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Functional Medicine University’s
Functional Diagnostic Medicine
Training Program
INSIDER’S GUIDE
Organic Acids and
Urinary Bile Acid
Sulfates
By Ron Grisanti, D.C. & Dicken Weatherby, N.D.
http://www.FunctionalMedicineUniversity.com
Limits of Liability & Disclaimer of Warranty
We have designed this book to provide information in regard to the subject matter covered. It is made available with the understanding that the
authors are not liable for the misconception or misuse of information provided. The purpose of this book is to educate. It is not meant to be a
comprehensive source for the topic covered, and is not intended as a substitute for medical diagnosis or treatment, or intended as a substitute
for medical counseling. Information contained in this book should not be construed as a claim or representation that any treatment, process or
interpretation mentioned constitutes a cure, palliative, or ameliorative. The information covered is intended to supplement the practitioner’s
knowledge of their patient. It should be considered as adjunctive support to other diagnostic medical procedures.
This material contains elements protected under International and Federal Copyright laws and treaties. Any unauthorized reprint or use of this
material is prohibited
Functional Medicine Training Program
Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Contents
CONTENTS .............................................................................................................................................................. 2
ORGANIC ACIDS OF DETOXIFICATION ................................................................................ 3
2-METHYLHIPPURATE .............................................................................................................................................. 3
XYLENE EXPOSURE ................................................................................................................................................. 4
OROTATE ................................................................................................................................................................ 5
Arginine deficiency symptoms: ......................................................................................................................... 5
Magnesium deficiency symptoms: .................................................................................................................... 6
GLUCARATE ............................................................................................................................................................ 6
X-HYDROXYBUTYRATE (AHB) .................................................................................................................................. 8
Diseases that increase glutathione demand:.................................................................................................... 9
PYROGLUTAMATE .................................................................................................................................................. 10
SULFATE ............................................................................................................................................................... 10
URINARY BILE ACID SULFATES (UBAS) .................................................................................................................. 12
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Organic Acids of Detoxification
2-Methylhippurate
Specific product of detoxification of xylene from environmental exposure.
Hepatic Phase II conjugation of glycine.
If HIGH:
Causes:
•
Xylene exposure
•
New paint, spray paint
•
New carpet
•
New cars
•
Dry cleaning fluid
•
Cleaning solvents
•
Paint thinners
•
Building products
•
Fuel and exhaust fumes
•
Industrial degreasers and solvents
Symptoms and conditions
Increase oxidative stress
Treatment:
•
Avoidance of xylenes
•
Glycine
•
Pantothenic acid
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Xylene Exposure
Exposure to xylene occurs in the workplace and when you use paint, gasoline, paint thinners
and other products that contain it. People who breathe high levels may have dizziness,
confusion, and a change in their sense of balance.
What is xylene?
There are three forms of xylene in which the methyl groups vary on the benzene ring: metaxylene, ortho-xylene, and para-xylene (m-, o-, and p-xylene). These different forms are
referred to as isomers.
Xylene is a colorless, sweet-smelling liquid that catches on fire easily. It occurs naturally in
petroleum and coal tar.
Chemical industries produce xylene from petroleum. It is one of the top 30 chemicals produced
in the United States in terms of volume.
Xylene is used as a solvent and in the printing, rubber, and leather industries. It is also used as
a cleaning agent, a thinner for paint, and in paints and varnishes. It is found in small amounts
in airplane fuel and gasoline.
What happens to xylene when it enters the environment?
Xylene evaporates quickly from the soil and surface water into the air.
In the air, it is broken down by sunlight into other less harmful chemicals in a couple of days.
It is broken down by microorganisms in soil and water.
Only a small amount of it builds up in fish, shellfish, plants, and other animals living in xylenecontaminated water.
How might I be exposed to xylene?
Using a variety of consumer products including gasoline, paint varnish, shellac, rust
preventatives, and cigarette smoke. Xylene can be absorbed through the respiratory tract and
through the skin.
Ingesting xylene-contaminated food or water, although these levels are likely to be very low.
Working in a job that involves the use of xylene such as painters, paint industry workers,
biomedical laboratory workers, automobile garage workers, metal workers, and furniture
refinishers.
How can xylene affect my health?
High levels of exposure for short or long periods can cause headaches, lack of muscle
coordination, dizziness, confusion, and changes in one’s sense of balance. Exposure of people
to high levels of xylene for short periods can also cause irritation of the skin, eyes, nose, and
throat; difficulty in breathing; problems with the lungs; delayed reaction time; memory
difficulties; stomach discomfort; and possibly changes in the liver and kidneys. It can cause
unconsciousness and even death at very high levels.
How can families reduce the risks of exposure to xylene?
Exposure to xylene as solvents (in paints or gasoline) can be reduced if the products are used
with adequate ventilation and if they are stored in tightly closed containers out of the reach of
small children.
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Sometimes older children sniff household chemicals in attempt to get high. Talk with your
children about the dangers of sniffing xylene.
