Association of Increased Homocysteine Levels with Impaired Folate Metabolism and Vitamin B Deficiency in Early-Onset Multiple Sclerosis.

The contents of homocysteine (HCy), cyanocobalamin (vitamin B12), folic acid (vitamin B9), and pyridoxine (vitamin B6) were analyzed and the genotypes of the main gene polymorphisms associated with folate metabolism (C677T and A1298C of the MTHFR gene, A2756G of the MTR gene and A66G of the MTRR gene) were determined in children at the onset of multiple sclerosis (MS) (with disease duration of no more than six months), healthy children under 18 years (control group), healthy adults without neurological pathology, adult patients with MS at the onset of disease, and adult patients with long-term MS. A significant increase in the HCy levels was found in children at the MS onset compared to healthy children of the corresponding age. It was established that the content of HCy in children has a high predictive value. At the same time, an increase in the HCy levels was not accompanied by the deficiency of vitamins B6, B9, and B12 in the blood. The lack of correlation between the laboratory signs of vitamin deficiency and HCy levels may be due to the polymorphic variants of folate cycle genes. An increased HCy level should be considered as a marker of functional disorders of folate metabolism accompanying the development of pathological process in pediatric MS. Our finding can be used to develop new approaches to the prevention of demyelination in children and treatment of pediatric MS.

Retinal changes associated with multivitamin deficiency before and after supplementation.

BACKGROUND: Nutritional visual defects are apparently uncommon nowadays in developed nations. Retinal change-related visual defects caused by hypovitaminoses may be underdiagnosed. AIM OF THE STUDY: To investigate the retinal structural and functional changes in a patient with multivitamin deficiency before and during vitamin supplementation. METHODS: A 51-year-old female had been on vegetarian diet as a child, and on restrict vegan diet during the last 2 years, developing severe bilateral deterioration of visual function and polyneuropathy. Blood test revealed low levels of vitamin A, B6 and D. The patient underwent examinations with optical coherence tomography (OCT), computerized visual field examination (VF), electroretinography (ERG), visual evoked potentials (VEP) and neurography before and after vitamin supplementation. RESULTS: Visual acuity (VA) was 20/1000 and VF examination showed central scotoma in both eyes. Color vision was significantly affected. Full-field ERG showed normal rod and cone function, but a clearly reduced central peak was registered in multifocal ERG (mf-ERG), indicating impaired fovea function. VEP showed delayed latency and low amplitude of P100 in both eyes. Neurography showed sensory polyneuropathy. OCT showed significant thinning of macular ganglion cell plus inner plexiform layer (GCIPL) with rapid progression. Retinal nerve fiber layer (RNFL) was preserved and normal, which is in contrast to neuroinflammatory conditions. After 2.5 years of multivitamin supplementation, the visual functions were improved. GCIPL thickness was stable without further deterioration. CONCLUSIONS: Multivitamin deficiency results in progressive thinning of GCIPL with severe visual deterioration. In contrast to neuroinflammation, RNFL is preserved and normal. Stabilized GCIPL during vitamin supplementation was associated with improved visual function. OCT provides a sensitive and objective measure for differential diagnosis, monitoring retinal change and response to therapy.

Metabolic Consequences of Supplemented Methionine in a Clinical Context.

The central position of methionine (Met) in protein metabolism indicates the importance of this essential amino acid for growth and maintenance of lean body mass. Therefore, Met might be a tempting candidate for supplementation. However, because Met is also the precursor of homocysteine (Hcy), a deficient intake of B vitamins or excessive intake of Met may result in hyperhomocysteinemia (HHcy), which is a risk factor for cardiovascular disease. This review discusses the evidence generated in preclinical and clinical studies on the importance and potentially harmful effects of Met supplementation and elaborates on potential clinical applications of supplemental Met with reference to clinical studies performed over the past 20 y. Recently acquired knowledge about the NOAEL (no observed adverse effect level) of 46.3 mg · kg-1 · d-1 and the LOAEL (lowest observed adverse effect level) of 91 mg · kg-1 · d-1 of supplemented Met will guide the design of future studies to further establish the role of Met as a potential (safe) candidate for nutritional supplementation in clinical applications.

