Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-06: Vitamin B12 Deficiency + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Macrocytic anemia Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils) Low serum vitamin B12 level +++ General Considerations ++ All vitamin B12 is absorbed from the diet (foods of animal origin) After ingestion, vitamin B12 binds to intrinsic factor, a protein secreted by gastric parietal cells Vitamin B12-intrinsic factor complex is absorbed in the terminal ileum by cells with specific receptors for the complex; it is then transported through the plasma and stored in the liver Liver stores are of such magnitude that it takes at least 3 years for vitamin B12 deficiency to develop after vitamin B12 absorption ceases Causes of vitamin B12 deficiency Decreased intrinsic factor production: pernicious anemia (most common cause), gastrectomy Dietary deficiency (rare but seen in vegans) Competition for B12 in gut: blind loop syndrome, fish tapeworm (rare) Decreased ileal B12 absorption: surgical resection, Crohn disease Prolonged use of proton pump inhibitors Pancreatic insufficiency Helicobacter pylori infection Transcobalamin II deficiency (rare) Pernicious anemia is associated with atrophic gastritis and other autoimmune diseases, eg, immunoglobulin A (IgA) deficiency, polyglandular endocrine failure syndromes + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Causes a moderate to severe anemia of slow onset such that patients may have few symptoms relative to their degree of anemia Pallor and mild icterus or sallow complexion Glossitis and vague gastrointestinal disturbances (eg, anorexia, diarrhea) Neurologic manifestations Peripheral neuropathy usually occurs first Then, subacute combined degeneration of the spinal cord affecting posterior columns may develop, causing difficulty with position and vibration sensation and balance In advanced cases, dementia and other neuropsychiatric changes may occur Neurologic manifestations occasionally precede hematologic changes; patients with suspicious neurologic symptoms and signs should be evaluated for vitamin B12 deficiency despite normal mean cell volume (MCV) and absence of anemia +++ Differential Diagnosis ++ Folic acid deficiency (other cause of megaloblastic anemia) Myelodysplastic syndrome (other cause of macrocytic anemia with abnormal morphology) Other causes of peripheral neuropathy, ataxia, or dementia + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Normal vitamin B12 level is > 210 pg/mL Serum levels in overt deficiency: < 170 pg/mL Serum levels in symptomatic patients: < 100 pg/mL The diagnosis is best confirmed by an elevated level of serum methylmalonic acid (>1000 nmol/L) or homocysteine (> 16.2 mmol/L) The anemia of vitamin B12 deficiency is typically moderate to severe with the MCV quite elevated (110–140 fL); however, MCV may be normal Peripheral blood smear is megaloblastic, defined as red blood cells that appear as macro-ovalocytes, (although other shape changes are usually present) and neutrophils that are hypersegmented Reticulocyte count is reduced In severe cases, white blood cell count and platelet count are reduced Serum lactate dehydrogenase (LD) is elevated and indirect bilirubin modestly increased +++ Diagnostic Procedures ++ Bone marrow morphology is characteristic Marked erythroid hyperplasia Megaloblastic changes in erythroid series Giant bands and metamyelocytes in myeloid series + Treatment Download Section PDF Listen +++ +++ Medications ++ Intramuscular or subcutaneous injections of 100–1000 mcg of vitamin B12 are adequate for each dose (with the higher dose recommended initially) Replacement is usually given daily for the first week, weekly for the next month, and then monthly for life Oral or sublingual methylcobalamin (1 mg/day) may be used instead of parenteral therapy once initial correction of the deficiency has occurred Oral or sublingual replacement is effective, even in pernicious anemia, since approximately 1% of the dose is absorbed in the intestine via passive diffusion in the absence of active transport For patients with neurologic symptoms caused by vitamin B12 deficiency, long-term parenteral rather than oral vitamin B12 therapy is recommended, though it has not conclusively been proven superior Vitamin B12 replacement must be continued indefinitely and serum vitamin B12 levels must be monitored to assure adequate replacement Simultaneous folic acid replacement (1 mg daily) is advised for the first several months of vitamin B12 replacement Red blood cell transfusions are rarely needed despite the severity of anemia, but when given, diuretics are also recommended to avoid heart failure + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Pernicious anemia is a lifelong disorder; if patients discontinue monthly therapy, the vitamin deficiency will recur Brisk reticulocytosis occurs 5–7 days after therapy, and the hematologic picture normalizes in 2 months Follow serum vitamin B12 level +++ Complications ++ Long-term nervous system complications consist of a complex neurologic syndrome (eg, altered cerebral function, frank dementia) Hypokalemia may complicate the first several days of parenteral vitamin B12 therapy in pernicious anemia, particularly if anemia is severe +++ Prognosis ++ Patients with pernicious anemia respond to parenteral vitamin B12 therapy with immediate improvement in sense of well-being Nervous system manifestations are potentially reversible if they are of relatively short duration (< 6 months) + References Download Section PDF Listen +++ + +Green R. Vitamin B(12) deficiency from the perspective of a practicing hematologist. Blood. 2017 May 11;129(19):2603–11. [PubMed: 28360040] + +Wolffenbuttel BHR et al. The many faces of cobalamin (vitamin B12) deficiency. Mayo Clin Proc Innov Qual Outcomes. 2019 May 27;3(2):200–14. [PubMed: 31193945]