The importance of vitamin B12 for individuals choosing plant-based diets.

Vitamin B12 is an essential nutrient that is not made by plants; consequently, unfortified plant-based foods are not a reliable supply. Recent estimates suggest high rates of vitamin B12 deficiency among the vegetarian and vegan populations, particularly in pregnant women or women of child-bearing age who, for ethical and health reasons, are shifting towards higher consumption of plant-based foods in ever-increasing numbers. Vitamin B12 plays crucial metabolic roles across the life-course and in particular during pregnancy and in early development (first 1000 days of life). Evidence now implicates vitamin B12 deficiency with increased risk to a range of neuro, vascular, immune, and inflammatory disorders. However, the current UK recommended nutrient intake for vitamin B12 does not adequately consider the vitamin B12 deficit for those choosing a plant-based diet, including vegetarianism and in particular veganism, representing a hidden hunger. We provide a cautionary note on the importance of preventing vitamin B12 deficits for those individuals choosing a plant-based diet and the health professionals advising them.

Vitamin B12 status in health and disease: a critical review. Diagnosis of deficiency and insufficiency - clinical and laboratory pitfalls.

Vitamin B12 (cobalamin) is an essential cofactor for two metabolic pathways. It is obtained principally from food of animal origin. Cobalamin becomes bioavailable through a series of steps pertaining to its release from dietary protein, intrinsic factor-mediated absorption, haptocorrin or transcobalamin-mediated transport, cellular uptake, and two enzymatic conversions (via methionine synthase and methylmalonyl-CoA-mutase) into cofactor forms: methylcobalamin and adenosylcobalamin. Vitamin B12 deficiency can masquerade as a multitude of illnesses, presenting different perspectives from the point of view of the hematologist, neurologist, gastroenterologist, general physician, or dietician. Increased physician vigilance and heightened patient awareness often account for its early presentation, and testing sometimes occurs during a phase of vitamin B12 insufficiency before the main onset of the disease. The chosen test often depends on its availability rather than on the diagnostic performance and sensitivity to irrelevant factors interfering with vitamin B12 markers. Although serum B12 is still the most commonly used and widely available test, diagnostics by holotranscobalamin, serum methylmalonic acid, and plasma homocysteine measurements have grown in the last several years in routine practice. The lack of a robust absorption test, coupled with compromised sensitivity and specificity of other tests (intrinsic factor and gastric parietal cell antibodies), hinders determination of the cause for depleted B12 status. This can lead to incorrect supplementation regimes and uncertainty regarding later treatment. This review discusses currently available knowledge on vitamin B12, informs the reader about the pitfalls of tests for assessing its deficiency, reviews B12 status in various populations at different disease stages, and provides recommendations for interpretation, treatment, and associated risks. Future directions for diagnostics of B12 status and health interventions are also discussed.

Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial.

BACKGROUND: Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known. OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12. METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment-Evaluation for Depression) trial. Participants defined as having "low" serum vitamin B-12 (vitamin B-12 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD). RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was -0.01 (95% CI: -0.06, 0.04; P = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 µg/L (95% CI: 8.13, 25.02 µg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 µg/L (95% CI: 387, 535 µg/L; P < 0.001). CONCLUSIONS: Supplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism.This trial was registered at www.isrctn.com as ISRCTN37558856.

Patient journeys: diagnosis and treatment of pernicious anaemia.

BACKGROUND: Instigating a patient support group for patients with pernicious anaemia (PA) revealed dissatisfaction with its current diagnosis and treatment. The authors investigated the clinical features, patient experience of diagnosis and treatment of PA in the UK. METHODS: A total of 889 patients registered with the PA Society support group completed an online survey or postal questionnaire. Outcome measures included clinical features, length of time to diagnosis and patient satisfaction with current treatment RESULTS: One-third of patients experienced symptoms for up to 1 year before diagnosis; 14% waited more than 10 years for a diagnosis. Neurological features were highly prevalent, the most common being memory loss and poor concentration. Nearly two-thirds of respondents were dissatisfied with current treatment; 10% used a non-licensed form of B12 to supplement their prescribed injections. CONCLUSION: The diagnosis and treatment of PA should be subject to a thorough review. This article discusses the patient survey and results and makes recommendations for how the diagnosis and treatment of PA may be evaluated.

Creating a Framework for Treating Autoimmune Gastritis-The Case for Replacing Lost Acid.

Autoimmune gastritis (AIG) is characterized by the destruction of gastric parietal cells, resulting in hypochlorhydria and eventual achlorhydria, as oxyntic glands in the corpus are destroyed and become atrophic. The permanent loss of gastric acid has many impacts-both theoretical and documented. The most concerning of these are hypergastrinemia and increased N-nitroso compounds, both of which increase the risk of gastric cancers. While known deficiencies of B12 and iron are often replaced in AIG, acid is not. Moreover, patients with AIG are often prescribed acid suppression for a stomach that is decidedly no longer acidic, worsening the sequelae of gastric atrophy. Betaine hydrochloride (BHCL) is a short-acting acidifying agent, available over the counter in capsule form. Mealtime acid supplementation has an historic basis and could ameliorate many AIG-related gastrointestinal symptoms. Theoretically, acidification could also reduce the potential for hypergastrinemia and the production of N-nitroso compounds, consequently reducing the risk of gastric cancers. Supplemental vitamin C may also help in preventing gastric N-nitroso formation, regardless of the gastric pH. This narrative review describes the functions of gastric acid in gastrointestinal and immune health, documents the effects of hypochlorhydria in AIG, and proposes potential options for safely re-establishing the acid milieu of the stomach for patients with AIG.

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency.

BACKGROUND: An increasing number of adult individuals are at risk of vitamin B12 deficiency, either from reduced nutritional intake or impaired gastrointestinal B12 absorption. OBJECTIVE: This study aims to review the current best practices for the diagnosis and treatment of individuals with vitamin B12 deficiency. METHODS: A narrative literature review of the diagnosis and treatment of vitamin B12 deficiency. RESULTS: Prevention and early treatment of B12 deficiency is essential to avoid irreversible neurological consequences. Diagnosis is often difficult due to diverse symptoms, marked differences in diagnostic assays' performance and the unreliability of second-line biomarkers, including holo-transcobalamin, methylmalonic acid and total homocysteine. Reduced dietary intake of B12 requires oral supplementation. In B12 malabsorption, oral supplementation is likely insufficient, and parenteral (i.e. intramuscular) supplementation is preferred. There is no consensus on the optimal long-term management of B12 deficiency with intramuscular therapy. According to the British National Formulary guidelines, many individuals with B12 deficiency due to malabsorption can be managed with 1000 µg intramuscular hydroxocobalamin once every two months after the initial loading. Long-term B12 supplementation is effective and safe, but responses to treatment may vary considerably. Clinical and patient experience strongly suggests that up to 50% of individuals require individualized injection regimens with more frequent administration, ranging from daily or twice weekly to every 2-4 weeks, to remain symptom-free and maintain a normal quality of life. 'Titration' of injection frequency based on measuring biomarkers such as serum B12 or MMA should not be practiced. There is currently no evidence to support that oral/sublingual supplementation can safely and effectively replace injections. CONCLUSIONS: This study highlights the interindividual differences in symptomatology and treatment of people with B12 deficiency. Treatment follows an individualized approach, based on the cause of the deficiency, and tailored to help someone to become and remain symptom-free.

