A 65-year-old man comes to the office due to a few weeks of progressive exertional dyspnea and fatigue. He has had no chest pain, fever, or cough. The patient has a history of mild aortic stenosis, gastroesophageal reflux disease, obesity, hypertension, and hypercholesterolemia. Temperature is 36.7 C (98 F), blood pressure is 130/78 mm Hg, pulse is 82/min, and respirations are 16/min. BMI is 28 kg/m². Pulse oximetry shows 96% on room air. Mucosal pallor is present, but there is no jaundice, lymphadenopathy, or jugular venous distension. Cardiopulmonary examination reveals a 2/6 systolic ejection murmur at the second right intercostal area. The abdomen is soft and nontender; there is no palpable hepatosplenomegaly. Peripheral pulses are normal. Laboratory results are as follows: Peripheral blood smear is shown below: Which of the following is most likely responsible for this patient's current condition?

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11ec160b_3afa_a9fa_9249_57a3b0c8f17b_MD0001_00 This patient with exertional dyspnea, fatigue, conjunctival pallor, and a systolic ejection murmur has symptomatic anemia. The presence peripheral blood smear findings of macrocytosis and a hypersegmented neutrophil indicate likely megaloblastic anemia. This condition sometimes arises in older individuals who take antacids for gastroesophageal reflux disease, as gastric acid is required for proper vitamin B₁₂ absorption. Vitamin B₁₂ acts as a cofactor in the recycling of 5-methyl-tetrahydrofolate to tetrahydrofolate (reduced form of folate), which serves as a one-carbon donor in the synthesis of amino acids, purines, and thymidine monophosphate. Therefore, folate or vitamin B₁₂ deficiency reduces available purines and thymidine, which impairs DNA synthesis and causes cell cycle arrest (in S-phase) or apoptotic cell death. Hematopoietic cells are primarily affected due to their high replication rate. In these cells, nuclear division slows relative to cytoplasmic maturation (nuclear-cytoplasmic desynchrony), which results in megaloblastic changes (eg, macrocytosis, hypersegmented neutrophils); in addition, increased apoptosis causes anemia and often mild thrombocytopenia/leukopenia. (Choice B) Iron deficiency anemia is associated with impaired production of heme; however, peripheral blood smear would show microcytosis (not macrocytosis), and no hypersegmented neutrophils would be seen. (Choice C) Chronic kidney disease can reduce production of erythropoietin in the peritubular cells of the kidney, which causes normocytic anemia due to reduced erythropoiesis. However, leukopenia and thrombocytopenia are not typically seen, and peripheral blood smear would not show megaloblastic changes. (Choice D) Aplastic anemia is associated with destruction of hematopoietic stem cells and replacement of the bone marrow with fat cells. Although patients usually have pancytopenia, peripheral blood smear would not show macrocytosis or hypersegmented neutrophils. (Choice E) Primary myelofibrosis is a chronic myeloproliferative disorder characterized by fibrosis of the bone marrow. Anemia is common but patients usually have dacrocytes (tear-drop cells) and nucleated red blood cells on peripheral blood smear, not macrocytosis and hypersegmented neutrophils. (Choice F) Aortic stenosis can sometimes cause traumatic hemolysis due to red blood cell shearing. However, peripheral smear generally shows schistocytes, and thrombocytopenia/leukopenia would be unusual. Educational objective: Vitamin B₁₂ is an essential cofactor in the recycling of 5-methyl-tetrahydrofolate to tetrahydrofolate, which is required for amino acid, purine, and thymidine synthesis. Deficiency primarily affects hematopoietic cell maturation and is marked by increased nuclear-cytoplasmic ratio, leading to macrocytic red blood cells and hypersegmented neutrophils; increased apoptosis often also leads to anemia and mild thrombocytopenia/leukopenia.

A 65-Year-Old Man Comes to the Office Due to a Few