INTRODUCTION — Deficiencies of vitamin B12 and/or folate can cause megaloblastic anemia (macrocytic anemia with other features due to impaired cell division). Vitamin B12 deficiency can also cause neuropsychiatric findings. In addition to correcting the deficiency, an important aspect of management is determining the underlying cause because the need for additional testing, the duration of therapy, and the route of administration may differ depending on the underlying cause.
This topic review discusses the major causes of vitamin B12 and folate deficiency, along with their pathophysiology.
Separate topic reviews discuss the clinical presentation, diagnosis, and treatment of these deficiencies:
●Clinical presentation and diagnosis – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
●Treatment – (See "Treatment of vitamin B12 and folate deficiencies".)
OVERVIEW OF INTAKE AND METABOLISM
Dietary sources and RDI — Human cells cannot synthesize vitamin B12 or folates. In most cases, a typical balanced diet will contain adequate amounts of both vitamins, with the notable exception that vegan diets do not contain adequate vitamin B12.
●Vitamin B12 – Vitamin B12 (also called cobalamin) is present in many animal products, including meats, dairy products, and eggs . The highest concentrations are in clams and liver, which explains the efficacy of consuming large amounts of liver for the treatment of pernicious anemia (PA) before the role of vitamin B12 was discovered . Many breakfast cereals are fortified with vitamin B12. In contrast, vitamin B12 is not present in foods derived from plants, with the exception of those that contain animal products or added vitamin B12. Seaweed is not a source of vitamin B12, although certain edible algae used in Japanese soups may contain some vitamin B12 .
As described in the Vitamin B12 Dietary Fact Sheet from the National Institutes of Health (NIH), the recommended daily intake (RDI) of vitamin B12 ranges from 0.4 mcg per day in young infants to 2.4 mcg per day in adults, with slightly higher requirements during pregnancy and lactation . A typical nonvegetarian diet contains adequate vitamin B12, but a vegan or strict vegetarian diet typically does not contain sufficient amounts of vitamin B12 and should be supplemented . (See "Treatment of vitamin B12 and folate deficiencies", section on 'Prevention of vitamin B12 deficiency'.)
Vitamin B12 supplements are available over the counter in tablets and liquids, as well as nasal and sublingual forms. We avoid the nasal formulation because it is no more effective than the oral form, is expensive and causes rhinorrhea. These supplements are typically labeled as vitamin B12, methylcobalamin, hydroxycobalamin, adenosylcobalamin, or cyanocobalamin (cyanide is introduced during certain manufacturing processes but does not add toxicity). Vitamin B12 is also present in multivitamins and B complex vitamins. All of these forms of the vitamin are effective in providing vitamin B12. However, we do not use "long-acting" vitamin B12 formulations to treat vitamin B12 deficiency or prevent it in high-risk people due to concerns about decreased bioavailability.
●Folate – Folate (also called vitamin B9 or pteroylglutamic acid) is present in many plant and animal products, especially dark green leafy vegetables and liver [6,7]. Naturally occurring folates include a number of polyglutamated compounds. These are mostly in the reduced form, such as 5-methyltetrahydrofolate (5-methyl-THF) or f-formyltetrahydrofolate (also called folinic acid, which is the active drug in leucovorin) . Folic acid is the term used to refer to the chemically synthesized form of the vitamin, which is used in dietary supplements and fortified foods; folic acid is an oxidized monoglutamate that is more chemically stable than food-derived folates.
The RDI of folate is expressed in dietary folate equivalents because folic acid is approximately twofold more bioavailable than naturally occurring folates from foods . As described in the Folate Dietary Fact Sheet from the NIH, the recommended daily intake of folate ranges from 65 mcg of dietary folate equivalents in infants to 400 mcg of dietary folate equivalents in adults, with higher requirements during pregnancy and lactation (600 and 500 mcg, respectively) . Since the late 1990s or early 2000s, many countries have instituted supplementation of cereals, flours, and grains, primarily aimed at reducing the risk of neural tube defects during embryogenesis (see "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Folate deficiency'); this includes the United States, Canada, Australia, the United Kingdom, and others listed under the Food Fortification Initiative [10,11].
●Vitamin B12 in foods is protein-bound, and this is dissociated in the acid milieu of the stomach with the help of pepsin.
●Additional vitamin B12-binding proteins known as R-binders or haptocorrins are secreted in the saliva and bind to the vitamin B12 in the stomach.
●Gastric parietal cells produce intrinsic factor. Pancreatic proteases secreted into the higher pH duodenum cleave off the R-binders, allowing the vitamin B12 to bind intrinsic factor.
●The vitamin B12-intrinsic factor complex is taken up by mucosal receptors in the ileum. The exact nature of the receptor is under investigation; it is thought to be composed of the proteins cubilin and amnionless and was named "cubam" to reflect these components [13-17].
●A small amount of ingested vitamin B12 (<1 percent) can be absorbed by passive diffusion . This is the basis for the use of high-dose oral vitamin B12 in PA. (See "Treatment of vitamin B12 and folate deficiencies", section on 'Prevention of vitamin B12 deficiency'.)
●Vitamin B12 is exported into the bloodstream by an ATP-binding cassette protein . The vitamin B12 is bound to a family of transcobalamins sometimes referred to as cobalophilins.
●Vitamin B12 bound to transcobalamin is taken up by other cells throughout the body by receptor-mediated endocytosis.
●Intracellular vitamin B12 is metabolized into adenosylcobalamin or methylcobalamin. The functions of these proteins are described below. (See 'Physiologic roles' below.)
Total body stores of vitamin B12 are in the range of 2 to 5 mg, with approximately half of this stored in the liver. If vitamin B12 intake or absorption ceases, deficiency typically does not develop for at least one to two years, sometimes longer.
Folate absorption and body stores — Folate polyglutamates are cleaved to monoglutamates and absorbed in the lumen of the jejunum. Absorption is predominately carrier-mediated, but passive absorption also occurs [8,20]. Carrier systems include the reduced folate carrier folate receptors and the proton-coupled folate transporter. Absorption is optimal at slightly acidic pH (pH 5.5 to 6.0).
Folate must be reduced to be effective in its biological role in one-carbon transfer. It is reduced to dihydrofolate and then to tetrahydrofolate (THF) by a series of enzymatic steps. THF is subsequently converted to 5,10-methylene THF, which is converted to L-5-methyl-THF by the enzyme methylenetetrahydrofolate reductase.
The predominant form of folate in plasma is L-5-methyl-THF. This is rapidly cleared by hepatocytes and other cells. Surgical biliary drainage results in a reduction in serum folate within six hours, whereas dietary restriction does not produce a comparable decrease for three weeks . This observation indicates that there is a large enterohepatic circulation of folate.
Folate enters cells by binding to a folate receptor. Megalin is a receptor related to the low-density lipoprotein receptor that can take up various proteins, including folates . Once inside the cell, folate is again polyglutamated to a biologically active form that cannot diffuse back out of the cell . Polyglutamated tetrahydrofolate acts as a one-carbon donor for biologic processes, including synthesis of the purines and pyrimidines used in DNA synthesis. (See 'DNA synthesis, RNA synthesis, DNA methylation' below.)
Total body folate stores are estimated to be approximately 500 to 20,000 mcg (0.5 to 20 mg). If folate intake ceases, deficiency may develop within weeks to months, or more rapidly if demands for folate are increased.
DNA synthesis, RNA synthesis, DNA methylation — Vitamin B12 and folate both play a critical role in DNA and RNA synthesis. Deficiency of either vitamin can therefore impair DNA synthesis, which in turn can cause a cell to arrest in the DNA synthesis (S) phase of the cell cycle, make DNA replication errors, and/or undergo apoptotic death .
Biochemical pathways involving vitamin B12 and folate are illustrated in the figure (figure 2). The principal role of folate in DNA synthesis is to supply methyl groups that are added to other molecules (ie, to act as a one-carbon donor). The principal role of vitamin B12 is to act as a cofactor in the reaction that recycles 5-methyl-tetrahydrofolate back to tetrahydrofolate (THF), which can then be converted to forms that can act as one-carbon donors. Generation of THF is coupled to the conversion of homocysteine to methionine. THF is then converted to the carbon-donating forms of folate, 10-formyl-THF and methylene-THF (also called 5,10-CH2-THF or 5,10-methyleneTHF) [7,12,20,22-25]. Lack of vitamin B12 may cause folate to become trapped in the 5-methyl-THF form (the methyl-THF trap hypothesis) . Additionally, lack of vitamin B12 may result in deficiency of methionine, which is used to make S-adenosylmethionine (SAM), also used as a one-carbon donor (the formate starvation hypothesis) .
One-carbon metabolism is used in several reactions needed to make the building blocks of DNA (figure 3).
●Purines – 10-formylTHF donates two methyl groups for purine synthesis (incorporated into the purine ring).
●Pyrimidines – 5,10-methyleneTHF donates a methyl group to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Deoxyuridine triphosphate (dUTP) may become accidentally incorporated into DNA instead of deoxythymidine triphosphate (dTTP), and normal excision repair processes may be unable to correct the mistake due to lack of available dTTP.
Repetitive cycles of defective DNA repair can result in DNA strand breaks and fragmentation. The S-phase delay in the setting of normal cytoplasmic maturation is referred to as nuclear-cytoplasmic dyssynchrony, and this forms the basis for megaloblastic changes in the bone marrow. The apoptotic cell death forms the basis for ineffective erythropoiesis. (See 'Hematopoiesis' below.)
The methyl groups generated during the conversion of SAM to S-adenosylhomocysteine (SAH) are also used in other processes, including DNA methylation, an epigenetic modification in which methyl groups are added to DNA or DNA-binding proteins, which can lead to increased or decreased gene expression (see "Principles of epigenetics"), and methylation of lipids and myelin basic protein, which may play a role in neuronal function [7,20,22,25]. (See 'Neuronal function' below.)
