Lactic, pyruvic - Elevated values (100-500 mmol/mol creatinine)
may indicate infection, recent vigorous exercise, B vitamin deficiency,
poor perfusion, or intestinal bacterial overgrowth.
Lactic, pyruvic - Extremely elevated values (500-100,000
mmol/mol creatinine) indicate genetic diseases such as pyruvate dehydrogenase
deficiency, glycogen storage diseases, disorders of fructose metabolism,
severe trauma, or life-threatening infections.
2-hydroxbutyric - Slightly elevated values may
indicate infection, recent vigorous exercise, B vitamin deficiency, and
poor perfusion.
2-hydroxybutyric - Significantly elevated values
(> 25 mmol/mol creatinine) may indicate genetic diseases such as pyruvate
dehydrogenase deficiency, glycogen storage disease, disorders of fructose
metabolism, severe trauma, and life-threatening infections.
Glyceric acid - Values greater than 150 mmol/mol
creatinine may be due to microbial sources such as yeast or due to dietary
sources containing glycerol.
Amino Acid Metabolites
2-hydroxyisovaleric, 2-oxoisovaleric, 3-methyloxovaleric,
2-hydroxyisocaproic, 2-oxoisocaproic - Elevated values are associated
with maple syrup urine disease and pyruvate dehydrogenase deficiency which
are genetic diseases. Slight elevations may be due to deficiencies of
the vitamins thiamine or lipoic acid.
2-oxo-4-methiobutyric - Elevated in the genetic
disease methioninemia
Phenyllactic, phenylpyruvic, mandelic - Elevated
in the genetic diseases PKU and tyrosinemia. Slight elevations may be
due to increased dietary intake of phenylalanine.
Homogentisic - elevated in the genetic disease
homogentisic aciduria (alkaptonuria).
4-hydroxyphenyllactic - Significantly elevated
in the genetic diseases tyrosinemia and in phenylketonuria. Slight increase
may be due to increased tyrosine intake.
Pyroglutamic - Pyroglutamic (oxoproline) is a
metabolite of the antioxidant gluthathione and is extremely elevated in
the genetic disease pyroglutamic acidurea and following the use of the
antibiotics flucloxacillin and netelmicin. Low values may be found due
to glutathione depletion following oxidative stress or after exposure
to toxic solvents or pesticides such as chloroform, DDT, or polybrominated
biphenyls (PBB's) and polychlorinatned biphenyls (PCB's). Supplementation
with glutathione, and N-acetyl cysteine are useful to replenish glutathione.
3-indoleacetic - A metabolite of the amino acid
tryptophan. Values greater than 200 mmol/mol creatinine may be found in
Hartnup's disease, a genetic neurological disease due to defective renal
and intestinal transport of certain neutral amino acids. Elevations of
lesser magnitude appear to be of bacterial origin.
Kynurenic acid - Kynurenic is a tryptophan metabolite
that may be elevated with vitamin B-6 deficiency or due to excessive tryptophan
uptake. The reaction by which kynurenine is converted to hydroxyanthranilate
is catalyzed by an enzyme requiring vitamin B-6. Thus, elevations of kynurenic
may indicate a vitamin B-6 deficiency. High values in individuals with
the yeast overgrowth syndrome may be due to yeast interference.
Fatty Acid Metabolites
3-hydroxybutyric, acetoacetic - Ketones derived
from excessive fatty acid oxidation may be elevated due to fasting or
starvation, diabetes mellitus, us of high fat (ketogenic) diets, and in
several genetic diseases.
Ethylmalonic, methylsuccinic, adipic, suberic, and sebacic
- These are fatty acid metabolites. Values may be elevated in ketosis,
fasting, deficiency of the fat-transporting molecule carnitine, genetic
deficiencies of fatty acid metabolism and the genetic disease multiple
acyl dehydrogenase deficiency, excessive intake of adipic acid-containing
foods such as Jell-O, and by increased intake of foods containing medium
chain triglycerides such as coconut oil. Isolated high values of adipic
acid only may be found in patients with ADD, lethargy and seizures.
