Download 4-5 (Galin)

Endo: 4:00-5:00
Tuesday, November 3, 2009
Dr. Galin
PTH- parathyroid hormone
Hormonal Control of Calcium Homeostasis
Scribe: Patricia Fulmer
Proof: Sheena Harper
Page 1 of 5
The audio didn’t pick up until slide 4, but he didn’t elaborate on anything much until that slide anyways.
I. Hormonal Control of Calcium Homeostasis [S1]
II. Ca2+/PO4 [S2]
a. He just pointed out that calcium and phosphate go together in most cases.
III. Overview [S3]
a. Just a list of different things that calcium and phosphate are involved in in the body.
b. The things that have a star by them should really be remembered!!!! He tests on the big concepts.
IV. Trousseau’s Sign of Tetany [S4] ***Audio picked up here
a. A good example of this is Trousseau’s Sign of Tetany. There are actually two kinds of tetany. The other is
Chvestok’s.
b. Tetany is a condition where you have hyperreflexia and low calcium. (INAUDIBLE, LOOKED UP ONLINE)
c. What you can do with Trousseau’s Sign is put a blood pressure cuff on and inflate it. This causes muscle
spasms in the hand that are uncontrollable.
d. Chvestok’s Sign- Tapping the facial nerve, and that will cause the ipsilateral nerve of the face to create facial
contractions.
e. This shows that you are hypocalcemic.
f. If you are hypocalcemic, then the nerve excitability is high. If you are hypercalcemic, then nerve
excitability is low.
[SQ]: Tetany is associated with high or low calcium?
[A]: Tetany is associated with low calcium.
V. Calcium Balance [S5]
a. Doesn’t expect us to know the numbers.
b. Shows how tightly and strictly regulated calcium levels are in the body. This is so we don’t get a hypo or hyper
situation or get tetany.
c. The typical diet is 1000mg of calcium/day taken in. You get rid of 900mg through the feces and 100mg through
the urine. So basically what you take in you get rid of.
d. During this process you have a shifting of calcium from the intracellular fluid to extracellular fluid.
e. 90% of calcium is in the bone. Bone is always turning over, so you’re always having calcium taken up and
calcium released.
f. The main thing is what you take in, you’ll get rid of.
g. We’ll talk about 3 hormones. Know where these hormones act.
h. The three places we’ll talk about are the GI tract, the bone, and the kidney. Know which hormones act where.
VI. Phosphate Balance [S6]
a. This one is just phosphate is the same way.
b. Remember that normally whatever calcium is doing, phosphate is doing the same thing.
c. If you are reabsorbing calcium, you’re reabsorbing phosphate. If you are excreting calcium, you’re excreting
phosphate.
d. There’s one exception to the rule: calcium and phosphate don’t go together--in the kidney. One will go
one way, and one will go the other way. This is under regulation of hormones in the kidney.
VII. Calcium Homeostasis and Bone Turnover/The Sacrificial Bone [S7-8]
a. Osteoblasts are important for building bone; osteoclasts are for breaking down bone.
b. How these hormones act on osteoblasts and osteoclasts will determine if you are building bone or breaking it
down.
c. Know which cell types have receptors for which hormones: this will tell you if the hormones have direct
or indirect action on the bone.
i. Osteoblasts have receptors for PTH, Vitamin D3, and Estrogen (very important). These are the blue cells.
ii. Osteoclasts have receptors for Calcitonin. These are the red cells.
VIII. Mechanisms of Action of Calcitropic Hormones [S9]
a. We’ll talk about Vitamin D, PTH, and Calcitonin
IX. ARS question 1 [S10]
a. Vitamin D is a hormone.
X. Synthesis of Vitamin D [S11]
a. We get Vitamin D from 2 sources: sunlight and supplement in foods like milk
Endo: 4:00-5:00
Scribe: Patricia Fulmer
Tuesday, November 3, 2009
Proof: Sheena Harper
Dr. Galin
Hormonal Control of Calcium Homeostasis
Page 2 of 5
b. That’s why it’s important to get 5-10 min of sunlight/day. That’s all it takes to get our Vitamin D fulfilled. Over the
past 5 years, there has been a trend toward more people becoming Vitamin D deficient. This is probably
because of our lifestyle.
c. Vitamin D is not a classic hormone because it is not produced and secreted by endocrine glands. The definition
of a hormone is something that is secreted by an endocrine gland that travels somewhere else and acts on a
receptor.
d. It is also not a true vitamin because it can be synthesized de novo—within your body. Vitamins cannot be made
in the body, but Vitamin D can.
e. Vitamin D is a true hormone because it is synthesized in the body and travels elsewhere to act on a receptor.
There are receptors for Vitamin D.
XI. Chemical Structures Slide [S12]
a. In our skin we have 7-dehydrocholesterol that gets converted to cholecalciferol with UV light present.
b. Cholecalciferol enters the liver and gets hydroxylated, forming 25-hydroxy-Cholecalciferol. This is the first
hydroxylation.
c. To have functional Vitamin D, you must have 2 hydroxylations: the first in the liver and the second in the kidney.
d. 25-hydroxy-Cholecalciferol enters the kidney and is acted upon by one of two enzymes: 1-alpha-hydroxylase
and 24-alpha-hydroxylase. YOU MUST KNOW THESE ENZYMES.
e. 1-alpha-hydroxylase creates the active form of Vitamin D, and 24-alpha-hydroxylase creates the inactive
form.
f. People that use alcohol or are on meds that affect the liver can often be admitted to the hospital for broken
bones. It’s not that they’ve fallen. It’s because they miss the first hydroxylation, and therefore cannot make
functional Vitamin D. This leads to an inability to reabsorb calcium and keep the bones strong.
g. Same thing with people who have kidney problems or renal disease. They can make the first precursor, but they
cannot make 1-alpha-hydroxylase and/or 24-alpha-hydroxylase. So they cannot get functional Vitamin D.
h. CYP Genes [S13]
i. It depends on what book you look at here. He’ll use 1-alpha-hydroxylase and 24-alpha-hydroxylase for the
names on the test, but they can be referred to as CYP genes sometimes.
XII. 25-OH-D3 [S14]
a. Precursor comes out of the liver in its first hydroxylated form.
b. If you are hypocalcemic (low calcium) or hypophosphatemic (low phosphate) you’ll turn on the 1-alphahydroxylase.
c. This is because the activity of Vitamin D is to reabsorb calcium from the bone. So you are low, you want to
reabsorb. You turn on the 1- alpha-hydroxylase and the active form of Vitamin D.
d. One thing noted here is that there is an increase in PTH will cause the same activation as hypocalcemiaactivation of 1- alpha-hydroxylase.
e. If you are hypercalcemic or hyperphosphatemic, you’ll turn on 24- alpha-hydroxylase.
f. There is also a negative feedback mechanism in place that causes the kidney to turn on 24- alpha-hydroxylase
if there is too much active Vitamin D present and turn off the active form.
XIII. Intestinal Ca++ Absorption [S15]
a. Main site of action for Vitamin D is the gut. We’ll talk about the gut, bone, and kidney.
b. It does three things to the gut:
i. Increase calcium channels so you can start the calcium reabsorption process
ii. Increase protein synthesis. The main one is Calbindin. This is because when calcium enters the cell, you
want it to go directly outside the cell. You want to reabsorb it. Calbindin is like a metro bus. It transports the
calcium across the cell so it can move outside the cell.
iii. Two other things turned on are the sodium-calcium exchanger and a hydrogen-calcium pump. These help
get the calcium out of the cell out of the basolateral membrane.
XIV.
Intestinal Phosphate Absorption [S16]
a. We don’t know what’s going on with phosphate, so he won’t ask about it on a test.
b. We know sodium-phosphate exchanger gets up-regulated and that Na/K ATPase is present.
c. KNOW WHAT HAPPENS WITH CALCIUM.
XV. The “Real Thing” or a Bad Thing/Kid Picture [S17-18]
a. This is not as important for us, but it is important for children.
b. It doesn’t matter whether it’s a regular or diet soda, they all have an extremely high concentration of phosphate.
c. If you are hyperphosphatemic, you turn on 24- alpha-hydroxylase and make inactive Vitamin D. Drinking a lot of
soda creates a situation where you have a lot of phosphate present. Therefore, you start producing the inactive
form of Vitamin D. This occurs even though you haven’t changed the calcium levels. This can inhibit bone
growth.
d. This is very important during puberty.
Endo: 4:00-5:00
Scribe: Patricia Fulmer
Tuesday, November 3, 2009
Proof: Sheena Harper
Dr. Galin
Hormonal Control of Calcium Homeostasis
Page 3 of 5
[SQ]: How much constitutes “a lot” of soda?
[A]: 4-6 or more, not one a day. Phosphate and calcium are highly regulated, but it takes time to do that.
When you drink a lot of these drinks, it makes the body seem like it is in a state of high phosphate.
XVI.
Review Slide 1 [S19]
a. He likes to put in review slides. This is the one for Vitamin D.
b. It shows that if you are hypocalcemic, you’ll turn on 1- alpha-hydroxylase in the kidney and make the active form
of Vitamin D.
c. The main site of Vitamin D action is the gut. That will cause reabsorption of calcium and phosphate and
increase plasma calcium and phosphate.
