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Key Features

Essentials of Diagnosis

  • Usually suspected because of elevated iron saturation or serum ferritin or a family history

  • Most patients are asymptomatic

  • Hepatic abnormalities and cirrhosis, heart failure, hypogonadism, and arthritis

  • The disease is rarely recognized clinically before the fifth decade

  • HFE gene mutation (usually C282Y/C282Y) is found in most cases

General Considerations

  • Increased accumulation of iron as hemosiderin in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys

  • Cirrhosis is more likely to develop in affected persons who drink alcohol excessively or have obesity-related hepatic steatosis

  • Autosomal recessive disease

  • About 85% of persons with well-established hemochromatosis are homozygous for the C282Y mutation

  • Population studies have shown an increased prevalence of liver disease but not of diabetes, arthritis, or heart disease in C282Y homozygotes

  • Hemochromatosis develops in 1–2% of C282Y/H63D compound heterozygotes

  • Heterozygotes do not develop cirrhosis in the absence of associated disorders such as viral hepatitis or nonalcoholic fatty liver disease

Demographics

  • The frequency of the gene mutation

    • Averages 7% in Northern European and North American white populations, resulting in a 0.5% frequency of homozygotes (iron overload will develop in 38–50% but clinical symptoms will develop in only 28% of men and 1% of women)

    • Uncommon in blacks and Asian-American populations

  • Risk factors for advanced fibrosis

    • Male sex

    • Excess alcohol consumption

    • Diabetes mellitus

Clinical Findings

Symptoms and Signs

  • The onset is usually after age 50—earlier in men than in women

  • Early symptoms are nonspecific (eg, fatigue, arthralgia)

Later clinical manifestations

  • Arthropathy (and the need for joint replacement surgery), hepatomegaly, and evidence of hepatic dysfunction

  • Skin pigmentation (combination of slate gray due to iron and brown due to melanin, sometimes resulting in a bronze color)

  • Cardiac enlargement with or without heart failure or conduction defects, diabetes mellitus with its complications, and erectile dysfunction in men

  • Bleeding from esophageal varices

Differential Diagnosis

  • Hepatomegaly due to other causes, eg, fatty liver

  • Diabetes mellitus due to other causes, eg, Cushing syndrome

  • Cardiac infiltrative disease due to other causes, eg, amyloidosis, sarcoidosis

  • Arthritis due to other causes, eg, rheumatoid arthritis, pseudogout

  • Hyperpigmentation due to other causes, eg, hyperbilirubinemia

  • Cirrhosis due to other causes

Diagnosis

Laboratory Tests

  • Mildly abnormal liver chemistries (aspartate aminotransferase [AST], alkaline phosphatase)

  • An elevated plasma iron with > 45% transferrin saturation

  • An elevated serum ferritin (although a normal iron saturation or a normal ferritin does not exclude the diagnosis)

  • Affected men are more likely than affected women to have an elevated ferritin level

  • Testing for HFE mutations is indicated in any patient with evidence of iron overload

Imaging Studies

  • CT and MRI may show changes consistent with iron overload of the liver

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