Update on Biotin Therapy in Dermatology: Time for a Change.

Biotin (vitamin B7 or H) is found in milk, nuts, egg yolks, cereals, supplements, synthesized by intestinal bacteria, and is required for gluconeogenesis, fatty acid synthesis and amino acid catabolism.

Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women.

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. INTRODUCTION: To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. METHODS: This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. RESULTS: A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04-1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. CONCLUSION: Accumulation of vitamin deficiencies was related to incident fractures.

Vitamin D deficiency exacerbates bleomycin-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated epithelial-mesenchymal transition.

BACKGROUND: Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis. METHODS: This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1+/+, Cyp27b1+/- and Cyp27b1-/- mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-ß)/Smad3 signaling was evaluated in the lungs of BLM-treated mice. RESULTS: The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-ß/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-ß/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-ß/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis. CONCLUSION: Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-ß/Smad2/3-mediated EMT in the lungs.

B Vitamins and Ageing.

Vitamin B contributes to the overall health and wellbeing, including that of energy metabolism, methylation, synthesis and DNA repair and proper immune function. Deficiency in B vitamins has been linked to neurocognitive disorders, mitochondrial dysfunction, immune dysfunction and inflammatory conditions. In ageing populations B vitamin deficiency has been linked to cardiovascular disorders, cognitive dysfunction, osteoporosis and methylation disorders and can increase the risk of developing degenerative diseases, particularly cardiovascular disease, cognitive diseases and osteoporosis. Optimization of B vitamin status in the elderly may prove beneficial in the prevention of degenerative diseases. Here we discuss broadly the role of B vitamins in ageing.

Selected B vitamins and their possible link to the aetiology of age-related sarcopenia: relevance of UK dietary recommendations.

The possible roles of selected B vitamins in the development and progression of sarcopenia are reviewed. Age-related declines in muscle mass and function are associated with huge and increasing costs to healthcare providers. Falls and loss of mobility and independence due to declining muscle mass/function are associated with poor clinical outcomes and their prevention and management are attractive research targets. Nutritional status appears a key modifiable and affordable intervention. There is emerging evidence of sarcopenia being the result not only of diminished anabolic activity but also of declining neurological integrity in older age, which is emerging as an important aspect of the development of age-related decline in muscle mass/function. In this connection, several B vitamins can be viewed as not only cofactors in muscle synthetic processes, but also as neurotrophic agents with involvements in both bioenergetic and trophic pathways. The B vitamins thus selected are examined with respect to their relevance to multiple aspects of neuromuscular function and evidence is considered that requirements, intakes or absorption may be altered in the elderly. In addition, the evidence base for recommended intakes (UK recommended daily allowance) is examined with particular reference to original datasets and their relevance to older individuals. It is possible that inconsistencies in the literature with respect to the nutritional management of sarcopenia may, in part at least, be the result of compromised micronutrient status in some study participants. It is suggested that in order, for example, for intervention with amino acids to be successful, underlying micronutrient deficiencies must first be addressed/eliminated.

Metabolomic Evaluation of the Consequences of Plasma Cystathionine Elevation in Adults with Stable Angina Pectoris.