Hematopoiesis — Hematopoietic precursor cells are among the most rapidly dividing cells in the body and hence are one of the cell types most sensitive to abnormal DNA synthesis caused by vitamin B12 and folate deficiencies. (See 'DNA synthesis, RNA synthesis, DNA methylation' above.)
There are two major effects of these deficiencies on hematopoiesis [20,24,26]:
●Megaloblastic changes – Megaloblastic changes are caused by slowing of the nuclear division cycle relative to the cytoplasmic maturation cycle (ie, nuclear-cytoplasmic dyssynchrony). Various megaloblastic changes may be seen in any of the nucleated precursor cells in the bone marrow, including immature or morphologically abnormal nuclei relative to the cytoplasmic maturity, giant metamyelocytes, and increased mitotic figures (picture 1 and picture 2). These changes may cause isolated anemia and/or other cytopenias, which are usually mild. Macrocytic red blood cells (or macro-ovalocytic red blood cells) (picture 3) and hypersegmented neutrophils (picture 4) are the classic findings on the peripheral blood smear. Temporally, hypersegmented neutrophils often precede macrocytosis, and macrocytosis often precedes anemia. The changes in cellular morphology and red blood cell indices cannot be used to determine which vitamin is deficient as they are identical in both deficiencies.
●Ineffective erythropoiesis – Ineffective erythropoiesis (also called intramedullary hemolysis) occurs when there is premature death (eg, phagocytosis or apoptosis) of the developing erythropoietic precursor cells in the bone marrow [27-29]. There may be hypercellularity of the bone marrow and laboratory findings of hemolysis, including elevated serum iron, indirect bilirubin, and lactate dehydrogenase (LDH), and low haptoglobin. The reticulocyte count is typically low.
Neuronal function — Vitamin B12 deficiency is known to adversely affect neuronal function, but the exact mechanisms remain elusive.
Reduced methylation of neuronal lipids and neuronal proteins, such as myelin basic protein, have been hypothesized to play a role in some of the neurologic deficits. Myelin basic protein makes up approximately one-third of myelin, and demyelination in the setting of vitamin B12 deficiency may explain many of the neurologic findings . (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Neuropsychiatric changes'.)
Neuronal defects are less likely to be attributed to folate deficiency, but the association has been reported . The mechanism is not well understood but may involve methylation reactions that affect neuronal function. Epidemiologic studies suggest that maternal folate status may affect the risk of developing autism spectrum disorders, but there are multiple confounding factors and difficulties in conducting and interpreting these types of studies .
Elevated levels of vitamin B12 or folate — Vitamin B12 and folate are both water-soluble vitamins. Overdose is not a major consideration since excess of either is excreted in the urine. (See "Overview of water-soluble vitamins".)
Elevated serum vitamin B12 levels may also simply reflect recent ingestion or injection of supplemental vitamin B12. Elevated serum vitamin B12 levels have sometimes been observed in individuals who are not receiving supplementation; however, we do not advocate testing vitamin B12 levels as a way to evaluate conditions other than vitamin B12 deficiency. The following observational studies have reported associations of increased vitamin B12 levels with other conditions:
●In a cohort of healthy Danish individuals who were not taking supplemental vitamin B12, vitamin B12 levels above the upper reference limit were found in 19,665 of 333,217 (6 percent) . At a median follow-up of 3.5 years, there was a correlation between higher vitamin B12 levels and increased risk of cancer, but the risks were low overall (eg, risk at one year was 2.3 percent in controls versus 6.6 percent in those with the highest plasma vitamin B12 levels) and the effect did not persist with longer follow-up (4.4 percent in both groups). Thus, the correlation has unclear clinical importance.
●In a retrospective review of hospitalized patients in France, elevated vitamin B12 levels were found in 447 of 3702 (12 percent) . Many of the patients had one or more systemic conditions such as liver disease, renal failure, an inflammatory condition (eg, rheumatoid arthritis, systemic lupus erythematosus), a hematologic malignancy (eg, acute leukemia, multiple myeloma, or other hematopoietic disorder [eg, myeloproliferative neoplasm, myelodysplastic syndrome, hypereosinophilic syndrome, transient neutrophilia]); these conditions tended to be more prevalent in individuals with higher vitamin B12 levels; the associations were strongest for liver disease and liver cancer.
The mechanisms that might link these conditions with elevated serum vitamin B12 levels are incompletely understood and may be related to release from damaged cells into the circulation (liver disease), reduced clearance (renal failure, liver disease), increased serum levels of transcobalamin II or other transcobalamins, or increased haptocorrin [32-37]. There is no evidence that elevated vitamin B12 levels play any role in the pathogenesis of these conditions and, and the finding is likely to simply be a marker of hepatic dysfunction or other systemic process.
