Doses Of B12 Research Articles

Vitamin B12-Related Biomarkers.

Adult vitamin B12 (B12) deficiency may present itself with nonspecific mainly neurological symptoms, and thus plasma biomarkers are often judged to be of major importance in the further diagnostic process. Four biomarkers are of special relevance: total B12, holotranscobalamin (the part of B12 bound to the active transport protein, transcobalamin, also named holoTC or active B12) and the 2 so-called metabolic markers that accumulate if B12 is lacking, methylmalonic acid (MMA) and homocysteine. This article briefly reviews the inherent limitation of biomarkers, discusses its use in establishing the diagnosis and cause of B12 deficiency, and when following or discontinuing treatment with B12. The review is based on published papers, but also on knowledge gained from working within the area. It is concluded that a combination of a B12 and a metabolic marker, for example, total B12 and MMA, may prove most useful in daily practice. An unexpectedly high level of total B12 is most often of no clinical importance, though sometimes related to the presence of underlying cancer. Measurement of total B12 is of limited value in patients on treatment with pharmacological doses of B12 but may be helpful if B12 treatment is discontinued.

Vitamin B12 deficiency and cognitive impairment: Is there a distinctive cognitive domain affected? A descriptive study in Buenos Aires

AbstractBackgroundVitamin B12 deficiency is associated with cognitive‐behavioral disorders, which may be potentially reversible. No specific associated cognitive domain has been established and alterations in episodic memory, verbal fluency, attention and executive functions, praxia and visuoconstruction have been described. The objective of this work is to evaluate and describe the cognitive domains affected in patients with cognitive impairment associated with vitamin B12 deficiency.MethodCross‐sectional observational study conducted at the Trinidad Mitre sanatorium of Buenos Aires City. Patients with cognitive impairment and vitamin B12 deficiency were analyzed. Information was collected on the cognitive domain affected (taking as altered value the Z score ≤‐1.5 according to age and educational level, obtained in the neurocognitive evaluations), cognitive profile, magnetic resonance imaging features and mean consultation‐supplementation time.Result25 patients with vitamin B12 deficiency and cognitive complaint were analyzed, with a mean age of 68.5 years. 83% presented multidomain mild cognitive impairment being 60% with subcortical pattern. Memory and attention were the most affected domains in 80% of the sample, followed by executive functions with 52%. The most deficient tests were the direct digit test (68%), serial memory (56%), deferred logical memory (52%) and Trail Making B (52%). Nearly 52% presented mild depressive symptomatology. A 56% of the sample presented with severe B12 deficiency with 32% elevation of plasma homocysteine. Supplementation was performed intramuscularly in 68% of the patients with a mean symptomatology‐supplementation onset time of 10.8 months. 92% of the patients presented subjective improvement after supplementation, 32% had control global test evaluation with improvement in all of them and 50% of this group presented control cognitive evaluation with improvement in previously deficient domains.ConclusionAccording to our findings we conclude that these patients with vitamin B12 deficiency present a multidomain pattern with special affectation of memory, attention and executive functions; of mild degree and potentially reversible. The reversibility of the picture could be related to high doses of B12 and early supplementation, using control cognitive assessments as an objective measure of improvement.ReferencesReynolds E. Lancet Neurol. 2006 Nov;5(11):949‐60. Eastley R. Int J Geriatr Psychiatry. 2000 Mar;15(3):226‐33. Robins Wahlin. Biol Psychol. 2001 Jun;56(3):247‐65.

A randomized controlled trial examining the effects of treatment with propylene glycol and injectable cyanocobalamin on naturally occurring disease, milk production, and reproductive outcomes of dairy cows diagnosed with concurrent hyperketonemia and hypoglycemia.

