Hereditary hemochromatosis is an autosomal recessive disorder that is the most common form of iron overload and one of the most common life-threatening genetic disorders. Homozygotes have inappropriately enhanced absorption of iron that results in a progressive increase in iron stores. Mutations in the HFE protein, whose gene is closely linked to the HLA genes on chromosome 6, are currently identified in 85% of patients who have the disease. The point mutation at C282Y is most common; a defect at H63D is seen less frequently. Only homozygotes are at risk for symptomatic iron overload, but with a gene frequency of 5% to 7%, 0.25% to 0.5% of the population are homozygotes. Clinically, decades are required for iron to reach dangerous levels in tissues. Significant organ damage usually is noted in middle age or later. Iron reaches dangerous levels in tissues in the fourth to fifth decade of life.

As the major storage site of iron, the liver is the first organ to be damaged in this disease. Mild-to-moderate hepatomegaly develops first, followed by shrinkage associated with fibrosis and cirrhosis. There is relatively little inflammatory response, so abnormalities in serum transaminases may be minor, even in the presence of significant hepatic damage. Disturbances in hepatic function occur with advanced disease. 

Cardiac iron deposition is very important. Congestive cardiomyopathy and sudden death due to arrhythmias are the most common causes of death. Other clinical complications include diabetes mellitus and both thyroid and pituitary dysfunction. Hyperpigmentation is very common. Arthropathy is common in hereditary hemochromatosis, but rare in patients who have secondary iron overload.

The heterozygous state rarely is associated with clinical problems. The critical genetic issue is that with a gene frequency of 5% to 7%, the obligate heterozygote child of a parent who has hereditary hemochromatosis has a 5% to 7% risk of being affected. Accordingly, children of affected adults should be tested. Because children may not manifest iron overload, as measured by serum iron levels, transferrin saturation, and ferritin concentrations, long-term follow-up frequently was required in the past. The current ability to identify specific DNA defects in most families should provide a much more accurate tool to identify children at risk.

Nonhereditary forms of iron overload exist but are much less frequent. Thalassemia major and sickle cell anemia are the most important  disorders associated with acquired hemosiderosis due to the long-term use of transfusions. These transfusions deposit large amounts of iron, which remain in the body because there is no effective mechanism for active excretion of iron. Iron overload also can result from dietary overload and is common in sub-Saharan Africa. It occasionally results from repeated but unnecessary parenteral iron injections.

Neonatal iron overload syndrome is a distinct familial disorder whose genetics are obscure. Most infants die of massive iron deposition and multiorgan failure within days of birth. It resembles hereditary hemochromatosis, but the mechanism involves enhanced transport of iron across the placenta. Gastrointestinal absorption is normal. Perinatal iron overload also rarely is associated with hereditary tyrosinemia, cerebrohepatorenal syndrome, and perinatal hemochromatosis.

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