If products containing xylene are spilled on the skin, then the excess should be wiped
off and the area cleaned with soap and water.
Orotate
Urea cycle overload with ammonia causes increase ororate synthesis
If HIGH:
Causes:
•
When orotate is high, check citrate, cis-aconitate and isocitrate – all are aspects of
ammonia clearance.
•
Orotate is a very sensitive to anything that increases ammonia in liver –meat intake or
dysbiosis (intestinal bacterial ammonia production)
•
Arginine deficiency – sensitive indicator
•
Magnesium deficiency
•
Long term oral glutamine supplementation above 10 gm/day
Symptoms and Conditions:
•
Hyper ammonemia (possibly mild, intermittent form)
•
Poor growth
•
Poor coordination
•
Ataxia
•
Lethargy
•
Neonatal HHH syndrome
Arginine deficiency symptoms:
Arginine is a conditionally essential amino acid that is critical for your cardiovascular health
and detoxification functions. The amino acid, arginine, is used to make the powerful blood
vessel regulator, nitric oxide. Nitric oxide acts to lower blood pressure.
Too little arginine can lead to high blood pressure. Too much arginine can lead to increased
aging from oxidative damage. High Citrate, Isocitrate, Cis-aconitate, or Orotate can indicate
arginine insufficiency for ammonia clearance through the Urea Cycle.
•
Hyperammonemia – failure of ammonia removal
•
Coronary artery disease
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
•
Angina
•
Hyper tension
•
Impaired insulin production
•
Possible hair loss
Magnesium deficiency symptoms:
•
Nausea
•
Vomiting
•
Hypotension
•
Weakness
•
Hyporeflexia
•
Confusion
Treatment:
•
Decrease protein or amino acid intake
•
Treat gut dysbiosis
•
Arginine, 500
•
Magnesium
Glucarate
Detoxification, liver enzyme induction – Phase 1 detoxification
Specific Marker for glucaronidation – Phase II detoxification
Glucarate serves as a biomarker for your exposure to a wide array of potentially toxic
chemicals.
Indicator of overall hepatic detoxification function
Part of the many degradation pathways:
•
Bile
•
Drugs
•
Food components
•
Products of gut microbial metabolism
This marker should not be used to assess the cancer-protective role of oral glucarate salts.
If HIGH:
•
Intestinal dysbiosis
•
Toxic exposure
•
Drugs
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
•
Food components
•
Dysbiosis
•
Xenobiotics
Exposure to:
•
Pesticides
•
Herbicides
•
Fungicides
•
Petrochemicals
•
Alcohol
•
Drugs
The following classes of compounds are cleared via Glucuronidation (Phase II
detoxification):
Polycyclic aromatic hydrocarbons
•
Benzo (a) pyrene
•
Benzanthracene
•
Naphthalene
Various nitrosamines:
•
Cured meats
•
Tobacco products
•
Rubber products
•
Pesticides
Fungal Toxins
Aflatoxin
Steroid hormones
•
Estrogen
•
Testosterone
Heterocyclic Amines
•
Well done meats
•
Fried foods
•
Barbequed meats
Pharmaceutical drugs
•
Aspirin
•
Lorazepam
•
Digoxin
•
Morphine
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Vitamins:
•
Vitamin A
•
Vitamin D
•
Vitamin E
•
Vitamin K
High urinary Glucarate suggests above normal exposure to pesticides, herbicides,
fungicides, petrochemicals, alcohol, pharmaceutical compounds, or toxins produced in
the gastrointestinal tract.
Symptoms and Conditions
Long term exposure to environmental pollutants and continued toxic load to the
detoxifying systems lead to a reduced capacity for phase II conjugation resulting in the
potential development of number of symptoms and conditions such as:
•
Oxidative stress
•
Fatigue
•
Headaches
•
Muscle pain
•
Mood disorders
•
Poor exercise tolerance
•
Chronic fatigue syndrome
Treatment
•
Treat dysbiosis
•
Toxicant (xenobiotic) avoidance
x-Hydroxybutyrate (AHB)
Marker of hepatic glutathione synthesis rate
By product of the final step in the hepatic pathway
Methionine -Æ homocysteine -Æ Cystathionine -Æ Cysteine
Alpha-hydroxybutyrate dehydrogenase (AHBD) enzyme is very active in cardiac tissue thus it
is a good marker to estimate myocardial infarct size and reperfusion rate.
If HIGH: may be due to:
•
Increase hepatic glutathionine synthesis
•
Oxidative stress causes reciprocal regulation so that homocysteine conversion to
methionine is inhibited while conversion to cysteine is stimulated.