Background: An elevated circulating cystathionine concentration, which arises in part from insufficiencies of vitamin B-6, B-12, or folate, has been shown to be associated with cardiovascular disease (CVD) risk. Hydrogen sulfide (H2S) is a gasotransmitter involved in vasodilation, neuromodulation, and inflammation. Most endogenously produced H2S is formed by pyridoxal phosphate (PLP)-dependent enzymes by noncanonical reactions of the transsulfuration pathway that yield H2S concurrently form lanthionine and homolanthionine. Thus, plasma lanthionine and homolanthionine concentrations can provide relative information about H2S production in vivo.Objective: To determine the metabolic consequences of an elevated plasma cystathionine concentration in adults with stable angina pectoris (SAP), we conducted both targeted and untargeted metabolomic analyses.Methods: We conducted NMR and LC-mass spectrometry (MS) metabolomic analyses on a subset of 80 plasma samples from the Western Norway Coronary Angiography Cohort and selected, based on plasma cystathionine concentrations, a group with high cystathionine concentrations [1.32 ± 0.60 µmol/L (mean ± SD); n = 40] and a group with low cystathionine concentrations [0.137 ± 0.011 µmol/L (mean ± SD); n = 40]. Targeted and untargeted metabolomic analyses were performed and assessed with the use of Student's t tests corrected for multiple testing. Overall differences between the cystathionine groups were assessed by untargeted NMR and LC-MS metabolomic methods and evaluated by partial least squares discriminant analysis (PLS-DA) with significant discriminating metabolites identified with 99% confidence.Results: Subjects with high cystathionine concentrations had 75% higher plasma lanthionine concentrations (0.12 ± 0.044 µmol/L) than subjects with low cystathionine concentrations [0.032 ± 0.013 µmol/L (P < 0.001)]. Although plasma homolanthionine concentrations were notably higher than lanthionine concentrations, they were not different between the groups (P = 0.47). PLS-DA results showed that a high plasma cystathionine concentration in SAP was associated with higher glucose, branched-chain amino acids, and phenylalanine concentrations, lower kidney function, and lower glutathione and plasma PLP concentrations due to greater catabolism. The high-cystathionine group had a greater proportion of subjects in the postprandial state.Conclusion: These data suggest that metabolic perturbations consistent with higher CVD risk exist in SAP patients with elevated plasma cystathionine concentrations.

Alcoholic Pellagra as a Cause of Altered Mental Status in the Emergency Department.

BACKGROUND: Pellagra, which is caused by a deficiency of niacin and tryptophan, the precursor of niacin, is a rare disease in developed countries where alcoholism is a major risk factor due to malnutrition and lack of B vitamins. Although pellagra involves treatable dementia and psychosis, it is often underdiagnosed, especially in developed countries. CASE REPORT: In Japan, a 37-year-old man presented to the emergency department with altered mental status and seizures. Wernicke encephalopathy and alcohol withdrawal were suspected. The patient was treated with multivitamins, which did not include nicotinic acid amide, and oral diazepam. Despite medical treatment, his cognitive impairment progressively worsened, and eventually, pellagra was suspected. His response to treatment with nicotinic acid amide was substantial, and he was discharged without any long-term sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Despite the treatable dementia and psychosis, pellagra is often underdiagnosed, especially in developed countries and alcoholic patients. Pellagra should be routinely suspected in alcoholic patients because the response to appropriate treatment is typically dramatic.

Identification of critical variants within SLC44A4, an ulcerative colitis susceptibility gene identified in a GWAS in north Indians.

SLC44A4 is one of the seven novel susceptibility genes that were discovered in the first ever genome-wide association study (GWAS) on ulcerative colitis (UC) in the genetically distinct north Indians. This gene seems to be functionally relevant to disease biology as it may contribute to the associated phenotype of Vitamin B1 deficiency among UC patients, hence playing a role in disease pathogenesis. A large number of single-nucleotide polymorphisms (SNPs) are known to be distributed throughout this gene, but the functional status of most are not known. Thus, an extensive investigation of structural and regulatory variants within this gene was undertaken in this study to identify the critical variants amongst them using a combination of fine mapping, in silico and in vitro approaches. A few intronic SNPs were predicted to have regulatory roles on the basis of in silico analysis, suggesting that they may be the critical variants within SLC44A4. This highlights the importance of this gene in UC biology, thus confirming the finding of the GWAS and also warranting additional studies.

Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case-control study.

