Type 4 haemochromatosis

Haemochromatosis type 4 has peculiar genetic and clinical features compared with the other forms. First, it is inherited as an autosomal dominant trait. Second, patients have increased serum ferritin levels, but may have a normal transferrin saturation. Third, at liver biopsy iron is increased in the reticuloendothelial cells, as well as in hepatocytes. These features suggest a different pathophysiology of the disease. Haemochromatosis type 4 is now known to be due to heterozygous mutations in the iron exporter, ferroportin 1, coded for on chromosome 2q32 (Figure 4.4). Along with missense mutations, a deletion of valine at amino acid 162 has been found in families from the UK, France, Italy and Australia, suggesting that this may be a relatively common cause of iron accumulation. The phenotype is similar to that found in the anaemia of chronic disease, and it is unlikely that a ferroportin 1 mutation would be suspected unless there was significant iron overload and a clear familial association. Figure 4.3 illustrates the difference between the parenchymal iron overload found in most cases of GH and the predominantly

Cytoplasm

Figure 4.4 Iron-loading mutations in the ferroportin 1 gene. The nine predicted transmembrane helices (1-9) are shown in relation to the lipid bilayer, with the mutations marked (red circles). The 12 Cys residues are marked with yellow circles and three putative exposed N-linked oligosaccharide sites (Y) are shown. The N- and

Cytoplasm

Figure 4.4 Iron-loading mutations in the ferroportin 1 gene. The nine predicted transmembrane helices (1-9) are shown in relation to the lipid bilayer, with the mutations marked (red circles). The 12 Cys residues are marked with yellow circles and three putative exposed N-linked oligosaccharide sites (Y) are shown. The N- and reticuloendothelial distribution in a case of type 4 haemo-chromatosis due to the valine 162 deletion. In one family, weekly venesection rapidly caused anaemia, and venesection with erythropoietin therapy was successful in reducing iron stores. It is not yet clear whether the degree of tissue damage at a given serum ferritin level is similar to type 1 haemochromatosis or whether the reticuloendothelial distribution is less toxic. In people of African origin, Gln248His in ferroportin 1 is a common variant that may be associated with a tendency to iron loading and mild anaemia.

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