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Toxin-stimulated up-regulation of detoxification:
1. Glutathione conjugation
2. Intestinal microbial products
3. Xenobiotics
4. Pharmaceuticals – especially acetaminophen
Sulfation
1. Intestinal microbial products
2. Xenobiotics
3. Pharmaceuticals
Diseases that increase glutathione demand:
•
Muscular dystrophy
•
Macular degeneration
•
Diabetes
•
Emphysema (COPD)
•
Respiratory distress syndromes
•
Hepatic cirrhosis
•
Parkinson’s disease
•
Crohn’s disease
•
Autism spectrum disorders
•
Cachexia
•
Radiation poisoning
•
Extreme endurance training
Symptoms and Conditions:
Any associated with the disease listed above
Aging effects associated with chronic oxidative stress and toxin loading
Treatment
•
Higher doses than those mentioned below may be needed for acetaminophen toxicity
and similar acute situations
•
IM or IV reduced glutathione – oral doses probably not absorbed
•
N-Acetylcysteine (NAC) 1500 mg/d
•
L-Methionine 1000 mg/d
•
Taurine 500
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
•
Alpha-lipoic acid 200
•
Whey protein isolate
Pyroglutamate
Renal amino acid recovery and small intestinal amino acid absorption mechanism that
consume up to 1/3 of circulating glutathione.
Glutathione normally re-synthesized in an energy-dependent pathway.
Glutathione depletion results if the re-synthesis pathway is impeded (glutathione wasting)
If HIGH:
Causes:
Inadequate organic sulfur sources for production of cysteine required for glutathione synthesis
– needs NAC or methionine
Combination of amino acid inadequacy (esp. glycine) and mitochondrial inefficiency
Symptoms and Conditions:
See conditions and diseases associated with x-hydroxybutyrate (AHB) elevation
Glutathione is constantly used up in the removal of toxic molecules and prevention of oxidative
damage. α-hydroxybutyrate is a by-product from the process in which the body forms more
glutathione. When that process is running at high rates, α-hydroxybutyrate excretion is
increased. Elevated levels of the marker Pyroglutamate also reveal that glutathione is being
lost at a high rate
Treatment
•
Higher doses than those mentioned below may be needed for acetaminophen toxicity
and similar acute situations
•
IM or IV reduced glutathione – oral doses probably not absorbed
•
N-Acetylcysteine (NAC) 1500 mg/d
•
L-Methionine 1000 mg/d
•
Taurine 500
•
Alpha-lipoic acid 200
•
Whey protein isolate
•
Carnitine, coenzyme Q10, or other nutrient factors needed for mitochondrial functional
as indicated by other specific organic acid abnormalities.
**Urinary Pyroglutamate levels reflect loss of glutathione available to the body that improves
when extra glycine is provided.
Sulfate
Is an important marker for sulfur metabolism.
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Elevated sulfate has also been closely paralleled with the severity of zinc deficiency.
The sulfation pathway is used in phase II liver detoxification for biotransformation of:
•
Many drugs
•
Steroid hormones
•
Phenolic compounds
•
Other compounds
If HIGH:
Early stages of:
•
Increased flow of sulfur compounds into hepatic glutathionie synthesis
•
Increased sulfate production for specific detoxification demanding sulfation
•
High intake of dietary sulfate
•
Exposure to sulfate salts
Treatment:
If glutathionine demand increase is confirmed, see AHB section above for treatments
If glutathione demand is ruled out, decreased exposure to inorganic sulfate
If LOW:
Causes:
•
Chronic high glutathione demand
•
Long term specific detoxification requiring sulfation
Low urinary sulfate is an indication that total body glutathione is low due to chronic demand
and sulfur-containing amino acids are needed. The amino acid N-acetylcysteine is one
effective agent for raising your glutathione and sulfate levels. Another sulfur-containing
nutrient, lipoic acid, should always be considered when there is evidence of detoxification
stress on the liver.
Treatment:
•
N-Acetylcysteine (NAC) 1500 mg/d
•
L-Methionine 1000 mg/d
•
Taurine 500
•
Alpha-lipoic acid 200
•
Whey protein isolate
Short term sulfate repletion may be achieved by dietary inorganic sulfate sources such as
glucosamine sulfate (1500 mg/d)
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Insider’s Guide – Organic Acids and Urinary Bile Acid Sulfates
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Copyright © 2008 Sequoia Education Systems, Inc
Urinary Bile Acid Sulfates (UBAS)
The Urinary Bile Acid Sulfates (UBAS) test uses a urine sample to provide a direct
assessment of liver function.
UBAS is a direct measurement of liver function. The enterohepatic circulation regulates bile
acid levels and under normal circumstances, given a healthy liver; little leaks into the
bloodstream and is converted to sulfate and excreted in the urine. Elevated bile acid sulfate
levels in the urine are associated with impaired liver function, hepatocellular damage, and a
high specificity toward hepatobiliary diseases. Since all chemicals including prescription drugs
are detoxified in the liver, the UBAS can be used to monitor the effects of drug therapies on the
liver and identify those who might experience problems taking prescription drugs.
Compromised liver function leads to a build up of toxic substances that can damage liver cells
and lead to increased risk for cancer and a variety of other degenerative diseases.
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Copyright © 2008 Sequoia Education Systems, Inc