Miscellaneous
Glutaric - Elevated in the genetic diseases glutaric academia types
1 and II. Moderate increases may be to deficiencies in riboflavin and
coenzyme Q-10, or celiac disease. Moderate increases are common in autism
possibly due to defective vitamin absorption or microbial production in
the GI tract.
Methylmalonic - Values over 150 mmol/mol creatinine
may be due to the genetic disease methylmalonic aciduria. Moderate increases
may be due to vitamin B-12 deficiency, defective B-12 absorption, or bacterial
overgrowth of the GI tract that uses up vitamin B-12.
N-acetyl aspartic acid - High values are due to
the genetic disease Carnavan's disease, a potentially fatal disease causing
spongy degeneration of the brain.
Ascorbic -Vitamin C, and important antioxidant,
with low values may indicate dietary deficiency (scurvy) and is frequently
low in chronic fatigue syndrome. High values are usually of no concern
except that in individuals with bacteria overgrowth of the GI tract, ascorbic
acid may be converted to oxalic acid, which can lead to kidney stones.
There is a low probability that elevated vitamin C will cause kidney stones
if oxalic acid is in the normal range.
Orotic acid - Elevated orotic is most commonly
associated with ammonia toxicity. When ammonia is elevated, it is biochemically
converted to carbamyl phosphate and then orotic acid. Elevated ammonia
may occur due to liver toxicity, viral liver infection, GI bleeding, portal
systemic shunting of blood, drug toxicity, Reye's syndrome, as well as
inborn errors of ammonia metabolism. Elevated orotic acid may also be
found in leukemias and lymphomas, possibly due to the increased production
of pyrimidines.
3-hydroxy-3-methylglutaric (HMG) - HMG is a precursor
in the production of cholesterol in both humans and yeast. Moderate increases
as high as 300 mmol/mol creatinine are probably due to yeast overgrowth
of the GI tract and might also implicate yeast overgrowth with elevated
serum cholesterol.. Both yeast and humans produce these same compounds
as a precursor of steroid hormones. Values from 200 - 11,000 mmol/mol
creatinine are found in the genetic disease 3-hydroxy-3-metylglutaric
aciduria. .
Hydroxyhippuric - A conjugate of the amino acid glycine and hydroxybenzoic
acid (salicylic acid). Elevated values may be due to the use of aspirin
(salicylates) or due to the growth of GI bacteria producing salicylates.
Also increased after the ingestion of the artificial sweetener aspartame
(Nutrasweet).
Yeast/fungal
Citramalic (methylmalic) - Citramalic acid is
a byproduct of Saccharomyces yeast species as well as Propionibacterium
acnes. This metabolite was not found in the culture media of a wide number
of other anaerobic bacteria isolated from stool samples. Thus, an increase
in citramalic acid may indicate Propionibacteria overgrowth rather than
a yeast overgrowth of the intestinal tract. Citramalic acid is a chemical
relative (analog) of the Krebs cycle compound malic acid. Presumably,
this compound may interfere with the production of malic acid in the Krebs
cycle.
5-hydroxymethyl-2-furoic - A substituted furan
that is a byproduct of the fungus Aspergillus and probably other species
of fungi and yeast as well.
3-oxoglutaric acid - A chemical relative (analog)
of the Krebs cycle compound 2-oxoglutaric (alpha-ketoglutaric). Presumably,
this compound is a byproduct of the amino acids lysine and tryptophan.
The highest value was found in a child with a severely malformed brain.
Slightly elevated values are found in autism and other disorders. 2-oxoglutaric,
the normal Krebs cycle metabolite may be low when 3-oxoglutaric is elevated,
possibly indicating an interference of 3-oxoglutaric in the Krebs cycle.
