Hereditary Hemochromatosis (Comprehensive)

Hereditary hemochromatosis is a genetic disorder of iron metabolism in which inappropriate hepcidin signaling causes excessive intestinal iron absorption and tissue iron deposition. The most common form (type 1) results from biallelic mutations in the HFE gene, particularly C282Y homozygosity, with H63D acting as a modifier. Rare juvenile and non-HFE forms involve HJV, HAMP, TFR2, and SLC40A1 genes.

Excess iron accumulates over decades in liver, pancreas, heart, joints, skin, and endocrine glands, causing fibrosis, cirrhosis, hepatocellular carcinoma, diabetes, restrictive or dilated cardiomyopathy, hypogonadism, and pseudogout. Many patients remain asymptomatic until midlife, while juvenile forms present in the second or third decade with cardiac and gonadal failure.

Diagnosis combines elevated transferrin saturation above 45 percent with raised ferritin, HFE genotyping, and quantification of hepatic iron by MRI T2*. Treatment is therapeutic phlebotomy until ferritin falls below 50 ng/mL, then maintenance bleeds; chelation with deferasirox or deferoxamine is used when phlebotomy is contraindicated. Family screening of first-degree relatives is essential.