A 62-year-old woman is brought to the physician by her son due to progressive forgetfulness over the last year. She has been less active than normal and is having some difficulty walking. The patient has no urinary incontinence. Her past medical history is significant for exertional angina and hypertension. She has recently been depending on her son to manage her medications, which include metoprolol, amlodipine, and aspirin. She does not smoke or consume alcohol. Her father had hypertension and stroke, and her mother had Alzheimer disease. The patient is oriented to person and place, but not time. She has difficulty with 3-word recall. Her gait is slightly unstable and she has problems balancing when she closes her eyes. Examination of the lower extremities show decreased vibratory sensation, spastic paresis, and hyperreflexia bilaterally.
Further evaluation of the patient shows a mild indirect hyperbilirubinemia. Which of the following is the most likely explanation of this finding?

Question

A 62-year-old woman is brought to the physician by her son due to progressive forgetfulness over the last year.  She has been less active than normal and is having some difficulty walking.  The patient has no urinary incontinence.  Her past medical history is significant for exertional angina and hypertension.  She has recently been depending on her son to manage her medications, which include metoprolol, amlodipine, and aspirin.  She does not smoke or consume alcohol.  Her father had hypertension and stroke, and her mother had Alzheimer disease.  The patient is oriented to person and place, but not time.  She has difficulty with 3-word recall.  Her gait is slightly unstable and she has problems balancing when she closes her eyes.  Examination of the lower extremities show decreased vibratory sensation, spastic paresis, and hyperreflexia bilaterally. 
Further evaluation of the patient shows a mild indirect hyperbilirubinemia.  Which of the following is the most likely explanation of this finding?

Quizplus · Accepted Answer

Explanation: Ineffective erythropoiesis is a well-known phenomenon that occurs in patients with vitamin B12 deficiency. The mechanism that leads to this phenomenon involves defective DNA synthesis with megaloblastic transformation of bone marrow and intramedullary hemolysis. Although intense erythroid hyperplasia occurs, the erythroid cells do not mature normally and subsequently die in the bone marrow. Markers of hemolytic anemia (eg, elevated lactate dehydrogenase, low haptoglobin, indirect hyperbilirubinemia) may become evident, but reticulocyte response is typically absent in such patients. (Choice A) Impaired bile excretion can occur with extrahepatic cholestasis (eg, choledocholithiasis, malignant obstruction, biliary stricture) or intrahepatic cholestasis (eg, primary biliary cirrhosis, primary sclerosing cholangitis). However, direct hyperbilirubinemia is expected in these conditions. (Choice B) Impaired hepatic conjugation is observed in patients with Gilbert syndrome, a benign hereditary condition that can result in isolated indirect hyperbilirubinemia. This patient's age and manifestations of vitamin B12 deficiency make the diagnosis unlikely. (Choice D) Intravascular hemolysis may result in indirect hyperbilirubinemia but is typically associated with microangiopathic hemolytic anemia (eg, thrombotic thrombocytopenic purpura), blood transfusions (eg, ABO incompatibility), or paroxysmal nocturnal hemoglobinuria. Reticulocyte count is usually elevated in these conditions. (Choice E) Liver parenchymal damage (eg, viral hepatitis, drug-induced liver injury, ischemic hepatopathy) usually causes direct hyperbilirubinemia. Educational objective: Vitamin B12 deficiency may cause erythroid hyperplasia and ineffective erythropoiesis in the bone marrow, which can result in markers of hemolytic anemia (eg, elevated lactate dehydrogenase, low haptoglobin, indirect hyperbilirubinemia) and an absent reticulocyte response. References: Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. (http://www.ncbi.nlm.nih.gov/pubmed/19094231)

A 62-Year-Old Woman Is Brought to the Physician by Her