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The causes and risk factors of vitamin B12 deficiency are many and varied. Importantly, they vary considerably across the lifespan, from infancy to old age. The complexity of the physiology of vitamin B12 bespeaks the myriad of possible causes of deficiency and possible disruptions of its functional integrity. These lead ultimately to the pathobiological effects witnessed in deficiency of this fascinating micronutrient. This brief overview of the multiplicity of mechanisms that can result in vitamin B12 deficiency, and the panoply of its manifestations explores the underlying reasons for the protean presentations of the disease. As the human organism progresses through the chronology and milestones of age, various susceptibility factors arise resulting from the interplay of environmental and genetic factors. Acting independently and in concert, these factors produce the common denominator of vitamin B12 deficiency. However, the rate at which such deficiency develops and the way in which it presents clinically vary widely, subject to such influences as genetic variability, end-organ susceptibility, and concomitant micronutrient status. Some examples of unusual cases of vitamin B12 deficiency are described. Much has been learned about the last of the numbered vitamins in almost a century. Much yet remains to be discovered.

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.

Background: Little attention has been given to prenatal cobalamin insufficiency in settings where dietary cobalamin intake is presumed adequate, such as populations with habitual intake of foods from animal sources.Results: However, low cobalamin status in women of fertile age has been reported in Europe, United States, and Canada. In India, where cobalamin deficiency is highly prevalent, it has been associated with an increased risk of miscarriage, intrauterine growth retardation, as well as insulin resistance and lower neurodevelopment scores in the offspring. Low cobalamin status in pregnancy has been associated with similar outcomes as those reported in the Indian studies although the evidence is scant and conflicting.Conclusions: Consideration should be given to maternal cobalamin status in the context of prevention of adverse pregnancy outcomes as well as cobalamin insufficiency both in the mother and the offspring during lactation. Further attention is now justified with the increasing tendency toward plant-based diets. Reference intervals for cobalamin status during each trimester of pregnancy are needed and further investigation of the long-term conse-quences of low cobalamin status during pregnancy for health and development in the offspring is warranted.

Background: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements.Objectives: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians.Results: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency.Conclusion: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Background: Vitamin B12 deficiency is a critical medical condition that, if left untreated, can lead to severe symptoms and potentially serious and life-threatening complications. Clinical guidelines are designed to provide a standardized approach to diagnosis and treatment, aiming for consistency and effectiveness. However, it is well-established that not all patients fit into general guidelines.Objective: To investigate the clinical relevance of the submitted research to support these protocols for diagnosing and treating a B12 deficiency.Approach: Conducting a literature review of the references focused and used on diagnosing and treating vitamin B12 deficiency in adults and children.Results: No robust clinical trial nor RCT has been found to back up the current protocols. The research used is primarily based on assumptions rather than solid clinical evidence.Conclusion: Existing guidelines for vitamin B12 deficiency need to be significantly revised and improved through clinical research, clinical experience by experts in the field with input from patient groups worldwide.

Plant-based diets are increasingly popular worldwide. A well-planned plant-based diet lowers the risk of cardiovascular disease, type 2 diabetes and certain cancers. In contrast, a poorly planned plant-based diet increases the risk of certain micronutrient deficiencies, chiefly, vitamin B12(B12). Because B12is not present in plants or in unfortified plant-based foodstuffs, the safest way to prevent its deficiency in plant-based diets is to take an oral B12supplement. Studies determining the dose and frequency of B12to be taken by healthy individuals on a plant-based diet to support an adequate B12status are scarce. Here, we summarize the natural sources, metabolic requirements, biomarker findings with and without supplementation with B12, and current recommendations to help prevent vitamin B12deficiency in healthy individuals adhering or transitioning to plant-based diets. This review focuses on the prevention of vitamin B12deficiency in healthy individuals adhering to plant-based diets. The information covered in this review does not apply to individuals suffering from autoimmune-based malabsorption of vitamin B12resulting from pernicious anemia due to atrophic gastritis, other acquired causes of B12malabsorption or to those with genetic disorders that impair vitamin B12absorption, transport and utilization.

Background: 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.Objective: 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.Methods: The review is based on published papers, but also on knowledge gained from working within the area.Conclusion: 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.

Background: Pernicious anemia (PA) is a type of macrocytic anemia caused by autoimmune gastritis. To facilitate timely diagnosis and treatment of PA there is a pressing need for improved understanding among Healthcare providers of the condition’s symptoms and diagnostic criteria.Objective: This systematic review aims to extend existing clinical knowledge on the presentation of PA by determining which symptoms and clinical complications are reported in published adult case studies.Methods: Relevant studies were identified through electronic searches of PsycINFO, Embase, and MEDLINE, via OvidSP. During data extraction symptoms were categorized according to the International Classification of Diseases and were grouped based on frequency.Results: Symptoms were documented for 103 adults with a diagnosis of PA; the most frequent symptoms were fatigue (55%), loss of sensation in limbs (32%), excessive weight loss (27%), and a sore tongue (23%).Conclusions: This review highlights the diverse symptomology of adults who are diagnosed with PA. Most symptoms documented in case studies are consistent with the core signs of B12and folate deficiencies. Research is needed to identify if there are common clusters of PA symptoms that can be used as prompts for diagnostic testing in patients with suspected B12deficiency.

Background: Vitamin B12 deficiency is commonly diagnosed using thresholds developed for adults, yet emerging evidence indicates these levels may not be appropriate for children and adolescents. This misalignment can lead to underdiagnosis in younger populations, with potential long-term health implications.Case Summary: Conclusion: The main takeaway from these cases is the importance of tailoring diagnostic adequate thresholds and treatment plans to the pediatric population to address and manage B12 deficiency effectively. This approach can significantly enhance patient outcomes and prevent the progression of potentially severe complications in later life.

