Hemochromatosis

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

• Symmetrical arthropathy that is similar to osteoarthritis and calcium pyrophosphate deposition disease (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

• A low unsaturated iron-binding capacity

• 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 ...