Vitamin B12 Deficiency

Vitamin B12 (cobalamin) is a water-soluble vitamin obtained mainly from foods of animal origin such as eggs, milk, red meat, poultry, fish and shellfish. ^[1] Cobalamin acts as a cofactor in one-carbon transfers through methylation and molecular rearrangement in fatty acid, amino acid and nucleic acid metabolic pathways. ^[2] Vitamin B12 deficiency occurs in approximately 2% to 3% of adults in the United States. ^[3] It is a common condition that can present with non-specific clinical features and, in severe cases, with neurological or haematological abnormalities. ^[4] Symptoms vary with the severity of deficiency and may include fatigue, brain fog, depression, peripheral neuropathy and ataxia. ^[3] Clinical effects include progressive demyelination, peripheral neuropathy and haematological abnormalities such as macrocytic anaemia and neutrophil hypersegmentation. ^[5] A missed diagnosis can lead to severe complications including spinal cord degeneration and pancytopenia, and some neurologic sequelae may become irreversible despite cobalamin replacement. ^{[4] [6]}

The most common explanations for poor vitamin B12 status are a low dietary intake of the vitamin, that is a low intake of animal-source foods, and malabsorption. ^[7] Although classically caused by pernicious anaemia, which now accounts for a minority of cases, vitamin B12 deficiency occurs most often due to food-bound cobalamin malabsorption. ^[4] Food-bound cobalamin malabsorption is most commonly due to gastric atrophy in the elderly, probably as a result of Helicobacter pylori infection. ^[7] In autoimmune gastritis, autoantibodies against the parietal cell proton pump induce hypochlorhydria and then achlorhydria, while autoantibodies against intrinsic factor impair vitamin B12 absorption, producing pernicious anaemia. ^{[8] [6]} Strict vegans are at risk, and low intakes of animal-source foods, as occur in some lacto-ovo vegetarians and many less-industrialized countries, also cause vitamin B12 depletion, reflecting the poor cobalamin content of plant-based diets. ^{[7] [2]}

There is no gold-standard test to define cobalamin deficiency, so the clinical picture is the most important factor in interpreting test results. ^[10] Universal screening is not recommended, but testing should be considered in patients with at least one risk factor and one clinical feature of deficiency. ^[3] An American Family Physician review considers total serum B12 below 180 pg/mL diagnostic, and borderline levels of 180 to 350 pg/mL an indication for methylmalonic acid measurement, which is diagnostic if elevated. ^[3] British haematology guidelines, by contrast, state that definitive cut-off points cannot be set given the variety of methods and technical issues, and recommend local reference ranges, with serum cobalamin as first-line test and plasma methylmalonic acid as second-line test. ^[10] Serum holotranscobalamin has the potential to be a first-line test, but an indeterminate grey area may still exist, and plasma homocysteine may help as a second-line test but is less specific than methylmalonic acid. ^[10] Methylmalonic acid is not specific to B12 status, since increased levels can also come from genetic mutations in propionate-pathway enzymes, the gut microbiota and aggressive cancers.

Patients without a clear cause of deficiency should be evaluated for atrophic gastritis with a Helicobacter pylori test and autoantibodies associated with autoimmune gastritis. ^[3] In inflammatory bowel disease, patients with extensive ileal disease or prior ileal surgery should be monitored for vitamin B12 deficiency. ^[12] High-dose folic acid (more than 5 mg/d) can reverse the megaloblastic anaemia of B12 deficiency while masking the deficiency and possibly worsening its neurological progression, so vigilance is advised in at-risk people taking excess folic acid, although this evidence is primarily correlative. ^[13] Oral vitamin B12 can be used in most patients and is noninferior to intramuscular supplementation, while intramuscular administration should be considered in severe deficiency or neurologic manifestations. ^[3] A network meta-analysis that included a total of 4275 patients found that intramuscular B12 ranked first for increasing vitamin B12 levels (MD = 94.09 pg/mL compared to the oral route) without reaching statistical significance, and no route differed significantly for haemoglobin, other blood count parameters or homocysteine. ^[14]