XVII.
Parathyroid Hormone (PTH) [S20]
a. Now we’ll go to PTH.
b. Again, these are not separate. PTH can control 1-alpha-hydroxylase.
XVIII. Anatomy Picture [S21]
a. PTH comes from parathyroid glands. We have four of these.
b. They’re located posterior to the thyroid glands.
c. If you have hyper or hypothyroidism, you can get goiter- an enlargement of the thyroid gland. You can remove
the thyroid and take thyroid hormone replacement to help. When they first started taking out the thyroid for
treatment, patients would die. This is because they were also taking the parathyroid. They are very small.
d. You can live with one or two parathyroids, but not with zero. They are essential to life.
XIX.
Parathyroid Gland [S22]
a. If we look histologically, we have chief cells- produce PTH
b. Also have oxyphil cells- no idea what they do. They may be support or burnt out chief cells.
XX. Calcium Sensor [S23]
a. This is recent data from the past 5-8 years.
b. Parathyroid gland or chief cells have receptors for calcium.
c. If you are hypercalcemic, you would want to turn off PTH. This is because PTH is responsible for the
reabsorption of calcium. So if you are already hypercalcemic, you’ll need to turn it off.
d. With most of the hormones we study, their secretion is triggered by an intracellular increase in calcium due to
activation of adenylate cyclase.
e. This is contrary to the norm. If you are hypercalcemic, these chief cells have a receptor for calcium, the chief
cells will bind calcium and bring it into the cell. The intracellular rise in calcium in the chief cell turns off the PTH
secretion.
f. If you are hypocalcemic, you aren’t bringing much calcium in, PTH secretion will constantly be stimulated.
XXI.
Elevated Ca++ will inhibit PTH secretion [S24]
a. You have your calcium sensing receptor.
b. An increase in calcium will inhibit the synthesis and secretion of PTH.
c. You must have no calcium coming into the chief cells to secrete PTH.
XXII. Flow Chart [S25]
a. We talk about calcium and phosphate together because they love to bind each other. This helps make
hydroxyapatite.
b. Calcium and phosphate will form salt, and an accumulation of salt forms crystals. In the kidney, it would be bad
to have crystals—that would lead to stones. PTH will differentially regulate calcium and phosphate reabsorption
in the kidney.
c. PTH will increase calcium absorption and increase phosphate excretion. If you don’t excrete phosphate when
you absorb calcium, you’ll get stones.
d. One of the main sites of PTH is the kidney, and it’s the one place calcium and phosphate are differentially
regulated.
XXIII. Bone Graphic [S26]
a. The other site of action of PTH is the bone
b. Vitamin D is the gut; PTH is the kidney and bone.
c. PTH will cause reabsorption of calcium from the bone. So it activates osteoclasts.
d. Osteoclasts do not have receptors for PTH. Osteoblasts do. So PTH binds to osteoblasts and secretes
cytokines.
e. Osteoclasts come from the same precursor as monocytes and macrophages (all the myeloid cells). So this is
why the osteoblasts release cytokines—to activate those stem cells. Osteoblasts turn on things like Macrophage
Colony Stimulating Factor (M-CSF), ILs, RANK ligand system, etc.
f. PTH acts on bone INDIRECTLY. It excites osteoblasts, which release paracrine factors. The paracrine factors
will cause osteoclasts to differentiate and become active. The osteoclasts attach to bone at the sealing zone
Endo: 4:00-5:00
Scribe: Patricia Fulmer
Tuesday, November 3, 2009
Proof: Sheena Harper
Dr. Galin
Hormonal Control of Calcium Homeostasis
Page 4 of 5
and start putting out their acids and proteases. The pH of the ceiling zone is 4. The break down the bone, and
you get calcium reabsorption.
g. This process is ongoing. We replace our bone every 3-7 years.
h. Estrogen is listed here because it decreases activity of PTH on reabsorption of bone.
i. Estrogen inhibits production of the paracrine hormones. It helps sub regulate that system so you don’t get over
activity of osteoclasts.
j. When estrogen goes down in a woman’s 50’s or so, the activity of osteoclasts due to PTH indirect stimulation
goes up. This is because there is not as much estrogen to control the paracrine stimulation of osteoclast
formation.
k. Osteoporosis is more common in women than men. Estrogen is made from testosterone, and a woman goes
through menopause around age 50 causing her to stop making estrogen. The cessation of testosterone
production in men (and therefore, estrogen production) is not until age 70-75. So you don’t see a drop in
estrogen production in men until that age, and you won’t see osteoporosis that late in life usually.