Plain language titleDiagnosis and Treatment of Vitamin B12 DeficiencyPlain language summaryThe number of people who are at risk of developing a deficiency of vitamin B12 is steadily increasing. B12 deficiency can develop when people consume too few B12-containing foods of animal origin, or when they develop a form of B12 malabsorption. B12 deficiency can lead to serious complications so prevention and early treatment are essential. Diagnosing B12 deficiency can be challenging: the symptoms vary from patient to patient, and the methods used to measure B12 in the blood, or certain biomarkers associated with B12 metabolism, such as holo-transcobalamin, methylmalonic acid, and total homocysteine are unreliable. When people do not consume enough B12-containing foods, supplementation with B12 tablets is needed. In the case of B12 malabsorption, intramuscular injections of B12 are mandatory. The usual treatment with B12 is starting with injections of 1000 µg hydroxocobalamin twice weekly or on every other day for a period of up to 5 weeks or longer, until all symptoms have disappeared, and thereafter, the frequency of injections is gradually reduced. There is, however, a large group of people who require more frequent administration to become and remain symptom-free: this may range from daily or twice weekly to every 2 to 4 weeks.

Examining the Diagnosis and Treatment Experiences of People Living With Autoimmune Gastritis and Pernicious Anemia.

There is limited research evaluating the diagnosis and treatment of patients with autoimmune gastritis (AIG) and pernicious anemia (PA). We used a 2-phase data collection process to examine the literature and individual patient accounts. Phase one comprised a systematically conducted literature review focusing on diagnosis and treatment, relationships with healthcare practitioners and health-related quality of life (HRQOL). Phase two involved analysis of individual accounts via posts in online patient forums. We identified 6 main themes: the diagnosis journey, seeking treatment, patient-provider relationships, HRQOL, patient disempowerment, and the "expert patient." Our findings confirm significant knowledge gaps concerning AIG/PA across the healthcare community. These have a cascading effect starting with delays in diagnosis and poor treatment protocols and often lead to complete withdrawal from care seeking. The establishment of standard consensus guidelines and improved clinical awareness should be urgently addressed. Interventions that better help patients understand their illness are also needed to improve psychological health. Without these changes disengagement from health systems, and poor health outcomes, will continue for this population group.

Homocysteine-a retrospective and prospective appraisal.

The biologically important amino acid homocysteine links sulfur, methionine, and one-carbon metabolism. This review describes its initial discovery, the identification of the clinical condition of "homocystinuria" and the recognition of its close relationship to folate and vitamin B12 metabolism. It discusses the history behind its current association with diverse diseases including neural tube defects, cardio- and cerebrovascular disease and, more recently, dementia and Alzheimer's Disease. It also explores current controversies and considers potential future research directions. It is intended to give a general overview of homocysteine in relation to health and disease.

Transcobalamin receptor gene polymorphisms and mutation in an elderly population.

BACKGROUND & AIMS: Cellular uptake of the essential nutrient vitamin B12 (cobalamin) occurs via the transcobalamin receptor (TCblR/CD320), a ubiquitous membrane receptor. Polymorphisms in the receptor exist, though the effect of such variants across patient populations is unknown. METHODS: We determined CD320 genotype in 377 randomly selected elderly individuals. RESULTS: Three polymorphisms and a codon deletion were identified in the exon 2 region. Haplotype variants had significantly higher holotranscobalamin (holo-TC) values and a higher holo-TC/total cobalamin ratio. TCblR haplotype explained 46% of the variability in holo-TC values. CONCLUSIONS: This has significant implications for the clinical utility of the 'combined indicator' of B12 status since it is based on a standard rate of intracellular flux via the TC-Cbl receptor. Modification of the model may be required to account for CD320 haplotype.

COVID-19: A methyl-group assault?

The socio-economic implications of COVID-19 are devastating. Considerable morbidity is attributed to 'long-COVID' - an increasingly recognized complication of infection. Its diverse symptoms are reminiscent of vitamin B12 deficiency, a condition in which methylation status is compromised. We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon metabolism. We propose these might explain the varied symptoms of long-COVID. Our suggested mechanismmight also apply to similar conditions such as myalgic encephalomyelitis/chronic fatigue syndrome. The hypothesis is evaluable by detailed determination of vitamin B12and folate status, including serum formate as well as homocysteine and methylmalonic acid, and correlation with viral and host RNA methylation and symptomatology. If confirmed, methyl-group support should prove beneficial in such individuals.

