Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both. Current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis. Parenteral or highdose oral vitamin B12 is effective therapy. The latest article in our Clinical Practice series, Vitamin B12 Deficiency, comes from Dr. Sally P. Stabler at the University of Colorado School of Medicine.
The recognition and treatment of vitamin B12 deficiency is critical, since it is a reversible cause of bone marrow failure and demyelinating nervous system disease. Vitamin B12 (cobalamin) is synthesized by microorganisms and detected in trace amounts mostly in foods of animal origin. Uptake in the gastrointestinal tract depends on intrinsic factor, which is synthesized by the gastric parietal cells, and on the “cubam receptor” in the distal ileum.
• What is the most frequent cause of vitamin B12 deficiency?
The most frequent cause of severe vitamin B12 deficiency is a loss of intrinsic factor due to autoimmune atrophic gastritis, historically called “pernicious anemia,” even though many patients present with mainly neurologic manifestations.
• What are the clinical characteristics of vitamin B12 deficiency?
The most common neurologic symptoms are symmetric paresthesias or numbness and gait problems. The physical examination may reveal pallor, edema, pigmentary changes in the skin, jaundice, or neurologic defects such as impaired vibration sense, impaired position and cutaneous sensation, ataxia, and weakness. For unclear reasons, the severity of megaloblastic anemia is inversely correlated with the degree of neurologic dysfunction. Less common conditions associated with vitamin B12 deficiency include glossitis, malabsorption, infertility, and thrombosis (including thrombosis at unusual sites such as cerebral venous sinus thrombosis). Thrombosis has been attributed to the marked hyperhomocysteinemia seen in severe cases of vitamin B12 deficiency. Patients occasionally have hyperpigmentation, which clears with treatment.
Morning Report Questions
Q: How is vitamin B12 deficiency diagnosed?
A: The first test performed to confirm the diagnosis of vitamin B12 deficiency is generally measurement of the serum vitamin B12 level. Although an extremely low level (<100 pg per milliliter is usually associated with clinical deficiency, such low levels are infrequently observed. Both false negative and false positive values are common (occurring in up to 50% of tests). The levels of both methylmalonic acid and total homocysteine are markedly elevated in the vast majority (>98%) of patients with clinical B12 deficiency, including those who have only neurologic manifestations of deficiency (i.e., no anemia). An elevated level of methylmalonic acid is reasonably specific for vitamin B12 deficiency, and the level always decreases with vitamin B12 therapy. Modest increases (to 300 to 700 nmol per liter) occur with renal failure. However, nearly all patients with megaloblastic anemia or myelopathy have levels of methylmalonic acid that are higher than 500 nmol per liter, and 86% have levels that are higher than 1000 nmol per liter. The level of serum total homocysteine is less specific, since it is also elevated in folate deficiency, classic homocystinuria, and renal failure.
Q: What are the current recommendations for evaluation and treatment of vitamin B12 deficiency?
A: In the absence of dietary restriction or a known cause of malabsorption, further evaluation is warranted — in particular, testing for pernicious anemia (anti-intrinsic factor antibodies). Parenteral vitamin B12 treatment (8 to 10 1000-microg loading injections, followed by monthly 1000-microg injections) and high-dose oral B12 treatment (1000 to 2000 microg daily) are both effective therapies. In cases of severe malabsorption, injected vitamin B12 is generally preferred. The American Society for Gastrointestinal Endoscopy recommends a single endoscopic evaluation at the diagnosis of pernicious anemia. This is largely to confirm gastritis and rule out gastric carcinoid and other gastric cancers, since patients with pernicious anemia are at increased risk for such cancers.