Hereditary hemochromatosis is characterized by iron accumulation in several tissues, i.e., in the parenchymal cells of the liver, heart, pancreas, and other endocrine organs. This toxic accumulation occurs as a result of increased intestinal uptake of dietary iron.
Hereditary hemochromatosis is a common disorder in France, Britain, Ireland, and Northern Europe. In the majority of cases, it is caused by a homozygous c.845G > A mutation in the HFE gene, located on chromosome 6p21.3, resulting in the C282Y change in the protein. The mutation is considered to have appeared about 1,500 years ago. The prevalence of C282Y homozygosity in Caucasians is about 1:250. However, the penetrance is low and depends on additional risk factors, e.g., male gender, alcohol use, and unknown factors. The age at disease onset is 40–50 years. Another mutation (H63D) in HFE may, when present as combined heterozygosity together with C282Y, cause steatosis or chronic hepatitis but with a less severe iron accumulation in the liver than in C282Y homozygosity. HFE protein is expressed in the crypt cells of duodenum and regulates iron transport by decreasing the iron uptake by transferrin.
The clinical picture of HFE-related hemochromatosis ranges from biochemical abnormalities in iron metabolism to severe disease with organ damage, including hepatosplenomegaly, liver cirrhosis, diabetes mellitus, hyperpigmentation, cardiomyopathy, and hypogonadism. Initial diagnostic findings are elevated serum iron levels with increased transferrin saturation and increased serum ferritin levels. Increased liver iron content verifies the diagnoses, assessed either with liver biopsy, specific iron content imaging, or magnetic resonance imaging. Diabetes mellitus is a risk factor for severe iron accumulation in HFE C287Y homozygotes.
In homozygotes for C287Y or in compound heterozygotes C287Y/H63D with increased serum ferritin level, treatment should be initiated with repeated blood withdrawings to achieve a serum ferritin level of 30–100 ug/L.
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