Biotin: biochemical, physiological and clinical aspects.

Significant progress has been made in our understanding of the biochemical, physiological and nutritional aspects of the water-soluble vitamin biotin (vitamin H). It is well know now that biotin plays important roles in a variety of critical metabolic reactions in the cell, and thus, is essential for normal human health, growth and development. This is underscored by the serious clinical abnormalities that occur in conditions of biotin deficiency, which include, among other things, growth retardation, neurological disorders, and dermatological abnormalities (reviewed in 1). Studies in animals have also shown that biotin deficiency during pregnancy leads to embryonic growth retardation, congenital malformation and death (Watanabe 1983; Cooper and Brown 1958; Mock et al. 2003; Zempleni and Mock 2000). The aim of this chapter is to provide coverage of current knowledge of the biochemical, physiological, and clinical aspects of biotin nutrition. Many sections of this chapter have been the subject of excellent recent reviews by others (Wolf 2001; McMahon 2002; Mock 2004; Rodriguez-Melendez and Zempleni 2003; Said 2004; Said et al. 2000; Said and Seetheram 2006), and thus, for more information the reader is advised to consider these additional sources.

Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans.

Mounting evidence indicates that marginal biotin deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA-carnitine) is a sensitive indicator of marginal biotin deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal biotin deficiency. Marginal, asymptomatic biotin deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography-tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA-carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA-carnitine is an early and sensitive indicator of marginal biotin deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies.

An Analysis of Biomarkers in Patients with Chronic Pain.

BACKGROUND: Because of the subjective nature of current pain assessments, limited efficacy of treatment options and risks associated with opioid abuse and diversion, the need for objective data to assist with chronic pain management has never been greater. Successful identification of mechanistic biomarkers would not only improve our understanding and ability to accurately diagnose pain disorders but would also facilitate the development of disease-modifying pain drugs. OBJECTIVES: The objective of this study was to determine and evaluate the prevalence of abnormal biomarker findings in a population of patients with chronic pain. STUDY DESIGN: Retrospective, observational study. SETTING: Data analysis of biomarker test results was performed at a single industry site (Ethos Research & Development, Newport, KY) from clinical samples collected and analyzed from July to December 2018. METHODS: A novel, pain-specific biomarker test panel that evaluates biomarkers of systemic inflammation, oxidative stress, neurotransmitter turnover, and micronutrient status was employed to determine the prevalence of abnormal findings in 17,834 unique patient samples analyzed at a national reference laboratory (Ethos Laboratories, Newport, KY). Patient biomarker results were considered abnormal if they were outside of the 95% confidence interval reference ranges established using a healthy population of donors who had no history of chronic pain or opioid use. RESULTS: A total of 77% of patients with chronic pain exhibited at least one abnormal biomarker result (n = 13,765). The most common abnormal biomarker finding was elevated quinolinic acid, which was observed in 29% of patients (n = 5,107). Elevated pyroglutamate, indicative of glutathione depletion, was observed in 19% of patients (n = 3,314). Elevated xanthurenic acid, indicative of vitamin B6 insufficiency, was observed in 17% of patients (3,025). Elevated levels of the acrolein metabolite 3-hydroxypropyl mercapturic acid were observed in 21% of patients (n = 3,667). Elevated methylmalonic acid, indicative of a vitamin B12 deficiency, was observed in 10% of patients (n = 1,827), whereas abnormally low levels of neurotransmitter metabolites were observed in 8% of patients (n = 1,456). LIMITATIONS: Medications and/or conditions other than those associated with chronic pain were not evaluated as potential causes of abnormal biomarker findings. CONCLUSIONS: A novel biomarker assay that measures objective correlates to the neurobiological processes underlying chronic pain reveals a high prevalence of atypical biochemistry in a population of patients with pain. Abnormal biomarker findings presented here provide objective support for the role of cytokine-mediated inflammation, oxidative stress, abnormally low production of neurotransmitters, and micronutrient deficiencies in the development or worsening of chronic pain. This unique panel of functional pain biomarkers provides practitioners with novel, objective insight into the underlying causes of pain, which will pave the way for truly personalized pain medicine. Correcting abnormal biomarker findings with targeted, nonopioid therapies to improve patient function and alleviate pain potentially could lessen the opioid burden and drastically reduce health care costs. KEY WORDS: Biomarker, pain, inflamation, oxidative stress, neurotransmitter, micronutrient deficiency, Kynurenine Pathway.

A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals.

