Long-term patterns of urinary pyroglutamic acid in healthy humans.

An investigation of human biological variation in urinary organic acids, including pyroglutamic acid along with 39 other compounds, was previously reported in which levels were determined for 8 weeks in healthy adult subjects. Here, unique, 4-week-long physiological trends for one of those compounds, pyroglutamic acid (PGA), are reported. When PGA levels for an individual rose above 40 µg/mg creatinine, 4-week downward progressions occurred until levels reached values near 15 µg/mg creatinine and the pattern was reversed when levels for an individual were below that level in the early weeks of the study. The pattern was especially prominent among 8 of the 13 menstruating female subjects suggesting a possible association with metabolic stress of the menstrual cycle. However, it also appeared in 3 of the 8 male subjects where other sources of metabolic stress may be present. The menstrual association is consistent with estrogen-mediated increase in oxidative stress. Since PGA is linked to glutathione turnover, the consistency of extreme values across all individuals displaying the pattern indicates that 15 and 40 µg/mg creatinine may represent limits that trigger shifts in sulfur amino acid metabolism. This is the first observation of approximate month-long cyclic responses in a glutathione-related urinary marker in humans.

Adult bile acid amino transferase deficiency.

PATIENT: Female, 70 FINAL DIAGNOSIS: Bile acid amino transferase deficiency Symptoms: Headache • indigestion • itching skin • nausea • vomiting MEDICATION: - Clinical Procedure: - Specialty: Gastroenterology and Hepatology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Bile acid synthesis impairments are difficult to diagnose due to non-specific manifestations related to progressive failure to absorb essential fatty acids and fat soluble vitamins and failure to maintain normal intestinal microbiota. CASE REPORT: A 70-year-old female presented with long-standing history of recurrent headaches, indigestion, dry, scaly, itching skin, and fluid around knee joints. Quantitative Electroencephalography (QEEG) revealed widespread excess theta maximum in the temporal regions. A rare pattern of elevated plasma glycine and taurine led to suspicion of BAATD. A stool profile employing molecular probes for commensal bacteria revealed elevation of Fusobacteria spp. Implementation of bile acid replacement therapy (BART) produced rapid remission of headache and other symptoms and a three-month follow up stool profile revealed normalization of fecal Fusobacteria populations that remained normal after one year of BART. QEEG analyses 4 weeks following BART showed evidence of significant improvement in CNS functioning. CONCLUSIONS: This case illustrates the potential for diagnosis of latent, adult BAATD by finding a unique pattern of plasma amino acids and monitoring of therapy by observing normalization of fecal commensal bacteria and functional brain assessments.

Clinical applications of urinary organic acids. Part I: Detoxification markers.

Modern instrumentation allows the measurement of organic acids in urine in their physiological concentration ranges. Eight of the compounds that are reported can serve as markers for specific toxicant exposure or detoxification challenges. Xylene exposure causes elevation of 2-methylhippurate, and orotic acid elevation reveals ammonia challenge that exceeds the capacity of the urea cycle. General hepatic detoxification stimulation by natural compounds, drugs, or xenobiotic compounds causes elevated levels of glucaric acid. Abnormalities of alpha-hydroxybutyrate, pyroglutamate, and sulfate can indicate up-regulated glutathione biosynthesis, impaired reformation of glutathione in the gamma-glutamyl cycle, and depleted total body glutathione status, respectively. Patterns of these compounds measured in a simple overnight urine specimen help to identify focal areas of clinical concern and monitor patient responses to detoxification interventions.

Clinical applications of urinary organic acids. Part 2. Dysbiosis markers.

Part 1 of this series focused on urinary organic acids as markers of detoxification; part 2 focuses on dysbiosis markers. Intestinal microbial growth is accompanied by the release of products of their metabolism that may be absorbed and excreted in urine. Several organic acids are known to be specific products of bacterial metabolic action on dietary polyphenols or unassimilated amino acids or carbohydrates. Associated gastrointestinal or neurological symptoms may result from irritation of the intestinal mucosa or systemic distribution of absorbed neurotoxic products. Detection of abnormally elevated levels of these products is a useful diagnostic tool for patients with gastrointestinal or toxicological symptoms. Test profiles of urinary organic acids associated with microbial overgrowth can include benzoate, hippurate, phenylacetate, phenylpropionate, cresol, hydroxybenzoate, hydroxyphenylacetate, hydroxyphenylpropionate and 3,4-dihydroxyphenylpropionate, indican, tricarballylate, D-lactate, and D-arabinitol. Effective treatments for the associated microbial overgrowths may be directed at reducing microbial populations, introducing favorable microbes, and restoring intestinal mucosal integrity.

Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites.

Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism.