G6PD Deficiency and Hereditary Spherocytosis are easy to mix up on the boards. Here's a side-by-side comparison — presentation, workup, imaging, and first-line treatment — drawn from our full outlines.
G6PD Deficiency vs Hereditary Spherocytosis at a glance
G6PD Deficiency: X-linked enzyme deficiency causing episodic oxidative hemolysis in response to drugs, infection, or fava beans.
Hereditary Spherocytosis: Inherited red cell membrane defect producing spherocytes, hemolysis, splenomegaly, and jaundice.
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Question 1HematologyMedium
A 26-year-old African American man presents 3 days after starting trimethoprim-sulfamethoxazole for a UTI with acute jaundice, dark urine, and fatigue. CBC shows Hgb 8.4 g/dL with reticulocytosis. Peripheral smear shows bite cells and Heinz bodies. Direct Coombs test is negative. Which is the most likely diagnosis?
ASickle cell disease
BHereditary spherocytosis
CPyruvate kinase deficiency
DG6PD deficiency
Reveal answer & full explanation
Correct answer: D — G6PD deficiency
ASickle cell disease
BHereditary spherocytosis
CPyruvate kinase deficiency
DG6PD deficiency✓
Why G6PD deficiency is correct
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzyme defect causing oxidative hemolysis
Triggered by drugs including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, primaquine, and nitrofurantoin, as well as infections or fava beans
Bite cells (from splenic phagocytosis of Heinz bodies) and Heinz bodies (denatured Hgb precipitates) are classic findings on peripheral smear
A negative direct Coombs test distinguishes G6PD deficiency from autoimmune hemolytic anemia
Why the others are wrong
Sickle cell disease — shows sickle cells on peripheral smear; not triggered acutely by sulfonamide drugs in this manner
Hereditary spherocytosis — shows spherocytes with increased osmotic fragility; not drug-triggered oxidative hemolysis
Pyruvate kinase deficiency — an autosomal recessive, Coombs-negative congenital hemolytic anemia that causes chronic lifelong hemolysis with echinocytes (burr cells) on smear; it is not precipitated by oxidant drugs such as TMP-SMX and does not produce bite cells or Heinz bodies
Question 2HematologyMedium
An 8-year-old boy of Northern European descent has had lifelong fatigue, intermittent scleral icterus, and palpable splenomegaly. He has required red cell transfusions roughly every 6 weeks to keep his hemoglobin above 7 g/dL. Labs show normocytic anemia with an elevated MCHC, reticulocytosis, elevated indirect bilirubin, low haptoglobin, and a negative direct antiglobulin test. Peripheral smear shows numerous spherocytes, and eosin-5-maleimide binding by flow cytometry is decreased. He has completed pneumococcal, meningococcal, and Haemophilus influenzae type b vaccination. Which of the following is the most appropriate definitive treatment?
ATotal splenectomy
BRituximab infusion
CMarrow transplant
DDeferasirox therapy
Reveal answer & full explanation
Correct answer: A — Total splenectomy
ATotal splenectomy✓
BRituximab infusion
CMarrow transplant
DDeferasirox therapy
Why Total splenectomy is correct
In severe, transfusion-dependent hereditary spherocytosis, splenectomy is the definitive guideline-supported treatment: it removes the site of spherocyte sequestration, abolishing the anemia and jaundice and ending transfusion dependence.
It is timed after age 6 years to lower the risk of overwhelming post-splenectomy infection, and vaccination against encapsulated organisms (pneumococcal, meningococcal, Hib) is completed beforehand; both criteria are satisfied in this 8-year-old.
Splenectomy does not correct the membrane defect, so spherocytes persist on the smear, but the hemolysis is functionally resolved.
Why the others are wrong
Marrow transplant is curative for some marrow-failure and severe hemoglobinopathy states, but its transplant-related mortality is not justified in HS, where splenectomy reliably controls the disease.
Deferasirox therapy treats the iron overload that results from chronic transfusion, so it manages a complication rather than the underlying hemolysis; splenectomy instead removes the source of transfusion-related iron loading.
Rituximab infusion is used for warm autoimmune hemolytic anemia, but the negative direct antiglobulin test plus decreased EMA binding confirm a membrane defect rather than an antibody-mediated process.
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X-linked enzyme deficiency causing episodic oxidative hemolysis in response to drugs, infection, or fava beans.
Inherited red cell membrane defect producing spherocytes, hemolysis, splenomegaly, and jaundice.
Classic presentation
Dark urine and jaundice 1-3 days after starting TMP-SMX (or dapsone, or fava bean ingestion) in a young man of African or Mediterranean descent.; Acute hemolytic episode 24-72 hours after oxidant exposure: dark/cola-colored urine (hemoglobinuria), back/abdominal pain, jaundice, fatigue, dyspnea; Neonatal jaundice — especially…
Triad of hemolytic anemia, jaundice, and splenomegaly with spherocytes on peripheral smear and a negative Coombs test.; Neonatal jaundice often requiring phototherapy or exchange transfusion; Fatigue, pallor, exertional dyspnea from chronic anemia; Intermittent scleral icterus, dark urine during hemolytic episodes; Right upper quadrant…
Workup / key labs
Low quantitative G6PD enzyme activity in a stable patient (away from acute hemolytic episode). Not part of routine US newborn screening in most states; measure G6PD activity in a jaundiced newborn with suspected hemolysis or bilirubin rising despite intensive phototherapy (AAP 2022).; CBC — normocytic anemia, reticulocytosis (peaks ~7…
Hemolytic anemia + spherocytes + negative DAT + family history OR positive EMA binding test. Genetic testing reserved for atypical/severe or recessive cases.; CBC — normocytic or mildly microcytic anemia with elevated MCHC (>36 g/dL is highly suggestive); Reticulocyte count — elevated; Peripheral smear — spherocytes lacking central…
Imaging
Not routinely indicated
Abdominal ultrasound — splenomegaly; screen for cholelithiasis in adolescents and adults
First-line treatment
Acute hemolysis: identify and remove offending agent immediately; Supportive care — IV fluids to maintain renal perfusion and clear hemoglobinuria; Transfusion for severe symptomatic anemia or hemodynamic instability; Prevention is primary: educate patient about drugs and foods to avoid; provide list of contraindicated medications;…
Folic acid supplementation (1 mg daily) in moderate-to-severe disease to support compensatory erythropoiesis; Transfusion support for severe anemia or aplastic crisis; Phototherapy or exchange transfusion for severe neonatal hyperbilirubinemia
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