A systematic review and meta-analysis was undertaken to examine and quantify the effects of B vitamin supplementation on mood in both healthy and 'at-risk' populations. A systematic search identified all available randomised controlled trials (RCTs) of daily supplementation with ≥3 B group vitamins with an intervention period of at least four weeks. Random effects models for a standardized mean difference were used to test for overall effect. Heterogeneity was tested using the I2 statistic. Eighteen articles (16 trials, 2015 participants) were included, of which 12 were eligible for meta-analysis. Eleven of the 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood. Of the eight studies in 'at-risk' cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress (n = 958, SMD = 0.23, 95% CI = 0.02, 0.45, p = 0.03). A benefit to depressive symptoms did not reach significance (n = 568, SMD = 0.15, 95% CI = -0.01, 0.32, p = 0.07), and there was no effect on anxiety (n = 562, SMD = 0.03, 95% CI = -0.13, 0.20, p = 0.71). The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress, but not for depressive symptoms or anxiety. B vitamin supplementation may particularly benefit populations who are at risk due to (1) poor nutrient status or (2) poor mood status.

B vitamins for stroke prevention.

Supplementation with B vitamins (vitamin B9(folic acid), vitamin B12 and vitamin B6) lowers blood total homocysteine (tHcy) concentrations by about 25% and reduces the relative risk of stroke overall by about 10% (risk ratio (RR) 0.90, 95% CI 0.82 to 0.99) compared with placebo. Homocysteine-lowering interventions have no significant effect on myocardial infarction, death from any cause or adverse outcomes. Factors that appear to modify the effect of B vitamins on stroke risk include low folic acid status, high tHcy, high cyanocobalamin dose in patients with impaired renal function and concurrent antiplatelet therapy. In regions with increasing levels or established policies of population folate supplementation, evidence from observational genetic epidemiological studies and randomised controlled clinical trials is concordant in suggesting an absence of benefit from lowering of homocysteine with folic acid for prevention of stroke. Clinical trials indicate that in countries which mandate folic acid fortification of food, folic acid supplementation has no significant effect on reducing stroke risk (RR 1.05, 95% CI 0.90 to 1.23). However, in countries without mandatory folic acid food fortification, folic acid supplementation reduces the risk of stroke by about 15% (RR 0.85, 95% CI 0.77 to 0.94). Folic acid alone or in combination with minimal cyanocobalamin (≤0.05 mg/day) is associated with an even greater reduction in risk of future stroke by 25% (RR 0.75, 95% CI 0.66 to 0.86), whereas the combination of folic acid and a higher dose of cyanocobalamin (≥0.4 mg/day) is not associated with a reduced risk of future stroke (RR 0.95, 95% CI 0.86 to 1.05). The lack of benefit of folic acid plus higher doses of cyanocobalamin (≥0.4 mg/day) was observed in trials which all included participants with chronic kidney disease. Because metabolic B12 deficiency is very common and usually not diagnosed, future randomised trials of homocysteine-lowering interventions for stroke prevention should probably test a combination of folic acid and methylcobalamin or hydroxocobalamin instead of cyanocobalamin, and perhaps vitamin B6.

B-vitamins and homocysteine in Spanish institutionalized elderly.

BACKGROUND: Hyperhomocysteinemia is an accepted risk factor for cardiovascular disease, and possibly also for cognitive impairment and dementia. It has also been proposed as a marker for the status of the B vitamins, which participate in the metabolism of homocysteine. Therefore, especially in the elderly, it is important to know the prevalence of high homocysteine (tHcy) levels and the influence that B vitamins have on them. MATERIAL AND METHODS: 218 elderly of both sexes, aged 60-105, living in an elderly home in Granada (Spain), were screened for serum folate, red blood cell (RBC) folate, serum cobalamin (B12) (Abbott, IMx), holotranscobalamin II (Holo-TC II) (HoloTC RIA, Axis-Shield), methylmalonic acid (MMA) (MS-GC), total pyridoxine (B6) (HPLC), and total homocysteine (tHcy) (Abbott, IMx). RESULTS: Hyperhomocysteinemia (tHcy >12 pmol/L) was detected in 80.7%. Serum folate deficiency was severe (< or =4 ng/mL) in 19.3% and moderate (4-7 ng/mL) in 43.1%. In 14.2% of the elderly RBC folate was < or =175 ng/mL, and in 61.0% it was between 175-400 ng/mL. Vitamin B12, measured in serum (< or =200 pg/mL), was deficient in 15.8%, but if measured as Holo-TC II (< or =45 pmol/L), deficiency ranged up to 39.1%. MMA was high (> or =300 nmol/L) in 45.6%. Vitamin B6 (< 20 nmol/L) was low only in one person. In order to identify the factors that could predict tHcy levels, a multiple regression analysis was performed. Best results corresponded to the combination of log serum folate and log Holo-TC II, which gave values of R > 0.5. If analyzed independently, the highest correlation was with log serum folate (r = -0.290), followed by RBC folate (r = -0.263), Holo-TC II (r = -0.228), log B12 (r = -0.175), and log B6 (r = -0.078). CONCLUSION: There is a high prevalence of vitamin B deficiency and hyperhomocysteinemia in the studied population. Our data confirm the influence of these vitamins, especially folate, on tHcy levels, but hyperhomocysteinemia cannot be used as the only diagnostic criterion to detect subclinical vitamin deficiency in elderly people, especially to detect vitamin B12 deficiency.