The objective of this study was to assess the effects of treatment with propylene glycol (PG) and cyanocobalamin (B12) on health, milk production, and reproductive outcomes of cows diagnosed with hyperketonemia (HK), hypoglycemia (HG), or concurrent HKHG. Glucose and β-hydroxybutyric acid (BHBA) concentrations were assessed in whole blood using a handheld device in lactating dairy cows (n = 2,418) between 3 and 9 d postpartum. Cows categorized as HK (n = 232, BHBA ≥1.2 mmol/L), HG (n = 161, glucose ≤2.2 mmol/L), and concurrent HKHG (n = 204, BHBA ≥1.2 mmol/L, and glucose ≤2.2 mmol/L) were randomized to receive treatment or to remain untreated (control). Treatment consisted of a single dose of B12 (10 mg, intramuscularly) and 300 mL of PG orally for 5 d, starting on the day of cow-side testing. Milk production, health, and reproductive outcomes were analyzed according to groups. Statistical analysis was carried out using SAS version 9.4 (SAS/STAT, SAS Institute Inc.). Treatment in HG cows decreased clinical ketosis, increased milk production in the fifth week of lactation for multiparous cows, and tended to increase 305-d mature-equivalent milk yield (305ME) for primiparous cows compared with untreated cows with the same metabolic profile. For cows with HKHG, treatment increased 305ME in multiparous cows and tended to increase 305ME in primiparous cows. No differences were found for treatment among any of the metabolic groups regarding reproductive outcomes, nor were any treatment effects found among HK cows. Glycemic status may help identify metabolically challenged early postpartum dairy cows, which may have differential response to PG and B12 treatment.

Responses of Fermentation Characteristics and Microbial Communities to Vitamin B12 Supplementation in In Vitro Ruminal Cultures

Vitamin B12, an important cofactor involved in propionate formation, is synthesized exclusively by bacteria and archaebacteria. Humans need to intake vitamin B12 through food, and dairy products are generally the best source of vitamin B12. In the present study, the effects of vitamin B12 supplementation in diets on in vitro ruminal fermentation characteristics and microbial communities were investigated to provide a reference for increasing the vitamin B12 content in milk by dietary supplementation. A completely randomized design was carried out using the in vitro rumen culture technique, and 5 vitamin B12 dose levels (0, 0.5, 1.0, 2.0, and 4 mg/g of dry matter) were used. The results showed that vitamin B12 supplementation in diets decreased acetate: propionate ratio and butyrate concentration. The change in the acetate: propionate ratio can be attributed to the increased relative abundances of the Proteobacteria phylum and the Negativicutes class, both of which are involved in propionate metabolism. The decrease in butyrate concentration can likely be attributed to a reduction in relative abundance of species belonging to the Clostridia class, which are known as the predominant butyrate producers in the mammalian intestine. In addition, vitamin B12 supplementation in diets reduced the CH4 production by altering the species composition of the archaeal community. In conclusion, dietary supplementation of vitamin B12 resulted in rumen perturbation. In vivo studies should be conducted cautiously when evaluating the effects of vitamin B12 supplementation on the synthesis and absorption of it, as well as its content in milk.

Perspective from 2021 Observations & Interventions in Micronutrient Research in Pune, India

Exciting research has happened in Pune since the publication in 2011 of our review on the role of maternal micronutrients in intrauterine programming of non-communicable diseases. We have completed a preconceptional micronutrient intervention in adolescents with the aim of improving the health of their offspring. This randomized controlled trial was based on our findings in the Pune Maternal Nutrition Study, and is called the Pune Rural Intervention in Young Adolescents (PRIYA) study. Interventions included: (1) vitamin B12 alone; (2) vitamin B12 with multi-micronutrients and milk powder; and (3) placebo. The vitamin B12 dose was 2 μg/day, to make it relevant in terms of physiology and public health. All groups received iron and folic acid as per the Indian national policy. A total of 557 adolescents (17 years of age, 291 boys and 266 girls) were enrolled; those with very low vitamin B12 levels were excluded and treated. Participants were carefully followed up to record marriages and pregnancies, and deliveries were attended to study neonatal outcomes. Very few of the boys married; by contrast, 182 of the girls married and 149 of them delivered a live child during the trial.

Vitamin B12 does not increase cell viability after hydrogen peroxide induced damage in mouse kidney proximal tubular cells and brain endothelial cells

Vitamin B12 (B12) is an essential co-factor for two enzymes in mammalian metabolism and can also act as a mimetic of superoxide dismutase (SOD) converting superoxide (O2•−) to hydrogen peroxide (H2O2). High oral dose B12 decreases renal O2•− and post-ischemia/reperfusion injury in mice and protects against damage induced by hypoxia/reperfusion in mouse kidney proximal tubular cells (BU.MPT). O2•− is unstable and rapidly converted to H2O2. H2O2 mediates oxidative stress associated with O2•−. Whether B12 protects against damage induced by H2O2 is unknown. Both BU.MPT cells and mouse brain endothelial cells (bEdn.3) were applied to test the effects of B12 on H2O2-induced cytotoxicity. Both types of cells were treated with different doses of H2O2 with or without different doses of B12. Cell viability was analyzed 24 h later. H2O2 caused cell death only at a very high dose, and high pharmacological dose of B12 did not prevent this detrimental effect in either cell type. In bEnd.3 cells, transcriptional levels of heme oxygenase-1 (HO-1) increased, while nuclear factor erythroid 2-related factor 2 (Nrf2) decreased by H2O2. The levels of transcripts were not affected by the B12 treatment. We conclude that the cytotoxic effects of exogenous H2O2 in BU.MPT and bEdn.3 cells are not prevented by B12.

Efficacy of B12 Fortified Nutrient Bar and Yogurt in Improving Plasma B12 Concentrations—Results From 2 Double-Blind Randomized Placebo Controlled Trials

Dietary vitamin B12 (B12) deficiency is common in Indians. Long-term compliance to tablet supplementation is poor in asymptomatic individuals. To study efficacy of B12 fortified nutrient bar and yogurt in improving plasma B12 concentrations in children and adults. Two double-blind, placebo-controlled directly observed therapy randomized controlled trials were conducted for 120 days: (1) Healthy children (10-13 years) were fed nutrient bar fortified with B12 (2 μg), multiple micronutrients B12 (1.8 μg) or placebo. (2) Healthy adults (18-50 years) were fed yogurt fortified with B12 (2 μg) or Propionibacterium (1 × 108 cfu/g) or placebo. B12, folate, homocysteine, and hemoglobin concentrations were measured before and post intervention. We randomized 164 children and 118 adults; adherence was 96% and 82%, respectively. In children, B12 fortified bars increased B12 concentrations significantly above baseline (B12 alone +91 pmol/L, B12+ multiple micronutrients +82 pmol/L) compared to placebo. In adults, B12 fortified yogurt increased B12 significantly (+38 pmol/L) but Propionibacterium and placebo did not. In both trials, homocysteine fell significantly with B12 supplementation. Rise of B12 and fall of homocysteine were influenced by dose of B12 and folic acid. There was no significant difference in change of anthropometry and hemoglobin between groups. B12 fortified foods are effective in improving B12 status in Indian children and adults. They could be used to improve B12 status in the national programs for children, adolescents, and women of reproductive age. They could also be used as over-the-counter products.

Vitamin B12 Inhibits Progression of Hypercholesterolemia and Atherosclerosis in Rabbits Fed a High Cholesterol Diet

The present study was undertaken to examine the effect of vitamin B12 on serum cholesterol levels and development of aortic atherosclerosis in New Zealand White male rabbits fed a high cholesterol diet. Twenty rabbits were divided into 4 groups matched for their baseline serum cholesterol values. Groups 1 and 2 received a normal diet, whereas groups 3 and 4 had cholesterol mixed with their chow. After 5 weeks, the serum cholesterol of groups 3 and 4 increased by approximately 12 fold compared to groups 1 and 2. At that point, vitamin B12 was administered in the drinking water (1000 micrograms/l) to rabbits in groups 2 and 4. At week 8, the Vitamin B12 dose was increased to 2400 micrograms/l for group 4. At 12 weeks into the study, rabbits in group 4 (high cholesterol diet plus vitamin B12) had a serum cholesterol level of 919 +/- 270 mg/dl while those of group 3 (high cholesterol diet) had a serum cholesterol level of 1417 +/- 250 mg/dl. At the end of the study, rabbit aortas were excised, fixed, and stained with fat-red-B, a dye for lipid. Comparison of the aortas of rabbits that received the lipid rich diet revealed that animals given additional vitamin B12 had significantly decreased surface area of fat deposition. These data suggest the potential role for vitamin B12 as a safe and inexpensive pharmacological intervention for the modification of the progression of human atherosclerosis.