Furan-2,5-dicarboxylic - A substituted furan that
is a byproduct of the fungus Aspergillus and probably other species of
fungi and yeast as well.
Furancarbonylglycine - A conjugate of furancarboxylic
acid and the amino acid glycine.
Tartaric (hydroxymalic acid) - Tartaric acid is
a toxic metabolite of Saccharomyces yeast species, the same species of
yeast that is used in baking and brewing industries. Saccharomyces species
may be important organisms in the immuno-compromised person. The fungal
origin of this compound was confirmed in my laboratory by showing that
this compound decreased dramatically in the urine after the use of antifungal
drugs. Tartaric acid is also found in grapes, grape products, and as a
food additive. Cream of tartar, used in baking, is basically tartaric
acid.
Arabinose - Arabinose (a five carbon sugar or
pentose) is not produced by yeast directly. A closely related sugar derivative
called arabitol is produced by Candida species including Candida albicans,
Candida tropicalis, and Candida parapsilosis. Arabitol produced in the
gastrointestinal tract is absorbed into the portal circulation, converted
to arabinose by the liver, and then released into the circulation. Since
arabinose is also a major sugar in apples, apple juice, and all apple
products must be avoided 24 hour prior to urine collection to prevent
test interference.
Carboxycitric - A chemical relative (analog) of
the Krebs cycle compound citric acid. Presumably, this compound may interfere
with the metabolism of citric acid in the Krebs cycle.
Bacterial
2-hydroxyphenylacetic - A metabolites of tyrosine
produced by overgrowth of several species of bacteria in the GI tract.
4-hydroxyphenylacetic - Also a metabolite of tyrosine
and the bacterial origin of this compound was confirmed by the finding
that this compound in urine decreased significantly after the use of the
antibiotic neomycin. Very elevated values for these compounds are present
in celiac disease (gluten sensitivity), enteritis, and intestinal resection.
Anaerobic Bacterial
HPHPA, 3- (3-hydroxyphenyl-3-hydroxypropionic acid - This is the
compound produced by Clostridia species including Clostridium difficile.
There are approximately 100 species of Clostridia in the gastrointestinal
tract so that this marker is NOT specific for Clostridium difficile. Elevated
values are common in autism, depression,
schizophrenia, seizures, and in chronic fatigue syndrome. This compound
is reduced by treatment with vancomycin, Flagyl (metronidazole), an herbal
product called Biocidin, and by probiotics.
VMA analog - Derivatives of the amino acid tyrosine
produced by species of the Clostridia genus. This byproduct may be important
for two reasons: First, dietary tyrosine which is the raw material for
the production of the neurotransmitters dopamine and norepinephrine may
be diverted into the production of these microbial compounds so that there
is not enough tyrosine available for neurotransmitters. Second, these
compounds may act as inhibitors of neurotransmitter production or metabolism.
Elevated values are common in autism, depression, schizophrenia, seizures,
and in chronic fatigue syndrome. This compound is reduced by treatment
with vancomycin, Flagyl (metronidazole), an herbal product called Biocidin,
and by probiotics.
Krebs Cycle
Succinic acid - A Krebs cycle compound that may be elevated due
to a deficiency or riboflavin or coenzyme Q-10. Values greater than 50
mmol/mol creatinine may be due to genetic diseases. High values may also
be due to bacterial conversion of glutamine to succinic acid in the gastrointestinal
tract.
Fumaric acid - A Krebs cycle compound produced
by the dehydrogenation of succinic acid by the enzyme succinic acid dehydrogenase.
2-oxoglutaric acid - A Krebs cycle compound that
is also called alpha-ketoglutaric acid. 2 oxoglutaric acid may be derived
from the conversion of glutamic acid to 2-oxoglutaric by deamination or
transamination. Very low values may sometimes be encountered in chronic
fatigue syndrome. Anecdotal reports indicate that improvement of some
autistic symptoms are associated with low values.