If an elevated vitamin B12 level is detected in an individual who has not recently received a vitamin B12 injection or taken a vitamin B12 supplement, it may be appropriate to review the medical history, examination, and laboratory testing to determine if one of these systemic conditions is present . We obtain a complete blood count (CBC) with differential, complete metabolic panel, and pursue further testing if abnormalities are found.
Investigational use of serum vitamin B12 levels and vitamin B12 binding capacity as a disease biomarker is discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Initial studies' and "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Abnormal laboratory tests' and "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma", section on 'Tumor markers'.)
Increased folate levels generally are regarded as not toxic for healthy individuals.
However, high-dose folic acid supplementation may be associated with irreversible neurologic injury when administered to individuals with undiagnosed pernicious anemia, as discussed separately. (See "Treatment of vitamin B12 and folate deficiencies".)
In addition, folate supplementation may affect seizure control or possibly interfere with intestinal zinc absorption . Other possible adverse effects of increased folate acid intake are discussed separately. (See "Vitamin intake and disease prevention", section on 'Folic acid'.)
CAUSES OF VITAMIN B12 DEFICIENCY — There are a number of potential causes of vitamin B12 deficiency, reflecting the relatively complex absorption process described above and numerous potential sources of interference with this process (table 1) (see 'Vitamin B12 absorption and body stores' above). The most common of these are pernicious anemia (PA), an autoimmune condition, and nonimmune disorders of the stomach or small intestine that interfere with vitamin B12 absorption (eg, bariatric or intestinal surgery).
Older individuals may have a combination of conditions that interfere with absorption of vitamin B12 from food, including gastric atrophy, achlorhydria due to proton pump inhibitor, intestinal bacterial overgrowth due to antibiotics, and/or excess alcohol. These individuals can adequately absorb crystalline vitamin B12 from supplements; thus, this condition is referred to as food cobalamin malabsorption. A similar phenomenon was reported in individuals infected with human immunodeficiency virus (HIV). (See 'Food cobalamin malabsorption' below.)
Pernicious anemia — PA is a common cause of vitamin B12 deficiency. In a prospective series that tested vitamin B12 levels and intrinsic factor antibodies in 729 ambulatory individuals ages 60 years or older, 17 (2.3 percent) had evidence of PA . PA was more common in women than men (2.7 versus 1.4 percent) and was equally likely in Black and White women.
PA is an autoimmune condition that prevents formation of the vitamin B12-intrinsic factor complex, which in turn dramatically decreases vitamin B12 absorption .
Autoantibodies play a role in the pathogenesis of PA and are also used diagnostically. Commonly seen autoantibodies in individuals with PA may be directed against intrinsic factor or against gastric parietal cell antigens, but only the antibodies to intrinsic factor are important in the pathogenesis [41,42]. Some investigators have proposed a role for CD4 T cells in gastric cell destruction [43,44]. A specific clone of T cells has not been identified, but in principle, such a clone could explain the clinical findings in PA, especially in individuals in whom anti-intrinsic factor autoantibodies are not present.
Neither antibody has ideal performance characteristics for diagnosis:
●Anti-intrinsic factor – Anti-intrinsic factor antibodies are relatively insensitive. They are reported to be seen in approximately 50 to 70 percent of individuals with PA. In a 1992 series of 324 patients with documented PA who had testing for anti-intrinsic factor antibodies, 228 (70 percent) had a positive result . In contrast to previous studies suggesting that PA was more likely in older White individuals, in this study, anti-intrinsic factor antibodies were more common in Black people than in White people (84 and 55 percent, respectively) and slightly more common in women than men (73 and 66 percent). Studies from Korea and China have reported prevalences of 78 and 73 percent [46,47].
●Antiparietal cell – Antiparietal cell antibodies, most of which react with the acid-producing H+ K+ ATPase on parietal cells, are relatively nonspecific. They are reported to be seen in approximately 85 to 90 percent of individuals with PA, but they are also seen in other autoimmune disorders and in healthy individuals without an autoimmune disease . The latter observation was illustrated in a series in which nearly 500 serum samples from a healthy population in Australia were tested for antiparietal cell antibodies; of these, approximately 5 percent were positive, with age-associated increases . Of interest, it has been proposed that antibodies against Helicobacter pylori are able to cross-react with the parietal cell H+ K+ ATPase, suggesting that molecular mimicry may play a role in the development of vitamin B12 deficiency in genetically susceptible individuals who become infected with H. pylori . (See 'H. pylori infection' below.)
Because antibody testing does not have ideal diagnostic accuracy, diagnosis of PA typically requires a combination of laboratory tests, including vitamin B12 levels, metabolites, and/or antibody testing. When we perform antibody testing, we measure antibodies to intrinsic factor but not to parietal cells, as discussed separately. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Diagnostic evaluation'.)
PA is often associated with additional autoimmune conditions and/or additional autoantibodies. As examples:
●Polyglandular autoimmune syndrome type 2 (PAS-2), a generalized autoimmune disorder characterized by autoimmune thyroid disease, adrenal insufficiency, type 1 diabetes mellitus, and/or autoimmune nonendocrine symptoms such as vitiligo. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 2 (polygenic)'.)
