problems among people taking certain medications to decrease risk of clots.
These include anticoagulant and antiplatelet medications like Coumadin. Supplements that provide
about a gram (1000 mg) of omega-3 fat daily can benefit persons with cardiovascular disease.
Higher dose (2–4 grams, or 2000-4000 mg) intakes appear to greatly improve high triglyceride
levels in particular. The higher doses (over 3 grams daily) should be taken only with physician
approval. (n-3 Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May
21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S. AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and
cardiovascular disease. Circulation 2002;106:2747-2757.)
The chart on the next page shows the families of oils and the names of the fats in each
family. To help me remember them, I gave each “family” a last name that reminds me of some of
the major food sources of each. The omega-3 family is the “Fishers,” the omega-6 family’s last
name is “Cornelius,” and the monounsaturated fats are the “Olivetti” family. The dotted line is the marker of
the forms of these fats found in plants, and the forms that are found only in “critters” like fish and animals, including
people. The critters themselves can usually make the EPA, DHA and ARA out of the plant forms that they eat, and they
also take them in by eating other critters.
Why we care about this:
Prostaglandins, thromboxanes, prostacyclins, and leukotrienes are made from 20 carbon
polyunsaturated fatty acids (EPA and ARA). Thromboxanes made from ARA are much more
aggregatory (promoting of blood clots) than those made of EPA. Prostaglandins made of ARA are
much more inflammatory than those made of EPA. Decreasing the ratio of omega 6 to omega 3
fatty acids in the diet decreases the likelihood of forming blood clots, and decreases
inflammation. This is particularly important in cardiovascular health, in diabetes, and in
autoimmune diseases such as MS, inflammatory bowel disease, lupus and arthritis. A typical
omega 6:omega 3 ratio in the US is often as high as 10:1. A suggested ratio goal for healthy
people: 4:1. A ratio of 2:1 has been suggested for people with inappropriately inflammatory or
aggregatory conditions.
10
The Unsaturated Fat Families:
______________________________________________
Number of Carbons:
Number of Double Bonds
Omega 3
“The Fisher family”
Omega 6
“The Cornelius family
Omega 9
“The Olivetti family”
(“Monounsaturated”)
______________________________________________________________________
Linoleic* 18:2
(plants)
18 carbons
Alpha Linolenic* 18:3
Gamma Linolenic 18:3
Oleic 18:1
------------------------------------------------------------------------------------EPA** 20:5
Arachidonic (ARA) 20:4
(critters)
20 carbons
22 carbons
DHA*** 22:6
_____________________________________________________________________________________
* Essential fatty acids
*linoleic = 18:2 *alpha linolenic = 18:3
** Eicosapentaenoic acid
Eicosa: 20 (carbons) Penta :with 5 Enoic: double bonds
*** Docosahexaenoic acid (an important component of the brain)
Docosa: 22 (carbons) Hexa: with 6 Enoic: double bonds
(New research issue: Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation,
our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004 Jan;134(1):183-6)
The chart on the next page shows the plant and animal food and oil sources for omega-3
fats in descending order. The animal sources (including fish) are on the right, and plant
sources are on the left. It is interesting to note that olive oil and peanut oil are not very
generous sources of omega-3 fat. Their contribution to heart health (for example, as a part of
the “Mediterranean Diet”) appears to be due to their displacement of other, less-healthful
fats in the diet, such as the omega-6 fats and saturated fats. Displacing some of the dietary
omega-6 fats is another way to decrease the ratio omega-6 toomega-3 fat.
11
Omega 3 Fatty Acids in Foods
Plant Forms:
_________________________________
Linolenic Acid (18:3)
_________________________________
omega-3 fatty acids mg per tablespoon
of food (unless otherwise noted)
Linseed oil (flax)
7300
Rapeseed (Canola) Oil
Walnuts, English, chopped
Walnut Oil
1500
1440
1400
Wheat germ
900
Soybean oil
900
Soybean Sprouts, cooked 1 oz 600
Hydrogenated Soybean Oil
300
Olive Oil
Safflower Oil
Sunflower Oil
Corn Oil
Peanut Oil
Palm Oil
Palm Kernel Oil
Cottonseed Oil
Coconut Oil
100
100
100
100
0
0
0
0
0
______________________________________
Source:
Omega 3 values from “Provisional Table on
Content of Omega-3 Fatty Acids and Other Fat
Components in Selected Foods” USDA Human
Nutrition Information Service 1986, and
Agriculture Handbook No. 8-4
US Dept. of Agriculture Science and
Education Administration
New Source: DHA produced by the use
of microorganisms. Biotechnological production
and applications of the omega-3 polyunsaturated fatty acid
docosahexaenoic acid. Appl Microbiol Biotechnol. 2004 Jan
22
Animal Forms:
_________________________________
EPA and DHA (20:5 and 22:6)
(Eicosapentaenoic Acid and
Docosahexaenoic Acid)
_________________________________
Seafood portion in ounces to provide
300 mg of omega-3 fatty acids
(uncooked weight)
Fish oil 300 mg capsule
1 capsule
Mackerel, Atlantic
0.4
Trout, Lake
0.5
Herring, Atlantic
Sardines
0.7
0.7
Anchovies, European
0.8
Salmon, Pink
1.0
Tuna, white
Bass, striped
1.3
1.3
Trout, Brook
1.8
Tuna, Light
2.1
Cod
Crab, king
3.5
3.5
Shrimp
Flounder
Haddock
Lobster
Scallops
Snapper, Red
Swordfish
5.3
5.3
5.3
5.3
5.3
5.3
5.3
Sole
10.5
12
MeritCare Health System’s
Aunt Cathy’s
Guide to Nutrition:
Aunt Cathy
2009
Cathy Breedon PhD, RD, CSP, FADA
Perinatal/Pediatric Nutrition Specialist
MeritCare Health Systems and
UND School of Medicine Dept. of Pediatrics
Fargo, ND
MAGNESIUM
Short Version with Minimal References Included
This shorter version includes only a few of the many references from the scientific literature. If you are interested in
seeing the rest of the references, you can access a version on line that includes this information. Go to
www.meritcare.com and type Cathy Breedon in the search box. A page will come up that has a box labeled “Cathy
Breedon’s Handouts” and you can check the one they have labeled “Guide to Nutrition: Magnesium (PDF)”
Other topics are also available at this site.
RDA:
Adult women 320; men 420mg
Pregnancy 350-400 mg
Lactation 320-360 mg
1) This mineral plays a role in over 300 functions in the body, including energy
production, nervous system activity, and bone flexibility.
2) Most American adults take in less that 2/3 of the RDA.
3) Some estimates indicate that as many as a third of hospitalized patients have a low
magnesium level in their blood that can complicate their care. Poor magnesium status
upon entering a hospital is a predictor of a less favorable outcome. Blood magnesium
level does not necessarily reflect magnesium adequacy, however. Usually it just
indicates that a person’s kidneys are on the job, since the blood Mg level is regulated
by the kidney. So if one’s blood level is low, it may reflect inadequate intake or
excessive losses (and so this is a very important laboratory finding.) However, a
normal blood level tells us very little about the adequacy of magnesium inside the
body’s cells, where most of the magnesium-dependent work is trying to be done. In
other words, the best way to know if people’s intake of magnesium is appropriate is
to obtain a careful history of their usual intake from foods and supplements. This is
rarely done.
4) Low magnesium status is associated with a number of adverse health conditions.
However, as is the case for most minerals, excessive intake from high-dose
supplements is not safe.
1
A Brief Overview of Associations of Magnesium Status
with Adverse Health Conditions:
Diabetes:
High blood sugar contributes to magnesium loss in the urine and at the same time
poor magnesium status can increase insulin resistance because magnesium is required
by the insulin receptors on the cells. Low magnesium intake may also contribute to the
development of diabetes, heart disease and stroke, and to certain complications of
diabetes such as retinopathy and neuropathy. Many studies have shown that people with
diabetes often have poor magnesium status. Improved blood sugar control is associated
with eating a “high fiber diet, ” which also provides a better intake of magnesium and
chromium, both of which play very important roles in blood sugar and lipid metabolism.
For example, recently researchers at Harvard University published the results of a
prospective study at of almost 84,000 women who were followed for 16 years. It was
found that those who ate nuts or peanut butter four times a week or more had 25%
less likelihood of developing Type II diabetes (the adult type) than was found for
women who ate these foods rarely or never. Nuts and peanut butter are especially rich in
magnesium, chromium, vitamin E, monounsaturated fat and omega-3 polyunsaturated
fats. All of these nutrients have the potential to have played a protective role in this study.
Later the data was analyzed differently, it was found that the same pattern existed when
the highest and lowest magnesium intake groups were compared. Magnesium
inadequacy also is being implicated as a contributor to the development of Type II
diabetes in young people that is evolving from the epidemic of childhood obesity .
Cardiovascular Disease and Hypertension:
Abnormal magnesium status is common in patients with cardiovascular diseases for a
number of reasons, including poor dietary intake or excessive losses due to use of
diuretics or diabetes. Dietary magnesium inadequacy is an independent risk factor in
predicting the development of hypertension and cardiovascular disease. Some of the
benefits of high fiber diets, legumes (especially peanuts) and nut consumption in
decreasing cardiovascular risk are likely due in part to the magnesium content.
Osteoporosis and Bone Health:
Healthy bone production relies on the implantation of calcium into a flexible core
called the bone “matrix.” Magnesium is crucial for the development of the bone matrix,
and so inadequacy can increase the fragility of bone (because it is less flexible) and it
can impair recovery from bone injury.
It is also important to note that calcium and magnesium also interact in other areas
of the body, such as nervous system function, blood pressure control and blood clotting,
so maintaining an appropriate ratio is extremely important. For example, there is concern
that excessively generous calcium supplementation without attention to the calcium:
2
magnesium ratio may increase risk of thrombosis and stroke. With so much calcium
fortification and supplementation taking place, we cannot afford to ignore the fact that
many Americans have a poor magnesium intake and/or high magnesium losses.
Pregnancy:
Some researchers feel that prenatal magnesium adequacy has a higher priority than
even iron supplementation because of the over 300 enzyme systems in the body that
depend on magnesium to function properly. Several measures of pregnancy outcome,
such as higher frequency of spontaneous abortions (miscarriage), fetal growth
retardation, birth defects, maternal hospitalizations, preterm delivery, SIDS and
referrals to NICUs have been found to be associated with poor magnesium status in
pregnancy. [These issues are related to general nutrition and are separate from issues
related to the acute therapeutic i.v. magnesium sometimes used in the treatment of preeclampsia or premature labor.]
Other studies have shown a benefit of assuring magnesium adequacy (i.e.
providing the RDA level of magnesium) in the reduction of leg cramps in pregnancy.
Pregnant women with diabetes need special attention to adequacy of magnesium intake
because of the potential for increased losses and the common finding of poor magnesium
status among people with diabetes in particular. In addition, inadequacy of magnesium is
a risk factor for the development of gestational diabetes as well as Type II diabetes.
Migraine Headaches:
For some migraine sufferers, assuring adequacy of magnesium intake resolves
migraine problems. For others, it decreases the frequency or intensity of the headaches.
So, while Mg status is certainly not the only factor involved in the development of migraines, this intervention can be helpful, and it is safe and inexpensive, so many experts
in headache treatment regard assuring magnesium adequacy as a primary intervention.
Premenstrual Syndrome (PMS):
Providing magnesium at the RDA level has been shown to improve “affect” (mood or
emotional well-being), and certain tissues of women suffering from PMS have been
shown to be low in magnesium. Brain levels of the neurotransmitter serotonin appear to
be significantly involved in PMS, and medications that adjust serotonin levels are now
being used. Assuring adequacy of magnesium may be a factor (both with and without
other medication) because it also is required for the production and metabolism of
serotonin (and all neurotransmitter metabolism.)
Cancer:
In 2005 a population-based prospective study of 61,433 women suggested that a high
magnesium intake may reduce the occurrence of colorectal cancer. Animal studies have
also suggested that a higher dietary intake of magnesium is associated with decreased risk
of colon cancer, possibly related to an effect of the magnesium-containing substance
3
called chlorophyll protecting against cancer-promoting properties of a structurally similar
substance in red meat called heme (or “haem” in the UK.) In addition, in 2004 it was
reported that a lower magnesium level in drinking water was associated with risk of death
from ovarian cancer.
Kidneys, stone forming, and other renal issues:
Low magnesium intake has a role in the development of kidney stones, and the kidney
has an important role in regulating magnesium in the blood.
Miscellaneous:
Magnesium adequacy has been found to be a factor in the development and/or
management of many chronic conditions, such as asthma, certain thyroid conditions,
alcoholism, pancreatitis, hearing loss, and possibly Tourette’s Syndrome, Raynaud's
phenomenon, pain management, corneal disease, skin problems, attempts to quit
smoking, and certain hyperexcitable states.
Magnesium Losses and Safety Issues:
Conditions like chronic diarrhea, high blood sugar, or the regular use of certain
drugs (such as thiazide diuretics) cause magnesium loss. As a rule, drugs for which
patients are advised to eat a high potassium diet or to take potassium supplements are
also likely to cause loss of magnesium. This problem is often unrecognized, however,
and because of an interaction between magnesium and potassium, the failure to correct
magnesium losses along with potassium losses further compromises the body’s ability to
achieve normal potassium status in the cells. As is the case with potassium, most
vitamin/mineral supplements contain little magnesium or none at all. And also like
potassium, there may be a need to take in less when one has certain kidney problems.
Excessive intake from supplements or magnesium-containing medications
can also cause problems, so never give nutritional supplements of magnesium above the
level described above unless prescribed by a doctor. It is also useful to know that
magnesium oxide, chloride and diglycinate are the kinds of magnesium that are usually
used as a supplement . . . magnesium sulfate (Epsom salts) and hydroxide ("milk of
magnesia") are less well absorbed and more likely to cause diarrhea instead (which is
why they are used to treat constipation . . . in fact, magnesium citrate is often used as a
pre-surgical bowel-cleaning product!) There are a number of magnesium-containing
medications, like some over-the-counter antacid products. Check with a pharmacist
about magnesium in specific products.
4
Food Sources of Magnesium:
Food sources are the best way to safely assure adequacy, with the added benefit of
the other nutrients they provide and the pleasure derived from eating them. Unlike
supplement sources, dietary sources of magnesium do not contribute to diarrhea, and
there is not a concern about potential overdose. Only individuals with renal failure or
another serious medical condition may be advised by a physician to limit intake of dietary
magnesium.
As can be seen below, the best sources or magnesium are also foods recommended as
healthy choices by the American Dietetic Association, and by many professional health
associations concerned with cardiovascular health, diabetes and cancer. And although the
nuts and peanut butter do contribute fat and calories, they can easily be included as a part
of a healthy diet when used in place of other high calorie or high fat foods. As an added
bonus, the form of fat in these foods is rich in monounsaturated fat and omega-3 fatty
acids. They are low in saturated fat and trans fatty acids, have no cholesterol, and
compared with other forms of fat, they are generally found to be protective against heart
disease, diabetes and cancer.
Some of the Best Dietary Sources of Magnesium:
Magnesium (mg per 1/2 cup)
500 mg or more
Peanuts and Peanut butter
100-300mg
Wheat germ*, Bran cereals*,
Wild rice
Lentils, Split peas, Tofu,
Cashews, Almonds
*Note that refining grains removes most of the magnesium and it is
not added back as iron is when grain is “enriched.” The phytate
content of the grain is also a factor in the availability of dietary
magnesium.
25-90 mg
Fortified breakfast cereals, Oatmeal,
Miso, Spinach,
Milk, Yogurt, Fish,
Brewer's yeast (80 mg/Tblsp),
Cocoa powder (25 mg/Tblsp)
5
Aunt Cathy’s
Guide to Nutrition:
2009
Nutrition Issues in
Multiple Sclerosis
MeritCare Health System
(“With References” Version)
Cathy Breedon PhD, RD, CSP, FADA
Clinical and Metabolic Nutrition Specialist
MeritCare Health Systems and
UND School of Medicine, Fargo, ND
(For people with MS, their
families and interested
health care professionals)
Multiple Sclerosis (MS) is an inflammatory disease of the myelin of the central
nervous system, the origin of which is still unknown. Genetic, infectious, immunological
and environmental factors have all been blamed, but none of these factors on their own
can explain the whole spectrum of this disease.
There Are Two Major Areas of Concern Regarding Nutrition and MS:
Nutrition factors in the development and progression of MS
Nutrition problems resulting from MS and its treatment
Nutrients of interest in the development and progression of MS *
*(Each of these will be discussed in the following pages.)
•
•
•
•
•
•
Vitamin D
Fats (amounts and forms, such as saturated fat, monounsaturated fat, and omega-3
and omega-6 polyunsaturated fats)
Antioxidants (e.g. vitamin E, selenium, alpha-lipoic acid, certain phytochemicals)
B vitamins (B6, B12, folic acid. biotin)
Minerals (magnesium, iron and phosphorus)
Carnitine
Nutrition issues will also interact with other factors:
•
•
•
•
Individual factors including genetic vulnerabilities, ethnicity, skin pigment and
gender.
Exposure to certain viral agents or other infectious agents during sensitive periods.
Age at which a nutritional contributing factor to MS is experienced.
Geographic variables such as latitude, altitude, soil mineral patterns and proximity to
sea coasts.
1
For ease of reading, only a few references will be included in the text.
A large number of references will be grouped at the end of each section,
and some annotated references / abstracts will be included at the end of the paper.
Vitamin D
The results of large recent studies supported a protective effect of vitamin D intake on
risk of developing MS. Some intervention trials have demonstrated that supplementation
with vitamin D or its metabolites is able to improve symptoms of multiple sclerosis.
(Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. Vitamin D and calcium
deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005. Vitamin D intake and incidence of multiple sclerosis
Neurology.,2004)
Vitamin D inadequacy is related to the ability of the sun’s rays to activate skin
receptors. There is a clear latitude gradient, so that the likelihood of making
inadequate vitamin D in the skin is greater in the north. Living in the north is also a
known risk factor for MS, which is why the northern tier is called the “MS Belt” as
well as the “Rickets Belt.”
The map below is from Tufts Health & Nutrition Newsletter 1996. It shows that sunlight
is too weak for vitamin D synthesis from November through February at the 42nd parallel.
Between the 40th and 42nd, the sunlight is too weak to make vitamin D in January and
February. At that rate, it suggests that for every degree of latitude, there is an additional
month of inadequate vitamin D production. The northern border is the 49th parallel across
much of the USA. Alaskans and Canadians are even farther up there.
Why have we assumed that people, especially those in the northern tier, are
obtaining adequate vitamin D? I think we have missed this because we do not
ordinarily obtain vitamin D levels as part of our regular health care assessment, and most
2
importantly, because people with vitamin D deficiency do not look funny unless they are
infants (who may develop the bowed legs of rickets, or other apparent bone deformity.)
After childhood, the effects of vitamin D deficiency are often far less visible and
unrecognized. Our nutrition health model has tended to be “If you don’t look funny, you
must be fine.” Now that vitamin D levels are beginning to be done as part of health
check-ups, it has been noted that there is actually “an unrecognized epidemic of vitamin
D deficiency in the northern tier.” [The vitamin D epidemic and its health consequences. J Nutr. 2005
Nov;135(11):2739S-48S.]
Fracture history and bone loss in patients with MS: MS patients have significantly
reduced bone mass and a high prevalence of abnormal vitamin D status. In one study, in
the absence of major trauma, fractures occurred in only 2% of controls but in 22%
of MS patients. After over two years of prospective follow-up both men and women
with MS lost substantially more bone annually in the spine and in the femoral neck (the
part of the leg bone where it meets the hip) than did the people without MS. Having had
steroid treatment for more than 5 months, and a person’s ambulatory status (ability to
walk) were both predictors of bone loss as well. (Vitamin D deficiency and reduced bone mineral density in
multiple sclerosis: effect of ambulatory status and functional capacity. J Bone Miner Metab. 2005 Long-term effects of intravenous
high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis. Eur J Neurol. 2005 (Fracture history
and bone loss in patients with MS. Neurology. 1998) Reduced bone mass and fat-free mass in women with multiple sclerosis: effects
of ambulatory status and glucocorticoid use. Calcif Tissue Int. 1997)
Nutrition Connection: Bone loss in the spine occurred significantly faster in MS patients
who had low 25-hydroxyvitamin D levels (<20 ng/mL). In those with normal levels,
bone loss was insignificant. At the femoral neck, bone loss was substantial in all MS
patients compared with controls, but was somewhat faster in the group with low vitamin
D. These authors concluded that MS patients have more frequent fractures and lose bone
mass more rapidly than do healthy age- and gender-matched peers, in part related to
insufficient vitamin D. Vitamin D repletion might reduce the rate of bone loss and
decrease osteoporosis-related fractures.
“Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional
capacity. J Bone Miner Metab. 2005;23(4):309-13 …In conclusion, BMD is significantly lower in MS patients than in healthy
controls, vitamin D deficiency is prevalent in MS, and ambulatory status is a determinative factor for osteoporosis in MS. Patients
should be encouraged to have adequate sunlight exposure and to increase their mobility. Specific strengthening exercises for hip and
back muscles in MS patients would have a substantial impact on bone density, osteoporosis, fracture risk, and mobility.”
[CB comment: Since this was published it has become apparent that trying to solve the problem with sunlight exposure alone will be
unsuccessful much of the year if you live up north. In other situations, the sunlight approach may be hampered by intolerance of warm
weather. These and other reasons often make it necessary to approach the problem with supplemental vitamin D, either in milk or in
vitamin pills. More on this later.]
Genetic Defect in Vitamin D Metabolism? 1,25-Dihydroxyvitamin D3 is the hormone
(biologically active) form of vitamin D. It exerts an immuno-suppressive effect and can
completely prevent experimental autoimmune encephalomyelitis (EAE – the mouse
model of MS.) Nataf et al (1996) and Cantorna et al (1996) reported that the nonactivated vitamin D from diet or sunlight has no effect on mice with this condition.
However, providing the 1,25 form of vitamin D resulted in decreased progression of
EAE, and in some mice actual improvement of myelin injury. It is possible that failure to
activate vitamin D may account for some forms of MS. Degrees of impaired activation
may account for the variation seen in the severity of symptoms. And clearly, some people
may have no genetic defect like this at all . . . they just have poor vitamin D intake and
poor production in the skin (e.g. they live up north.)
3
The active (1,25-dihydroxy vitamin D exerts most of its actions only after it has bound to
its specific receptors in the nucleus of a cell. Fukazawa et al. (1999) found an association
of MS with Vit D Receptor Gene (VDRG) polymorphism. Polymorphism just means
that the receptors on body cells that are looking for vitamin D apparently come in
different forms in different groups of people. In other words, there appears to be variation
in the form of the vitamin D receptor in some people. This may be another genetic trait
involved in the development of MS. [Variation in the vitamin D receptor gene is associated with multiple sclerosis
in an Australian population. J Neurogenet. 2005 Jan-Mar;19(1):25-38. …Our results support a role for the VDR gene increasing the
risk of developing multiple sclerosis, particularly the progressive clinical subtypes of MS. CTLA-4 gene polymorphism may
modulate disease in Japanese multiple sclerosis patients. J Neurol Sci. 1999 Dec 1;171(1):49-55.]
Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.
Except in those with conditions causing hypersensitivity, there is no evidence of adverse
effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin
D supply of 250 mcg (10000 IU)/d to attain. Published cases of vitamin D toxicity with
hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all
involve intake of > or = 1000 mcg (40000 IU)/d. Because vitamin D is potentially toxic,
intake of >25 mcg (1000 IU)/d has been avoided even though the weight of evidence
shows that the currently accepted “no observed adverse effect limit” of 50 mcg (2000
IU)/d is too low by at least 5-fold. (Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18. Critique of
the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr. 2006
Apr;136(4):1117-22.)
Point: Since it now looks like 1000-2000 iu is needed up north just to assure adequate
blood levels of vitamin D (which is important for many reasons,) and since this level is
clearly safe, and since some people with MS are avoiding milk (the major dietary source
of vitamin D,) vitamin D supplementation is a very good idea. It is not invasive or
expensive. Assuring vitamin D adequacy may help to prevent the “excess” cases of MS
seen in northern latitudes. Variations in diet or sun exposure that alter adequacy may
explain some differences in severity and relapsing of symptoms. Some people may have a
defect in activation of vitamin D to the active form, and may need to receive “calcitriol”
(a prescription form of vitamin D that is already activated). A one-time blood test of
1,25 dihydroxy vitamin D level may be useful in identifying this problem if it exists. For
more on vitamin D, please refer to one of my other handouts: “Aunt Cathy’s Guide to
Calcium and Vitamin D Supplements”
As can be seen below, the scientific research in this area is growing incredibly
rapidly in just a short time. I have put some shortened versions of the abstracts of some
recent studies at the end of this paper for those of you who are interested in the actual
studies, including the health care professionals who may be looking at this handout.
(I want to be sure they believe me that I am not making this stuff up! ☺ )
However, the summary of it all is
“Yes . . . Vitamin D adequacy is a really big deal in
MS.” The vitamin D recommendations will be reviewed in the summary at the end of
this paper. In the meantime, here is just a list of some vitamin D / MS References from
2000-2007.
4
2000- spring 2009 vitamin D and MS references
2009
Diet and nutrition: vitamin D regulates MS gene. Environ Health Perspect. 2009 May;117(5):A196.
Clinical implications of a possible role of vitamin D in multiple sclerosis. J Neurol. 2009 Apr 28.
The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis. Autoimmun Rev. 2009
Jun;8(7):621-6.
Metabolism of 1alpha,25-dihydroxyvitamin D2 by human CYP24A1. Biochem Biophys Res Commun. 2009 Jun 26;384(2):144-8.
Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol. 2009 Jun;22(3):219-25.
Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction.
Mult Scler. 2009 May;15(5):563-570.
Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis.
Mult Scler. 2009 Jun;15(6):735-40.
Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis. J Neuroimmunol. 2009
Feb 15;207(1-2):117-21.
Serum vitamin B12, folate, and homocysteine levels and their association with clinical and electrophysiological parameters in multiple
sclerosis. J Clin Neurosci. 2009 Mar;16(3):399-403.
A salmon based diet protects mice from behavioural changes in the cuprizone model for demyelination. Clin Nutr. 2009;28(1):83-7.
2008
Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505.
Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008 Feb;194(1-2):7-17.
Vitamin D and multiple sclerosis: an update. Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8.
A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses.
2008;71(1):85-90.
Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505.
Coagulation status and biochemical and inflammatory markers in multiple sclerosis. J Clin Neurosci. 2008 Apr;15(4):393-7.
Future research directions in multiple sclerosis therapies. Semin Neurol. 2008 Feb;28(1):121-7.
Epidemiology of multiple sclerosis: from risk factors to prevention. Semin Neurol. 2008 Feb;28(1):17-28.
Ectopic thymic parathyroid adenoma and vitamin D deficiency rickets: a 5-year-follow-up case report and review of literature. Bone.
2008 Apr;42(4):819-24.
Hormonal influences in multiple sclerosis. Curr Top Microbiol Immunol. 2008;318:267-311.
A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and
calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7.
Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis.
Med Hypotheses. 2008;70(1):66-9.
Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis. Arch Neurol. 2008 Jun;65(6):809-11.
Update on the etiology and pathogenesis of multiple sclerosis and neuromyelitis optica. Nippon Rinsho. 2008 Jun;66(6):1087-91.
The immunology of multiple sclerosis: disease mechanisms and therapeutic targets. Minerva Med. 2008 Apr;99(2):119-40.
Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc. FEBS J. 2008 May;275(10):2585-96.
A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses.
2008;71(1):85-90.
Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology.
2008;30(3):140-6.
Vitamin D(3) in fat tissue. Endocrine. 2008 Feb;33(1):90-4.
Vitamin D and multiple sclerosis: an update. Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8.
Assessment of vitamin D status and definition of a normal circulating range of 25-hydroxyvitamin D.
Curr Opin Endocrinol Diabetes Obes. 2008 Dec;15(6):489-94.
Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-9.
2007
The immunological basis for treatment of multiple sclerosis. Scand J Immunol. 2007 Oct;66(4):374-82.
Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci.
2007 Aug;1109:385-400.
1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte
trafficking. Neurosci Res. 2007 Aug 15;85(11):2480-90.2007
Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.
2006
Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases.
Anticancer Res. 2006 Jul-Aug;26(4A):2581-8.
New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3. Ann N Y Acad Sci. 2006;1068:194203.
5
Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54
The role of vitamin D in multiple sclerosis. Ann Pharmacother. 2006 Jun;40(6):1158-61
Vitamin D & autoimmune disease--implications for practice from the MS literature. J Am Diet Assoc. 2006 Mar;106(3):418-24.
Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8.
Vitamin D and its role in immunology: MS, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006 Sep;92(1):60-4
Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8.
1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic
encephalomyelitis. J Neurosci Res. 2006 May 15;83(7):1299-309.
Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol. 2006 Sep;92(1):65-79.
The photobiology of vitamin D--a topic of renewed focus. Tidsskr Nor Laegeforen. 2006 Apr 6;126(8):1048-52.
IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol.
2006 Nov 1;177(9):6030-7.
Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8.
Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr.
2006 Apr;136(4):1117-22.
Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006
Dec;14(12):1032-40.]
2005
25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005 Jun;11(3):266-71.
Why we should offer routine vitamin D supplementation in pregnancy & childhood to prevent MS. Med Hypotheses. 2005;64(3):608-18.
Effects of alfacalcidol therapy on serum cytokine levels in patients w multiple sclerosis. Srp Arh Celok Lek.2005;133 Suppl 2:124-8.
A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry.
2005 Sep;76(9):1294-6.
Vitamin D deficiency & reduced bone mineral density in MS: effect of ambulatory status & functional capacity. J Bone Miner Metab. 2005
Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with MS. Eur J Neurol. 2005.
Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005.
The vitamin D epidemic and its health consequences. J Nutr. 2005 Nov;135(11): 2739S-48S.
Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet. 2005;19(1):25-38.
2000-2004
Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid
Biochem Mol Biol. 2004 May;89-90(1-5):575-9.
Mounting evidence for vit. D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med 2004;229(11):1136-42.
Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004 Aug;58(8):1095-109.
Vitamin D intake and incidence of multiple sclerosis Neurology. 2004 Jan 13;62(1):60-5.
Dodging MS & RA with vitamin D. Health News. 2004;10 (3):4.
The pleiotropic actions of vitamin D. Bioessays. 2004;26(1):21-8.
D-vitamin: old paradoxes & new perspectives Ugeskr Laeger. 2004; 166(1-2):36-40.
The vitamin D deficit. Science. 2003 12;302(5652):1886-8.
Vitamin D target proteins: function & regulation. J Cell Biochem. 2003; 88(2):238-44.
Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003.
Ultraviolet radiation & autoimmune disease: insights from epidemiological research. Toxicology. 2002;181-182:71-8.
Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002; 287(23):3127-9.
Vitamin D: its role & uses in immunology. FASEB J. 2001;15(14): 2579-85
Vitamin D & autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence?. Proc Soc Experi
Biol Med. 2000.
1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune
encephalomyelitis. J Neuroimmunol. 2000.
Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc. 2000.
Total Fat Intake:
The Swank Studies (Swank & Dugan 1990.)
In this famous study, 144 MS patients followed a very low-fat diet for 34 years. Patients
who adhered to the diet (which contained less than 20 g fat/day – a VERY small amount)
showed significantly less deterioration and much lower death rates than did those who ate
more fat. The greatest benefit was seen in those with minimum disability at the start of
the trial. In this group, when those who died from non-MS diseases were excluded from
the analysis, 95% survived and remained physically active. Only 20% who did not
follow the diet survived for the whole the study period. Interpretation Caution: It has
6
been argued that maybe those for whom the diet appeared to be helpful (that is, people
doing well in terms of their MS) stayed on the diet, and those for whom it appeared to be
unhelpful (those with worsening MS for whatever reason) gave up the diet and quit. So,
maybe it was not the diet that accounted for the difference in outcome. Or maybe it was.
Other observations: Swank (1991) also found that women did better than men, and that
patients treated early did better than when treatment was delayed. “High sensitivity to
fats suggests that saturated animal fats are directly involved in the genesis of multiple
sclerosis.” In addition to the issue of Total Amount of Fat in the diet, the Forms of Fat
may be an important factor. The distinctions between the various forms of dietary fats
being investigated now in this area had not been identified at the time the Swank studies
were undertaken.
Biological effects of fish oils in relation to chronic diseases. Omega-3 marine lipids
(polyunsaturated fish oils) affect the types of substances called eicosanoids produced in
the body. These include important substances like prostaglandins, leukotrienes,
prostacyclins, and thromboxanes. The involvement of prostaglandins and leukotrienes in
immune responses has led to studies on the effects of fish oil on various chronic diseases
associated with abnormalities of the immune system, such as MS. One example of an
early observation was that Greenland Eskimos have a high intake of seal, whale and fish,
(rich sources of Omega-3 marine lipids), and MS is uncommon in Eskimos.
Supplementation of Polyunsaturated Fatty Acids (PUFAs). In 1990, Bates reviewed
published controlled trials of omega-6 PUFAs involving 172 patients with acute remitting
MS and one study with omega-3 PUFAs in a double blind controlled study of 312
patients. A trend was found suggesting that the addition of omega-6 and omega-3
PUFAs to the diet of patients with MS results in a reduction of the severity and frequency
of relapses and in a mild overall benefit in a two year period.
Omega-3 polyunsaturated fatty acids and cytokine production in health and disease.
In 1997, Calder studied eicosanoids made from omega-6 oils because they modulate the
production of pro-inflammatory and immunoregulatory substances called cytokines.
Overproduction of these cytokines is associated with both septic shock and chronic
inflammatory diseases. The omega-3 polyunsaturated fatty acids (PUFAs) called EPA
and DHA are found in fish oils. They suppress the production of the eicosanoids made
from Omega-6 PUFAs. EPA is used for making an alternative family of eicosanoids that
are less inflammatory. So, dietary fats which are rich in omega-3 PUFAs have the
potential to alter cytokine production (Gallai et al. 1995 Endres & von Schacky 1996.) Deficiencies of
PUFAs and replacement by nonessential forms of fat has been reported in the plasma
lipids in multiple sclerosis (Holman et al. 1989.) They found that phospholipids in people with
MS have normal levels of (omega 6) linoleic acid and the next fatty acid in the pathway
to make eicosanoids was elevated. But all the omega 6 fatty acids greater than 18 carbons
long were subnormal in MS. This pattern is an indication of impaired ability to add
carbons to lengthen the carbon chain to make the eicosanoids. All the omega-3 acids
were found to be subnormal in people with MS.
7
Depression in MS Hibbeln and Salem (1995) reported that decreased omega-3 fatty
acid intake (especially DHA) correlates with increasing rates of depression, and this may
be a factor in depression in MS. Depressed individuals with MS have a worse outcome
than non-depressed individuals. There is now evidence of impaired phospholipid
metabolism and impaired fatty acid-related cell communication processes. Impaired
phospholipid and fatty acid metabolism (e.g. involving DHA – an omega-3 fat that is
critical for brain function) may be a primary cause of depression in many patients and
may explain the interactions with MS and other diseases (Horrobin & Bennett, 1999.) Additionally,
there are depression issues related to (what else?) Vitamin D and folic acid (a B vitamin
discussed later.) Specific MS-related research with omega-3 fats and other
polyunsaturated fats is limited, although the research on benefits of these fats in many
aspects of human health is quite impressive. More information about wider applications
is available in my handouts on line on various types of fats and oils. [Vitamin D deficiency is
associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40.]
Here are some of the most recent reports investigating the role of various forms of fat
specifically in MS:
Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. This review summarizes
the knowledge of the role of dietary PUFAs, especially omega-3, on normal brain function. It reports the evidence pointing to
potential mechanisms of omega-3 fatty acids in development of neurological disorders and efficacy of their supplementation in terms
of symptom management.
Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. These authors
concluded that “Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific
pathomechanisms and supporting recovery in MS.”
Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot
Essent Fatty Acids. 2005 Nov;73(5):397-404. This study suggests that “a low fat diet supplemented with omega-3 PUFA can have
moderate benefits in RRMS patients on concurrent disease modifying therapies.”
Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. This article focuses on polyunsaturated fatty
acid (PUFA) supplementation. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA supplementation
is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant caution. A
review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials are
required to confirm the benefits.
Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Evid Rep Technol Assess
(Summ). 2005 Feb;(114):1-3.
Omega-3 fatty acids in health and disease: part 2--health effects of omega-3 fatty acids in autoimmune diseases, mental health,
and gene expression. J Med Food. 2005 Summer;8(2):133-48.
Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505. “… There have been a
number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune
diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple
sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant
benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.”
Antioxidants.
Reactive Oxygen Species (ROS) are byproducts of metabolism that are thought to be
involved in causing or contributing to MS and also to experimental allergic
encephalomyelitis (EAE – the mouse model of MS.) Another common name for ROS is
“free radical.” These substances can cause injury to a person’s cells if they are not
handled properly (that is “quenched” or “extinguished” by substances called antioxidants.)
8
Van der Goes et al. (1998) found that phagocytosis of myelin by macrophages triggers
the production of ROS. Free radical action has been suggested as a causal factor in
multiple sclerosis (J Neurol 1999.) For example: malondialdehyde in the blood (a marker
for low vitamin E or other antioxidant protection) was increased by 38% during MS
exacerbations (periods of worsening symptoms.) These changes suggest that there is
increased free radical (ROS) production and consumption of the scavenger molecules
during the active phase of the disease.
Demyelination: the role of reactive oxygen and nitrogen species. Smith et al.(1999)
found that reactive oxygen (ROS) and nitrogen species (RNS) play a role in
demyelination, such as in the inflammatory demyelinating disorders like multiple
sclerosis. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide,
nitric oxide & peroxynitrite) can increase dramatically under conditions such as
inflammation. This can overwhelm the person’s antioxidant defenses within tissues.
Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of
cells and mitochondria, potentially causing cell death. The reactive species (ROS and
RNS) may also damage the myelin sheath, promoting its attack by macrophages.
Damage can occur directly by lipid peroxidation, and indirectly by the activation of
proteases and phospholipase A2. The neurological deficit resulting from experimental
autoimmune demyelinating disease has generally been reduced by trial therapies [that is,
antioxidants] that diminish the concentration of reactive oxygen species. However,
therapies aimed at diminishing reactive nitrogen species have had a more variable
outcome, sometimes exacerbating disease.
Selenium Issues: Selenium (Se) is a mineral in the news in many areas of medical
research, such as diabetes, prostate cancer, thyroid disease, immune system function and
multiple sclerosis (Foster HD,1993.) Glutathione peroxidase is a very important antioxidant in
the body and selenium is a key component of it. Mazzella et al., (1983) found that the
Se-dependent glutathione peroxidase activity in the red blood cells was lower in the
MS patients.
In addition, the Se concentration in the diet of MS patients was studied and found to
be less than the minimum values suggested by the US Food and Nutrition Board.
The authors’ interpretation: “Modified glutathione peroxidase activity found in
erythrocytes [red blood cells] of MS patients is independent from the Se concentration in
blood.” The reported dietary inadequacy was not addressed further.
My observations: It is likely that suboptimal Se intake affects various tissues differently,
and that possibly the blood levels had a “higher priority” for the Se available. In view of
new knowledge about the significant health risks associated with Se inadequacy, it is a
good idea to assure an intake within recommended ranges (60-150 mcg). Studies in the late
‘90s have revealed that dietary Se intakes are sub-optimal in diets of many people. This is
especially true in certain geographic regions (such as Phoenix, AZ) where the soil is quite
low in selenium.
9
It is very hard to estimate a person’s actual selenium intake because it is so variable in
foods. Selenium is an unusual mineral because the amount in a food depends on where it
was produced, and especially in this country, that can be difficult to determine. Excessive
selenium intake can be toxic however, so the upper limit of safety is set at 600 mcg/day,
and the level regarded as toxic is a regular intake of 800 mcg/day. My handouts on
“Nutrition and Eye Health” and “Nutrition in Prostate Cancer” both contain additional
information, as selenium and the selenium-containing antioxidant glutathione peroxidase
are looking very important in general. It is also being found to be very important in the
operation of the immune system and the thyroid gland.
Other potent antioxidants are also being explored in relation to MS, such as “alphalipoic acid.” This substance is also looking to be potentially very beneficial in diabetes,
most specifically with some of the neurologic problems (neuropathy) experienced by
people with diabetes over time. In general, it appears that any inflammatory or
autoimmune condition results in greater production of free radicals, and so as a
generality, a more generous intake of antioxidants is reasonable.
Alpha-lipoic acid is similar to B vitamins in several ways. It is extremely unlikely to be
toxic ven at high doses. Most studies have shown that about 600 mg/day over time is the
level associated with measurable benefits in diabetes research.
It is also reasonable (and a very good idea) to seek out generous potent dietary
antioxidants (like the brightly colored pigments fruits and vegetables . . . lycopene,
anthocyanins, lutein, etc.) The antioxidant vitamins (C and E) are not nearly as potent as
antioxidants as the plant pigments are. For example, lycopene (the red color in tomatoes)
is 200 times as potent an antioxidant as vitamin E. These substances are not vitamins or
minerals, but they fall into a class called “phytochemicals” which just means “plant
chemicals.”
Not all plant chemicals in the world are safe, of course . . . consider poison ivy and
opium, for example. However, the family of these plant pigments (called carotenoids) are
very safe. The only side effect is that eating lots of beta-carotene in carrots, squash and
sweet potatoes may give your skin a harmless orange-ish glow. [That can pass for a tan
up her in North Dakota! ☺] The huge health benefits now being recognized is the
reason behind the recent change from the familiar “Five-a-Day” recommendation for
fruits and vegetables in everyone’s diet to something approximating:
“Eat a whole bunch of brightly colored vegetables and fruits
every day for a whole bunch of reasons!!!!”
Antioxidants and MS:
Here is a list of some research specifically about antioxidants and MS. There is
much more since 2006 but I didn’t get a chance to add it all here.
10
An annotated set of references / abstracts follows at the end of this paper for people
who want more detail.
2006
Dietary chelators as antioxidant enzyme mimetics: implications for dietary intervention in neurodegenerative diseases.
Behav Pharmacol. 2006 Sep;17(5-6):425-30.
Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs. 2006;20(6):433-41.
Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection
via suppression of glia-mediated inflammation. Curr Pharm Des. 2006;12(27):3521-33.
2005
Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61.
Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005 Feb;11(1):24-32.
The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci.
2005 Jun;1051:88-96
Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during
experimental autoimmune encephalomyelitis. Neuroscience. 2005;132(4):1135-49.
2004
Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune
encephalomyelitis. J Immunol. 2004 Nov 1;173(9):5794-800.
Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004 Nov 1;78(3):36270.
Protective effects of caffeic acid phenethyl ester against experimental allergic encephalo-myelitis-induced oxidative stress in
rats. Free Radic Biol Med. 2004 Aug 1;37(3):386-94
The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol.
2004 Mar;251(3):261-8.
Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol.
2004 Mar;148(1-2):146-53.
2003
Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of
oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003 Jun;139(1-2):27-35.
2002
Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune
encephalomyelitis. J Neuroimmunol 2002 Oct;131(1-2):104-14.
My comments on all these fat and antioxidant issues:
Different types of fat and the adequacy of antioxidant protection interact with each other.
Clearly there is deranged metabolism of fatty acids in MS. Is it a cause of MS, or the
result of having MS? Can it be manipulated? Future directions of research should include
evaluating these substances together and not just as individual agents. For example, it
would be useful to study:
•
Comparisons of ratios of omega 3 to omega 6 PUFAs (PolyUnsaturated Fatty Acids), with
attention also paid to the ratios of antioxidants to PUFAs.
•
Evaluation of fat issues while accounting for oxidation status.
•
Fish x Fat x Antioxidants Antioxidants inhibit the enzyme lipoxygenase and so inhibits
leukotriene synthesis. The fish oil leads to production of less inflammatory leukotrienes.
Antioxidants also protect the fish oils from oxidation We need to learn which of these factors
can be useful in trying to prevent the development of MS, or slow its progress.
•
Differentiate in the study between omega-3 and omega-6 PUFAs in terms of the size of the
molecule (shorter vs longer chain length,) because this is now looking like an important
feature to consider in research related to many other health conditions.
Issues involving dietary fat and antioxidants are intimately related. For more detail on
these issues, including food sources and supplement considerations, please see my other
11
handouts “Aunt Cathy’s Guide to Eye Health” (for more information about
antioxidants) and “Aunt Cathy’s Guide to Omega 3 Fatty Acids.”
Other areas of investigation-- B Vitamins:
Biotin, Vitamin B6, Vitamin B12, and Folic Acid
What the Heck is Biotin? It is a B vitamin involved in many body functions that process
carbohydrates, fats and proteins. The recommended intake is 30-100 mcg (based on
reported dietary intakes in healthy people in the US.) Biotin is not toxic, even at levels as
high as 10,000 mcg/day (1000 times the upper end of the assumed adequacy level.)
Bacteria in the intestine produce biotin and they contribute a significant amount, so
getting an adequate amount is unlikely for any person who chronically uses
antibiotics, unless biotin is supplemented. Symptoms of inadequacy include “tingling
in extremities.”
Biotin is a B vitamin that usually receives little attention, since most people obtain an
adequate amount from the intestinal bacteria. However, it is looking interesting in other
autoimmune diseases such as diabetes. (The effect of chromium picolinate and biotin supplementation on glycemic
control in poorly controlled patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized trial. Diabetes
Technol Ther. 2006 Dec;8(6):636-43. Use of chromium picolinate and biotin in the management of type 2 diabetes: an economic
analysis. Dis Manag. 2005 Aug;8(4):265-75.)
There is little activity in the MS research at present. However, Anagnostouli et al.(1999),
looked at concentrations in human cerebral-spinal fluid (CSF) & blood serum. Patients
with common neurologic disorders (including MS) were compared with people who had
no evidence of nutritional or neurologic disorders. They found significantly lower values
for biotin in people with MS (both CSF & serum). They concluded that this low level
could be the result of poor biotin absorption in the intestine caused by the underlying
disease, or related to a biotin-binding immunoglobulin which may be involved in MS
development and progression.
Vitamin B6 (Pyridoxine) It is well known that this vitamin plays a vital role in
many physiological processes, such as nerve communication, processing protein and fats,
and supporting the immune system. Levels higher than the RDA appear to have be of
some benefit in decreasing damage to nerves in other autoimmune conditions such as
diabetes. In many of these activities, vitamin B6 is paired with the mineral magnesium
(more on magnesium later) and it appears that both substances need to be present at the
same time for efficient operation. This is just one more situation in which studying a
single nutrient is unlikely to be as useful as studying them in combination.
Of all the B vitamins, B6 is the most likely to be a problem in very high doses fora pretty
long time . . . such as 200-500 mg/day chronically in the most sensitive individuals. (The
RDA level is only 1-2 mg.) Interestingly, the symptoms associated with the highest
doses, while rare, include some MS-like tingling in the arms. The idea that an
unrecognized inadequacy of vitamin B6 might be a factor in MS comes from just one
study: “Serious dangers to health may be associated with undetected, lingering
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subclinical deficiencies . . . This includes induction of and predisposition to diseases such
as atherosclerosis and multiple sclerosis” (Kesel et al. 1999.)
Vitamin B12: Vitamin B12 levels have been low in MS patients in many studies. The
significance of this is unclear. Is it related to poor absorption? Is it poorly utilized or kept
in the wrong compartments in the body? (Goodkin, 1994) Low vitamin B12 status may
increase vulnerability to the viral and immunologic processes which are suspected as
being factors in causing MS. Certainly, adequacy of vitamin B-12 has critical
importance to neurologic health (for everyone).
Some individuals are at special risk of poor vitamin B12 status. Some patients may
be following strict vegetarian diets with inadequate vitamin B12, or using
medications such as Glucophage (also called Metformin) for diabetes. Others take
medications that block production of stomach acid called “proton pump inhibitors,”
such as Prilosec, Prevacid, Protonix, Pepcid AC, and Nexium.
Any of these situations will increase the likelihood of impaired vitamin B-12 availability
and/or absorption. Additionally, as we age, some people simply begin to produce much
less acid in their stomachs. Inadequate stomach acid decreases our ability to absorb
vitamin B12 from food sources. However, the form found in vitamin pills and
fortified cereals is far more reliably absorbed in spite of these problems.
Because of this, 15-30% of the elderly are found to be deficient in this critical
vitamin when their level is actually checked with a sensitive measure. (Waiting and
watching for changes to appear in red blood cell size is not a sensitive measure because it
is a very late-appearing symptom of vitamin B12 deficiency.) Assuring a generous intake
of absorbable vitamin B-12 is not difficult or expensive. For most people simply taking a
multivitamin supplement prevents this problem. In some studies described below,
vitamin B12 administered with other therapeutic agents may have some benefit in MS,
although a straightforward vitamin B12 deficiency is apparently not the reason. For more
information about vitamin B-12 issues, please see my other hand-out “Aunt Cathy’s
Guide to Vitamin B-12.”
Here are some research regarding Vitamin B12 and MS. An annotated /
abstract reference list follows at the end of this paper.
Newer references are available but not in time for this publication
2006
Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006 Nov;5(11):949-60.
Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood? Biofactors.
2006;26(1):45-57.
Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):189-92.
2005
Vitamin B12, demyelination, remyelination and repair in multiple sclerosis J Neurol Sci. 2005 Jun 15;233(1-2):93-7.
2004
Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12:
treatment to modify notch-1/sonic hedgehog balance. J Immunol. 2004 May 15;172(10):6418-26.
2003
Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by
blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003 Jun;9(3):239-45.
Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis.
Nutr Neurosci. 2003 Jun;6(3):189-96.
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2002
Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical
importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses. 2002 Nov;59(5):594602.
A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder
regime") in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):246-9
Other B-vitamins and Iron: Regeneration of myelin requires both adequacy of iron and
of B vitamins, especially vitamin B12 and folic acid. This situation is a good illustration
of the problems inherent in evaluating the effects of manipulating or measuring a single
nutrient to detect benefit. Many if not most important nutrient-related effects require the
adequacy of several nutrients working together and so the common type of “singlenutrient research” will often fail to detect and identify important roles of that nutrient.
Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis. J Neurol. 2008 Jan;255(1):64-9.
Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis. 2006 Sep;21(2-3):121-37. Some
subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that
iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are
iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and
homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. Results: In relapsingremitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian
female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month
pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved
significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were
significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by
13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that
methylation is necessary but not sufficient for myelin regeneration.
Magnesium: Magnesium (Mg) is involved in the activity of over 300 enzymes in the
body, and it is very critical in neurologic health. As mentioned earlier, magnesium and
vitamin B6 very often work together in this role. Stelmasiak et al. (1995), found a
significant decrease of Mg concentration in red blood cells and no changes in blood
plasma of MS patients compared with controls. This suggests the presence of changes
in red blood cells which could be connected with their shorter life and impaired function
in MS. Magnesium is known to be decreased in central nervous system (CNS) tissues of
people with MS. Yasui & Ota (1992) note that with Mg depletion, pathologic changes are
seen especially in white matter, and this may contribute to the development of MS.
Magnesium Adequacy: Inadequate Mg intake is common in the general population.
In fact, a large national survey* of Americans done every ten years by the Center for
Disease Control (the CDC) found that the majority of Americans obtain less than 2/3 of
the Recommended Dietary Allowance for this nutrient. Certainly there is every reason
to assure that the common dietary inadequacy of magnesium does not complicate
problems for individuals with MS, since magnesium has so many important roles in
(*NHANES – National Health And Nutrition Examination Survey.)
neurologic function.
There is little MS-specific magnesium research being reported, but I found three items to
include here:
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Importance of magnesium depletion with hypofunction of the biological clock in the
pathophysiology of headhaches with photophobia, sudden infant death and some clinical
forms of multiple sclerosis. Magnes Res. 2004 Dec;17(4):314-26. … MS may be associated with
primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal
exacerbations and relapses during fair seasons….
The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001
Feb;56(2):163-70. …The very small probability that all the variables affecting Mg levels will
behave favorably, results in a high probability of a gradually intensifying Mg deficiency. It is
highly regrettable that the deficiency of such an inexpensive, low-toxicity nutrient result in
diseases that cause incalculable suffering and expense throughout the world. The range of
pathologies associated with Mg deficiency is staggering: hypertension (cardiovascular disease,
kidney and liver damage, etc.), peroxynitrite damage (migraine, multiple sclerosis, glaucoma,
Alzheimer's disease, etc.)
The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis. Eur J
Neurol. 2000 Nov;7(6):741-4. The effects of magnesium glycerophosphate oral therapy on
spasticity was studied in a 35-year-old woman with severe spastic paraplegia resulting from
multiple sclerosis (MS). We found a significant improvement in the spasticity after only 1
week from the onset of the treatment on the modified Ashworth scale, an improvement in the
range of motion and in the measures of angles at resting position in lower limbs. No side-effects
were reported and there was no weakness in the arms during the treatment.
In view of the many roles of Mg (especially in the central nervous system) and the true
likelihood that one’s diet may in fact provide too little magnesium, it is reasonable to take
steps to assure that Mg intake at least meets RDA levels. Magnesium Food Sources:
Best are nuts, peanuts and other legumes, whole grains, wheat germ and bran. If a person
avoids these foods (e.g. out of concern about the fat content or the calories in nuts or
peanut butter,) realize that a supplement is likely necessary to prevent inadequacy. Most
general multivitamins have only 0-25% of the RDA, so read the label. For more
information about magnesium, please see my other handout “Aunt Cathy’s Guide to
Magnesium.”
One study suggested that phosphate adequacy may be a factor in MS:
Phosphate depletion is the link between growth, stress and diet in the aetiology of MS. Med Hypotheses. 2004;63(2):262-7. . . .
Phosphate depletion results in demyelinization. Phosphate depletion (PD) can lead to neurological complications, which have been
characterized in experimental & clinical studies. Hypophosphataemia, whether acute or chronic, induced by stress from accident,
surgery or burns, by infection and/or undernutrition, is therefore an important etiological factor. Low SP levels have been reported in
MS patients & the hypothesis that PD causes MS is presented here.
Carnitine
Carnitine is a substance made by the body and also found in meats. It is important inside
cells for converting fat into energy. There is currently a lot of interest in carnitine in a
wide variety of medical applications. In MS, the applications have been aimed at helping
with fatigue, as reported in these studies:
Levocarnitine administration in multiple sclerosis patients with immunosuppressive therapy-induced fatigue. Mult Scler. 2006
Jun;12(3):321-4. Nutritional factors and comedications are among the postulated causes of fatigue, a highly prevalent symptom in the
multiple sclerosis (MS) population, with serious impact on patients' quality of life. Deficiency of carnitine may play a role by reducing
energy production through fatty acid oxidation and numerous MS therapies can induce fatigue syndrome. The aim of this prospective
open-labelled study was to collect and study serum carnitine levels in MS patients with and without disease-modifying treatmentinduced fatigue syndrome. We investigated whether restoration of the carnitine pool might improve treatment-induced fatigue in MS
15
patients. In our study, there was no statistical difference in fatigue frequency between treated and untreated patients (P=0.5). Matched
to age, gender and treatments, carnitine levels were lower for MS treated patients compared to untreated MS patients (P <0.05) or
controls (P <0.001). Consecutive patients with low plasma carnitine levels who experienced fatigue were substituted. Treatment
consisted of oral levocarnitine, 3-6 g daily. All patients achieved normal plasma carnitine levels. For 63% of patients treated with
immunosuppressive or immunomodulatory therapies, oral levocarnitine adjunction decreased fatigue intensity, especially in
patients treated with cyclophosphamide and interferon beta.