XXIV. Review Slide 2 [S27]
a. Summary slide for PTH with a little Vitamin D
b. Decrease in plasma, increase in PTH because not activating the calcium receptors on the chief cell. So you’ll
turn on PTH production and secretion.
c. PTH is a direct signal in the kidney to turn on 1-alpha-hydroxylase. PTH and Vitamin D like to work together but
have separate sites of action. So PTH needs to turn on Vitamin D so it can work in the gut while PTH works in
the bone and kidney.
d. Ultimately you’ll increase plasma calcium, but if you’re talking about the kidney, you’re going to decrease
plasma phosphate
e. So if you’re looking at the action of PTH on the kidney- increase plasma calcium and decrease plasma
phosphate. Overall in the body, it will increase reabsorption of both. This is because it is going to increase
plasma calcium and phosphate in the bone, and it is going to activate Vitamin D, which will increase plasma
calcium and phosphate in the gut. It is a net reabsorption of both. Only if you look at the kidney will you see a
difference.
XXV. Calcitonin [S28]
a. Calcitonin comes from the thyroid gland and is made in C-cells.
b. You have follicles in the thyroid with parafollicular cells around them. These parafollicular cells line a colloid.
c. Thyroid hormone is the only endocrine hormone made outside the cell.
d. Surrounding these follicles, on the outside of the parafollicular cells, are C-cells. These are called that because
they make Calcitonin.
e. We don’t really know why you make Calcitonin. It’s not essential for life. You don’t see a lot of problems if you
don’t make it. We do know the effect of Calcitonin on some of the things we’re talking about.
XXVI. Flow Chart 2 [S29] That is if you start
a. If you start with PTH and Vitamin D acting, you get a rise in serum calcium. When calcium goes up, it signals
calcitonin secretion.
b. Calcitonin effects are opposite the effects of Vitamin D and PTH. So you’ll get excretion of phosphate and
calcium.
c. Even though we don’t know the role exactly on a normal physiological basis, we know that in osteoporosis, it is
a good thing. If calcitonin binds to receptors on osteoclasts, it will inhibit them. This is a good therapy for
osteoporosis.
XXVII. Review Slide 3 [S30]
a. Summary slide for all three; puts it all together
b. If you understand this slide, you’re good
XXVIII. Are your bones healthy? [S31]
a. End with pathology
XXIX. Osteoporosis [S32]
a. Osteoporosis is becoming a major problem. It is affecting more than 44 million Americans with 80% being
female.
b. One in 2 women and one in 8 men over 50 will have an osteoporosis related fracture. This is important when
you look at cost—38 million per day.
XXX. Osteoporosis 2 [S33]
a. Osteoporosis is most common in post-menopausal women.
b. One of the common signs is dorsal kyphosis (widow’s humpback). This is caused because once you start
breaking down vertebrae, they collapse on each other. That will cause the humpback and [INAUDIBLE]. So it’s
a compression of the vertebrae as osteoclast activity gets higher.
Endo: 4:00-5:00
Scribe: Patricia Fulmer
Tuesday, November 3, 2009
Proof: Sheena Harper
Dr. Galin
Hormonal Control of Calcium Homeostasis
Page 5 of 5
c. Reminder about estrogen: decreased estrogen tends to increase paracrine release of cytokines from
osteoblasts to activate osteoclasts
XXXI. ARS question 2 [S34]
a. Transplant patients are susceptible to osteoporosis because of steroids. The steroids act on the hormones’
activity in the bone. It is both direct and indirect activity.
XXXII. Bone Graphic 2 [S35]
a. Steroids can inhibit these paracrine hormones like estrogen, but if they get too high, they can actually increase
the reproduction of osteoclasts and cause a direct increase in differentiation into osteoclasts.
b. Won’t ask about that. DO KNOW ESTROGEN
XXXIII. Vitamin D Deficiency [S36]
a. Know that Rickets and Osteomalacia are the same thing (Rickets in kids, osteomalacia in adults)
b. They are a deficiency in Vitamin D
c. Common in the 1920’s, but now with Vitamin D supplements we don’t have this problem as much
d. Bowing of the legs is common. See it in legs (not arms) because they are weight bearing.
XXXIV. Primary Hyperparathyroidism [S37]
a. You get an increase in PTH despite an increase in calcium and decrease in phosphate
b. It is a primarily a problem with the targeted layers of the parathyroid glands—usually deals with hyperplasia
c. You’ll get increased calcium with increased PTH—leads to lethargy, muscle weakness, constipation
d. You’ll get low nerve excitation with the increased calcium
e. Common problem is kidney stones
f. Treatment is calcitonin and bisphosphonates.
g. Bisphosphonates have a direct effect on osteoclasts so that they don’t act on the bone.