Biotin responsive limb weakness.

We report acute onset quadriplegia in a ten year old boy associated with basal ganglia lesions due to biotin deficiency. Prolonged raw egg consumption was identified as predisposing factor for biotin deficiency. Treatment with biotin resulted in remarkable recovery.

Low essential fatty acid and B-vitamin status in a subgroup of patients with schizophrenia and its response to dietary supplementation.

We assessed essential fatty acid (EFA) and B-vitamin status, together with their determinants, in 61 patients with schizophrenia and established whether those with poor status responded biochemically to the appropriate dietary supplements. As a group, the patients had high erythrocyte saturated fatty acids (FAs), monounsaturated FA and low polyunsaturated FA of the omega3 and omega6 series. Patients reporting not to take vitamin supplements had low vitamin B12 and high homocysteine. Homocysteine variance proved best explained by folate in both the total group and male patients, and by vitamins B12 and B6 in females. Alcohol consumption and duration of illness are risk factors for low polyunsaturated FA status (< P2.5 of reference range), while male gender and absence of fish consumption predict hyperhomocysteinemia (> P97.5 of reference range). Two patients exhibited biochemical EFA deficiency and seven showed biochemical signs of omega3/docosahexaenoic acid (DHA) marginality. Four patients exhibited moderate hyperhomocysteinemia with plasma values ranging from 57.5 to 74.8 micromol/L. None of the five patients with either moderate hyperhomocysteinemia, biochemical EFA deficiency, or both, was predicted by their clinicians to have poor diets. That diet was nevertheless at the basis of these abnormalities became confirmed after supplementing 4 of them with B vitamins and with soybean and fish oils. We conclude that a subgroup of patients with schizophrenia has biochemical EFA deficiency, omega3/DHA marginality, moderate hyperhomocysteinemia, or combinations. Correction seems indicated in view of the possible relation of poor EFA and B-vitamin status with some of their psychiatric symptoms, but notably to reduce their high risk of cardiovascular disease.

[To 20-years anniversary of Chernobyl catastrophe: an attempt to study the vitamin, calcium, iron and selenium status of children and adult population in Slavutich and to correct elicited deficiencies].

The article concisely illustrates the vitamin and mineral state of population of town of Slavutich, including personal of Chernobyl Nuclear Power Station, children of pre-school age and pregnancy women, studied in 1992. Vitamins and minerals deficiency in the main of C and B vitamins and selenium was revealed in all the studied groups. Appropriate measures were developed and introduced to eliminate the detected dusturbances; but however some unsolved problems remained. Taking into account the forthcoming 20th anniversary of Chernobyl disarter, the authors of the come back to considering the obtained data in hope to atlract attention of medical scientific and public to the remained unsolved problems of micronutrient deficiency.

Vitamins, minerals and supplements: part two.

Vitamins and minerals are organic food substances found only in plants and animals and are essential to the normal functioning of the body. Although only required in small amounts, as previously discussed in the past decade there has been an increased use of vitamin, mineral, herbal and nutritional supplements in the general population. While deficiencies in such nutrients can be harmful to health, conflicting claims have been made about the health benefits of such supplementation. In the second of an occasional series on vitamins, minerals, and supplements, JUNE THOMPSON gives an overview of the role that water-soluble vitamins play in the health of the individual, including their functions, and the potential impact of any deficiency of these.

Dietary Sources of Vitamin B-12 and Their Association with Vitamin B-12 Status Markers in Healthy Older Adults in the B-PROOF Study.