Treatment of multiple sclerosis-related fatigue: pharmacological and non-pharmacological approaches. Neurol Sci. 2006
Sep;27(Supplement 4):s297-s299. Fatigue is a common symptom in multiple sclerosis (MS). As fatigue includes a variety of aspects,
its treatment is best approached in a multidisciplinary fashion that includes nonpharmacological interventions and medications. In
individuals with mild fatigue non-pharmacological treatment including yoga, aerobic exercises, cooling therapy and energy
conservation techniques might be considered. Several pharmacological treatments for patients with significant fatigue have proved to
be effective. Among these agents, amantadine and aminopyridines are the most frequently used. More recently also aspirin and
carnitine have been used to treat MS fatigue but they need to be confirmed in larger studies.
Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a
pilot, randomised, double-blind, crossover trial. J Neurol Sci. 2004 Mar 15;218(1-2):103-8. Treatment with acetyl L-carnitine
(ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of
ALCAR for treating fatigue in multiple sclerosis (MS)…Statistical analysis showed significant effects of ALCAR compared with
amantadine for the Fatigue Severity Scale (p = 0.039). … The results of this study show that ALCAR is better tolerated and more
effective than amantadine for the treatment of MS-related fatigue.
Nutrition problems due to MS and its treatment
•
•
•
•
•
•
avoidance of “suspect” foods
dysphagia
weight / body composition
pressure ulcers (also called “bed sores”)
bladder infection
drug/nutrient interactions
Avoidance of “suspect” foods.
Many people try a variety of dietary changes in the hope that it will help control the
symptoms of MS. It is especially important in this situation that a knowledgeable person
review the total intake picture to assure that important nutrients are not accidentally
obtained in inadequate or excessive amounts.
Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. …Our results indicate that oral
flavonoids fail to beneficially influence the course of EAE in mice but, instead, suppress recovery from acute inflammatory damage.
Biochem Pharmacol. 2005 Jul 15;70(2):220-8.
Exacerbation of protracted-relapsing experimental allergic encephalomyelitis in DA rats by gluten-free diet. … Here we study
the effects of a gluten-free diet on the course of protracted-relapsing EAE in DA rats, serving as a preclinical model of human MS.
The data show not only that this nutritional approach failed to ameliorate development of the disease but rather that it exacerbated the
course. APMIS. 2004 Oct;112(10):651-5
Dysphagia
Abnormal swallowing is common in MS although people often do not complained of it. It
is associated with disordered brainstem/cerebellar function, overall disability, depressed
mood and low vital capacity (Thomas & Wiles, 1999.) Assure that any textural manipulations to
facilitate safe eating (such as thickening beverages) do not disrupt nutritional adequacy.
For example, some people actually get a third of their calories just from the starchy
thickeners. This will either result in excessive weight gain if they continue to eat the
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same amount of food, or it will contribute to poor nutrient intake if the total food
intake is cut back to avoid weight gain.
The best foods are those which have generous amounts of vitamins, minerals and
beneficial phytochemicals relative to the number of calories they provide. These
desirable foods are said to be “nutrient dense.” Starchy thickeners are not nutrient dense
at all, and if a person must use them for safety of swallowing, appropriate nutrient
supplementation will be even more important than usual. A few commercial thickening
products are available that do contribute some vitamins and minerals, but most do not. If
assuring adequate food/nutrient intake orally becomes a problem, it has been shown that a
percutaneous gastrostomy tube can be very useful and improve quality of life
significantly. (Acta Gastroenterol Latinoam 2004)
Weight / Body Composition:
Many evaluations of nutritional status only look at Body Mass Index (BMI) or some
other weight-related measure. It is important to consider the alterations in body
composition that occur with increasing immobility. As mobility decreases, a person’s
“Lean Body Mass” will also decrease, resulting in a lower requirement for total calories.
Failure to adjust calories downward can contribute to overweight and increased mobility
for people with MS. However, as described above, when caloric requirements and total
intake decrease, there is an increased risk of missing out on essential nutrients.
Supplementation is reasonable, and it will be necessary in almost all instances.
Pressure Ulcers:
Weight influences on mobility can affect risk of pressure ulcers. However, although
optimal protein and micronutrient nutrition is critical in preventing or healing pressure
ulcers, they are often poorly provided when the calorie intake is low. Immobilization
contributes to both the “pressure” and to the likelihood of inadequate intake of
micronutrients. Again, supplementation will be necessary in almost all instances.
Bladder Infection:
Cranberry juice may be helpful, not because of acidification of urine, but because of the
effects of a natural substance in cranberries that helps make bacteria less likely to adhere
to the bladder lining. A generous intake of fluids is also helpful. However, remember
to watch the calories provided by beverages. For example, “cranberry juice cocktail”
has a lot of sugar added because it is otherwise too tart. The result is a beverage with 20
calories per oz -- the same calories as whole milk! Using artificially sweetened cranberry
juice provides the benefits of cranberry in a very small amount of calories.
Drug/Nutrition Interactions: Chronic use of antibiotics is known to impair folic acid
absorption, and it also stops biotin and vitamin K production by intestinal bacteria.
Several specific interactions were described in the section of vitamin B-12 earlier, and
there are many other interactions of potential importance. Some medications can also
affect appetite, swallowing, mouth dryness, and elimination patterns which indirectly
influence the likelihood of obtaining appropriate nutrition. It is always important to
evaluate the potential for drug/nutrient interactions, so ask your physician,
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pharmacist or dietitian if there are any important issues with the particular
medications you are taking.
Reproductive Health Note:
Infant health of mothers with multiple sclerosis. West J Nurs Res. 2004 Oct;26(6):632-49. “Controversy
surrounds whether mothers with multiple sclerosis (MS) who wish to breast-feed their infants should
forego breast-feeding in order to resume immunomodulating therapy following birth even though breastfeeding has not been shown to have deleterious effects on these mothers. … Significantly more non-breastfed than breast-fed infants experienced otitis media, lower respiratory illness, constipation, milk
intolerance, & allergy during the 1st year. Study results support the need to encourage mothers with MS
who wish to breast-feed their infants to do so and to delay immunomodulating therapy until breast-feeding
cessation.”
IN SUMMARY:
My Best Guess (subject to change at any moment based on new
research) about diet/nutrients to decrease risk of MS and/or decrease
the rate of progression:
First: Try not to be Scottish, Irish, female, or to have lived up here in North Dakota
when you were 15. Select your parents and other family members very carefully.
[I realize, of course, that we have no control over these particular factors. However,
recognizing these factors as important may help individuals to evaluate or even take steps
to modify their own personal risk or the risk to others in the family.]
Second: Look Closely to Assure Adequacy of All Nutrients. This is true for everyone,
of course. The diet should be “nutrient dense” (lots of nutrients per calorie, or per
volume) because total food intake is often low. Realize that some people with MS are
avoiding fat, milk and meat, so vitamin D, vitamin B6, calcium, zinc, iron and protein
intake are all likely to be suspect.
Third: Specific Food and Nutrient Risk Issues
Realize that to achieve adequacy of Vitamin D requires 2000 iu for many people up
north – more than the usual RDA level-- and that inadequacy may be a factor in the
development and/or progression of MS. Any people who are covered up, who have
dark skin, who have old skin, who use sunscreen, or who often stay indoors should
certainly aim for this amount of vitamin D from food and/or supplements. Interestingly,
the same goes for people who have none of these risks . . . it may be protective against a
number of serious health problems, and that amount is clearly safe even if one regularly
sunbathes in the nude by the equator!
A multivitamin supplement will provide the RDA level of 400 iu. Milk is the major
dietary source because it has been fortified with vitamin D in an effort to decrease the
problem of rickets / bone deformity in children. One cup (8 oz) provides 100 iu. Until
very recently there was no vitamin D in yogurt, cheese, ice cream, or in the calciumfortified orange juice. Now some brands are beginning to add it. Again, look VERY
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closely at this one! Some people are avoiding milk, and they may be injuring themselves
substantially if vitamin D is not provided optimally in some other way. The only other
generous food source is salmon and tuna . . . and as with milk, one would need to eat
them frequently to count on these foods to prevent deficiency. Realize that one does
not “have to” drink milk . . . one must simply recognize that if people drink little or
no milk, they will definitely need some other reliable and generous vitamin D source
. . . like a supplement. Assuring a reasonable calcium intake from non-milk sources will
also be import, of course, but the calcium need not be in the same foods or supplements
as the vitamin D provided. It will be well absorbed as long as the total amount of vitamin
D is adequate, regardless of the timing.
Pending further research, if MS is diagnosed (or if it is especially severe), consider
getting a one-time-only measure of 1,25-dihydroxyvitamin D level to rule out a
metabolic problem converting the vitamin to its active form. If that kind of problem is
found, the individual will need a special prescription form of active vitamin D called
“calcitriol.” This kind of metabolic problem has now been found in at least some people
with MS.
Check that calcium intake is at the recommended level for age (e.g. 1000-1500 mg). This
can be especially difficult to achieve if one is avoiding dairy foods. In this situation (low
dairy or low total calories,) a separate calcium supplement will likely be needed because
most multivitamins with minerals provide only about 200 mg of calcium. A supplement
that provides vitamin D along with the calcium is a very good idea in MS and up
north, even with the 400 iu of vitamin D being provided in a multivitamin.
As a rule of thumb, (for everyone) it is a good idea to assure that the magnesium-tocalcium ratio is near the RDA ratio of 1-to-4. Supplementation of large amounts of
calcium in the absence of adequate magnesium may increase risk of blood clots and
stroke, and also bone fragility. Magnesium is often inadequate in the diets of
Americans, so make sure it isn’t inadequate in yours. A person may need a
supplement beyond a “multi with minerals” to achieve the RDA intake, depending on
food choices. The RDA for Mg is 320 mg for women and 420mg for men. Do not take
more than the RDA in supplement form without consulting your doctor. If a person
does take the RDA amount as a supplement, and then also eats magnesium-rich
foods, there is still no problem.
Selenium can be inadequate in low-protein diets especially, and there are other reasons
(e.g geography) why many people have a poor intake. Low selenium intake has negative
implications for cancer and diabetes as well as MS. An intake at 1-2 times the RDA
seems reasonable for all. For example, a goal might be to provide a multi-vitamin with
minerals that contains selenium (check the label) plus food content, for about 100-150
mcg total intake. As described earlier, the RDA = 60 mcg, the upper chronic intake
limit = 600 mcg , and the toxic level = 800 mcg. If the multivitamin does not provide
selenium, it is easy and inexpensive to simply add a small 50 mcg tablet.
A person who follows a strictly vegetarian diet may have a vitamin B-12 level that is
seriously low. Other factors (such as a person’s age or using drugs that decrease stomach
19
acid) can impair absorption of vitamin B12 from food sources. Vitamin B-12
requirements may be higher than normal in MS. It is easy to provide a safe, generous,
inexpensive and absorbable amount, such as the 25 mcg usually included in a “silver”
type multivitamin. The RDA level = 2-3 mcg. The crystalline form of the vitamin
provided in pills does not require stomach acid for absorption the way the form in
food does.
Folic acid availability from foods is also known to be quite variable with measurable
differences in health as a result. The best known and studied example of this is a gene
called the methylenetetrahydrofolate reductase (MTHFR) gene that appears to decrease in
the ability of dietary folate to to its job in preventing birth defects, depression and stroke.
This gene is especially common among people of Irish and Scots heritage (also a
group at higher risk of MS,) and most people who have it are unaware that they do.
However, as with vitamin B12, providing folic acid in the form found in standard
vitamin pills or fortified cereals has been shown to bypass the genetic problem and
make folic acid available to do its job.
This is just one more reason why taking at least a standard multivitamin daily is a very
good idea. (And remember . . . I am NOT selling anything! ☺) For one thing, the
typically recommended levels of nutrients (RDAs and RDIs, etc.) are based on the
needs of the “healthy” population. They were never intended to address the needs of
people with serious health issues. The idea that a person should “just eat right” is no
longer reasonable based on literally thousands of scientific studies.
In fact, as described above, it is actually potentially harmful advice to discourage a
person from taking a standard multivitamin with minerals. Of course, a vitamin pill
does not make up for a poor diet. Many important nutrients are not even provided by
vitamin pills. A much more scientifically sound position today is: “Eat right AND take
a daily multivitamin with minerals.” These are not mutually exclusive goals.
A generous “B-complex” supplement (e.g. “B-100”) in addition to a “multivitamin with
minerals” may be helpful by raising the intake of vitamins B-6, B-12, folic acid and
biotin in particular. The levels of all B-vitamins are safe at this intake level. Avoid taking
more than one general “multivitamin with minerals” daily because the amount of iron,
zinc and vitamin A (as retinol) may be too high.
Foods to Eat Less Of:
Choose a diet generally low in:
• total fat and saturated fat,
• dairy products;
• meats that are smoked or preserved with nitrites. If you do eat cured meat, eat a
vitamin C-rich food with it to decrease the formation of “nitrosamines” that are
thought to contribute to cancer.
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Foods to Eat More Of:
Of the dietary fat consumed, generally choose fats rich in omega-3 fatty acids (flax and
especially fish) and high in PUFAs relative to other animal fat and saturated fat.
Supplemental EPA/DHA fish oil or flax oil capsules may be helpful, especially if fisheating is not desirable. The American Heart Association recommends eating fish twice a
week if one has NO risk of cardiovascular disease . . . no high cholesterol, no diabetes, no
family history, no smoking, etc. However, the higher than usual free radical
production and inflammation associated with MS are certainly cardiovascular risk
factors on their own. For people with some cardiovascular risk, a daily fish oil
capsule is suggested:
Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New
York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S.
AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular
disease. Circulation 2002;106:2747-2757
“Supplements that provide about a gram (1000 mg) of omega-3 fat daily can benefit persons
with cardiovascular disease. Higher dose (2–4 grams, or 2000-4000 mg) intakes appear to
greatly improve high triglyceride levels in particular. The higher doses (over 3 grams daily)
should be taken only with physician approval.”
For EVERYONE for MANY Reasons:
Assure a generous antioxidant intake relative to PUFAs. If a person has
MS, an even more generous intake of antioxidants is needed because of increased
free radical production. This increased need for antioxidant protection appears to be the
case in many other autoimmune conditions as well, such as diabetes. Be aware that a
“very low fat” diet naturally provides only minimal vitamin E as well. A good idea for
all: a separate vitamin E supplement providing 200 iu and a vitamin C supplement
that provides 200-500 mg. More may be added with a physician’s approval. Most
multi-vitamins will provide only the RDA value of 30 iu of vitamin E and 60-100 mg of
vitamin C. Again, the RDA levels, by definition, are based on the presumed needs of the
“healthy population,” so additional consideration of specific health problems associated
with MS often results in some departure from the RDA levels as a goal.
Aim for a generous intake of brightly colored fruits and vegetables.
These foods are rich in nutrients and low in calories. They also provide lots of protective
“phytochemicals” like lutein, lycopene, anthocyanins, carotenes, flavones, etc., which are
very potent antioxidants. Other antioxidants may also be found to be helpful with new
research (e.g. CoQ-10, new B-6 analogs, etc.)
Fourth:
Troubleshooting other nutrition pitfalls for the individual with MS:
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Watch for dysphagia problems in MS, and assure that manipulations of food texture do
not disrupt nutritional balance or add excessive calories. If eating becomes too difficult to
maintain nutritional status, consider a percutaneous gastrostomy as a tool.
Good nutrition helps prevent pressure ulcers; but if they develop, treat with aggressive,
supportive nutrition (especially generous protein and zinc, copper, and vitamin C.)
Check for potential nutrition interaction effects of all medications, and make
nutritional adjustments as necessary. This is not just a “take with food / don’t take with
food” issue.
Remember to consider body composition and activity level changes in assessment of
nutritional status and in making recommendations for calories, etc.:
1) weight:height ratio; 2) lean body mass-to-weight ratio; and 3) activity level..
Fifth:
Stay tuned for new information!
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A COLLECTION OF ANNOTATED REFERENCES AND PARTIAL
ABSTRACTSFOR THOSE WHO ARE INTERESTED:
---------------------------------------------------------------------------------------------------------------------------------
Vitamin D (2000-2007; selected annotated references)
2007
Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18. The objective of this review was to apply the risk assessment
methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D.
New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those
benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing
concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB
for vitamin D (50 mug, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing
research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the
establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on
relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy
adults that used vitamin D dose >/=250 mug/d (10 000 IU vitamin D(3)) supports the confident selection of this value as the
UL.
2006
Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. Prospective, nested casecontrol study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum
Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and
diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and
dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples
collected before the date of initial multiple sclerosis symptoms. Conclusion: The results of our study suggest that high circulating
levels of vitamin D are associated with a lower risk of multiple sclerosis.
IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis.
J Immunol. 2006 Nov 1;177(9):6030-7. Conclusion: Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving
hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a
similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuroprotective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an
environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.
Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases.
Anticancer Res. 2006 Jul-Aug;26(4A):2581-8. Extensive research on the CYP27B1-encoded 25-(OH)D-1alpha-hydroxylase has
contributed much to our understanding about how locally produced 1,25-(OH)2D3 exerts tissue-specific control of cellular growth,
differentiation and function. Because many types of epithelial, mesenchymal and immune cells express the 25-(OH)D-1alphahydroxylase, many organ functions are necessarily affected by changes in the activity of the enzyme. It is hypothesized that this is
likely to occur under conditions of hypovitaminosis D, i.e., at serum 25-(OH)D levels below 30 nM, because extra-renal 25-(OH) D1alpha-hydroxylase activity is critically limited by the availability of its substrate. This can provide an explanation, on a molecular
and cellular basis, for the many observations that significant associations exist between a compromised vitamin D status and
the pathogenesis of frequent chronic diseases. In addition to skeletal disorders, vitamin D insufficiency is a risk factor for
malignancies, particularly of the colon, breast and prostate gland, as well as for chronic inflammatory and autoimmune
diseases (insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis, etc.).
New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3.Ann N Y Acad Sci. 2006
Apr;1068:194-203. Vitamin D functions to regulate calcium homeostasis in intestine, kidney, and bone. Vitamin D deficiency during
bone development causes rickets and in adults vitamin D deficiency, which has been shown to be common in the elderly population,
can cause secondary hyperparathyroidism that can result in osteomalacia and increased risk of fracture. Recent evidence has
suggested that vitamin D can have numerous other physiological functions including protection against certain autoimmune
diseases, such as diabetes and multiple sclerosis and inhibition of proliferation of a number of malignant cells including breast
and prostate cancer cells. Exactly how vitamin D affects numerous different systems is a subject of continuing investigation. This
article will review new developments related to the function and regulation of vitamin D target proteins in classic vitamin D target
tissues that have provided novel insight into the mechanism of vitamin D action.
Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54.PURPOSE OF
REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental
factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the
association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and
suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior
Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis
and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence
rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk….
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The role of vitamin D in multiple sclerosis. Ann Pharmacother. 2006 Jun;40(6):1158-61.OBJECTIVE: To evaluate the literature
about the role of vitamin D in the prevention and treatment of multiple sclerosis (MS). DATA SOURCES: MEDLINE (1966-April
2006) and International Pharmaceutical Abstracts (1970-April 2006) searches were performed. In addition, pertinent references from
identified articles were obtained. Key search terms included vitamin D, 25-hydroxyvitamin D, vitamin D deficiency, and multiple
sclerosis. Data synthesis: Vitamin D supplementation prevented the development and progression of experimental autoimmune
encephalitis, an animal model of MS, in mice. A large, prospective, cohort study found that vitamin D supplementation was
associated with a 40% reduction in the risk of developing MS. Four small, noncontrolled studies suggested that vitamin D
supplementation may decrease exacerbation of MS symptoms. CONCLUSIONS: Vitamin D supplementation may help
prevent the development of MS and may be a useful addition to therapy. However, current studies are in small populations and
are confounded by other variables, such as additional vitamin and mineral supplementation.
Vitamin D and autoimmune disease--implications for practice from the multiple sclerosis literature. J Am Diet Assoc. 2006
Mar;106(3):418-24. Recent studies and commentaries link vitamin D with several autoimmune diseases, including multiple sclerosis
(MS). Adequate vitamin D intake reduces inflammatory cytokines through control of gene expression, thus inadequate vitamin D
intake is suggested as a mechanism that could contribute to inflammation and, consequently, development of MS. Poor vitamin D
status has been associated with increased risk for development of MS, and patients with MS may suffer consequences of vitamin D
deficiency, such as bone loss. Animal studies and very limited human data suggest possible benefit from vitamin D
supplementation in patients with MS. Based on the current state of research, a key principle for practicing dietetics
professionals is to include vitamin D status in nutritional assessment. For those at risk for poor vitamin D status, intake can be
enhanced by food-based advice and, when indicated, vitamin D supplementation.
[CB Note about the conclusion of the above citation – the “food-based advice” means that the vitamin D “should” be obtained
from milk, salmon and some tuna. . . as there are very few other food sources. Interesting to me is the tendency for health
professionals to be unaware of the fact that the vitamin D in milk is ADDED to it. It is not naturally rich in vitamin D. This
kind of advice (that people “should” take their supplemental D preferentially in the form of a liquid dairy product) is not
central to the fact that they simply must get enough vitamin D. Nutrition is not a religion . . . there are many ways to solve a
problem. It is now known that many people require 1000-2000 iu of vitamin D daily to assure adequate levels in their blood.
This is the amount provided by10 -20 cups of milk daily … clearly unreasonable and also poor nutrition as there would be
room for nothing else. .Even if the milk is skim, this is rather a lot of calories (900-1800) especially for people with MS, and it
obliges the displacement of other important foods. Clearly some supplemental vitamin D must be provided in a form other than
“vitamin D added to milk.” A multivitamin provides 400 iu of vitamin D. An additional amount can be obtained from an
inexpensive tablet (it comes in 400 iu, 1000 iu and 2000 iu and likely other strengths will become more common. It may also be
obtained from vitamin D fortified calcium pills (usually 200-400 iu) or as 100 iu per cup of milk. Please see my vitamin D
handout and “Top Five” handout for specific suggestions of many ways to be sure to obtain the right amount.]
The photobiology of vitamin D--a topic of renewed focus. Tidsskr Nor Laegeforen. 2006 Apr 6;126(8):1048-52. The sun is our
most important source of vitamin D. Exposure to solaria, in sub-erythemogenic doses, also gives large amounts of this vitamin. The
ultraviolet radiation in these sources converts 7-dihydrocholesterol to previtamin D3 in the skin. Furthermore, heat isomerization to
vitamin D3 takes place, then transport to the liver and hydroxylation to calcidiol, which is transported to the kidneys and hydroxylated
to the active hormone calcitriol. The vitamin D3 status of the body is supposed to be reliably imaged by calcidiol measurements.
Calcidiol levels above 12.5 nmol/l prevent rickets and osteomalacia, but optimal levels are probably higher, in the range 100-250
nmol/l. A daily food intake of 100-200 microg vitamin D3 (50-100 g cod-liver oil), or a weekly exposure to two minimal erythemal
doses of ultraviolet radiation (20 to 40 minutes whole body exposure to midday midsummer sun in Oslo, Norway), will give this level.
An adequate supply of vitamin D3 seems to reduce the incidence rates or improve the prognosis of several cancer forms,
including prostate, breast and colon cancer, as well as of lymphomas. Several other diseases are related to a low vitamin D3
status: heart diseases, multiple sclerosis, diabetes, and arthritis. The action mechanisms of vitamin D are thought to be mainly
related to its known cell-differentiating and immuno-modulating effects. Even though most of the 250 annual death cases from skin
cancer in Norway are caused by sun exposure, we should, in view of the health effects of ultraviolet radiation, consider modifying our
restrictive attitude towards sun exposure and use of solaria.
[CB note on the last sentence of the above citation: Perhaps a multivitamin would be a bit safer intervention to suggest rather than
ignoring the recognized risk of melanoma from sun exposure. It is also easier to do than the “weekly exposure to two minimal
erythemal doses of ultraviolet radiation (20 to 40 minutes whole body exposure to midday midsummer sun in Oslo, Norway,)”
especially for those of us who are shy about the whole-body exposure part.
Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8 … The active metabolite 1,25(OH)2D has an antiproliferative
effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is
important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a
role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the
active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many
genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. …
Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006
Sep;92(1):60-4 Autoimmune diseases like multiple sclerosis (MS) and inflammatory bowel disease (IBD) occur because of an
inappropriate immune-mediated attack against self-tissue. Analyses of genetically identical twins shows that besides genetics there are
24
important environmental factors that contribute to MS and IBD development. Vitamin D availability due to sunshine exposure or
diet may play a role in the development of MS and IBD. Compelling data in mice show that vitamin D and signaling through
the vitamin D receptor dictate the outcome of experimental MS and IBD. Furthermore, the evidence points to the direct and
indirect regulation of T cell development and function by vitamin D. In the absence of vitamin D and signals delivered through
the vitamin D receptor, auto reactive T cells develop and in the presence of active vitamin D (1,25(OH)(2)D(3) ) and a
functional vitamin D receptor the balance in the T cell response is restored and autoimmunity avoided.
1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental
allergic encephalomyelitis. J Neurosci Res. 2006 May 15;83(7):1299-309. … These findings highlight the fact that vitamin D
modulates JAK-STAT signaling pathway in IL-12/IFNgamma axis leading to Th1 differentiation and further suggest its use in the
treatment of MS and other Th1 cell-mediated autoimmune diseases.
Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol. 2006 Sep;92(1):65-79. Vitamin D
from ultraviolet-B (UVB) irradiance, food, and supplements is receiving increased attention lately for its role in maintaining optimal
health. Although the calcemic effects of vitamin D have been known for about a century, the non-calcemic effects have been studied
intently only during the past two-three decades. The strongest links to the beneficial roles of UVB and vitamin D to date are for bone
and muscle conditions and diseases. There is also a preponderance of evidence from a variety of studies that vitamin D reduces the
risk of colon cancer, with 1000 IU/day of vitamin D or serum 25-hydroxyvitamin D levels >33 ng/mL (82 nmol/L) associated with a
50% lower incidence of colorectal cancer. There is also reasonable evidence that vitamin D reduces the risk of breast, lung, ovarian,
and prostate cancer and non-Hodgkin's lymphoma. There is weaker, primarily ecologic, evidence for the role of vitamin D in reducing
the risk of an additional dozen types of cancer. There is reasonably strong ecologic and case-control evidence that vitamin D reduces
the risk of autoimmune diseases including such as multiple sclerosis and type 1 diabetes mellitus, and weaker evidence for rheumatoid
arthritis, osteoarthritis, type 2 diabetes mellitus, hypertension and stroke. It is noted that mechanisms whereby vitamin D exerts its
effect are generally well understood for the various conditions and diseases discussed here.
2005
Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis. Srp Arh Celok Lek. 2005 Dec;133
Suppl 2:124-8 The aim of our study was to investigate the immunomodulatory effect of alfacalcidol, a vitamin D analogue, on
cytokine levels in RRMS patients in relapse. … Result: Alfacalcidol therapy in RRMS patients did not provoke any side effects.
Vitamin D and its analogues, such as alfacalcidol, act as immunomodulatory agents, with potential therapeutic effects for
patients with multiple sclerosis.
Why we should offer routine vitamin D supplementation in pregnancy and childhood to prevent multiple sclerosis. Med
Hypotheses. 2005;64(3):608-18.... In areas of high MS prevalence, dietary supplementation of vitamin D in early life may reduce the
incidence of MS. In addition, like folic acid, vitamin D supplementation should also be routinely recommended in pregnancy.
Prevention of MS by modifying an important environmental factor (sunlight exposure and vitamin D level) offers a practical and costeffective way to reduce the burden of the disease in the future generations.
A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg
Psychiatry. 2005 Sep;76(9):1294-6. …Conclusions: Oral calcitriol is safe and well tolerated for up to one year by diet compliant
relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.
25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005 Jun;11(3):266-71.…We conclude that the
vitamin D stores in most MS patients are adequate for their normal bone metabolism. However, lower vitamin D levels during MS
relapses than in remission suggest that vitamin D could be involved in the regulation of the clinical disease activity of MS. The
optimal serum levels of vitamin D for the regulation of immune responses remain to be determined.
2004
Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med
(Maywood). 2004 Dec;229(11):1136-42. Low vitamin D status has been implicated in the etiology of autoimmune diseases such as
multiple sclerosis, rheu-matoid arthritis, insulin-dependent diabetes mellitus, & inflammatory bowel disease. The optimal level of
vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones.
Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. … This review discusses the
accumulating evidence pointing to a link between vitamin D & autoimmunity. Increased vitamin D intakes might decrease the
incidence & severity of autoimmune diseases and the rate of bone fracture.
Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J
Steroid Biochem Mol Biol. 2004 May;89-90(1-5):575-9. The physiologic range for circulating 25-hydroxyvitamin D3 [25(OH)D; the
measure of Vit. D nutrient status] concentration in humans & other primates extends to beyond 200 nmol/L (>80 ng/mL). This
biologic "normal" value is greater than current population norms for 25(OH)D. Concentrations of 25-(OH)D that correlate with
desirable effects extend to at least 70 nmol/L, with no obvious threshold. Randomized clinical trials using 20 mcg (800 IU) per day of
Vit. D show that this suppresses parathyroid hormone, preserves bone mineral density, prevents fractures, lowers blood pressure &
improves balance. Calcium absorption from diet correlates with 25(OH)D in the normal range. Health effects of Vita. D beyond
osteoporosis are mostly supported by the circumstantial evidence of epidemiologic studies & laboratory research. These include
prevention of cancer & the auto-immune diseases, insulin-dependent diabetes & multiple sclerosis. One mcg per day of Vit. D(3)
(cholecalciferol) increases circulating 25(OH)D by about 1 nmol/L (0.4 ng/mL). A recommended dietary allowance (RDA) is the
long-term daily intake level that meets the total requirements for the nutrient by nearly all healthy individuals (it would presume no
25
sunshine). If 70 nmol/L is regarded as a minimum desirable target 25(OH)D concentration, then current recommendations of 15 mcg
per day do not meet the criterion of an RDA.
Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004 Aug;58(8):1095-109. …The prevalence of MS is highest where
environmental supplies of vitamin D are lowest. … Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary
vitamin D(3) intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly
be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to
obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone
resorption, fractures, and muscle weakness.
Vitamin D intake and incidence of multiple sclerosis Neurology. 2004 Jan 13;62(1):60-5. … Dietary vitamin D intake was
examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed
from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). ... CONCLUSION: These
results support a protective effect of vitamin D intake on risk of developing MS.
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Annotated References / Abstracts for FATS
Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. This review summarizes
the knowledge of the role of dietary PUFAs, especially omega-3, on normal brain function. Furthermore, it reports the evidence
pointing to potential mechanisms of omega-3 fatty acids in development of neurological disorders and efficacy of their
supplementation in terms of symptom management.
Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis J Neurol Sci. 2006 May 15;244(12):123-6. Epub 2006 Mar 6. BACKGROUND: There is no good explanation why a proportion of patients with multiple sclerosis (MS)
have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the
disease course of MS. AIM: To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long
term dietary FA consumption, is different between patients with benign and progressive MS. METHODS: The erythrocyte membrane
FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary
progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS: No
significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found
between controls and patients with the different subtypes of MS. Conclusion: Our data suggest that factors other than dietary
fatty acid consumption are responsible for the different disease courses of MS.
Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. This article focuses on polyunsaturated fatty
acid (PUFA) supplementation, which is a popular form of complementary and alternative therapy among people with MS. Owing to
their popularity, clinicians should be knowledgeable about the PUFA supplements that are widely available, and the efficacy and
safety data from clinical studies. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA
supplementation is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant
caution. A review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials
are required to confirm the benefits.
Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot
Essent Fatty Acids. 2005 Nov;73(5):397-404. OBJECTIVES: To determine whether a low fat diet supplemented with omega-3
positively affects quality of life (QOL) in relapsing-remitting MS (RRMS) patients. In this 1-year long double-blind, randomized trial,
patients were randomized to two dietary interventions: the "Fish Oil" (FO) group received a low fat diet (15% fat) with omega-3 FOs
and the "Olive Oil" (OO) group received the AHA Step I diet (fat 30%) with OO supplements. The primary outcome measure was the
Physical Components Summary Scale (PCS) of the Short Health Status Questionnaire (SF-36). Additional measures using MS specific
QOL questionnaires, neurological status and relapse rate were obtained. RESULTS: 31 RRMS patients were enrolled, with mean
follow up over 9-14 months. Clinical benefits favoring the FO group were observed on PCS/SF-36 and MHI. at 6 months. Reduced
fatigue was seen on the OO diet at 6 months. The relapse rate decreased in both groups relative to the rates during the 1 year
preceding the study: mean change in relapse rate in the FO group: -0.79 +/- SD 1.12 relapses/year vs. -0.69 +/- SD 1.11 in the OO
group. This study suggests that a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients
on modifying therapies.
Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Multiple sclerosis
(MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal
demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative
stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary
intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular
antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental
allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may
support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein
expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their
incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the
potential to diminish disease symptoms by targeting specific pathomechanisms and supporting therapies.
26
Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs. 2006;20(6):433-41. Multiple sclerosis (MS) is an
immune-mediated disease, with inflammation and neurodegeneration contributing to neuronal demyelination and axonal injury.
Current therapies for MS are directed toward modulation of the immune response; however, there is increasing evidence that oxidative
stress is an important component in the pathogenesis of MS. The inflammatory environment in demyelinating lesions is conducive to
the generation of reactive oxygen species. When these species are generated in MS and animal models of MS, products such as
peroxynitrite and superoxide are formed that are highly toxic to cells. There are several examples of potential beneficial effects from
various antioxidants in animal models of MS, but the efficacy may vary between different agents and, in some instances, may yield
deleterious effects. Despite these promising results in animal models, there is limited and conflicting evidence of potential therapeutic
effects of antioxidants such as vitamins C and E in treating MS. However, clinical trials in MS patients with more potent
antioxidants, identified in animal studies, have been initiated.
Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via
suppression of glia-mediated inflammation. Curr Pharm Des. 2006;12(27):3521-33. Oxidative stress, in which production of highly
reactive oxygen species (ROS) and reactive nitrogen species (RNS) overwhelms antioxidant defenses, is a feature of many
neurological diseases and neurodegeneration. ROS and RNS generated extracellularly and intracellularly by various processes initiate
and promote neurodegeneration in CNS. ROS and RNS can directly oxidize and damage macromolecules such as DNA, proteins, and
lipids, culminating in neurodegeneration in the CNS. … We propose that combinations of agents which act at sequential steps in
the neurodegenerative process can produce additive neuroprotective effects. A cocktail of multiple antioxidants with antiinflammatory agents may be more beneficial in the prevention of neurodegenerative disease. A clearer appreciation of the
potential therapeutic utility of antioxidants would emerge only when the complexity of their effects on mechanisms that
interact to determine the extent of oxidative damage in vivo are more fully defined and understood.
Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Multiple sclerosis
(MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal
demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative
stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary
intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular
antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental
allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may
support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein
expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their
incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the
potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.
Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005 Feb;11(1):24-32. Lipoic acid (LA) is an antioxidant that suppresses
and treats an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. … We conclude that oral LA is
generally well tolerated and appears capable of reducing serum MMP-9 and sICAM-1 levels. LA may prove useful in treating
MS by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS.
Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune
encephalomyelitis. J Neuroimmunol 2002 Oct;131(1-2):104-14
Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Aug 24.…Both dietary antioxidants and
PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.
The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci. 2005
Jun;1051:88-96. … In this review we summarize recent progress in understanding the regulation and function of methallothioneins
during experimental autoimmune encephalomyelitis and MS. Ann N Y Acad Sci. 2005 Jun;1051:88-96.
Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during
experimental autoimmune encephalomyelitis. Neuroscience. 2005;132(4):1135-49. … suggest that metallothionein proteins are
implicated in the clinical recovery of EAE and perhaps these antioxidant proteins may provide therapeutic benefits in MS.
Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune
encephalomyelitis. J Immunol. 2004 Nov 1;173(9):5794-800. … We show that the major green tea constituent, (-)-epigallocatechin3-gallate (EGCG), dramatically suppresses EAE induced by proteolipid protein 139-151. EGCG reduced clinical severity when given
at initiation or after the onset of EAE by both limiting brain inflammation and reducing neuronal damage. …Because its structure
implicates additional antioxidative properties, EGCG was capable of protecting against neuronal injury in living brain tissue induced
by N-methyl-D-aspartate or TRAIL and of directly blocking the formation of neurotoxic reactive oxygen species in neurons. Thus, a
natural green tea constituent may open up a new therapeutic avenue for young disabled adults with inflammatory brain disease by
combining, on one hand, anti-inflammatory and, on the other hand, neuroprotective capacities.
Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004 Nov 1;78(3):362-70.
We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple
sclerosis (MS), relapsing experimental autoimmune encephalo-myelitis (EAE). … These data, coupled with its ability to treat
relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.
Protective effects of caffeic acid phenethyl ester against experimental allergic encephalo-myelitis-induced oxidative stress in
rats. Free Radic Biol Med. 2004 Aug 1;37(3):386-94. … Caffeic acid phenethyl ester (CAPE), an active component of honeybee
27
propolis, has been determined to have antioxidant, anti-inflammatory, antiviral, & anticancer activities. … Treatment with CAPE
significantly inhibited reactive oxygen species (ROS) production induced by EAE, & ameliorated clinical symptoms in rats. These
results suggest that CAPE may exert its anti-inflammatory effect by inhibiting ROS production at the transcriptional level through the
suppression of nuclear factor kappaB activation, & by directly inhibiting the catalytic activity of inducible nitric oxide synthase.
The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004
Mar;251(3):261-8.Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis
(MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as
mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model.
… treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological
outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or
reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on
the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as
investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake
together with other conventional treatments, might be beneficial in treating MS.
Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol.
2004 Mar;148(1-2):146-53.Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the
blood brain barrier. We tested whether alpha-LA is capable to prevent MOG35-55-induced experimental autoimmune
encephalomyelitis (EAE), an established model of multiple sclerosis (MS). … Our data indicate that alpha-LA can effectively
interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports
further studies on the use of alpha-LA as a potential therapy for MS.
Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of
oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003 Jun;139(1-2):27-35. Increasing evidence shows
that oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental
autoimmune encephalomyelitis (EAE).
Annotated References / Abstracts for Vitamin B12
Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006 Nov;5(11):949-60.
There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate
relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their
overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin
B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to
methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may
have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and
vascular dementia in elderly people.
Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood? Biofactors.
2006;26(1):45-57. The mechanism by which Vitamin B12 prevents demyelination of nerve tissue is still not known. The evidence
indicates that the critical site of B12 function in nerve tissue is in the enzyme, methionine synthase, in a system which requires Sadenosylmethionine. In recent years it has been recognized that S-adenosylmethionine gives rise to the deoxyadenosyl radical which
catalyzes many reactions including the rearrangement of lysine to beta-lysine. Evidence is reviewed which suggests that there is an
analogy between the two systems and that S-adenosyl methionine may catalyze a rearrangement of homocysteine on methionine
synthase giving rise to iso- or beta-methionine. The rearranged product is readily degraded to CH3-SH, providing a mechanism for
removing toxic homocysteine.
Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):189-92. BACKGROUND: There
is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been
observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased
in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients
with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary
progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12,
tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative
stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls
(10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical
subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and
controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or
TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine
occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a
deficiency in vitamin B6, vitamin B12, or folate.
Vitamin B12, demyelination, remyelination and repair in multiple sclerosis J Neurol Sci. 2005 Jun 15;233(1-2):93-7. Multiple
Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics.
Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS
may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent
studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory
and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and
28
suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for
supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.
Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12:
treatment to modify notch-1/sonic hedgehog balance. J Immunol. 2004;172(10):6418-26. Interferon-beta is a mainstay therapy of
demyelinating diseases, but its effects are incomplete in human multiple sclerosis & several of its animal models. In this study, we
demonstrate dramatic improvements of clinical, histological, & laboratory parameters in in vivo mouse models of demyelinating
disease through combination therapy with IFN-beta plus vitamin B(12) cyanocobalamin (B(12)CN) in nonautoimmune
primary demyelinating ND4 (DM20) transgenics, and in acute and chronic experimental autoimmune encephalomyelitis in
SJL mice. Clinical improvement (p values <0.0001) was paralleled by near normal motor function, reduced astrocytosis, and reduced
demyelination. IFN-beta plus B(12)CN enhanced in vivo and in vitro oligodendrocyte maturation. In vivo & in vitro altered
expression patterns of reduced Notch-1 & enhanced expression of sonic hedgehog & its receptor were consistent with oligodendrocyte
maturation & remyelination. IFN-beta-B(12)CN combination therapy may be promising for the treatment of multiple sclerosis.
Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by
blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003 Jun;9(3):239-45. Objective: The aim of
this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. Methods: We measured
serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid
(CSF) MMA and tHcy in 72 patients with MS and 23 controls. Results: The mean plasma tHcy level was significantly increased in
MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12
levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels
did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests
of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients
and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum
MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age.
Conclusions: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin
B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism
relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in
plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other
factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status
better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.
Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Nutr
Neurosci. 2003 Jun;6(3):189-96. Free radical-mediated peroxidation of biological molecules, especially of lipids, is implicated in the
pathogenesis of a number of diseases like multiple sclerosis. Low concentration of antioxidant vitamins: beta carotene, retinol,
alpha tocopherol and ascorbic acid have been observed in serum or cerebrospinal fluid of multiple sclerosis patients. On the
basis of these observations, we studied the potential lipoprotein oxidation and total antioxidant capacity in the pathogenesis of
multiple sclerosis. Lipoprotein oxidizability for plasma in vitro, serum levels of autoantibodies against oxidized low-density
lipoproteins, plasma total homocysteine levels with vitamin B12 and folate, and plasma total antioxidant capacity were measured in
twenty four patients with multiple sclerosis and twenty four healthy sex- and age-matched person as control. In multiple sclerosis
patients during an attack, a significant increase in both in vitro lipid oxidizability for plasma and in the levels of autoantibodies against
oxidized low-density lipoproteins, and a strong decrease in plasma total antioxidant capacity were detected. Plasma total
homocysteine levels were significantly higher in multiple sclerosis patients whose plasma vitamin B12 and folate levels were
lower but not statistically significant, than controls. The present study indicates that lipoprotein oxidation may be important
factor in the course of multiple sclerosis and in vitro measurements of plasma oxidation kinetics as an indication for
lipoprotein oxidation might be useful as an additional tool for the clinical diagnosis of multiple sclerosis.
Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical
importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses. 2002 Nov;59(5):594-602. In a
randomized, placebo-controlled double-blind trial a combination of lofepramine, phenylalanine and vitamin B(12) was found to
be effective in relieving the symptoms of multiple sclerosis (MS). The effect occurred within 2-4 weeks, and improved all types of
symptoms in all types of MS. The combination was also effective in relieving symptoms in patients with chronic pain and chronic
fatigue. We hypothesize that the action of this combined therapy may relate to activation of the noradrenergic locus coeruleus/lateral
tegmentum (LC/LT) system which has the potential to influence the functioning of large areas of the brain and spinal cord.
A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder
regime") in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):246-9 OBJECTIVE: To determine
whether combination therapy with lofepramine, L-phenylalanine, and intramuscular vitamin B-12 (the "Cari Loder regime") reduces
disability in patients with multiple sclerosis. METHODS: A placebo controlled, double blind, randomised study carried out in five
United Kingdom centres on outpatients with clinically definite multiple sclerosis, measurable disability on Guy's neurological
disability scale (GNDS), no relapse in the preceding six months, and not on antidepressant drugs. Over 24 weeks all patients received
vitamin B-12, 1 mg intramuscularly weekly, and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily, or matching
placebo tablets. Outcome was assessed using the GNDS, the Kurtzke expanded disability status scale; the Beck depression inventory,
the Chalder fatigue scale, and the Gulick MS specific symptom scale. RESULTS: 138 patients were entered, and two were lost from
each group. There was no statistically significant difference between the groups at entry or at follow up. Analysis of covariance
suggested that treated patients had better outcomes on four of the five scales used. Both groups showed a reduction of 2 GNDS points
within the first two weeks, and when data from all time points were considered, the treated group had a significant improvement of 0.6
GNDS points from two weeks onwards. CONCLUSIONS: Patients with multiple sclerosis improved by 2 GNDS points after
starting vitamin B-12 injections. The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit. More
research is needed to confirm and explore the significance of this clinically small difference.
29
Sanford Medical Center
2011
Aunt Cathy’s Guide to Nutrition:
The Prader Willi Syndrome
Association’s Food Guide
Pyramid for Weight Control
(with some editorial
comments from me)
Cathy Breedon PhD, RD, CSP, FADA
Clinical/ Metabolic Nutrition Specialist
and Pediatric Nutrition Specialist
Sanford Medical Center, Dept. of Pediatrics
University of North Dakota School of
Medicine, Dept. of Pediatrics, Fargo, ND
Introductory comments from CB:
Children with a genetic condition called Prader Willi Syndrome usually struggle with
their weight all of their lives. They appear to use up fewer calories each day, so just eating
“normally” can still cause them to gain weight extremely fast. Losing weight is extremely
difficult. The following is a 2003 Food Guide Pyramid that was designed for people with PWS,
but potentially useful for any people with very low calorie requirements (such as people whose
movement is impaired.) This pyramid has some helpful ideas (especially the suggestion to place
vegetables as the “base” of the pyramid instead of the grains and cereals food group in the
“regular” USDA Food Guide Pyramid.)
In addition to calorie concerns, however, I am very concerned about assuring that
micronutrients (vitamins and minerals) and protein are provided in appropriate amounts
in spite of the decreased total food intake. There are some other serious concerns as well.
Unfortunately, there are some problems in that area in the 2003 Prader Willi Food Guide
presented below. As it appears to continue to be used in practice in spite of these important
issues, I have taken the liberty of interjecting my thoughts on this issue as you look over this
otherwise helpful way of adjusting the base of the pyramid.
My comments are clearly delineated from those of the PWS Pyramid designer
(Beverly Ekaitis, DTR, registered dietetic technician) by brackets [ ] and by bold print.
1
Start of the original 2003 article:
________________________________________________________________________________________
Prader-Willi Syndrome Association (USA)
A PRADER-WILLI FOOD PYRAMID
by Beverly Ekaitis, DTR, dietetic technician The Children's Institute of Pittsburgh (TRI)
PWSA Editors’ Note: The USDA’s Food Guide Pyramid provides an appealing graphic tool
for thinking about a day’s food portions, but it simply adds up to too much food for someone on
a Prader-Willi diet.
We asked the Children's Institute if they could adapt the new pyramid to the typical PW diet
for families that might wish to use it as an alternative to the Exchange System, the Red-YellowGreen (Stoplight) Diet, or other methods of counting calories.
The Institute was glad to oblige but urges those who have been through the Institute’s
program to continue using the Red-Yellow-Green Diet that they learned there. The Prader-Willi
Food Pyramid that follows may not be appropriate for young children or for those on growth
hormone therapy, and it should not be considered a substitute for individualized dietary
guidance. Dietary guidance preferably should come from a nutritionist who is familiar with
PWS.
2
The Food Pyramid Guide to Daily Food Choices, designed by the U.S. Department of
Agriculture for adults who need 1,600 to 2,800 calories a day, represents the relative portions of
foods to eat each day to maintain a healthy weight and body. To make the Food Pyramid usable
for people with Prader-Willi syndrome, a few changes have to be made.
CB note :
It is potentially useful for others with very low caloric requirements as
well, with the same caveats described below.
The first change needed is to adjust the number of daily servings for each food group in
order to reduce the total calorie level to 800 to 1,200 a day. These lower levels will provide for
weight loss or maintenance for the adult or teenager with PWS, whose calorie needs are about 60
percent of those without PWS.
CB note:
Actual calorie goals for PWS and non-PWS individuals will vary
considerably. Also, when establishing such a low calorie goal, consider
that the daily values and other guidelines are usually based on a 2000
calorie diet. It is important to remember that such low calorie levels will
invariably be inadequate in a number of nutrients unless careful
supplementation is done. Failure to replace these nutrients is not benign.
Second, although the five main food groups—bread, vegetable, fruit, meat, and milk—remain
the same, the positions of two of the groups need to be changed on the pyramid to reflect a
change in the recommended number of servings. Each group has a specific number of servings
that determines its position on the pyramid.
The Food Groups
The first USDA Food Pyramid (which had horizontal lines) has a base of the Bread group,
which would provide the highest number of daily servings. The PW Pyramid, on the other hand,
has as its base the Vegetable group, with 6-8 servings a day. For those familiar with the RedYellow-Green Diet, these would be "GO" foods, i.e., foods low in calories and fat. Making the
vegetable group the base of the pyramid and the bulk of the diet will allow a large volume of
food to be eaten without many additional calories.
3
The Bread group, which includes cereal, pasta, and rice, moves up the pyramid with a
decrease in number of servings to three to five per day. We would also include starchy
vegetables like corn, peas, and potatoes in this group because they have the same amount of
calories per serving as breads.
CB note:
Try to use whole grains and foods that are naturally high in fiber
whenever able to improve the micronutrient content of the diet (especially
magnesium, chromium and natural forms of vitamin E) and to decrease
the potential for insulin resistance problems.
(See my “Magnesium” and “Top Five Recommendations” handouts for more on this.)
The Fruit group includes fresh fruit, canned fruit, juice, and dried fruits. Many people think of
fruit as a "free" food. While it is a good snack and a good source of fiber and vitamins, it does
have calories that should be counted if one is on a restricted diet. The daily servings should be
four—one at each meal and one for snack.
CB note:
Choose whole fruit as much as possible instead of juices. If you use canned
fruit the juice-packed or water-packed are preferred over syrup-packed
products. Liquid carbohydrate calories consumed may be less well recognized
as calories consumed by the body of some individuals, and so additional
calories may be accidentally taken in. Excessive juice and “regular” pop
consumption is suspected of being contributory to increased weight gain in
children in general.
The Milk group includes yogurt, milk, and cheese. To fit the needs of the person with PWS,
the servings per day should be two, and the products chosen should be nonfat or low in fat. Fatfree, sugar-free frozen yogurt also can be used as a milk serving.
CB note:
Be sure to provide additional calcium and vitamin D, as the amount
provided by the serving number shown here is clearly inadequate for optimal
health. MANY people (and over-weight individuals in particular) have been
shown to require an intake of vitamin D well above the present RDA level.
Now that blood levels are beginning to be checked more often, the very large
number of people with inadequate vitamin D levels in their blood is being
4
identified, and inadequacy is now recognized as being very detrimental to
heart health, muscle function, immune system function, prevention of cancer,
autoimmune disorders, osteoporosis and bone pain More on vitamin D will
be discussed later.
Back to the specifics of the Pyramid:
Note that the two cups of milk suggested will provide only 200 iu of
vitamin D, but PWS individuals should be provided with at least 2000 iu
daily simply to maintain levels associated with optimal health. Even more
may be shown to be needed for individuals. Also, the 2000 iu is a
maintenance level, not a level to treat deficiency, which could be much more
than that.
Most cheese, yogurt and other dairy products do not provide any
vitamin D at all … and if some has been added in certain brands, it is still at
the same too-low amount as is added to milk (i.e. 100 iu/cup.)
Vitamin D deficiency is extremely common, generally unrecognized, and
contributory to increased risk of cancer, muscle weakness, muscle pain, heart
disease, MS, arthritis, diabetes, compromised immune function and more. It
is now being described as an “unrecognized epidemic.”
People who are overweight have an additional risk of vitamin D
deficiency. A good plan would be to check the vitamin D level in the winter
and if deficiency is found, the physician would then order a special high-dose
catch-up amount (a “therapeutic dose”), which would be followed by an
intake equivalent to at least a 2000 iu/daily maintenance level. One example
of a therapeutic dose is 50,000 iu/week for 8 weeks, followed by a re-check
and sometimes another round of that level of supplementation.
The serum level that is associated with optimal health is 40 iu; the older
lab sheets say that 25 is the lower end of normal, but that level has been
shown to be insufficient for some of the known functions of vitamin D, such
as cancer prevention and muscle strength.
People with PWS have several additional risk factors for deficiency that
lead me to recommend that it would be wise to get a vitamin D level
measured annually in the winter (the lab to order is the “25-hydroxy vitamin
D” measurement.)
(See my “Top Five Recommendations” handout for more information on vitamin D)
The Meat group includes meat, fish, poultry, eggs, peanut butter, and cooked dried beans.
The USDA also includes nuts in this group, but due to their high fat content they should be
eliminated from the PW Pyramid.
5
CB note:
Although nuts and peanut butter are higher in calories than some foods,
they are also quite nutrient dense and they are among the richest source of
dietary magnesium, a mineral that is often low in American diets, and which is
extremely metabolically important.
In children and adults who are significantly overweight, magnesium may
make a difference between whether or not one goes on to develop insulin
resistant (type 2) diabetes. Additionally, magnesium inadequacy can contribute
to obesity itself by making it hard to convert fuel from food into usable energy.
(See “Magnesium” handout and “Top Five Recommendations” handout.)
The fat in nuts and legumes is of the more “heart friendly” type – rich in
the type of fat called “monounsaturated” fat. Also, although fat has more
calories per ounce than carbohydrate or protein, it is useful to note that in nonPWS individuals a more generous fat content per se does not seem to be
associated with increased fatness or decreased weight loss as long as one stays
within the target caloric level.
However, people with PWS appear to have difficulty doing anything with
the fat they eat except store it. Restricting the proportion of calories from fat is
reasonable, but as is discussed later, there are ways to help them use the fat
more normally. In that situation, restricting fat specifically would become a
much less important goal. Similarly, limiting consumption of fat does not
prevent the production of fat from extra calories taken in from protein
carbohydrate.
Nuts and peanuts also provide protein and the protein and fat content both
contribute to a sense of satiety for most people. It helps them not get hungry
again so soon, and it has been shown to be true for many other groups of people
who are trying to “watch calories.” Whether this is true for people with PWS is
not known … it appears that the drive to eat is controlled by a different
mechanism than the sense of satiety associated with stomach fullness, as
described below.
And the USDA suggests two to three meat servings per day of 2½-to-3-oz. portions. To
decrease the calories for the PW meal plan, we changed the portion size to 2 oz. and suggest
one to two servings a day. This means that a person on 800 calories could divide the 2 oz.
serving to provide 1 oz. at lunch and 1 oz. at dinner, and a person on 1,200 calories could
have 2 oz. at lunch and 2 oz. at dinner.
6
CB note :
Dried beans and peas –kidney beans, navy beans, lentils, split peas, etc. –
are terrific foods for people with weight problems. They are generous in
magnesium, chromium and many other nutrients that help us use our calories
appropriately, and they are also low in fat and high in fiber. They are a good
source of protein, they are ‘filling,’ and their carbohydrate is in a form that has
a low ‘glycemic index.’
Diets based on ‘low glycemic index’ foods appear to result in more weight
loss than a “low fat” diet even when both diets provided the same number of
calories. However … as before … these observations may not be that useful in
coping with the metabolic problems of people with PWS.
However, it may be helpful to people with PWS as well if it results in fewer
episodes of elevated blood sugar after eating, perhaps by avoiding excessive
stimulation of insulin. Hyperinsulinemia itself can be contributory to excessive
weight gain.
It is also reasonable to provide 1000 mg fish oil daily or to eat “fatty fish”
twice weekly (as is recommended for everyone by the American Heart
Association.) There are many reasons for this … please see my Top Five
Recommendations paper for more general explanation. The reason it would be
particularly reasonable in PWS is because missing part of a chromosome (or
other metabolic conditions like diabetes) can affect production of many things
we usually make for ourselves, such as the omega-3 fats EPA and DHA.
