Impaired DNA synthesis secondary to vitamin B12 (cobalamin) or folate deficiency leads to megaloblastic anemia. Vitamin B12 deficiency is caused by intestinal malabsorption, traditionally from pernicious anemia (autoimmune destruction of parietal cells, which produce the intrinsic factor needed for cobalamin absorption), gastrectomy, pancreatic insufficiency, Crohn disease, celiac disease, topical sprue, tapeworms, or low dietary intake (eg, vegetarian or vegan diet). Folate deficiency results from alcoholism, low dietary folate, malabsorption, psoriasis, sulfa drugs, and phenytoin. Drugs that interfere with DNA synthesis, including chemotherapeutic agents (methotrexate, 6-mercaptopurine), may lead to megaloblastic anemia.
History/PE – Megaloblastic Anemia
Subacute combined degeneration of the cord seen in B12 deficiency presents as peripheral neuropathy, vibration and proprioception dysfunction, dementia, and spasticity.
- Presents with fatigue, pallor, glossitis, cheilosis, diarrhea, loss of appetite, and headache.
- B12 deficiency affects the nervous system. Neurologic and neuropsychiatric signs and symptoms can be present (eg, irritability, depression, psychosis, dementia, paraesthesia, and peripheral neuropathy).
- Patients may develop a demyelinating disorder and present with subacute combined degeneration of the cord. There is a combination of symmetrical posterior (dorsal) column loss, causing sensory and lower motor neuron (LMN) signs, and symmetrical corticospinal tract loss, causing motor and upper motor neuron (UMN) signs.
B12 deficiency can be caused by infection by a tapeworm, Diphyllobothrium latum. Folate deficiency can occur secondary to chronic phenytoin use, causing malabsorption.
Diagnosis – Megaloblastic Anemia
- Best initial test: CBC with smear showing RBCs with an elevated MCV and hypersegmented (six or more lobes) neutrophils (see Figure 1). B12 and folate deficiency are identical hematologically and on blood smear.
- ↓ Hb, ↑ MCV, ↓ B12 and folate levels, ↓ reticulocyte count, pancytopenia if severe, ↑ LDH, ↑ indirect bilirubin levels.
- Serum vitamin levels should be measured and adjunctive tests, including methylmalonic acid (MMA) and homocysteine levels can be assessed if vitamin levels are non-diagnostic and clinical suspicion persists:
- B12 deficiency: ↑ MMA and ↑ homocysteine.
- Folate deficiency: Normal MMA and ↑ homocysteine.
- Bone marrow sample reveals giant neutrophils and hypersegmented mature neutrophils.
- Anti-intrinsic factor and antiparietal cell antibodies in pernicious anemia.
- Schilling test measures the absorption of cobalamin via ingestion of radiolabeled cobalamin with and without intrinsic factor. This test is rarely performed, but its interpretation is tested. The patient is given an unlabeled B12 IM shot to saturate B12 receptors in the liver and an oral challenge of radiolabeled B12. The radiolabeled B12 will pass into the urine if properly absorbed, as the liver’s B12 receptors will be saturated from the IM dose.
- Radiolabeled B12 in urine: Dietary B12 deficiency.
- No radiolabeled B12 in urine: Consider pernicious anemia, bacterial overgrowth, or pancreatic enzyme deficiency; test the hypothesis with the addition of intrinsic factor, antibiotics, or pancreatic enzymes to radiolabeled B12.
Treatment – Megaloblastic Anemia
Correct the underlying cause of the anemia. If B12 deficiency is caused by malabsorption, replenish stores with IM hydroxycobalamin. If the cause is dietary, give oral B12. Folate replacement corrects the hematologic problems of B12, but not the neurologic problems.