Low vitamin B-12 concentrations are frequently observed among older adults. Malabsorption is hypothesized to be an important cause of vitamin B-12 inadequacy, but serum vitamin B-12 may also be differently affected by vitamin B-12 intake depending on food source. We examined associations between dietary sources of vitamin B-12 (meat, fish and shellfish, eggs, dairy) and serum vitamin B-12, using cross-sectional data of 600 Dutch community-dwelling adults (≥65 years). Dietary intake was assessed with a validated food frequency questionnaire. Vitamin B-12 concentrations were measured in serum. Associations were studied over tertiles of vitamin B-12 intake using P for trend, by calculating prevalence ratios (PRs), and splines. Whereas men had significantly higher vitamin B-12 intakes than women (median (25th-75th percentile): 4.18 (3.29-5.38) versus 3.47 (2.64-4.40) µg/day), serum vitamin B-12 did not differ between the two sexes (mean ± standard deviation (SD): 275 ± 104 pmol/L versus 290 ± 113 pmol/L). Higher intakes of dairy, meat, and fish and shellfish were significantly associated with higher serum vitamin B-12 concentrations, where meat and dairy-predominantly milk were the most potent sources. Egg intake did not significantly contribute to higher serum vitamin B-12 concentrations. Thus, dairy and meat were the most important contributors to serum vitamin B-12, followed by fish and shellfish.

Unusual diagnoses among violent patients.

Several medical disorders rarely cause violent behavior. When they do so, it is dramatic because the violence and other bizarre behaviors are not in keeping with the premorbid picture of the individual. Often, medical and neurologic symptoms are present, but occasionally psychiatric symptoms may present alone with the aggression and violence, which points out the importance of complete medical psychiatric evaluations of patients who present with recent histories of violent behavior. Most violence involves "horses," but the rare "zebras" should be kept in mind because they are often treatable.

Adaptation of coenzyme stimulation assays for the nutritional assessment of vitamins B1, B2 and B6 using the Cobas Bio centrifugal analyser.

Adaptation of coenzyme stimulation assays for the nutritional assessment of thiamine, riboflavin and pyridoxine on the Cobas Bio centrifugal analyser are described. Whole blood was collected into acid-citrate dextrose, which preserves the erythrocytes, prior to assay for several days. Washed erythrocytes stored at -70 degrees C and subsequently thawed, showed altered enzyme activities. The methods offer improved precision over existing procedures and take advantage of the high throughput capabilities of the instrumentation.

Detection and incidence of B and C vitamin deficiency in alcohol-related illness.

The activity of the red blood cell enzymes transketolase, glutathione reductase, and aspartate transaminase, and their activation by the coenzymes thiamine, riboflavin, and pyridoxine, the pyruvate tolerance test, the leucocyte vitamin C concentration, and the activity in serum of gamma-glutamyl transferase were measured in a series of 35 patients with alcohol-related illness. The incidence of thiamine deficiency was 31% as assessed by the activation of transketolase, and 55% as assessed by the pyruvate tolerance test. The incidence of riboflavin deficiency was 23% and of ascorbic acid deficiency 91%. No cases of pyridoxine deficiency were detected. The pyruvate tolerance test was found to be a more sensitive test of thiamine deficiency than the transketolase activation, and the activation of red blood cell aspartate transaminase was found to be a poor indicator of pyridoxine deficiency. There was a poor correlation of the gamma-glutamyl transferase activity with the degree of vitamin deficiency, suggesting that alcohol exposure is only partly responsible for the observed vitamin deficiency.

Clinical chemical methods for the routine assessment of the vitamin status in human populations. Part II: The water-soluble vitamins B1, B2 and B6.

Simple and proven techniques for the assay of the coenzyme stimulation of the erythrocyte enzymes transketolase, glutathione reductase and glutamate oxaloacetate aminotransferase are described. The results found in a cohort of 150 blood donors and their comparison with the values for total thiamine in whole blood and pyridoxal phosphate in erythrocytes are presented.

The vitamin B1, B2 and B6 status of school children in two resettlement areas in Northeast Thailand.

The vitamin B1, B2 and B6 status of school children were studied in the Khon Kaen resettlement and irrigation area and in the Lam-takong settlement in northease Thailand using the in vitro tests based on the erythrocyte transketolase, glutathione reductase and glutamate-oxaloacetate transaminase activities. Healthy school children from the Khon Kaen University School were selected as a reference group. The results demonstrate that the vitamin B1 status in the resettlement area is sufficient, but about 20% to 35% of all the children show evidence of vitamin B2 and B6 deficiencies. It is noticed that besides a high prevalence of parasitic infections and poor hygienic conditions the protein and vitamin intake is low and improvement of the situation is necessary.

Deficiency of vitamins A, B, and C. Something to watch for.

Although specific vitamin deficiency syndromes are relatively rare in the United States, primary care physicians may encounter them in elderly patients and persons who consume minimal diets. Knowledge of such deficiencies is crucial in the evaluation of these patients. The authors discuss manifestations of deficiency of vitamins A, B, and C and recommend appropriate methods of diagnosis and treatment.