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Vitamin B-12 deficiency is often considered synonymous with pernicious anemia, a rare condition in which severe malabsorption of the vitamin requires high-dose parenteral treatment. In developing countries such as India, inadequate dietary intake of B-12 due to socio-cultural factors leads to widely prevalent asymptomatic low B-12 status. In this scenario, lower doses of oral B-12 may be effective, safer and more affordable. To examine the effects of oral B-12 treatment at physiological doses on hematological and biochemical indices and peripheral nerve function in B-12 deficient rural Indian adolescent women. Thirty-nine women with B-12 deficiency who were excluded from a community based B-12 supplementation trial (Pune Rural Intervention in Young Adolescents (PRIYA)) received oral B-12 2μg/day, either alone (n = 19) or with multiple micronutrients (UNIMAPP formula + 20gm milk powder, n = 20) for 11 months. Hematological indices, nutrients (B-12, folate), metabolites (homocysteine) and peripheral nerve function (SUDOSCAN, Impetomedical, Paris and sensory nerve conduction velocity (NCV) of median and sural nerves) were assessed at baseline and after 11 months of B-12 treatment. Results were similar in the two treatment allocation groups, which were therefore combined. At baseline, all women had B-12 concentration <100pmol/L, 79% were anemic and 33% had macrocytosis, but none had neuropathy. After 11 months of treatment, B-12 levels increased, while folate did not change. The prevalence of anemia fell to 59% and mean corpuscular volume (MCV) and plasma homocysteine concentrations decreased. Sudomotor nerve function in the feet improved by an average of 14.7%, and sensory conduction velocity in median and sural nerves increased by 16.2% and 29.4% respectively. We document clinically beneficial effects of supplementation with a physiological dose of oral B-12 in asymptomatic rural Indian adolescent women with very low B-12 status. These findings support a public health approach to tackle the widely prevalent low B-12 status in young Indians.

Vitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency. This is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 μg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development. In this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries. ClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

Background/Objectives: Vitamins D and B12 play a crucial role in maintaining bone health, immune function, and neurological integrity. Combined deficiencies in these vitamins can lead to severe health consequences. Current treatment approaches, such as dietary changes and single-vitamin supplementation, often fail to address these deficiencies comprehensively. This study evaluates the effectiveness of concurrent vitamin D and B12 supplementation to correct these insufficiencies. Methods: A prospective, multicenter, randomized controlled trial was conducted in Greece from October 2024 to December 2024. Participants aged 20 to 80 years, with insufficient levels of 25-hydroxyvitamin D (serum < 20 ng/mL) and B12 (serum < 250 ng/L), were eligible for inclusion. Results: A total of 124 patients were randomized into three groups: one receiving vitamins B12 and D in a single supplement (2500 IU + 1000 mcg), one receiving separate doses of each vitamin (2000 IU + 1000 mcg), and a control group receiving no supplementation. The results demonstrated a significant increase in B12 and 25-hydroxyvitamin D levels among the supplemented groups. Particularly, participants in the combined supplementation group showed higher average serum levels of both vitamins. By the end of this study, 37.1% of those in the combined supplement group achieved adequate vitamin levels, compared to 29.4% in the separate supplementation group. Conclusions: In conclusion, combined supplementation may improve patient adherence and compliance, leading to better health outcomes for individuals with combined vitamins D and B12 deficiencies.

Lactovegetarians (n = 35) with low vitamin B12 (B12) status were intervened for eight weeks capsules containing cyano-B12 (CN-B12), (2 × 2.8 µg/day), or equivalent doses of endogenous B12 (mainly hydroxo-B12 (HO-B12)) in whey powder. Blood samples were examined at baseline, every second week during the intervention, and two weeks post-intervention. The groups did not differ at baseline in [global median (min/max)] plasma B12 [112(61/185)] pmol/L, holotranscobalamin [20(4/99)] pmol/L, folate [13(11/16)], the metabolites total homocysteine [18(9/52)] µmol/L and methylmalonic acid [0.90(0.28/2.5)] µmol/L, and the combined indicator of B12 status (4cB12) [−1.7(−3.0/−0.33)]. Both supplements caused significant effects, though none of the biomarkers returned to normal values. Total plasma B12 showed a higher increase in the capsule group compared to the whey powder group (p = 0.02). However, the increase of plasma holotranscobalamin (p = 0.06) and the lowering of the metabolites (p > 0.07) were alike in both groups. Thereby, the high total plasma B12 in the capsule group was not mirrored in enhanced B12 metabolism, possibly because the B12 surplus was mainly accumulated on an “inert” carrier haptocorrin, considered to be of marginal importance for tissue delivery of B12. In conclusion, we demonstrate that administration of whey powder (HO-B12) or capsules (CN-B12) equivalent to 5.6 µg of B12 daily for eight weeks similarly improves B12 status but does not normalize it. We document that the results for plasma B12 should be interpreted with caution following administration of CN-B12, since the change is disproportionately high compared to the responses of complementary biomarkers.