●Chronic atrophic gastritis due to the antiparietal cell antibodies [40,50]. (See "Metaplastic (chronic) atrophic gastritis", section on 'Autoimmune metaplastic atrophic gastritis'.)
PA is also associated with an increased risk of gastrointestinal cancer. Achlorhydria can lead to compensatory hypergastrinemia and cellular metaplasia, as well as increased microbial colonization with production of genotoxic byproducts (see "Risk factors for gastric cancer"). This association informs the recommendation to perform an initial endoscopy and to have a lower threshold for evaluating gastrointestinal symptoms in individuals with PA. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Determining the underlying cause of vitamin B12 deficiency'.)
Inadequate dietary intake — As noted above, vitamin B12 is present in animal-based foods (see 'Dietary sources and RDI' above). Vegans, strict vegetarians, and some pregnant or lactating women who limit animal protein can become vitamin B12-deficient [51,52]. Many of these individuals are aware of the need to take supplements. It is prudent to review the recommended dietary intake and available forms of supplemental vitamin B12 with the patient to ensure that intake is adequate. (See "Treatment of vitamin B12 and folate deficiencies", section on 'Prevention of vitamin B12 deficiency'.)
Food cobalamin malabsorption — Food cobalamin malabsorption is a term used to describe vitamin B12 deficiency despite normal dietary levels of vitamin B12 in food . The primary problem is an inability to release vitamin B12 from dietary proteins. Thus, these individuals can absorb vitamin B12 supplements in which the vitamin is not protein-bound, but they are less able to absorb dietary vitamin B12 bound to food proteins due to conditions that interfere with dissociation of the vitamin from food proteins. They often have one or more predisposing factors, such as atrophic gastritis; gastric surgery; chronic H. pylori infection; achlorhydria from chronic use of antacids, H2 receptor blockers, or proton pump inhibitors; chronic excess alcohol use; pancreatic insufficiency; or antibiotic use with intestinal bacterial overgrowth.
The phenomenon of food cobalamin malabsorption is especially common in older individuals [12,53-55]. Mild and/or subclinical vitamin B12 deficiency has been documented at relatively high frequency in older adults, with various observational studies describing a prevalence of approximately 5 to 20 percent depending on the population studied and the laboratory criteria used to define deficiency [56-60].
Many individuals with food cobalamin malabsorption are not anemic and do not have other features of megaloblastic anemia, such as macrocytosis or hypersegmented neutrophils, sometimes referred to as subclinical deficiency. However, it may be prudent to supplement these individuals with vitamin B12 as it may not be clear whether subtle symptoms are attributable to the deficiency until after it is corrected. (See "Treatment of vitamin B12 and folate deficiencies".)
Human immunodeficiency virus (HIV) infection was reported to be associated with a high prevalence of vitamin B12 deficiency (reported to be as high as 10 to 39 percent in the era from the 1980s to the 1990s) [61-64]. This association was thought to be caused by an HIV-associated enteropathy with diarrhea and ileal dysfunction, along with poor nutritional status. This phenomenon has lessened with more effective treatment for HIV infection and is no longer considered a clinically important issue in most patients on effective treatment.
Gastrectomy/bariatric surgery and gastritis — Gastrectomy, bariatric surgery, and gastritis are relatively common causes of vitamin B12 deficiency [26,65-69]. The absence of gastric acid and pepsin in these disorders results in impaired liberation of vitamin B12 from food proteins, and the reduced production of intrinsic factor impairs vitamin B12 absorption. The prevalence of vitamin B12 deficiency following gastric cancer surgery was illustrated in a 2013 retrospective review from China and Korea that included data on 645 patients who underwent total gastrectomy or distal subtotal gastrectomy for gastric cancer and found that by four years after the procedure, all of the patients who underwent total gastrectomy and 16 percent of those who underwent subtotal gastrectomy had developed vitamin B12 deficiency .
●Vitamin B12 supplementation is routine (and imperative) following gastric surgery, as discussed separately. (See "Surgical management of invasive gastric cancer", section on 'Post-treatment surveillance'.)
●Vitamin B12 supplementation, as well as supplementation with folic acid and other nutrients, is presented separately. (See "Bariatric surgery: Postoperative nutritional management".)
H. pylori infection — The role of H. pylori infection in causing vitamin B12 deficiency is less well established, although there is support for a proposed mechanism in which the bacteria elicit production of antibodies that cross-react with the gastric parietal H+ K+ ATPase, as discussed above. (See 'Pernicious anemia' above.)
A 2000 prospective cohort study from Turkey involving 138 patients with vitamin B12 deficiency and anemia who underwent upper endoscopy and histologic examination found that 77 (56 percent) had evidence of H. pylori . In the 31 individuals for whom H. pylori eradication therapy was effective, all (100 percent) had improvement of their hematocrit, mean corpuscular volume (MCV), and vitamin B12 levels by four weeks and normalization of these parameters by three to six months without vitamin B12 administration. In contrast, there was no improvement in these parameters in any of the individuals for whom H. pylori eradication was not effective; these individuals all required vitamin B12 administration. An editorialist postulated that the response may have been due to H. pylori eradication or to eradication of bacteria in the small intestine that interfered with uptake of the vitamin B12-IF complex (ie, the response may have been due to a mechanism unrelated to H. pylori) .