L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline.

Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.

Vitamin B(12) and redox homeostasis: cob(II)alamin reacts with superoxide at rates approaching superoxide dismutase (SOD).

We report a kinetic study of the reaction between superoxide and an important intracellular form of vitamin B(12), cob(II)alamin. Superoxide is implicated in the pathophysiology of many inflammatory diseases, whereas vitamin B(12) derivatives are often beneficial in their treatment. We found that cob(II)alamin reacts with superoxide at rates approaching those of superoxide dismutase itself, suggesting a probable mechanism by which vitamin B(12) protects against chronic inflammation and modulates redox homeostasis.

Synthesis, synchrotron X-ray diffraction, and kinetic studies on the formation of a novel thiolatocobalamin of captopril: evidence for cis-trans isomerization in the beta-axial ligand.

The orally administered therapeutic captopril is widely used for treating hypertension, congestive heart failure, and cardiovascular disease. However, a number of undesirable side effects are associated with high doses of captopril. By coordinating a therapeutic to the upper (= beta) axial site of the naturally occurring macrocycle cobalamin (vitamin B(12)), the absorption and cellular uptake of the therapeutic can be significantly enhanced. We report the synthesis of captopril-cobalamin, a derivative of vitamin B(12) in which captopril is bound via its thiol group at the beta-axial site of cobalamin. Characterization of captopril-cobalamin by (1)H NMR spectroscopy and X-ray diffraction shows that captopril-cobalamin exists in both solution and the solid state as a mixture of geometric isomers. Kinetic studies on the formation of captopril-cobalamin have been carried out, and the data fits a model in which the thiol form (RSH, k(1) = 40.9 +/- 1.2 M(-1) s(-1)) and the thiolate form of captopril (RS(-), k(2) = 660 +/- 170 M(-1) s(-1)) react rapidly with aquacobalamin.

Alzheimer's Amyloidopathy: An Alternative Aspect.

The 'amyloid hypothesis' dominates Alzheimer's disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1 (PSEN1) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12. These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials.

Homocysteine and Dementia: An International Consensus Statement.

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 µmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

Methylmalonic acid and cognitive function in the Medical Research Council Cognitive Function and Ageing Study.

BACKGROUND: An elevated blood concentration of homocysteine is an established risk factor for cognitive impairment and dementia, but associations between cognition and methylmalonic acid (MMA), a related metabolic marker of vitamin B-12 deficiency, are less clear. OBJECTIVE: The aim was to determine the utility of serum MMA and holotranscobalamin as markers of vitamin B-12 status in relation to cognitive function and to investigate their association with discrete cognitive domains. DESIGN: This was a cross-sectional survey of 84 nondemented elderly participants (aged >69 y) from the Welsh cohort of the Medical Research Council's Cognitive Function and Ageing Study. Cognitive status was determined by Mini-Mental State Examination (MMSE) and the Cognitive Section of the Cambridge Mental Disorders of the Elderly Examination (CAMCOG). RESULTS: Nearly one-half (43%) of the persons selected had likely metabolically significant vitamin B-12 deficiency. Higher MMA concentrations were associated with lower MMSE scores independent of age and education (P = 0.007). MMA concentration correlated inversely with CAMCOG scores of ideational praxis (P < 0.05) and language comprehension (P < 0.05) and expression (P < 0.01). Serum folate correlated weakly but significantly with language (P < 0.05), remote memory (P < 0.05), and constructional and ideational praxis scores (P < 0.05 and P < 0.01, respectively). CONCLUSION: The high prevalence of likely metabolically significant vitamin B-12 deficiency in the elderly is associated with lower cognitive function scores and particularly with lower scores of language comprehension and expression.

Homocysteine and cognition--a historical perspective.