Many studies have suggested that folate-related one-carbon metabolism-related nutrients may play a role in certain cancer risks, but few studies have assessed their associations with the risk for nasopharyngeal carcinoma (NPC). In this study, we investigated the association between four folate-related one-carbon metabolism-related nutrients (folate, vitamin B6, vitamin B12 and methionine) and NPC risk in Chinese adults. A total of 600 patients newly diagnosed (within 3 months) with NPC were individually matched with 600 hospital-based controls by age, sex and household type (urban v. rural). Folate, vitamin B6, vitamin B12 and methionine intakes were measured using a validated seventy-eight-item FFQ. A higher dietary folate or vitamin B6 intake was associated with a lower NPC risk after adjusting for potential confounders. The adjusted OR of NPC for quartiles 2-4 (v. 1) were 0·66 (95% CI 0·48, 0·91), 0·52 (95% CI 0·37, 0·74) and 0·34 (95% CI 0·23, 0·50) (P(trend)<0·001) for folate and 0·72 (95% CI 0·52, 1·00), 0·55 (95% CI 0·39, 0·78) and 0·44 (95% CI 0·30, 0·63) (P(trend)<0·001) for vitamin B6. No significant association with NPC risk was observed for dietary vitamin B12 or methionine intake. The risk for NPC with dietary folate intake was more evident in the participants who were not exposed to toxic substances than in those who were exposed (P(interaction)=0·014). This study suggests that dietary folate and vitamin B6 may be protective for NPC in a high-risk population.

Vitamin D Levels in Infants With Biliary Atresia: Pre- and Post-Kasai Portoenterostomy.

OBJECTIVES: Infants with biliary atresia (BA) are at high risk of vitamin D deficiency. We aimed to determine the prevalence and factors influencing vitamin D levels at presentation and post-Kasai portoenterostomy (KPE). METHODS: Single-centre retrospective review of infants with BA who underwent KPE. Pre- and postoperatively 25-hydroxyvitamin D (25-OHVD), liver and bone biochemistry data were collected. 25-OHVD levels <10 and 10 to 20 ng/mL were defined as vitamin D "deficiency" and "insufficiency," respectively. RESULTS: One hundred twenty-nine infants with BA (isolated n = 101, developmental n = 28, and white n = 79; non-white n = 50) were included in this study. At presentation, 75 of 92 (81%) were vitamin D deficient and only 1 infant had a level >20 ng/mL. Median 25-OHVD levels were 5(2-23), 17(2-72), 15(2-80), 17(2-69), and 23(2-98) ng/mL at pre-KPE, 1, 4, 6, and 12 months postoperation. There was no difference in 25-OHVD levels between the isolated and developmental groups with BA. Pre-KPE, white infants had significantly higher levels than non-white infants (6[2-23] vs 3[2-14] ng/mL, P = 0.01). Post-KPE 25-OHVD levels correlated well with liver and bone biochemical variables (eg, at 6 months: bilirubin rs = -0.34; P < 0.001, alkaline phosphatase rs = -0.46; P < 0.00001, and phosphate rs = 0.49; P < 0.00001). CONCLUSIONS: 25-OHVD deficiency is invariable at presentation in infants with BA, irrespective of its likely aetiology, and is more severe in non-white infants. Despite routine parenteral and enteral supplementation, low 25-OHVD levels persist post KPE especially in icteric infants. More aggressive vitamin D supplementation and monitoring in this population is paramount.

Multiple sclerosis-like diagnosis as a complication of previously treated malaria in an iron and vitamin D deficient Nigerian patient.

In contrast to malaria, multiple sclerosis (MS) is infrequently found in Black Africans. We describe a 29 year old Nigerian female who developed an MS-like condition with symptoms similar to relapsing-remitting MS following malaria infection, leading to a diagnosis of MS. However, absence of hyperintense lesions in the brain and spinal cord presented a conundrum since not all the diagnostic criteria for MS were met. Pathology supported genetic testing (PSGT) was applied to combine family and personal medical history, lifestyle factors, and biochemical test results for interpretation of genetic findings. This approach provides a means of identifying risk factors for different subtypes of demyelinating disease. The patient was subsequently treated according to an individualised intervention program including nutritional supplementation as well as a change in diet and lifestyle. Deficiencies of vitamin B12, iron and vitamin D were addressed. Genetic analysis revealed absence of the HLA DRB1*1501 allele, considered to be the most prominent genetic risk factor for MS. Extended mutation analysis identified variations in three genes in the folate-vitamin B12 metabolic pathway, which could have increased the patient's sensitivity to the antifolate drugs used to treat the malaria. A glutathione-S-transferase GSTM1 null allele, previously associated with neurological complications of malaria, was also detected. Furthermore, a heterozygous variation in the iron-related transmembrane protease serine 6 (TMPRSS6) gene, rs855791 was found, which could have impacted the patient's iron status following two successive blood donations and exposure to malaria preceding the MS diagnosis. PSGT identifies relevant risk factors for demyelinating disorders resembling MS and uses the data for individualised treatment programs, and to systematically build a database that can provide evidence in large patient cohorts. Follow-up investigations may be suggested, such as whole exome sequencing in selected cases, to ensure that remyelination and restoration of function are achieved.

[A rare complication of bariatric surgery: Polyradiculoneuropathy as a type of Guillain-Barré syndrome].

The number of bariatric (weight loss) surgeries have increased steadily in the past decade. Along with the tangible benefit of this treatment, there is a risk for postoperative complications, the main cause of which is impaired absorption of nutrients. The paper describes polyradiculoneuropathy running as a type of Guillain-Barré syndrome.

B-vitamin interventions for women and children in low-income populations.

PURPOSE OF REVIEW: This review examines the effect of B vitamins on women and child health from recent evidence available. RECENT FINDINGS: Findings were related to functional outcomes. In terms of foetal growth, although supplementation with B12 increased B12 status of nonpregnant and pregnant women and infants, maternal plasma homocysteine, which is related to multiple deficiencies of vitamin B12, B6, riboflavin or folate, has been shown to be associated with lower birth size rather than solely plasma B12. However, an experimental study with thiamine supplementation showed improvement in status in thiamine-deficient mothers and breast milk concentration, but not in infant status. Given the multiple aetiology of anaemia, the use of multiple micronutrient fortification has expectedly shown a reduction in anaemia prevalence in women. Furthermore, these micronutrients can interact with each other: high maternal folate intakes coupled with low B12 intakes were associated with a higher risk of delivering a small-for-gestational age infant. A high maternal plasma folate was also associated with insulin resistance in children aged 9.5 and 13.5 years. SUMMARY: Interventions with B vitamins were found to be efficacious in improving the status in women and children. In multiple micronutrient supplementation programmes, the optimum composition of the supplement needs to be determined. The deleterious effect of high folate intakes with low B12 intakes needs to be explored further.

CROSSTALK BETWEEN VITAMIN B AND IMMUNITY.

Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38-MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL-6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity.

[Wernicke encephalopathy accompanying linitis plastica]. / Wernicke-encephalopathia linitis plasticában.

Wernicke encephalopathy (or Wernicke-Korsakoff encephalopathy) is a rarely diagnosed neurological disorder, which is caused by vitamin B1 deficiency. In the classical form it is characterized by a typical triad (confusion, oculomotor disturbance and ataxia), however, in the majority of the cases only confusion is present. It can be frequently observed in subjects with chronic alcohol consumption, but it may accompany different pathological states of which end stage malignant diseases are the most importants, where confusion may have different backgrounds. The authors present the case of an old male patient with advanced gastric cancer recognised and treated vitamin B1 deficiency, and they draw attention to difficulties of the diagnosis of Wernicke's disease.

[B vitamins and diseases of the peripheral nervous system]. / Vitaminy gruppy B i zabolevaniya perifericheskoi nervnoi sistemy.

Various diseases of the peripheral nervous system are associated with metabolic disorders of B vitamins. A lack of neurotropic vitamins, which began in the early stages of the development of a bacterial disease, led to its more rapid development. The article analyzes data on B vitamin deficiency in the pathogenesis of the most dangerous diseases of the peripheral nervous system. Information is provided about the dangers of the clinical use of the drug Combilipen for the treatment of such patients.