Oral high dose vitamin B12 decreases renal superoxide and post-ischemia/reperfusion injury in mice

Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), a potentially fatal syndrome characterized by a rapid decline in kidney function. Excess production of superoxide contributes to the injury. We hypothesized that oral administration of a high dose of vitamin B12 (B12 - cyanocobalamin), which possesses a superoxide scavenging function, would protect kidneys against IRI and provide a safe means of treatment. Following unilateral renal IR surgery, C57BL/6J wild type (WT) mice were administered B12 via drinking water at a dose of 50 mg/L. After 5 days of the treatment, plasma B12 levels increased by 1.2-1.5x, and kidney B12 levels increased by 7-8x. IRI mice treated with B12 showed near normal renal function and morphology. Further, IRI-induced changes in RNA and protein markers of inflammation, fibrosis, apoptosis, and DNA damage response (DDR) were significantly attenuated by at least 50% compared to those in untreated mice. Moreover, the presence of B12 at 0.3 μM in the culture medium of mouse proximal tubular cells subjected to 3 hr of hypoxia followed by 1 hr of reperfusion in vitro showed similar protective effects, including increased cell viability and decreased reactive oxygen species (ROS) level. We conclude that a high dose of B12 protects against perfusion injury both in vivo and in vitro without observable adverse effects in mice and suggest that B12 merits evaluation as a treatment for I/R-mediated AKI in humans.

14C-Cobalamin Absorption from Endogenously Labeled Chicken Eggs Assessed in Humans Using Accelerator Mass Spectrometry.

Traditionally, the bioavailability of vitamin B-12 (B12) from in vivo labeled foods was determined by labeling the vitamin with radiocobalt (57Co, 58Co or 60Co). This required use of penetrating radioactivity and sometimes used higher doses of B12 than the physiological limit of B12 absorption. The aim of this study was to determine the bioavailability and absorbed B12 from chicken eggs endogenously labeled with 14C-B12 using accelerator mass spectrometry (AMS). 14C-B12 was injected intramuscularly into hens to produce eggs enriched in vivo with the 14C labeled vitamin. The eggs, which provided 1.4 to 2.6 μg of B12 (~1.1 kBq) per serving, were scrambled, cooked and fed to 10 human volunteers. Baseline and post-ingestion blood, urine and stool samples were collected over a one-week period and assessed for 14C-B12 content using AMS. Bioavailability ranged from 13.2 to 57.7% (mean 30.2 ± 16.4%). Difference among subjects was explained by dose of B12, with percent bioavailability from 2.6 μg only half that from 1.4 μg. The total amount of B12 absorbed was limited to 0.5–0.8 μg (mean 0.55 ± 0.19 μg B12) and was relatively unaffected by the amount consumed. The use of 14C-B12 offers the only currently available method for quantifying B12 absorption in humans, including food cobalamin absorption. An egg is confirmed as a good source of B12, supplying approximately 20% of the average adult daily requirement (RDA for adults = 2.4 μg/day).

Vitamin B12 deficiency in the elderly: is it worth screening?

Vitamin B12 deficiency is common among the elderly. Elderly people are particularly at risk of vitamin B12 deficiency because of the high prevalence of atrophic gastritis-associated food-cobalamin (vitamin B12) malabsorption, and the increasing prevalence of pernicious anaemia with advancing age. The deficiency most often goes unrecognised because the clinical manifestations are highly variable, often subtle and non-specific, but if left undiagnosed the consequences can be serious. Diagnosis of vitamin B12 deficiency, however, is not straightforward as laboratory tests have certain limitations. Setting a cut-off level to define serum vitamin B12 deficiency is difficult; though homocysteine and methylmalonic acid are more sensitive for vitamin B12 deficiency, it may give false result in some conditions and the reference intervals are not standardised. At present, there is no consensus or guideline for diagnosis of this deficiency. It is most often based on the clinical symptoms together with laboratory assessment (low serum vitamin B12 level and elevated serum homocysteine or methylmalonic acid level) and the response to treatment to make definitive diagnosis. Treatment and replacement with oral vitamin B12 can be as effective as parenteral administration even in patients with pernicious anaemia. The suggested oral vitamin B12 dose is 1 mg daily for a month, and then maintenance dose of 125 to 250 µg for patients with dietary insufficiency and 1 mg daily for those with pernicious anaemia. Vitamin B12 replacement is safe and without side-effects, but prompt treatment is required to reverse the damage before it becomes extensive or irreversible. At present, there is no recommendation for mass screening for vitamin B12 in the elderly. Nevertheless, the higher prevalence with age, increasing risk of vitamin B12 deficiency in the elderly, symptoms being difficult to recognise, and availability of safe treatment options make screening a favourable option. However, the unavailability of reliable diagnostic tool or gold standard test makes screening difficult to carry out.