Aconitic
Citric - These Krebs cycle compounds may be elevated due to a deficiency
of glutathione since the enzyme aconitase requires reduced glutathione.
Neurotransmitters
HVA - A metabolite of the neurotransmitter dopamine.
Elevated values are encountered in the tumors neuroblastoma, ganglioblastoma,
and pheochromacytoma. Values may also be elevated due to L-DOPA administration
or after IV dopamine drips.
VMA - Elevated values are found in the tumors
pheochromacytoma, neuroblastoma, ganglioneuroma, and carcinoid tumors.
May be elevated after catecholamine L-DOPA administration.
5-hydroxyindoleacetic acid - A metabolite of tryptophan
that is commonly elevated in carcinoid syndrome, celiac sprue, tropical
sprue, Whipple's disease, oat cell carcinoma of the bronchus, and in bronchial
adenoma of carcinoid type. May be elevated to intake of foods high in
hydroxyindoles such as walnuts, bananas, avocados, eggplants, pineapples,
plums and tomatoes. Low values may be found in depressive illnesses, small
intestine resection, mastocytosis, PKU, and Hartnup's disease.
Pyrimidines
Uracil - A pyrimidine (DNA building block) that
is elevated in the genetic disease dihydropyrimidine dehydrogenase deficiency.
In this genetic disease, the pyrimidine thymine is also elevated. Elevations
of uracil and orotic acid are found in the genetic diseases OTC deficiency
and citrullinemia.
Thymine - Thymine is a pyrimidine (DNA building
bock) that is elevated in the genetic disease dihydropyrimidine dehydrogenase
deficiency. In this genetic disease, the pyrimidine uracil is also elevated.
Miscellaneous
Glycolic - Elevated glycolic may be due to the genetic
disease hyperoxaluria type I, if oxalic acid is also elevated. Elevated
glycolic without elevated oxalic is most likely a result of GI yeast overgrowth.
Oxalic - Elevated values may be due to primary
hyperoxaluria, diabetes mellitus, cirrhosis, vitamin B-6 deficiency, sarcoidosis,
steatorrhea due to pancreatic insufficiency, celiac disease, bacteria
overgrowth, ileal resection, biliary tract disease, small bowel disease,
ethylene glycol poisoning, increased intake of foods high in oxalate including
rhubarbs, strawberries, spinach, and tomatoes, and increased vitamin C
intake. Hyperoxaluria type I is associated with elevated glycolic acid
while hyperoxaluria type II is associated with elevated glyceric acid.
Malonic - Elevated values may be associated with
the genetic disease malonyl CoA decarboxylase deficiency.
Methylglutaric - Elevated values may be associated
with the genetic deseases 3-hydroxy-3-methylglutaric aciduria and in 3-methylglutaconic
aciduria.
Hippuric - Hippuric acid is a conjugate of benzoic
acid and glycine formed in the liver. Hippuric acid may be elevated due
to bacteria overgrowth of the GI tract. Benzoic acid formed in the gastrointestinal
tract by bacteria is absorbed into the portal circulation. In the liver,
it is conjugated with the amino acid glycine to form benzoylglycine (huppuric
acid). Other sources that increase benzoic acid are the solvent toluene
and the food preservative sodium benzoate. Toluene exposure may occur
due to industrial exposure or due to out gassing from new carpets. Low
values of hippuric acid may be due to depletion of glycine die to competing
detoxification reactions or due to low amounts of bacteria after antibiotic
use.
4-hydroxybutyric - Elevated values indicate the
rare genetic disease 3-methylglutaconic aciduria or after the intake of
the muscle builder 4-hydroxybutyric (also called gamma-hydroxybutyric
acid) which can cause severe myalgia or death.
Phenylcarboxylic -Elevated values indicate overgrowth
of GI bacteria
Indole-like compound - Most likely derived from
tryptophan. Elevated values indicate overgrowth of GI bacteria and is
commonly elevated along with 3-indoleacetic.
