hereditary hemochromatosis
Summary
Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism caused by mutations in the HFE gene (most commonly C282Y homozygosity). It leads to excessive iron absorption in the duodenum, resulting in iron overload with deposition in multiple organs including liver, heart, pancreas, and joints.
Detail
Hereditary hemochromatosis results from defective hepcidin regulation due to HFE gene mutations. The HFE protein normally helps regulate iron absorption by interacting with transferrin receptor and hepcidin pathways. When defective, there is inadequate hepcidin production, leading to increased duodenal iron absorption via DMT1 and ferroportin transporters. Iron accumulates as hemosiderin in hepatocytes, cardiac myocytes, pancreatic islet cells, and synovial tissue. Clinical manifestations follow the classic triad of cirrhosis, diabetes mellitus ('bronze diabetes'), and cardiomyopathy, though this complete presentation is less common with early detection. Additional features include arthropathy (especially metacarpophalangeal joints), hypogonadism, and 'bronze' skin pigmentation. Diagnosis involves elevated transferrin saturation (>45%) and serum ferritin levels, confirmed by genetic testing for HFE mutations. Treatment consists of phlebotomy to achieve iron depletion, preventing or reversing organ damage if caught early. Complications include hepatocellular carcinoma (20-30x increased risk), heart failure, and endocrine dysfunction.
Sources
- First Aid for the USMLE Step 1
- Harrison's Principles of Internal Medicine
- Robbins Basic Pathology
- UpToDate
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