Vitamin B12 Deficiency in Pregnancy and Lactation: Is there a Need for Pre and Post-natal Supplementation?

This article reviews vitamin B12 (B12) status and deficiency during pregnancy and lactation, its effect on pregnancy, and the health of the offspring, with the aim to underscore the need for a sustainable strategy to improve maternal and infant vitamin B12 status of low and middle income countries. Vitamin B12 is a basic nutrient required for maintenance of normal erythropoiesis, cell reproduction, nucleoprotein and myelin synthesis. B12 deficiency is associated with adverse pregnancy outcomes and neurodevelopmental morbidity during infancy. Very few studies have indicated that B12 deficiency may contribute to altered immune responses in animals and humans. Additionally, no studies have shown modulation of infant motor development in response to maternal B12 supplementation. Despite the high global prevalence of B12 deficiency and its serious effects on pregnant women and offspring, there is still no consensus on the cut-off of biochemical markers (indicator of B12 deficiency) to correctly diagnose B12 deficiency in mother-infant dyad. Also, the optimum dose of B12 to normalize B12 status of mother-infant pairs in a deficient population is not known yet. In addition, markers of other functions such as neurodevelopment, immune response that may be affected by vitamin B12 deficiency should be measured to determine if they respond to supplementation. Thus, there is an urgent need to conduct more trials to find out the optimum dose, to investigate whether intervention with such pre-and post natal vitamin B12 supplementation would improve maternal, neonatal and child health outcomes in population at risk, giving emphasis on neurological processes, immune functions and epigenetic modifications. Other strategies including food based approach also require evidence based results which will help to understand effectiveness of a targeted and well-designed intervention among this population.

RETRACTED ARTICLE: Neuropathological and neuroprotective features of vitamin B12 on the dorsal spinal ganglion of rats after the experimental crush of sciatic nerve: an experimental study

BackgroundSpinal motoneuron neuroprotection by vitaminB12 was previously reported; the present study was carried out to evaluate neuroprotectivity in the dorsal root ganglion sensory neuron.MethodsIn present study thirty-six Wister-Albino rats (aged 8–9 weeks and weighing 200–250 g) were tested. The animals were randomly divided into 6 groups which every group contained 6 rats. Group A: received normal saline (for 42 days); Group B: vitamin B12 was administered (0.5 mg/kg/day for 21 days); Group C: received vitamin B12 (1 mg/kg/day for 21days); Group D: received vitamin B12 (0.5 mg/kg/day for 42 days); Group E; received vitamin B12 (1 mg/kg/day for 42 days); Group F; received no treatment. The L5 Dorsal Root Ganglion (DRG) neurons count compared to the number of left and right neurons .Furthermore, DRG sensory neurons for regeneration were evaluated 21 or 42 days after injury (each group was analyzed by One-Way ANOVA test).Results(1): The comparison of left crushed neurons (LCN) number with right non-crushed neurons in all experimental groups (B, C, D and C), indicating a significant decline in their neurons enumeration (p<0/05). (2): The comparison of test group’s LCN with the control group’s LCN revealed a significant rise in the number of experimental group neurons (p<0/05). (3): Moreover, comparing the number of right neurons in experimental groups with the number of neurons in crushed neurons indicated that the average number of right neurons showed a significant increase in experimental groups (p<0/05).ConclusionConsequently, the probability of nerve regeneration will be increased by the increment of the administered drug dosage and duration. On the other hand, the regeneration and healing in Dorsal Spinal Ganglion will be improved by increase of administration time and vitamin B12 dose, indicating that such vitamin was able to progress recovery process of peripheral nerves damage in experimental rats. Finally, our results have important implications for elucidating the mechanisms of nerve regeneration. Moreover, the results showed that vitaminB12 had a proliferative effect on the dorsal root ganglion sensory neuron.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7395141841009256