These fats have many special roles in health, including eye health, brain
development and decreasing inflammatory conditions. The ready-to-go form of
EPA and DHA is in fish oil. The caloric contribution is very small compared to
the health benefit. I standardly recommended it for all the children I work with
who have metabolic problems … and also for all those who do not have any
particular health problem. I take it myself and make my husband take it too.
One additional caveat is that some people with PWS develop Type II diabetes
and may be put on the medication Metformin/Glucophage. This medication has
been shown to cause significant impairment of vitamin B12 status, which can
cause neurologic injury. I recommend that anyone on this medication be
monitored with an annual vitamin B12 level.
Note that if the level is dropping even though still in the normal range, it
suggests that they are using up stored vitamin B12 and are likely to develop
deficiency even if it is not seen now. [Mean cell volume is a very late-appearing
symptom of vitamin B12 deficiency. The changes in cell size occur because the
person is no longer able to make DNA adequately … this should not be used as
a screening test.]
If generous oral vitamin B12 does not correct the problem, consider a
vitamin B12 shot to bypass the intestinal impairment of vitamin B12 absorption
7
that is associated with use of this medication. Vitamin B12 deficiency is very
dangerous. I have found it in several adolescents with PWS who were new to
our clinic and whio had never had it evaluated.
[Please see my “Vitamin B12” handout or my “Other Nutrition Issues in
Diabetes” handout for more detail on this phenomenon, and some other
monitoring issues.
Serving Sizes
Except for the meat group, the serving sizes on our PW Pyramid are unchanged from the
USDA Food Pyramid. They are as follows:
Vegetable: ½ cup cooked or 1 cup raw
Bread: 1 slice bread; ½ C. rice, pasta, or starchy vegetable; 1 oz. Cereal
Fruit: ½ C. canned, ½ C. or 1 piece fresh, 1/4 C. dried; ½ C. juice
Milk: 1 C. skim milk or lite yogurt, 1 oz. cheese, ½ C. frozen fat-free sugar-free yogurt
Meat: 2 oz. cooked lean meat, fish, poultry; 1 egg; ½ C. cooked dried beans; 2 T peanut butter
Fats, Oils, and Sweets
The top of the USDA Pyramid shows fats, oils, and sweets. These are denoted by symbols
that are concentrated in this area and dispersed throughout the other groups. The USDA
suggests that these foods be used sparingly to add extra calories. These foods include butter,
margarine, regular dressings, candy, sugars, sweets, fatty desserts, gravy, and fried foods, to
name a few. The foods from this group add unwanted calories and few nutrients to the PraderWilli diet. They should be limited to once a month for an 800-calorie plan and once a week
for a 1,200-calorie plan. We have deleted the fat symbols throughout the PW Pyramid,
because all foods chosen should be low in fat and sugar.
Using this modified pyramid as a guide to weight loss and maintenance, in conjunction with a
favorite exercise program, can be an easy way to ensure a healthy, nutritious diet for the
person with Prader-Willi syndrome.
CB note:
Following this plan will result in very poor micronutrient balance
unless a number of vitamins and minerals are supplemented.
This includes inadequacies of many nutrients that are not included in a
standard multivitamin with minerals.
8
Another extremely important consideration is that is that there is clearly a
metabolic component to weight issues in Prader Willi Syndrome. They are not
being “piggy” or “lazy.” Something in their bodies is not working right and they
are trying desperately to compensate for it … with predictable results:
The well-recognized features of PWS include an intense drive to eat even
when allowed to consume a very generous amount of food. Additionally, they
often accumulate very generous body fat, and they tend to have hypotonia (low
muscle tone) and very poor exercise endurance. These features of the syndrome
make it necessary to look at more than severely cutting their calories and
pushing for increase physical activity in an effort to avoid fatness.
Restricting calories does not help the drive to eat at all, nor does it truly
solve the excess fat accretion or muscle issues. This collection of symptoms can
often reflect a metabolic problem that requires the person to be provided with a
substance called carnitine, and our experience with children who have received
carnitine supplementation has borne this out. Carnitine is normally made in
ample amounts in one’s body, but there are a number of situations in which it is
not made in normal amounts, or in which a person has much higher than usual
needs. In a nutshell, carnitine has an important role in one’s ability to burn fat
for fuel.
Failure to efficiently burn fat for fuel means that fat will be stored but then
it is unable to be made available for use as fuel. That means that for practical
purposes, the fat consumed with a meal and the fat already stored in the body do
not contribute to the job of running a person’s body.
One’s brain then makes “getting some fuel” an extremely high priority …
hence the intense food-seeking behavior even in the presence of clearly generous
energy stores and a generous amount of food eaten.
Maintaining normal muscle tone also requires carnitine because muscles
preferentially burn fat for fuel, especially in endurance activities. Muscle
weakness and poor exercise tolerance result from inability to burn fat fuel
normally, which then impairs the pursuit of the physical activity encouraged as
part of a weight management program. Further, the heart is a muscle …
cardiomyopathy and hypotonia (low muscle tone) is often associated with
carnitine insufficiency.
When health care professionals only focus on the caloric restriction issue,
they contribute to big problems for families. They often put the responsibility
for preventing obesity on the shoulders of the caretakers with messages like “It’s
your job to just tell her ‘no’ when she wants more food.”
Consider that when health professionals say this kind of thing, they are
asking a parent to consistently refuse food to a child who is begging and pleading
for it.
9
Imagine the hungriest you have ever felt, and then imagine that people with
PWS feel that way all the time. They experience intense discomfort from hunger
… cutting their food intake down to half the amount other people get to eat does
not solve this problem. It may prevent obesity to some degree, but it makes their
discomfort worse and it can have a very negative on behavior and relationships.
One promising non-nutritional intervention is the use of growth hormone.
There are nutrition-related substances under investigation as potentially helpful
in muscle operation in PWS as well, such as CoQ-10. In our clinic, we have seen
tremendous benefit to individual babies and children from the combination of
growth hormone, carnitine and CoQ-10. It has worked better in combination
than with the (already standardly used) growth hormone therapy alone. The
metabolic adjustment seems to make that expensive growth hormone more
effective.
The benefits include better lean body mass, BMI or weight-for-length, and
muscle tone. It has significantly improved the classic intense food-seeking
behavior. Severely hypotonic babies who started the carnitine and CoQ-10 upon
diagnosis in the nursery have been able to suck well enough to go home without
the gastrostomy tube placement often needed in early life. They move more
vigorously.
There is a lot more to learn, but the carnitine and CoQ-10 are very safe and
very promising in some reports and small studies for children with PWS and
other serious medical conditions with metabolic derangements. But large-scale
long-term randomly-assigned prospective studies will take a long time to get.
For that reason the use of carnitine and CoQ-10 in this application is not the
official recommendation of large medical groups yet.
Please note that I do not sell anything nor do I have any relationship with
manufacturers of these substances. Additionally, I never go ANYWHERE near
“scary” in my recommendations. But if it were MY child who had PWS I would
surely do a trial on these substances while we await the long-term large research
studies that are always needed. There are supportive preliminary reports in the
scientific literature, and also anecdotal information from parents and from
people like me who follow patients with PWS. For any particular child it will
either help or it won’t, and I think it is certainly worth a trial. Stay tuned!
Summary about the use of the PWS Pyramid:
The PWS pyramid above is a reasonable starting place for approaching a
weight problem in general … it illustrates a simple way to identify the food
groups with various calorie levels. However, the individual who put it together
was a well-intentioned registered dietary technician and not a registered
dietitian or licensed nutritionist. She was essentially only addressing the issue of
calories, as she had been requested to do.
10
This discussion is not a criticism of her … she would not be expected to be
aware of the other complex issues of nutrient inadequacy and metabolic
disturbance such as those described above. She was asked to help with
arranging a pyramid by the calorie content of food groups and she did that
nicely.
However, as pointed out in the boxes above, there are many other issues
besides calories and weight in PWS. There is the potential for doing great harm
by just cutting calories back when these other issues are not corrected.
It is very important that the nutrition regimens of people with PWS be
carefully evaluated by a health professional familiar with these problems.
11
MeritCare Medical Center
Aunt Cathy’s Guide to Nutrition:
2010
Why Are Children with Chronic
Illnesses or Handicapping
Conditions at High Risk of
Receiving Suboptimal Nutrition?
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Pediatric and Clinical Nutrition Specialist,
MeritCare Medical Center, Dept. of Pediatrics &
UND School of Medicine Dept. of Pediatrics
Fargo, ND
A Quick Overview of Reasons:
1) Some children have higher than usual needs for energy (calories)
Sometimes this is because of the increased effort required for breathing in children
with broncho-pulmonary dysplasia or congenital heart defects, or because of being
especially physically active. Some children need to continually heal wounds. At the same
time, they may have decreased ability to take food because of the effort required to eat
or because a fluid limit is imposed. As a result, they often fail to grow optimally. Their
intake of vitamins, minerals and protein can also be compromised, leading to: poor
immune function, inadequate energy to explore and learn, poor skin integrity and wound
healing and other problems.
Increasing the calories of formulas usually involves concentrating the product to
make a higher caloric density. For example, using only 9 oz of water instead of the usual
13 oz when preparing a 13 oz can of infant formula concentrate will make the formula
have 24 calories per ounce instead of the usual 20. The nice thing about this approach is
that it provides ALL nutrients in higher amounts (not just calories,) it does not distort the
ratios of nutrients per calorie, it contributes no additional cost, and it is safe to use.
Sometimes fat or carbohydrate calories will still need to be added, but these should
generally be used only to add calories beyond the 24-26 calorie per ounce concentration.
How to increase calories beyond the 24-26 calories per ounce should be determined with
the help of a person familiar with these issues, as there are sometimes important reasons to
use one additive over another in a particular child’s case.
Many of the substances added to foods or formulas to add calories can seriously
distort the nutritional balance unless the protein, vitamins and minerals are carefully
adjusted. For example, corn syrup, sugar, glucose polymers (like “Polycose ®” by Ross),
butter/margarine, cream, regular vegetable oil, MCT oil ® (Mead Johnson/Novartis), and
emulsified fat products like Microlipid and Intralipid all have one thing in common. They
all just add empty calories. In small amounts there is no concern, but if a significant
percentage of the child’s calories is contributed by these products there is potential for
distorting the ratio of calories relative to the nutrients needed to metabolize them.
1
Some children will have higher needs for all nutrients in addition to calories. In
this situation it is important to recognize that just adding protein and/or calories will not
work well in the absence of the critically important vitamins and minerals that the body
needs to convert fuel (calories) to make usable energy, and or to construct tissues. This is
key in conditions that require extra production of tissue, such as wound healing and
increased need for immune system activity. Failure to assure adequacy of micronutrients
can make other efforts unsuccessful.
Unfortunately, this issue often does not get the attention it deserves and it is not
uncommon for children to be given protein-only supplements without assuring
adequacy of the necessary vitamins and minerals to use the protein. Also, giving just
protein in the absence of adequate calories will result in the protein being burned as an
energy source instead of using it for construction. Most nutrients have many important
roles, some of which will be described further a bit later.
One should keep in mind that the usual recommended amounts of calories and
nutrients such as the RDAs or RDIs or AIs are based on the needs of “most healthy
people.” They do not address the needs of people with illness or other health conditions.
The health care professionals will need to think through the particular challenges of a
child’s situation and make adjustments in goals accordingly.
A good example is zinc, a mineral needed in over 200 different places in a
person’s body. Every time we try to make a new cell, we need zinc to make the DNA in
the center of it. That means that people who need to make a lot of new tissue will
need a more generous intake of zinc. Poor zinc status impairs growth in children, and it
limits the ability to heal wounds – another situation that requires a lot of new tissue
formation. Recovery from wounds and staying healthy in general also depend on zinc
because the production of T-cells of the immune system is very dependent on adequate
zinc. At the same time, excessive amounts of zinc can cause problems. Determining the
right amount requires a close look at the individual’s situation.
A generous intake of vitamin B12 and folic acid (another B vitamin) is also required
for making DNA (for making all cells) and in particular for making new red blood cells.
Sometimes anemia is not caused by inadequate iron but by a relative inadequacy of
these nutrients, or others (like vitamin E) that are needed to keep red blood cells
from being broken apart too soon. Vitamin C helps protect the white blood cells of the
immune system to let them live longer to keep on killing germs. Vitamin C and copper
are also players on the team that lets us build connective tissue for wound healing, and
both are also required to use iron in the body.
And on and on. These are just a few of many examples of the critical role played by
vitamins and minerals in health, and why this aspect of children’s nutrition cannot be
ignored. For some specific additional information, please see my handouts on MeritCare’s
website (www.meritcare.com) on folic acid, vitamin B12, magnesium, chromium, vitamin
D, copper, zinc and iron. Just type my name in the key word box and then click
“handouts.”
2
Another issue is cost. The “regular food” items are many times cheaper than the
commercial additives. For example, consider fat additives commonly used: MCT oil ®
is about $1 an ounce ($65 per quart) and the calories are about 5 calories less per teaspoon
than most food fats. The advantage of using emulsified products is that they are better at
staying mixed into formulas. But unless that is a major problem, it is useful to know that
they are even higher in cost.
This is because they are primarily designed to be used in i.v. feedings. Microlipid ® is
88 cents per oz, but has only half the calories of other fats so you need to use twice as
much. Compare these with the cost of canola oil (a good choice for a general vegetable
oil.) Some other issues about the use of particular forms of fat will be discussed later.
Protein additives are also much more expensive than excellent quality protein in
foods. At about 7 g protein per egg, egg protein costs about a penny a gram and it
contains some additional nutritional value like choline and biotin. A can of “Resource
Beneprotein ®” provides about 192 g protein per can (as whey protein,) and I found prices
on line of $13-$15 per can, purchased as a case of 6 cans. That means that it can cost
anywhere from 6.5 to 7.8 cents per gram of protein, or 6-8 times as much as egg protein.
The liquid pasteurized “no yolk” egg protein products available in grocery stores are
more expensive than eggs, but cheaper than special additive products. “EggBeaters ®,” for
example, provides 6 g protein per ¼ cup. They have the advantage of being pasteurized so
they can be added to foods that are not intended to be cooked, such as a smoothie or
eggnog, or in a tube feeding. Powdered milk is another very inexpensive product, with 1.5
g protein per tablespoon, and some calcium and other nutrients provided with it.
Glucose polymers (such as “Polycose ®” by Ross) are simply starch in solution and
they have no advantage over regular food carbohydrates like sugar or food starch.
They are designed primarily as a carbohydrate that can be added to beverages without
adding a sweet taste. There is usually no reason to avoid sweetness in children’s feedings.
The risk of tooth decay is identical because any carbohydrate fed orally is food for
bacteria in the mouth. The main factors that increase risk of tooth decay are frequency of
carbohydrate-containing feedings and contact time of carbohydrate with the teeth.
Whether the carbohydrate is in the form of sugar (mono- or di-saccharides) or starch
(polysaccharide) appears to make little difference.
Similarly, there is not a significant difference in osmolality (the number of particles
per amount of fluid) because the starch is digested very promptly to the sugars maltose
and glucose once it reaches the small intestine. That means that it is not less likely to
contribute to loose stools.
There is no danger of causing a “sweet tooth” to be developed in the child. Children
just come that way . . . human milk is sweet and it is all part of the design to make babies
want to nurse. I have found that using regular table sugar can often make many foods and
formulas more palatable for children, and therefore it is more effective because they eat
more. And, of course, the dental and sweet tooth concerns are even less of a concern when
the child is fed through a tube instead of orally.
3
A teaspoon of sugar weighs 4 grams and adds
16 “empty calories” from carbohydrate;
A teaspoon of glucose polymer products weighs 2 grams and provides only
8 “empty calories” from carbohydrate.
That means you need only half as much sugar to get the same calories. A 12.3 oz (350
grams) can of a glucose polymer product costs about $8.30 from one of the cheapest online sources. Compare that with table sugar. Nutritionally and calorically they are the same.
In most circumstances there is no need to use these expensive special products at
all. MCT oil ®, for example, is designed for special needs related to certain liver diseases
or intestinal malabsorption problems such as Cystic Fibrosis. It is often inappropriate for
other uses because besides being very costly, it is all saturated fat (from coconut oil) and
so it provides no “essential” fats or any omega-3 and omega-6 polyunsaturated fats at
all . . . just calories. I have found that using regularly available food products also has the
psychological advantage of “de-medicalizing” at least one part of the child’s care.
Sometimes health care professionals are not familiar with these issues, because
they have to know so much about everything else. So, it might be beneficial to show
this paper to them if these very costly products are suggested in order to use them only
when regular carbohydrates and fats available at the grocery store will not do. And in
addition, remember that just adding fat or carbohydrate calories or just protein from
any source will contribute no other nutrients and so should be used as a small part of
the child’s higher calorie feeding regimen.
And finally, it may be necessary to use other feeding routes in order to achieve
appropriate growth and the best possible health. This may involve feeding through a tube from
the nose to the tummy (an NG tube – a “naso-gastric” tube.) Sometimes tubes are placed through
the skin to go directly into the tummy. They are called a PG tube, a PEG tube, or other variations.
PG stands for “Percutaneous” (through the skin) “gastrostomy” (through an opening into the
stomach.) Sometimes it is positioned into the jejunum of the small intestine instead. The health
care professionals will know the benefits and problems associated with using one approach over
another for a particular child.
At times it may be necessary to feed the child through the veins (i.v.) and bypass the usual
feeding route completely. This is called TPN (Total Parenteral Nutrition”) or some variant.
Sometimes it is called PPN (Partial Parenteral Nutrition) if it is used to supplement a feeding that
uses the intestines. [The word “enteral” means using the intestines; “parenteral” is short for “para
enteral,” which means the feeding route is outside of or along side (but not by way of) the
intestines.] This kind of feeding is not done if the stomach and intestines are able to be used well
enough to meet the child’s nutrition needs.
4
2) Some children have physical eating problems.
Poor head control, chewing, swallowing, mouth control, or mouth sores, etc., can also lead
to poor nutrition. Children may receive an inadequate intake because of the time and effort
required to eat even a small volume of food. Sometimes they get enough calories but inadequate
protein, vitamins and minerals because of textural manipulations that can seriously limit the
amount and variety of foods eaten.
Children with neurologic injury (such as cerebral palsy) may continue to struggle with infant
feeding reflexes that do not fade away. “Tongue thrust” is an example of the reflexive pushing
of food out of the mouth. Poor lip closure, an excessive or absent gag reflex, a “bite reflex,”
and dental problems (such as “malocclusion” and difficulty providing appropriate dental
care) are other common problems that make oral feeding difficult. Unfortunately, careful
analysis of the diet is often not undertaken and the diet is assumed to be appropriate and
adequate as long as some food is found that can be easily/safely fed and the child’s weight seems
to be adequate.
For some neurologically impaired children with unrecognized dysphagia (poor control of
swallowing,) even the safety of oral feeding may not be considered, and aspiration pneumonia
can result from food going into the lungs. Also, texture adjustments for dysphagia themselves
can cause nutritional imbalance. The diet can easily be too high in starchy thickeners and too
low in foods that provide other nutrients such as protein, vitamins and minerals. Careful
adjustment of the diet can minimize these problems. “Video fluoroscopy” is test to be sure that
the child is not swallowing unsafely. Speech pathologists have programs to help children gain
eating skills or to become less “orally defensive”(being very resistant to being fed by mouth.)
If increasing the caloric density of the feeding is a goal, the same cautions involved in
Section 1 above will also apply here. Sometimes a tube feeding is necessary to provide some or
all of the child’s nutrition. If swallowing is unsafe, it will need to provide all of it. The timing
of tube feedings can be planned to fit inbest with the family’s schedule or situation. For
example, all tube feedings might be given during the day, or some (or all) may be administered
by a pump overnight. The latter approach can be especially helpful when one wants the child to
be most interested in working on eating skills during the day, or if the child is very intolerant of
high volume intakes at feedings. If the child can eat but just cannot eat enough, the tube feeding
can be an excellent help because it allows the child to be passively fed as needed. It can also
help administer medications. Bad tasting medications certainly do not help a child just learning
to eat look forward to taking anything by mouth.
This combination approach also lets the child continue to work on eating skills, to eat just
preferred or safe foods, and the rest of the nutrition can be easily fed passively. I think of this as
contributing to another important feeding issue: “the happiness factor.” Check the part of
Section 1 above: (“Some children will have higher needs for all nutrients in addition to
calories”) as the vitamin and mineral issues will be important here as well.
3) Some children are unable to perceive hunger or satiety, or they may
perceive it but be unable to communicate it to the caretaker.
Some children behave as if they are simply uninterested in eating, or unaware of eating in
general, or they may limit their food choices to only a very few items. In such cases, there can
be great pressure on the caretaker to “just get SOMETHING into the child,” and so serious
5
imbalances in nutrition can easily occur even when calories are adequate and effort is huge.
Many children with autism present problems of this kind. And with so many major issues for
the caretakers to deal with, nutritional adequacy may be pretty far down on the list of things that
grab their attention. In such cases, individual problem solving with a nutrition professional
familiar with these issues would be especially helpful.
After infancy, most children with Prader-Willi Syndrome (PWS) have the opposite problem:
They behave as if they are ALWAYS hungry and in search of food. They seem to be “driven to
eat” and they tend to eat many more than their bodies appear to need. However, new
understanding of the metabolism problems in this genetic condition helps explain the reasons for
this particular behavior and have provided some new approaches that are very helpful. Recent
research suggests that there are ways to help with this specific serious problem associated
with PWD, including the supplementation of carnitine and CoQ10 and treatments that
involve growth hormone. Discussion of carnitine continues in the next section.
4) Some children have markedly decreased energy needs
This may be because of very low energy expenditure and/or low muscle tone (e.g. spina
bifida, Down Syndrome, muscular dystrophy, Prader-Willi Syndrome (PWS) and “general
hypotonia”). They may need a very low calorie intake to prevent debilitating obesity.
Excessive fat accumulation can make it much harder for the child to develop mobility skills . . .
it’s like trying to learn to crawl with weak muscles and a ten-pound weight on your back. It
makes it harder for the caretakers to safely lift the child, and it can also result in more frequent
adjustments of braces, wheel chairs, car seats and other equipment.
The child with less muscle mass because of less physical activity can often appear to receive
adequate-but-not-excessive calories when actual calories taken in are much higher than needed.
This is because we are looking at arms and legs with certain general assumptions about how
much is muscle, how much is bone and how much is fat. An overly fat child who has low muscle
and/or bone mass will often have fairly normal limb contours and appearance. The excessive fat
the child has to deal with in terms of extra weight to move around, etc., can be hidden.
That is one reason why other measurements besides height and weight can be very helpful in
assessing the nutritional appropriateness of feeding plans for children with non-average body
composition. By measuring fat on the arm and back with a caliper, for example, one can see
if the child has fat stores that are too low, too high or just right. These measures are also helpful
when we are making adjustments in feedings of children who are unable to express hunger or
satiety. As a rule-of-thumb, the less typical a child’s mobility or muscle tone, the less likely
standard weight and height growth charts will provide the key information needed.
Interestingly, for some types of low muscle tone, supplemental carnitine has been shown to
help very much. Carnitine is usually made in an adequate amount in our bodies, but certain
medical conditions or medication use can result in a general inadequacy of this important substance.
This situation is a bit similar to the fact that although most people make plenty of insulin, children
with diabetes can’t make enough, and it simply has to be provided to them.
The carnitine helps the child move fat into the furnaces in the cells of the muscles so it can be
burned for fuel. Having too little carnitine can result in low muscle tone from inadequate fat
fuel to the muscles, very poor exercise endurance, lethargy, excessive sleepiness, hunger and
unwanted high-fat weight gain because it can’t be used for fuel normally.
6
Some medications interfere accidentally with carnitine adequacy, and these symptoms show up
as side effects of the drug. More will be discussed about carnitine in the section on drug/nutrient
interactions later in this paper. However, if these descriptions describe your child, you may want to
download my handout on this topic to learn a bit more about this important substance. It’s called:
“By Request: A Short Carnitine Discussion that Might Be Helpful”
It has now been shown that vitamin D inadequacy can be an important cause of muscle
weakness as well, with many consequences including increased risk of falls and even congestive
heart failure, a type of heart problem in which the heart muscle is too weak to pump blood
normally. Inadequacy of vitamin D at present is actually extremely common even in the
general population. It has now been identified as a previously unrecognized epidemic! The
failure to recognize deficiency was because, until very recently, it was simply not checked as
part of a normal doctor’s visit. We all just assumed it was fine.
In the population of children with special medical problems, the likelihood of
inadequacy is even greater, in part because of certain medications (e.g. seizure medications) or
being unable to be outside enough even in sunny summer weather. The vitamin D issue is
discussed in much greater detail in my downloadable handout called:
“Aunt Cathy’s Guide: My Current Top Five Easy
Ways to Improve Your Family’s Nutrition
(subject to change at any moment! ☺)”
In general, children with low caloric requirements or low volume intake for any reason
will benefit from careful micronutrient supplementation. Simply adding a standard vitamin
drop will not solve the problem, nor will just adding the standard “complete type” children’s
chewable vitamin with minerals. There are still big holes in the diet regimen. Intake of essential
nutrients is inadequate on very low calorie diets unless the health professional looks closely
at the feeding plan and makes adjustments to replace inadequate nutrients. Check the part of
Section 1 above because the vitamin/mineral issues will be important here as well.
5) Some children have troubles with constipation, including some of those
whose caloric needs are low and some whose caloric needs are high.
For children with lower caloric requirements: Children with lower-body
paralysis like those with spina bifida or other spinal cord injury, or those with a surgicallycorrectible condition called Hirschprung’s disease, may experience constipation because of
difficulty moving things along in the intestines. Some children may also have problems with
bladder infection. A number of the traditional dietary interventions (such as corn syrup,
cranberry or prune juice, etc.) contribute an unacceptably high number of calories for this group
of children. Cranberries may have a role in decreasing recurrence of bladder infection (as was
shown in a study of elderly women) but an artificially sweetened product may be needed.
Regular “cranberry juice cocktail” or prune juice provides about 20 calories per
ounce, which is equal to the calories in whole milk. Corn syrup provides 60 “empty”
sugar calories per tablespoon. Well-intentioned interventions to solve one problem can
make another problem much worse. Low/non-calorie approaches to helping with
constipation (e.g. milk of magnesia, lactulose, etc.) are available and some of these are
discussed below.
7
Contrary to popular belief, simply increasing water or other fluids will not
resolve constipation unless inadequate fluid intake was a contributing problem.
Extra fluid is clearly needed if fiber is being added, but in the absence of added fiber any
additional fluid is simply absorbed from the intestine and excreted via the kidney.
In addition, adding fiber may not be a helpful approach to constipation for a child
whose neurologic ability to push food through the lower intestinal tract may be impaired.
In fact, it may actually contribute to bowel obstruction. Some types of fiber actually slow transit
time through the intestine instead of moving things along. Extra fluids are also beneficial for
decreasing risk of bladder infections and kidney stones, but for the child with low calorie needs,
it is important that the calories from the added fluids do not contribute to weight problems.
Additional information about constipation issues in general is included in the section below.
For children with constipation problems for whom a nutrient-dense
high-calorie diet is needed: In contrast to the issues described above, it is useful to
know that there are pretty generous calories in some of the foods and beverages we
commonly use for constipation or kidney health. Examples include cranberry juice
(“cocktail”) or prune juice (20 calories per ounce – as high as whole milk,) and corn syrup (60
kcal per Tablespoon.) When trying to increase fluids for this child, remember that juices are
99.9% water. That means that they contribute the same amount of fluid as plain water would,
but they have the advantage of adding some calories, some beneficial phytochemicals and a few
nutrients. It makes little sense to concentrate a child’s formula and then feed plain water . . .
it just re-dilutes the feeding.
Consider whether some of the ways we add extra calories are possible contributors to
the constipation. For example, “casein” is a curd-forming milk protein that can be quite
constipating for some people. Whey protein is not curd-forming, and therefore it is generally less
constipating. There are several commercial nutritional beverage products used for children that
are readily available, such as Boost ® or KinderCal ® (by Mead Johnson), Carnation Instant
Breakfast ® or Nutren Jr. ® (by Nestle), or PediaSure ® (by Abbott.)
If using these products, check the label to see if the protein is primarily in the form of casein.
You may see the word “caseinate” on the label. This is a perfectly fine protein source for
growth, but for the chronically constipated child it would be worth trying one that had less
casein. Powdered products added to milk (like instant breakfast products) often include
powdered milk as the protein source, so the protein would still be 82% casein.
This is also an issue in infant feeding. Mother’s milk is very useful for MANY reasons,
including fat blend, immune-boosting factors and better absorbability of many nutrients. In
addition to these great benefits, it is unusual for babies to be constipated when exclusively fed
breastmilk. However, some children’s health situations can result in a degree of constipation
even when fed with mother’s milk.
Soy formulas are milk-free and so they have no casein, although for some children soy
is constipating, too. Of the milk-based products, a variety of protein sources are available:
Nestle Good Start Supreme ® is all whey (no casein) and the whey is partly chopped up. This
product has been helpful for use with chronically constipated babies. Standard Enfamil Lipil ®
(Mead Johnson) and Similac Advance ® (Abbott) products have adjusted the casein-to whey
ratio from 82%-to-18% (regular milk) to an easier to digest 40% to 60% ratio in an effort to try
to approach the ratios in human milk.
8
The protein in all the “lactose free” milk-based formulas is 100% casein. Enfamil’s
“GentleEase ®” product has less lactose than their standard Enfamil Lipil ® and it has both
casein and whey in the same ratio (40% casein to 60% whey.) The difference is that they have
hydrolyzed (chopped up) both of these proteins. This may be helpful for constipation. Similac’s
lactose free infant formula recently had a name change to “Similac Sensitive ®.” It still has
100% of the protein as casein.
Dairy fat (butterfat) can also be quite constipating. Butterfat is the form of fat in cream,
whole and 2% milk, butter and cheese. In addition to the constipation issue, it is a very saturated
fat and (like MCT oil ®) it always a very poor source of the essential fatty acids, including any
type of omega-3 or omega-6 polyunsaturated fats. In spite of this, some diets, such as the
ketogenic diet for seizure control, may contain a very high amount of cream.
The ketogenic diet is (not surprisingly) constipating for many children. Using other forms of
fat in place of at least some of the cream can help a lot, both for constipation relief and for good
nutrition. The heavy cream is used in that diet because it is more palatable when the child has to
be fed orally. However, for the tube-fed child ketogenic diet, it is much easier to provide a more
nutritious and less constipating feeding, starting with a base product like Abbott Nutrition’s
“RCF ®” formula (“Ross Carbohydrate Free.”) It has all the nutrition of a standard infant
formula except the carbohydrate is omitted, including a standard fat blend.
Some iron sources can contribute to constipation, and it is not uncommon to find that the
heavily iron-fortified infant cereal can contribute to the problem. High doses of “inorganic”
iron (that is, the “ferrous” or “ferric” forms found in plants or in pills) can be constipating and
since they are also far less well-absorbed, they are actually not the best route to improving iron
deficiency in an individual. Iron in breastmilk is “organic” and it is not constipating and it
is very well absorbed. The standard amount of inorganic iron in formulas is not constipating.
For example, “Nestle Good Start Supreme ®” formula (a whey based product) is often useful for
helping constipated babies and it only comes with iron. [Note that none of the standard infant
formulas are made in “low iron” versions anymore because it was not useful for constipation and
it was also nutritionally incomplete.]
Highly absorbable and non-constipating “organic” iron is also the kind found in meat. It is called
“heme” iron, and there is also a substance in meat called “Meat Protein Factor” that improves the
absorption of the inorganic iron in the meal as well. For more detail on solving iron problems, please
download my handout called:
“Aunt Cathy’s Guide to: Nutrition Support of Iron Deficiency”
Products to relieve constipation: Both Milk of Magnesia ® (magnesium hydroxide) and
MiraLax ® (polyethylene glycol) attract water to the bowel by osmosis and so they can be
useful for keeping stools from hardening. This is especially helpful when intestinal transit time
is slower than average … the slow transit time gives the large intestine more time to extract
water, contributing to harder stools.
Both of these products contribute no calories. Prune juice and corn syrup add considerable
calories, but they act the same way (an osmotic effect,) and the prune juice naturally has
additional phytochemical substances that encourage defecation. The prunes themselves are
helpful . . . not just the juice.
9
Glycerol suppositories can act locally at the rectum to ease passage of stools, but they do
not prevent the formation of dry/hard stools. Other products such as those containing senna can
work by means of irritating the bowel to stimulate activity. Others can interfere with the
absorption of nutrients. For this reason it is important to talk with your pharmacist or other
health care provider about the usefulness or safety of any constipation products or
approaches for your child.
6) There are many pediatric conditions that greatly alter nutrient
requirements and metabolism such as cystic fibrosis, diabetes, inborn
metabolic errors (such as PKU) and inflammatory bowel disease.
The health care professional must examine diet alterations for children with these
conditions. As always, adjustments of the child's diet must not only correct the obvious problem
(such as glucose control in diabetes,) but it is also essential to examine the feeding plan to be
sure it provides adequate and appropriate levels of all of the other nutrients. This step is often
overlooked. Different patterns of growth and body composition associated with certain
conditions must also be considered in the nutrition plan.
Increased nutrient excretion or turnover, or decreased absorption will also alter
nutrient requirements so that the "normal" guidelines of adequacy or safety (such as the
"RDA" or “RDI” or “AI” level) or expected patterns of “normal” growth rates may not
apply. They may not apply for other reasons as well, such as altered body composition or the
effects of medications. Most guidelines only address intake goals and growth expectations
for "healthy" people.
In many cases, special levels of certain nutrients can greatly affect the risk of
complications and worsening of chronic conditions. One area of encouraging micronutrient
research is diabetes and antioxidants such as vitamins E and C, minerals like selenium and zinc,
and a number of brightly colored plant pigments described later. Other substances that look
promising are the B vitamins (all, but especially B6 and biotin,) magnesium, carnitine, alphalipoic acid, and gamma linolenic acid.
The same patterns are emerging for many conditions that feature altered metabolism
and/or inflammation. Please see my handouts specifically focusing on each of certain
conditions for more information: Diabetes, Hemochromatosis, Multiple Sclerosis (MS,)
Epidermolysis Bullosa (EB – a severe skin condition) and Celiac Disease are currently available.
A) Antioxidants
For diabetes and many other autoimmune diseases like lupus, juvenile rheumatoid arthritis,
and inflammatory bowel disease, and for genetic conditions like Down Syndrome and apparently
many others, the medical condition itself (or the therapy) results in increased production of
damaging free radicals. This leads to increased frequency and severity of complications
beyond those due to the condition or medication use alone. For this reason, appropriate
generous antioxidant supplementation is advisable.
10
In addition to vitamin/mineral antioxidants, there are many potent antioxidants available in
brightly colored fruits and vegetables. The food pigments themselves are often antioxidants.
Examples include orange colored “beta-carotene” in carrots and squash, red “lycopene” in
tomatoes and watermelon, green “lutein” in dark leafy greens, red/blue “anthocyanins” in
blueberries and beets, yellow xeazanthin in corn and kale, and white/yellow “flavones” in onions
and garlic.
This class of substances is usually called “phytochemicals,” which simply means “plant
chemicals.” [Note that all “plant chemicals” are NOT heath-promoting. Poison ivy comes right
to mind as an example of a phytochemical that is not friendly.] Many vegetables and fruits have
a wide variety of phytochemicals that have benefits in addition to the antioxidant content, so
children’s diets (and the diets of adults) should be as generous in these foods as possible. A
great example: Lycopene, the red pigment in tomatoes, is 200 times as potent as a protective
antioxidant than vitamin E. There is much to be gained from including brightly colored fruits
and vegetables in the diets of everyone in the family.
I have had some success using pureed fruits and vegetables that are frozen in an ice-cube
tray and then popped out and stored in a freezer bag. These are then quick and easy to add to
strongly-flavored foods like soups, spaghetti sauce, chili, meatloaf, etc. For a tube-fed child, any
combination of fruits and vegetables can be pureed all together with formula or other nutritious
liquids (e.g. prune juice) and frozen as described. Blenderizing the “veggie cubes” with the
formula to be fed will usually thin it down enough, but it can also be strained if there is a
concern about clogging the tube.
This sounds time-consuming, but it can be done all at once for a month’s supply. One can
use canned, frozen or fresh (use low sodium vegetables if using the canned type.) Some folks
have a routine of freezing any leftover fruits and vegetables immediately after a meal in a freezer
bag and then blenderizing them all at once when a good amount has been stored up. Also, many
Grandmas or friends who keep asking how they can help are often very happy to take on this
kind of project. For everyone, of course, clean and safe food-handling techniques are very
important.
Another option is to add readily available fruit and/or vegetable juices (e.g. carrot juice, cranberry
juice, prune juice, low sodium “V-8” type) as part of the liquid used to reconstitute infant formula. Variety
is very important because the various beneficial phytochemicals are not all in the same food. There are
many new products out there to investigate now that the public is becoming aware of the importance of
these phytochemicals for health. Some are powders, juice concentrates or combinations of vegetable and
fruit juice. For the latter, be sure to check the calories, and whether or not they are additionally sweetened
when choosing. More information on this topic is available in my handouts:
“Aunt Cathy’s Guide to: Nutrition and Eye Health”
“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition
(subject to change at any moment! ☺)”
and
“Aunt Cathy’s Guide to: Some Ideas for Trying to Eat More of Those
Terrific Antioxidant Phytochemicals. . . and Liking It.”
11
B) Omega-3 / Omega-6 Oils
Along with antioxidant supplementation, manipulation of the inflammatory response by
altering the ratio of omega-3 to omega-6 fatty acids is also looking very promising in the
autoimmune and inflammatory diseases in particular. This ratio also appears to be very
important in other areas of health research as well, such as risk of heart disease, cancer, HIV,
depression, epilepsy, cognitive function, and degenerative eye diseases.
In each case, the direction of change that shows benefit is increasing the proportion of
dietary fats that are rich in oils of the omega-3 family in relation to the intake of fats from
the omega-6 family. Vegetable oils that are high in “omega-6” (such as corn oil) contribute to a
strong inflammatory response. Adjusting the intake of dietary fat to displace some omega-6 oils
with oils from the omega-3 family can significantly reduce the strength of an inflammatory
response. This is particularly important in conditions characterized by excessive inflammation.
Compared with corn oil, other vegetable oils like canola oil, flaxseed oil, walnut oil and
soy oil (only if non-hydrogenated) contribute to a much better balance of omega –3 to
omega-6 oils. Ground flax seeds, soybeans, walnuts and other nuts and seeds have other
nutritional benefits that the oil alone will not have. Additionally, displacing some omega-6 fat
with oils rich in a form of fat called monounsaturated oils (like peanut oil or olive oil) will
have a favorable effect on the omega-3 to omega-6 ratio.
At present, the relative ratio of these fats is an area of some difference in the general
pediatric oral/tube-feeding complete nutrition products. For example, Nutren Jr. ® (Nestle)
has a lower ratio of omega-6 to omega-3 fats compared with PediaSure (Ross Labs) and
Kindercal ® (Mead Johnson.) This might be a consideration especially in conditions with a
strong inflammation component. Some products are being especially designed to provide fats
with a less inflammatory potential, such as Modulen IBD ® for inflammatory bowel disease
(Nestle.) New products and reformulations will likely be forthcoming as this aspect of nutrition
receives greater attention.
As mentioned above, olive oil and peanut oil are mostly “friendly” monounsaturated oils.
They are not rich in either omega-3 or omega-6 polyunsaturated oils, but if they replace the high
omega-6 corn oil in the typical US diet, they can have a big beneficial effect on the ratio of the
remaining omega-6 to omega-3 oils. This contributes to decreasing the strength of inflammatory
substances that the body makes out of these two families of oil. It has the added advantage of
displacing some of the less beneficial fats in the diet, like the saturated fats in coconut oil, palm
oil and butterfat. All these oils have about the same number of calories … about 9 per gram.
Fish oils contain a generous amount of the omega-3 oils, and they are in a form that is
especially easily utilized in the effort to control inflammation. It is becoming very clear that
many individuals benefit greatly from having the fish oil form in particular provided
because it contains “ready-to-use” EPA and DHA.
These two fats (EPA and DHA) have direct anti-inflammatory effects, and DHA is a
critical fat of the brain tissue. Newer forms of supplements are appearing on the market
which can facilitate their use by children. More information is available in my handout on
“lipids” … the family of substances that includes fats and oils and cholesterol:
“Aunt Cathy's Guide To: All Those Lipids: Recommendations for Using
Different Types of Vegetable Oils (Omega-3, Omega-6 and Monounsaturated Oils)”
12
7) Therapeutic diets that eliminate certain foods or entire food groups are in
need of careful attention to the nutritional adequacy provided by the
foods remaining.
This includes special diets for allergies, celiac disease (“gluten-sensitive enteropathy”),
autism, inborn metabolic errors, diabetes or the ketogenic diet for seizure control. It is
critical that the nutritional adequacy of the diet is not compromised. Sometimes small
adjustments in the foods offered can solve any problems caused by food group limitation, but in
the more restrictive diets it is virtually impossible to obtain appropriate levels of vitamins and
minerals without careful supplementation.
As the nutrient content of supplement products on the market can be quite variable, it
is reasonable to have the diet and supplement plan evaluated carefully by a credentialed
nutrition professional (e.g. an RD – a Registered Dietitian) using a computer analysis
program. [Some RDs are also “Certified Specialists in Pediatric Nutrition.” Those with this
credential will have the letters CSP in addition to the RD after their names.]
Such computer programs for nutrient analysis are available in many hospitals and
clinics and in many university settings. They allow for the clinician and the family to be very
sure that there are no accidental nutrient inadequacies or excesses in the feeding regimen that
could harm the child’s overall health. Most computer programs in stores that sell health products
and vitamin supplements are inadequate for the kind of careful micronutrient assessment that is
needed in this situation, and in addition, they are often primarily programmed to promote and
increase sales of particular nutrition products.
8) Many children are maintained on medications with important
nutritional implications.
Here are a few examples:
Chronic use of seizure medications [like phenobarbital, valproate (Depekene®,)
phenytoin (Dilantin®,) Tegretol®, and many others] can cause increased turnover of vitamin
D, contributing to osteoporosis and fractures, among other problems. This is a special concern
now that the epidemic nature of vitamin D deficiency even among healthy people is becoming
recognized; people with health problems are at even higher risk for many reasons.
Vitamin D inadequacy has been found to be quite common especially in the northern
half of the country (but all over in the south as well.) It is common among people with
dark skin, those whose skin is often covered up or injured, or old, and those who are
frequently indoors. It increases risk of developing arthritis, MS, diabetes, muscle
weakness, muscle pain, lung problems, cardiovascular disease and several types of cancer.
Other nutrients are also affected by these medications. Health professionals need to
consider the influence of the medications when assessing the adequacy of nutrient intake, and
they may need to provide a different level of supplementation to safely assure adequacy. Again,
for lots more information on this topic and specific recommendations, please see my handout:
“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition
(subject to change at any moment! ☺)”
13
Phenytoin (Dilantin®) also interacts in a complex way with folic acid and several other
vitamins, and its absorption is altered by the presence of food. When folate is found to be
inadequate and then supplements are given to people on this medication to correct the deficiency,
breakthrough seizures can occur. This does not happen when their folate level is never allowed
to be depleted in the first place.
Chronic users of this medication often have low erythrocyte (red blood cell) folate levels.
Inadequate folic acid is also associated with depression, poor response to antidepressants, and
risk of heart disease, stroke, colon cancer, and Alzheimer’s disease. In pregnancy, the relatively
poor folate status increases risk of significant birth defects. It is recommended that anyone
starting to use Dilantin should automatically receive supplementation at the RDA level of
folic acid to prevent serious difficulties. If the drug is already in use, the physician should
carefully correct the deficiency, possibly by using a temporary increase in the drug during the
adjustment period to prevent breakthrough seizures.
Valproic acid (Depakene®) specifically interacts with carnitine and can cause metabolic
disturbances including severe hypoglycemia and lethargy that impairs the child’s ability to
function. It also severely impairs endurance. One reason is that it can inhibit production of
carnitine in the body, increasing dependence on external sources. Valproic acid also seems to
require carnitine for optimal drug effectiveness. Therefore, inadequate carnitine increases the
amount of drug required for seizure control and it is associated with “break-through
seizures” and a much greater risk of serious liver toxicity from the drug.
Carnitine is usually made by a person’s liver and kidneys in adequate amounts so it has not
been thought of as an “essential” substance. (“Essential” in nutrition means that you have to take it
in ready-made from outside either in foods or in supplements.) However, it is now clear that in
circumstances like this, carnitine can become “essential.” You may see carnitine described as a
“conditionally essential” nutrient for that reason. Relative carnitine inadequacy (unrelated to
medications) has also been found to be a factor in many conditions involving low muscle tone,
poor endurance, and/or disturbed metabolism, including diabetes.
Other Common Nutrition/Medication Interactions:
Methotrexate also interacts with folic acid. This drug is used as a chemotherapy drug for
cancer, but it is also an important medication in treatment of psoriasis and juvenile
rheumatoid arthritis. Assuring adequacy of folic acid has been shown to help the patient
tolerate the use of the medication. Inadequate folic acid status is associated with having to stop
using methotrexate because of discomfort even when it is clearly helping treat the disease.
Hydrocortisone (an anti-inflammatory) can cause growth failure, increase excretion of
nitrogen and zinc, and decrease absorption of calcium and phosphorus. Vitamin D status is also a
factor here.
Sulfasalazine (Azulfidine®) an antibiotic used for inflammatory bowel disease impairs
absorption of folic acid, and diets of people with this condition are often also low in fruits and
vegetables because of bowel discomfort. Their diet may also be lacking in dairy foods and high
fiber foods by doctor’s order. The risk of multi-nutrient inadequacy is great due to the
combination of dietary limitation, drug-induced nutrient absorption problems, high needs for
healing the intestine and high losses of nutrients via gut “weeping.”
14
It is not surprising that these children need help to grow normally. There is evidence that
the thrombotic (blood clots / strokes) and affective problems (mood issues) and higher
risk of colon cancer all noted in this population may be related to the very common folic
acid inadequacy.
Any antibiotics when used chronically can compromise status of biotin, vitamin K (which
can cause bleeding and bone, kidney and blood pressure problems,) and significantly impair folic
acid absorption. Antibiotics can also induce a chronic diarrhea (and this may in turn be treated
inappropriately with a clear liquid diet or half-strength feedings, resulting in further
malnutrition.)
Many people are commonly maintained on chronic antibiotics, including those with spinal
cord injury (to prevent bladder infection), cystic fibrosis, acne, certain heart conditions, HIV or
other immune-compromised individuals. Some antibiotics contribute to gastrointestinal distress
such as stomach pain and diarrhea.
Theophyllin (a broncho-dilator) absorption is influenced significantly by the timing of its
administration in relation to food intake.
Acid control medications: Zantac®, Tagamet®, (the “H2 blockers”) and especially
Prilosec®, Nexium®, Pepcid® Protonix® and Prevacid® (all PPI’s: “Proton Pump
Inhibitors”) are drugs that decrease acid production in the stomach. Loss of stomach acid can
impair absorption of vitamin B12 from natural food sources because stomach acid is required for
getting it into a form that can be absorbed.
This means that eating a “well balanced diet” will fail to provide adequate vitamin B12
when these medications are used. Vitamin B12 deficiency is very serious, so this issue should not
be ignored. However, absorption of the form found in vitamin supplements is NOT affected
by loss of acid, so this problem can easily be avoided with the regular use of a multivitamin
product.
Because of increasing use of the PPI medications in infants as an attempt to treat
gastroesophageal reflux (throwing up after feedings,) it is useful to know that a breastfed baby
maintained on these drugs will need a vitamin drop that contains vitamin B12 in addition to
assuring a vitamin D drop. Any standard drop will do and it can contain both easily. A
formula-fed infant is already receiving vitamin B12 in a crystalline form that does not require
acid for its absorption. [They will still need the extra vitamin D drop, of course.]
One other consideration with PPI’s is they decrease the effectiveness of infant formula
products like Enfamil AR ®. This is a standard infant formula that includes rice as part of the
carbohydrate. It is designed to help with decreasing gastroesophageal reflux in infants with this
problem by causing the formula to thicken and form a gel in the tummy after the baby drinks it.
This thickening is accomplished via exposure to stomach acid, however, so the formula product
will not do its gel-forming tricks if the baby is also being treated with a PPI.
Metformin (Glucophage®) is a medication for people with Type II (insulin resistant)
diabetes. It also interferes with vitamin B12 absorption. The mechanism is different from the
acid-reducing effects described above. This form of diabetes (Type II) has generally not been a
pediatric problem in the past, but the incidence of “adult type” diabetes is increasing
markedly along with increased incidence of obesity in children.
15
For more information on the vitamin B12 issue, please see my handouts:
“Aunt Cathy's Guide to Nutrition: A Vitamin B12 Update”
and
“Aunt Cathy’s Guide to: Thinking About OTHER Nutrition Issues in Diabetes”
Serotonin Re-uptake Inhibitors (such as Zoloft®) are used both for depression and for
inflammatory bowel disease, especially of the primarily constipation type. This class of drug
does not work well when an individual has a poor intake of folic acid. This is an example of
how careful attention to nutrition can improve the clinical response to a drug, thus avoiding the
potential side effects due to raising the drug dosage or changing to a stronger drug.
Many drugs (including “herbal” drugs) can also affect intake by causing nausea,
vomiting, constipation, taste changes, lethargy, or altered appetite. For example,
Methylphenidate (Ritalin®) for attention deficit disorders may impair appetite enough to slow
growth, although there is some evidence now that this may be less of a problem than originally
thought. Narcotic pain medications often cause constipation and decreased appetite.
“Herbal remedies” are not nutrients but many people have been given the impression
that they are. They are often marketed as “dietary supplements” because by law, the people
selling them do not have to prove that their product is safe or effective. It is a loophole in the
Food and Drug Administration’s laws that many people are unaware of.
People assume that in America a company could not package and sell health products that
were inadequately tested (or not tested at all.) But although labeled as “dietary supplements” in
order to avoid having to test them, these products are actually in the category of drugs and
medications. This is because whether they are in a natural state or packaged as a pill, the goal of
using them is to achieve some pharmacologic reaction.
For children with complex medical conditions and especially those who must use
medications of various types, there can be significant and dangerous interactions when
unknown to the physician, herbal products (or any “over-the-counter” products) are added
to the mix.
As one example, the herbal supplement “St. John’s Wort” which has been promoted as a
“natural antidepressant with no side effects” actually interacts with a wide variety of medications
and causes the medications to stop working sooner than they should. This effect of St. John’s
Wort has been found with medications for heart disease, HIV/AIDS, birth control pills, and drugs
that prevent the rejection of transplanted organs. Serious injury has resulted.
This is just one example of why it is very important to discuss the use of ANY herbal
product or other over-the-counter product with the child’s physician. “Natural” products
certainly CAN have side effects – after all, some of the most potent (and also dangerous) drugs
come from plants. For example, digitalis (an important heart medicine) comes from the foxglove
plant, and even heroin, cocaine and marijuana are “herbal” products.
16
Summary:
Providing optimal nutrition for the child with special health needs can:
• optimize physical, intellectual and psychological development.
• prevent serious complications like fractures and medication toxicity.
• optimize immune function to reduce the incidence/severity of illness.
• decrease pain due to inflammation or nutritional inadequacy.
• optimize the safety and effectiveness of any medications used.
• facilitate the care of the individual.
• improve the quality of life of the child and the caretakers.
These goals will only be realized when health professionals are
able to take a close look at this important aspect of the child’s care.
17
MeritCare Medical Center’s
Aunt Cathy’s Guide to:
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Clinical Nutrition Specialist
Perinatal/Pediatric Nutrition Specialist
MeritCare Health Systems, Fargo, ND
and UND School of Medicine
A Top Ten Nutrition
Plan for Optimizing
Pregnancy Outcome
(Subject to Change at Any Moment ☺)
An important note to the reader:
This is a quick summary of my main conclusions on nutrition in pregnancy based on the current
medical literature (as of date shown). My workshops include considerable detail describing the research
leading to these conclusions, and the complete bibliography is far too large to include here. Some pertinent
references are cited, however. This “Top Ten” list was designed at the request of health professionals in
practice who have attended a workshop at which the supporting literature was presented because they felt a
quick “bottom line” summary would assist in applying the research to patient care. Readers who have not
attended the workshops will be viewing this list of suggestions out of context. References regarding a
particular suggestion can be provided if you send an e-mail requesting it to the address above.
And now, the current “Top Ten”:
1. The physician or other primary health care person should emphasize the importance of
eating a good variety of foods and taking appropriate supplements.
This is in addition to the support of other health care professionals (nurses, dietitians, etc.) who may be
encouraging good nutrition. Reason: many patients believe that if the doctor does not mention diet and
nutrition, it must not be very important. Patients are more likely to take the issue seriously when the point is
reinforced by all the team members, including the team leader especially.
2. Establish a simple nutrition screening protocol and refer women for appropriate nutrition
counseling.
Utilize settings other than pregnancy visits to optimize effectiveness in birth defects prevention. For
example, evaluate nutrition at other OB visits for birth control or for annual exams, and provide advice to help
correct nutrition problems before a pregnancy is established
3. Start supplementation with a multivitamin with minerals and begin providing nutrition
advice preconceptionally.
It used to be standard practice to postpone nutrition discussions and/or nutrient supplementation until the
first pregnancy visit, which was often scheduled at the end of the first trimester. It is now well documented
that nutritional status in the preconceptional period and throughout the entire pregnancy is truly critical for
optimizing outcome. Similarly, the old practice of discontinuing vitamin/mineral supplements because of
nausea in early pregnancy is no longer recommended because (in addition to concerns about nutrient
inadequacy during critical construction periods) research shows that the supplements (minus the high-dose
iron) can actually decrease nausea, vomiting and vertigo in pregnancy. The discomfort associated with taking
prenatal vitamins appears to be more related to the extremely high iron content of some prenatal products.
Such a high amount of extra iron is contributory to GI distress and it is not needed in early pregnancy.
Additionally, the form of iron in supplements (i.e, inorganic ferrous and ferric iron) is clearly not the most
efficient or biologically absorbable form at any time. Most are far less than 2% absorbed, which is
substantially less than the 20% iron absorption from “heme” iron forms in meat, for example. [Please see my
“Nutrition Support of Iron Deficiency” handout for more on this topic.]
[J Obstet Gynaecol Can. 2007 Dec;29(12):1003-26. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination
with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2007
Dec;29(12):1003-26. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Prenatal multivitamin supplementation and rates of congenital anomalies: a metaanalysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Relationship between vitamin use, smoking, and nausea and vomiting of pregnancy. Acta
Obstet Gynecol Scand. 2003 Oct;82(10):916-20. Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation.
Clin Invest Med. 1999 Jun;22(3):106-10. Periconceptional folic acid containing multivitamin supplementation. Eur J Obstet Gynecol Reprod Biol.
1998 Jun;78(2):151-61.]
The EXTRA folic acid in prenatal products (800 mcg instead of 400 mcg) is also generally not needed in
EARLY pregnancy. In preconception and early pregnancy, 400 mcg of folic acid in supplement form appears
to be is sufficient to prevent neural tube defects in most situations, and the fetus has priority for this nutrient
over the mother’s needs. A fetus sequesters folic acid for its own use and then “leaves town” with it,
potentially leaving the mother folate deficient after delivery unless intake is sufficient to meet both of their
needs. The EXTRA 400 mcg in the prenatal vitamin is to prevent the mother from becoming depleted as the
pregnancy progresses, both for her own health and to prevent birth defects should a pregnancy occur within a
few months of delivery of the present infant.