Abstract Background Vitamin B12 deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B12 . Oral vitamin B12 formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. Objective The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B12 formulation (oral B12 ) with intramuscular (IM) vitamin B12 (IM B12 ) in restoring normal serum B12 concentrations in patients with low cobalamin levels (<350 pg/mL). Methods Patients were recruited from 5 centers and randomly assigned to receive oral B12 1000 μg, taken daily for 90 days, or IM B12 1000 μg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged ≥60 years or aged ≥18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (≥350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B12 levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B12 ) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. Results Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B12 group and 26 patients [100%] in the IM B12 group). All patients (100%) in both treatment groups and in both populations had a cobalamin level ≥350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance ( P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 ( P = 0.033), with lower values in the oral B12 group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels ≥40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. Conclusions In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B12 (1000 μg/d) or IM B12 (1000 μg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831.

ObjectiveTo evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).Methods373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset).ResultsNo significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months’ duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups.ConclusionAlthough ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.Trial registration number NCT00444613.

Vitamin B (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.

Vitamin B 12 deficiency occurs in approximately 2% to 3% of adults in the United States. Risk factors include malabsorptive processes, limited dietary intake of vitamin B 12, use of certain medications (eg, metformin, proton pump inhibitors), and older age. Symptoms vary based on the severity of vitamin B 12 deficiency but may include fatigue, brain fog, depression, peripheral neuropathy, and ataxia. Although universal screening is not recommended, testing should be considered in patients with at least one risk factor for and one clinical feature of vitamin B 12 deficiency. Initial testing includes total serum vitamin B 12 level, which is diagnostic for deficiency if less than 180 pg/mL. Borderline levels (180–350 pg/mL) warrant a methylmalonic acid measurement, which is diagnostic for vitamin B 12 deficiency if elevated. Patients without a clear cause of deficiency should undergo further testing for atrophic gastritis with a Helicobacter pylori test and evaluation for autoantibodies associated with autoimmune gastritis. Oral vitamin B 12 supplementation can be used in most patients and is noninferior to intramuscular supplementation. Intramuscular administration should be considered in patients with severe deficiency or neurologic manifestations. Vitamin B 12 levels that are persistently elevated (greater than 1,000 pg/mL on two measurements) have been associated with solid tumors, hematologic malignancy, and increased risk of cardiovascular death.

Vitamin B12 (cobalamin) is a critical micronutrient involved in hematopoiesis and neurological function. Its deficiency, commonly presenting with anemia and neurological symptoms, is particularly relevant in oncology. While anemia affects up to 60% of cancer patients, the contribution of vitamin B12 deficiency to cancer-related anemia remains underexplored. Additionally, cobalamin-related neuropathy manifests or exacerbates existing chemotherapy-induced peripheral neuropathy (CIPN), a serious side effect of chemotherapy. Prevalence estimates in cancer populations range widely (6–48%), with higher rates in elderly and gastrointestinal cancer patients. This review summarizes current evidence on the prevalence and implications of both vitamin B12 deficiency and excess in patients with solid tumors. It discusses laboratory markers (such as serum vitamin B12, holotranscobalamin, methylmalonic acid, and homocysteine) that could improve diagnostic accuracy in oncology settings. Additionally, it evaluates supplementation strategies and discusses its role in mitigating CIPN. Additionally, it addresses B12′s emerging immunological role in cancer therapy.

Vitamin B12 deficiency is a common condition which can present with non-specific clinical features, and in severe cases with neurological or haematological abnormalities. Although classically caused by pernicious anaemia, this condition now accounts for a minority of cases and vitamin B12 deficiency occurs most often due to food-bound cobalamin malabsorption. Since missing the diagnosis can result in potentially severe complications, including degeneration of the spinal cord and pancytopaenia, vitamin B12 deficiency must be diagnosed early and managed appropriately. Intramuscular injections have been the mainstay of treatment, but oral replacement therapy can be effective in many cases. There is accumulating evidence that high vitamin B12 levels (values varied from 350-1,200 pmol/l) are associated with haematological and hepatic disorders, in particular with malignancy. This review focuses on the developments in the clinical features and management of vitamin B12 deficiency over the last decade.