Response of vitamin B12 status to a controlled B12 intake in nonpregnant, pregnant, and lactating women

As part of a 12‐wk controlled feeding study, pregnant (n=26, 27 wk gestation), lactating (n=28, 5 wk postpartum), and nonpregnant (n=21) women consumed the study vitamin B12 dose of 7.5 μg/d [prenatal supplement (2.6 μg/d) and natural food (~4.9 μg/d)]. All participants achieved adequate vitamin B12 status throughout the study. Serum total vitamin B12 remained constant in pregnant and lactating women, whereas it increased in nonpregnant women (P=0.001). At study end, total B12 (mean ± SD) was lower in pregnant women (335 ± 104 pmol/L) than lactating (496 ± 127 pmol/L, P&lt;0.001) and nonpregnant (422 ± 82 pmol/L, P=0.015) women. The consumption of the study B12 dose increased both serum holotranscobalamin (holoTC) and the fraction of total serum vitamin B12 bound to TC (holoTC/B12 ratio) within physiologic groups (P ≤0.001 and P ≤0.037, respectively). At study end, pregnant women had higher holoTC/B12 ratio (31%) than nonpregnant women (22%, P=0.035) and lactating women (24%, P=0.056) suggesting that pregnancy increased the tissue availability of circulating B12. Overall, these data suggest that consumption of the study vitamin B12 dose (~ 2.5 times the RDA) met the vitamin B12 requirements of our study participants and maintained B12 concentrations in third trimester pregnant women by increasing holoTC concentrations. Funded in part by USDA, AEB‐ENC and the Beef Checkoff.

B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes

Therapy to lower homocysteine with B vitamins does reduce the risk of stroke, if not myocardial infarction. The apparent lack of efficacy of vitamin therapy in most of the large clinical trials was probably determined by the failure to take account of the metabolic deficiency of vitamin B12, which is very common and often missed, and by the failure to take account of impaired renal function. Metabolic B12 deficiency is present in 20% of people over 65 years of age, and in 30% of vascular patients above 70 years, so higher doses of B12 are needed in elderly patients. However, high-dose cyanocobalamin leads to accumulation of cyanide in patients with renal failure. B vitamin therapy is beneficial in patients with good renal function, but harmful in patients with significantly impaired renal function (a glomerular filtration rate <50). It seems likely that in patients with renal impairment, methylcobalamin should be used instead cyanocobalamin.

