Background: Hereditary Hemochromatosis(HH) is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables.

Summary Hereditary haemochromatosis is the prototype disease for primary iron overload. The disorder is very common, especially amongst subjects of Northern European extraction. It is characterized by an autosomal recessive mode of inheritance, and most cases are homozygous for the C282Y mutation in the HFE gene. Haemochromatosis is now recognized to be a complex genetic disease with probable significant environmental and genetic modifying factors. The early diagnosis of individuals at risk for the development of haemochromatosis is important, because survival and morbidity are improved if phlebotomy therapy is instituted before the development of cirrhosis. The cost‐effectiveness and utility of large‐scale screening for haemochromatosis have been questioned given that many individuals with the homozygous C282Y mutation do not have iron overload or end‐organ damage. However, the use of phenotypic tests, such as serum transferrin‐iron saturation, for initial screening avoids the problem of the identification of non‐expressing homozygotes. Liver biopsy remains important in management to determine the presence or absence of cirrhosis, particularly amongst patients with serum ferritin levels greater than 1000 ng/mL or elevated liver enzymes. Those with non‐HFE haemochromatosis who cannot be identified on genotypic testing should have a liver biopsy to establish diagnosis. Patients with end‐stage liver disease may develop liver failure or primary liver cancer, and liver transplantation may be required. Liver transplantation for haemochromatosis is associated with a poorer outcome compared with other indications because of infections and cardiac complications.

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