Hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism caused most commonly by homozygous C282Y mutation in the HFE gene on chromosome 6. The HFE protein normally interacts with transferrin receptor 1 and bone morphogenetic protein (BMP) signaling to regulate hepcidin synthesis in the liver. Hepcidin is the master iron-regulatory hormone: it binds to ferroportin (the sole cellular iron exporter) on enterocytes and macrophages, causing ferroportin internalization and degradation, thereby limiting iron absorption and iron release into plasma. In HFE-related hemochromatosis, defective HFE signaling results in inappropriately low hepcidin levels, leading to unregulated iron absorption from the duodenum (3-4 mg/day versus normal 1 mg/day) and unrestricted iron release from macrophages. Since there is no physiological mechanism for iron excretion, total body iron progressively accumulates from the normal 3-4 grams to 20-40 grams over decades. Excess iron deposits in parenchymal cells as ferritin and hemosiderin, generating reactive oxygen species (hydroxyl radicals) through Fenton chemistry (Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH•). These free radicals cause lipid peroxidation of cell membranes, protein oxidation, DNA damage, mitochondrial dysfunction, and activation of hepatic stellate cells leading to fibrosis. Target organs include liver (hepatomegaly, cirrhosis, 200-fold increased hepatocellular carcinoma risk), pancreas (bronze diabetes from beta-cell destruction), heart (dilated cardiomyopathy, arrhythmias), joints (calcium pyrophosphate deposition causing pseudogout, classically affecting 2nd and 3rd MCP joints), pituitary (hypogonadotropic hypogonadism), and skin (bronzing from melanin and iron deposition). Clinical penetrance is incomplete — only 28% of C282Y homozygotes develop clinical disease. The clinician orders transferrin saturation (>45% is screening threshold), serum ferritin (reflects total body iron stores), HFE genotyping for confirmation, hepatic MRI for iron quantification, and liver biopsy for fibrosis staging when ferritin >1000 ng/mL or abnormal liver enzymes.