Background: An optimal cobalamin status is necessary for normal neurodevelopment.Objective: To give a description of the epidemiology, pathophysiology and diagnostic challenges related to cobalamin insufficiency in neonates and infants in order to prevent its occurence.Results: Inadequate cobalamin status is prevalent among neonates and young infants, due to a high prevalence of maternal cobalamin deficiency, exclusive breastfeeding for extended periods and late introduction of animal food. Cobalamin insufficiency is associated with delayed neurodevelopment and subtle clinical symptoms like feeding difficulties, regurgitations and constipation in young infants. Early diagnosis and treatment of impaired cobalamin status is important to prevent neurologic damage.Conclusion: Clinical suspicion of cobalamin insufficiency in infants should infer immediate biochemical testing and a plasma total homocysteine > 5.0 µmol/L indicate cobalamin insufficiency in need of intramuscular treatment with hydroxycobalamin, followed by introduction of animal food after 4 months of age.

Background: It is difficult to recognize vitamin B12 deficiency and to evaluate the effect of B12 treatment due to a broad range of variable clinical symptoms overlapping with other diseases and diagnostic biomarkers that quickly normalize during treatment. This poses a risk of delay in diagnosis and a challenge to uniformly monitor the effect of B12 treatment. There is a need for a new clinical outcome measure suitable for clinical practice and clinical evaluation studies.Objective: To develop a Patient-Reported Outcome Measure (PROM) which measures the severity of vitamin B12 deficiency symptoms.Methods: The B12 PROM was developed by (1) gathering input from experts and literature review to define a construct and develop a conceptual model, (2) processing input from health care providers, scientists, and patients to develop items and response options, and (3) improving items based on the feedback from laypersons, test interviews, semi-structured cognitive interviews with patients, and forward and backward translation (ENG-NL).Results: The B12 PROM includes 62 items grouped into 8 categories of symptoms related to vitamin B12 deficiency (General, Senses, Thinking, In limbs and/or face, Movement, Emotions, Mouth & Abdomen, Urinary tract & Reproductive organs). Cognitive interviews demonstrated good comprehensibility and comprehensiveness.Conclusions: This study is the first step in the development of a disease-specific PROM for vitamin B12 deficiency to measure the burden of symptoms. Further validation and reliability testing are necessary before the PROM can be applied in clinical practice and research.

Vitamin B12 deficiency can present with a variety of neurological and cognitive symptoms. Especially in elderly patients, vitamin B12 deficiency can be easily overlooked because symptoms may be attributed to comorbid conditions or solely to the aging process. In this case study, we present two patients, a 71-year-old man and a 74-year-old female, with vitamin B12 deficiency. The male patient had a history of (partial) resection of the ileum/jejunum/colon because of intestinal ischemia. The female patient had a history of hypothyroidism, type 2 diabetes with complications (including peripheral neuropathy), mitochondrial myopathy, and chronic lymphocytic leukemia. Both patients presented with severe fatigue, cognitive impairment, and impaired walking. Next to this, the male patient suffered from depressive symptoms and mild disorientation, and the female patient experienced neuropathic pain. She also mentioned a positive family history for B12 deficiency. The first patient had normal to high B12 levels because he was already on B12 injections (once every three weeks) because of an earlier diagnosed B12 deficiency. The female patient had B12 levels within normal range (holotranscobalamin 54 pmol/L) and her diagnosis was confirmed by elevated homocysteine and methylmalonic acid levels. Treatment with frequent hydroxocobalamin injections and other supplements significantly improved their cognitive, emotional, and motor functions. These cases underscore the need for a high level of clinical suspicion in elderly patients, also in cases of normal B12 levels but with clinical signs of deficiency and a positive risk factor, such as stomach or small bowel surgery or positive family history.

This article is a commentary on the role of vitamin B12in age-related cognitive decline, with a meta-commentary on the misuse of the term “Alzheimer’s Disease.” The article describes the historical origins of the term “Alzheimer’s Disease” and argues that the term should be restricted to a narrower segment of the age-related dementia spectrum. The article also outlines the role of vitamin B12in age-related cognitive decline and outlines the rationale for the treatment of B12deficiency to address a potentially reversible factor in cognitive decline.

This supplement of the Food and Nutrition Bulletinis dedicated to the proceedings of “the International B12 Conference in Clinical Practice,” held in Rotterdam in June 2023. The conference brought together physicians, scientists, patient groups, and health care professionals with substantial expertise in diagnosing and treating vitamin B12 deficiency from many universities around the world. With a collective commitment to advancing clinical practice and improving patient outcomes, this event was instrumental in addressing the many complex and challenging aspects of vitamin B12 deficiency. The subjects explored at the conference ranged from the latest research findings to real-world case studies, spanning diverse medical disciplines, including pediatrics, obstetrics, neurology, internal medicine, gastroenterology, psychiatry, clinical chemistry, nutrition, public health, biomedical science, and nursing. The broad spectrum of disciplines reflects the multifaceted nature of vitamin B12 deficiency and underscores the necessity of a comprehensive and multidisciplinary approach to its diagnosis and treatment. This supplement aims to distill into a concise and accessible format the knowledge shared by stimulating and provocative presentations at the B12 Conference and to make the information available for the broader scientific and health care community. The compendium bridges the insights generated at the conference and the wider audience of health care practitioners, researchers, and policymakers who recognize the urgency of addressing the critical public health concerns surrounding vitamin B12 deficiency.