Toward this end, a STANDARD vitamin/mineral product can be very helpful, especially for women who
eat poorly at this time due to nausea (or general poor diet) and are therefore obtaining suboptimal amounts of
vitamins and minerals. A standard product (which generally provides about 18 mg iron) is also less
constipating than the very high iron products. Most research now suggests that the very high iron products
are more problematic than they are helpful – other interventions improve iron status more effectively without
the unpleasant side effects. If providing 800 mcg of folic acid is preferred, simply add a small and
inexpensive OTC 400 mcg folic acid tablet. Folic acid adequacy is also now recognized to be a factor in
decreasing risk of miscarriage, depression, stroke and cancer of the colon and breast, so our advice to women
to take a multivitamin during childbearing years should be expanded to all of a woman’s life. The use of this
kind of product is now generally regarded as “prudent for most adults.”
Recently a large epidemiologic study suggested that use of a general multivitamin in the
periconceptional period may actually decrease risk of developing pre-eclampsia. Because the report is
quite new at the time of this update, and the topic is so important, I am including the abstract below.
Periconceptional Multivitamin Use Reduces the Risk of Preeclampsia. Am J Epidemiol. 2006 Jun 13; The
objective was to assess the independent effect of regular periconceptional multivitamin use on the risk of preeclampsia.
Pregnant women (n = 1,835) enrolled in the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh,
Pennsylvania, 1997-2001) at less than 16 weeks' gestation were asked whether they regularly used multivitamins or
prenatal vitamins in the past 6 months. Women were classified as users or nonusers. The unadjusted prevalence of
preeclampsia was 4.4% in nonusers and 3.8% in users. After adjustment for race/ethnicity, marital status, parity,
prepregnancy physical activity, and income in a multiple logistic regression model, regular use of multivitamins was
associated with a 45% reduction in preeclampsia risk compared with nonuse (odds ratio (OR) = 0.55, 95% confidence
interval (CI): 0.32, 0.95). Prepregnancy overweight modified this effect. After confounder adjustment, lean
multivitamin
2
users had a 71% reduction in preeclampsia risk compared with lean nonusers (OR = 0.29, 95% CI: 0.12, 0.65). In
contrast, there was no relation between multivitamin use and preeclampsia among overweight women (OR = 1.08, 95%
CI: 0.52, 2.25). A sensitivity analysis for unmeasured confounding by fruit and vegetable intake supported these conclusions. If
confirmed by others, these results suggest that regular use of a multivitamin supplement in the
periconceptional period may help to prevent preeclampsia, particularly among lean women.
Similarly interesting in regard to nutrition and pre-eclampsia prevention (and deserving of the “boxof-its-own”) is a new report from the Cochrane Database: Calcium supplementation during pregnancy for
preventing hypertensive disorders and related problems. [Cochrane Database Syst Rev. 2006 Jul
19;3:CD001059.]
The authors concluded: “Calcium supplementation appears to almost halve the risk of preeclampsia, and to reduce the rare occurrence of the composite outcome 'death or serious morbidity'.
There were no other clear benefits, or harms.” This observation is particularly noteworthy because the
Cochrane Database group has a mandate to be very picky and skeptical; it takes quite a lot of consistency
among reports of what they regard as quality studies for this organization to conclude something other than
“there is not enough evidence” to come to any conclusions.
[Multivitamin use and the risk of preterm birth. Am J Epidemiol. 2004 Nov 1;160(9):886-92. A role for supplements in optimizing health: the
metabolic tune-up. Arch Biochem Biophys. 2004 Mar 1;423(1):227-34. Vitamins for chronic disease prevention in adults: clinical applications. JAMA.
2002 Jun 19;287(23):3127-9. Eat Right and Take a Multivitamin NEJM 338 (15):1060-1061 1998], and particularly so for any who may become
pregnant. [Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet. 2004 Feb 15;125C(1): 12-21.
Impact of folic Acid fortification in the United States: markedly diminished high maternal serum alpha-fetoprotein values. Obstet Gynecol. 2004
Mar;103(3):474-9. The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2003
Nov;25(11):959-73. Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J
Nutr. 2004 Jan;134(1):162-6.]
Assume that at least some nutrients are NOT adequate unless you have actually checked that they
are. Just as one example, the most recent National Health and Nutrition Examination Survey of the CDC
found that the majority of Americans obtain less than 2/3 of the RDA for magnesium. As magnesium is
known to be a critical cofactor in over 300 metabolic pathways, it is a very key nutrient in perinatal health and
suboptimal intake of this nutrient is a very serious problem. [More on magnesium will be discussed later.]
In general, choose a multivitamin/mineral supplement product that is as complete as possible but inexpensive.
Generics are fine. A complete-type “prenatal” product that is not of the very high-iron type can also be
helpful.
It seems prudent during pregnancy in particular to choose a vitamin/mineral supplement product with no
more than the RDA for vitamin A. Preferably one should be selected which provides some (at least 25-50%)
of the vitamin A in the precursor form “as ß-carotene” instead of providing it all as retinyl palmitate or retinyl
acetate, since the retinol (hormonal) form in high amounts is a risk factor for birth defects.
A closer look at vitamin A: Vitamin A has important functions in cell differentiation, and similar types
of birth defects are associated with both vitamin A deficiency and vitamin A excess. This is an area of
considerable interest at present. Opinions differ regarding the teratogenicity of various forms of vitamin A.
For example, one group of researchers concluded “the available human data suggest that threshold
concentrations of these retinoids resulting in teratogenesis were unlikely to be exceeded following vitamin A
supplements of 25,000 IU/day.” Another study found no association between periconceptional vitamin A
exposure at doses >8000 IU or >10,000 IU per day and malformations in general, cranial neural crest defects,
or neural tube defects. They concluded that if vitamin A is a teratogen, the minimum teratogenic dose
appeared to be well above the level consumed by most women during organogenesis.
3
[Model predicting the teratogenic potential of retinyl palmitate, using a combined in vivo/in vitro approach. Teratology 1998 Sep-Oct;58(3-4):
113-23. Vitamin A and birth defects. Am J Obstet Gynecol 1997 Jul;177(1):31-6.]
However, other maternal factors may result in increased risk of teratogenicity. For example,
hyperglycemia increases embryonic susceptibility to the teratogenic effects of vitamin A in diabetic mice,
and normalization of blood sugar completely the erased increased susceptibility. The damaging effects of
high dose retinol can also be affected by folate and methionine status, and genetic predisposition.
[Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice. Diabetologia. 2004 Feb 14. Antagonism of
hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture. J Nutr. 2003
Nov;133(11):3561-70. Combination therapy with folic acid and methionine in the prevention of retinoic acid-induced cleft palate in mice. Birth Defects
Res Part A Clin Mol Teratol. 2003 Mar;67(3):168-73. Increased susceptibility to retinoid-induced teratogenesis in TGF-beta2 knockout mice. Reprod
Toxicol. 2002 Nov-Dec;16(6):741-7. Maternal diabetes increases the risk of caudal regression caused by retinoic acid. Diabetes. 2002 Sep;51(9):28116. Retinoids and cardiovascular developmental defects. Cardiovasc Toxicol. 2002;2(1):25-39. Vitamin A during pregnancy. Nutr Health. 2001;15(34):237-43. All-trans-retinoic acid-mediated modulation of p53 during neural differentiation in murine embryonic stem cells. Cell Biol Toxicol.
2002;18(4):243-57. Teratogenic effects of chronic ingestion of high levels of vitamin A in cats. J Anim Physiol Anim Nutr (Berl). 2003 Feb;87(12):42-51.Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology 2000
Oct;62(4):214-26. Vitamin A teratogenicity and risk assessment in the macaque retinoid model. Reprod Toxicol 2000 Jul-Aug;14(4):311-23. Dietary
vitamin A and teratogenic risk: European Teratology Society discussion paper. Eur J Obstet Gynecol Reprod Biol 1999 Mar;83(1):31-6. Prevention of
congenital abnormalities by vitamin A. Int J Vitam Nutr Res 1998;68(4):219-31. Safety of vitamin A: recent results. Int J Vitam Nutr Res
1998;68(6):411-6. Periconceptional vitamin A use: how much is teratogenic? Reprod Toxicol 1998 Jan-Feb;12(1):75-88. Teratogenic effects of vitamin
A and its derivates Arch Pediatr 1997 Sep;4(9):867-74.]
It also appears that the FORM of vitamin A used can greatly alter the toxicity of supplements in
addition to the dichotomy between beta-carotene (the vitamin A precursor) and a variety of the hormonal
forms of vitamin A in foods and supplements (retinol, retinoic acid and retinyl esters.) It was shown that the
degree of toxicity of vitamin A also depends greatly on whether it is provided in a oil-based
preparation, or as water-miscible, emulsified, or solid preparation. The results of a recent important
animal study were as follows: “Chronic hypervitaminosis A is induced after daily doses of 2 mg retinol/kg in
oil-based preparations for many months or years. In contrast, doses as low as 0.2 mg retinol. kg(-1). d(-1) in
water-miscible, emulsified, and solid preparations for only a few weeks caused chronic hypervitaminosis A.
Thus, water-miscible, emulsified, and solid preparations of retinol are approximately 10 times as toxic as are
oil-based retinol preparations. The safe upper single dose of retinol in oil or liver seems to be approximately
4-6 mg/kg body wt. These thresholds do not vary considerably with age.” Another form of vitamin A (a
metabolite called isotretinoin – the drug Accutane) is well recognized as causing birth defects. And as a
rule, because it is a very rich source of the hormonal forms of vitamin A, some researchers have raised
concerns about frequent consumption of liver during pregnancy. Positions taken on “the liver question” vary
greatly in the official recommendations of experts in various nations, ranging from alarm to unconcern.
[Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr. 2003 Dec;78(6):11529. A call for action--prevention of fetal exposure to isotretinoin. A position paper by The Organization of Teratology Information Services Public
Affairs Committee.Reprod Toxicol. 2001 Nov-Dec;15(6):729. Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic
acid. J Am Acad Dermatol. 2001 Nov;45(5):S183-7. The problem of a high content of vitamin A in the liver of calves, cattle, sheep and swine for the
consumer. Amount of accumulation and mechanism of teratogenic effect (review article). Berl Munch Tierarztl Wochenschr. 1994 Oct;107(10):342-7.
Survey of animal livers for vitamin A content. Food Addit Contam. 1992 May-Jun;9(3):237-42. A survey of vitamin A concentrations in the liver of
food-producing animals. Food Addit Contam. 1998 Jan;15(1):10-8. Health risks related to high content of vitamin A in liver Nord Med.
1990;105(5):149-50, 153. Evaluation of vitamin A toxicity. Am J Clin Nutr. 1990 Aug;52(2):183-202.]
Use a children’s chewable version (one daily) if needed or desired for people who have trouble with pills
or for those with nausea. Use the regular dosage of one tablet per day, (the standard dose for people ages
4-to-adult). Do not suggest taking two tablets (“because the product is designed for children”) because the
vitamin A (retinol) content would then be higher than is desirable during pregnancy, and as noted above, in
early pregnancy this could increase the risk of birth defects. If most of the vitamin A is provided in the form
4
of beta carotene, the risk of contributing to birth defects is much less. In general, children’s products are quite
similar to those formulated for adults.
Choose a product with at least 400-800 mcg folic acid. If the mother previously had a child with a neural
tube defect (NTD), providing the usually recommended amount of folic acid preconceptionally may be
adequate. However, for some women it may not be adequate for genetic reasons (e.g. some women who have
high homocysteine levels that are unresponsive to the usual intake levels of folic acid) or those who are
chronic users of antibiotics, certain epilepsy medications or alcohol (all of which impair folic acid absorption
or metabolism.) In some unusual cases, up to 4000 mcg/day (4 mg) may be needed to normalize folic aciddependent metabolism.
If a genetic or other medical condition that greatly increases requirements for folic acid is suspected, the
physician can order a one-time “methionine-load homocysteine” level in the mother when not pregnant to
determine if her folic acid needs are higher than usual. This test is unnecessary in the vast majority of
situations, however, as even for those with the MTHFR gene (known to affect folic acid metabolism),
provision of the RDA level in a vitamin pill form (i.e. the crystalline well-absorbed form) almost always
corrects the problem. Identifying those with higher than average requirements will both protect her future
babies from birth defects and it will also significantly reduce her own risk of stroke, DVT, depression and
cancer. High-dose folic acid can also help those with a family history of cleft lip or palate (one study used 10
mg/day), NTD-affected previous pregnancy or family history, insulin-dependent diabetes, epilepsy treatment
with valproic acid, phenytoin or carbamazepine.
A recent summary of recommendations of the major association of obstetricians in Canada was that for
these women “high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be
taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such
as vitamin A.” Other seizure medications can increase folic acid requirements as well, such as phenytoin
(Dilantin), which when taken during pregnancy has been associated with cleft lip/palate and heart and urogenital defects. Norwegian experts make the following recommendations: “Valproate and carbamazepine
have been associated with neural tube defects and phenytoin with cleft lip/palate and heart and urogenital
defects. All women taking valproate and carbamazepine are advised to take 4 mg/day of folic acid at least one
month before pregnancy and during the first trimester. Other women with epilepsy in fertile age are
recommended to take 0.4 mg/day. Vitamin K 10 mg/day should be given the last 4 weeks to women on liver
enzyme-inducing AEDs.”[Anti-Epilepsy Drugs] Ideally, women taking phenytoin would already be receiving
folic acid supplementation since the time that she began to use the drug “because of the hypothesized cofactor
mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no
perturbation of phenytoin pharmacokinetics.” However, if this has not been done (and it may not have been) it
is important to increase folic acid intake gradually and under the physician’s supervision, as a sudden increase
in intake could have a negative effect on seizure control in this situation.
[A sample of some references on this very large topic: The use of folic acid for the prevention of neural tube defects and other congenital
anomalies. J Obstet Gynaecol Can. 2003 Nov;25 (11):959-73. Folic acid and homocysteine affect neural crest and neuro-epithelial cell outgrowth and
differentiation in vitro. Dev Dyn. 2003 Jun;227(2):301-8. Vitamin and homocysteine status of mothers and infants and the risk of nonsyndromic orofacial clefts. Am J Obstet Gynecol. 2003 Oct;189(4):1155-60. Is there more to folates than neural-tube defects? Proc Nutr Soc. 2003 Aug;62(3): 591-8.
The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2003 Nov;25(11): 959-73.
Pregnancy and birth in women with epilepsy. Tidsskr Nor Laegeforen. 2003 Jun 12;123(12):1695-7. Management issues for women with epilepsy:
neural tube defects and folic acid supplementation. Neurology. 2003 Sep 1;61(6 Suppl 2):S23-6. The effects of folic acid in the prevention of neural
tube development defects caused by phenytoin in early chick embryos. Spine. 2003 Mar 1;28(5):442-5. Primary prevention of neural-tube defects and
some other major congenital abnormalities: recommendations for the appropriate use of folic acid during pregnancy. Paediatr Drugs. 2000 Nov-Dec;2
(6):437-49. Nonsyndromic orofacial clefts: association with maternal hyperhomocysteinemia. Teratology. 1999 Nov;60(5):253-7. Folic acid for the
prevention of congenital anomalies. Eur J Pediatr. 1998 Jun;157(6):445-50. Neural tube and craniofacial defects with special emphasis on folate
pathway genes. Crit Rev Oral Biol Med. 1998;9(1):38-53. Reduced recurrence of orofacial clefts after periconceptional supplementation with highdose folic acid and multivitamins. Teratology. 1995 Feb;51(2):71-8. Phenytoin-folic acid interaction. Ann Pharmacother. 1995 Jul;29 (7-8):726-35.
Regarding dietary sources of folate, it is often not recognized that many popular fruits and vegetables do
not even contain folate (e.g. apples and grapes have none), and that not all food sources of folate are equally
5
well absorbed or utilized. The form in vitamin pills, fortified grains and cereals (“folic acid”) IS well
absorbed. In view of the importance of assuring folic acid adequacy at this critical phase of fetal development
and the studies showing that the most reliable way to assure an adequate intake of a bioavailable form of folic
acid is via supplementation, it is prudent to simply provide a multivitamin. Interestingly, several countries have
attempted to improve women’s preconceptional folic acid intake via ad campaigns urging supplement use. In
several cases it has been quite unsuccessful, not because the supplements did not prevent birth defects, but
because women simply have still not adopted the practice of reliably taking the supplements. As a result, there
is considerable pressure in several countries at present to establish a folic acid food-fortification program such
as that initiated in 1998 in the US.
Since January 1998, folic acid (in a well-absorbed form) has been added to grains in the U.S. The results of
this large public health undertaking were recently reported. Compared with the incidence before fortification,
the supplementation of grains has decreased the incidence of neural tube defects by an astounding 70%. During
the same period, stroke and stroke deaths have declined by an impressive 15%. [Improvement in stroke mortality in
Canada and the United States, 1990 to 2002. Circulation. 2006 Mar 14;113(10):1335-43.] No problems were identified as a result of
the fortification.
In several studies throughout Europe, it has been found that although there is clear evidence for NTD
prevention by assuring adequacy of periconceptional folic acid, it continues to be found that public health
messages urging women to take folic acid supplements have been ineffective in bringing about the kind of
changes observed with food fortification with folic acid. The reason is that with supplementation of food, one
does not need awareness of the issue nor the motivation to plan ahead. Further, there are no limitations of
willingness/ablilty to purchase supplements limits. [Example: Promotion of folate for the prevention of neural tube defects: who
benefits? Paediatr Perinat Epidemiol. 2005 Nov;19(6):435-44.]
Studies continue to show that the simple use of a multivitamin can decrease risk of quite a number of birth
defects besides the well-documented neural tube defects of spina bifida and anencephaly. For example,
periconceptional intake of thiamine, niacin and pyridoxine seems to contribute to the prevention of oral-facial
clefts. A multivitamin will also decrease risk of birth defects associated with vitamin B12 deficiency, which
has been shown to occur in unsupplemented vegans and also (surprisingly) among people with gastroesophageal reflux problems (GERD) who use medications that decrease stomach acid production (such as
Prilosec®, Prevacid ®, Nexium®, Protonix® and others.) Low stomach acid production impairs absorption of
vitamin B12 from food, but it is easily corrected by providing the crystalline form of vitamin B12 found in
vitamin supplements. Glucophage® (Metformin) is a medication for diabetes that has been shown to
negatively affect absorption of vitamin B12.[For more information on these issues, please see “Aunt Cathy’s
Guide to Nutrition: New Discoveries about Folic Acid and Health.” And “Aunt Cathy’s Guide to Nutrition: a
Vitamin B12 Update.”]
Folic acid supplementation, fortification and/or multivitamin supplementation has been associated with
significant reduction of risk for many anomalies besides neural tube defects.
1) incidence of all birth defects overall;
2) cardiovascular anomalies,
3) orofacial clefts;
4) limb deficiencies ;
5) urinary tract defects;
6) nonsyndromic omphalocele;
7) imperforate anus; and
8) incidence of pediatric cancers.
[Prenatal supplementation with multivitamins and the incidence of pediatric cancers: clinical and methodological considerations. Pediatr Blood Cancer.
2008 Feb;50(2 Suppl):487-9. Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis. Clin Pharmacol Ther. 2007
May;81(5):685-91. Periconceptional folates and the prevention of orofacial clefts: role of dietary intakes in France Rev Epidemiol Sante Publique.
2005 Sep;53(4):351-60. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet. 2004;125C(1): 12-
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21. Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the offspring. Eur J Nutr. 2004;43(1):7-14. Maternal
myo-inositol, glucose, and zinc status is associated with the risk of offspring with spina bifida. Am J Obstet Gynecol. 2003;189(6): 1713-9. Effects of
short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized,
placebo-controlled trial. J Intern Med. 2003;254(5):455-63. The syndrome of food-cobalamin malabsorption revisited in a department of internal
medicine. A monocentric cohort study of 80 patients. Eur J Intern Med. 2003;14(4):221-226. Should we screen diabetic patients using biguanides for
megaloblastic anemia? Aust Fam Physician. 2003;32(5):383-4. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002
28;162(19):2251-2. Side effects: Calcium supplements help metformin users absorb vitamin B12. Treatment update. 2000;12(7):6-7. Increased intake
of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9): 1227-31. Ambulatory care increased vitamin B12
requirement associated with chronic acid suppression therapy. Ann Pharmacother. 2003;37(4): 490-3. Changes in gastric mucosa and luminal
environment during acid-suppressive therapy: a review in depth. Dig Liver Dis. 2001;33(8):707-19. Maternal periconceptional vitamins: interactions
with selected factors and con-genital anomalies? Epidemiology. 2002;13(6):625-30. Maternal multivitamin use and orofacial clefts in offspring.
Teratology. 2001;63(2):79-86. Neural tube defects associated with maternal periconceptional dietary intake of simple sugars and glycemic index. Am J
Clin Nutr. 2003;78(5):972-8. Oral clefts and vitamin supplementation. Cleft Palate Craniofac J. 2001;38(1):76-83. Maternal diet during pregnancy and
risk of brain tumors in children. Int J Cancer Suppl. 1998;11:23-5. Neural tube defects associated with maternal periconceptional dietary intake of
simple sugars and glycemic index. Am J Clin Nutr. 2003;78(5):972-8. Effects of retinoic acid on the neural crest-controlled organs of fetal rats. Pediatr
Surg Int. 2003;19(5):-355-8. Marginal biotin deficiency is teratogenic in ICR mice. J Nutr. 2003;133(8: 2519-25. Folic acid and neural tube defects in
pregnancy: a review. J Perinat Neonatal Nurs. 2003;17(4): 268-79.]
4. Assure adequate magnesium, calcium, vitamin D and iodine intake in particular; these are nutrients
that are often inadequate in the diets of Americans and they are often needed in amounts beyond
that provided by most multivitamin/mineral supplements.
Maternal magnesium status has been shown to be related to pregnancy outcome. Dietary magnesium
inadequacy has been demonstrated to be quite common among American women, although it is rarely
recognized or evaluated. Consider a magnesium supplement at about the RDA levels (e.g. 250-500 mg)
especially if the woman has any of the following conditions:
• a magnesium-poor diet (not uncommon)
• a need for generous calcium supplements (to maintain a normal Mg:Ca ratio)
• preeclampsia,
• a medication that causes magnesium loss (e.g. thiazide diuretics).
• leg cramps,
• diabetes, or
• PMS when not pregnant
The best dietary sources include: peanuts, bran, wheat germ, nuts, legumes. If a supplement is used, try Mg
oxide or chloride instead of sulfate or hydrochloride for better absorption and less of a laxative side-effect.
Most prenatal vitamins contain only 10-25% of the RDA for magnesium. Please see “Aunt Cathy’s Guide to
Nutrition: Magnesium” for more detail.
Some researchers feel that prenatal magnesium adequacy has a higher priority than even iron
supplementation because of the over 300 enzyme systems in the body that depend on magnesium to function
properly. Several measures of pregnancy outcome such as higher frequency of spontaneous abortions
(miscarriage), fetal growth retardation, maternal hospitalizations, preterm delivery, SIDS and referrals
to NICUs have been found to be associated with poor magnesium status in pregnancy. These issues are
related to general nutrition and are quite separate from issues related to the acute therapeutic i.v. magnesium
sometimes used in the treatment of pre-eclampsia or premature labor, and even from the magnesium levels as
measured in blood tests. The laboratory values often do not reflect cellular levels at all, primarily reflecting
the ability of the kidney to hormonally regulate magnesium levels in the blood.
Other studies have shown a benefit of assuring magnesium adequacy (i.e. providing the RDA level of
magnesium) in the reduction of leg cramps in pregnancy. Pregnant women with diabetes need special
attention to adequacy of magnesium intake because of the potential for increased losses and the common
finding of poor magnesium status among people with diabetes in particular. In addition, inadequacy of
magnesium is a risk factor for the development of gestational diabetes as well as Type II diabetes. One
7
contributing factor may be the role magnesium plays in ATP production in the TCA Cycle, and another is
very likely its key role in the functioning of insulin receptors.
[Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care. 2004;27(1):134-40. Role of cellular magnesium in
health and human disease. Front Biosci. 2004 1;9:262-76. Dietary magnesium intake in relation to plasma insulin levels and risk of
type 2 diabetes in women. Diabetes Care. 2004;27(1):59-65. Randomised, cross-over, placebo controlled trial of magnesium citrate in
the treatment of chronic persistent leg cramps. Med Sci Monit. 2002 May;8(5):CR326-30.Interventions for leg cramps in pregnancy.
Cochrane Database Syst Rev. 2002;(1):CD000121; Magnesium in drinking water and the risk of delivering a child of very low birth
weight. Magnes Res. 2002;15(3-4):207-13; Magnesium deficit and sudden infant death syndrome (SIDS): SIDS due to magnesium
deficiency and SIDS due to various forms of magnesium depletion: possible importance of the chronopathological form. Magnes Res.
2002;15(3-4):269-78. Gestational diabetes and its impact on the neonate” Neonatal Netw. 2001;20(6):17-23. The apparent impact of
gestational magnesium (Mg) deficiency on the sudden infant death syndrome (SIDS). Magnes Res. 2001;14(4):291-303.
Micronutrients in pregnancy. Br J Nutr. 2001;85 Suppl 2:S193-7. Gestational magnesium deficiency is deleterious to fetal outcome.
Biol Neonate. 1999;76(1):26-32. Nutritional and antimicrobial interventions to prevent preterm birth: an overview of randomized
controlled trials. Obstet Gynecol Surv. 1998;53(9):575-85.Vitamin and mineral deficiencies which may predispose to glucose
intolerance of pregnancy.J Am Coll Nutr. 1996;15(1):14-20. The effect of oral magnesium substitution on pregnancy-induced leg
cramps. Am J Obstet Gynecol. 1995;173(1):175-80.]
Calcium and vitamin D intake status. Be sure that AT LEAST the RDA level is usually provided
for calcium. Give dietary guidance to correct inadequacy (see “Aunt Cathy’s Guide to Nutrition: Calcium
Supplements” for more detail.) Supplement with calcium and vitamin D if unable to meet goals with foods
(ideally without using bone meal, dolomite, or oyster shell calcium.) Remember that the RDA for vitamin
D (400 iu) appears to be inadequate for people in the northern latitudes or for those whose skin is dark
or covered; some researchers are now suggesting that 1000 - 2000 iu may be needed by these people in
order to maintain appropriate blood levels. Interestingly, after years of continually increasing
recommendations for calcium intake, it appears that the old RDA level of 800 mg calcium may well be
adequate IF the adequacy of vitamin D is assured.
The critical point is that “assuring adequacy” is quite different from “assuring an intake at the RDA
level.” There is now a large effort on the part of experts in this field around the world to induce an increase in
the officially recommended intake levels. Such things are notoriously slow to become official, but the data is
very clear that such a change is needed.
The role of vitamin D inadequacy and risk of perinatal problems is now beginning to be
explored. Remember that the amount of vitamin D currently included in a standard prenatal vitamin is 400 iu
… the same as in a standard vitamin for when one is not pregnant. This is clearly an amount insufficient to
meet the needs of both Mom and Baby. Here are some new reports:
Maternal vitamin d deficiency increases
the risk of preeclampsia. … Results: Adjusted serum 25(OH)D concentrations in early
J Clin Endocrinol Metab. 2007 Sep;92(9):3517-22.
pregnancy were lower in women who subsequently developed preeclampsia compared with
controls [geometric mean, 45.4 nmol/liter, and 95% confidence interval (CI), 38.6-53.4 nmol/liter,
vs. 53.1 and 47.1-59.9 nmol/liter; P < 0.01]. There was a monotonic dose-response relation
between serum 25(OH)D concentrations at less than 22 wk and risk of preeclampsia. After
confounder adjustment, a 50-nmol/liter decline in 25(OH)D concentration doubled the risk of
preeclampsia (adjusted odds ratio, 2.4; 95% CI, 1.1-5.4). Newborns of preeclamptic mothers were
twice as likely as control newborns to have 25(OH)D less than 37.5 nmol/liter (adjusted odds ratio,
2.2; 95% CI, 1.2-4.1). Conclusions: Maternal vitamin D deficiency may be an independent risk
factor for preeclampsia. Vitamin D supplementation in early pregnancy should be explored for
preventing preeclampsia and promoting neonatal well-being.
J Nutr. 2007 Feb;137(2):447-52. High
prevalence of vitamin D insufficiency in black and
white pregnant women residing in the northern United States and their neonates.
8
In utero or early-life vitamin D deficiency is associated with skeletal problems, type 1 diabetes, and
schizophrenia, but the prevalence of vitamin D deficiency in U.S. pregnant women is unexplored. We sought
to assess vitamin D status of pregnant women and their neonates residing in Pittsburgh by race and season.
Serum 25-hydroxyvitamin D (25(OH)D) was measured at 4-21 wk gestation and predelivery in 200 white and
200 black pregnant women and in cord blood of their neonates. Over 90% of women used prenatal vitamins.
Women and neonates were classified as vitamin D deficient [25(OH)D<37.5 nmol/L], insufficient [25(OH)D
37.5-80 nmol/L], or sufficient [25(OH)D>80 nmol/L]. At delivery, vitamin D deficiency and insufficiency
occurred in 29.2% and 54.1% of black women and 45.6% and 46.8% black neonates, respectively. Five
percent and 42.1% of white women and 9.7% and 56.4% of white neonates were vitamin D deficient and
insufficient, respectively. Results were similar at <22 wk gestation. After adjustment for prepregnancy BMI
and periconceptional multivitamin use, black women had a smaller mean increase in maternal 25(OH)D
compared with white women from winter to summer (16.0+/-3.3 nmol/L vs. 23.2+/-3.7 nmol/L) and from
spring to summer (13.2+/-3.0 nmol/L vs. 27.6+/-4.7 nmol/L) (P<0.01). These results suggest that black and
white pregnant women and neonates residing in the northern US are at high risk of vitamin D insufficiency,
even when mothers are compliant with prenatal vitamins. Higher-dose supplementation is needed to improve
maternal and neonatal vitamin D nutriture.
The vitamin D research has critical implications for pregnancy as well as
neonatal health and a wide range of health problems. For example, recently,
vitamin D deficiency was shown to be associated with increased risk of death
from ALL causes.
Arch Intern Med. 2007;167:1730-1737. (Sept. 10) Vitamin D Supplementation and Total Mortality: A Meta-analysis of
Randomized Controlled Trials Arch Intern Med. 2007;167:1709-1710. (Sept. 10) Can Vitamin D Reduce Total Mortality?
Recently it has been suggested that the vitamin D deficiency during pregnancy may be
related to the increasing prevalence of autism. This is certainly just a very interesting hypothesis at
this stage, but because assuring adequacy has MANY other benefits during pregnancy and
throughout life, it is reasonable to simply assure (not assume) adequacy among pregnant women …
and everyone else. There are likely many benefits that have not yet been recognized related to
preventing vitamin D deficiency.
Here’s an abstract of a paper that describes why this issue worth looking into:
Med Hypotheses. 2008;70(4):750-9. Autism and Vitamin D. Any theory of autism's etiology must
take into account its strong genetic basis while explaining its striking epidemiology. The apparent
increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice
to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly
lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown
that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain
development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities
similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly
elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism.
Children with vitamin D deficient rickets have several autistic markers that apparently disappear with
high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol's
metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol downregulates production of inflammatory cytokines in the brain, cytokines that have been associated with
autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in
offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes,
urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in
dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the darkskinned. Conclusion: simple Gaussian distributions of the enzyme that activates neural calcitriol
combined with widespread gestational and/or early childhood vitamin D deficiency may explain both
9
the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical
advice to avoid the sun. Several types of studies could easily test the theory.
-----------------Other related recent reports: Prevalence of autism in children born to Somali parents living in Sweden: a brief
report. Dev Med Child Neurol. 2008 Aug;50(8):598-601. Increased occurrence of autism among Somali children-does vitamin D deficiency play a role? Tidsskr Nor Laegeforen. 2008 Sep 11;128(17):1986-7. Stay tuned!
For more on vitamin D issues please see my on-line handouts
“Vitamin D: It’s Not Just for Bones Anymore!” and
“My Current Top Five Easy Ways to Improve Your Family’s Nutrition.”
Vitamin D is added to milk and for many people it is not well known that it is rarely added to other
dairy products. Only in the recent past has vitamin D begun to be added to a few brands of yogurt, cheese,
and calcium-fortified orange juice [Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional
health. Am J Clin Nutr. 2003;77(6):1478-83.] Because the amount of vitamin D added to milk is 100 iu/cup, it is quite
unrealistic to expect that most people would obtain that the RDA for vitamin D from food. Also, note that the
Food Guide Pyramid suggests 3 servings daily “from the dairy group.” Women following that pattern would
not be likely to obtain the RDA of 400 iu of vitamin D, much less the higher amounts suggested in the north
or among those with dark skin.
Unfortunately, many people (including health professionals) are unaware of these fine points, and for this
reason (when it is actually checked) serum vitamin D levels are often found to be inadequate even when
calcium intake is appropriate and the RDA for vitamin D is provided. The new version of the Food Guide
Pyramid fails to address the problem. It shows a sample2000 kcal diet that provides the (too low) RDA for
vitamin D obtained in a week only by being heavily weighted with fortified milk and salmon. There is no
caveat included regarding supplementation being important especially for those who do not drink a lot of milk
or eat salmon . . . quite a lot of folks. The problem is completely ignored because of the simple fact that the
pyramid planners chose not to even list vitamin D at all on the list of essential nutrients! [Vitamin K –
another nutrient of increasing concern because of its newly discovered role in bone formation and the poor
utilization of the form we have relied on from intestinal bacteria -- is not on the list either.]
Poor vitamin D status is now identified as a risk factor for such diverse conditions as pre-eclampsia,
breast cancer, prostate cancer, colon cancer, multiple sclerosis, diabetes (both Type I and Type II), depression,
rheumatoid arthritis, osteoarthritis, osteoporosis, impaired fetal development, schizophrenia, myopathy
(muscle damage, including heart muscle damage), lupus, increased absorption of lead, schizophrenia and
fibromyalgia. This is due to the fact that vitamin D is activated by converting it into a key steroid hormone
(the 1,25dihydroxychole-calciferol form) that is structurally very similar to estrogen and testosterone.
Inadequacy has great potential for serious health consequences. So far, over 200 different tissues
throughout the body have been determined to have receptors for vitamin D hormone.
A few of the many references on this topic: Vitamin D deficiency in recently pregnant women. Rev Med Liege. 2008
Feb;63(2):87-91. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007 Sep;92(9):3517-22.Vitamin D
supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res. 2004 1;67(2-3):237-45. Beneficial
effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost.
2004;91(2):373-80. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia. 2004 31. Maternal blood
lead concentration, diet during pregnancy, and anthropometry predict neonatal blood lead in a socioeconomically disadvantaged population. Environ
Health Perspect. 2003;111(2):195-200. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin
Nutr. 2004;79(3):362-71. Vitamin D status of middle-aged women at 65-71 degrees N in relation to dietary intake and exposure to ultraviolet radiation.
Public Health Nutr. 2004;7(2):327-35. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study.
The prostate 25-hydroxyvitamin D-1{alpha}-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer
chemoprevention by vitamin D. Carcinogenesis. 2004 Jan 16. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-5. The
pleiotropic actions of vitamin D. Bioessays. 2004;26(1):21-8. Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev.
2003;61(7):227-38. The potential benefits of dietary and/or supplemental calcium and vitamin D. Urol Oncol. 2003;21 (5):384-91. Can vitamin D
10
supplementation in infancy prevent type 1 diabetes? Nutr Rev. 2002 60(4):118-21. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
Lancet. 2001;358(9292):1500-3. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a
large, population-based, case-control study. Am J Clin Nutr. 2003;78(6):1128-34. Nutritional risk predictors of beta cell autoimmunity and type 1
diabetes at a young age. Am J Clin Nutr. 2003;78(6):1053-67. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care.
2003;26(12):3237-42. Nutrition. The vitamin D deficit. Science. 2003 12;302(5652):1886-8. Vitamin D status as a determinant of peak bone mass in
young Finnish men. Arthritis Rheum. 2004;50(1):72-7. J Clin Endocrinol Metab. 2004;89(1):76-80. Vitamin D insufficiency in Greenlanders on a
westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes. Calcif Tissue Int. 2004;74(3):255-63. High prevalence
of vitamin D insufficiency in healthy elderly people living at home in Argentina. Eur J Clin Nutr. 2004;58(2):337-42. Vitamin D and prostate cancer
prevention and treatment. Trends Endocrinol Metab. 2003;14(9):423-30. Vitamin D: its role and uses in immunology. FASEB J. 2001;15(14):2579-85..
Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol. 2001;28(11):2535-9. Preeclampsia is associated with
low circulating levels of insulin-like growth factor I and 1,25-dihydroxyvitamin D in maternal and umbilical cord compartments. J Clin Endocrinol
Metab. 2000;85(5):1828-33.]
Because of the explosion of information on the critical functions of vitamin D hormone, adequacy is an
issue that must be looked at carefully both for a healthy pregnancy and for the long-term health of the
mother and child. This is also behind the 2008 recommendation of the American Academy of Pediatrics that
all infants and children should receive at least 400 iu vitamin D daily starting soon after birth, and that breastfed infants in particular are at risk of inadequacy without supplementation. This is in part a reflection of
the newly recognized reality that many babies are actually born vitamin D deficient because of
inadeqacy during pregnancy. Whether or not the disease relationships described above are
confirmed by subsequent research, it does illustrate the potentially broad implications of
inadequacy (or excessive intake) of this important hormone, and suggests that it would be prudent to
assess maternal intake carefully. [Prevention of rickets and vitamin D deficiency in infants, children and adlescents. Pediatrics October
13, 2008. 2008;122:1142-1152. The Canadian recommendation is 400 iu for infants. Vitamin D-deficiency rickets among children in Canada. CMAJ.
2007 Jul 17;177(2):161-6. Bones and beyond: an update on the role of vitamin D in child and adolescent health in Canada. Appl Physiol Nutr Metab.
2007 Aug;32(4):770-7.]
A newly recognized problem with perinatal iodine deficiency in the US
(and elsewhere) with serious reproductive consequences:
Iodine deficiency is a nutrition problem with well-known potential to harm fetal and infant neurologic
development. Since salt was iodized in the US it has been assumed that this problem was eradicated and it
has essentially gone off our radar screen. Emerging research (beginning in 2005) is demonstrating that this
problem continues to be a very serious threat. The issue is new enough and important enough that I have put
together a separate paper with current recommendations and descriptions of some key research.about this
critical topic.
Please see “Aunt Cathy’s Guide to Nutrition: New Attention to an Old Problem: Iodine Deficiency in Pregnancy and Lactation. 2009”
5. Evaluate the ratio of a woman’s intake of omega 6: omega 3 fatty acids, with a ratio of 4:1 as a goal,
and consider providing a generous amount of the omega-3 fatty acids as pre-formed EPA and DHA.
Most Americans consume these fats in a 10:1 ratio. A considerable body of research suggests that as a
start there are major health advantages associated with consuming these fats at a 4:1 ratio. The ratio appears
to be very important in areas such as risk of heart disease, cancer, HIV, depression, epilepsy, and
degenerative eye diseases. In each case, the direction of change that shows benefit is increasing
the proportion of dietary fats that are rich in oils of the omega-3 family in relation to the
intake of fats from the omega-6 family. In addition to the ratio of these two families of fat, consumption
of some of them as preformed 20-22 carbon long chain fatty acids appears to have special benefit in general
and in pregnancy in particular. The long chain omega-3 fats (EPA = eicosapentaenoic acid; DHA =
docosahexa-enoic acid) are found in fish and fish oil supplements.
11
Various advisories regarding hazardous levels of mercury or other toxins in certain fish have made it
more difficult to recommend fish consumption in general, especially during pregnancy. However, a recent
report on EPA-DHA (NOT on cod-liver oil, which is different in a number of ways) supplements available in
the U.S. appeared in Consumer Reports (2003.Jul;68(7): 30-2.) They evaluated the safety of products on the market
(e.g. related to mercury concerns, etc.,) the actual content of each product, and the price. The good news is
that they found all to be safe, and all products contained what the label said was in there. However the price
per 300 mg of supplemental fish oil ranged from 6 to 60 cents each!
[FDA warns on mercury in tuna. JAMA. 2004 Jan 14;291(2):171. Toxicology. Salmon survey stokes debate about farmed fish. Science. 2004 Jan
9;303(5655):154-5. Weighing health benefit and health risk information when consuming sport-caught fish. Risk Anal. 2003 Dec;23(6):1185-97.
Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol. 2003 Aug;102(2):346-51.]
Oils rich in omega-3 fatty acids appear to have important implications in pregnancy and infant
nutrition in particular. DHA (a 22 carbon omega-3 fatty acid) is a major fat of the brain, and the research
is growing that suggests that providing some pre-formed DHA is often advantageous. In a study over infants
in various parts of the world, values of arachidonic acid and docosahexaenoic acid showed two-fold
variability in cord blood of full term infants. The highest values of docosahexaenoic acid were observed in
countries with apparently higher consumption of dietary fat from sea fish. DHA is also known to be essential
for retinal development in infants.
Maternal essential fatty acid status declines during pregnancy, and as a result, neonatal concentrations of
docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) may not be optimal. Importantly,
maternal supplementation with the essential fatty acids linoleic and alpha linolenic acid did not promote
neonatal DHA+AA status. Maternal DHA supplementation significantly increases maternal DHA status and
limits the last trimester decline in maternal status, aiding preferential transfer of DHA from mother to fetus.
Long-chain PUFA (EPA, DHA, ARA) are therefore conditionally essential substrates during early life that
are related to the quality of growth and development. The amount of DHA in human milk varies widely and is
positively correlated with visual and language development in breast-fed infants. A dietary supply during
pregnancy, lactation, and early childhood that avoids the occurrence of LC-PUFA depletion is desirable, as
was recently recommended by an expert consensus workshop of the Child Health Foundation. Fetal growth
requires n-3 docosahexaenoic acid (DHA), which is derived from the n-3 fatty acids in the maternal diet.
Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal
relationships. DHA can be formed in the liver from alpha linolenic acid, but it is unclear if the rate of DHA
synthesis in humans is sufficient to support optimal brain and retinal development.
Differences in DHA status between women both in the non-pregnant state and in pregnancy may
reflect variations in metabolic capacity for DHA synthesis. One group of researchers noted that available
estimates suggest that 67 mg DHA/d is accumulated by the fetus during the third trimester of gestation.
Human milk concentrations of DHA have been noted to decrease in recent years and a low intake of DHA
among some pregnant women has been observed. The balance between the n-6 and n-3 PUFA in the maternal
diet rather than amount of n-6 or n-3 PUFA per se could be important for adipose tissue growth and for
maintaining adequate serum leptin levels in the offspring. In multiple pregnancies, fetal demand for ‘docosahexaenoic acid may not be entirely satisfied. It may be that a greater maternal intake of
docosahexaenoic acid should be encouraged for optimal tissue perfusion. Omega-3 fats are also associated
with decreased risk of premature delivery. As premature delivery is the most common cause of low infant
birth weight, and infant morbidity and mortality, this is a very important observation.
There may be a role for omega-3 fatty acids in allergy development, and possibly beneficial effects of n 3 PUFAs in diabetic pregnancy and in the prevention and treatment of long-term metabolic abnormalities
associated with macrosomia. It has also been reported that maternal alcohol intake can alter fatty acid
transport by the human placenta, decreasing fetal availability of polyunsaturated fats in general and of DHA
12
especially. It may be that this decreased DHA transport is one of the (many) mechanisms of FAS (Fetal
Alcohol Syndrome.)
There is not an official pregnancy-specific recommendation as yet, but the following
recommendations from the American Heart Association provide an idea of the range suggested in yet another
health condition for which these issues are being found to be important:
American Heart Association Recommendations for Omega-3 Fat Intake (2002)
People without
documented heart disease
People with
documented heart disease
People with high
triglycerides
Eat a variety of (preferable oily) fish at least twice a week.
Include oils and foods rich in alpha-linolenic acid (flaxseed,
canola and soybean oils; flaxseeds; and walnuts.
Eat about a gram of EPA+DHA daily. This can come from oily
fish or from fish-oil supplements.*
Take 2-4 grams of EPA+DHA provided as fish oil supplements.*
*As always, you should discuss this with your physician, since in certain situations
(like people on certain medications) there may be reasons to do things differently.
Rev Obstet Gynecol. 2008 Fall;1(4):162-9. Omega–3
Fatty Acid supplementation during pregnancy.
Omega-3 fatty acids are essential and can only be obtained from the diet. The requirements during
pregnancy have not been established, but likely exceed that of a nonpregnant state. Omega-3 fatty acids are
critical for fetal neurodevelopment and may be important for the timing of gestation and birth weight as
well. Most pregnant women likely do not get enough omega-3 fatty acids because the major dietary source,
seafood, is restricted to 2 servings a week. For pregnant women to obtain adequate omega-3 fatty acids, a
variety of sources should be consumed: vegetable oils, 2 low-mercury fish servings a week, and
supplements (fish oil or algae-based docosahexaenoic acid).
Some references on this topic: [Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy.
Acta Paediatr. 2009 Jun 1.Systematic review of fatty acid composition of plasma phospholipids of venous cord blood in full-term
infants. Eur J Nutr. 2002;41(3):125-31. Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal
polyun-saturated fatty acid status and pregnancy outcome. Am J Clin Nutr. 2004;79(2):251-60. Maternal docosahexaenoic acid
supplementation and fetal accretion. Br J Nutr. 2003;90(1):135-45. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy
and lactation augments children's IQ at 4 years of age. Pediatrics 2003; 111(1):e39-44; Maternal docosahexaenoic acid supplementation during
pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial. Arch Dis Child Fetal Neonatal
Ed.2003;88(5):F383-F390. Long chain polyunsaturated fatty acids improve cognitive development. Perinatal biochemistry and physiology of longchain polyunsaturated fatty acids. J Pediatr. 2003;143(4 Suppl) :S1-8. J Fam Health Care. 2002;12(6 Suppl):5. Higher maternal plasma
docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Am J Clin Nutr. 2002;76(3):608-13.
Neuroprotective effect of developmental docosahexaenoic acid supplement against excitotoxic brain damage in infant rats. Neuroscience.
2003;119(4):999-1012. Determinants of polychlorin-ated biphenyls and methylmercury exposure in Inuit women of childbearing age. Environ Health
Perspect. 2001;109(9):957-63. Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am J Clin Nutr. 2000;71(1
Suppl):307S-11S. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003;143(4 Suppl):S1-8. Synaptic lipid
signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res. 2003;44(12):2221-33. Effect of dietary n-3 fatty acids
on the composition of long- and very-long-chain polyenoic fatty acid in rat retina. J Nutr Sci Vitaminol (Tokyo). 2003;49(3): 210-3. Protective effect
of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors. Invest Ophthalmol Vis Sci. 2003;44(5):2252-9. Visual acuity
and retinal function in infant monkeys fed long-chain PUFA. Lipids. 2002;37(9):839-48. Scotopic electroretinogram in term infants born of mothers
supplemented with docosahexaenoic acid during pregnancy. Invest Ophthalmol Vis Sci.2003;44(8):3685-9. Docosahexaenoic and arachidonic acid
influence on preterm baboon retinal composition and function. Invest Ophthalmol Vis Sci. 2003;44(10):4559-66. Retinal sensitivity loss in thirdgeneration n-3 PUFA-deficient rats. Lipids. 2002;37(8):759-65. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J
Pediatr. 2003; 143(4 Suppl):S1-8.] Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of
the nervous system. Ann N Y Acad Sci. 2002;967:299-310. Pediatr Res. 2002;52(5):750-5. Conversion of alpha-linolenic acid to eicosapentaenoic,
docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr. 2002 88(4):411-20. Supplementing lactating women with flaxseed oil does
not increase docosahexaenoic acid in their milk. Am J Clin Nutr. 2003;77(1):226-33. Intakes of essential n-6 and n-3 polyunsaturated fatty acids among
pregnant Canadian women. Am J Clin Nutr. 2003;77(2):473-8. Leptin levels in rat offspring are modified by the ratio of linoleic to alpha-linolenic acid
in the maternal diet. J Lipid Res. 2002 Oct;43(10):1743-9. Maternal and umbilical cord erythrocyte omega-3 and omega-6 fatty acids and
13
haemorheology in singleton and twin pregnancies. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F134-8. A randomized trial of docosahexaenoic acid
supplementation during the third trimester of pregnancy. Obstet Gynecol. 2003;101(3):469-79. J Nutr.2003133(5 Suppl 2): 1606S-1625S. Exp Biol
Med (Maywood).2001;(226(6):498-506; BMJ.2002;324(7335): 447; Obstet Gynecol Serv.2001;56(5 Suppl 1):S1-S13; Pediatrics. 2001;108(2):35971; Obstet Gynecol Surv. 2001;56(5 Suppl 1):S1-13; Pediatr Clin North Am.2001;48(1):173-88; BJOG.2000;107 (3):382-95.) [Maternal and umbilical
cord erythrocyte omega-3 and omega-6 fatty acids and haemorheology in singleton and twin pregnancies. Arch Dis Child Fetal Neonatal Ed.
2003;88(2):F134-8. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at
high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003;112(6):1178-84. Implication of lipids in macrosomia of diabetic
pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects? Clin Sci (Lond). 2003;105(5):519-29.] Fish oil supplementation of rats during
pregnancy reduces adult disease risks in their offspring. J Nutr. 2003;133(10):3170-4. Decline in fish consumption among pregnant women after a
national mercury advisory. Obstet Gynecol. 2003;102(2):346-51 Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked
potential development in term infants: a double blind, prospective, randomised trial. Arch Dis Child Fetal Neonatal Ed. 2003;88(5):F383-90. Effects of
n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition. Eur J Clin Nutr. 2004;58(3):42937. The effect of maternal smoking and ethanol on fatty acid transport by the human placenta. Br J Nutr. 2002;87(3):247-52. The role of
docosahexaenoic acid in brain development and fetal alcohol syndrome. Biochem Soc Trans. 1998;26(2):246-52. Dietary fatty acids and alcohol:
effects on cellular membranes. Alcohol Alcohol. 1993;28(5):607-8. Effects of prenatal ethanol and long-chain n-3 fatty acid supplementation on
development in mice. 1. Body and brain growth, sensorimotor development, and water T-maze reversal learning. Alcohol Clin Exp Res.
1990;14(3):405-12. Effects of prenatal ethanol and long-chain n-3 fatty acid supplemen-tation on development in mice. 2. Fatty acid composition of
brain membrane phospholipids. Alcohol Clin Exp Res. 1990;14(3):413-20.
Because the omega-3 PUFAs contain a greater number of double bonds, a generous antioxidant
intake is advisable. In addition to the well-known nutrient antioxidants (vitamins C and E, selenium, etc.) the
pigments of brightly colored fruits and vegetables are now known to be especially potent antioxidants. These
include lycopene in tomatoes, lutein in leafy greens, anthocyanins in beets and raspberries, beta-carotene in
orange-colored foods, allicin and SAC in garlic, and many others. Because conditions like diabetes (or
other conditions involving altered metabolism, auto-immunity or inflammation) result in a greatly
increased production of free radicals, generous antioxidant intake is also recommended in these
situations. It appears to be protective at least against the increased risk of fetal damage due to the free
radical component. There are, of course, many additional health benefits for everyone associated with a
generous intake of brightly colored fruits and vegetables as well. See “Aunt Cathy’s Guide: Nutrition in Eye
Health” for some specifics about antioxidant sources and amounts.
Oxidative and antioxidative status in pregnant women with either gestational or type 1 diabetes. Clin Biochem. 2004;37(4):293-8. Changes in plasma
lipids and markers of oxidative stress in normal pregnancy and pregnancies complicated by diabetes. Clin Sci (Lond). 2004;106(1):93-8. Glutathione
metabolism and oxidative stress in neonatal rat tissues from streptozotocin-induced diabetic mothers. Diabetes Metab Res Rev. 2004;20(1):72-8.
Ascorbic acid, glycation, glycohemoglobin and aging. Med Hypotheses. 2004;62(2):275-9. Antioxidant, antidiabetic, antihyperlipidemic, reproduc-tion
stimulatory properties and safety of essential oil of Satureja Khuzestanica in rat in vivo: a oxicopharmacological study. Med Sci Monit. 2003;9
(9):BR331-5Reduced SOD activity and increased neural tube defects in embryos of the sensitive but not of the resistant Cohen diabetic rats cultured
under diabetic conditions. Birth Defects Res Part A Clin Mol Teratol. 2003;67(6):429-37.Lipid peroxidation and vitamin E status in gestational
diabetes mellitus. J Obstet Gynaecol Res. 2003;29(5):300-4. Circulating biomarkers of oxidative stress in complicated pregnancies. Arch Gynecol
Obstet. 2003;267(4):189-95. Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos. Diabetes. 2003;52(5): 12228. The role of reactive oxygen species in diabetes-induced anomalies in embryos of Cohen diabetic rats. Int J Exp Diabetes Res. 2002;3(4):247-55.
gamma-Linoleic acid and ascorbic acid ameliorate the effects of experimental diabetes on electrolyte and bone homeostasis in pregnant rats. J
Endocrinol. 2002;173(2):273-84.Effects of ergothioneine on diabetic embryopathy in pregnant rats. Food Chem Toxicol. 2002;40(12):1751-5. Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res.
2001;49(6):755-62.Vitamins C and E improve rat embryonic antioxidant defense mechanism in diabetic culture medium. Teratology. 2001;64(1):3344. Lipid peroxidation and scavenging enzyme activity in streptozotocin-induced diabetes. Acta Diabetol. 2000;37(4):179-83. Antioxidant therapy and
streptozotocin-induced diabetes in pregnant rats. Acta Diabetol. 1999;36(3):113-7. Lipoic acid prevention of neural tube defects in offspring of rats
with streptozocin-induced diabetes. Am J Obstet Gynecol. 1999;180(1 Pt 1):188-93.Role of reactive oxygen species (ROS) in the diabetes-induced
anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for
increased anomalies. Teratology. 1999;60(6):376-86. Teratogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabet-ologia.
1996;39(9):1041-6.Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol. 1996;175(4
Pt 1):793-9. Maternal antioxidant treatments prevent diabetes-induced alterations of mitochondrial morphology in rat embryos. Anat Rec.
1998;251(3):303-15The effect of vitamin E on antioxidant tissue activity in pregnant rats with streptozocin-induced diabetes Przegl Lek. 1998;55(6):
320-4. Prevention of diabetic embryopathy in offspring of diabetic rats with use of a cocktail of deficient substrates and an antioxidant. Am J Obstet
Gynecol. 1997;176(4):790-7Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes. 1997;46(6):1054-61.
Congenital malformations in experimental diabetic pregnancy: aetiology and antioxidative treatment. Minireview based on a doctoral thesis. Ups J Med
Sci. 1997;102(2):61-98.Antioxidant status and lipid peroxidation in diabetic pregnancy. Br J Nutr. 1997;78(4):523-32.Vitamin C supplement-ation of
the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia. 1997;40(12):1416-24.6):320-4.
6. If blood pressure begins to go up in the second half of pregnancy: Do not automatically decrease
sodium intake, and never recommend a diet restricted to 2 g sodium/day or less during pregnancy unless
special conditions like renal disease or congestive heart failure are involved and the physician has a special
reason for needing such a low level. In women with pre-eclampsia, a severe sodium restriction can actually
14
precipitate a seizure. Puffy feet and ankles in pregnancy are not caused by diet. With physician approval,
increase calcium to 2000 mg supplement (in addition to diet) and give magnesium at the RDA Ca:Mg ratio
(e.g. about 400 mg, since the RDA ratio is 300 mg Mg to 1200 mg Ca, the ratio with supplemental calcium
described above = 400 Mg : 2000 Ca.) High dose calcium in the absence of adequate magnesium may
increase risk of thrombotic events. In addition, remember to assure adequacy of vitamin D in order for the
calcium to be absorbed appropriately. This plan may or may not be helpful in the prevention or control of PIH
based on conflicting results from studies, but some individuals may respond favorably, and the intervention
appears to be benign. And since prevention is always preferable to treatment, there is evidence [described
earlier] that nutrition issues in the periconceptional period may also play a role in risk of development of preeclampsia later in pregnancy.
