ABSTRACT

Hereditary haemochromatosis is an inherited disorder of iron metabolism leading to increased intestinal absorption of iron and progressive iron overload. Excess iron is deposited in organs including the liver, heart and pancreas and may lead to liver cirrhosis, hepatocellular carcinoma, diabetes, and heart complications. Since the association between HFE gene mutations and haemochromatosis was found in 1996, many new aspects of the biochemistry and regulation of iron homeostasis have been unveiled. Phenotypic screening has shown a prevalence of haemochromatosis in approximately one of 250 individuals, which is close to the homozygosity frequency for the HFE 845 G → A mutation in Denmark.

A general population screening has been suggested since early diagnosis during the asymptomatic phase to be more effective for preventive treatment and prolong life expectancy. The main objective of this study was to determine the prevalence of increased iron overload in a population of Danish men from Storstrøm County by an initial genetic screening followed by a biochemical screening of subjects with at least one HFE mutation. In total 6,020 men were HFE genotyped, of these biochemical information was available in 1,453 (24%) men and additional information was available in 1,295 (22%). The allele frequencies of HFE 187 C → G, 193 A → T and 845 G → A were 12.8%, 1.8% and 5.3%, respectively. Several factors including HFE genotypes, environmental factors and disease of subject or in close family were evaluated. Subjects with two HFE mutations had significantly higher transferrin saturation than wt/wt subjects, however, only HFE 845 G → A homozygous and HFE 845 G → A/187 C → G compound heterozygous subjects had significantly higher serum ferritin. In summary, the phenotypic penetrance (transferrin saturation ≥50% and serum ferritin ≥300 μ g/l) of haemochromatosis in HFE 845 G → A homozygous men aged 30-53 years is at least 53%. HFE genotyping has a good prognostic value in prediction of iron overload. However, in rare cases other genes are involved in development of haemochromatosis. In collaboration with Membrane Transport Laboratory, Queensland Institute of Medical Research, Brisbane, Australia, a 3 base pair deletion of the ferroportin1 gene was found associated with autosomal dominant haemochromatosis in an Australian family.