primary hemochromatosis
Summary
Primary (hereditary) hemochromatosis is an autosomal recessive disorder, most commonly caused by mutations in the HFE gene (C282Y homozygosity), leading to inappropriately low hepcidin levels and increased intestinal iron absorption. This results in progressive iron overload deposited in the liver, heart, pancreas, joints, skin, and pituitary gland. Classic triad: cirrhosis, diabetes mellitus ("bronze diabetes"), and skin hyperpigmentation.
Detail
Primary hemochromatosis is caused by mutations in the HFE gene (chromosome 6, associated with HLA-A3), most commonly C282Y homozygosity, less commonly C282Y/H63D compound heterozygosity. HFE protein normally regulates hepcidin production by hepatocytes; hepcidin inhibits ferroportin, limiting iron absorption from enterocytes and release from macrophages. Mutant HFE leads to decreased hepcidin, unregulated ferroportin activity, and excessive iron absorption from the gut, causing systemic iron accumulation over decades.
Clinical manifestations typically appear in men aged 40-60 (women present later due to menstrual blood loss) and include: - Liver: hepatomegaly, cirrhosis, increased risk of hepatocellular carcinoma - Pancreas: diabetes mellitus ("bronze diabetes") due to iron deposition in islet cells - Skin: bronze/slate-gray hyperpigmentation from iron and increased melanin - Heart: restrictive/dilated cardiomyopathy, arrhythmias, heart failure - Joints: arthropathy, particularly of the 2nd/3rd MCP joints (pseudogout) - Pituitary: hypogonadism, decreased libido
Laboratory findings: elevated serum ferritin, elevated transferrin saturation (>45%), decreased TIBC, elevated serum iron. Diagnosis confirmed with HFE genetic testing; liver biopsy with Prussian blue stain shows hemosiderin deposition and can assess fibrosis/cirrhosis; MRI can quantify hepatic iron non-invasively.
Treatment: therapeutic phlebotomy is first-line, aiming to reduce ferritin to normal levels. Iron chelation therapy (deferoxamine, deferasirox) is used if phlebotomy is contraindicated (e.g., anemia). Dietary modification (avoid iron/vitamin C supplements, limit alcohol) is recommended. Screening of first-degree relatives is important given autosomal recessive inheritance.
Distinguish from secondary hemochromatosis, which results from chronic transfusions (e.g., thalassemia, sideroblastic anemia) or excessive iron intake rather than genetic mutation—pathophysiology involves iron overload without primary HFE defect, though presentation can be similar.
Sources
- First Aid for the USMLE Step 1
- Robbins and Cotran Pathologic Basis of Disease
- UpToDate: Hereditary Hemochromatosis
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