7. For nausea/hyperemesis problems, have M. Erick’s video “Morning Sickness: All Day and All Night”
(Lemon-Aid Films), and book “No More Morning Sickness” available for clients. In addition, the following
ideas may be helpful (many of which were initially published by Ms. Erick.)
•
Continued use of a multivitamin (they actually decrease nausea), and as described earlier, since the
prenatal type is not necessary in early pregnancy and they can be harder to tolerate, a standard multivitamin with minerals or a children’s chewable product taken with food is the best choice. If she is “gun
shy” about iron or vitamins in general because of poor tolerance of her prenatal vitamin, the psychological
advantage of a children’s vitamin can help (“It’s so gentle it’s for little children!”) as can the use of a
“silver” type product with little or no iron. In general, remember that the woman having problems with
eating is precisely the woman who is most in need of supplemental vitamins and minerals, so it is all the
more important to help her find one she can tolerate. Do not advise her to “just skip it until you feel
better.”
•
Ms Erick found that sniffing lemons and eating citrus foods (grapefruit, lemonade, etc.) often have a
marked diminishing effect on the feeling of nausea, especially among women whose nausea is triggered by
increased sensitivity to odors. Avoiding strong smells is helpful, so eating outdoors in nice weather is
pleasant, as is having someone else do the cooking while she goes for a walk. Cold foods usually are less
aromatic than hot foods. Even cooking smells that are normally pleasant (coffee brewing, sauces
simmering, etc.) can induce nausea in many pregnant women. And, of course, things that are unpleasant
under any circumstances can be even worse (garbage, the cat box, dirty diapers, etc.) so these are excellent
tasks for significant others who want to help. ☺)
•
Do not restrict the diet or advocate “clear liquids” as a treatment. For many women, liquids like water,
juice and pop are the most difficult to keep down. However, many can tolerate lemonade, and for some
ginger ale or ginger tea are helpful. Ginger appears to be safe in the amounts tested in hyperemesis
patients, and studies have supported that it apparently helps in some cases. In a survey of obstetricians,
51.8% reported using ginger in this context. “The most commonly cited herbs for morning sickness were
ginger, chamomile, peppermint and raspberry leaf (55, 37, 44 and 63% cited respectively). There was no
consensus in the popular literature about whether or not each of these herbs was safe for use in pregnancy.
Seven sources (6%) cited chamomile and peppermint as unsafe, while 16 (12%) cited the use of ginger and
11 (15%) the use of raspberry leaf as unsafe during pregnancy.” Another survey of 300 non-medical
sources studied 75 cited the use of herbs in pregnancy.
[A randomized comparison of ginger and vitamin B6 in the treatment of nausea and vomiting of pregnancy. J Med Assoc Thai. 2003 Sep;86(9):
846-53. A survey on the management of nausea and vomiting in pregnancy by obstetrician/gynecologists. Prim. Care Update Ob Gyns. 2001 Mar;
8(2):69-72.] [What do we know about herbal morning sickness treatments? A literature survey. Midwifery. 2000 Sep;16(3):224-8.]
15
•
Vitamin B6 (pyridoxine) and antihistamines have been shown to be helpful in some women, and the
research available suggests that these interventions are safe. However, the amount of vitamin B6 in multivitamins is only the RDA level (2 – 2.5 mg) and not the therapeutic level. Oral therapeutic levels used
range from 25-100 mg/day, and sometimes pyridoxine is administered as an injection. In any case, these
interventions during pregnancy require the approval of the physician or other primary care professional.
However, this level of intake IS available over the counter in the form of “B-100 Complex” supplements.
[Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2003;(4): CD000145. Nausea and vomiting of pregnancy.
Am Fam Physician. 2003 Jul 1;68(1):121-8. Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy. J
Perinatol. 2003 Oct;23(7):531-5. Bendectin and birth defects. II: Ecological analyses. Birth Defects Res Part A Clin Mol Teratol. 2003
Feb;67(2):88-97. Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. Am J Obstet Gynecol. 2002 May;186(5
Suppl Understanding):S253-5. The use of CAM by women suffering from nausea and vomiting during pregnancy. BMC Complement Altern Med.
2002 May 17;2(1):5. Health risks over the Internet: advice offered by "medical herbalists" to a pregnant woman. Wien Med Wochenschr.
2002;152(7-8):190-2. A survey on the management of nausea and vomiting in pregnancy by obstetrician/gynecologists. Prim. Care Update Ob
Gyns. 2001 Mar;8(2):69-72.]
•
Do not presume that her nausea has a psychological etiology. A few years back it was common in the
medical literature to find that the woman was blamed for the puzzle of hyperemesis gravidarum. (“She is
expressing her subconscious ambivalence about the pregnancy”, etc.) Old textbooks may still refer to this
sort of theory. The evidence that it was “all in her head” was sometimes based on her rapid improvement
when hospitalized and hooked up to i.v. glucose, which was described as a placebo. (“She responded to
simply getting attention.”) However, in this situation, the i.v. glucose was definitely not a placebo, but an
interruption of the fasting/nausea pattern. The glucose arriving in the bloodstream shuts off ketone
production, which may be one of the triggers of nausea in pregnancy. Note that once the glucose has
decreased the nausea, she needs to be told to begin “grazing” regularly on carbohydrate (and to eat other
foods, too, of course, as able) and to avoid fasting.
•
“Grazing,” (eating a little bit frequently and especially keeping the carbohydrate coming in) is an
important concept. It encourages small servings, which may be helpful, but it is the “frequent feedings”
aspect that seems to be the most beneficial. Old advice like “eat 6 small dry meals with 6 servings of
liquids half an hour after each meal” has been standardly given out and it can be helpful. However, it
appears that its usefulness is related less to the specific juggling of liquids and solids than it is to the fact
that she is taking in small meals of carbohydrate 12 times a day! Some women even set an alarm to go off
every two hours to make sure that carbohydrate is provided regularly because they feel nauseated once
they fast longer than that. The old advice about eating crackers or dry toast half an hour before getting out
of bed is probably helpful in the sense that it sends some carbohydrate down. Interestingly, there are no
studies showing a special benefit of dry toast or crackers at the bedside instead of any other carbohydratecontaining food, but this particular advice is regularly included in materials given to pregnant women.
Instead of just the old “cracker” advice, give her a larger “menu” of carbohydrate-containing food
suggestions. This is especially important if she is somewhat dehydrated; soda crackers can be unpleasant
when the mouth feels dry. In this regard, even the “avoid high fat food” advice often given may have been
useful (when it was helpful) primarily because if she ate isocalorically she would necessarily increase
carbohydrate intake by displacing fat. Plus, the presence of fat in food decreases the speed of stomach
emptying, thus delaying the absorption of carbohydrate and the shut-off of ketone production.
•
As a rule, do not tell her to automatically avoid particular foods, because (for example) even though some
women find greasy foods less palatable, others have good luck with them. In fact, one of the most well
tolerated foods is potato chips. In some cases reported, consuming a small bag of potato chips about half
an hour before supper significantly improved the women’s ability to eat the meal. Interestingly, potato
chips are less “empty calories” than one might expect . . . they provide carbohydrate (“Yes!!”), sodium,
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potassium, a little vitamin C, and energy to a woman desperately in need of all. At the very least, the chips
are better than not keeping anything down! Wash them down a little later with some lemonade!
•
Instead of telling her to avoid large numbers or types of foods, find out what foods she thinks she can eat,
and then find ways to make them available to her. In addition to chips, many women report tolerating
spaghetti, hard cooked eggs, chocolate milk, etc. At this stage the foods do not have to be particularly
“nutritious” . . . breaking the fasting/nausea cycle is the goal. Good nutrition is the focus a bit later.
•
Be aware of the potential serious danger from micronutrient deficiency (e.g. Wernicke’s encephalopathy
and other overt deficiency diseases have been documented), especially when primarily glucose or other
carbohydrates are provided via i.v. or “clear liquid’ diet without concomitant vitamin and mineral
supplementation in a woman who has been unable to eat well. At least 12 cases of this unfortunate
outcome have been reported in the literature, and all would have been prevented simply by the regular
provision of a multivitamin (oral or added to the i.v.)
[Memory loss and ataxia after hyperemesis gravidarum: a case of Wernicke-Korsakoff syndrome. Eur J Obstet Gynecol Reprod Biol. 2002 Apr
10;102(1):100-1. Hyperemesis gravidarum complicated by Wernicke's encephalopathy. Obstet Gynecol. 2002 May;99(5 Pt 2):875-7.]
•
For heartburn, chewing gum has been shown to be helpful because it increases saliva production and helps
neutralize stomach acid. Sugar-free gum is the choice from a dental perspective, but if a sugar-containing
gum is found to help a woman suffering from nausea and vomiting to control it by “grazing” on carbohydrates, that would likely be the preferred product. The “acid bath” from regular vomiting would certainly be
at least as detrimental to the tooth enamel as gum. There are also some new “antacid” gums available that
utilize calcium carbonate. An expert panel in the Netherlands recommended calcium/ magnesium-based
antacids as the treatment of choice for pregnant women because of their good safety profile.
[Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. Aliment
Pharmacol Ther. 2003 Aug 1;18(3):291-301 Clinical effectiveness of a new antacid chewing gum on heartburn and oesophageal pH control.
Aliment Pharmacol Ther. 2002 Dec;16(12):2029-35. Effects of gum chewing on pharyngeal and esophageal pH. Ann Otol Rhinol Laryngol. 2001
Dec;110(12):1117-9. Walking and chewing reduce postprandial acid reflux. Aliment Pharmacol Ther. 2001 Feb;15(2):151-5.]
8. Advise women to avoid:
•
Caffeine: Caffeine may increase risk of miscarriage and may affect fetal growth, although data are
conflicting. There are many phytochemical substances in coffee besides caffeine, so there is quite a lot of
sorting out to do. To the surprise of most people, several recent studies reported some benefits of both
substances in relation to health conditions like diabetes and parkinsonism. In pregnancy, the prudent
course is (and has been for some time) to “limit” intake of both substances. One recent publication had
this to say: “Currently available evidence suggests that it may be prudent for pregnant women to limit
coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased
probability of spontaneous abortion or impaired fetal growth.” [Coffee and health: a review of recent human
research. Crit Rev Food Sci Nutr. 2006;46(2):101-23. Association of maternal caffeine consumption with decrements in fetal
growth. Am J Epidemiol. 2003 Mar 1;157(5):456-66. Maternal serum caffeine metabolites and small-for-gestational age birth.
Am J Epidemiol. 2002 Jan 1;155(1):32-7.]
•
Alcohol: Alcohol is the number one preventable cause of mental retardation in America. Note that
the nutritional status of the mother is a critical variable in the degree to which exposure to potential
teratogens damages the fetus. For example, exposure to alcohol is significantly more damaging to the
fetus when the mother also has poor zinc status (a common finding among heavy users of alcohol). It
also appears that providing a generous antioxidant intake may decrease some of the toxic effects.
(References cited earlier.) Avoiding alcohol is the best advice, of course, but there is good that can be done
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with nutrition interventions, even among those who are unable to stop drinking. Many “problem drinkers”
WILL take nutritional supplements especially when the benefits to the fetus are explained. As a rule,
regular heavy drinkers are frequently found to have poor nutrition status with extremely detrimental
results, in particular in relation to zinc, folic acid, and thiamin. Folic acid absorption is specifically
inhibited by chronic alcohol use. Many other nutrients are often inadequate as well, but they are less
commonly recognized.
To optimize the care of this woman, don’t WONDER if she might be poorly nourished . . . ASSUME
that she is poorly nourished and ACT on it. If you are wrong and her nutritional status is actually
excellent, no harm will be done by providing levels of nutrients at the levels usually regarded as
appropriate for a healthy pregnant woman (i.e. RDA, RDI, etc.). But if she IS poorly nourished, there is the
potential to do great good by implementing relatively small, simple, safe and inexpensive interventions.
(For more information, see “Aunt Cathy’s Guide to Nutrition: Fetal Alcohol Syndrome”)
•
Smoking: Smoking exposes the fetus to carbon monoxide, nicotine, lead, cadmium, and to transport of
carcinogens. It reduces transport of nutrition and oxygen to the fetus, increasing risk of being born “smallfor Gestational age” (SGA.) A recent study “found that moderate smoking mothers deliver neonates with
decreased birth weight and highly correlated to placental cadmium concentration. Decreased metal
nutrient/pollutant ratios, a condition here found in smokers, may indicate a placental dysfunction,
contributing to impair birth weight.” [Metals content in placentas from moderate cigarette consumers: correlation with newborn birth
weight. Biometals. 2005 Jun;18(3):233-41.]
Cigarette smoking during pregnancy generates free radicals (as it always does regardless of pregnancy
status) and it has been implicated in oxidative cellular damage in fetuses. Two recent studies measured
vitamin E in maternal and cord blood of smokers and nonsmokers (as a marker of antioxidants available
to quench free radicals.) The women who smoked during pregnancy and the cord blood of their newborns
had a lower concentration of vitamin E in plasma and in erythrocytes as compared with group of nonsmoking women. The same researchers also measured malondialdehyde levels (a marker of lipid
peroxidation.) They found that malondialdehyde was higher in plasma and in erythrocytes of mothers
and babies in the “smoking” dyad, and concluded that smoking during pregnancy promotes free radical
damage in growing fetus and newborns and stimulates metabolic disorders dependent on oxidative stress.
This is likely an indication that antioxidant intake from vitamins, minerals and phytochemicals needs
special attention in these women. [The effect of tobacco smoking during pregnancy on concentration of malondialdehyde in blood of
mothers and in umbilical cord blood Ginekol Pol. 2005 Dec;76(12):960-5 The effect of tobacco smoking during pregnancy on concentration of
vitamin E in blood of mothers and their newborns in umbilical cord blood Ginekol Pol. 2006 Apr;77(4):263-8.]
•
Unsafe Food and Water: Undercooked meat, unpasteurized milk products, unpasteurized apple cider,
raw oysters, swordfish, etc., are potential sources of listeria, E. Coli O:157, toxoplasma gondii, mercury
and others organisms and substances that are especially dangerous in pregnancy. Avoid frequent
consumption of liver during pregnancy due to the finding that the retinol content is much higher than was
previously believed. Have well water checked for lead and other contaminants, along with the presence of
submersible pumps or faucets with bronze fittings that can leach lead into the water. The EPA Safe
Drinking Water Hotline has specific information about these issues: 1-800-426-4791. Poor nutrition also
plays a part because it compromises the ability of the immune system to protect against infection, it
impairs detoxification of harmful agents (e.g. by affecting the functioning of the cytochrome P450
system), and it also leads to greater absorption of certain toxic substances.
9.
Encourage weight gains within the currently accepted ranges (25-35 lbs for the “average” woman, etc.)
Weight gain in the first trimester has only recently been found to be very contributory to birth weight, so
helping women avoid significant weight loss due to nausea may be more important than was realized
earlier. This has huge public health implications, because low birth weight, specifically “small for
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gestational age” (SGA), appears to be a significant predictor of risk of several chronic diseases of
adulthood (diabetes, heart disease, etc.). This relationship is referred to as the “Fetal Origins Hypothesis”
or the “Barker Hypothesis.”
This topic has been the subject of a huge amount of research in the past few years, and just a small amount
some is noted below. Basically, it is quite clear that prenatal nutrition and other factors that affect
the growth and metabolism of the fetus can contribute to a number of very significant health
problems in later life. Some of the most studied relationships have been related to SIZE of babies as a
predictor of later health. At present the central research focus is teasing out exactly what factor is doing
what to whom and when. This is an onerous task, however, as the factors do not operate in isolation.
It is clear that being either a large- for-gestational age infant or a small-for-gestational age infant is at
higher risk of several negative outcomes in the long term. Why this is so is a tremendously complex
question. For example, if an effect is seen with excessive caloric intake in pregnancy, is it a function of:
•
•
•
•
•
•
•
•
the amount of calories?
the particular substances used to provide the excessive calories?
the timing of the exposure to excessive calories in relation to a critical fetal development period?
the genetic peculiarities of the study subjects?
the underlying health conditions of the subjects such as the mother’s metabolic state?
a disruption of the ratios of calories to the nutrients needed to appropriately metabolism them?
an interaction with other related factors?
the resultant size of the infant, or is size just a marker for some other problem?
How can we tell? Most studies can only chip away at a few questions at a time. However, we will need
to keep working to determine some answers to these kinds of questions or we may embark on promotion
of prenatal goals and policies that are not only unhelpful but potentially injurious.
Some references about the “Fetal Origins Hypothesis” concept: [Folate supplementation during pregnancy improves
offspring cardiovascular dysfunction induced by protein restriction. Hypertension. 2006 May;47(5):982-7. Nutritional control of fetal growth. Nutr
Rev. 2006 May;64(5 Pt 2):S50-1; discussion S72-91. Normal and abnormal fetal growth. Horm Res. 2006;65 Suppl 3:19-27. The late effects of fetal
growth patterns. Arch Dis Child Fetal Neonatal Ed. 2006 Jul;91(4):F299-304. Wheezing & eczema in relation to infant anthropometry: evi-dence of
developmental programming of disease in childhood. Matern Child Nutr. 2006 Jan;2(1):51-61. The developmental origins of adult disease. Matern
Child Nutr. 2005 Jul;1(3):130-41. Metabolic syndrome in childhood: association with birth weight, maternal obesity, & gestational diabetes mellitus.
Pediatrics. 2005 Mar;115(3):e290-6. Experimental models of developmental programming: consequences of exposure to an energy rich diet during
development. J Physiol. 2005 May 15;565(Pt 1). Life-long echoes--a critical analysis of the developmental origins of adult disease model. Biol
Neonate. 2005;87(2):127-39. 39. Blood pressure, serum lipids, fasting insulin, & adrenal hormones in 12-year-old children born with maternal
preeclampsia. J Clin Endocrinol Metab. 2003;88(3):1217-22. Maternal dietary ethanol consumption is associated with hyper-triglyceridemia in
adult rat offspring. Alcohol Clin Exp Res. 2002;26(6):848-55. Impaired glucose tolerance & elevated blood pressure in low birth weight, nonobese,
young South African adults: early programming of cortisol axis. J Clin Endocrinol Metab. 2000;85 (12):4611-8. Does birth weight predict adult
serum cortisol concentrations? 24-hour profiles in the United kingdom 1920-1930 Hertfordshire Birth Cohort. J Clin Endocrin-ol Metab.
2002;87(5):2001-7. Striking variation in the sex ratio of pups born to mice according to whether maternal diet is high in fat or carbohydrate. Proc
Natl Acad Sci. 2003;100(8):4628-32. Low birth weight & weight in infancy are associated with adult insulin resistance & type 2 diabetes. A
proposed mechanism is programming of the hypothalamic-pituitary-adrenal axis by intrauterine undernutrition, leading to persistently elevated
cortisol concentrations. Long-term programming of blood pressure by maternal dietary iron restriction in the rat. Br J Nutr. 2002 88(3): 283-90.
Maternal blood lead concentration, diet during pregnancy, & anthropometry predict neonatal blood lead in a socioeconomically disad-vantaged
population. Environ Health Perspect. 2003;111(2):195-200. Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clin Sci (Lond). 2002;103(6):633-9. Gender-linked hypertension in offspring of lard-fed pregnant
rats. Hypertension. 2003;41(1):168-75. Maternal energy stores & diet composition during pregnancy program adolescent blood pressure. Circulation. 2001;104(9):1034-9 Maternal nutrition during gestation & blood pressure in later life. J Hypertens. 2001;19(1):29-34. Size at birth, gestational
age & cortisol secretion in adult life: foetal programming of both hyper- & hypocortisolism? Clin Endocrinol (Oxf). 2002;57 (5):635-41. A deficient
maternal calcium intake during pregnancy increases blood pressure of the offspring in adult rats. BJOG. 2002;109(5): 540- 5. Insulin resistance in
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adult rat offspring associated with maternal dietary fat & alcohol consumption. J Endocrinol. 2002;173(1): 63-71. Diet in late pregnancy & glucoseinsulin metabolism of the offspring 40 years later. BJOG. 2000;107(7):890-5. Maternal consumption of a high-meat, low-carbohydrate diet in late
pregnancy: relation to adult cortisol concentrations in the offspring. J Clin Endocrinol Metab. 2003;88(8): 3554-60. Whole body insulin resistance in
rat offspring of mothers consuming alcohol during pregnancy or lactation: com-paring prenatal & postnatal exposure. J Appl Physiol.2004;
96(1):167-72. Olive oil consumption during pregnancy & lactation in rats influences mammary cancer development in female offspring. Nutr
Cancer. 2003;46(1):59-65. Effects of maternal ethanol consumption on hematopoietic cells in the rat fetal liver. Alcohol. 2002;28(3):151-6.]
Be wary of nutritionally inadequate weight loss diets undertaken prior to conception in order to
be at a “healthier” weight going into pregnancy. Weight may be more “ideal” but nutrient stores could be
severely compromised at a time when the fetus is most vulnerable to inadequacy.
For example, there is a higher risk of neural tube defects (NTDs) seen among the offspring of obese
women. However, it is unlikely to be corrected by a diet that provides inadequate folic acid, vitamin B-12,
vitamin B-6 and selenium, all of which have been shown to have a role in the prevention of NTDs. Some
studies find the folic acid – NTD relationship to be quite different among overweight mothers. This may
be because several other threats to a healthy pregnancy have not been corrected. Preconceptional weight
loss is not contraindicated, but it must be undertaken with careful attention to nutritional adequacy,
and appropriately planned vitamin/ mineral supplementation is advisable.
Another related issue is pregnancy after gastric bypass surgery. As this “bariatric” [weight
reduction] surgery is becoming more common, subsequent pregnancy is becoming a much larger issue.
Serious micronutrient inadequacies are appearing in the scientific literature in this population, including
devastating conditions like Wernicke’s encephalopathy from thiamine deficiency (multiple references cited
below.) Wernicke’s Encephalopathy has very overt symptoms and it is therefore far more recognizable
than deficiencies of many other nutrients. I believe the multiple cases reported of overt thiamine deficiency
after gastric bypass to be the “canary in the mine-shaft” -- it is likely a marker for other serious problems
that are much less visible. Bottom line: careful consideration of micronutrient intake levels and absorption
factors are especially critical in pregnancy post-bypass.
It is also useful to note that research is just in its infancy (no pun intended) regarding understanding of
the issues involved in post-bariatric surgery pregnancy and of bariatric surgery in general. Some reports
indicate that after weight-loss surgery certain pregnancy complications were indeed less than those
found in control groups of women similarly obese but not undergoing surgery. Obesity is well known
to be associated with an increase in many risks to a successful pregnancy, such as diabetes, pre-eclampsia,
diabetes complications and c-section. However, reports describing pregnancy after bariatric surgery
as “safe” have so far only compared those immediate pregnancy complications as the outcome
measurement of the study. Additionally, the number of cases studied in this way is still quite small, and
the women were (by definition) those receiving prenatal health care. Its “safety” in terms of the optimal
health and development of the fetus and the continued health of the mother in terms of nutrient
adequacy (and not just changes in degree of fatness) is only beginning to be investigated.
A recent report demonstrated that individuals who are morbidly obese and planning gastric
bypass surgery are ALREADY deficient in a number of nutrients before the surgery takes place.
[Preoperative Nutritional Status of Patients Undergoing Roux-en-Y Gastric Bypass for Morbid Obesity. J Gastrointest Surg. 2006 JulAug;10(7):1033-7.] One might reasonably extrapolate from this situation as well to question whether the
overall nutritional status of other seriously obese individuals might be similarly affected (whether planning
surgery or not,) and to consider what might be done to correct things prior to conception.
Again, the first critical step is simply recognizing that:
•
micronutrient inadequacies in the general public are not uncommon;
20
•
•
•
women are generally at higher risk;
people who battle with overweight could easily be at additional risk because of a history of food
restricting weight-loss attempts, and the use of medications or purging to induce weight loss;
“malnutrition” includes micronutrient inadequacy and not just calories and protein; in
America malnutrition is not at all limited to people who are underweight.
Some additional references on this topic: Pregnancy after bariatric surgery: a comprehensive review. Arch Gynecol Obstet. 2008
May;277(5):381-8. Reproductive Considerations and Pregnancy after Bariatric Surgery: Current Evidence & Recommendations. Obes Surg. 2008
Apr 8. Pregnancy Following Gastric Bypass Surgery for Morbid Obesity: Maternal & Neonatal Outcomes. Obes Surg. 2008 Mar 4. Pregnancy
outcomes after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2008 Jan-Feb;4(1):39-45. Reproductive implications of bariatric
surgery: pre- & postoperative considerations for extremely obese women of childbearing age. Curr Diab Rep. 2007 Aug;7(4):281-8. Effect of Body
Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies. BMC Public Health. 2007 Jul 24;7(147): 168 Nutritional
consequences of bariatric surgery. Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):489-496. Acute psychotic disorder after gastric bypass surgery:
differential diagnosis & treatment. Am J Psychiatry. 2006 Jan;163(1):15-9. Wernicke encephalopathy after bariatric surgery: losing more than just
weight. Neurology. 2005 Dec 27;65(12):1987. Eating avoidance disorder & Wernicke-Korsakoff syndrome following gastric bypass: an underdiagnosed association. Obes Surg. 2005 Sep;15(8):1207-10. Wernicke encephalopathy--an emerging trend after bariatric surgery. Am J Med. 2004
Nov 15;117(10):804-5. Wernicke's encephalopathy after Roux-en-Y gastric bypass. Obes Surg. 2004 Sep;14(8):1135-7. Stroke & seizure following
a recent laparoscopic Roux-en-Y gastric bypass. Obes Surg. 2004 Jun-Jul;14(6):857-60. Acute Wernicke's encephalopathy following bariatric
surgery: clinical course & MRI correlation. Obes Surg. 2004 Jan;14 (1):129-32. Rapid onset of Wernicke's encephalopathy following gastric
restrictive surgery. Obes Surg. 2003 Aug;13(4):661-2. .A cluster of polyneuropathy and Wernicke-Korsakoff syndrome in a bariatric unit. Obes
Surg. 2002 Jun;12(3):328-34. Wernicke encephalopathy in non-alcoholic patients. Am J Med Sci. 2002 Feb;323(2):107-11. Wernicke's syndrome
after bariatric surgery. Clin Nutr. 2000 Oct;19(5):371-3. Wernicke-korsakoff encephalopathy & polyneuropathy after gastroplasty for morbid
obesity: report of a case. Arch Neurol. 2000 Sep;57(9): 1356-9. A rare complication of adjustable gastric banding: Wernicke's encephalopathy.
Obes Surg. 2000 Jun;10(3):274-5. A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness immediately after
intravenous infusion of thiamine No To Shinkei. 2000 Jan;52(1):59-63. Alcohol & poor compliance as factors in Wernicke's encephalopathy
diagnosed 13 years after gastric bypass. Can J Surg. 1998 Oct;41(5):389-92. Starvation injury after gastric reduction for obesity. World J Surg.
1998 Sep;22(9):1002-7. Wernicke's encephalopathy developed several years after total gastrectomy. Report of 2 cases Rinsho Shinkeigaku. 1997
Nov;37(11):1027-9. Wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity. Eur J Surg. 1997 Jun;163(6):473-4.
Wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity. BMJ. 1996 Feb 17;312(7028):434. ]
10. Pregnant women with metabolic conditions such as diabetes (Type I or II or gestational), Lupus,
Crohn’s disease, Celiac disease, MS, Epilepsy or multiple allergies have special nutrition problems
that are often unrecognized.
These include altered requirements for specific nutrients, and drug/nutrient interactions of
special concern in pregnancy. These metabolic conditions result in significantly more inflammation and a
greater production of injurious free radicals.
It has been shown that women with diabetes can decrease the risk of birth defects and other
complications by maintaining good glycemic control prior to and throughout pregnancy. However, careful
attention to micronutrients such as providing generous antioxidants, an appropriate omega-3 to omega-6
ratio, and adequacy of vitamins and minerals (e.g. selenium and magnesium) has been shown to further
decrease the risk.
B vitamin adequacy appears to be even more important in women with insulin resistance / gestational
diabetes in regulating homocysteine levels. As there are pregnancy complications specifically associated
with elevated homocysteine in women with gestational diabetes, attention to this interaction may be very
important. [Total plasma homocysteine correlates in women with gestational diabetes. Arch Gynecol Obstet. 2008 Jan 31. Teratogenicity
associated with pre-existing and gestational diabetes. J Obstet Gynaecol Can. 2007 Nov;29(11):927-44.]
Other examples and references were included earlier (such as epilepsy control medications and their
interactions with folic acid, vitamin D, vitamin K and carnitine.)
21
Here are a few additional references regarding nutrition and epilepsy treatment:
[Carnitine status of
pregnant women: effect of carnitine supplementation and correlation between iron status and plasma carnitine concentration. Eur J Clin Nutr. 2009
Jun 3. Importance of monotherapy in women across the reproductive cycle. Neurology. 2007 Dec 11;69(24 Suppl 3):S10-6. Pregnancy and
epilepsy : Retrospective analysis of 118 patients. Nervenarzt. 2008 Apr 4. Antiepileptic drug use, folic acid supplementation, and congenital
abnormalities: a population-based case-control study. BJOG. 2008 Jan;115(1):98-103. Management of epilepsy in women of childbearing age:
practical recommendations. CNS Drugs. 2006;20(5):373-87. Valproic acid in epilepsy : pregnancy-related issues. Drug Saf. 2006;29(1):1-21.
Recent advances on neural tube defects with special reference to Valproic Acid. Endocr Metab Immune Disord Drug Targets. 2006 Mar;6(1):2531.Antiepileptic drugs: a case report in a pregnancy with a neural tube defect. Pediatr Neurol. 2006 Apr;34(4):323-4. Best practice guidelines for
the management of women with epilepsy. Epilepsia. 2005;46 Suppl 9:117-24.]
Note that the standard recommended nutrient intakes for pregnant women are (by definition) based on the
needs of “98% of the healthy population” and they simply cannot be relied upon to meet the needs of
women who are not members of that group. Carefully assessing and adjusting the diet or supplement
regimen can significantly improve outcomes for these women and their babies, especially when any
necessary adjustments are made prior to conception.
Stay Tuned!
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MeritCare Medical Center
Aunt Cathy’s Guide:
My Current Top Five
Easy Ways to Improve
Your Family’s Nutrition
Aunt Cathy
(subject to change at any moment! ☺)
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical/Metabolic Nutrition Specialist
MeritCare Medical Center, Fargo, ND
This is a quick summary of some things in the nutrition news that can make a big
difference in people’s health. Although references are not provided in this brief version,
all the suggestions are based on reports in the legitimate scientific literature and the
references are available on my more thorough papers that are also on this website (see
page 10.) The recommendations are not based on goofy things found on the internet.
When “researching” a topic on the internet, it is important to consider the reliability of the
source. After all, there is no law against fiction in America! People can pretty much
print anything. For example, websites that end in .edu (colleges and universities) tend to
be more reliable than sites designed primarily to sell you something. And of course, none
of the following suggestions are intended to take the place of the advice of your health
care provider.
1. Eat lots of brightly colored fruits and vegetables. There are many beneficial
phytochemicals (plant chemicals) that have been found to have a potentially protective
role against a variety of common health problems such as cancer, heart disease, diabetes,
MS, birth defects, and macular degeneration (a form of blindness.) Some of them act as
protective “antioxidants,” but they have many other benefits as well.
Some of the beneficial substances are actually the pigments that give the plants their
color. Some examples are: lutein in green leafy vegetables, lycopene in tomatoes and
watermelon, beta-carotene in peaches and carrots, anthocyanin in blueberries and beets
and zeaxanthin in corn. It turns out that white is a color too, in terms of phytochemicals.
Apples for example, have quercetin, a flavonol phytochemical with a number of
potentially beneficial effects.
An example of other beneficial substances in fruits and vegetables is sulforaphane in
broccoli, which appears to decrease risk of colon cancer especially. Compared with meats,
and high fat dairy foods, they are much lower in fat and calories. We tend to eat way too
little of these terrific foods, and it hurts us.
To get the best of all of them, eat a wide variety of fruits and vegetables of many
colors, and aim for 9 servings a day (an amount that has been shown to be beneficial in
some studies.) Some expert groups suggest even more. My official recommendation is
“Eat all the brightly colored vegetables and fruits that you can get your hands on!”
1
Nine servings seems like a lot to most folks, since many people eat very few. In fact,
the french fry is the most commonly eaten vegetable in America. Hmmmm. Not an
ideal pattern. Start by adding a couple servings and working up. Throw some chopped
green pepper and dried tomatoes on the pizza. Keep those ready-to-eat baby carrots on
hand. Make it EASY for us to grab the healthier snack as we run out the door.
Canned, frozen or fresh fruits and vegetables all count because the brightly colored
antioxidants are not destroyed by heat! If you use canned veggies, watch out for the salt
they often can them with. Choose low sodium versions, or at least rinse them off. This is
not an issue with fruits, or with frozen veggies except if they are packed in some kind of
sauce. Remember that color is a big deal, so choosing only iceberg lettuce won’t provide
the dark green lutein found more generously in romaine or spinach. Color variety is key.
Check out “Aunt Cathy’s Ideas for Trying to Eat More of Those Terrific Antioxidant Phytochemicals . . .
and Liking It” for ideas for adding them to our diet. This and many other nutrition topics are available at
meritcare.com, including any mentioned throughout this paper as having more information on a topic.
Information on how to find them is included at the end of this paper.
The dark leafy veggies are also terrific sources of vitamin K, a nutrient just now being
recognized as critical to decrease risk of osteoporosis, cardiovascular disease, kidney
stones, liver and colon cancer and arthritis. It is also a nutrient found to be low in the diets
of many Americans. It appears that the elderly need more than the current RDA of 90-120
mcg/day. This information is so new that vitamin K is not even included in most
multivitamins currently on the market, and many health professionals will not yet have
heard about these new issues.
[Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-5.]
If you are taking medications to prevent blood clots, be sure to show this
information to your doctor before adding a lot of vegetables to your diet.
New research on the relationship between vitamin K and these drugs will result in
changes in how we do things. But because the information in support of these changes
is very new, it will also be new to many healthcare providers, so I have put a ‘Vitamin
K” handout on line that includes all the scientific references and detail that your doctor
will want to see before making any changes in diet or medication. Your doctor can
also contact me for the most recent reports on this topic.
2. When you eat grains, try to use whole grain whenever possible. The “germ” (the part
that becomes the baby plant) and the bran (the fibrous coating) of grains are removed in
processing when grains are “refined.” These are the parts that would have contributed the
most magnesium, chromium, vitamin E, fiber and many other nutrients. Magnesium and
chromium have important roles in using the rest of the grain (the starchy part) for energy
and for avoiding diabetes.
Large national studies (such as NHANES by the National Center for Disease Control in
Atlanta) have shown that the majority of Americans have a diet too low in these minerals.
2
This inadequacy contributes to weight problems, diabetes, heart disease and some
neurologic problems that are too common in our society.
“Enriched” grain products have only a few nutrients replaced (vitamins B1, B2, B3,
and iron) out of all the nutrients that are removed when refining grain. This label can be
confusing because the word “enriched” sounds like something was made to be even better.
Instead, it means “not as nutritious as whole grain.” If you don’t like whole grain bread
and pasta, you can still add back the nutrients they contain by adding wheat germ and bran
to other foods. Check out “Aunt Cathy’s Industrial Strength ‘Instant’ Oatmeal Recipe” for
some ideas.
3. Nuts, seeds, peanuts and dried beans/peas are terrific nutrient-rich foods because
they are essentially the germ of new plants. For example, in one study from Harvard,
eating an ounce of nuts or peanuts four times a week or more was shown to be related to
25% less likelihood of developing diabetes. This appears to be associated with the
generous magnesium in these foods. They also have more “satiety value” – you feel like
you actually ATE something” -- and they are terrific nutritious snacks including for people
who are watching their weight or who have diabetes.
Although all fats have about 9 calories per gram, the forms of fat in nuts and peanuts
(mostly “monounsaturated” and “omega-3” fats) are less contributory to heart disease than
many other forms of fat. Also they are rich in nutrient content so they are not an “empty
calorie” food. So, although they do have calories, I think of these forms of fat as
potentially “Dangerous to your butt, but not to your heart!” Additionally, dried beans and
peas are also very low in fat and high in fiber. It looks like that means chili beans, lima
beans, split peas, chick peas, navy beans, lentils, pinto beans, etc., are “health foods!”
These foods, and assuring adequacy of magnesium (and chromium, another key
mineral in the same foods) in general, are especially beneficial for people who appear to
be genetically (or for whatever reason) at greater risk of developing diabetes. This
includes people who have family members with diabetes, people who are overweight, and
some ethnic groups who appear to be disproportionately at risk.
For example, serious health problems related to diabetes have been found to be
causing much more injury to Native Americans and African Americans than to some other
groups of folks. There are many contributing factors, of course, but assuring adequacy of
magnesium and chromium (another key mineral in the same foods) is one factor that can
be easily corrected if people just hear about it. [Vitamin D is another, as discussed later.]
4. Another important form of fat to include in our diet is called “omega-3” fat. A lot of
research shows that it is associated with a decreased risk of cancer, heart disease,
inflammatory disease, depression, pregnancy problems, and much more. We Americans
tend to eat too much of another family of fat called omega-6 fat, such as that found in corn
oil. To improve the balance in the American diet, flax, canola and walnuts are great plant
sources of omega-3 fat.
3
Additionally, there is a huge amount of research showing that the special forms of
omega-3 fats found in fish and fish-oil supplements (EPA and DHA) have certain very
important advantages for many people. EPA decreases inflammation in a wide range of
inflammatory diseases like MS, cardiovascular disease and arthritis. I think of EPA
(whose real name is eicosapentaenoic acid) should be thought of as “Environmental
Protection Agency” instead, because it seems to be very protective against a number of
health problems.
DHA in particular appears to be very important for the development of the brain and
the retina of the eye, so it is critical during pregnancy and infancy. It has also been shown
to be helpful in the continued good operation of the brain (e.g. in possibly helping to ward
off age-related problems like alzheimers and other forms of dementia,) and for decreased
risk of, or progression of, depression, blindness due to macular degeneration, attention
deficit disorder and Parkinson’s disease.
More research is ALWAYS needed, of course, but the cumulative results of a great
many studies have been in the same direction. Assuring an adequate intake of these fats
looks like a VERY good idea. Additionally, it is now recognized that for some people it
is difficult to efficiently convert the plant omega-3 oils (like those in canola, flax and
walnuts) into the important EPA and DHA oils that are found ready-made in the fish
oil. This may be a factor in a broad range of inflammatory conditions and critical in
pregnancy.
The American Heart Association recommends 1000 mg of fish oil for most people
with risk of heart disease. People at risk include those who smoke, who have disturbed
blood lipids (too much LDL cholesterol or triglycerides, or too little HDL cholesterol,)
who are overweight or sedentary, or who have high blood pressure, diabetes, or a family
history of heart disease. Other factors contribute to heart disease risk as well.
[Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3 Fatty
Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005.
Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S.]
Saturated fats have long been on our list of “foods to eat less of.” These include
lard/meat fat, butter/dairy fat, and “hydrogenated” (solidified) oils like shortening or
margarine. None of these is a good source of omega-3 fat. Eating less of them and
choosing foods that are more generous in their omega-3 fat content is a very good idea.
Some shortenings and margarines accidentally contain “trans” fat, another “good-toavoid” form of fat that must be shown on the nutrition labels of foods if there is more than
½ gram per serving. It is usually in food because the oil was “partially hydrogenated” to
make it solid at room temperature like margarine or shortening. It is gradually being
removed from our food supply because it is quite unhealthy. The biggest source at present
is in baked goods made with shortening. Some margarines and shortenings are now made
that have no trans fat in them, and they usually note this on the label because it is such a
good thing.
4
5. Increase your regular intake of vitamin D to assure an intake that averages at least
1000 iu per day (for some folks 2000) and take a multivitamin with minerals daily in
addition to “eating right.” This is a markedly different recommendation because new
research shows that older recommendations of 200-400 iu of vitamin D were simply too
low to assure adequacy. Some researchers have found that even 1000 iu may be too little
for some people in terms of optimizing health and minimizing disease risks, especially
among people with dark skin or who live up north. In certain situations, 2000 iu appears to
be needed. (More on that later.) In the northern third of the country vitamin D
deficiency is now being described as “an unrecognized epidemic.” [See map on p. 12]
It is now known that inadequate vitamin D status is very common, and that it is associated
with increased risk of diabetes, lupus, scleroderma, fibromyalgia, multiple sclerosis,
cancer of the breast, colon, prostate, endometrium and pancreas, heart disease, muscle
pain, osteoporosis, rheumatoid arthritis, osteoarthritis, obesity, muscle weakness and poss
preserving cognitive function in older adults.
Other associations of inadequate vitamin D are now beginning to be explored such as
increased risk of parkinsons disease, autism, asthma, impairment of the immune system,
pre-eclampsia and cancer of the lung. This is not surprising because it has now been
recognized that vitamin D actually functions as a key steroid hormone -- one that your
body would make as needed … if you just give it enough of the material to do the job.
Over 200 different body tissues have been identified so far that have receptors for the
vitamin D hormone, and they need it in order to work properly. “Vitamin D is a
unique vitamin. Its metabolic product, calcitriol, is a profound secosteroid hormone that
has impact on over 1000 genes in the human body.” Modern concepts in the diagnosis and treatment of
vitamin D deficiency and its clinical consequences. J Environ Pathol Toxicol Oncol. 2009;28(1):1-4.
[Vitamin D and aging. J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):78-84. Vitamin D and type 2 diabetes Is there a link? Prim
Care Diabetes. 2009 Apr 21. Behavioural and physical characteristics associated with vitamin D status in women. Bone. 2009
Jun;44(6):1085-91 Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus
Erythematosus. J Pediatr. 2009 May 14. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged
and older European men. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):722-9. Sex-specific association of serum vitamin D levels with
physical function in older adults.Osteoporos Int. 2009 May;20(5):751-60. Vitamin D status and muscle function in post-menarchal
adolescent girls. J Clin Endocrinol Metab. 2009 Feb;94(2):559-63. 25. Vitamin D Supplementation and Reduced Risk of Preeclampsia
in Nulliparous Women. Epidemiology. 2009 May 15. Association of 25-Hydroxyvitamin D With Blood Pressure in Predominantly 25Hydroxyvitamin D Deficient Hispanic and African Americans. Am J Hypertens. 2009 May 14. Effect of vitamin D supplementation in
the institutionalized elderly. J Bone Miner Metab. 2009 May 15. Association between serum 25-hydroxyvitamin D level and upper
respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):38490. Nutrition and health: guidelines for dental practitioners.Oral Dis. 2009 May 15. Hypovitaminosis D in obese children and
adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008 Feb;57(2):183-91. 25Hydroxyvitamin D and Risk of Myocardial Infarction in Men A Prospective Study Arch Intern Med. 2008;168(11):1174-1180.
Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Vitamin D in Health and Disease.
Clin J Am Soc Nephrol. 2008 Jun 4. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology.
2008;31(4):271-9]
Another emerging area of research is the role of vitamin D inadequacy as a factor in
heart disease. Cardiovascular disease is the most common cause of death in the US, so this
is a very important issue. In a “meta-analysis” (looking at data of many studies at once)
published recently the risk for mortality (death) from all causes was found to be
significantly less among people taking an ordinary dose of a vitamin D supplement
compared with those who did not. Another prospective study concluded that a low vitamin
D level in the blood was associated with a higher risk of death from all causes, and
specifically with heart attack as well.
5
[Circulating calcitriol concentrations and total mortality. Clin Chem. 2009 Jun;55(6):1163-70. Vitamin D and cardiovascular disease.
Pharmacotherapy. 2009 Jun;29(6):691-708.Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis.
2009 Jun 6. Prospective Study of Serum 25-Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All-Cause Mortality in
Older U.S. Adults. J Am Geriatr Soc. 2009 Jun 22 Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After
Rosuvastatin Treatment: A Novel Pleiotropic Effect of Statins? [Crestor] Cardiovasc Drugs Ther. 2009 Jun 20. Independent association
of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med.
2008:168(12):1340-1349. Vitamin D and cardiovascular disease risk. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):7-12. Macro- and
micronutrients in patients with congestive heart failure, particularly African-Americans. Vasc Health Risk Manag. 2007;3(5):743-7.
Vitamin D supplementation & total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 10;167:1730-7]
Can we make adequate vitamin D in our skin?
We can make adequate vitamin D in our skin, but only
1. if we live where the angle of the sun is more directly overhead (i.e. not up north,)
2. if we are not covered up with clothes or sunscreen most of the time,
3. if our skin is not old or darkly pigmented,
4. if we do not take anti-seizure medications and
5. if we are not severely overweight.
Even at the equator there are many reports of people being found to have serious
vitamin D deficiency simply because they are covered up much of the time. Some are
covered up for religious reasons, some to prevent skin cancer (melanoma) and some of us
are just covered up as a public service! ☺ We all need to be sure to get adequate vitamin
D some other way. People who work nights also need to think about this. It is estimated
that about 50% of the earth’s population is at risk of vitamin D deficiency.
[Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin
D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.]
Did you know that the men at greatest risk of prostate cancer are older AfricanAmerican men living in the north? African-American women living in the north also have a
higher incidence of breast cancer, which appears to also be associated with low vitamin D
status. Many researchers believe that we can lower the risk by correcting the inadequacy of
vitamin D that is so common among people up north and among people of color.
For example, recently blood tests evaluating the ACTUAL vitamin D status of AfricanAmerican mothers and their newborns in Pittsburgh found that over half in each
group was vitamin D deficient, even if prenatal vitamins were regularly used. This has
many very serious implications, but it could be remedied by more generous supplementation
of this key vitamin. Attention to this is long overdue. About a third of white mothers and
babies in the same northern study were also found to be deficient.
In another new report it was found that a daily intake of 2000 iu of vitamin D assured
that dark-skinned northern women maintained a desirable blood level of greater than 50
ng/ml. Another study found that 2000 iu daily could raise the storage form of vitamin D in
blood to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer
in observational studies. Ironically, 2000 iu daily had long been set as the presumed upper
level of safety for vitamin D intake. Many experts have expressed the opinion that the
upper level of safety should be changed to a chronic intake of 10,000 iu daily.
What serum (blood) levels of vitamin D are associated with good health?
6
A recent report found evidence suggesting that higher vitamin D intakes beyond
current recommendations may be associated with better health outcomes. They looked at
a number of studies related to bone mineral density (BMD), lower extremity function,
dental health, risk of falls, admission to nursing homes, fractures, cancer prevention and
hypertension (high blood pressure.)
Their conclusion: “For all endpoints, the most advantageous serum levels for
25(OH)D appeared to be at least 75 nmol/l (30 ng/ml) and for cancer prevention,
desirable 25(OH)D levels are between 90-120 nmol/l (36-48 ng/ml). An intake of no
less than 1000 IU (25 mcg) of vitamin D3 (cholecalciferol) per day for all adults may
bring at least 50% of the population up to 75 nmol/l. Thus, higher doses of vitamin
D are needed to bring most individuals into the desired range. While estimates
suggest that 2000 IU vitamin D3 per day may successfully and safely achieve this goal,
the implications of 2000 IU or higher doses for the total adult population need to be
addressed in future studies.”
[Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.]
[Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Prevalence of vitamin D deficiency
among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008:162(6):505-512 Hypovitaminosis D among healthy children in the
United States. .Arch Pediatr Adolesc Med. 2008:162(6):513-519. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of
deficiency. J Perinatol. 2007 Sep;27(9):568-71. Dose response to vitamin D supplementation among postmenopausal African American
women. Am J Clin Nutr. 2007 Dec;86(6):1657-62. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr.
2007 Mar;85(3):649-50. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3-5):708-11]
Clearly a lot more research is needed … it is ALWAYS needed …but these new reports
are a great illustration of the emerging broad importance of this issue. The 1000 iu level is
safe in general and the 2000 iu level is safe (and may be necessary) in some cases . . .
what is clearly NOT safe is allowing a person to have a low vitamin D level.
[Vitamin D Status: Measurement, Interpretation, and Clinical Application. Ann Epidemiol. 2008 Mar 8. Sunlight, UV-radiation,
vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin D deficiency: a worldwide
problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.]
Taking in this amount of vitamin D will require using a supplement. The primary
supplemented food in our diet is fortified milk with 100 iu/cup, but ten cups of milk is not
reasonable, and it is also not good nutrition. One would have no room left for other foods.
Start with a regular multivitamin with minerals. That provides 400 iu. If you drink a lot of
milk, that combination may be adequate. Otherwise, you can easily add a tiny, easy-toswallow inexpensive 400 –2000 iu vitamin D capsule, or a calcium supplement with a similar
amount of vitamin D. There are even tiny 1000 iu “gummi”-type vitamin D products available.
Vitamin D can be stored well in the body, so some people prefer taking a week’s
worth of extra vitamin D all on one day. There are few foods naturally high in vitamin D –
really just salmon, tuna and cod-liver oil – which are problem foods for many people.
We will begin to see more foods being supplemented now that the public is becoming aware
of the problem. Some yogurt and cheese now have a little vitamin D added, and the calciumfortified orange juices are now supplemented as well. Other foods will likely be fortified in
the coming years. However, if you are in an at-risk group (e.g. dark skin, living up north, etc.)
it is likely necessary to take an additional vitamin D supplement even if you do drink a lot of
milk and take a multivitamin. Note also that milk “straight from the cow” does not contain
any vitamin D, so some of our farm families get none and are quite unaware if it.
7
Some people are hesitant to take supplements for one reason or another. So, just for fun,
I have put together four daily meal plans that would provide 1000-2000 iu various ways:
Four Daily Meal Plans that Would Provide 1000-2000 iu Vitamin D
Plan 1 -- The “I love milk plan”:
400 iu
400 iu
Total = 1800
Plan 2 -- The “I hate milk and salmon plan”: 1 multivitamin
400 iu
0 iu
Total = 1400
1 multivitamin
4 cups milk
1,000 iu vitamin D supplement
0 cups milk
1,000 vitamin D supplement
Plan 3 – The “I insist on getting my vitamin D only in the form of fortified foods
and not from pills” plan: 0 vitamin supplements
0 iu
4 oz daily salmon (110 iu/oz)
10 cups of milk (WHATTTT???)
440 iu
Total = 1440
Plan 4 – The “I insist on getting my vitamin D only in the form naturally
occurring in the foods I eat and not from any fortification or pills” plan:
0 vitamin supplements
0 iu
0 cups milk
0 iu
14 oz daily salmon (110 iu/oz) 1540 iu
Total = 1540 iu
As you can see, one cannot realistically get there from here without supplementation.
Vitamin D Inadequacy in Breastfeeding Alert
Interestingly, mother’s milk is an amazingly nutritious food and breastfeeding is certainly encouraged.
However, the milk does not contain vitamin D. This is probably because when people were invented nobody
lived in Fargo. As an adaptation to live well up here, we need to have a furnace, a coat, really good mittens
and vitamin D. It is that simple.
Because of the finding of serious vitamin D deficiency in many breast-fed babies, in 2003 the American
Academy of Pediatrics recommended that breastfed babies be given “at least 200 iu of vitamin D by two
months of age.” In 2008 that recommendation was changed to 400 iu/day for all infants
and they recommended starting it right away because many babies were actually born
with inadequate stores of vitamin D because their mothers were deficient during
pregnancy (in spite of taking prenatal vitamins.) This change brings US recommendations in line
with those of their Canadian colleagues who have recommended 400 iu for babies, and at least 800 iu for
everyone else up there for several years now. Here are some details of the kind of research that led to this
change in recommendation:
A recent study in Boston of 380 healthy infants and toddlers who were seen for a routine health visit
found that the prevalence of vitamin D deficiency (<20 ng/mL) was 12% (44 of 365 children), and 146
children (40%) had levels below an accepted optimal threshold (<30 ng/mL.*)
8
[Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Neonatal
vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71.]
The same Boston authors studied the therapeutic amounts of vitamin D supplementation needed to
correct the low vitamin D status of the children. They concluded that these two approaches were effective
for bringing low vitamin D levels into the range of >30 ng/mL* within a 6 week treatment period:
Daily 2000 IU vitamin D2 or D3
or
Weekly 50,000 IU vitamin D2
[Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512.
Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15.]
*However, note that a report described earlier suggested that the healthiest ranges of serum vitamin D may
in fact be above this “optimal threshold” of >30 ng/mL, and that it might be in the range of 36-48 ng/mL.
[Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.]
Take that multivitamin with minerals for other important reasons as well.
Besides the welcome 400 iu of vitamin D, multivitamins provide folic acid and vitamin
B12 in forms that are easier to absorb and use by people taking certain common medications,
those who have certain genetic traits, and people who experience some age-related changes in
the stomach.
For example, some people take “proton pump inhibitor” medications (strong
blockers of stomach acid production for heartburn or “gastro-esophageal reflux.”) They can
be unable to obtain vitamin B12 from normal food sources because the process requires the
presence of acid in the stomach. However, they CAN absorb the vitamin B12 in the vitamin
pill form. Similarly, a third of the elderly are found to be vitamin B12 deficient when the
most sensitive tests are used. That’s a lot of people! Often it happens for the same reason
…an age-related decreased production of stomach acid.
Both of these invisible vitamin B12 absorption situations can cause very serious
health problems … and both are prevented by simply taking a regular multivitamin! So,
without having to know if you are personally at risk or a family member is at risk, the
simple use of the multivitamin will prevent a number of serious problems. The problems to
be avoided in this way include nerve damage, cancer, depression, stroke and birth defects.
However, some other causes of vitamin B12 deficiency will NOT be corrected just
by the multivitamin (although people should still take one for other reasons, of course.) For
example, the diabetes medication Metformin (Glucophage) also can also have a negative
effect on vitamin B12 status. This is also true of a very serious vitamin B12 deficiency
condition called “pernicious anemia.” These are both caused by factors other than the
changes in stomach acid. Vitamin B12 issues with Metformin or pernicious anemia will
need to be monitored and corrected by your health care provider, as the simple
multivitamin will not solve those problems. (For more information on vitamin B12 issues and monitoring
vitamin B12 status, please see my vitamin B12 handout.)
I do not sell anything. I just think that the evidence is quite clear that taking a
multivitamin is a very good idea for everyone, and more and more professional health
9
associations are of the same opinion. A low cost product is just fine, contrary to the claims of
people who are trying to sell you a pricier “pyramid scheme” product.
Children’s chewable vitamins are very similar to adult products, and they can be very
useful for people with trouble taking pills or who have concerns about the vitamin’s ability to
dissolve and be well absorbed in the intestine. Most product labels say for ages under four
give ½ tablet daily, and for ages four-through-adult, take a whole one daily. Read the label.
Note that many children’s and adult vitamins are not very complete. Some very
popular products like some “gummi” vitamin products are actually quite incomplete and
therefore not the best choice for a multivitamin. It is a good idea to pick a product that says
“Complete” on the label (even though NONE of the vitamins on the market are actually
complete.) The labels show that some products clearly provide nutrients that other products
(including others by the same manufacturer) have left out. Some products will advertise some
special feature to make them stand out in the crowd, and it is often an unimportant distinction.
For the most part, just a complete-type generic is just fine, and much less costly.
Another nutrient problem that has recently been found to need more attention is
IODINE DEFICIENCY. In many parts of the world (including the US --- see map on p. 12)
iodine deficiency is common, and the traditional international approach to solving it has been
to add iodine to salt. However, it appears that the amount obtained from iodized salt is
actually not sufficient during pregnancy, and that even in areas that have been thought to have
corrected iodine deficiency many women obtain too little.
Iodine deficiency is the number one cause of preventable mental retardation in the
world. Iodine deficiency can also result in a serious lack of energy in anyone affected because
it impairs the function of the thyroid gland. The World Health Organization is now increasing
the recommendation for iodine intake, especially in pregnancy.
Back home in America, many people are unaware that they should
select “iodized salt” …the packaging is often very similar and they are side-by-side on the
shelf at the store. Most specialty salts that are popular now, like sea salt or exotic salts, are
also not iodized. Additionally, we frequently are advised to cut back on salt for other health
reasons, which can further limit iodine intake. The choice of salt as the way to supplement
iodine was made well before ideas of sodium restriction were common for health reasons.
Because it has long been assumed that the iodine deficiency problem was “solved” in
the US, at present many vitamin pills contain no iodine at all, including many prenatal
vitamins. So, this is one more nutrient that a person should check for when they select a
multivitamin. Choose iodized salt if you use salt, and people who use little salt should be sure
to find an iodine supplement especially if they live in the northern half of the country.
The problem of iodine deficiency has simply not been in our radar for many years. This
is a very newly recognized and extremely important health problem that needs attention.
10
[Iodine Content of prenatal multivitamins in the United States. NEJM. 2009;360:939-940. Iodine deficiency in
pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009
Feb;89(2):668S-72S. Iodine status of the U.S. population, National Health and Nutrition Examination Survey 20032004. Thyroid. 2008 Nov;18(11):1207-14.]
And finally:
Of course, taking a multivitamin does not take the place of eating healthy foods.
Do I have to say this? For example, the vitamin pills contain no protein, no omega-3
fats, and little or no beneficial phytochemicals, potassium, magnesium, selenium, chromium,
calcium, phosphorus, etc. The people who design the pills assume that taking a multivitamin
does not take the place of eating healthy foods. It is up to us to eat more of the really great
nutritious foods as described in this paper. For people who say that they “don’t believe in”
taking a vitamin, I usually try to point out that nutrition is not a religion, so belief is not really
a central issue. It’s a biological / biochemical science. At this time in history, the science
indicates that it is advantageous to take a multivitamin, some fish oil, and for some folks
additional vitamin D, vitamin K and iodine IN ADDITION TO eating lots of healthy
nutritious foods.
Bottom line:
Eat lots of healthy foods including plenty of brightly colored fruits and
vegetables, nuts, legumes, seeds and whole grains
AND
Take a multivitamin with minerals. Many people will also need extra
vitamin D (some will need quite a bit more), vitamin K and iodine.
AND
For many people, for many reasons, fish oil supplements are advisable.
For additional information on these and other topics you can go to MeritCare’s website
(www.meritcare.com)
and find other articles in the “Aunt Cathy’s Guide to Nutrition” series.
Just type Cathy Breedon in the “search box” and a page comes up where you can click “Cathy
Breedon’s Handouts.”
Topics there include information and references especially for people interested in:
Specific health problem issues as diabetes, celiac disease, cancer, eye health,
multiple sclerosis, hemochromatosis, epidermolysis bullosa and the nutrition needs
11
of children with several types of chronic health issues.
Pregnancy and infant nutrition issues
Nutrient-specific summaries providing much more detail about nutrients discussed
here, such as magnesium, iron, chromium, iodine, vitamins D, K and B12 and
different kinds of fat and oil.
12
MAPS of INTEREST: VITAMIN D and IODINE
Cathy Breedon
VITAMIN D:
https://www.health.harvard.edu/newsweek/images/latitude-vitaminD.jpg
Except during the summer months, the skin makes little if any vitamin D from the sun at
latitudes above 37 degrees north (in the United States, the shaded region in the map) or below
37 degrees south of the equator. People who live in these areas are at relatively greater risk for
vitamin D deficiency.
(Actually, that’s where I live … but you can see why it’s a really big deal Up North!”)
IODINE: Map showing spatial correlation between the former "Goiter Belt*" in the
northern U.S. and areas where the iodine content of drinking water is naturally low.
www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm
13
[*Goiter is an abnormal enlargement of the
thyroid gland, often due to iodine deficiency.]
9/2009
MeritCare Health System
Aunt Cathy's
Guide to Nutrition:
A Vitamin B12 Update
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Perinatal/Pediatric Nutrition Specialist
MeritCare Health Systems and
UND School of Medicine
Full Reference Version
Vitamin B12 is needed in only tiny amounts, and unlike most B vitamins, it is
stored well in the body. Most Americans eat foods that provide lots of it. So there
shouldn't be any problem with vitamin B12, right? This is a Trick Question of
course; if there were no problem I would not be here talking about it! ☺
Most references for the information provided here are included at the end.
A few newer ones are sprinkled around in the text. As always, this handout is not
intended to take the place of your physician or health care provider. It is simply a
summary of the most recent information available in the scientific literature on this
topic as of the date shown.
What does B12 do?
1. B12 is involved in making important chemical messengers and myelin in the
brain and nervous system, so some of the major symptoms of deficiency are
neurologic problems.
2. B12 is involved in the making DNA, the genetic center of every cell in the body.
It is especially important during periods of growth (pregnancy, infancy and
childhood), and in tissues that continually make a lot of new cells (red blood cells
and the armies of cells in the immune system.)
What happens if B12 is too low?
Besides serious nerve damage and mental confusion, B12 deficiency
damages the retina of the eye, and may play a role in conditions such as
heart disease, stroke, Alzheimer's disease, incontinence and loss of hearing.
When deficiency is severe, people can have unusually high heart rates and
1
have trouble breathing. Vitamin B12 deficiency causes changes in testicular
tissues in men, and it may be related to increased risk of breast cancer in
older women.
During pregnancy, inadequate B12 causes birth defects such as neural
tube defects and brain damage. A new study suggests that underlying
vitamin B12 deficiency may be involved in the development of HELLP
Syndrome, a serious complication of pregnancy. [HELLP syndrome-like by vitamin B12
Deficiency: Report of seven cases. J Gynecol Obstet Biol Reprod (Paris). 2009 Mar 20]
What foods have B12?
The only natural food sources are animal products like meat, poultry, fish,
milk, cheese and eggs. Other foods may have it added.
Who is at risk of low B12 status?
1. People with inadequate B12 in their diet.
Strict Vegans (people who use no animal products) and their breast-fed
babies are at high risk unless they take a B12 supplement. Some people just
eat a really poor diet that happens to be very low in both meats and dairy
foods.
2. Some people do not absorb B12 well in spite of an adequate diet.
Stomach problems that may decrease B12 absorption:
Gastrectomy (stomach removal);
Gastric surgery for weight loss
[Anemia after bariatric surgery: more than just iron deficiency. Nutr Clin Pract. 2009]
Low stomach acid production or atopic gastritis (both common problems
among the elderly);
Infection with H. Pylori, a bacteria that causes ulcers and gastritis;
Genetic factors causing low levels of "Intrinsic Factor," a B12 carrier made in
the stomach.
Conditions that affect the part of the small intestine where it joins
the large intestine (called the "terminal ileum"):
2
Surgical removal of that part of the intestine;
Crohn's disease (inflammatory bowel disease) or celiac disease;
Overgrowth of the intestine surface by bacteria or parasites such as
giardia. This is especially common among adults older than 70
who have chronic diarrhea, loss of appetite, or nausea.
[Vitamin B12 status, methylmalonic acidemia, and bacterial overgrowth in short bowel
syndrome. J Pediatr Gastroenterol Nutr. 2009 Apr;48(4):495-7.]
Some medications interfere with absorption of B12 from food.
Medications probably account for the surprisingly greater number of
younger adults now being found to be deficient in B12. Drugs that block
stomach acid production (like Tagamet, Zantac and especially “proton
pump inhibitors” like Prilosec, Nexium, Previcid and Protonics) and the
diabetes drug Metformin (Glucophage) all interfere with B12 absorption.
Additionally, people with low vitamin B12 status are at great risk if nitrous
oxide anesthesia is used.
People with autoimmune disorders such as insulin-dependent
diabetes, celiac disease, multiple sclerosis, and certain thyroid disorders
have a higher risk of deficiency for several reasons.
Sometimes it is related to nutrient malabsorption related to intestinal
damage from poorly controlled celiac disease. However, as another
autoimmune disorder, the severe vitamin B12 deficiency called pernicious
anemia is also more common in this population. In some people with celiac
disease, neurologic symptoms are not uncommon … it is important to monitor
their B12 levels carefully.
In insulin dependent diabetes or multiple sclerosis, however,
neurologic symptoms of pernicious anemia are often missed because they
are written off as likely due to neurologic damage from those overriding
conditions. An adult friend of mine with type 1diabetes experienced
extremely debilitating neurologic symptoms because of having developed the
autoimmune disease pernicious anemia. She could no longer walk and the
pain was severe. Her symptoms were ascribed to complications of diabetes,
and I am sorry to report that it took quite a lot of pressure and several months
3
to get the health care professionals involved in her care to check her vitamin
B12 level.
She has improved greatly on vitamin B12 shots since then, but the
painful neurologic damage will never be completely gone. Pernicious anemia
has been documented in adolescents with diabetes, celiac disease, and
autoimmune thyroid disorders as well as in adults, especially among those
already identified as having two or more autoimmune diseases. [
Pernicious anemia in an adolescent with type 1 diabetes mellitus. Arch Pediatr Apr;16(4):357-9]
Interestingly, parenteral vitamin B12 does look like it can be helpful in
diabetic neuropathy, whether related to underlying pernicious anemia or not.
[Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int. J. Food Sci 2009
Feb 12:1-6)]
How is B12 deficiency recognized?
Most commonly it is recognized when a blood test called a CBC shows red
blood cells that are very large ("macrocytic anemia.") Unfortunately, this is a very
late-appearing symptom and some nerve damage will have already happened by
the time the problem is recognized. It takes up to three years for symptoms of
deficiency to develop, so people often fail to associate the symptoms with a change
in diet or health (such as having had stomach surgery, starting to use a certain
medication, or deciding to follow a vegan diet.)
Some researchers estimate that as many as 30% of elderly people have
unrecognized B12 deficiency, often due to changes in the stomach and intestine
caused by aging. This can contribute to symptoms such as confusion and other
mental changes; correcting B12 inadequacy often results in great improvement.
Doctors can check B12 levels in the blood, and there are other markers called
homocysteine and methylmalonic acid (MMA). This testing is not commonly
done unless symptoms or risk factors suggest that there is a problem. However, it is
impractical, expensive and unnecessary to do these tests regularly on everyone.
What should be done?
4
Quite a lot can be done to decrease the likelihood of B12 deficiency ever
developing. Why risk possible inadequacy? Assuring adequacy is by far more
cost-effective, health-protective and safe than waiting to act until symptoms of
inadequacy become apparent.
1. An inexpensive generic standard multivitamin with minerals is likely a very
good investment for most people. These provide the adult RDA of 2 mcg of
well-absorbed B12. Products designed for older adults ("Silver"-type
multivitamins) often have 25 mcg. Some have quite a lot more, as do some “B100 complex” supplements. Some researches now recommend >50 mcg/day.
B12 is a very safe vitamin and overdose is extremely unlikely. For some of the
conditions (such as low stomach acid), simply taking a generous amount of
vitamin B12 in a supplement form can solve the problem.
2. For other conditions (such as surgical removal of the stomach or part of the
intestine or autoimmune-related pernicious anemia), prescription B12 shots
are often needed to assure that there is enough in the body. New techniques
include nasal inhalers, sub-lingual (under the tongue) versions, or extremely high
oral doses of B12. As always, it is extremely important to monitor the
effectiveness of any of these methods.
Summary:
Vitamin B12 deficiency is not uncommon (although it is often
unrecognized) and it is very dangerous.
Certain diet patterns or health conditions increase the risk of
unrecognized B12 deficiency. People with any of the risk factors described above
should be sure to ask their doctors about this issue. Sharing this column with the
doctor may be helpful.
The problem of unrecognized vitamin B12 deficiency is just one of the
many reasons why it is regarded as “prudent” for all adults to take a daily
multivitamin. (Journal of the American Medical Association, June 2002.)
(Some references, abstracts and comments follow.)
---------------------------------------------------------------------------------------------------------------------------------------------------------
5
Some references for vitamin B12 and the elderly, proton
pump inhibitors and/or metformin
Jensen RT.Consequences of long-term proton pump blockade: insights from studies of patients with
gastrinomas. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):4-19. Proton pump inhibitors are being increasingly used and for
longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies
and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of
hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump
inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion
when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the
possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and
the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with
idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known
to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long
hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of
tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of
the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies
dealing with the safety concerns above, are briefly reviewed.
Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing. 2006 Mar;35(2):200-1.
Metformin is an invaluable hypoglycaemic agent. We report two cases who had symptomatic vitamin B12 deficiency related to
metformin use; the mechanisms are discussed. The clinician must be aware of the possibility of metformin-associated B12 deficiency
in users who suffer cognitive impairment, peripheral neuropathy, subacute combined degeneration of the cord or anaemia.
Kilicdag EB, Bagis T, Tarim E. Administration
of B-group vitamins reduces circulating homocysteine in
polycystic ovarian syndrome patients treated with metformin: a randomized trial. Hum Reprod. 2005
Jun;20(6):1521-8. Background: The aim of the current study was to assess the effects of B-group vitamins and folic acid
administration on serum levels of homocysteine (Hcy) in patients with polycystic ovarian syndrome (PCOS) on short-term metformin
treatment. Methods: Patients were randomly assigned to one of three treatment groups. Group 1 patients (n = 20) received metformin
(850 mg twice daily); group 2 patients (n = 20) received metformin (850 mg twice daily) and B-group vitamins (vitamin B1, 250 mg;
vitamin B6, 250 mg; vitamin B12, 1000 microg twice daily); and group 3 patients (n = 20) received metformin (850 mg twice daily)
and folic acid (174 microg twice daily). In all groups, lipid profiles and plasma total Hcy, vitamin B12, folic acid and glucose levels
were recorded at baseline and at 3 months. Results: A 26.5% increase in Hcy levels was seen after 12 weeks of metformin therapy,
while 21.17 and 8.33% decreases in Hcy levels were detected when B-group vitamins or folic acid plus metformin were given
respectively. There were no statistically significant differences recorded in insulin sensitivity using homeostasis model assessment in
the three groups. Conclusion: These findings suggest that B-group vitamins and folic acid administration counteract the Hcyincreasing effect seen with metformin therapy.
Elphick DA, Chew TS, Higham SE, Small bowel bacterial overgrowth in symptomatic older people: can it be
diagnosed earlier? Gerontology. 2005 Nov-Dec;51(6):396-401. Background/Objectives In older people, small bowel bacterial
overgrowth syndrome may be a common, but under-diagnosed, cause of diarrhoea and nutrient malab-sorption. We aim to determine which
clinical features and baseline laboratory investigations indicate a high likelihood of small bowel bacterial overgrowth as defined by a
positive glucose breath test. Methods: A retrospective analysis of records for all patients referred for glucose breath test over a 6-year period
to a teaching hospital. Results: Out of 197 referrals, 168 patient records were located and analysed (62 male, 106 female; median age 65).
Patient characteristics predictive of a positive glucose breath test were: increasing age (p < 0.01), low serum vitamin B12 (p = 0.02), low
serum albumin (p = 0.03), previous partial gastrectomy (p < 0.01), previous right hemi-colectomy (p < 0.01), presence of small bowel
diverticulae (p = 0.01) and concurrent use of a proton pump inhibitor (p < 0.01). 52.5% (n = 21/40) of patients studied who were over 75
years old versus 21.8% (n = 28/128) of those under 75 years old had a positive glucose breath test (p < 0.01). The median time to diagnosis,
from first hospital visit to positive glucose breath test, was 39 weeks. Conclusions: There is often a significant delay in diagnosis of small
bowel bacterial overgrowth. We suggest that this diagnosis should be considered earlier in the investigative algorithm in older patients with
indicative symptoms and a predisposing factor (including previous partial gastrectomy, previous right hemi-colectomy, small bowel
diverticulae or use of a proton pump inhibitor) or concurring laboratory indices (low vitamin B12 or albumin).
Wiersinga WJ, de Rooij SE, Huijmans JG. Diagnosis of vitamin B12 deficiency revised Ned Tijdschr Geneeskd. 2005
Dec 10;149(50):2789-94.Vitamin B12 (cobalamin) deficiency is a common disorder with potential irreversible haematological
and neurological consequences. Currently used diagnostic tests such as the evaluation of serum vitamin B12 and the Schilling
test are insufficient, e.g. the positive predictive value of a low serum vitamin B12 level for actual vitamin B12 deficiency (i.e. tissue
deficiency) is low. Insufficient availability of vitamin B12 will lead to the accumulation of methylmalonic acid and homocysteine in
the body. Nearly all patients with vitamin B12 deficiency also have substantially increased levels of methylmalonic acid and
homocysteine. New tests of serum methylmalonic acid and homocysteine are highly sensitive for vitamin B12 deficiency and may
obviate the need for the somewhat cumbersome Schilling test.
6
Wolters M, Strohle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66. Vitamin
B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is
considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol/L (300-350 pg/mL) is
recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid
(MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor
cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and
pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of
the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result
in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton
pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced
vitamin B(12) level is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive
performance. Furthermore, a poor vitamin B(12) status is assumed to be involved in the development and progression of dementia
(e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the
cobalamin status of elderly persons (>/=60 years) should be regularly controlled and a general supplementation with vitamin B(12)
(>50 microg/day) should be considered.
Pongchaidecha M, Srikusalanukul V, Chattananon A.
Effect of metformin on plasma homocysteine, vitamin
B12 and folic acid: a cross-sectional study in patients with type 2 diabetes mellitus. J Med Assoc Thai.
2004 Jul;87(7):780-7. .OBJECTIVE: To determine the effect of metformin on the levels of plasma homocysteine (Hcy), serum
vitamin B12 and folic acid in patients with type 2 diabetes mellitus and the relationship between cumulative metformin exposure and
levels of plasma homocysteine (Hcy). MATERIAL AND METHOD: The cross sectional study was conducted to assess the effect of
metformin treatment on plasma homocysteine (Hcy), serum vitamin B12 and folic acid in 152 type 2 diabetic out-patients aged
between 35-65 years old at the Diabetes Clinic of The Makaruk Hospital, Kanchanaburi, Thailand Among those, 88 and 64 patients
were categorised to the metformin and non-metformin group according to their records of receiving metformin treatment for a period
of a minimal 6 consecutive months before the study. Fasting blood was drawn from each patient and analysed for plasma
homocysteine using the Fluorescence Polarization Immunoassay (FPIA) method (IMX Analyzer), and serum vitamin B12 and folic
acid using the radioimmunoassay method RESULTS: The plasma Hcy levels showed no significant difference (p = 0.544) among
patients in the metformin group compared with those in the non-metformin group (10.6+/-5.8 mol/L vs 10.4+/-4.0 mol/L). There was a
significant difference (p = 0.011) in the levels of serum vitamin B12 among patients in the metformin group and among those in the
non-metformin group (318.0+/-192.2 pg/mL vs 434.3+/-300.7 pg/mL). However, there was no significant difference (p = 0.090) in
serum folic acid levels between patients in the metformin and those in the non-metformin group (8.8+/-5.1 ng/mL vs 7.7+/-3.8 ng/mL).
The plasma Hcy levels showed a significant correlation with the duration of metformin treatment (p = 0.014) and the amount of
metformin received (p = 0.015) with the Spearman correlation coefficient of 0.260 and 0.258 respectively. CONCLUSION: Even
though the direct effect of metformin treatment on the plasma Hcy could not be concluded from the present study, it was found that
there was a significant depletion of level of serum vitamin B12 among patients who had been on long-term metformin treatment.
Therefore, vitamin B12 supplement is suggested for diabetic patients who are receiving metformin medication.
Buvat DR. Use of metformin
264, 266. No abstract available.
is a cause of vitamin B12 deficiency. Am Fam Physician. 2004 Jan 15;69(2):264;
Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use
and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004 Apr;57(4):422-8 Objective: Acidsuppressant drugs are commonly prescribed for elderly patients, a population in which vitamin B(12) deficiency is a common
disorder. The purpose of this study was to examine the possible association between use of prescription histamine H-2 receptor
antagonists (H2RA) or proton pump inhibitors (PPI) and vitamin B(12) deficiency in older adults. Study Design and Setting:
This was a case-control study in a University-based geriatric primary care setting. Among patients aged 65 years or older with
documented serum vitamin B(12) studies between 1990 and 1997, 53 vitamin B(12)-deficient cases were compared with 212 controls
for past or current use of prescription H2RA/PPI according to information in subjects' medical records. Results: Controlling for age,
gender, multivitamin use, and Helicobacter pylori infection, chronic (#10878;12 months) current use of H2RA/PPI was
associated with a significantly increased risk of vitamin B(12) deficiency (OR 4.45; 95% CI 1.47-13.34). No association was
found between past or short-term current use of H2RA/PPI and vitamin B(12) deficiency. Conclusion: These findings support
an association between chronic use of H2RA/PPI by older adults and development of vitamin B(12) deficiency. Additional
studies are needed to confirm these findings.
Force RW, Meeker AD, Cady PS.Ambulatory care increased vitamin B12 requirement associated with chronic
acid suppression therapy. Ann Pharmacother. 2003 Apr;37(4):490-3. Background: Assimilation of vitamin B(12) from dietary
sources requires gastric acid. By decreasing acid production, the proton pump inhibitors (PPIs) and histamine(2) (H(2))-blockers
may reduce vitamin B(12) absorption. Objective: To determine whether chronic acid suppression therapy is associated with the
initiation of vitamin B(12) supplementation, we conducted a retrospective case-control study using a state-wide Medicaid
population. Methods: Case patients were identified as those who initiated vitamin B(12) supplementation during the study period. Four
control patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and
September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H(2)-blockers or PPIs for
>/=10 of the 12 months prior to the first vitamin B(12) injection. Comparisons were made between the case and control groups regarding
exposure to chronic acid suppression therapy. Results: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients
7
(18.4%) had been exposed to chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% CI
1.08 to 3.09). Conclusions: Initiation of vitamin B(12) supplementation was associated with chronic gastric acid suppression therapy.
Wulffele MG, Kooy A, Lehert P. Effects
of short-term treatment with metformin on serum concentrations of
homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial.
J Intern Med. 2003 Nov;254(5):455-63. Objective: Metformin is a key treatment option in type 2 diabetes. However, metformin may
decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of
treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with
insulin. Design: Placebo-controlled, randomized trial. Measurements: at baseline and 16 weeks later. Setting : This trial was conducted in
the outpatient clinics of three general hospitals in The Netherlands. Subjects: A total of 745 patients with type 2 diabetes, treated with
insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study.
Thirty-seven subjects dropped out (12 placebo and 25 metformin users). Intervention: Addition of metformin or placebo to insulin therapy.
Primary Outcome Parameters: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. Results: Amongst
those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of
4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In
addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. Conclusion: In patients with type 2
diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in
homocysteine. The clinical significance of these findings remains to be investigated.
Schubert ML.Gastric secretion. Curr Opin Gastroenterol. 2003 Nov;19(6):519-25. Purpose of review: Gastric acid facilitates the
digestion of protein and the absorption of iron, calcium, and vitamin B12. It also protects against bacterial overgrowth and enteric
infection, including prion disease. When homeostatic mechanisms malfunction, the volume and concentration of acid may overwhelm
mucosal defense mechanisms, leading to duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. This article reviews recent
knowledge contributing to understanding of the regulation of gastric acid secretion at the central, peripheral, and intra-cellular levels.
Recent Findings: The vagus nerve contains afferent fibers that transmit sensory information from the stomach to the nucleus of the solitary
tract. Input from the nucleus of the solitary tract is relayed to vagal efferent neurons that originate from two brain stem nuclei: the nucleus
ambiguus and the dorsal motor nucleus of the vagus. The latter is also influenced by thyrotropin-releasing hormone neurons that act
centrally to stimulate acid secretion. The main peripheral stimulants of acid secretion are the hormone gastrin and the paracrine amine
histamine. Gastrin stimulates acid secretion directly and, more importantly, indirectly by releasing histamine from fundic entero-chromaffinlike cells. Gastrin also exerts trophic effects on various tissues, including the gastric and intestinal mucosa. The main inhibitor of acid
secretion is somatostatin. Somatostatin, acting via ssTR2 receptors, exerts a tonic paracrine inhibitory influence on the secretion of gastrin,
histamine, and acid secretion. Calcitonin gene-related peptide, adrenomedullin, amylin, atrial natriuretic peptide, and pituitary adenylate
cyclase-activating polypeptide all stimulate somatostatin secretion and thus inhibit acid secretion. HK-ATPase, the proton pump of the
parietal cell, is stored within cytoplasmic tubulovesicles during the resting state, but during stimulation, it is shuttled to the canalicular
membrane by a poorly understood mechanism that probably involves soluble N-ethylmaleimid- sensitive factor attachment protein receptor
proteins. The proton pump inhibitor, pantoprazole, is unique in that it binds cysteine 822, located deep within the membrane domain of the
alpha-subunit. The difficulty that reducing agents, such as glutathione, have in reaching cysteine 822 may be responsible for the longer halftime for acid recovery observed with pantoprazole. Hypergastrin-emia, induced by proton pump inhibitors, enhances expression of
cyclooxygenase-2 and hence prostaglandins within parietal cells, a feedback pathway that may protect the stomach against acid-induced
damage. Summary: In the past year, significant advances have been made in understanding of the regulation of gastric acid secretion.
Ultimately, these advances should lead to improved therapies to prevent and treat acid-related disorders. Gastric acid secretion must be
precisely controlled at a variety of levels to prevent disease caused by hyperchlorhydria and hypochlorhydria. The mechanisms include
neural (central and peripheral), hormonal, paracrine, and intracellular pathways that operate in concert to switch acid secretion on during
ingestion of a meal and off during the interdigestive period. A better understanding of the physiology of acid secretion in health and disease
should eventually lead to improved therapies to prevent and treat acid-related disorders.
Andres E, Perrin AE, Demangeat C. The syndrome of food-cobalamin malabsorption revisited in a department
of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med. 2003 Jul;14(4):221-226.
Background: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific
populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to
food-cobalamin malabsorption. Methods: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted
from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a
department of internal medicine. Results: The median age of patients was 66 years and the female to male ratio was 1.2. The mean
hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean
serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 mumol/l (range 8-97 mumol/l),
respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia
(18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with
evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjogren's syndrome and one had systemic
sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum
vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral
crystalline cyanocobalamin. Conclusion: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12
deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several
other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological
abnormalities and, in many cases, they also relieve symptoms.
8
Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic
anaemia? Aust Fam Physician. 2003 May;32(5):383-4. Background: Patients taking biguanides on a continuous basis sometimes
develop vitamin B12 deficient megaloblastic anaemia. The prevalence of this side effect has not been estimated. Methods: We
screened 600 patients with type 2 diabetes treated with biguanides (phenformin or metformin) for a mean of 11.8 years (SD: 3.6 years)
with complete blood counts, red cell indices and red cell morphology. If this showed macrocytosis, we measured total serum vitamin
B12 and antiparietal cells antibodies (APCA). Patients with macrocytosis and low serum vitamin B12 levels were treated with
cyanocobalamin 1 mg injection daily for seven days. Results: 54 (9%) of the patients had megaloblastic anaemia with low serum total
vitamin B12 levels, only three (0.5%) also had abnormally raised APCA. All 54 patients responded to cyanocobalamin with a
reticulocyte increase within 10 days. Conclusion: Annual screening for megaloblastic anaemia in patients on long term treatment with
biguanides may be worthwhile. The anaemia is easily remediable and does not necessitate withdrawal of the drug.
Fujita H, Narita T, Yoshioka N, Hosoba M, Ito S. A case of megaloblastic anemia due to vitamin B12 deficiency
precipitated in a totally gastrectomized type II diabetic patient following the introduction of
metformin therapy. Endocr J. 2003 Aug;50(4):483-4. No abstract available.
Andres E, Noel E, Kaltenbach G, Perrin AE, Vinzio S, Goichot B, Schlienger JL,.Metformin-associated
deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2. No abstract available
Heine RJ. Does the vitamin B12 deficiency caused by metformin disappear
drug? Ned Tijdschr Geneeskd. 2002 Nov 16;146(46):2213-4. Dutch. No abstract available.
Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs
cardiovascular risk. Drugs. 2002;62(4):605-16.
Gilligan MA. Metformin
vitamin B12
again after stopping this
affecting homocysteine metabolism: impact on
and vitamin B12 deficiency. Arch Intern Med. 2002 Feb 25;162(4):484-5. No abstract available.
Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor
antagonists and a proton-pump inhibitor. Ann Pharmacother. 2002 May;36(5):812-6. Objective: To report a case of
vitamin B(12) deficiency associated with long-term use (approximately 4 1/2 y) of histamine(2) (H(2))-receptor antagonists and a
proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux. Case Summary: A 78-year-old nonvegetarian white woman
with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 times daily in February 1990 and took various other
antisecretory medications over the course of the next 4 1/2 years. She had a normal serum vitamin B(12) concentration of 413 pg/mL in
August 1992. In June 1994, her serum vitamin B(12) concentration was found to be in the low normal range at 256 pg/mL. Biochemical
markers of vitamin B(12)-dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine
(HCYS) were elevated at 757 nmol/L and 27.3 micromol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and
serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of
vitamin B(12) 1000 microg/d, which confirmed vitamin B(12) deficiency. Oral replacement also demonstrated that the woman was able to
adequately absorb nonprotein-bound vitamin B(12) from the gastrointestinal tract, suggesting that her deficiency was a result of foodcobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites
dramatically decreased with vitamin B(12) replacement. Discussions: Malabsorption of dietary protein-bound vitamin B(12) has been
demonstrated with the use of H(2)-receptor antagonists and PPIs. One previous case report of vitamin B(12) deficiency resulting from
long-term use of omeprazole has been published. The malabsorption of dietary vitamin B(12) is thought to be a result of its impaired
release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process. Conclusions: The use of
H(2)-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B(12) and could contribute to
the development of vitamin B(12) deficiency with prolonged use. Patients taking these medications for extended periods of time,
particularly >4 years, should be monitored for vitamin B(12) status.
CB comment: Italics above are mine. I would have suggested moving to simply prevent it with
appropriate supplementation of B12, since monitoring regularly misses large numbers of deficient
people.
Mitchell SL, Rockwood K. The association between antiulcer medication and initiation of cobalamin
replacement in older persons. J Clin Epidemiol. 2001 May;54(5):531-4. As chronic use of antiulcer medications might
predispose older persons to cobalamin deficiency, we studied participants (> 65 years) in the clinical examination of the Canadian
Study of Health and Aging to test the association between the use of an antiulcer medication (histamine-2 blocker or proton pump
inhibitor) at baseline with initiation of cobalamin replacement during the 5 year follow-up period. Of 1054 eligible subjects, 125
(11.7%) were taking an antiulcer medication at baseline. At follow-up, 49 (4.6%) had started cobalamin replacement. Antiulcer
medication use at baseline was significantly associated with the initiation of cobalamin therapy (odds ratio 2.56, 95% confidence
interval 1.30-5.05), even after adjusting for age, gender and institutional residence (odds ratio 2.61, 95% confidence interval 1.315.23). There is an independent association between the use of antiulcer medication and initiation of cobalamin therapy. While the
relationship is not unambiguously causal, this finding underscores the need for judicious prescribing of antiulcer medications for
older persons.
9
CB comment: Italics above are mine. While judicious prescribing is always appropriate it does not
prevent B12 deficiency in the folks who are (judiciously) found to need to use proton pump inhibitors.
Why can’t we mention the idea of preventing the problem with appropriate supplementation?
Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2. No abstract available.
ter Heide H, Hendriks HJ, Heijmans H. Are children with cystic fibrosis who are treated with a proton-pump
inhibitor at risk for vitamin B(12) deficiency? J Pediatr Gastroenterol Nutr. 2001 Sep;33(3):342-5. Background: In a
recent study, the authors demonstrated the beneficial effect of proton-pump inhibitors (PPI) on fat malabsorption and bone mineral content
in children with cystic fibrosis (CF). Prolonged use of PPI could result in vitamin B(12) deficiency as a consequence of impaired release of
vitamin B(12) from food in a nonacid environment. The aim of this study was to evaluate the vitamin B 12 status of CF patients either
treated with a PPI or not by measuring vitamin B(12) and homocysteine blood levels, the latter being a sensitive indicator of vitamin B(12)
deficiency. Methods: The study population consisted of 20 CF patients, 11 patients treated with a PPI for at least 2 years and 9 patients not
treated with a PPI, and 10 healthy, age-matched control participants. Homocysteine blood levels were measured by high-performance
liquid chromatography, and vitamin B(12) levels were measured by a competitive protein-binding assay. Results: Vitamin B(12) levels
were significantly higher in both CF groups compared with the control participants (PPI+, P = 0.02; PPI-, P = 0.009). There was no
significant difference in vitamin B(12) levels between both CF groups. Homocysteine levels were normal and similar in all groups.
Conclusions: Cystic fibrosis patients treated with a PPI for at least 2 years show no signs of vitamin B(12) deficiency.
CB comment: Italics above are mine. It would have been very surprising to have found B12 deficiency
in this situation, since children with CF are routinely supplemented with higher dose supplemental
vitamins. So, rather than being interpreted as evidence that the proton pump inhibitors do not impair
vitamin B12 absorption from food, it should be interpreted as showing that adequate provision of
vitamin B12 in supplement form can protect against deficiency among persons using these medications.
Jolobe OM. Prevalence of hypochromia (without microcytosis) vs microcytosis (without hypochromia) in
iron deficiency. Clinical & Laboratory Haematology. 22(2):79-80, 2000 Apr. The usefulness of hypochromia (MCH deficiency was
examined in 365 geriatric patients aged 67-96 years with either one or both or these characteristics. Of these, 201 proved to be iron
deficient with a serum ferritin of 18 mcg/l. There was a highly significant difference (P < 0.001) between the proportion of iron deficient
patients with a mean corpuscular haemoglobin (MCH) < 26 pg (in the presence of a mean corpuscular volume (MCV) > 80 (fl) vs.
counterparts with MCV < 80 fl (in the presence of MCH >26 pg). Fifteen per cent of the 201 iron deficient subjects were also shown to
have coexisting vitamin B12 deficiency. There was a comparable (16%) prevalence of this haematinic deficiency in the subgroup of 31
iron deficient patients with MCH < 26 pg in the presence of MCH >80 fl.
CB comment: Italics above are mine. This study shows that megaloblastic anemia as a marker of B12
deficiency can be masked by a concomitant iron deficiency, thus making its usefulness as a marker even
less reliable. It is a very poor measure to use for screening in any case, since megaloblastic anemia is a
very late-appearing symptom of vitamin B12 deficiency, and significant harm can be done long before
the red cell size is affected.
Side effects.Calcium supplements help metformin users absorb vitamin B12. Treatmentupdate. 2000
Oct;12(7):6-7. No abstract available.
Bauman WA, Shaw S, Jayatilleke E. .Increased intake of calcium reverses vitamin B12 malabsorption
induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31.
Pautas E. Cherin P. De Jaeger C. Godeau P. Vitamin B 12 deficiency in the aged. Presse Medicale. 28(32):1767-70, 1999 Oct
23. A COMMON CONDITION: Vitamin B12 deficiency is common in the elderly. Search for deficiency should be undertaken whenever
the clinical situation could lead to vitamin deficiency whether macrocytic anemia is present or not as its development may come late.
PATHOPHYSIOLOGICAL IMPLICATIONS: The potential relationships between degenerative neuropsychiatric disorders and
cerebrovascular or cardiovascular disease, mainly via hyperhomocysteinemia, emphasize the importance of searching for vitamin
B12 deficiency in the elderly. SPECIFIC CAUSES: In the elderly, it is important to recognize specific causes of vitamin B12
deficiency, mainly resulting from vitamin malabsorption.
10
Bopp-Kistler I. Ruegger-Frey B. Grob D. Six P. Vitamin B12 deficiency in geriatrics. Schweizerische Rundschau fur Medizin
Praxis. 88(45):1867-75, 1999 Nov 4. Cobalamin deficiency increases with advancing age. The cut-off point of serum concentration
should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in
cobalamin. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended. Cobalamin deficiency may
result in a variety of atypical symptoms. Hematological changes typical of megaloblastic anemia are absent in a majority of patients with
neuropsychiatric disorders. Generally underlying pernicious anemia is not the main cause of cobalamin deficiency in the elderly. Proteinbound cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria is a common cause of cobalamin deficiency in elderly
people. An important manifestation of cobalamin deficiency is cognitive impairment. Much controversy exists on the subject of the
association of dementia of the Alzheimer type with cobalamin deficiency. In several studies dementia has been related to low serum
cobalamin levels. Physicians should be liberal of cobalamin therapy. The window of opportunity for effective intervention may be
as short as one year from the onset of medical symptoms. At last a compilation of recommendations is given.
Bradford GS. Taylor CT. Omeprazole and vitamin B12 deficiency. Annals of Pharmacotherapy. 33(5):641-3, 1999
May. The mainstay for cobalamin deficiency is correction of the underlying disorder and replacement therapy. Because the defect is
often one of absorption, parenteral or intranasal routes are recommended. In most cases, replacement therapy is all that is needed. The
vitamin preparation most commonly used is cyanocobalamin (also called vitamin B12), which has no known physiologic role but
instead is converted to a biologically active form before it can be used by tissues. The studies reviewed in this article clearly show
that omeprazole therapy will decrease the absorption of vitamin B12 by preventing its cleavage from dietary proteins.
However, these data are insufficient to infer that clinically significant deficiency will occur over time. In fact, some of the studies
suggest that the simple addition of juices or other acidic drinks into the diet may dramatically increase cobalamin absorption. Clearly,
well-designed clinical trials are needed to evaluate this theory over an extended follow-up period to determine the clinical significance
of omeprazole-associated vitamin B12 deficiency and possibly identify patients at risk for deficiency. In conclusion, the possibility of
dietary vitamin B12 malabsorption should be considered in patients receiving chronic omeprazole treatment and presenting
with signs and symptoms of deficiency. All healthcare workers should be made aware of the potential clinical complications of
omeprazole-associated vitamin B12 deficiency since it may go unrecognized and is easily corrected. This is particularly
relevant for elderly patients with poor dietary intake of vitamin B12, impaired vitamin B12 stores, and certain gastrointestinal
disorders.
CB comments from an earlier version of references regarding the above report:
I see a problem with this plan.
1. They note that B12 deficiency often goes unrecognized.
2. In spite of this, the action suggested is to “watch for signs and symptoms of deficiency” before doing
anything, since not everyone may be in fact deficient.
3. This is going to miss a bunch of folks. Also, some of the “signs and symptoms” are relatively lateappearing symptoms like macrocytosis. By then, one can no longer efficiently make DNA, and some
neurologic damage may not be totally reparable.
4. Why not simply assure adequacy by suggesting that patients on this drug simply take vitamin B12 in a
cheap and readily available form that dos not require acid for absorption (e.g. in a multivitamin – no
protein molecule attached) and prevent the whole thing? It is cheap, safe and helpful in a bunch of other
situations at the same time. I don’t get it.
5.
They note that they will have to wait a number of years to see how many people actually become
deficient, so the “present study” cannot answer this question. True. But just because this study is unable
to measure a potentially seriously negative clinical outcome, I am not sure that waiting to see how many
people are injured down the road before suggesting benign supplementation is the moral high ground
here. Prevention is a snap and the potential injury associated with deficiency is too great.
Baik HW. Russell RM. Vitamin B12 deficiency in the elderly, Annual Review of Nutrition. 19:357-77, 1999. Vitamin B12
deficiency is estimated to affect 10%-15% of people over the age of 60, and the laboratory diagnosis is usually based on low serum
vitamin B12 levels or elevated serum methylmalonic acid and homocysteine levels. Although elderly people with low vitamin B12
status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and
treatment in this population is important. Absorption of crystalline vitamin B12 does not decline with advancing age. However,
compared with the younger population, absorption of protein-bound vitamin B12 is decreased in the elderly, owing to a high prevalence of
atrophic gastritis in this age group. Atrophic gastritis results in a low acid-pepsin secretion by the gastric mucosa, which in turn results in a
reduced release of free vitamin B12 from food proteins. Furthermore, hypochlorhydria in atrophic gastritis results in bacterial overgrowth
of the stomach and small intestine, and these bacteria may bind vitamin B12 for their own use. The ability to absorb crystalline vitamin
B12 remains intact in older people with atrophic gastritis. The 1998 recommended daily allowance for vitamin B12 is 2.4
micrograms, but elderly people should try to obtain their vitamin B12 from either supplements or fortified foods (e.g. fortified
ready-to-eat breakfast cereals) to ensure adequate absorption from the gastrointestinal tract. Because the American food supply is
now being fortified with folic acid, concern is increasing about neurologic exacerbation in individuals with marginal vitamin B12 status
and high-dose folate intake.
11
Shaw JT, McWhinney B, Tate JR. Plasma homocysteine levels in indigenous Australians. Med J Aust. 1999 ;170(1):1922.
Nutrition & Health. 12(4):215-26, 1998. Vitamin B12 deficiency damages nerve cells and aggravates nervous
system disorders even in the absence of evidence of anaemia. Prevalence of B12 deficiency increases with age
especially over 65 and is frequently associated with Alzheimer's disease. Recent American surveys record a higher prevalence of B12
deficiency and of undiagnosed and untreated pernicious anaemia in the elderly than reported earlier. B12 deficiency is also
reported to be a risk factor for heart disease, stroke and accelerated ageing.
Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy. Drugs &
Aging. 12(4):277-92, 1998 Apr Cobalamin (vitamin B12) deficiency is more common in the elderly than in younger patients. This is
because of the increased prevalence of cobalamin malabsorption in this age group, which is mainly caused by (autoimmune)
atrophic body gastritis. Cobalamin supplementation is affordable and nontoxic, and it may prevent irreversible neurological
damage if started early. Elderly individuals with cobalamin deficiency may present with neuropsychiatric or metabolic
deficiencies, without frank macrocytic anaemia. An investigation of symptoms and/or signs includes the diagnosis of deficiency as well
as any underlying cause. Deficiency states can still exist even when serum cobalamin levels are higher than the traditional lower reference
limit. Cobalamin-responsive elevations of serum methylmalonic acid (MMA) and homocysteine are helpful laboratory tools for the
diagnosis. The health-related reference ranges for homocysteine and MMA appear to vary with age and gender. Atrophic body gastritis is
indirectly diagnosed by measuring serum levels of gastrin and pepsinogens, and it may cause dietary cobalamin malabsorption despite a
normal traditional Schilling's test. The use of gastroscopy may also be considered to diagnose dysplasia, bacterial overgrowth and
intestinal villous atrophy in healthy patients with atrophic body gastritis or concomitant iron or folic acid deficiency. Elderly patients
respond to cobalamin treatment as fully as younger patients, with complete haematological recovery and complete or good partial
resolution of neurological deficits. Chronic dementia responds poorly but should, nevertheless, be treated if there is a metabolic deficiency
(as indicated by elevated homocysteine and/or MMA levels). Patients who are at risk from cobalamin deficiency include those with a
gastrointestinal predisposition (e.g. atrophic body gastritis or previous partial gastrectomy), autoimmune disorders [type 1 (insulindependent) diabetes mellitus and thyroid disorders], those receiving long term therapy with gastric acid inhibitors or biguanides, and those
undergoing nitrous oxide anaes-thesia. To date, inadequate cobalamin intake has not proven to be a major risk factor. Intervention trials of
cobal-amin, folic acid and pyridoxine (vitamin B6) in unselected elderly populations are currently under way. [Ref: 165]
Aarsand AK, Carlsen SM. Folate administration reduces circulating homocysteine levels in NIDDM
patients on long-term metformin treatment. J Intern Med. 1998 Aug;244(2):169-74.
Riordan SM. McIver CJ. Wakefield D.. Small intestinal bacterial overgrowth in the symptomatic elderly.
American Journal of Gastroenterology. 92(1):47-51, 1997 Jan. OBJECTIVE: 1) To determine the prevalence of small intestinal
overgrowth with colonic-type bacteria in symptomatic elderly subjects, particularly those without important "clues" such as clinically
apparent predisposition or vitamin B12 deficiency, and 2) to investigate defense mechanisms such as gastric acidity, small intestinal
motility, and luminal IgA in this setting. METHODS: Fifty-two symptomatic subjects without vitamin B12 deficiency or clinically
apparent predisposition to bacterial overgrowth or disturbed mucosal immunity, including 22 subjects > or = 75 yr old, underwent
culture of small intestinal luminal secretions. Indicator paper was used to measure fasting gastric pH. The presence of bacteria of
confirmed nonsalivary origin in small intestinal secretions served as an index of small intestinal dysmotility. Small intestinal luminal
IgA concentrations were measured by radial immunodiffusion. RESULTS: Small intestinal overgrowth with colonic-type flora was not
present in any subject investigated for dyspepsia, irrespective of age. In subjects with chronic diarrhea, anorexia, or nausea,
overgrowth with colonic-type flora (Enterobacteriaceae) was present in 0/12 (0%), 1/10 (10.0%), and 9/14 (64.3%) subjects aged < 50
yr, 50-74 yr, and > or = 75 yr, respectively. Enterobacteriaceae were not concurrently recovered from saliva of any subject > or = 75 yr
old with small intestinal overgrowth with these bacteria. Fasting hypochlorhydria was present in only 1/9 (11.1%) such subjects.
Luminal IgA concentrations were significantly greater in subjects > or = 75 yr old with bacterial overgrowth than in culture-negative
subjects (p < or = 0.003). CONCLUSIONS: Small intestinal overgrowth with colonic-type bacterial should be considered in
subjects > or = 75 yr old with chronic diarrhea, anorexia, or nausea, even in the absence of clues such as clinically apparent
predisposition or vitamin B12 deficiency. Small intestinal dysmotility, rather than fasting hypochlorhydria or mucosal
immunosenescence, probably is responsible for the prevalence of bacterial overgrowth in this group.
12
Sanford Medical Center
Aunt Cathy's Guide To:
Vitamin B12 Absorption
(not scientifically correct)
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Clinical/Metabolic Nutrition Specialist
Sanford Medical Center and
UND School of Medicine, Fargo, ND
-------------------------------------------------------------------------------------------------------------------
Health situations that can impair vitamin B12 absorption:
1. Having inadequate stomach acid due to aging (achlorhydria) or the use of PPI acid blocking
medications for gastroesophageal reflux means that the protein glob cannot be removed and the B12 is
too big to absorb. Solution: The form in vitamin pills is just the vitamin B12 without the protein glob,
so the problem is eliminated.
2. Failure to make or use intrinsic factor in the stomach (as in the genetic condition pernicious anemia or
in people with stomach removal, stomach damage or gastric bypass surgery.) Solution: The “handle”
is not available to efficiently absorb B12 regardless of the molecular size. This requires an alternate
route of administration, such as B12 shots or supplement forms that are inhaled or sublingual.
3. The diabetes medication Metformin (Glucophage) impairs vitamin B12 absorption in the intestine.
Solution: A generous intake can help, but vitamin B12 levels should be monitored for anyone on this
medication, especially with long term use. Again, looking at “Mean Cell Volume” on a blood test will
not detect a problem soon enough. At least a vitamin B12 serum level should be monitored.
4. Injury to terminal ileum can impair absorption as well: bacterial overgrowth, inflammatory bowel
disease, poorly controlled celiac disease, surgical removal, etc. Solution: This may require an alternate
route of administration, such as B12 shots or supplement forms that are inhaled or sublingual.
MeritCare Medical Center
10/2010
Aunt Cathy’s Guide:
Vitamin D: A Quick Review
of Forms, Labs and Other
Things People Have Asked
Me About Recently
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
MeritCare Medical Center, Fargo, ND
and UND School of Medicine
I regularly get questions about some of the confusing aspects about nutrition
information in the news. Vitamin D issues can be especially complex and crazymaking. But there is a new understanding of the international epidemic nature of
vitamin D deficiency. Additionally, we have a rapidly-expanding understanding of
its critical role in the functioning of over 200 tissues and its role as a factor in an
ever increasing number of serious health problems (like cancer, heart disease,
diabetes, arthritis, multiple sclerosis, lupus, fibromyalgia, immune compromise and
more.) Health care professionals need to have this sorted out more now than ever.
[Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.
Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med.
2008 Jun;162(6):513-9. Prevalence of vitamin D deficiency among healthy infants and toddlers.
Arch Pediatr Adolesc Med. 2008 Jun;162(6):505-12. Lots more references are in my other papers.]
This little paper evolved from a question emailed to me recently from a
dietitian. As I was typing away with an answer, it occurred to me that other health
professionals might find this information helpful as well. And so … a new handout
is born!
For more information about vitamin D or other nutrition issues, just Google my name and
something pops up that says “Cathy Breedon’s Handouts” on the Sanford Health website. opics
will pop up, including:
“My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change
at any moment! ☺)” This paper addresses vitamin D as one of the Top Five issues, but in
much less detail than the Vitamin D paper described above. It is designed for those who want
just a cut-to-the-chase version of why this matters so much and what are we supposed to do
about it.
As always, my handouts are intended to provide some summarizing of interesting
nutrition information in the news. They are not intended to take the place of the guidance and
recommendations of an individual’s health care providers.
1
And of course everything is way more complicated than my descriptions suggest, but this
is just an attempt at a nice simplified discussion trying to sort things out sufficiently to give
direction in thinking about functional applications and doing some good.
Here was the original inspiring question:
“What are all those different forms of vitamin D, what factors affect absorption or
utilization, what are the right tests to order and how should they be interpreted …
etc. etc.”
My rambling response:
First, here are two areas of two big distinctions each in the vitamin D world.
(So what is NOT confusing about all this?!):
1. There are two major forms of vitamin D that come into the body as food or
supplements: Cholecalciferol (D3) Ergocalciferol (D2)
2. There are two major forms of vitamin D floating around in the body:
25-hydroxycholecalciferol (25-hydroxyD) and
1, 25-dihydroxycholecalciferol (1,25-dihydroxyD)
Here’s a look at all four:
1. Food and Supplement Vitamin D
Sources Coming in from Outside
2. Forms of Vitamin D Floating
Around in the Body
Vitamin D-2
in plants and some supplements
25-hydroxycholecalciferol
Ergocalciferol
also called Calcidiol; a storage form of
circulating non-activated vitamin D
1,25-dihydroxycholecalciferol
Vitamin D-3
in animal foods and some supplements. also called Calcitriol; the active steroid
This is also the kind one makes in the
hormonal form of vitamin D
skin from exposure to ultraviolet light.
Cholecalciferol
2
The difference between the plant source vs animal source
(ergocalciferol D2 vs cholecalciferol D3)
The kind we make (out of 7-dehydrocholesterol in the skin + UV light) and the
kind we use in the body is the chole type (because we are animals.) But we can
make chole out of ergo so the questions are NOT about ABSORPTION (i.e. getting
it into the body from out there in the intestinal lumen) but about whether the same
number of mg or iu's of ergo is equal to the same amount of chole.
At the moment there is no official differentiation, but there have been reports that
the chole form may be superior in certain instances especially. For example, in a
recent study of elderly people with vitamin D deficiency, the cholecalciferol and
ergocalciferol forms were compared as agents to correct the deficiency. They found
that cholecalciferol was almost twice as potent as ergocalciferol in raising serum
25(OH)D, when administered either by mouth or as an injection. [Short and Long Term
Variations in Serum Calciotrophic Hormones after a Single Very Large Dose of Ergocalciferol (Vitamin D2) or
Cholecalciferol (Vitamin D3) in the Elderly. J Clin Endocrinol Metab. 2008 May 20. ]
Other studies have shown correction of vitamin D deficiency using very high
dose ergocalciferol supplements, but they generally are not studied in terms of
efficacy in comparison with using chole … just whether or not they correct the
deficiency. Since the ergocalciferol must be converted to cholecalciferol, the simple
solution -- in my non-opinionated opinion ☺ -- is to just get the “chole” type and
quit worrying about that particular issue. Very high-dose ergocalciferol is effective for correcting
vitamin D deficiency in children and young adults with cystic fibrosis. J Cyst Fibros. 2009 May 14.
One other concern would be the healthiness of the liver, since the conversion
occurs there. If a person has a very sick liver or a very immature one (like preterm
infants), it would be prudent to provide the form that does not require conversion.)
Absorption is not usually the major problem with vitamin D unless a person
has a condition that makes one have significant fat malabsorption ... like
steatorrhea in Cystic Fibrosis, as a major example. Anything that makes people
malabsorb fat will make them malabsorb the fat soluble vitamins (A, D, E and K) as
well.
For other people, in some comparisons the gel caps and liquids have somewhat
better absorption than solid tablets, and in general, taking the supplements daily
appears to be more effective than weekly or monthly supplementation regimens.
3
Taking the vitamin D supplements with the largest meal of the day also appears to
enhance absorption. However, in general, if the amount provided is generous these
last two issues become far less important. The biggest problem is not these
gradations of efficiency of absorption but simply failure to provide a generous
amount sufficient to assure adequacy.
The biggest problems with supplementation regimens are that:
1) the amount of vitamin D being supplemented is often far too low to correct
deficiency, let alone bring about rapid correction of deficiency; and
2) people simply don’t take them reliably.
Because of the poor adherence to therapeutic or maintenance regimens, some
other approaches are being tried. For example, a one-time dose of 300,000 iu has
been shown to be effective in correcting severe deficiency without negative effects.
Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. J Bone
Miner Res. 2010 Feb 8. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled
trials. BMJ. 2009 Oct 1;339:b3692. Efficacy and safety of oral continuous low-dose versus short-term high-dose vitamin D: a
prospective randomised trial conducted in a clinical setting. Med J Aust. 2010 Jun 21;192(12):686-9. Are commonly recommended
dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D
levels-an observational study during clinical practice conditions. Osteoporos Int. 2010 Jun 17. Clinical responses to a mega-dose of
vitamin D3 in infants and toddlers with vitamin D deficiency rickets. J Trop Pediatr. 2010 Feb;56(1):19-26. Vitamin D: what is an
adequate vitamin D level and how much supplementation is necessary? Bone. 2009 Oct;45(4):747-9. Best Pract Res Clin
Rheumatol. 2009 Dec;23(6):789-95. Combination of bolus dose vitamin D with routine vaccination in infants: a randomised trial.
Singapore Med J. 2010 May;51(5):440-5. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.
Neurology. 2010 Jun 8;74(23):1852-9. Cholecalciferol loading dose guideline for vitamin D-deficient adults. Eur J Endocrinol.
2010 Apr;162(4):805-11. Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease. Pediatr
Nephrol. 2010 Sep 25. Effect of high dose ergocalciferol in chronic kidney disease patients with 25-hydroxyvitamin D deficiency. J
Med Assoc Thai. 2010 Aug;93(8):885-91.Low vitamin D status: definition, prevalence, consequences, and correction. Endocrinol
Metab Clin North Am. 2010 Jun;39(2):287-301 Vitamin D intake needed to maintain target serum 25-hydroxyvitamin D
concentrations in participants with low sun exposure and dark skin pigmentation is substantially higher than current
recommendations. J Nutr. 2010 Mar;140(3):542-50. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3)
in breast cancer patients with bone metastases. Cancer. 2010 Jan 15;116(2):284-91.Serum 25-hydroxyvitamin D levels in vitamin
D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol. Bone. 2009 Nov;45(5):870-5.
Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home
residents. Osteoporos Int. 2008 May;19(5):663-71.
I am including an abstract here of a very important recent report that evaluated randomized
double blind studies and addressed the question of how much vitamin D supplementation was
needed to achieve health targets for risk of falls, fractures, cardiovascular disease and color cancer.
It also addresses the issue of the safety of these levels. The authors are all very well known and
respected researchers:
4
Benefit-risk assessment of vitamin D supplementation.
Osteoporos Int. 2009 Dec 3.
Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC.
Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient
for important disease outcomes reduced by vitamin D. INTRODUCTION: This study assessed
the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any
associated risk.
METHODS AND RESULTS: Based on double-blind randomized control trials (RCTs),
eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant
dose-response relationship between higher-dose and higher achieved 25(OH)D and greater
fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for
700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml).
Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested
increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l).
In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per
day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most
RCTs with 1,800 to 4,000 IU vitamin D per day without risk.
CONCLUSION: Our analysis suggests that mean serum 25(OH)D levels of
about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints
without increasing health risks. These levels can be best obtained with oral
doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed,
including subject and environment factors, to better define the doses that will
achieve optimal blood levels in the large majority of the population.
In the world of renal disease and chemotherapy adjuncts, however, there are other
specialized vitamin D analogs available and questions in the professional literature
about the relative efficacy of various injectable forms of D2 vs D3, etc. This is
beyond the scope of this brief discussion about the most typical nutrition-related
issues encountered by health professionals.
1. The difference between two lab values:
25-hydroxy D vs 1,25-dihydroxy D.
This is not about any food forms or any of that business in #1
above. It is about what one does with vitamin D in the body.
The 25-hydroxy form is the non-activated-yet-but-stored-and-available-to-beused form. (And that’s just its nickname!) It is made in the liver from cholecalciferol
5
(obtained from any source: food, supplement, skin production) by attaching a
hydroxyl group (an OH group) at the #25 carbon of the molecule.
This form (25-hydroxycholecalciferol or 25-hydroxyD,) is the storage form that
we ordinarily test to check for plain old “deficiency vs adequacy” in the
person's body. (I am using the simple letter D to stand for the word cholecalciferol
in more and more of these descriptions because it is tedious to keep writing it out.)
As you know, we health professional types need to begin a habit of
regularly checking this in everybody because just counting up the amount we
think people took in misses the boat in most circumstances. I think an automatic
'standing orders' scenario would be very informative and helpful. I just found eight
more people this week who were overtly deficient in spite of what "should have been
enough" vitamin D. You can only know for sure by checking their blood.
When we need the active hormonal form (for one of the 200 different tissues
with vitamin D receptors that are looking for it,) the 25-hydroxyD storage form is
sent to the kidney and another hydroxyl group is attached there at the #1 carbon on
the molecule. The product ... the active hormonal form of vitamin D ... is 1,25dihydroxycholecalciferol.
This is not something one would ordinarily check as a blood test unless
the person had some sort of potentially vitamin-D related symptoms in spite of
a good intake of vitamin D. It would usually be done to identify people with
kidney disease who have lost the ability to make the 1,25 vitamin D. There is also a
much smaller group of people who have an inborn error of vitamin D metabolism
that results in the same problem. While this is likely to be rare, I have found this
situation to exist in five out of five people for whom I asked to have it checked.
I certainly check this when their symptoms are unusual, such as extremely
severe or rapidly progressing MS (e.g. in a 10-year-old.) Another time I might ask
to have it checked is if the person has vitamin D deficiency symptoms but it has
already been shown that their blood 25-hydroxyD level is OK. In that situation I
know it is not simple inadequacy that is contributing to any problems.
Additionally, there are certain genetic factors that impair the utilization of
vitamin D. For example, there are “polymorphisms” (different forms) of vitamin D
receptors found on some people’s cells that contribute to having vitamin D related
problems in spite of a good vitamin D intake and normal ability to activate it to the
6
active form. In other words, vitamin D hormone knocks on the door of a cell with a
message but nobody answers the door. But this kind of metabolism problem is only
a tiny part of the problem of vitamin D adequacy. Most folks just aren’t getting
enough sun or enough vitamin D supplementation, so that is where we need to look
first in order to identify problems and do some serious good.
7
So, a good order of thinking about this for a patient is:
First Get a regular 25-hydroxy D level (for EVERYBODY!!!) --- ideally annually
in the winter -- and if it is low give them a therapeutic supplemental amount of
vitamin D to get them up to normal. Then figure out a maintenance dose to switch
to once subsequent tests show that the low level has been corrected. Also, it is wise
not to assume it has been corrected after some prescribed number of doses. We
really need to check it.
For many people, getting the level during the winter is most likely to pick up
any inadequacy issues. A level drawn any time of year will help identify problems
for people who are not regularly in the sun even in the summer. This includes a large
number of people, for a variety of reasons.
I continue to hear every week from a surprising number of health
professionals (including dietitians, physicians, pharmacists and nurses) who have
had their levels checked after hearing me go on and on about the vitamin D
deficiency problem. They had been startled to find that they were themselves
vitamin D deficient. This is in spite of “eating right” and taking a multivitamin!
What would be the likelihood of non–health-care-professionals also having this kind
of problem?
Second If the person has good blood levels of 25-hydroxyD but still looks
“suspicious” in terms of vitamin D-related conditions, then one might get a 1,25 D
level to see if they have a metabolic defect in hydroxylation in the kidney or some
other condition like kidney disease that is impairing production of the hormonal
form. In that situation, one would utilize a special prescription form of supplemental
vitamin D to get around the problem: the ready-to-go form of the active hormone
1,25-dihydroxyD which is usually ordered as calcitriol.
This problem is much less common than the problem of simple inadequacy of
vitamin D, but I have found four individuals with this as the unrecognized basis of
some very severe symptoms. These people were not kidney patients. That tells me
that the problem is likely more common than we think but generally unrecognized.
Here is an example to illustrate why I think doing this in the
order described above is potentially useful:
8
1. It was recently found in an observational study that pre-dialysis kidney patients
who start earlier on calcitriol supplementation may have improved survival and
quality of life, etc. (Arch Intern Med. 2008;168:397-403) compared with those who began to use
it later. By early, they appeared to mean not waiting for severe deficiency symptoms
to show up before providing it, or not waiting until the person had to go on dialysis
because of kidney failure. This meshes nicely with another recent finding of an
association between increased risk of death from all causes and low vitamin D status,
including cardiovascular disease, and contribution of adequate vitamin D in
decreasing the risk of progression to kidney disease in people with diabetes.
[E.g.: Vitamin D and chronic kidney disease. Ethn Dis. 2009 Autumn;19(4 Suppl 5):S5-8-11.Vitamin D, proteinuria,
diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. 2009 Sep;4(9):1523-8. 25-hydroxyvitamin D
and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008 Jun 9;168 (11):1174-80. Low
serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography. Cancer
Epidemiol Biomarkers Prev. 2008 May;17(5):1228-33. Vitamin D, cardiovascular disease, and survival in dialysis
patients. J Bone Miner Res. 2007 Dec;22 Suppl 2:V95-9. Can vitamin D reduce total mortality? Arch Intern Med.
2007 Sep 10;167(16):1709-10, 1730-37. ]
Interestingly, in the pre-dialysis study described above, apparently plain old 25hydroxy D levels were not regularly evaluated, so although calcitriol was shown to
be helpful in many ways for preventing deficiency consequences, it may NOT have
been a kidney-related hydroxylation problem that needed the earlier intervention. It
may have been just the same old unrecognized common inadequacy of vitamin D
intake that was the limiting factor for many of these folks.
For many people with serious kidney disease, foods like milk and salmon are
restricted. As these are about the only reliable and rich sources of vitamin D in our
diet, simple inadequacy of vitamin D should not be an unexpected finding … if we
check for it. This possibility was not addressed in the study, but I think it has
important implications for patient care:
Although giving calcitriol (a significantly more expensive and prescriptiononly pharmacy product) was clearly associated with benefit in this situation,
assuring vitamin D adequacy with generous plain old cheap vitamin D
supplementation may have done the trick just as well for many of the people
involved.
This is another argument for a regular planned 25-hydroxy D level check for
everybody. We could save the big guns (calcitriol) for those who really need it.
Additionally, as described in the report below, there is evidence that even folks for
whom calcitriol IS actually needed, there are other roles for 25-hydroxy vitamin D
9
and therefore good reason to maintain that level in the safe and adequate range at the
same time as providing ready-made calcitriol.
Vitamin D in Health and Disease. Clin J Am Soc Nephrol. 2008 Jun 4.
“Vitamin D functions in the body through both an endocrine mechanism (regulation of
calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former
acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the
metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol
exclusively intracellularly.
In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled;
however, the autocrine mechanism is able to function normally so long as the patient has
adequate serum levels of 25(OH)D, on which its function is absolutely dependent.
For this reason, calcitriol and its analogs do not constitute adequate replacement in
managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater
than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased
risk of various chronic diseases, ranging from hypertension to diabetes to cancer.
The safest and most economical way to ensure adequate vitamin D status is to use oral
dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum
25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of
additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D3) is
substantially more potent than ergocalciferol (vitamin D2) and that the safe upper intake level
for vitamin D3 is 10,000 IU/d.”
The levels described as “normal” in many research studies set the level of
insufficiency and deficiency at significantly lower levels than what appears to be
needed for optimal health benefit. This accounts for some of the confusing research
outcomes. For example, a study finding no benefit of supplemental vitamin D on
some outcome in a population would not be surprising if only low levels of
supplementation were tested. In most cases, blood levels were most often not
evaluated to determine the success of the supplementation for achieving “adequacy.”
Additionally, the ranges perceived to be “normal” were often set too low so that true
comparisons of adequacy vs inadequacy did not take place…only gradations of
inadequacy.
In fact, one of my old books actually had two sets of “normal values” to
evaluate vitamin D adequacy. The cut-off to use in winter was much lower because
it was “average” and “expected” to have a much lower level during those months. It
10
is a classic illustration that just because something is average or expected does not
mean it is good or safe. Live and learn …
Here’s another report with some information about what serum vitamin D
levels might be better indicators of adequacy:
Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes.
Adv Exp Med Biol. 2008;624:55-71.
“Recent evidence suggests that higher vitamin D intakes beyond current
recommendations may be associated with better health outcomes. In this chapter,
evidence is summarized from different studies that evaluate threshold levels for serum
25(OH)D levels in relation to bone mineral density (BMD), lower extremity function, dental
health, risk of falls, admission to nursing home, fractures, cancer prevention and incident
hypertension. For all endpoints, the most advantageous serum levels for 25(OH)D
appeared to be at least 75 nmol/l (30 ng/ml) and for cancer prevention, desirable
25(OH)D levels are between 90-120 nmol/l (36-48 ng/ml). An intake of no less than 1000
IU (25 mcg) of vitamin D3 (cholecalciferol) per day for all adults may bring at least 50%
of the population up to 75 nmol/l. Thus, higher doses of vitamin D are needed to bring
most individuals into the desired range. While estimates suggest that 2000 IU vitamin D3
per day may successfully and safely achieve this goal, the implications of 2000 IU or higher
doses for the total adult population need to be addressed in future studies
2. The risk of injury from overdose in an individual is much higher if the active
hormone form is given instead of just a precursor form. This is analogous to the
higher potential for injury from giving high dose retinol (an active hormonal form of
vitamin A primarily in liver and some supplements) compared with high doses of the
pre-cursor form of vitamin A, the orange pigment beta-carotene in fruits, vegetables
and some supplements. [Remember that the upper level of safety of “regular” vitamin
D is now described as a chronic intake of 10,000 iu/day. It is WAY less toxic than
most of us were taught. “Therapeutic” levels to correct deficiency are often
something like 50,000 iu/week for 8 weeks, or as described earlier, a one-time dose
of 300,000 iu.]
2. Regularly monitoring 1,25-dihydroxyD levels would be a reasonable plan
for folks with kidney disease so we can catch them when production just starts
to decrease. That way we can intervene BEFORE they suffer the multiple severe
consequences associated with inadequacy of this vital steroid hormone. I would also
like to see a one-time-only 1,25-dihydroxy D level for people with autoimmune
diseases like MS, arthritis, lupus, diabetes, etc., for reasons beyond the scope of this
paper. (Details are available in the other handouts listed earlier.)
11
For additional information on these and other topics you can go to
MeritCare’s website (www.meritcare.com) and find other articles in the
“Aunt Cathy’s Guide to Nutrition” series.
Just type Cathy Breedon in the “search box” and a page comes up where you
can click “Cathy Breedon’s Handouts.”
-General nutrition for health
(“Top Five Easy Ways to Improve Your Family’s Nutrition”)
-Specific health problems
(such as diabetes, celiac disease, cancer, multiple sclerosis,
hemochromatosis, epidermolysis bullosa, and others.)
-Pregnancy and infant nutrition
-Summaries providing much more detail about specific nutrients
(such as iron, magnesium, vitamin D, vitamin K, B-vitamins, and
different kinds of fat and oil.
12
MeritCare Medical Center
Aunt Cathy’s Guide to:
2/2010
Vitamin K -Focus on the Vitamin K
and Warfarin/Coumadin
Anticoagulant Drugs Issue
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
MeritCare Medical Center, Fargo, ND
and UND School of Medicine
This paper is in response to the many questions I get from health care professionals
about the problem of actual vitamin K insufficiency in many people already using
these drugs. It is a follow-up clarification of the drug-nutrient interaction issue only,
and it is intended only for health care professionals who have read my more
complete paper on many aspects of the vitamin K inadequacy problem:
“Aunt Cathy’s Guide to: Vitamin K --New Issues in Cardiovascular Health, Osteoporosis,
Cancer of the Liver and Colon, Diabetes, Pregnancy & Varicose Veins.
—------------------------------------------------------------------------------
Question 1:
“What should we tell people already on
Coumadin/warfarin regarding vitamin K?”
My Answer:
Here's our problem ... overt vitamin K deficiency is (unfortunately) common in this
population and quite often unrecognized because it is rarely evaluated, either by lab tests or dietary
evaluations. A great many multivitamin supplements do not even include vitamin K because (until
recently) it had been assumed to be provided in adequate amounts by intestinal bacteria. It is not
even included in the list of nutrients in the “mypyramid.gov” diet information. It is not on our radar.
Many health professionals are totally unaware of this. Some automatically tell patients to quit
taking their multivitamins without checking to see if the product even contains any vitamin K. This
is clearly not benign for many reasons, many of which are explained in another paper:
“Aunt Cathy’s Guide: My Current Top Five Easy Ways to
Improve Your Family’s Nutrition (subject to change at any moment! ☺)”
Back to the topic: Normally dietitians and nurses are dead-set against allowing any actual
vitamin deficiency diseases in their patients, and now that we know it is such a big problem, we
want to fix it. But we are usually not in control of this situation.
It needs to be corrected because vitamin deficiency hurts people in several different ways,
both related to the coagulation issue and also related to a number of other serious complications
of inadequacy (arteriocalcinosis, liver and colon cancer, osteoporosis, diabetes, arthritis, etc.)
However, if patients are already on this drug
AND they are vitamin K deficient, the doctor
(or PA or NP) has to be the one in charge of
incrementally improving the vitamin K status.
This can be accomplished most effectively (because of consistency) with a regular (daily)
supplement. A daily supplement providing the advisable intake is actually recommended by
many researchers as a way to minimize the problem of volatility of blood coagulation for people
on these medications. It should be pretty easy to do ... just walk the amount up incrementally and
monitor coagulation while doing it and adjusting the dosage of medication. But if the doctor
doesn't "believe in" this new research there is not a thing we can do about it. We can't tell
patients to add a bunch (even a "consistent" bunch) of vitamin K because it might cause
problems for a person whose coagulation balance was calculated counting on a baseline
vitamin K deficiency state.
Question 2:
“What if the person is not yet on Coumadin/warfarin but
he/she may be put on this medication?”
If a person is contemplating going on Coumadin, it is of course safe to beef up their
vitamin K intake "up front" to a consistent "assured adequacy" amount. Then the person
prescribing it simply sets the new drug prescription based on the underlying consistent and
adequate vitamin K status. That would be ideal. (Actually, ideal would be a situation in which
nobody had vitamin K insufficiency to begin with. ☺)
Nutrition folks and other health care professionals need to have a clear understanding that
vitamin K is not a scary nutrient. It is just that there is an important drug/nutrient interaction that
needs attention when people are put on that particular drug. We also need to be very aware that
low vitamin K can also increase the dangerous volatility of a warfarin patient's blood
coagulation. (This is another reason why vitamin K deficiency is NOT benign.)
Vitamin K is only a safety issue in relation to folks on this medication. Vitamin K does not
"make you" coagulate your blood. It's just a tool (a vitamin cofactor) that needs to be there for
normal coagulation to take place. (Other things set coagulation into motion.) There is no upper
level of safety even established for this vitamin in its natural forms (vitamin K-1
philoquinone and vitamin K-2 menaquinone) because no problems have ever been seen
apart from the altered situation that exists when a person is prescribed a warfarin/
Coumadin type of anticoagulant medication. They are of a class called “vitamin K
antagonists” because they exert their influence on the vitamin K piece of the process of
coagulation.
However, all we can really do about vitamin K for
people on warfarin or those about to start warfarin
is to share this new information with the people in
charge of prescribing their medications.
An additional note:
This discussion is only about the importance of simple nutritional adequacy of vitamin K
in relation to warfarin use. It is not addressing therapeutic applications of high-dose vitamin K
as a treatment for warfarin overdose or drug-related bleeding. That intervention is not a
nutrition-related use of vitamin K but a pharmacologic use in an acute situation. It is outside of
the scope of this discussion.
Another additional note:
There are other types of medications sometimes used to decrease risk of inappropriate
blood clotting that do not interact with vitamin K, such as “antiplatelet agents” (some are listed
below.) This is mentioned here to be sure that health care people recognize that inducing
vitamin K inadequacy by restricting intake is especially inappropriate when the medication does
not operate as a vitamin-K antagonist at all.
Antiplatelet Agents
Generic Name
Clopidogrel
Ticlopidine
Dipyridamole
Dipyridamole ER plus aspirin (25mg)
Yet another additional note:
Trade Names
Plavix
Ticlid
Persantine
Aggrenox
Similarly, the nutritional intervention of decreasing the ratio of omega-6 to omega-3 fats
in the diet has the ability to decrease clotting time because it alters the strength of thromboxanes
produced. Again, vitamin K is not involved in this effect. Thromboxanes made from the omega-6
fatty acid arachidonic acid (ARA) are much more aggregatory than are those made from the
omega-3 fat eicosapentaenoic acid (EPA.) [A good way to remember this is that “the bigger
number (that is 6, which is bigger than 3) is associated with the bigger aggregation effect.”]
The American diet typically provides about 10 to 20 omega-6 fats for every omega-3 fat.
In societies that regularly have intake ratios of about 4 omega-6 fats per omega-3 fat (such as
those eating the “Mediterranean Diet,”) the problem of excessive and inappropriate clotting is
much less common. It benefits other health parameters as well. While change in the 4:1 ratio
direction has been shown to be an excellent idea overall for general health (including
cardiovascular health,) this form of intervention needs to be discussed with
physicians/Pas/NPs if they are treating a person with any anti-clotting medication.
Actually, the dietary change can sometimes make it unnecessary to be on anti-clotting
medications at all, but as before, incorporating this kind of diet change also needs to be
managed by the person prescribing the medication.
FYI: Here's the recommendation from page 2 of my
"Top Five" handout about this:
"The dark leafy veggies are also terrific sources of vitamin K, a nutrient just now being
recognized as critical to decrease risk of osteoporosis, cardiovascular disease, kidney stones,
liver cancer and arthritis. It is also a nutrient found to be low in the diets of many Americans. It
appears that the elderly need more than the current Advisable Intake of 90-120 mcg/day. This
information is so new that vitamin K is not even included in many multivitamins currently on the
market, and many health professionals will not yet have heard about these new issues.
[Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-5.]
If you are taking medications to prevent blood clots, be sure to show this information to
your doctor before adding more vitamin K–rich vegetables to your diet or taking any vitamin K
supplements. New research on the relationship between vitamin K and these drugs will result in
changes in how we do things. But because the information in support of these changes is very
new, it will also be new to many healthcare providers, so I have put a ‘Vitamin K” handout on
line that includes all the scientific references and detail. Your doctor would want to read more
about it before he/she decides to make any changes in your personal diet or medication regimen."
References for this and many other emerging health issues related to vitamin K are
included in my paper on MeritCare’s website described earlier:
Vitamin K --New Issues in Cardiovascular Health, Osteoporosis,
Cancer of the Liver and Colon, Diabetes, Pregnancy & Varicose Veins.
Sanford Medical Center
11/2010
Aunt Cathy’s Guide to:
Vitamin K --New Issues
in Cardiovascular Health,
Renal Health, Osteoporosis,
Liver & Colon Cancer,
Diabetes, Pregnancy &
Varicose Veins (Short Version)
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical Nutrition Specialist
Sanford Medical Center, Fargo, ND
and UND School of Medicine
1. Overview/Summary: Vitamin K Top Ten
2. Some Vitamin K Facts and Figures
(All the important useful information is on pp. 1-9)
3. References from the Scientific Literature:
Inadequacy of Vitamin K and:
I.
Contribution to Cardiovascular Disease and Arterial and Renal Calcinosis
II.
Contribution to Unsafe Variability of Anticoagulation Therapy
III. Contribution to Osteoporosis and Osteoarthritis and Rheumatoid Arthritis
IV. Potential Issues in Liver Cancer and Colorectal Cancer
V. Miscellaneous Health Issues: Non-warfarin-related hemorrhage, cholestasis,
diarrhea, celiac disease, cystic fibrosis, short bowel syndrome, pregnancy,
and odds and ends
This is the short form of this paper with just the references at the end. Another version is available
that includes the abstracts of the referenced articles. As always, this paper is a review of new issues
in the scientific literature and not intended to take the place of your personal health care provider.
In particular, individuals using anticoagulant medications like Coumadin/warfarin must not
make changes in their vitamin K intake without consulting their physician/PA/NP.
A separate paper for health professionals is available that discusses this issue in more detail.
1
Overview/Summary: Vitamin K Issues
1. Vitamin K has been found to be involved in carboxylation reactions in various tissues.
As a result, it is now recognized as playing a critical role in bone health, growth, diabetes,
pregnancy, cardiovascular health, renal health, and certain cancers, in addition to its wellknown role in blood coagulation. Allowing (or inducing) vitamin K deficiency for any
reason is clearly not benign.
2. Foods that are generous in vitamin K1 are also excellent sources of beneficial antioxidant
phytochemicals. This includes lutein, a pigment in leafy greens that appears to have an
additional unique potential benefit in the prevention or the slowing of the progression of
blindness due to macular degeneration. These foods are also very low in calories and rich
in other vitamins and minerals as well. However, many Americans eat very few of these
foods and as a result, relative vitamin K inadequacy is not at all uncommon when it is
actually checked. (It is currently only very rarely checked.) The most generous dietary
vitamin K2 sources include bacterially fermented foods. One of the richest is natto … a
strong flavored soy bean product popular in Japan but considerably less so in the US.
3. Elderly people appear to require a regular intake of vitamin K above the 2001
“Adequate Intake” (AI) level in order to assure adequacy. Note that the recommended
amounts for everyone (AIs, RDI, RDA, etc.) were set at a time when it was assumed that
intestinal bacteria provided about half of one’s requirements. As this source has been found
to be more unreliable than was thought, it is very reasonable to aim toward an intake that is
generous. People using the drug Coumadin need to discuss this issue with their physician as
described below in #6 and #8 because of a drug/nutrient interaction. However, except for
this well-known drug/nutrient interaction, there is no upper level of safety for vitamin
K and foods rich in vitamin K are rich in many other nutrients as well.
4. Vitamin K as phylloquinone (K1) and menaquinone (K2) are not toxic, and for that
reason there is no “Upper Limit of Safety” established for this vitamin. In contrast,
menadione (K3) is potentially harmful and it is generally no longer used as a vitamin K
supplement. It was previously assumed that about half of a person’s vitamin K
requirements were met via production by intestinal bacteria. It is now clear that healthy
people are in fact MUCH more dependent on vitamin K from foods and/or
supplements to assure adequacy than we thought.
5. Misunderstanding about recommendations for vitamin K intake for people on
anticoagulant therapy has resulted in many people avoiding all sources of vitamin K
(instead of taking in a CONSISTENT but ADEQUATE amount of vitamin K as
recommended by the drug manufacturers.) One result, for example, is the association seen
between anticoagulant use and increased risk of osteoporosis and cardiac and renal
calcification . Initially it was thought to be due to the drug itself, but it turned out to be
related to the far too common inappropriate excessive restriction of vitamin K.
2
6. It appears that dangerous VARIABILITY of blood clotting among some patients
taking anticoagulants can be controlled significantly by assuring a consistent daily
intake of an adequate amount of vitamin K. Coagulation variability is a much greater
problem among patients whose usual vitamin K status is low. Those are the people most
greatly affected by fluctuations in vitamin K content of diet or supplements. Persons with
a reliable adequate intake level are far less affected by additional intake in vitamin K.
7. Vascular calcification, a known cardiovascular risk factor, is another side effect
related to the problem of inducing low vitamin K status in patients on anticoagulants
and among the population at large. Failure to activate the hormone osteocalcin because of
inadequate vitamin K results in failure to move calcium from the bloodstream into bone.
Instead, calcium is deposited inappropriately in other tissues, such as blood vessel walls
and the kidneys. This results in arteriocalcinosis (an independent risk factor for
cardiovascular disease.) It also results in renal calcinosis because increased calcium
needs to be excreted.
8. Vitamin K inadequacy is now being identified even among healthy children when
vitamin K status is evaluated …however, at present it is only very rarely evaluated. People
with conditions that result in malabsorption are at very high risk of deficiency. This
includes conditions like cystic fibrosis, poorly controlled celiac disease, Crohn’s
disease (inflammatory bowel disease or IBD,) biliary atresia, short bowel syndrome
and intractable diarrhea.
Others at particular risk of inadequacy of vitamin K include people using drugs that
interfere with vitamin K such as salicylates (e.g. aspirin) and many seizure-control
medications. Similarly, some renal medications used to bind phosphate in the intestine
(e.g. sevelamer-HCl) can greatly impair vitamin K absorption. [Metal ion and vitamin
adsorption profiles of phosphate binder ion-exchange resins. Clin Nephrol. 2010 Jan;73(1):30-5.
Assuring vitamin K adequacy in pregnant and breast-feeding women is an important
new focus. Vitamin K inadequacy in pregnancy has recently been identified as a risk factor
for pregnancy complications like hyperemesis gravidarum, pre-eclampsia, intracranial
bleeding in the infant, and excessive blood loss at delivery. Although vitamin K transfer
across the placenta is noted to be poor, relative inadequacy in pregnancy can also
contribute to poor nutrient stores in infants.
Whether more generous maternal stores of vitamin K might enhance the transfer to the
fetus has not been evaluated. The recommendation of the American Academy of Pediatrics
is to provide vitamin K to newborns. Additionally, breast-fed babies are noted to be at
higher risk of inadequacy apparently for the same reason … low vitamin K content of
mother’s milk. Again, whether relative maternal vitamin K inadequacy is a factor in the
breastmilk vitamin K content has not been evaluated yet.
[American Academy of Pediatrics Policy Statement: Controversies Concerning Vitamin K and the
Newborn Committee on Fetus and Newborn Pediatrics Vol. 112 No. 1 July 2003, pp. 191-192]
3
9. New roles of vitamin K are being recognized. For example, failure to activate
osteocalcin because of inadequate vitamin K appears to have a negative effect on energy
metabolism, including insulin metabolism. A possible role of vitamin K inadequacy in
diabetes and obesity is just beginning to be examined. This is in addition to the
cardiovascular, bone, and renal health issues.
Assuring vitamin K adequacy appears to be a factor in some aspects in the prevention
or treatment of cancers of the liver, colon/rectum, prostate, pancreas and ovaries. Other
recent areas of investigation include a role of vitamin K inadequacy in hypertension (high
blood pressure) and inflammatory diseases such as arthritis. Dietary vitamin K appears
to have a role in sulfatide metabolism, myelin structure and behavior functions.
10. All of the health concerns described above are made
less severe by the same intervention:
Assure adequacy of vitamin K status for everyone from foods and/or
supplements. (Do not ASSUME adequacy.)
If a person is on the anticoagulant medication Coumadin*, assure
that the vitamin K is administered in a consistent manner
each day and that the physician has approved any
adjustments of vitamin K intake.
Remember that inducing a vitamin K deficiency is common in this
context, makes the drug use more dangerous, and causes
damage to the cardiovascular system, the renal system,
bone health and increases risk of certain cancers.
*Note that many anticoagulants do not involve vitamin K in
their function as Coumadin does, so it makes even less sense
to restrict vitamin K with these medications.
Adjust intake recommendations to compensate for conditions
associated with malabsorption and the effects of aging.
4
Some Vitamin K Facts and Figures
Adequate Intake (AI) for Vitamin K
Life Stage
Age
mcg/day
Infants
0-6 months
2.0
Infants
7-12 months
2.5
Children
1-3 years
30
Children
4-13 years
55
Adolescents
14-18 years
75
Adults *
19 years and older
Males 120
Females 90
Pregnancy or Breastfeeding 18 years and younger
75
Pregnancy or Breastfeeding 19 years and older
90
Food and Nutrition Board, Institute of Medicine. Vitamin K. Dietary Reference Intakes for Vitamin A, Vitamin K,
Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and
Zinc. Washington D.C.: National Academy Press; 2001:162-196.
*Older adults [for sure] may benefit from higher regular intakes than are listed in the
the Advisable Intakes (AIs.) These were developed with the assumption that
intestinal production of usable vitamin K provided a more significant amount. Current
AIs for other age groups have not been re-evaluated since the discovery that the
intestinal bacterial sources are far less available than was believed, so it is not just the
elderly who may be at risk. The rest have not been checked yet.
Vitamin K status in the elderly. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):20-3.
5
Sources
Leafy Vegetable Food Sources
Phylloquinone (vitamin K1) is a major dietary form of vitamin K, and the major food
source is leafy green vegetables. Not all green vegetables are good sources . . . it’s the darker
leafy ones that have the most! Additional benefits of these foods are the extremely low calories
and the generous provision of other vitamins (such as vitamin C and vitamin A as beta
carotene) and potent antioxidant phytochemicals such as lutein.
There are many excellent reasons to include these foods in one’s diet. This is also true
for people using anticoagulation medications like Coumadin (warfarin.) As described earlier,
the goal is to assure both an adequate intake of vitamin K and a consistent level of intake. No
one benefits from vitamin K deficiency.
Food
Serving
Vitamin K1 (mcg)
Seaweed, dulse dried
100g (3.5 oz)
1700
Kale, raw
1 cup (chopped)
547
Broccoli, cooked
1 cup (chopped)
420
Parsley, raw
1 cup (chopped)
324
Swiss chard, raw
1 cup (chopped)
299
Green tea, dried
1 oz (28 g)
199
1 cup (chopped)
120
Leaf lettuce, raw
1 cup (shredded)
118
Iceberg lettuce
1 leaf (20 g)
22
Watercress, raw
1 cup (chopped)
20-85 (various refs)
Spinach, raw
Pennington, JA. Bowes & Church’s Food Values of Portions Commonly Used, Ed. 16 Phil: Lippincott Co., 1994
Some is available in vegetable oils as shown on the next page, but they contribute far
less vitamin K than leafy green vegetables. And, it is fairly impractical and also unwise to
suggest that people attempt to meet their vitamin K requirements by increasing fat intake
substantially. Additionally, hydrogenation of vegetable oils may decrease the absorption and
biological effect of dietary vitamin K.
(Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001;74(6):783-790.)
6
Oil Food Sources:
Food
Serving
Vitamin K1 (mcg)
Soybean oil
1 Tablespoon
26 – 76 (various refs)
Canola oil
1 Tablespoon
20
Mayonnaise
1 Tablespoon
12
Corn oil
1 Tablespoon
0 - 7 (various refs)
Olive oil
1 Tablespoon
8
Animal Food Sources:
Food
Serving
Vitamin K1 (mcg)
Meat
3.5 oz
4
Raw Beef Liver (others less)
3.5 oz
104
Milk
8 oz
10
Egg Yolk
1 large
25
Fermented Food Sources:
Food
Serving
Vitamin K2 (mcg)
Natto (fermented soybeans)
1 oz
245
Curd Cheese
1 oz
20
Non-Food Sources: Intestinal Bacteria
Bacteria that normally colonize the large intestine synthesize menaquinones (vitamin
K2), which are active forms of vitamin K. Until recently it was thought that up to 50% of the
human vitamin K requirement might be met by this bacterial synthesis. Recent research
7
indicates that the contribution of intestinal bacterial synthesis is much less than previously
thought, although the exact contribution remains unclear. Most of our menaquinones we
actually make ourselves from phylloquinone. The likelihood is that even healthy people are
more dependent on food sources of vitamin K than we previously believed. Individuals
taking chronic antibiotics are far more dependent on food or supplement sources, of course,
because these “friendly” colonic bacteria are killed by the medication as well.
(Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr. 1995;15:399-417.)
Non-Food Sources: Supplements
In the U.S. vitamin K1 is available without a prescription in multivitamin and other
supplements in doses that generally range from 10-120 mcg per dose. Vitamin K2 supplements
are also available now.
(PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.)
The amount of vitamin K associated with a decreased risk of hip fracture in the
Framingham Heart Study was about 250 mcg/day. This can be obtained from a little more
than 1/2 cup of chopped broccoli or a large salad of mixed greens every day. A multivitamin
with minerals that provides at least the AI level of vitamin K would also be an excellent
idea, and the label should be checked closely because vitamin K is notoriously variable
between various products.
Many vitamin supplement products contain none because of the earlier assumptions
about the GI bacterial sources providing a significant amount. Some chewable calcium
supplements provide some vitamin K and vitamin D. Again, check the label. A form of vitamin
K2, menatetrenone (MK-4) has been used to treat osteoporosis in Japan and is currently under
study in the U.S National Institutes of Health. K2 as MK-7 is the form produced in natto.
Many earlier references state that vitamin K inadequacy is extremely unusual in adults.
Testing for vitamin K inadequacy is also generally rare because inadequacy is assumed to not be
a problem. Traditionally testing involves measuring prothrombin time. However, it appears that
this hematological manifestation of inadequacy may not reflect adequacy of vitamin K for other
functions. For example, newer studies use undercarboxylated osteocalcin or other measures as
a marker of vitamin K inadequacy in bone and cardiovascular applications in particular.
Vitamin K adequacy has not been in the public health radar … or the radar of health
care professionals. Consider, for example, the mypyramid.gov guidelines*, which are an effort
to help people achieve an advisable intake of all nutrients over two weeks in 2000 kcals/day.
Vitamin K is simply not included in the analysis. Vitamin D is missing as well. Apparently
these nutrients are assumed to be adequate because “you can make your own.” In the case of
vitamin D, this assumed adequacy is now being discarded because of the overwhelming
evidence that vitamin D deficiency is actually a huge but previously unrecognized public
health problem. It is possible that the assumption of vitamin K adequacy may turn out to be
8
similarly suspect. In any case, with the clear safety of generous vitamin K in normal
circumstances, it would be advisable to simply assure adequacy rather than to assume it.
*(http://www.mypyramid.gov/downloads/sample_menu.pdf)
Vitamin K Nomenclature
Older nomenclature
IUPAC (abbreviation)
K1
Phylloquinone (K)
K 2(n)
Menaquinone-n
K2(4)
Menatetrenone (MK-4)
K2(35)
Menaquinone-7 (MK-7)
K3
Menadione
(MK-n)
From Machlin, LJ. Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects.
New York: Marcel Dekker, Inc.,1984
Toxicity Issues
There is no known toxicity associated with high doses of phylloquinone
(vitamin K1), or menaquinone (vitamin K2) forms of vitamin K.
No tolerable upper level (UL) of intake of these forms of
vitamin K has been established.
(Food and Nutrition Board, Institute of Medicine. Vitamin K. Dietary Reference Intakes for Vitamin
A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel,
Silicon, Vanadium, and Zinc. Washington DC: National Academy Press; 2001:162-196.)
The same is not true for menadione (vitamin K3) and its derivatives. Menadione can
interfere with the function of glutathione, one of the body's natural antioxidants, resulting in
oxidative damage to cell membranes. Menadione given by injection has induced liver toxicity,
9
jaundice, and hemolytic anemia (due to the rupture of red blood cells) in infants, and is no
longer used for treatment of vitamin K deficiency.
Contrary to popular belief, the fat-soluble status of vitamin K
does NOT make it more likely to be toxic than water soluble vitamins.
The toxicity traditionally ascribed somewhat globally to the fat soluble vitamins is in fact
due to the fact that two of them (vitamins A and D) have actual hormonal messenger roles in
the body. For this reason, relative inadequacy or excess of the active hormonal form of these
two vitamins can actually induce metabolic changes to occur. The other two fat soluble
vitamins (E and K) and the water soluble vitamins (C and the B vitamins) are much less likely
to be toxic because they exert no hormonal influence on tissues.
The fact that a substance dissolves in butter is not a measure of
its potential toxicity, although most of us were taught that it is.
This is an important big change in our understanding
Mnemonic Devices:
I always find it hard to keep these kinds of terms and numbers straight, so I usually
make up a little mnemonic device to help me out. Here’s the one I use for remembering which
form of vitamin K comes from which source, and which is K1 and which is K2 (Feel free to
disregard this section and make up your own if you find these unhelpful. ☺)
Phylloquinone starts with a P … as in “Plants.”
(“Leafy greens” vitamin K is Phylloquinone)
I think of the kind made in people’s intestines by bacteria or made in man from
phylloquinone is menaquinone … that is, the kind made “in men.”
(The kind of vitamin K made in men is menaquinone. Women too, of course.)
Because we convert phylloquinone to menaquinone for many of its uses, I think of
phylloquinone (the spinach one) coming first (K1) and menaquinone (the kind made
in man out of K1) as coming along secondarily (K2)
10
References by Topic:
(A version with abstracts of these references is also available.)
I.
Inadequacy of Vitamin K:
Contribution to Cardiovascular Disease: Arterial Calcinosis,
Renal Calcinosis, Diabetes, Inflammation and Hypertension
2010
Clin J Am Soc Nephrol. 2010 Feb 4. The circulating inactive form of matrix GLA Protein is a surrogate marker
for vascular calcification in chronic kidney disease: a preliminary report.
J Nutr Biochem. 2010 Feb 8. Vitamin K suppresses the lipopolysaccharide-induced expression of
inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of
nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation.
Clin J Am Soc Nephrol. 2010 Feb 18 Vitamins K and D status in stages 3-5 chronic kidney disease.
Kidney Int. 2010 Oct 20. The dualistic role of vitamin D in vascular calcifications.
Clin J Am Soc Nephrol. 2010 Apr;5(4):568-75. The circulating inactive form of matrix gla protein is a
surrogate marker for vascular calcification in chronic kidney disease: a preliminary report.
Thromb Haemost. 2010 Oct;104(4):811-22. Characterisation and potential diagnostic value of
circulating matrix Gla protein (MGP) species.
Urol Int. 2010 Jul;85(1):94-9. Activity and expression of vitamin K-dependent gamma-glutamyl
carboxylase in patients with calcium oxalate urolithiasis.
Thromb Haemost. 2009 Apr;101(4):706-13. Relation of circulating Matrix Gla-Protein and
anticoagulation status in patients with aortic valve calcification.
Clin J Am Soc Nephrol. 2010 Apr;5(4):590-7 Vitamins K and D status in stages 3-5 chronic kidney
disease
Kidney Int. 2010 Sep 22 Recent progress in the treatment of vascular calcification.
Clin Nephrol. 2010 Jan;73(1):30-5. Metal ion and vitamin adsorption profiles of phosphate binder ionexchange resins.
2009
Clin Exp Immunol. 2009 Dec 17. Vitamin K(3) attenuates lipopolysaccharide-induced acute lung injury
through inhibition of nuclear factor-kappaB activation.
J Mal Vasc. 2009 Apr 2. Origin of the mediacalcosis in kidney failure
Nephrol Dial Transplant. 2009 Jul;24(7):2095-101. Association of kidney function and
uncarboxylated matrix GLA protein: data from the Heart and Soul Study.
J Thromb Haemost. 2009 Feb;101(2):359-66. Uncarboxylated matrix GLA protein (ucMGP) is
associated with coronary artery calcification in haemodialysis patients.
J Thromb Haemost 2009;Sept 28. Warfarin use and the risk of valvular calcification.
Int J Artif Organs. 2009 Feb;32(2):67-74. Coagulation meets calcification: The vitamin K system.
J Bone Miner Res. 2009 Vitamin k and bone: past, present, and future.
Br J Nutr. 2009 Apr 1:1-16 Minerals and vitamins in bone health: the potential value of dietary
enhancement.
11
Osteoporos Int. 2009 Mar 12Prior treatment with vitamin K(2) significantly improves the efficacy of
risedronate.
J Bone Miner Metab. 2009;27(3):333-40.Short-term menatetrenone therapy increases gammacarboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal
osteoporosis: a randomized prospective study.
Bioorg Med Chem Lett. 2009 Feb 15;19(4):1054-7. Elucidation of the mechanism producing
menaquinone-4 in osteoblastic cells.
J Bone Miner Res. 2009 Jun;24(6):983-91.Vitamin k treatment reduces undercarboxylated osteocalcin
but does not alter bone turnover, density, or geometry in healthy postmenopausal north
american women.
J Mal Vasc. 2009 Apr 2. Origin of the mediacalcosis in kidney failure.
2008
Am J Clin Nutr. 2008 Jul;88(1):210-5. Phylloquinone intake, insulin sensitivity, and glycemic status
in men and women.
Atherosclerosis. 2008 Jul 19Thromb Res. 2008;122(3):411-7. High dietary menaquinone intake is
associated with reduced coronary calcification. Effects of the blood coagulation vitamin K as an
inhibitor of arterial calcification.
J Vasc Res. 2008 Apr 10;45(5):427-436. The Circulating Inactive Form of Matrix Gla Protein
(ucMGP) as a Biomarker for Cardiovascular Calcification.
Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):771-6. Vitamin K epoxide reductase complex subunit
1 (VKORC1) polymorphism and aortic calcification: the Rotterdam Study.
Am J Epidemiol. 2008 Feb 1;167(3):313-20. Vitamin K and vitamin D status: associations with
inflammatory markers in the Framingham Offspring Study.
Clin J Am Soc Nephrol. 2008 May 21. Vitamin K-dependent Proteins, Warfarin, and Vascular
Calcification.
Am J Clin Nutr. 2008 Jul;88(1):210-5. Phylloquinone intake, insulin sensitivity, and glycemic status
in men and women.
Cell Cycle. 2008 Jun;7(11):1575-9. Does the absence of ABCC6 (multidrug resistance protein 6) in
patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to
the periphery?
J Pharm Pharmacol. 2008 Jul;60(7):889-93. Mechanisms underlying the biphasic effect of vitamin K1
(phylloquinone) on arterial blood pressure.
Curr Opin Lipidol. 2008 Feb;19(1):39-42. Vitamin K intake and atherosclerosis.
2007
J Atheroscler Thromb. 2007 Dec;14(6):317-24. Treatment with vitamin k(2) combined with
bisphosphonates synergistically inhibits calcification in cultured smooth muscle cells.
Nat Clin Pract Nephrol. 2007 Oct;3(10):522-3. Vascular calcification in chronic kidney disease: the
role of vitamin K.
Rhinology. 2007 Sep;45(3):208-13. Vitamin D3, vitamin K2, and warfarin regulate bone metabolism in
human paranasal sinus bones.
Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent.
Exp Anim. 2007 Jul;56(4):273-8. Vitamin K Deficiency of Germfree Mice Caused by Feeding Standard
Purified Diet Sterilized by gamma-Irradiation. .
Nutr Metab Cardiovasc Dis. 2007 Jan;17(1):58-62. Phylloquinone intake and risk of cardiovascular
diseases in men.
12
2005-2006
Blood. 2006 Nov 30; Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin
K in rats.
Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81 Vitamin K in the treatment and prevention of
osteoporosis and arterial calcification
Eur J Clin Nutr. 2005 Feb;59(2):196-204 Phylloquinone intake as a marker for coronary heart disease
risk but not stroke in women.
Nutr Res. 2009 Apr;29(4):221-8. High-dose vitamin K supplementation reduces fracture incidence in
postmenopausal women: a review of the literature.
II.
Inadequacy of Vitamin K:
Contribution to Unsafe Variability of Anticoagulation Therapy
2010
Br J Haematol. 2010 Feb 11. Influence of dietary vitamin K intake on subtherapeutic oral
anticoagulant therapy.
2009
Am J Transl Res. 2009 Jul 15;1(4):381-92.Activated protein C: a potential cardioprotective factor
against ischemic injury during ischemia/reperfusion.
J Manag Care Pharm. 2009 Apr;15(3):244-52. Meta-analysis to assess the quality of warfarin control
in atrial fibrillation patients in the United States.
Blood Coagul Fibrinolysis. 2009 Apr 3. Erythrocyte folate and 5-methyltetrahydrofolate levels
decline during 6 months of oral anticoagulation with warfarin.
2008
Hamostaseologie. 2008 Feb;28(1-2):44-50 New insight in therapeutic anticoagulation by Coumarin
Derivatives.
J Thromb Haemost. 2008 Jul;6(7):1226-8. Vitamin K epoxide reductase complex subunit 1
(VKORC1 ) polymorphism influences the anticoagulation response subsequent to vitamin K
intake: a pilot study
Vitam Horm. 2008;78:265-79 Vitamin K and thrombosis.
2007
J Thromb Haemost. 2007 Oct;5(10):2043-8..Daily vitamin K supplementation improves
anticoagulant stability.
Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent.
INRJ Thromb Thrombolysis. 2007 Feb 24; Prospective study of supplemental vitamin K therapy in
patients on oral anticoagulants with unstable international normalized ratios.
J Am Diet Assoc. 2007 Nov;107(11):2022.Vitamin K: what are the current dietary recommendations
for patients taking coumadin?
Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):1-5. Dietary vitamin K intake & anticoagulation in
elderly patients.
13
2006
Blood. 2006 Nov 16 Vitamin K supplementation can improve stability of anticoagulation for patients
with unexplained variability in response to warfarin.
Int J Vitam Nutr Res. 2006 Mar;76(2):65-74. Dietary vitamin K variability affects International
Normalized Ratio (INR) coagulation indices.
2004-2005
Pharmacotherapy. 2005 Dec;25(12):1746-51. Low-dose vitamin K to augment anticoagulation control.
Am J Cardiovasc Drugs. 2004;4(1):43-55. The use of vitamin K in patients on anticoagulant therapy: a
practical guide.
III. Inadequacy of Vitamin K:
Contribution to Osteoporosis, Osteoarthritis, Bone Development,
Rheumatoid Arthritis, and Related Conditions
2010
Transplantation. 2010 Feb 27;89(4):458-464. Dietary vitamin K2 supplement improves bone status after
lung and heart transplant.
Proc Nutr Soc. 2010 Feb;69(1):25-33. Session 2:Other diseases: Dietary management of osteoporosis
throughout the life course.
2009
J Bone Miner Metab. 2009 Dec 19. Hop rho iso-alpha acids, berberine, vitamin D(3) and vitamin K(1)
favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial.
Clin Calcium. 2009 Dec;19(12):1815-21. Clinical implications of undercarboxylated osteocalcin.
Clin Calcium. 2009 Dec;19(12):1805-14Anti-fracture efficacy of vitamin K.
Clin Calcium. 2009 Dec;19(12):1797-804. Effect of vitamin K on bone material properties.
Clin Calcium. 2009 Dec;19(12):1788-96.Biological effects of vitamin K2 on bone quality.
Clin Calcium. 2009 Dec;19(12):1779-87. In vivo metabolism of vitamin K: in relation to the
conversion of vitamin K1 to MK-4.
Clin Calcium. 2009 Dec;19(12):1770-8.Vitamin K function mediated by activation of steroid and
xenobiotic receptor
Curr Osteoporos Rep. 2009 Dec;7(4):111-7. Osteoporosis prevention and nutrition.
J Orthop Sci. 2009 Nov;14(6):687-92 Association of low dietary vitamin K intake with radiographic
knee osteoarthritis in the Japanese elderly population: dieary survey in a population-based
cohort of the ROAD study.
Nutr Res. 2009 Apr;29(4):221-8. High-dose vitamin K supplementation reduces fracture incidence in
postmenopausal women: a review of the literature.
Br J Nutr. 2009 May 19:1-8. The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin
carboxylation in healthy prepubertal children.
J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):15-21. Effect of low dose vitamin K2 (MK-4)
supplementation on bio-indices in postmenopausal Japanese women.
14
2008
Calcif Tissue Int. 2008 Aug;83(2):121-8. Effects of vitamin k(2) and risedronate on bone formation
and resorption, osteocyte lacunar system, & porosity in the cortical bone of glucocorticoidtreated rats.
Ann Rheum Dis. 2008 Jul 14 Vitamin K in hand osteoarthritis: results from a Randomized Clinical
Trial.
Bone. 2008 Aug;43(2):230-7. Uptake of postprandial lipoproteins into bone in vivo: Impact on
osteoblast function.
Br J Nutr. 2008 Feb 18:1-7. Vitamin K status is associated with childhood bone mineral content.
J Bone Miner Metab. 2008;26(3):260-4. Response of serum carboxylated and undercarboxylated
osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in
postmenopausal women.
Am J Clin Nutr. 2008 May;87(5):1513-20. Vitamin K1 intake is associated with higher bone mineral
density and reduced bone resorption in early postmenopausal Scottish women: no evidence of
gene-nutrient interaction with apolipoprotein E polymorphisms.
J Pharmacol Sci. 2008 Apr;106(4):530-5. Pharmacological topics of bone metabolism: recent
advances in pharmacological management of osteoporosis.
Proc Nutr Soc. 2008 May;67(2):163-76.Importance of calcium, vitamin D and vitamin K for
osteoporosis prevention and treatment.
J Biol Regul Homeost Agents. 2008 Jan-Mar;22(1):35-44. Vitamin K and D association stimulates in
vitro osteoblast differentiation of fracture site derived human mesenchymal stem cells.
Arch Pediatr. 2008 Mar;15(3):301-12. Recommendations for the management of bone
demineralization in cystic fibrosis
J Clin Endocrinol Metab. 2008 Apr;93(4):1217-23. Effect of vitamin K supplementation on bone loss
in elderly men and women.
Clin Calcium. 2008 Feb;18(2):224-32. Genomic approaches to bone and joint diseases. New insights
into molecular mechanisms underlying protective effects of vitamin K on bone health
Eur J Epidemiol. 2008;23(3):219-25. Association of hip fracture incidence and intake of calcium,
magnesium, vitamin D, and vitamin K.
J Cyst Fibros. 2008 Jul;7(4):307-12. Undercarboxylated osteocalcin and bone mass in 8-12 year old
children with cystic fibrosis.
J Nutr. 2008 Jan;138(1):172S-177S. The balance of bone health: tipping the scales in favor of
potassium-rich, bicarbonate-rich foods.
J Bone Miner Metab. 2008;26(1):79-85. Low plasma phylloquinone concentration is associated with
high incidence of vertebral fracture in Japanese women.
J Bone Miner Metab. 2008;26(1):9-12. Steroid and xenobiotic receptor mediates a novel vitamin K2
signaling pathway in osteoblastic cells.
Br J Nutr. 2008 Jan;99(1):198-205. Nutrition and bone health projects funded by the UK Food
Standards Agency: have they helped to inform public health policy?
Clin Exp Rheumatol. 2008 May-Jun;26(3):484-91. Extremes in vitamin K status of bone are related
to bone ultrasound properties in children with juvenile idiopathic arthritis.
2007
Mayo Clin Health Lett. 2007 Nov;25(11):4. Vitamin K linked to bone strength.
Pediatr Res. 2007 Mar;61(3):366-70 Pronounced elevation of undercarboxylated osteocalcin in
healthy children.
J Nutr Sci Vitaminol (Tokyo). 2007 Dec;53(6):464-70. Vitamin K content of foods and dietary
vitamin K intake in Japanese young women.
J Nutr Sci Vitaminol (Tokyo). 2007 Oct;53(5):419-25. Nutritional effects of gamma-glutamyl
carboxylase gene polymorphism on the correlation between the vitamin K status and gammacarboxylation of osteocalcin in young males.
15
Clin Calcium. 2007 Nov;17(11):1752-60. Experience of vitamin K2 in Thailand
Clin Calcium. 2007 Nov;17(11):1709-16. Clinical application of undercarboxylated osteocalcin
Clin Calcium. 2007 Nov;17(11):1702-8. Measurement of serum undercarboxylated osteocalcin by
ECLIA with the "Picolumi ucOC" kit.
Osteoporos Int. 2007 Jul;18(7):963-72. Vitamin K2 supplementation improves hip bone geometry and
bone strength indices in postmenopausal women.
Int J Cardiol. 2007 Jun 12;118(3):338-44. Fracture risk in users of oral anticoagulants: a nationwide
case-control study.
Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent.
Curr Rheumatol Rep. 2007 Apr;9(1):85-92. Not just calcium and vitamin D: other nutritional
considerations in osteoporosis.
Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):20-3. Vitamin K status in the elderly.
Int J Cardiol. 2007 Jun 12;118(3):338-44. Fracture risk in users of oral anticoagulants: a nationwide
case-control study.
Comp Biochem Physiol B Biochem Mol Biol. 2007 May 29; Vitamin K deficiency inhibits mineralization & enhances deformity in vertebrae of haddock (Melanogrammus aeglefinus L.)
Br J Nutr. 2007 Apr;97(4):661-6. Serum percentage undercarboxylated osteocalcin, a sensitive measure
of vitamin K status, and its relationship to bone health indices in Danish girls.
Exp Anim. 2007 Apr;56(2):103-10. Additive effect of vitamin K2 and risedronate on long bone mass in
hypophysectomized young rats.
J Bone Miner Metab. 2007;25(1):46-53. Effect of vitamin K2 and growth hormone on the long bones in
hypophysectomized young rats: a bone histomorphometry study.
Am J Kidney Dis. 2007 Mar;49(3):432-9. Subclinical vitamin K deficiency in hemodialysis patients.
J Nutr Sci Vitaminol (Tokyo). 2007 Jun;53(3):219-24. vitamin K2 (menaquinone-4) on intestinal
alkaline phosphatase activity in rats.
2006
Curr Drug Saf. 2006 Jan;1(1):87-97Role of vitamin K2 in the treatment of postmenopausal
osteoporosis.
Clin Calcium. 2006 Sep;16(9):106-14 and Nutrition. 2006 Jul-Aug;22(7-8):845-52. (same article in
both journals) Protective effects of vitamin K against osteoporosis and its pleiotropic actions
J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):307-15. Beneficial effect of pretreatment and treatment
continuation with risedronate and vitamin K2 on cancellous bone loss after ovariectomy in rats:
a bone histomorphometry study.
Arthritis Rheum. 2006 Apr;54(4):1255-61. Low vitamin K status is associated with osteoarthritis in the
hand and knee.
Calcif Tissue Int. 2006 Nov;79(5):318-25. Synergistic effect of vitamin K2 and prostaglandin E2 on
cancellous bone mass in hypophysectomized young rats.
Clin Calcium. 2006 Dec;16(12):2017-25. Present knowledge in nutritional aspects of fracture.