Medications/drugs (vitamin B12)
Proton pump inhibitors/H2 receptor blockers/antacids — Medications that reduce gastric acid may decrease vitamin B12 absorption since gastric acid plays a role in dissociation of vitamin B12 from food proteins, which allows it to bind IF (see 'Vitamin B12 absorption and body stores' above). Long-term use more likely to cause clinically significant vitamin B12 deficiency. This effect has been illustrated in several studies:
●In one trial, healthy volunteers underwent a Schilling test to measure vitamin B12 absorption before and after two weeks of daily therapy with the proton pump inhibitor omeprazole . Vitamin B12 absorption decreased from 3.2 to 0.9 percent in those receiving omeprazole 20 mg daily and from 3.4 to 0.4 percent in those receiving 40 mg daily.
●In a case-control study of adults age 65 years or older, chronic use (>1 year) of a proton pump inhibitor or H2 receptor antagonist was associated with an increased risk of vitamin B12 deficiency (odds ratio [OR]: 4.5; 95% CI 1.5-13.3) .
●In a larger case-control study of adults living in the community, an increased risk of vitamin B12 deficiency was observed with chronic use of a proton pump inhibitor or an H2 receptor antagonist (ORs, 1.7 and 1.3, respectively) .
Periodic testing of vitamin B12 levels is prudent in individuals receiving long-term gastric acid-suppressing medications. Unexplained macrocytosis and/or macrocytic anemia in these individuals should prompt testing for vitamin B12 deficiency. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)
Metformin — Reduced absorption of vitamin B12 is a known adverse effect of long-term use of metformin (and other biguanides), affecting a relatively large proportion of patients (as high as 30 percent in some studies) [76,77]. The role of long-term metformin use in causing vitamin B12 deficiency has been confirmed in analyses of trials that have randomly assigned patients with diabetes to receive metformin or other drugs, as well as in case control studies in which the risk of vitamin B12 deficiency has been shown to correlate with greater dose and longer duration of metformin use. Low serum vitamin B12 levels can be seen as early as three to four months after starting metformin, although symptomatic deficiency is more likely to present after 5 to 10 years of metformin therapy .
The mechanism of reduced vitamin B12 absorption with metformin use is related to altered calcium homeostasis. Intestinal uptake of the vitamin B12-intrinsic factor complex requires calcium, and calcium supplementation reverses the metformin effect on vitamin B12 absorption . The mechanism involves decreased vitamin B12 absorption in the ileum, thought to be caused by effects of metformin on calcium-dependent membrane action. It has been suggested that administration of calcium is able to reverse this effect . The associated neuropathy may be particularly concerning because individuals with diabetes are already at increased risk of peripheral neuropathy due to diabetic vascular disease.
The approach to monitoring for and preventing this complication is discussed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Vitamin B12 deficiency'.)
Nitrous oxide — Nitrous oxide (N2O; laughing gas) may be used as an inhalant anesthetic or as a recreational drug (eg, "whippets" or "hippy crack") [80,81]. N2O inactivates vitamin B12 and impairs its ability to act as a cofactor for methionine synthase, in turn leading to reduced one carbon metabolism and effects on DNA synthesis and methylation reactions. (See 'Physiologic roles' above.)
Use of N2O (for any purpose) may precipitate rapid onset of findings related to vitamin B12 deficiency, such as anemia, neurologic, or psychiatric symptoms, while in some causes spuriously raising serum vitamin B12 levels . This is most often an issue in individuals with preexisting vitamin B12 deficiency or borderline vitamin B12 status.
This phenomenon and our approach to preventing adverse sequelae are discussed separately. (See "Inhalant misuse in children and adolescents", section on 'Nitrous oxide' and "Treatment of vitamin B12 and folate deficiencies", section on 'Prevention of vitamin B12 deficiency'.)
Disorders affecting absorption in the small intestine — Pancreatic insufficiency can prevent normal binding of vitamin B12 to IF, and a number of disorders of the small bowel can reduce the absorptive surface for the vitamin B12-IF complex; organisms such as bacteria or fish tapeworms can compete for vitamin B12 uptake.
Pancreatic insufficiency — Pancreatic enzymes are necessary to dissociate vitamin B12 from salivary and food proteins and allow it to bind to IF. This process may be impaired in individuals with pancreatic insufficiency or chronic pancreatic disease (affecting approximately 6 to 30 percent depending on the series) [83,84]. (See "Exocrine pancreatic insufficiency".)
Small intestinal inflammation or surgery — A number of disorders of the small intestine have the potential to interfere with vitamin B12 absorption and may lead to clinically important vitamin B12 deficiency, especially if intake is low and/or if stores are borderline.
