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Most patients are asymptomatic, but a few have extrahepatic manifestations of iron overload. Some patients are identified by screening the family members of affected individuals.


  1. An autosomal recessive disease causing deficiency of the iron regulatory hormone hepcidin, leading to increased intestinal iron absorption and accumulation in tissues

  2. Iron deposition occurs throughout the reticuloendothelial system, leading to a broad range of potential manifestations.

    1. Liver manifestations range from hepatomegaly to fibrosis to cirrhosis; hepatocellular carcinoma risk is increased only in patients with cirrhosis.

    2. Any joint can be affected, but the second and third metacarpophalangeal joints are typical.

    3. Cardiac infiltration leads to cardiomyopathy.

    4. Other manifestations include secondary hypogonadism (pituitary infiltration), diabetes (pancreatic infiltration), and hypothyroidism (thyroid infiltration).

  3. There are several possible gene mutations; the most common is the HFE C282Y mutation, thought to have initially occurred in a Viking or Celtic ancestor.

    1. In a meta-analysis of people of European ancestry with iron overload, 81% were homozygous for the HFE C282Y mutation.

    2. 5% were compound heterozygous for the C282Y/H63D mutation.

    3. In another study, nearly 100,000 primary care patients were screened for iron overload and HFE mutations; 299 homozygotes were found.

      1. The prevalence of homozygosity was 0.44% in whites, 0.11% in Native Americans, 0.027% in Hispanics, 0.014% in blacks, 0.012% in Pacific Islanders, and 0.000039% in Asians.

      2. The prevalence of heterozygosity for the mutation was 10% in whites, 5.7% in Native Americans, 2.9% in Hispanics, 2.3% in blacks, 2% in Pacific Islanders, and 0.12% in Asians.

  4. The gene expression is quite variable, with the penetrance of iron overload in homozygotes (abnormal transferrin saturation or ferritin) ranging from 38% to 76%; clinical disease is found in only 2–38% of men and 1–10% of women.

  5. 72% of patients with serum ferritin levels > 1000 mcg/L have cirrhosis, compared with 7.4% of those with ferritin levels < 1000 mcg/L.

  6. Screening primary care populations for hemochromatosis is not recommended by the US Preventive Services Task Force or the American College of Physicians.


  1. Liver biopsy with measurement of hepatic iron index is the gold standard.

  2. Initial testing should be done with a transferrin saturation (serum iron/TIBC) and a serum ferritin (the test characteristics are for identifying homozygous patients).

    1. Transferrin saturation ≥ 50% in men

      1. Sensitivity, 82.4%; specificity, 92.5%

      2. LR+, 10.9; LR−, 0.19

    2. Transferrin saturation ≥ 45% in women

      1. Sensitivity, 73.8%; specificity, 93.1%

      2. LR+, 10.8; LR−, 0.28

    3. Ferritin ≥ 200 ng/mL in men

      1. Sensitivity, 78%; specificity, 76%

      2. LR+, 3.25; LR−, 0.23

    4. Ferritin ≥ 200 ng/mL in women

      1. Sensitivity, 54%; specificity, 95%

      2. LR+, 11; LR−, 0.48

  3. Patients who have a transferrin saturation ≥ 45% and an elevated ferritin should undergo HFE gene testing, looking for the hereditary hemochromatosis mutations.

    image All first-degree relatives of patients with hereditary hemochromatosis should undergo gene testing, regardless of the results of the iron studies.

    1. If C282Y/C282Y homozygous mutation is found

      1. If age is < 40 years, ferritin < ...

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