Am J Clin Nutr. 2006 Feb;83(2):380-6. Vitamin K status of healthy Japanese women: age-related
vitamin K requirement for gamma-carboxylation of osteocalcin.
Int J Vitam Nutr Res. 2006 Nov;76(6):385-90. A preliminary assessment of vitamin K1 intakes and
serum undercarboxylated osteocalcin levels in 11-13 year old Irish girls.
Br J Nutr. 2006 May;95(5):982-8 Phylloquinone (vitamin K1) intakes and serum undercarboxylated
osteocalcin levels in Irish postmenopausal women.
2004-2005
Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81 Vitamin K in the treatment and prevention of
osteoporosis and arterial calcification.
Curr Pharm Des. 2004;10(21):2557-76. Effects of vitamin K2 on osteoporosis.
16
IV.
Inadequacy of Vitamin K:
Cancer:
Liver, Colorectal, Prostate, Ovarian, Pancreatic
and Cancer Risk in General
2010
Am J Clin Nutr. 2010 Mar 24. Dietary vitamin K intake in relation to cancer incidence and mortality:
results from the Heidelberg cohort of the European Prospective Investigation into Cancer and
Nutrition (EPIC-Heidelberg).
Int J Cancer. 2010 Feb 15;126(4):992-1003. Antioxidant intake from fruits, vegetables and other
sources and risk of non-Hodgkin's lymphoma: the Iowa Women's Health Study.
J Cell Physiol. 2010 Mar 18. Sorafenib combined vitamin K induces apoptosis in human pancreatic
cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways.
2009
Gastroenterol Hepatol. 2009 Nov 19. Naturally occurring K vitamins inhibit pancreatic cancer cell
survival through a caspase-dependent pathway.
Endocr J. 2009;56(7):843-9. Epub 2009 Jun 24. Vitamin K2 suppresses proliferation and motility of
hepatocellular carcinoma cells by activating steroid and xenobiotic receptor.
J Gastroenterol Hepatol. 2009 Nov 19. Naturally occurring K vitamins inhibit pancreatic cancer cell
survival through a caspase-dependent pathway.
Nutr Res. 2009 Sep;29(9):676-83. Prevalence of vitamin K and vitamin D deficiency in patients with
hepatobiliary and pancreatic disorders.
Am J Clin Nutr. 2009 Oct;90(4):889-907. Vitamin K, an example of triage theory: is micronutrient
inadequacy linked to diseases of aging?
J Hepatol. 2009 Aug;51(2):315-21. Combination of vitamin K2 and angiotensin-converting enzyme
inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma.
Int J Toxicol. 2009 Jan-Feb;28(1):33-42.Menadione reduction by pharmacological doses of ascorbate
induces an oxidative stress that kills breast cancer cells.
Cancer Chemother Pharmacol. 2009 Dec;65(1):143-50. The potential of vitamin K3 as an anticancer
agent against breast cancer that acts via the mitochondria-related apoptotic pathway.
J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):227-32. Antiproliferative action of menadione and
1,25(OH)2D3 on breast cancer cells.
Curr Med Chem. 2009;16(15):1821-30 In situ modulation of oxidative stress: a novel and efficient
strategy to kill cancer cells.
Int J Mol Med. 2009 Jun;23(6):709-16. Growth inhibitory effects of vitamin K2 on colon cancer cell
lines via different types of cell death including autophagy and apoptosis.
Jpn J Clin Oncol. 2009 Apr;39(4):251-9..Effect of cell differentiation for neuroblastoma by vitamin k
analogs.
J Gastroenterol. 2009;44(3):228-35. Involvement of hepatoma-derived growth factor in the growth
inhibition of hepatocellular carcinoma cells by vitamin K(2).
Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):49-56. Serum undercarboxylated osteocalcin as
biomarker of vitamin K intake and risk of prostate cancer: a nested case-control study in the
Heidelberg cohort of the European prospective investigation into cancer and nutrition.
Apoptosis. 2009 Jan;14(1):108-23. Arsenic induced apoptosis in malignant melanoma cells is enhanced
by menadione through ROS generation, p38 signaling and p53 activation.
17
2008
Anticancer Res. 2008 Sep-Oct;28(5A):2727-32 Altered deoxyribonuclease activity in cancer cells and its role
in non toxic adjuvant cancer therapy with mixed vitamins C and K3.
Am J Clin Nutr. 2008 Apr;87(4):985-92. Dietary intake of vitamin K and risk of prostate cancer in the
Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPICHeidelberg).
Biol Pharm Bull. 2008 Jun;31(6):1270-3. An attempt to evaluate the effect of vitamin K3 using as an
enhancer of anticancer agents.
Vitam Horm. 2008;78:435-42 Hepatocellular carcinoma and vitamin K.
Am J Clin Nutr. 2008 Apr;87(4):985-92. Dietary intake of vitamin K and risk of prostate cancer in the
Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPICHeidelberg).
Cancer Sci. 2008 May;99(5):1040-8. DNA polymerase gamma inhibition by vitamin K3 induces
mitochondria-mediated cytotoxicity in human cancer cells.
Cancer Lett. 2008 May 8;263(1):53-60. Vitamin K2 suppresses malignancy of HuH7 hepatoma cells
via inhibition of connexin 43.
Anticancer Res. 2008 Jan-Feb;28(1A):45-50. The utility of vitamin K3 (menadione) against
pancreatic cancer.
J Clin Pathol. 2008 Apr;61(4):537-40. A study of the prevalence of vitamin K deficiency in patients
with cancer referred to a hospital palliative care team and its association with abnormal
haemostasis.
J Cancer Res Clin Oncol. 2008 Jul;134(7):803-12. Induction of apoptosis in PA-1 ovarian cancer cells
by vitamin K(2) is associated with an increase in the level of TR3/Nur77 and its accumulation
in mitochondria and nuclei.
2007
Hepatogastroenterology. 2007 Oct-Nov;54(79):2073-7. Effect of vitamin K2 on the recurrence in
patients with hepatocellular carcinoma.
Clin Calcium. 2007 Nov;17(11):1693-9. Clinical application of vitamin K for hepatocellular
carcinoma.
Int J Mol Med. 2007 Dec;20(6):801-8. Vitamin K2-induced cell growth inhibition via autophagy
formation in cholangiocellular carcinoma cell lines.
Int J Oncol. 2007 Aug;31(2):323-31. Vitamins K2, K3 and K5 exert antitumor effects on established
colorectal cancer in mice by inducing apoptotic death of tumor cells.
Hepatol Res. 2007 Sep;37 Suppl 2:S303-7. Potential role of vitamin K(2) as a chemopreventive agent
against hepatocellular carcinoma.
Hepatol Res. 2007 Sep;37 Suppl 2:S299-302. Chemoprevention of liver carcinogenesis with retinoids:
Basic and clinical aspects.
World J Gastroenterol. 2007 Jun 21;13(23):3259-61. Combined treatment of vitamin K(2) and
angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with
liver cirrhosis.
Intern Med. 2007;46(11):711-5. Hepatocellular carcinoma with peritoneal dissemination which was
regressed during vitamin K2 and vitamin E administration.
Am J Surg. 2007 Apr;193(4):431-7. A review of the prognostic factors in patients with recurrence after
liver resection for hepatocellular carcinoma.
J Gastroenterol Hepatol. 2007 Apr;22(4):518-22. Preventive effects of vitamin K on recurrent disease in
patients with hepatocellular carcinoma arising from hepatitis C viral infection.
Int J Oncol. 2007 Aug;31(2):323-31.Vitamins K2, K3 and K5 exert antitumor effects on established
colorectal cancer in mice by inducing apoptotic death of tumor cells.
Cancer Sci. 2007 Mar;98(3):431-7. Synergistic growth inhibition by acyclic retinoid and vitamin K2 in
human hepatocellular carcinoma cells.
18
Clin Cancer Res. 2007 Apr 1;13(7):2236-45. Menatetrenone, a vitamin K2 analogue, inhibits
hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of
nuclear factor kappaB activation.
J Gastroenterol Hepatol. 2007 Apr;22(4):518-22. Preventive effects of vitamin K on recurrent disease in
patients with hepatocellular carcinoma arising from hepatitis C viral infection.
2006
Clin Calcium. 2006 Sep;16(9):106-14 and Nutrition. 2006 Jul-Aug;22(7-8):845-52. (same article in
both journals) Protective effects of vitamin K against osteoporosis and its pleiotropic actions
Cancer. 2006 Feb 15;106(4):867-72. The effect of menatetrenone, a vitamin K2 analog, on disease
recurrence & survival in patients with hepatocellular carcinoma after curative treatment: a pilot
study.
Miscellaneous
Vitamin K Deficiency Associated with Intestinal Malabsorption Problems
2010
Am J Clin Nutr. 2010 Sep;92(3):660-7. Suboptimal vitamin K status despite supplementation in
children and young adults with cystic fibrosis.
Thromb Res 2010 Jan 3. Small intestinal bacterial overgrowth and warfarin dose requirement
variability.
2009
Gastroenterology. 2009 Nov;137(5 Suppl):S105-18. Vitamin K in parenteral nutrition.
Pediatr Clin North Am. 2009 Oct;56(5):1035-53. Nutritional deficiencies during normal growth.
Clin Calcium. 2009 Dec;19(12):1779-87. In vivo metabolism of vitamin K: in relation to the conversion
of vitamin K1 to MK-4.
2008
Pediatrics. 2008 Nov;122(5):1014-20. Prevalence of low bone mass and deficiencies of vitamins D and
K in pediatric patients with cystic fibrosis from 3 Canadian centers.
J Cyst Fibros. 2008 May 27. Efficacy of high dose phylloquinone in correcting vitamin K deficiency
in cystic fibrosis.
Arch Pediatr. 2008 Mar;15(3):301-12. Epub 2008 Mar 5. Recommendations for the management of
bone demineralization in cystic fibrosis
J Cyst Fibros. 2008 Jul;7(4):307-12. Undercarboxylated osteocalcin and bone mass in 8-12 year old
children with cystic fibrosis.
Nutrition. 2008 Apr;24(4):330-9. Nutrient intake from habitual oral diet in patients with severe short
bowel syndrome living in the southeastern United States.
2007
Tohoku J Exp Med. 2007 Jul;212(3):335-9. Vitamin K-deficient intracranial hemorrhage as the first
symptom of cytomegalovirus hepatitis with cholestasis.
Masui. 2007 Feb;56(2):181-5.Suspicious case of epidural hematoma due to coagulopathy caused by
vitamin K deficiency associated with antibiotics.
J Hum Nutr Diet. 2007 Dec;20(6):605-10. Vitamin K prescribing patterns and bone health
surveillance in UK children with cystic fibrosis.
Bone. 2007 Dec;41(6):965-72. Shwachman-Diamond syndrome is associated with low-turnover
19
osteoporosis.
Adv Ther. 2007 Nov-Dec;24(6):1286-9 Celiac disease with diffuse cutaneous vitamin K-deficiency
bleeding.
J Child Neurol. 2007 Jan;22(1):114-5.Cerebral hemorrhage as the initial manifestation of cystic
fibrosis.
Gastroenterol Clin Biol. 2007 Jun;31(6-7):614-5. Severe vitamin K deficiency during a drug wash-out
procedure with cholestyramine.
2006
Adv Ther. 2006 May-Jun;23(3):469-74. Evaluation of vitamin K deficiency in children with acute
and intractable diarrhea.
Pediatr Neurosurg. 2006;42(6):362-7 Intracranial hemorrhage and vitamin K deficiency associated
with biliary atresia: summary of 15 cases and review of the literature.
Odds and Ends:
2010
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000229. Vitamin K prior to preterm birth for
preventing neonatal periventricular hemorrhage.
Early Hum Dev. 2010 Jan 28. Vitamin K the basics-What's new?
Early Hum Dev. 2010 Jan 25. Vitamin K prophylaxis for preterm infants.
2009
Acta Paediatr. 2009 Dec 3. Evaluation of the acceptability of a new oral vitamin K prophylaxis for
breastfed infants.
Hematol Oncol. 2009 Dec;31(12):985-8. Third trimester fetal intracranial hemorrhage owing to vitamin
K deficiency associated with hyperemesis gravidarum.
2008
Eur J Pediatr. 2008 Feb;167(2):165-9. Incidence of late vitamin K deficiency bleeding in
newborns in the Netherlands in 2005: evaluation of the current guideline.
Pediatrics. 2008 Apr;121(4):e857-63.Prevention of vitamin K deficiency bleeding in breastfed
infants: lessons from the Dutch and Danish biliary atresia registries.
Prenat Diagn. 2008 Jan;28(1):59-61. Vitamin K deficiency in hyperemesis gravidarum as a
potential cause of fetal intracranial hemorrhage and hydrocephalus.
2007
J Matern Fetal Neonatal Med. 2007 Sep;20(9):661-7. Preeclampsia is associated with low
concentrations of protein Z.
Am J Med Genet A. 2007 Jan 15;143(2):200-4. Gray matter heterotopias and brachytelephalangic
chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K
deficiency?
Neurology. 2007 Dec 11;69(24 Suppl 3):S10-6. Importance of monotherapy in women across the
reproductive cycle. [Seizure Medications]
J Am Diet Assoc. 2007 Dec;107(12):2091-9. Poor nutrient intakes during 1-year follow-up with
community-dwelling older adults with early-stage Alzheimer dementia compared to
cognitively intact matched controls.
Arch Dis Child. 2007 May 23; Vitamin K deficiency bleeding: the readiness is all.
N Engl J Med. 2007 Jan 11;356(2):174-82. Case records of the Massachusetts General Hospital. Case
20
1-2007. A 40-year-old woman with epistaxis, hematemesis, and altered mental status.
Arch Dis Child. 2007 May 30; Vitamin K deficiency bleeding in the Great Britain and Ireland;
British Paediatric Surveillance Unit Surveys, 1993 - 94 and 2001 - 02.
Pediatrics. 2006 Dec;118(6):e1657-66Vitamin K prophylaxis for preterm infants: a randomized,
controlled trial of 3 regimens.
Some Basic Science References: some recent study topics.
2010
J Nutr Biochem. 2010 Jan 19. Age- and brain region-specific effects of dietary vitamin K on myelin
sulfatides.
Transplantation. 2010 Feb 27;89(4):458-464. Quantitative determination of plasma vitamin K1
byHPLC coupled isotope-dilution tandem mass spectrometry.
2008
Bioelectrochemistry. 2008 May 12. Direct and indirect methods for the determination of vitamin K(3) using
differential pulse polarography and application to pharmaceuticals
Biochemistry. 2008 Jun 17;47(24):6301-10. Transmembrane domain interactions and residue proline 378 are
essential for proper structure, especially disulfide bond formation, in the human vitamin Kdependent gamma-glutamyl carboxylase.
J Biol Chem. 2008 Jun 27;283(26):17991-8 001. Periostin, a member of a novel family of vitamin Kdependent proteins, is expressed by mesenchymal stromal cells.
Vitam Horm. 2008;78:185-209. Vitamin K-dependent actions of Gas6.
Vitam Horm. 2008;78:131-56. Vitamin K-dependent carboxylation.
Vitam Horm. 2008;78:103-30. Structure and function of vitamin K epoxide reductase.
Vitam Horm. 2008;78:85-101. Quinone oxidoreductases and vitamin K metabolism.
Bioorg Med Chem Lett. 2007 Nov 15;17(22):6383-6. Effects of quinones on free-radical processes of
oxidation and fragmentation of hydroxyl-containing organic compounds.
Vitam Horm. 2008;78:63-84. Structure, function, and mechanism of cytosolic quinone reductases.
Vitam Horm. 2008;78:35-62. The vitamin K cycle.
Vitam Horm. 2008;78:23-33. VKORC1 and the vitamin K cycle.
Vitam Horm. 2008;78:1-22. Determinants of vitamin K status in humans.
Vitam Horm. 2008;78:XIX-XX. Vitamin K. Preface.
Methods Mol Biol. 2008;446:85-94. gamma-Glutamate and beta-hydroxyaspartate in proteins.
J Nutr. 2008 Mar;138(3):492-6. Age and dietary form of vitamin K affect menaquinone-4
concentrations in male Fischer 344 rats.
J Biol Chem. 2008 Apr 25;283(17):11270-9. Conversion of phylloquinone (Vitamin K1) into
menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation
in cerebra of mice.
21
MeritCare Medical Center
9/2010
Aunt Cathy’s Guide to Nutrition:
Carnitine
Aunt Cathy
Cathy Breedon PhD, RD, CSP, FADA
Prenatal/Pediatric Nutrition Specialist
Clinical/Metabolic Nutrition Specialist
MeritCare Medical Center, Fargo, ND
Some Sorted References from the
Scientific Literature:
2006 to Sept. 2010
(plus one from 1989 of particular interest as
noted in my accompanying paper on carnitine.)
Altern Med Rev. 2010 Apr;15(1):76-83.
Acetyl-L-carnitine. Monograph.
Cancer-related:
2010
Clin Cancer Res. 2010 Jun 18.
Metabolic Approach to the Enhancement of Antitumor Effect of Chemotherapy: A Key Role of
Acetyl-L-Carnitine.
J Pediatr Hematol Oncol. 2010 Apr;32(3):e114-7.
Vincristine-induced peripheral neuropathy in a neonate with congenital acute lymphoblastic
leukemia.
Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):292-301.
Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer
cachexia.
J Pediatr Hematol Oncol. 2010 Mar;32(2):e61-9.
Serum carnitine levels in childhood leukemia.
Oncologist. 2010;15(2):200-11.
Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer
cachexia.
J Biol Chem. 2010 Feb 26;285(9):6275-84.
The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer
polyamine analogue bleomycin-A5.
Nutr Metab (Lond). 2010 Apr 16;7:30.
Role of carnitine in disease.
1
2009
J Pediatr Hematol Oncol. 2009 Sep;31(9):664-9.
Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or
doxorubicin.
Nutrition. 2009 Nov-Dec;25(11-12):1193-201.
In vitro studies on the inhibition of colon cancer by butyrate and carnitine.
Cell Tissue Res. 2009 Aug;337(2):269-80.
Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase.
J Pain Symptom Manage. 2009 Apr;37(4):622-31.
L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a doubleblind, placebo-controlled study.
Gynecol Oncol. 2009 Mar;112(3):631-6.
Effect of acetyl-l-carnitine on ovarian cancer cells' proliferation, nerve growth factor receptor (TrkA and p75) expression, and the cytotoxic potential of paclitaxel and carboplatin.
2008
Curr Opin Support Palliat Care. 2008 Sep;2(3):180-6.
Fatigue in chronically ill patients.
Int J Cancer. 2008 Sep 15;123(6):1227-39.
Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the
evidence from randomized controlled trials.
Eur J Cancer. 2008 Jul;44(11):1507-15.
Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies.
2007
Cancer Biol Ther. 2007 Oct;6(10):1606-13.
Carnitine palmitoyltransferase I in human carcinomas: a novel role in histone deacetylation?
CNS Drugs. 2007;21 Suppl 1:39-43; discussion 45-6.
Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short
review.
Aging/Neuodegenerative Conditions/ Eye:
2010
Chem Biol Interact. 2010 Mar 30;184(3):346-51.
Regulatory effect of acetyl-l-carnitine on expression of lenticular antioxidant and apoptotic genes in
selenite-induced cataract.
2
Mech Ageing Dev. 2010 Jul-Aug;131(7-8):473-9. Epub 2010 Apr 24.
Optimal micronutrients delay mitochondrial decay and age-associated
diseases.
Rejuvenation Res. 2010 Apr-Jun;13(2-3):148-51.
Acetyl-L-carnitine supplementation to old rats partially reverts the agerelated mitochondrial decay of soleus muscle by activating peroxisome
proliferator-activated receptor gamma coactivator-1alpha-dependent
mitochondrial biogenesis.
Methods Mol Biol. 2010;610:285-308.
Redox homeostasis and cellular stress response in aging and
neurodegeneration.
Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S99-106.
Acetyl-L-carnitine improves aged brain function.
Aging Cell. 2010 Aug;9(4):570-9. Epub 2010 Jun 9.
Acetyl-L-carnitine protects yeast cells from apoptosis and aging and
inhibits mitochondrial fission.
J Psychiatr Pract. 2010 Jan;16(1):5-14.
Clinical outcomes and low-dose levocarnitine supplementation in psychiatric inpatients with
documented hypocarnitinemia: a retrospective chart review.
Methods Mol Biol. 2010;610:285-308.
Redox homeostasis and cellular stress response in aging and neurodegeneration.
Invest Ophthalmol Vis Sci. 2010 Jan;51(1):430-6. Epub 2009 Aug 13.
Involvement of OCTN2 in the transport of acetyl-L-carnitine across the
inner blood-retinal barrier.
Arq Bras Endocrinol Metabol. 2010 Feb;54(1):37-44.
3
Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular
model of Parkinson's disease.
J Altern Complement Med. 2010 Mar;16(3):235-49.
Alternative medical interventions used in the treatment and management of myalgic
encephalomyelitis/chronic fatigue syndrome and fibromyalgia.
J Neurochem. 2010 Apr 1;113(2):515-29.
Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further
development of a potential model of autism spectrum disorders.
IUBMB Life. 2010 May;62(5):357-62.
Acetyl-l-carnitine increases artemin level and prevents neurotrophic factor alterations during
neuropathy.
Ageing Res Rev. 2010 Mar 17.
Mechanistic contribution of carnitine deficiency to geriatric frailty.
Nutr Metab (Lond). 2010 Apr 16;7:30.
Role of carnitine in disease.
Schizophr Bull. 2010 May 21. [Epub ahead of print]
Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral
Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents.
2009
J Neurol Sci. 2009 Aug 15;283(1-2):199-206.
The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of
human Alzheimer's disease.
Nutr Res. 2009 Jan;29(1):70-4.
Dietary supplementation with a combination of alpha-lipoic acid, acetyl-L-carnitine,
glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to
murine brain and improves cognitive performance.
J Biol Chem. 2009 Aug 21;284(34):22840-52. Epub 2009 Jun 24.
Carnitine insufficiency caused by aging and overnutrition compromises
mitochondrial performance and metabolic control.
Exp Brain Res. 2009 Aug;197(3):287-96. Epub 2009 Jun 30.
Early nerve ending rescue from oxidative damage and energy failure by L: -carnitine as posttreatment in two neurotoxic models in rat: recovery of antioxidant and reductive capacities.
Ann Clin Psychiatry. 2009 Oct-Dec;21(4):213-36.
Novel and emerging treatments for autism spectrum disorders: a systematic review.
Mol Vis. 2009 Jul 31;15:1485-91.
4
Evaluation of lenticular antioxidant and redox system components in the lenses of acetyl-L-carnitine
treatment in BSO-induced glutathione deprivation.
Altern Ther Health Med. 2009 Jul-Aug;15(4):34-43.
Syndrome of allergy, apraxia, and malabsorption: characterization of a neurodevelopmental
phenotype that responds to omega 3 and vitamin E supplementation.
Optom Vis Sci. 2009 Feb;86(2):E132-8.
L-carnitine and short chain ester in tears from patients with dry eye.
Front Biosci. 2009 Jan 1;14:376-97.
Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.
Exp Eye Res. 2009 May;88(5):938-44.
The effect of acetyl-L-carnitine on lenticular calpain activity in prevention of selenite-induced
cataractogenesis.
Vestn Oftalmol. 2009 Sep-Oct;125(5):34-7.
Stress protection therapy in the prevention of macular morphological lesions in patients with
diabetes mellitus at cataract microsurgery.
2008
Drugs R D. 2008;9 Suppl 1:3-14.
The aging eye and the role of L-carnitine and its derivatives.
Expert Opin Investig Drugs. 2008 Jun;17(6):827-43.
Acetyl-L-carnitine and alpha-lipoic acid: possible neurotherapeutic agents for mood disorders?
J Neurochem. 2008 May;105(3):677-89. Epub 2008 Jan 10.
Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant
and neuroprotective effects of L-carnitine.
Clin Exp Pharmacol Physiol. 2008 Feb;35(2):168-73.
Changes in redox ratio and protein glycation in precataractous lens from fructose-fed rats: effects of
exogenous L-carnitine.
Neurosurg Rev. 2008 Apr;31(2):205-13; discussion 213.
Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced
brain and retinal damages.
Arch Gerontol Geriatr. 2008 Mar-Apr;46(2):181-90.
Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.
Altern Med Rev. 2008 Jun;13(2):85-115.
Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment:
current understanding and progress toward integrative prevention.
Drugs R D. 2008;9 Suppl 1:15-22
Ocular disorders secondary to systemic disease and the potential role of carnitines.
Drugs R D. 2008;9 Suppl 1:23-32.
Inherited ocular disorders, ophthalmic procedures and carnitines.
Drugs R D. 2008;9 Suppl 1:15-22.
5
Ocular disorders secondary to systemic disease and the potential role of carnitines.
2007
Neuromolecular Med. 2007;9(3):264-9.
Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl
methionine on cognitive performance and aggression in normal mice and mice expressing human
ApoE4.
Am J Clin Nutr. 2007 Dec;86(6):1738-44.
L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive
functions in centenarians: a randomized and controlled clinical trial.
Orv Hetil. 2007 Dec 2;148(48):2259-68.
Metabolic therapy for early treatment of age-related macular degeneration
Curr Eye Res. 2007 Nov;32(11):961-71.
Acetyl-L-carnitine prevents selenite-induced cataractogenesis in an experimental animal model.
6
Curr Eye Res. 2007 Jun;32(6):575-84.
L-carnitine protects human retinal pigment epithelial cells from oxidative damage.
Neuromolecular Med. 2007;9(3):264-9.
Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl
methionine on cognitive performance and aggression in normal mice and mice expressing human
ApoE4.
Reproduction:
Free Radic Biol Med. 2010 Aug 15;49(4):674-81.
Effect of oxidative stress during repeated ovulation on the structure and
functions of the ovary, oocytes, and their mitochondria.
J Endocrinol Invest. 2010 Apr 22.
Acetyl-L-Carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic
women with functional hypothalamic amenorrhea.
EXS. 2010;100:397-460.
Pro-inflammatory and oxidative stress pathways which compromise sperm motility and survival may
be altered by L-carnitine.
Nutr Metab (Lond). 2010 Apr 16;7:30.
Role of carnitine in disease.
Cell Tissue Res. 2009 Aug;337(2):269-80.
Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase.
Hum Reprod. 2008 Jul;23(7):1602-6.
Serum total L-carnitine levels in non-obese women with polycystic ovary syndrome.
Cell Biochem Funct. 2007 Nov-Dec;25(6):611-8.
Protective effect of L-carnitine on testicular ischaemia-reperfusion injury in rats.
Zhonghua Nan Ke Xue. 2006 Aug;12(8):726-9.
Carnitines and male reproduction
Cardiovascular/Diabetes/Respiratory:
2010
Endocr Res. 2010 May;35(2):51-8.
7
Inspiratory muscle strength is correlated with carnitine levels in type 2
diabetes.
Diabetologia. 2010 Jun;53(6):1210-6. Epub 2010 Mar 9.
Type 2 diabetes impairs pulmonary function in morbidly obese women:
a case-control study.
Intern Med. 2010;49(16):1717-25. Epub 2010 Aug 13.
Sibutramine and L-carnitine compared to sibutramine alone on insulin
resistance in diabetic patients.
Nutr Metab (Lond). 2010 Apr 16;7(1):30.
Role of carnitine in disease.
Metabolism. 2010 Apr 26. [Epub ahead of print]
Effects of combination of sibutramine and l-carnitine compared with
sibutramine monotherapy on inflammatory parameters in diabetic
patients.
Endocr J. 2010 Jul 30. [Epub ahead of print]
Orlistat and L-carnitine compared to orlistat alone on insulin resistance
in obese diabetic patients.
JPEN J Parenter Enteral Nutr. 2010 May-Jun;34(3):295-9.
Caloric restriction and L-carnitine administration improves insulin
sensitivity in patients with impaired glucose metabolism.
Diabetes. 2010 Aug 3. [Epub ahead of print]
Increased ROS production and lower abundance of complex I subunits
and carnitine palmitoyltransferase 1B protein despite normal
mitochondrial respiration in insulin resistant human skeletal muscle.
Eur J Clin Invest. 2010 Jul 29. [Epub ahead of print]
Effects of acetyl-L-carnitine and oxfenicine on aorta stiffness in diabetic
rats.
8
Schizophr Bull. 2010 May 21. [Epub ahead of print]
Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral
Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents.
Endocr Res. 2010 May;35(2):51-8.
Inspiratory muscle strength is correlated with carnitine levels in type 2 diabetes.
Toxicol In Vitro. 2010 Apr 3.
Natural Antioxidants and Hypertension: Promise and Challenges.
Cardiovasc Ther. 2010 Mar 29.
The therapeutic prospects of using l-carnitine to manage hypertension-related organ damage.
Arq Bras Endocrinol Metabol. 2010 Feb;54(1):37-44.
The supplementation of L-carnitine does not promote alterations in the resting metabolic rate and in
the use of energetic substrates in physically active individuals.
J Cell Mol Med. 2010 Jan;14(1-2):215-25.
Clinical efficacy of intravenous L-carnitine in patients with right-sided heart failure induced by
pulmonary arterial hypertension.
2009
Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S45-9.
Carnitine and type 2 diabetes.
Diabetol Metab Syndr. 2009 Oct 16;1(1):17.
Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats.
World J Pediatr. 2009 Feb;5(1):60-2.
Serum total and free carnitine levels in children with asthma.
Hypertension. 2009 Sep;54(3):567-74. Epub 2009 Jul 20.
Ameliorating hypertension and insulin resistance in subjects at
increased cardiovascular risk: effects of acetyl-L-carnitine therapy.
Curr Clin Pharmacol. 2009 Jan;4(1):4-37.
State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic
prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a
highly evolved histidyl-hydrazide structure in the treatment and therapeutic management of a group
of sight-threatening eye diseases.
J Biol Chem. 2009 Aug 21;284(34):22840-52.
Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance
and metabolic control.
Diabetes. 2009 Mar;58(3):550-8.
Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty
acid oxidation and improve high-fat diet-induced insulin resistance.
9
J Physiol Biochem. 2009 Sep;65(3):225-33.
Comparison of vitamin E, L-carnitine and melatonin in ameliorating
carbon tetrachloride and diabetes induced hepatic oxidative stress.
Curr Med Res Opin. 2009 Sep;25(9):2223-8.
Effect of propionyl-L-carnitine, L-arginine and nicotinic acid on the efficacy of vardenafil in the
treatment of erectile dysfunction in diabetes.
Hypertension. 2009 Sep;54(3):567-74..
Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects
of acetyl-L-carnitine therapy.
Expert Opin Pharmacother. 2009 Aug;10(12):1875-82.
Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2
diabetes mellitus.
Metabolism. 2009 Nov;58(11):1618-23.
Effect of L-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus
patients treated with simvastatin.
Am J Clin Nutr. 2009 Jan;89(1):71-6.
L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes.
Nutr Metab (Lond). 2009 Jun 2;6:25.
Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in prediabetics.
Pathophysiology. 2009 Jun;16(1):53-56..
Effect of short term treatment of L-carnitine on tissue ACE activity in streptozotocin-induced
diabetic rats.
Am J Clin Nutr. 2009 Jan;89(1):71-6. Epub 2008 Dec 3.
L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes.
J Nutr. 2009 Jun;139(6):1073-81.
Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered
tricarboxylic acid cycle activity in type 2 diabetic African-American women.
Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S45-9.
Carnitine and type 2 diabetes.
Diabetol Metab Syndr. 2009 Oct 16;1(1):17.
Effect of Carnitine and herbal mixture extract on obesity induced by high
fat diet in rats.
2008
Asia Pac J Clin Nutr. 2008;17 Suppl 1:306-8.
Effects of L-carnitine on obesity, diabetes, and as an ergogenic aid.
10
Ann Pharmacother. 2008 Nov;42(11):1686-91..
Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy.
Clin Drug Investig. 2008;28(8):495-500.
Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a
randomized, double-blind, comparative study.
Urol Int. 2008;81(3):340-6.
L-carnitine treatment partially restores urinary bladder function of streptozotocin diabetic rats.
Pharmacol Ther. 2008 Nov;120(2):149-56.
Carnitine in metabolic disease: potential for pharmacological intervention.
Ann Nutr Metab. 2008;52(4):335-8.
Effect of oral L-carnitine administration on insulin sensitivity and lipid profile in type 2 diabetes
mellitus patients.
Eur J Pharmacol. 2008 Jul 7;588(2-3):213-6..
Preventive effect of acetyl-L-carnitine on the thermal hypoalgesia in streptozotocin-induced diabetic
mice.
2007
Diabetologia. 2007 Apr;50(4):824-32.
Carnitine revisited: potential use as adjunctive treatment in diabetes.
1989
Am J Dis Child. 1989 Nov;143(11):1337-9.
Relative carnitine insufficiency in children with type I diabetes mellitus.
Valproic Acid:
Pharm Res. 2010 Apr 13.
Participation of lipid transport and fatty acid metabolism in valproate sodium-induced
hepatotoxicity in HepG2 cells.
Altern Med Rev. 2010 Mar;15(1):76-83.
Drugs and pharmaceuticals: management of intoxication and antidotes.
Am J Ther. 2010 Mar 11.
Valproate-Induced Hyperacute Hyperammonemic Coma in a Patient With Hypocarnitinemia.
Nutr Metab (Lond). 2010 Apr 16;7:30.
Role of carnitine in disease.
Clin Toxicol (Phila). 2009 Feb;47(2):101-11.
Carnitine in the treatment of valproic acid-induced toxicity.
Epilepsy Res. 2009 Sep;86(1):32-41.
The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with
valproate: relationship to blood carnitine status.
11
J Gen Intern Med. 2008 Feb;23(2):210-3.
Hyperammonemic encephalopathy caused by carnitine deficiency.
Dig Dis Sci. 2008 Nov;53(11):3018-25.
Acetyl-L-carnitine treatment in minimal hepatic encephalopathy.
Dig Dis Sci. 2008 Sep;53(9):2330-3.
Is oral L-acyl-carnitine an effective therapy for hepatic encephalopathy? Review of the literature.
J Am Board Fam Med. 2007 Sep-Oct;20(5):499-502.
Valproate-associated hyperammonemic encephalopathy.
Hum Exp Toxicol. 2007 Dec;26(12):967-9.
Two cases of valproic acid poisoning treated with L-carnitine
Klin Padiatr. 2006 Sep-Oct;218(5):260-3.
Asymptomatic carnitine depletion on ketogenic diet in patients with pharmacoresistant epilepsies.
Miscellaneous:
Zhonghua Xin Xue Guan Bing Za Zhi. 2010 Feb;38(2):152-5
Quantitative Measurement of Plasma 3-Hydroxyisovaleryl Carnitine by LC-MS/MS as a Novel
Biomarker of Biotin Status in Humans.
Anal Chem. 2010 Apr 16.
Enhanced Bioavailability of L-Carnitine After Painless Intradermal Delivery vs. Oral
Administration in Rats.
Drug Discov Today. 2010 Apr 2.
Acetyl-L-carnitine - monograph.
Curr Opin Pharmacol. 2010 Mar 29.
Enzymology of the carnitine biosynthesis pathway.
Oxid Med Cell Longev. 2009 Apr;2(2):73-81.
Metabolic myopathies: the challenge of new treatments.
J Physiol Biochem. 2009 Sep;65(3):225-33.
Comparison of vitamin E, L-carnitine and melatonin in ameliorating
carbon tetrachloride and diabetes induced hepatic oxidative stress.
12
Here are the 310 carnitine references that have
appeared since January 1 of this year. They are not
sorted … just a PubMed search. Cathy B.
1.
Effect of oxidative stress during repeated ovulation on the structure and functions of the ovary, oocytes,
and their mitochondria.
Miyamoto K, Sato EF, Kasahara E, Jikumaru M, Hiramoto K, Tabata H, Katsuragi M, Odo S, Utsumi K,
Inoue M.
Free Radic Biol Med. 2010 Aug 15;49(4):674-681. Epub 2010 Jun 8.PMID: 20621580 [PubMed - as
supplied by publisher]Related citations
2.
Effects of trans-10,cis-12 CLA on liver size and fatty acid oxidation under energy restriction conditions in
hamsters.
Lasa A, Simón E, Churruca I, Fernández-Quintela A, Macarulla MT, Martínez JA, Portillo MP.
Nutrition. 2010 Jul 8. [Epub ahead of print]PMID: 20619605 [PubMed - as supplied by publisher]Related
citations
3.
Ethylene Glycol Monomethyl Ether-Induced Toxicity is Mediated through the Inhibition of Flavoprotein
Dehydrogenase Enzyme Family.
Takei M, Ando Y, Saitoh W, Tanimoto T, Kiyosawa N, Manabe S, Sanbuissho A, Okazaki O, Iwabuchi H,
Yamoto T, Adam KP, Weiel JE, Ryals JA, Milburn MV, Guo L.
Toxicol Sci. 2010 Jul 8. [Epub ahead of print]PMID: 20616209 [PubMed - as supplied by
publisher]Related citations
4.
Synthesis and biological evaluation of cyclic nitrogen mustards based on carnitine framework.
Leiris S, Lucas M, Dupuy d'Angeac A, Morère A.
Eur J Med Chem. 2010 Jun 9. [Epub ahead of print]PMID: 20615582 [PubMed - as supplied by
publisher]Related citations
5.
NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone
homeostasis in mice.
Shi YC, Lin S, Wong IP, Baldock PA, Aljanova A, Enriquez RF, Castillo L, Mitchell NF, Ye JM, Zhang L,
Macia L, Yulyaningsih E, Nguyen AD, Riepler SJ, Herzog H, Sainsbury A.
PLoS One. 2010 Jun 29;5(6):e11361.PMID: 20613867 [PubMed - in process]Free PMC ArticleFree
textRelated citations
6.
Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study.
Lara-Corrales I, Mellerio JE, Martinez AE, Green A, Lucky AW, Azizkhan RG, Murrell DF, Agero AL,
Kantor PF, Pope E.
Pediatr Dermatol. 2010 May;27(3):238-43.PMID: 20609141 [PubMed - in process]Related citations
7.
[Expressions of sperm-specific genes in carnitine-cultured testis sperm of obstructive azoospermia patients]
Shi JZ, Zhang SS, Zhang Z, Liang Q, Shi Y, Hua JL, Sun T.
Zhonghua Nan Ke Xue. 2010 Jun;16(6):504-9. Chinese. PMID: 20608353 [PubMed - in process]Related
citations
8.
Cannabinoid receptor 1 and 2 agonists increase lipid accumulation in hepatocytes.
De Gottardi A, Spahr L, Ravier-Dall'antonia F, Hadengue A.
Liver Int. 2010 Jun 29. [Epub ahead of print]PMID: 20602678 [PubMed - as supplied by publisher]Related
citations
9.
Functional Expression of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in mouse small intestine
and liver.
Sugiura T, Kato S, Shimizu T, Wakayama T, Nakamichi N, Kubo Y, Iwata D, Suzuki K, Soga T, Asano M,
Iseki S, Tamai I, Tsuji A, Kato Y.
Drug Metab Dispos. 2010 Jul 2. [Epub ahead of print]PMID: 20601551 [PubMed - as supplied by
publisher]Related citations
10.
Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine
palmitoyltransferase 1B (CPT1B).
Boukouvala E, Leaver MJ, Favre-Krey L, Theodoridou M, Krey G.
Comp Biochem Physiol B Biochem Mol Biol. 2010 Jun 23. [Epub ahead of print]PMID: 20601065
[PubMed - as supplied by publisher]Related citations
11.
Metformin selectively attenuates mitochondrial H(2)O(2) emission without affecting respiratory capacity in
skeletal muscle of obese rats.
Kane DA, Anderson EJ, Price JW 3rd, Woodlief TL, Lin CT, Bikman BT, Cortright RN, Neufer D.
Free Radic Biol Med. 2010 Jun 28. [Epub ahead of print]PMID: 20600832 [PubMed - as supplied by
publisher]Related citations
12.
Why We Should be Vigilant: Drug Cytotoxicity Observed with In Vitro Transporter Inhibition Studies.
Zheng X, Diao L, Ekins S, Polli JE.
Biochem Pharmacol. 2010 Jun 23. [Epub ahead of print]PMID: 20599790 [PubMed - as supplied by
publisher]Related citations
13.
Crystal structure of human gamma-butyrobetaine hydroxylase.
Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Saripo J, Viksna A, Kuka J, Liepinsh
E, Dambrova M.
Biochem Biophys Res Commun. 2010 Jul 1. [Epub ahead of print]PMID: 20599753 [PubMed - as supplied
by publisher]Related citations
14.
AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase:
Role of nuclear respiratory factor-1.
Adam T, Opie LH, Essop MF.
Biochem Biophys Res Commun. 2010 Jul 1. [Epub ahead of print]PMID: 20599696 [PubMed - as supplied
by publisher]Related citations
15.
Acetyl-L-Carnitine for Alcohol Craving and Relapse Prevention in Anhedonic Alcoholics: A Randomized,
Double-Blind, Placebo-Controlled Pilot Trial.
Martinotti G, Reina D, Di Nicola M, Andreoli S, Tedeschi D, Ortolani I, Pozzi G, Iannoni E, D'Iddio S,
Janiri L.
Alcohol Alcohol. 2010 Jun 30. [Epub ahead of print]PMID: 20595193 [PubMed - as supplied by
publisher]Related citations
16.
L-carnitine for acute valproic Acid overdose: a systematic review of published cases.
Perrott J, Murphy NG, Zed PJ.
Ann Pharmacother. 2010 Jul-Aug;44(7-8):1287-93. Epub 2010 Jun 29.PMID: 20587742 [PubMed - in
process]Related citations
17.
Clinical correlates of low serum carnitine levels in hospitalized psychiatric patients.
Cuturic M, Abramson RK, Moran RR, Hardin JW, Hall AV.
World J Biol Psychiatry. 2010 Jun 29. [Epub ahead of print]PMID: 20586533 [PubMed - as supplied by
publisher]Related citations
18.
A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease.
Musso G, Gambino R, Cassader M, Pagano G.
Hepatology. 2010 Jul;52(1):79-104.PMID: 20578268 [PubMed - in process]Related citations
19.
Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic
carnitine deficiency.
Li FY, El-Hattab AW, Bawle EV, Boles RG, Schmitt ES, Scaglia F, Wong LJ.
Hum Mutat. 2010 Jun 22. [Epub ahead of print]PMID: 20574985 [PubMed - as supplied by
publisher]Related citations
20.
[Effects of carnitine on peripheral blood mitochondrial DNA copy number and liver function in nonalcoholic Fatty liver disease.]
22.
Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan.
Niu DM, Chien YH, Chiang CC, Ho HC, Hwu WL, Kao SM, Chiang SH, Kao CH, Liu TT, Chiang H,
Hsiao KJ.
J Inherit Metab Dis. 2010 Jun 22. [Epub ahead of print]PMID: 20567911 [PubMed - as supplied by
publisher]Related citations
23.
Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive
implications.
Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Al-Zaidan H, Al-Odaib
A, Rashed MS.
J Inherit Metab Dis. 2010 Jun 22. [Epub ahead of print]PMID: 20567907 [PubMed - as supplied by
publisher]Related citations
24.
Pharmacological preconditioning with l-carnitine: Relevance to myocardial hemodynamic function and
glycogen and lactate content.
Najafi M, Javidnia A, Ghorbani-Haghjo A, Mohammadi S, Garjani A.
Pak J Pharm Sci. 2010 Jul;23(3):250-5.PMID: 20566435 [PubMed - in process]Related citations
25.
Checks before bolus epidural injection.
Wildsmith JA.
Anaesthesia. 2010 Jun;65(6):650; author reply 650-1. No abstract available. PMID: 20565404 [PubMed indexed for MEDLINE]Related citations
26.
Metabolic Approach to the Enhancement of Antitumor Effect of Chemotherapy: A Key Role of Acetyl-LCarnitine.
Pisano C, Vesci L, Milazzo FM, Guglielmi MB, Foderà R, Barbarino M, D'Incalci M, Zucchetti M,
Petrangolini G, Tortoreto M, Perego P, Zuco V, Orlandi A, Passeri D, Carminati P, Cavazza C, Zunino F.
Clin Cancer Res. 2010 Jun 18. [Epub ahead of print]PMID: 20562210 [PubMed - as supplied by
publisher]Related citations
27.
Redesign of Cosubstrate Specificity and Identification of Important Residues for Substrate Binding to
hChAT.
Green KD, Porter VR, Zhang Y, Garneau-Tsodikova S.
Biochemistry. 2010 Jun 29. [Epub ahead of print]PMID: 20560540 [PubMed - as supplied by
publisher]Related citations
28.
Colon OCTN2 gene expression is up-regulated by PPAR{gamma} in humans and mice, and contributes to
local and systemic carnitine homeostasis.
D'Argenio G, Petillo O, Margarucci S, Torpedine A, Calarco A, Koverech A, Boccia A, Paolella G, Peluso
G.
J Biol Chem. 2010 Jun 17. [Epub ahead of print]PMID: 20558736 [PubMed - as supplied by
publisher]Free ArticleRelated citations
29.
A Mitochondria-Targeted Vitamin E Derivative Decreases Hepatic Oxidative Stress and Inhibits Fat
Deposition in Mice.
Mao G, Kraus GA, Kim I, Spurlock ME, Bailey TB, Zhang Q, Beitz DC.
J Nutr. 2010 Jun 16. [Epub ahead of print]PMID: 20554905 [PubMed - as supplied by publisher]Related
citations
30.
Acetyl-L-carnitine protects yeast cells from apoptosis and aging and inhibits mitochondrial fission.
Palermo V, Falcone C, Calvani M, Mazzoni C.
Aging Cell. 2010 Jun 9. [Epub ahead of print]PMID: 20550520 [PubMed - as supplied by
publisher]Related citations
31.
Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of
malonyl-CoA decarboxylase deficiency with cardiomyopathy.
Footitt EJ, Stafford J, Dixon M, Burch M, Jakobs C, Salomons GS, Cleary MA.
J Inherit Metab Dis. 2010 Jun 15. [Epub ahead of print]PMID: 20549361 [PubMed - as supplied by
publisher]Related citations
32.
Attenuated progression of diet-induced steatohepatitis in glutathione-deficient mice.
Haque JA, McMahan RS, Campbell JS, Shimizu-Albergine M, Wilson AM, Botta D, Bammler TK, Beyer
RP, Montine TJ, Yeh MM, Kavanagh TJ, Fausto N.
Lab Invest. 2010 Jun 14. [Epub ahead of print]PMID: 20548286 [PubMed - as supplied by
publisher]Related citations
33.
Effects of in ovo injection of L-carnitine on hatchability and subsequent broiler performance and slaughter
yield.
Keralapurath MM, Corzo A, Pulikanti R, Zhai W, Peebles ED.
Poult Sci. 2010 Jul;89(7):1497-501.PMID: 20548078 [PubMed - in process]Related citations
34.
Tandem Mass Spectrometry Screening for Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: The
Value of Second-Tier Enzyme Testing.
Spiekerkoetter U, Haussmann U, Mueller M, Ter Veld F, Stehn M, Santer R, Lukacs Z.
J Pediatr. 2010 Jun 12. [Epub ahead of print]PMID: 20547398 [PubMed - as supplied by publisher]Related
citations
35.
Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2methylbutyrylglycinuria identified by newborn screening.
Alfardan J, Mohsen AW, Copeland S, Ellison J, Keppen-Davis L, Rohrbach M, Powell BR, Gillis J,
Matern D, Kant J, Vockley J.
Mol Genet Metab. 2010 May 21. [Epub ahead of print]PMID: 20547083 [PubMed - as supplied by
publisher]Related citations
36.
Activity of hepatic but not skeletal muscle carnitine palmitoyltransferase enzyme is depressed by
intravenous glucose infusions in lactating dairy cows*
Al-Trad B, Wittek T, Gäbel G, Fürll M, Reisberg K, Aschenbach JR.
J Anim Physiol Anim Nutr (Berl). 2010 Jun 9. [Epub ahead of print]PMID: 20546068 [PubMed - as
supplied by publisher]Related citations
37.
Carnitine palmitoyltransferase 2 deficiency: the time-course of blood and urinary acylcarnitine levels
during initial L-carnitine supplementation.
Hori T, Fukao T, Kobayashi H, Teramoto T, Takayanagi M, Hasegawa Y, Yasuno T, Yamaguchi S, Kondo
N.
Tohoku J Exp Med. 2010;221(3):191-5.PMID: 20543534 [PubMed - in process]Free ArticleRelated
citations
38.
Assessment of 3-nitropropionic acid-evoked peripheral neuropathy in rats: Neuroprotective effects of
acetyl-l-carnitine and resveratrol.
Binienda ZK, Beaudoin MA, Gough B, Ali SF, Virmani A.
Neurosci Lett. 2010 Aug 16;480(2):117-21. Epub 2010 Jun 11.PMID: 20542088 [PubMed - in
process]Related citations
39.
Carnitine palmitoyltransferase 2: New insights on the substrate specificity and implications for
acylcarnitine profiling.
Violante S, Ijlst L, van Lenthe H, de Almeida IT, Wanders RJ, Ventura FV.
Biochim Biophys Acta. 2010 Jun 9. [Epub ahead of print]PMID: 20538056 [PubMed - as supplied by
publisher]Related citations
40.
L-carnitine-supplemented parenteral nutrition improves fat metabolism but fails to support compensatory
growth in premature Korean infants.
Seong SH, Cho SC, Park Y, Cha YS.
Nutr Res. 2010 Apr;30(4):233-9.PMID: 20534325 [PubMed - in process]
Enhancement of shortening velocity, power, and acto-myosin crossbridge (CB) kinetics following longterm treatment with propionyl-L-carnitine, coenzyme Q10, and omega-3 fatty acids in BIO TO-2
cardiomyopathic Syrian hamsters papillary muscle.
Vargiu R, Littarru GP, Fraschini M, Perinu A, Tiano L, Capra A, Mancinelli R.
Biofactors. 2010 May-Jun;36(3):229-39.PMID: 20533397 [PubMed - in process]Related citations
42.
Determination of carnitine in food and food supplements by capillary electrophoresis with contactless
conductivity detection.
Pormsila W, Krähenbühl S, Hauser PC.
Electrophoresis. 2010 Jul;31(13):2186-91.PMID: 20533327 [PubMed - in process]Related citations
43.
Oxidative stress in response to forearm ischemia-reperfusion with and without carnitine administration.
Bloomer RJ, Smith WA, Fisher-Wellman KH.
Int J Vitam Nutr Res. 2010 Jan;80(1):12-23.PMID: 20533241 [PubMed - in process]Related citations
44.
Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models.
Spiekerkoetter U, Wood PA.
J Inherit Metab Dis. 2010 Jun 8. [Epub ahead of print]PMID: 20532823 [PubMed - as supplied by
publisher]Related citations
45.
Biochemical characterization of L-carnitine dehydrogenases from Rhizobium sp. and Xanthomonas
translucens.
Arima J, Uesumi A, Mitsuzumi H, Mori N.
Biosci Biotechnol Biochem. 2010 Jun 23;74(6):1237-42. Epub 2010 Jun 7.PMID: 20530902 [PubMed - in
process]Free ArticleRelated citations
46.
Contributions of carnitine acetyl-transferases to intracellular acetyl unit transport in Candida albicans.
Strijbis K, van Roermund CW, van den Burg J, van den Berg M, Hardy GP, Wanders RJ, Distel B.
J Biol Chem. 2010 Jun 3. [Epub ahead of print]PMID: 20522553 [PubMed - as supplied by publisher]Free
ArticleRelated citations
47.
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Mate A, Miguel-Carrasco JL, Monserrat MT, Vázquez CM.
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Comparison of pre-workout nitric oxide stimulating dietary supplements on skeletal muscle oxygen
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Iron chelation therapy in Upper Egyptian transfusion-dependent pediatric homozygous beta-thalassemia
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Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular
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Khalid JM, Oerton J, Besley G, Dalton N, Downing M, Green A, Henderson M, Krywawych S, Wiley V,
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132.
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136.
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Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, Kagaya T, Wakayama T, Hirayama A, Sugimoto M,
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Stasi MA, Scioli MG, Arcuri G, Mattera GG, Lombardo K, Marcellini M, Riccioni T, De Falco S, Pisano
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Sensitivity of cardiac carnitine palmitoyltransferase to malonyl-CoA is regulated by leptin: similarities with
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Guzmán-Ruiz R, Somoza B, Gil-Ortega M, Merino B, Cano V, Attané C, Castan-Laurell I, Valet P,
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Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, Staels B, Kersten S, Müller M.
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The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine
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Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn
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Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical,
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Structural and functional characterization of plant aminoaldehyde dehydrogenase from Pisum sativum with
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Tylichová M, Kopecný D, Moréra S, Briozzo P, Lenobel R, Snégaroff J, Sebela M.
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Olive leaf extract prevents spontaneous occurrence of non-alcoholic steatohepatitis in SHR/NDmcr-cp rats.
Omagari K, Kato S, Tsuneyama K, Hatta H, Sato M, Hamasaki M, Sadakane Y, Tashiro T, Fukuhata M,
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Effects of different ratios of monounsaturated and polyunsaturated fatty acids to saturated fatty acids on
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243.
A diet supplemented with L-carnitine improves the sperm quality of Piétrain but not of Duroc and Large
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Yeste M, Sancho S, Briz M, Pinart E, Bussalleu E, Bonet S.
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244.
Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic
cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated
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Nakamura T, Nakanishi T, Haruta T, Shirasaka Y, Keogh JP, Tamai I.
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Redox homeostasis and cellular stress response in aging and neurodegeneration.
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Hypertension. 2010 Feb;55(2):e13. Epub 2009 Dec 14. No abstract available. PMID: 20008672 [PubMed indexed for MEDLINE]Related citations
247.
Characterization of urinary biomarkers of hepatocellular carcinoma using magnetic resonance spectroscopy
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Flavin adenine dinucleotide status and the effects of high-dose riboflavin treatment in short-chain acyl-CoA
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Nuclear receptors and hepatic lipidogenic enzyme response to a dyslipidemic sucrose-rich diet and its
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Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of the peroxisome
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Comparison of the effects of L: -carnitine and alpha-tocopherol on acute ureteral obstruction-induced renal
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Moosavi SM, Ashtiyani SC, Hosseinkhani S, Shirazi M.
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Replacement of C305 in heart/muscle-type isozyme of human carnitine palmitoyltransferase I with aspartic
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Matsuo T, Yamamoto A, Yamamoto T, Otsuki K, Yamazaki N, Kataoka M, Terada H, Shinohara Y.
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Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute
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Facilitation of fatty acid uptake by CD36 in insulin-producing cells reduces fatty-acid-induced insulin
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Wallin T, Ma Z, Ogata H, Jørgensen IH, Iezzi M, Wang H, Wollheim CB, Björklund A.
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The neuropathy-protective agent acetyl-L-carnitine activates protein kinase C-gamma and MAPKs in a rat
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Di Cesare Mannelli L, Ghelardini C, Toscano A, Pacini A, Bartolini A.
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Zhang L, Macia L, Turner N, Enriquez RF, Riepler SJ, Nguyen AD, Lin S, Lee NJ, Shi YC, Yulyaningsih
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Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta
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Frigerio F, Brun T, Bartley C, Usardi A, Bosco D, Ravnskjaer K, Mandrup S, Maechler P.
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Organic cation/carnitine transporter, OCTN2, transcriptional activity is regulated by osmotic stress in
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Cotton LM, Rodriguez CM, Suzuki K, Orgebin-Crist MC, Hinton BT.
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Vitamin E tocotrienols improve insulin sensitivity through activating peroxisome proliferator-activated
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Cardiomyopathy and kidney disease in a patient with maternally inherited diabetes and deafness caused by
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Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism
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