A 9-year-old boy with beta-thalassemia major is brought to the office for a routine red blood cell transfusion. He was diagnosed at age 6 months and has since received numerous blood transfusions. The patient has tolerated each transfusion well with no immediate reactions. Vital signs are normal. On physical examination, the patient has mild frontal bossing, hepatosplenomegaly, and jaundice. A recent liver biopsy showed Kupffer cells containing coarse, yellow-brown cytoplasmic granules. The granules are most likely composed of which of the following?
Patients with chronic hemolytic anemia (eg, beta-thalassemia major) depend on recurrent red blood cell (RBC) transfusions to maintain an adequate hemoglobin level. Iron overload (hemosiderosis) from increased iron absorption is a common complication resulting from both the primary condition (eg, hemolysis) and its treatment (frequent RBC transfusions).
Circulating iron is carried by transferrin. Once deposited in cells, iron binds to apoferritin to form ferritin micelles. Because iron is used poorly in patients with thalassemia and cannot be excreted actively, the ferritin micelles accumulate in macrophages of the reticuloendothelial system. The resulting iron-storage complex is known as hemosiderin and microscopically appears as brown or yellow-brown pigments in either granular or crystalline form. Hemosiderin can be confirmed histologically with Prussian-blue staining. In the liver, hemosiderin is typically seen in Kupffer cells (hepatic macrophages that line the walls of the sinusoids and participate in RBC breakdown).
Eventually, the iron burden will overwhelm the reticuloendothelial cells' capacity to sequester iron, resulting in parenchymal iron overload in the liver, myocardium, skin, and pancreas (eg, "bronze diabetes"). Patients receiving regular transfusions should undergo routine iron chelation therapy to reduce the overall iron load within the body and improve survival.
(Choice A) Amyloid protein appears as an amorphous, pink, extracellular material that shows apple-green birefringence under polarized light after Congo red staining. Hepatic amyloid can be seen in primary (eg, multiple myeloma) or secondary (eg, chronic inflammation) amyloidosis.
(Choice B) Bilirubin is the primary pigment found within bile, which has a brown, yellow, or green appearance microscopically. Accumulation in hepatocytes and canaliculi (ie, cholestasis) is associated with defects in bile production or flow (eg, duct obstruction).
(Choice C) Copper accumulation is seen in Wilson disease, an autosomal recessive disease characterized by cirrhosis and neurologic complications.
(Choice D) Glycogen appears as clear cytoplasmic vacuoles and stains pink-purple with the periodic acid-Schiff reaction. Glycogen is abundant in the liver shortly after a meal.
(Choice E) Patients with Gaucher disease (glucocerebrosidase enzyme deficiency) have pancytopenia, hepatosplenomegaly, and pathologic fractures. Gaucher cells, macrophages laden with cerebrosides and other glycolipids, have a "wrinkled tissue paper" appearance microscopically.
(Choice G) Lipofuscin is an insoluble yellow-brown pigment composed of lipids and phospholipids complexed with proteins. This pigment accumulates with age (ie, typically seen in adults) and "wear and tear" of multiple organs.
Educational objective:
Iron overload (hemosiderosis) is a common and serious complication of chronic hemolytic anemia and frequent blood transfusions. Accumulation of yellow-brown hemosiderin pigment is the cardinal histologic finding. Chelation therapy is indicated to reduce parenchymal iron deposition.