A 22-year-old man of African descent presents to the emergency department with a 2-day history of dark-colored urine and yellowing of the eyes. He reports feeling increasingly fatigued and short of breath over the same period. He recently completed a course of trimethoprim-sulfamethoxazole for a urinary tract infection. Vital signs are within normal limits. Physical examination is notable for scleral icterus and a palpable spleen.
Laboratory studies show the following:
Hemoglobin: 8.2 g/dL (Baseline: 14.1 g/dL)
Reticulocyte count: 8%
Indirect bilirubin: 3.4 mg/dL
Serum haptoglobin: Decreased
Peripheral blood smear: Bite cells and several red blood cells with dark inclusions when stained with crystal violet.
Which of the following is the most likely primary defect in this patient?
The correct answer is:
C) Inability to protect hemoglobin from oxidative stress
This patient is experiencing an episode of acute hemolytic anemia triggered by a sulfa drug, which is characteristic of glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD is the rate-limiting enzyme in the pentose phosphate pathway, which produces NADPH. NADPH is essential for maintaining a pool of reduced glutathione, which neutralizes reactive oxygen species like H2O2 that would otherwise damage hemoglobin. When G6PD is deficient, oxidative stress, triggered by infections, fava beans, or drugs like sulfonamides and antimalarials, causes hemoglobin to denature and precipitate into Heinz bodies. These inclusions are visible with supravital stains like crystal violet. As these cells pass through the splenic sinusoids, splenic macrophages bite out the Heinz bodies, resulting in the characteristic bite cells seen on the peripheral smear.
Answer choice A: Deficiency of an enzyme in the glycolytic pathway, is incorrect. This describes pyruvate kinase deficiency. While it also causes a chronic non-spherocytic hemolytic anemia, it does not typically present with the acute, trigger-induced episodes or the specific finding of Heinz bodies/bite cells.
Answer choice B: Impaired production of the beta-globin chain, is incorrect. This describes beta-thalassemia. Thalassemia presents with microcytic anemia and target cells, rather than a normocytic hemolytic crisis following oxidative stress.
Answer choice D: Mutation in a red blood cell membrane anchoring protein, is incorrect. This describes hereditary spherocytosis, which is caused by defects in proteins like spectrin or ankyrin. This leads to the formation of spherocytes and an increased mean corpuscular hemoglobin concentration (MCHC), but not bite cells or Heinz bodies.
Answer choice E: Substitution of valine for glutamic acid in the globin chain, is incorrect. This is the specific mutation for sickle cell disease. While sickle cell disease causes hemolysis, the trigger is typically deoxygenation leading to vaso-occlusion, and the smear would demonstrate sickle-shaped cells.
Key Learning Point
G6PD deficiency is an X-linked recessive disorder that results in episodic hemolytic anemia. The hallmark laboratory findings during an acute crisis include bite cells and Heinz bodies (precipitated hemoglobin). Common triggers include fava beans, infections, and certain medications such as sulfonamides, nitrofurantoin, and primaquine.
