Review Question - QID 214897

This patient presents with fever, leukocytosis, mild transaminitis, elevated alkaline phosphatase, and right upper quadrant pain consistent with acute cholecystitis. Concurrently, the patient has jaundice, dark urine, hemolytic anemia (elevated lactate dehydrogenase [LDH], high reticulocyte count, elevated indirect bilirubin, and low haptoglobin), and elevated mean corpuscular hemoglobin concentration (MCHC) suggestive of hereditary spherocytosis leading to pigmented gallstones as the underlying causative etiology of her acute cholecystitis.

Hereditary spherocytosis is an autosomal dominant defect in erythrocyte membrane cytoskeleton attachment proteins (spectrin and ankyrin), which gives rise to small, round erythrocytes (spherocytes). Spherocytes have a reduced membrane surface area per hemoglobin content and thus an elevated MCHC, a defining feature of hereditary spherocytosis. Patients with hereditary spherocytosis often have normocytic anemia from chronic extravascular hemolysis (elevated LDH, reticulocytosis, indirect bilirubinemia, and low haptoglobin), which can precipitate pigmented gallstones from excess bilirubin breakdown products in bile. Acute illness, such as cholecystitis due to pigmented gallstones obstruction of the cystic duct, can accelerate hemolysis in patients with hereditary spherocytosis. In particular, in these cases, there may be a more pronounced indirect bilirubinemia from hemolysis relative to direct bilirubinemia from cholecystitis. Hereditary spherocytosis is treated by red blood cell transfusions, folic acid supplementation, and inhibition of components of the terminal complement (e.g., eculizumab). Splenectomy is the definitive treatment.

Lee et al. study the efficacy of the long-acting complement C5 inhibitor, ravulizumab, compared to eculizumab in adult patients with PNH. The authors find that ravulizumab was non-inferior compared to eculizumab in keeping patients transfusion-free. The authors recommend the use of ravulizumab as a reasonable alternative to eculizumab in patients with PNH.

Incorrect Answers:
Answer 1: Autoimmune hemolytic anemia (AHA) can present similarly to this patient, with jaundice and evidence of extravascular hemolysis in the setting of an infection (e.g., Mycoplasma pneumonia and mononucleosis). However, while spherocytes are present in both AHA and hereditary spherocytosis, AHA is defined by a positive direct Coombs test (agglutination of red blood cells in the presence of antihuman antibodies), which was negative in this patient.

Answer 2: Gilbert disease presents with asymptomatic jaundice during times of stress or fasting secondary to indirect bilirubinemia from an underactive conjugation of bilirubin by UDP-glucuronosyltransferase. However, hemolysis is normally not present.

Answer 3: Glucose-6-phosphate dehydrogenase deficiency (G6PD) gives rise to erythrocytes with decreased resistance to oxidative stress (often from infections, antibiotics, and antimalarial drugs) resulting in episodic hemolytic anemia. However, MCHC is normal in patients with G6PD deficiency.

Answer 5: Paroxysmal nocturnal hemoglobinuria (PNH) presents with morning dark urine from overnight complement-mediated intravascular hemolysis, due to dysfunction of erythrocyte membrane protective proteins. However, MCHC is normal in PNH.

Bullet Summary:
Hereditary spherocytosis can be exacerbated by an acute illness (i.e., cholecystitis from underlying pigmented gallstones) and presents with hemolytic anemia (elevated lactate dehydrogenase, reticulocytosis, indirect bilirubinemia, and low haptoglobin) and an elevated mean corpuscular hemoglobin concentration.