Review Question - QID 221261

This patient presents with right upper quadrant pain consistent with acute cholecystitis. In the context of concurrent jaundice, hemolytic anemia, and elevated mean corpuscular hemoglobin concentration, this is 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, which gives rise to small, round erythrocytes known as spherocytes. Spherocytes have a reduced membrane surface area per hemoglobin content and thus an elevated MCHC, which is a defining feature of hereditary spherocytosis. Patients with hereditary spherocytosis often have normocytic anemia from chronic extravascular hemolysis and will present with an elevated LDH, reticulocytosis, indirect bilirubinemia, and low haptoglobin. These patients may also develop pigmented gallstones due to excess bilirubin breakdown products in bile. Acute illness can accelerate hemolysis in patients with hereditary spherocytosis. There may be a more pronounced indirect bilirubinemia from hemolysis relative to direct bilirubinemia in acute infection or physiologic stress. Hereditary spherocytosis is treated with red blood cell transfusions, folic acid supplementation, and inhibition of components of the terminal complement with eculizumab. Splenectomy is the definitive treatment.

Lee et al. studied the efficacy of the long-acting complement C5 inhibitor, ravulizumab, compared to eculizumab in adult patients with Paroxysmal nocturnal hemoglobinuria. They discuss how ravulizumab was non-inferior compared to eculizumab in keeping patients transfusion-free. They recommend the use of ravulizumab as a reasonable alternative to eculizumab in patients with PNH.

Figure/Illustration A is an ultrasound of the gallbladder demonstrating gallstones (red circle). These findings are consistent with a diagnosis of cholecystitis.

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. While spherocytes are present in both AHA and hereditary spherocytosis, AHA is defined by a positive direct Coombs test, 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. Hemolysis is normally not present.

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

Bullet Summary:
Hereditary spherocytosis can lead to cholecystitis from underlying pigmented gallstones from underlying hemolytic anemia.