B12 deficiency anemia is a common cause of macrocytic anemia. Causes of B12 deficiency include inadequate intake (seen with strict vegetarian diets), pernicious anemia, total gastrectomy, pancreatic insufficiency, ileal resection, Crohns disease, celiac sprue, Diphyllobothrium latum infestation, intestinal bacterial overgrowth, alcohol abuse, post gastric bypass surgery, or medication side effect (colchicine, proton-pump inhibitors, metformin). Pernicious anemia is the most common cause. Hypothyroidism may cause decreased intrinsic factor synthesis with a resultant impairment of B12 absorption.
Body stores of B12 are disproportionately large compared to daily requirements and enterohepatic circulation is very efficient; therefore, once malabsorption of B12 begins, it takes years to develop deficient body stores. Dietary B12 is primarily supplied by the ingestion of animal products. In the acidic environment of the stomach, B12 is liberated from its dietary protein bound state and binds to R proteins. Upon entering the second portion of the duodenum, proteases cause degradation of the R protein, and intrinsic factor, which originates from gastric parietal cells, then binds with the B12. The B12-intrinsic factor complex attaches to epithelial cell mucosal receptors in the terminal ileum and absorption occurs. Approximately 70% of ingested B12 is absorbed in the presence of intrinsic factor; whereas, absorption decreases to less than 20% when intrinsic factor is deficient. Serum B12 levels may be falsely decreased in the presence of normal tissues stores in association with pregnancy, folate deficiency and iron deficiency.
Symptoms of B12 deficiency include those caused by the anemia (shortness of breath, fatigue, and weakness) plus paresthesias, loss of deep tendon reflexes, long tract signs, impaired proprioception and vibratory senses, unsteady gait, spastic paraplegia, loss of sphincter control, memory loss, irritability, and even dementia or psychosis. On physical exam, there is often a positive Rhombergs sign along with sensory ataxia and loss of vibration and position sensation. The associated neurologic signs are the result of demyelination and axonal destruction of the posterior and lateral columns of the spinal cord.
Lab abnormalities include a macrocytic anemia with hypersegmented neutrophils and macro ovalocytosis noted on peripheral smear. With severe deficiency, leukopenia and thrombocytopenia may be noted. Serum assays for B12 are low, and indirect hyperbilirubinemia along with an elevated LDH level may result from ineffective erythropoiesis. Low B12 levels are less than 150 and normal levels are above 350; therefore levels between 151 and 349 are indeterminate and require alternate tests to determine if the B12 level is sufficient. With B12 deficiency, both the serum homocysteine and methylmalonyl acid levels will be elevated. Another test that is useful when the diagnosis is in doubt is the serum holotranscobalamin II. Holotranscobalamin II is the protein which carries B12 to the cells. Levels of this protein decline even before serum B12 levels in patients who are B12 deficient. If the diagnosis is still not established, bone marrow examination will reveal large myeloid precursors.
Pernicious anemia is the term given to B12 deficiency anemia when decreased intrinsic factor levels are the underlying pathology. The cause is autoantibodies against either intrinsic factor or the gastric parietal cells. This anemia occurs in persons of all races and is often associated with other autoimmune diseases. Pernicious anemia is diagnosed when there are low serum B12 levels along with serum intrinsic factor antibodies. However, intrinsic factor antibodies are present in only 60% of cases of pernicious anemia; therefore, the absence of these antibodies does not rule out pernicious anemia as the etiology. Gastric biopsy on EGD examination may help establish the diagnosis. When the diagnosis is in doubt, a Schilling test may helpful but is rarely performed in clinical medicine.
The Schilling test employs the use of radiolabeled B12 to determine the etiology of any B12 deficiency anemia. In the first phase, patients are given an oral load of radiolabeled B12 plus an intramuscular injection of B12 to saturate hepatic stores, and then a 24-hour urine is collected to determine how much B12 was absorbed. If the 24-hour urine level of B12 is less than 8% after the first phase, the patients are administered the second phase in which they receive an oral load of radiolabeled B12-intrinsic factor complex. Again, after the oral load, a 24-hour urine is collected to determine how much B12 was absorbed. If the urine level rises greater than 8% in the second phase, pernicious anemia is the underlying etiology. If the second phase urinary B12 level is still less than 8%, malabsorption syndromes, bacterial overgrowth or infestation with Diphyllobothrium latum should be pursued as potential underlying etiologies. Testing for other deficiencies such as iron, folate, or vitamin D may suggest malabsorption. Mild steatorrhea and a markedly elevated folate level in patients with decreased peristalsis or post gastric bypass suggests small bowel bacterial overgrowth. Confirmation would be resolution of the B12 deficiency and steatorrhea after appropriate antibiotics. A stool ova and parasite collection is sufficient to diagnose Diphyllobothrium latum infestation.
Treatment of B12 deficiency is to determine the underlying etiology, and if possible, correct the pathologic state. If the underlying etiology can not be corrected, as in pernicious anemia, then lifelong B12 replacement therapy (1,000 U IM QD x 7 days followed by 1,000 U IM Q month or 1 to 2 mg orally per day) is necessary. Serial measurement of the methylmallonic acid may be used to assess compliance with therapy.