Vitamin B₁₂ Deficiency

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

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

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

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

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)