Understanding the Complexity of Homocysteine Lowering With Vitamins

SINCE THE PUBLICATION OF SEVERAL RANDOMIZED TRIALS and a meta-analysis indicating that lowering homocysteine levels with B vitamins (to reduce the effects of homocysteine on the vascular endothelium) did not result in cardiovascular benefit, the use of vitamin therapy to lower homocysteine levels is widely regarded as ineffective. However, there has been renewed interest in the issue because an analysis of studies from the National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis showed that adding total homocysteine level to a Framingham risk score was associated with an approximately 20% net reclassification of intermediate-risk patients. A recent meta-analysis raised the question of whether population folate intake and polymorphisms of methylenetetrahydrofolate reductase may alter interpretation of these clinical trials; mendelian randomization analysis suggested that the polymorphisms might be important only among individuals with low folate status. A commentary about that article noted the hazards of the “spinal reflex” that leads to “automatic rejection of observational data when they appear to be discrepant from trials.” A similar spinal reflex, automatic rejection of subgroup analyses, is another hazard of interpretation of clinical trials. Subgroup analyses founded in biology may have the potential to importantly inform interpretation of clinical trial results, provided sufficient caution is exercised. Thoughtfully derived subgroups, especially those formed a priori and not derived post hoc from the same data set, can stimulate further work and reinterpretation of existing data. The question of whether B vitamin therapy to lower homocysteine levels may reduce the risk of stroke is becoming more complicated, and analyses that depended on grouping all patients together may have obscured important differences among patient (and perhaps population) subgroups. For instance, the main results of the Vitamin Intervention for Stroke Prevention (VISP) trial showed no effect of B vitamins (folic acid/pyridoxine/cyanocobalamin) on the risk of recurrent stroke, death, or myocardial infarction, whereas a subgroup analysis of the VISP trial showed benefit of B vitamins in a defined subset of the population. More recently, House et al reported that B vitamin therapy was shown to increase cardiovascular risk in patients with diabetic nephropathy. Hence, subgroup analyses have shown beneficial as well as adverse effects of B vitamin therapy. The VISP subgroup analysis excluded patients with B12 deficiency (because they were all receiving injections of cyanocobalamin, regardless of the treatment to which they were randomized), and patients with significant renal impairment (because it was thought they would not respond to vitamin therapy). There was a significant reduction of stroke or myocardial infarction with B vitamins in the remaining participants, and this finding was more pronounced when patients were stratified by baseline serum B12 level. The difference between patients who entered the study with a serum B12 level above the median (ie, they could absorb B12 reasonably well) and received high-dose vitamins and those who entered the study with a serum B12 level below the median and received low-dose vitamins was a 34% reduction of stroke, death, or myocardial infarction (P=.02). At the time, it seemed that the findings were explained mainly by exclusion of patients receiving vitamin B12 injections, and this seemed supported by the finding in the Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial (the only large trial to use an adequate dose of B12 for elderly patients) that B vitamins significantly reduced the risk of stroke. In 2011, Hsu et al reported that in the VISP trial, a subgroup of patients with the GG phenotype of transcobalamin 2, a transport protein for vitamin B12, were responsive to high-dose vitamin therapy. Vitamin B12 may thus have a key role in stroke prevention interventions involving vitamin therapy used to lower homocysteine levels. Homocysteine increases thrombosis and is associated with a markedly increased risk of stroke in atrial fibrillation. The prevalence of atrial fibrillation increases steeply with age, as do metabolic B12 deficiency (not necessarily reflected in serum B12 levels, discussed below) and plasma total homocysteine levels. In the Framingham cohort, 1.5% of strokes at ages 50 through 59 years were attributable to atrial fibrillation, whereas by ages 80 through

Serum B12 Concentration Is Elevated in Patients Receiving Chronic Parenteral Nutrition, But Is Not a Marker of Intestinal Failure-Associated Liver Disease

Cobalamin is released during hepatic cytolysis associated with liver injury. Serum B12 concentration is frequently elevated in patients that receive long-term parenteral nutrition (PN). We hypothesized that serum B12 concentration would become elevated in intestinal failure-associated liver disease and would reflect in disease severity. We retrospectively evaluated 13 patients with short bowel syndrome (<200 cm residual small intestine) that included complete terminal ileum resection (3 male and 10 female, aged 42 to 78 y) that had received parenteral nutrition (PN) 6.1+/-3 years. All 13 patients had received at least 1 liver biopsy for presumed intestinal failure-associated liver disease. At the time of biopsy, patients had received PN between 2 and 7 days a week (4.7+/-1.9 d). The liver biopsies were evaluated and prospectively scored for pathology using 3 independent scoring systems validated for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease [Brunt, NAFLD activity score (NAS) and Dixon methods], whereby numeric values were assigned to degrees of steatosis, inflammation, and fibrosis. Serum B12 concentration and hepatic chemistries (aspartate transaminase, alanine transaminase, alkaline phosphatase, and bilirubin) were recorded within 1 week of the biopsies. Thirteen biopsies were available for analysis. Serum B12 concentration and hepatic chemistries were available for all biopsy times. The mean serum B12 concentration was 619+/-222 pg/mL. The mean daily parenteral B12 dose was 3.3+/-1.3 mcg. Mean NAS, Brunt, and Dixon scores were 2, 1, and 1, respectively. The Spearman correlation coefficients between serum B12 concentration and liver biopsy scores were 0.15, 0.1, and 0.1 for the NAS, Brunt, and Dixon scores, respectively, indicating that there was no correlation between serum B12 concentration and liver pathology. The Spearman correlation coefficient between the NAS inflammation subscore and serum B12 concentration was 0.02. B12 concentration also failed to correlate with hepatic chemistries. There was surprisingly little correlation between serum B12 concentration and exogenous B12 daily dose through PN (r=0.19, P=0.45). Elevated serum B12 concentration is commonly encountered in patients who receive long-term parenteral nutrition. This does not seem to be an indicator of hepatic pathology; rather it may reflect the provision of excessive intravenous vitamin B12 and other as yet unknown factors.

Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India

Vitamin B(12) (B(12)) deficiency is common in Indians and a major contributor to hyperhomocysteinemia, which may influence fetal growth, risk of type II diabetes and cardiovascular disease. The purpose of this paper was to study the effect of physiological doses of B(12) and folic acid on plasma total homocysteine (tHcy) concentration. A cluster randomized, placebo-controlled, double-blind, 2 x 3 factorial trial, using the family as the randomization unit. B(12) was given as 2 or 10 microg capsules, with or without 200 microg folic acid, forming six groups (B(0)F(0), B(2)F(0), B(10)F(0), B(0)F(200), B(2)F(200) and B(10)F(200)). Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation. From 119 families in the Pune Maternal Nutrition Study, 300 individuals were randomized. There was no interaction between B(12) and folic acid (P=0.14) in relation to tHcy concentration change and their effects were analyzed separately: B(0) vs. B(2) vs. B(10); and F(0) vs. F(200). At 12 months, tHcy concentration reduced by a mean 5.9 (95% CI: -7.8, -4.1) micromol/l in B(2), and by 7.1 (95% CI: -8.9, -5.4) micromol/l in B(10), compared to nonsignificant rise of 1.2 (95% CI: -0.5, 2.9) micromol/l in B(0). B(2) and B(10) did not differ significantly. In F(200), tHcy concentration decreased by 4.8 (95% CI: -6.3, -3.3) micromol/l compared to 2.8 (95% CI: -4.3, -1.2) micromol/l in F(0). Daily oral supplementation with physiological doses of B(12) is an effective community intervention to reduce tHcy. Folic acid (200 microg per day) showed no additional benefit, neither had any unfavorable effects.

Model to estimate labeled vitamin B12 in eggs for studies of food‐bound B12 absorption

About 25% of elderly in the US have impaired absorption for vitamin B12 from food. Study of this condition has been limited by lack of food that contain intrinsically labeled B12. Supplementation of laying hens with B12 increases B12 in eggs (Naber, 1993). However, relationships between B12 dose, transfer rates between tissues and B12 uptake into egg is unknown. To estimate vitamin B12 kinetics and transfer into eggs in a laying hen, a computer model of B12 metabolism was created based on experimental data from Denton et al. (1954) and Edwards (1967) representing 6 dose‐response treatments. The model has 5 state variables representing B12 in blood, gut, muscle, other tissues and eggs. Exchanges between state variables are based on mass action kinetics. Despite different experimental protocols and dosing schemes, predicted exchange rates of B12 between tissues were remarkably similar with fecal excretion 0.08 %/d, urinary excretion 0.15 %/d, absorption 0.1%/d, exchange between muscle and other tissues with blood 0.5 %/d, and uptake into eggs from 0.03 to 0.2 %/d. Model estimates of total 57Co B12 absorbed, retained, and in eggs from Edwards (1967), and model estimates of μg B12/egg from Denton et al. (1954) were within 5% of data. Therefore the model can be used to estimate B12 enrichment of eggs using different dosing protocols, for use in human absorption studies.

Homocysteine and Stroke Prevention: Have the Trials Settled the Issue?

Recent publicity surrounding disappointing results of clinical trials of homocysteine lowering has led to the claim that 'homocysteine is dead'. However, there is strong evidence that elevated plasma total homocysteine is an important independent risk factor, and the highly plausible biological rationale is the following: total homocysteine increases coagulation, impairs endothelial function, increases oxidative stress and low density lipoprotein oxidation, and treatment with vitamins reverses these effects and halts progression of carotid plaque. Some studies have shown clinical benefit of vitamin therapy in coronary angioplasty and peripheral vascular disease. It has recently become apparent that vitamin B12 absorption is impaired in the elderly, and that metabolic B12 deficiency is much commoner than would be appreciated by statistical definitions of 'normal' serum B12; higher doses of B12 and perhaps other therapies such as betaine and thiols may be needed to achieve adequate reductions of total homocysteine. It remains likely that effective lowering of total homocysteine will reduce stroke and other vascular events.