The discovery of a relationship between homocysteine and cognition stems from clinical observations of an association between vitamin B12 and folate deficiency and cognitive dysfunction. This retrospective details the history of vitamin B12 and folic acid and the conceptual evolution of their association with dementia. The hematological and neuropsychiatric manifestations of these deficiencies are discussed, together with the nature of their relationship with dementia, generalized cognitive decline and discrete neuropsychological function. An evaluation of the potential of reversing "homocysteine-associated" and/or "vitamin-associated" cognitive decline raises questions as to whether current interventions can unequivocally determine if homocysteine independently impacts on cognitive function. Alternative approaches specifically designed to address this issue are discussed.

Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology.

The British Association for Psychopharmacology (BAP) coordinated a meeting of experts to review the evidence on the drug treatment for dementia. The level of evidence (types) was rated using a standard system: Types 1a and 1b (evidence from meta-analysis of randomised controlled trials or at least one controlled trial respectively); types 2a and 2b (one well-designed study or one other type of quasi experimental study respectively); type 3 (non-experimental descriptive studies); and type 4 (expert opinion). There is type 1a evidence for cholinesterase inhibitors (donepezil, rivastigmine and galantamine) for mild to moderate Alzheimer's disease; memantine for moderate to severe Alzheimer's disease; and for the use of bright light therapy and aromatherapy. There is type 1a evidence of no effect of anti inflammatory drugs or statins. There is conflicting evidence regarding oestrogens, with type 2a evidence of a protective effect of oestrogens but 1b evidence of a harmful effect. Type 1a evidence for any effect of B12 and folate will be forthcoming when current trials report. There is type 1b evidence for gingko biloba in producing a modest benefit of cognitive function; cholinesterase inhibitors for the treatment of people with Lewy body disease (particularly neuropsychiatric symptoms); cholinesterase inhibitors and memantine in treatment cognitive impairment associated with vascular dementia; and the effect of metal collating agents (although these should not be prescribed until more data on safety and efficacy are available). There is type 1b evidence to show that neither cholinesterase inhibitors nor vitamin E reduce the risk of developing Alzheimer's disease in people with mild cognitive impairment; and there is no evidence that there is any intervention that can prevent the onset of dementia. There is type 1b evidence for the beneficial effects of adding memantine to cholinesterase inhibitors, and type 2b evidence of positive switching outcomes from one cholinesterase inhibitor to another. There is type 2a evidence for a positive effect of reminiscence therapy, and type 2a evidence that cognitive training does not work. There is type 3 evidence to support the use of psychological interventions in dementia. There is type 2 evidence that a clinical diagnosis of dementia can be made accurately and that brain imaging increases that accuracy. Although the consensus statement dealt largely with medication, the role of dementia care in secondary services (geriatric medicine and old age psychiatry) and primary care, along with health economics, was discussed. There is ample evidence that there are effective treatments for people with dementia, and Alzheimer's disease in particular. Patients, their carers, and clinicians deserve to be optimistic in a field which often attracts therapeutic nihilism.

Homocysteine and cognitive impairment; a case series in a General Practice setting.

BACKGROUND: An elevated blood level of homocysteine is a risk factor for cognitive impairment and dementia. Homocysteine can be lowered by folate and/or vitamin B12 supplementation; antioxidants might also be required for optimal reduction in neurovascular tissue. This report presents clinical and radiological findings from administering the antioxidant N-acetylcysteine together with B vitamins to cognitively impaired patients with hyperhomocysteinaemia. METHODS: A case series (n = 7) performed in a semi-rural General Practice setting. Formal cognitive assessments were performed in five patients, and radiological assessments in one patient, before and after supplementation. RESULTS AND DISCUSSION: The addition of N-acetylcysteine resulted in subjective clinical improvement in all patients, and an objective improvement in cognitive scores in five patients. One patient had radiological evidence of halted disease progression over a twelve month period. CONCLUSION: N-acetylcysteine, together with B vitamin supplements, improves cognitive status in hyperhomocysteinaemic patients. Randomized controlled clinical trials are required to formally evaluate this treatment approach.

Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality.

Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill's criteria for assessing "causality," and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22,000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed.