A 52-year-old man presents with progressive fatigue, arthralgia of the 2nd and 3rd metacarpophalangeal joints, and hepatomegaly. Laboratory studies show transferrin saturation 58%, serum ferritin 1200 ng/mL, and low TIBC. Liver biopsy with Prussian blue staining reveals the pattern shown in the diagram. The iron granules marked **A** are predominantly localized to hepatocytes in a periportal distribution, with sparing of Kupffer cells. HFE genetic testing confirms C282Y homozygosity. Which of the following best explains the pathophysiology of iron deposition in this patient's liver?

Explanation

## Why "Defective hepcidin regulation leading to increased intestinal iron absorption and parenchymal cell deposition" is right Hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder caused by HFE gene mutations (most commonly C282Y homozygosity). The pathophysiology centers on defective hepcidin regulation, the master iron-regulatory hormone. Loss of hepcidin function leads to uncontrolled intestinal iron absorption and progressive iron deposition in parenchymal cells—hepatocytes, myocardium, pancreatic islets, and pituitary. The Prussian blue–positive iron granules marked **A** in the periportal (Zone 1) hepatocyte distribution with sparing of Kupffer cells is the histologic hallmark of hereditary (primary) hemochromatosis and directly reflects parenchymal iron loading. This patient's clinical presentation (fatigue, arthralgia of 2nd/3rd MCPs—classic for HH, hepatomegaly, elevated transferrin saturation >50%, ferritin >1000, and C282Y homozygosity) confirms the diagnosis and mechanism (Robbins 10e Ch 18; Harrison 21e Ch 407). ## Why each distractor is wrong - **Chronic transfusion-induced iron overload with preferential reticuloendothelial system loading**: Secondary iron overload from transfusions preferentially loads Kupffer cells and the reticuloendothelial system first, NOT hepatocytes. The diagram explicitly shows sparing of Kupffer cells, which excludes secondary iron overload and is pathognomonic for hereditary hemochromatosis. - **Secondary iron overload from chronic hemolysis with Kupffer cell iron sequestration**: Hemolysis-related iron overload similarly loads Kupffer cells and RES tissue before parenchymal cells. The periportal hepatocyte distribution with Kupffer cell sparing rules out this mechanism entirely. - **Alcoholic cirrhosis with iron redistribution from portal inflammation**: While alcohol can worsen iron overload in HH patients, alcoholic cirrhosis alone does not produce the characteristic periportal parenchymal iron deposition seen here. The HFE C282Y homozygosity and iron study pattern confirm primary HH, not secondary iron loading from alcohol. **High-Yield:** Periportal hepatocyte iron deposition with Kupffer cell sparing = hereditary hemochromatosis (HFE mutation); periportal + Kupffer cell loading = secondary iron overload (transfusion, hemolysis). [cite:Robbins 10e Ch 18; Harrison 21e Ch 407]