These disorders include small intestinal bacterial overgrowth, inflammatory bowel disease (IBD), radiation enteritis, celiac disease (especially if the patient is nonadherent to a gluten-free diet), lymphoma, tuberculous ileitis, amyloidosis, or ileal resection for any reason (eg, IBD, bowel ischemia, urinary diversion). Clinical manifestations and diagnosis of these disorders are discussed in more detail in separate topic reviews.
Vitamin B12 levels are monitored in these individuals periodically (eg, every six months) but data are limited to guide the specific testing interval.
Fish tapeworm — Infestation with the fish tapeworm Dibothriocephalus latus causes vitamin B12 deficiency because the worm has an affinity for vitamin B12 and competes for its absorption in the ileum. Infection can result from ingestion of raw freshwater fish (several types), either in endemic areas or when affected fish are imported. Diagnosis is typically done by stool analysis. (See "Tapeworm infections", section on 'Diphyllobothriasis'.)
Genetic disorders (vitamin B12) — In rare cases, vitamin B12 deficiency is caused by mutations that affect one of the factors involved in its absorption or metabolism [85,86]. (See 'Vitamin B12 absorption and body stores' above.)
Genetic causes of vitamin B12 deficiency are usually transmitted in an autosomal recessive pattern. Examples include the following:
●Imerslund-Gräsbeck syndrome (also called juvenile megaloblastic anemia or hereditary megaloblastic anemia), which is caused by biallelic mutations affecting one of the components of the ileal receptor for the vitamin B12-IF complex (cubilin [CUBN] or amnionless [AMN]) [87-89]. (See 'Vitamin B12 absorption and body stores' above.)
Patients with Imerslund-Gräsbeck syndrome caused by CUBN mutations also have varying degrees of proteinuria and abnormal vitamin D metabolism. This is thought to be because cubilin plays an important role in reabsorption of filtered albumin from the renal proximal tubule and in the reabsorption of the complex of 25-hydroxyvitamin D with its binding protein [90,91]. (See "Overview of vitamin D", section on 'Metabolism'.)
●Juvenile cobalamin deficiency, which is caused by biallelic mutations affecting the gene for IF; a founder mutation in individuals of African ancestry has been posited [92,93].
●Polymorphisms in genes encoding transcobalamins, which transport vitamin B12 in the bloodstream [94-96].
●Polymorphisms in genes involved in intracellular vitamin B12 metabolism [97-100].
It is worth noting that genetic polymorphisms affecting the intracellular metabolism or trafficking of vitamin B12 can be associated with a normal serum vitamin B12 level and normal mean corpuscular volume (MCV) on the complete blood count . Affected individuals may have organic acidemia and/or a thrombotic microangiopathy picture with schistocytes on the blood smear. (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia' and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Regulators of vitamin B12 metabolism' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)
CAUSES OF FOLATE DEFICIENCY — Folate deficiency has become less common in the United States and many other resource-rich countries following the implementation of routine folic acid supplementation of foods. However, populations with poor access to nutritious foods or reduced dietary intake are still at risk.
Inadequate dietary intake — It is virtually impossible to develop folate deficiency if consuming a varied diet while residing in a country with routine folic acid fortification of foods. This is because so many cereals and grains are fortified with folic acid, and there are many other dietary sources. (See 'Dietary sources and RDI' above.)
However, individuals who are unable to consume a varied, nutrient-rich diet may develop folate deficiency. Examples include those with restrictive diets, chronic alcohol use with a limited diet, severe anorexia, or reduced oral intake in the setting of a systemic illness (table 2). Cooking foods destroys most naturally occurring folates, so individuals who consume exclusively cooked foods may also be at risk. Less common examples include exclusive feeding of infants with goat's milk, which has significantly less folate than cow's milk, or rare genetic defects. (See "Dietary recommendations for toddlers, preschool, and school-age children", section on 'Dairy products'.)
As noted above, body stores of folate are relatively small, and individuals who do not take in folate can develop clinical findings of deficiency within a few months. (See 'Folate absorption and body stores' above.)
Increased requirements — Certain settings associated with rapid cell proliferation may confer an increased requirement for folate. These include :
●Pregnancy and lactation
●Chronic hemolytic anemias
●Exfoliative skin diseases
These conditions are associated with increased cell proliferation, which results in an increased need for folates for DNA synthesis. (See 'DNA synthesis, RNA synthesis, DNA methylation' above.)
Individuals with chronic hemolytic anemias or exfoliative skin diseases, such as severe eczema, are often given daily folic acid to prevent deficiency. A typical dose is 1 mg daily. Folic acid supplementation during the preconception period, pregnancy, and lactation is presented separately. (See "Preconception and prenatal folic acid supplementation".)
Intestinal malabsorption — Malabsorption of folates (or folic acid supplements) can occur if the intestinal absorptive surface has been removed or is dysfunctional. This can result from surgery (eg, gastric bypass) or inflammatory disorders such as celiac disease and tropical sprue .
Medications (folate) — Several medications can interfere with folate metabolism and may cause folate deficiency and/or megaloblastic anemia due to effects on DNA synthesis. (See 'DNA synthesis, RNA synthesis, DNA methylation' above.)
●Methotrexate – Methotrexate inhibits dihydrofolate reductase (DHFR)
Inhibition of DHFR blocks reduction of DHF to tetrahydrofolate (THF), which is needed for conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (figure 3). In addition to inhibiting DHFR, polyglutamated methotrexate also inhibits thymidylate synthase (TS), thus affecting both purine and pyrimidine syntheses, as well as interfering with epigenetic regulation and the cellular responses to oxidative stress . These pathways are discussed above. (See 'DNA synthesis, RNA synthesis, DNA methylation' above.)
Supplementation with folic acid (or folinic acid [leucovorin] in some individuals receiving methotrexate) is discussed in separate topic reviews. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period" and "Overview of the management of epilepsy in adults", section on 'Specific adverse reactions' and "Major side effects of low-dose methotrexate", section on 'Prevention of side effects with folate' and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Leucovorin administration'.)
Genetic disorders (folate) — Genetic disorders that interfere with folate absorption (eg, hereditary folate malabsorption) or metabolism are very rare. These autosomal recessive disorders may involve mutations affecting the proton-coupled folate transporter (PCFT) [103-107]. Affected individuals may have neurologic deterioration (ataxia, seizures, cognitive deficits) and immune defects. Other genetic disorders affect enzymes involved in folate metabolism, such as methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency .
CAUSES OF COMBINED DEFICIENCY — Certain malabsorptive conditions can be associated with combined deficiency of vitamin B12 and folate or combined deficiency of one of these vitamins and iron. Examples include bariatric surgery, malabsorptive states, and severely limited diets.
In a 2014 study in which vitamin B12 and folate levels were screened in 1170 women in Northwest China's Shaanxi province (approximately two-thirds of whom were living in a rural setting), 36 percent had isolated vitamin B12 deficiency (defined as level <200 pg/mL), 5 percent had isolated folate deficiency (<3 ng/mL), and 10 percent had combined deficiency of both vitamins . Almost 60 percent had marginal folate status. Dietary intake of animal protein and fresh fruits and vegetables was low, suggesting that dietary deficiencies may persist in certain regions and populations.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Pernicious anemia (The Basics)" and "Patient education: Epilepsy and pregnancy (The Basics)" and "Patient education: Nutrition before and during pregnancy (The Basics)" and "Patient education: Vitamin supplements (The Basics)")
●Dietary sources – In most cases, a varied diet will contain adequate amounts of vitamin B12 and folate. Vitamin B12 (also called cobalamin) is present in many animal products, including meats, dairy products, and eggs. Various forms of folate (also called vitamin B9) are present in many plant- and animal-based foods; breads and cereals in many parts of the world are fortified with folic acid. (See 'Dietary sources and RDI' above.)
●Physiologic roles – Vitamin B12 and folate both play a critical role in methylation reactions and one-carbon transfers, which are required for DNA and RNA synthesis, as well as gene methylation and proteins important for neuronal myelination (figure 2). (See 'Physiologic roles' above.)
●Vitamin B12 absorption – Vitamin B12 is a chemically complex molecule; a number of mechanisms ensure its stability and absorption, bound to intrinsic factor (IF) (figure 1). Common causes of vitamin B12 deficiency include pernicious anemia (PA; impaired absorption due to autoantibodies to IF) and food cobalamin malabsorption (impaired absorption due to reduced gastric acidity, medications including metformin, pancreatic dysfunction, and/or disorders affecting the small intestine). Reduced dietary intake (particularly in vegans) and genetic disorders account for a smaller proportion of cases. (See 'Vitamin B12 absorption and body stores' above and 'Causes of vitamin B12 deficiency' above.)
●Folate absorption – Folate deficiency is rare in individuals consuming a balanced, healthy diet but may be seen in settings such as poor nutrition or restricted diets, intestinal malabsorption syndromes, certain medications, and (rarely) genetic disorders. Individuals with chronic hemolytic anemias and exfoliative skin disorders may have increased folate requirements. (See 'Folate absorption and body stores' above and 'Causes of folate deficiency' above.)
●Combined deficiencies – Certain conditions may be associated with combined deficiency of both vitamin B12 and folate, such as malabsorptive states and severely limited diets. (See 'Causes of combined deficiency' above.)
●Folate requirements in pregnancy – Folate requirements are also increased in pregnancy and lactation. Folic acid supplementation preconception and during pregnancy is discussed in detail separately. (See "Preconception and prenatal folic acid supplementation".)
●Diagnosis, treatment, and monitoring – Separate topic reviews discuss the diagnosis and treatment of vitamin B12 and folate deficiencies, and the monitoring of vitamin B12 levels in individuals taking metformin. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Treatment of vitamin B12 and folate deficiencies" and "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Vitamin B12 deficiency'.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.
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