A 24-year-old woman comes to the office due to a month of progressive exertional dyspnea. The patient does not have chest pain or palpitations. She has no chronic medical conditions and takes no medications regularly. Temperature is 37 C (98.6 F), blood pressure is 114/68 mm Hg, pulse is 90/min, and respirations are 12/min. BMI is 23 kg/m². Examination shows mucosal pallor and bilateral cervical lymphadenopathy. Cardiopulmonary auscultation reveals clear lung fields and no murmurs. Laboratory results are as follows: Chest x-ray reveals significant bilateral mediastinal lymphadenopathy. What is the most likely cause of this patient's anemia?

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11ec25c8_d2fd_3892_bc81_6f7ceb18ee5b_MD0003_00 Microcytic anemia with an inappropriately low reticulocyte response is primarily seen in iron deficiency anemia and anemia of chronic disease (ACD). In this case, the presence of a significant cervical and mediastinal lymphadenopathy (likely compressing the bronchus and causing dyspnea) in an otherwise young, healthy patient raises suspicion for ACD due to underlying malignancy (eg, Hodgkin lymphoma). ACD develops due to long-term elevations in serum inflammatory cytokines; most cases are triggered by underlying rheumatologic disease, chronic infection, obesity, diabetes mellitus, or malignancy. Although a wide range of inflammatory cytokines (eg, IL-1, IL-6, tumor necrosis factor-alpha, interferon gamma) contribute to the hematologic changes associated with ACD, the primary mediator is hepcidin, a small peptide produced by the liver in response to inflammation or bacterial lipopolysaccharide. Hepcidin binds to and destroys iron channels (ferroportin) on enterocytes and reticuloendothelial macrophages, leading to reduced iron absorption in the gut and reduced iron release from the reticuloendothelial system (which scavenges senescent erythrocytes and provides 95% of daily iron). This dramatically reduces iron availability for the generation of new erythrocytes, which causes a normocytic or slightly microcytic anemia with low reticulocyte response. (Choice A) Immune-mediated hemolysis is marked by rapid-onset normocytic anemia with a high reticulocyte response. Indirect bilirubin and lactate dehydrogenase are usually elevated and haptoglobin is reduced. Although thymoma can cause pure red cell aplasia due to immune-mediated causes, it is typically marked by a mediastinal mass with no lymphadenopathy. (Choice C) Macrophages in the reticuloendothelial system process senescent erythrocytes and provide approximately 95% of the iron needed for erythrocytosis. ACD is marked by reduced (not increased) erythrocyte recycling due to the destruction of iron channels on the plasma membrane of reticuloendothelial macrophages, which reduces iron release. (Choice D) Intratumor hemorrhage is uncommon but would be marked by acute pain and reticulocytosis due to acute blood-loss anemia. (Choice E) Patients with malignancy are at increased risk for thrombotic microangiopathy, which causes microangiopathic hemolytic anemia. In this condition, reticulocytes are increased (due to stimulation of erythrocytosis) and severe thrombocytopenia is present (due to the consumption of platelets in the microvasculature). Educational objective: Anemia of chronic disease is caused by long-term elevation in inflammatory cytokines. It is primarily mediated by hepcidin, a small peptide produced by the liver that destroys iron channels on enterocytes and reticuloendothelial macrophages. This limits iron availability for erythropoiesis, which causes a normocytic or slightly microcytic anemia with a low reticulocyte response.

A 24-Year-Old Woman Comes to the Office Due to a Month