Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells.

BACKGROUND AND OBJECTIVES: The HFE protein interacts with the transferrin receptor (TfR) to regulate cellular iron uptake. Nucleated erythroid cells have the highest number of TfR and the greatest iron uptake. The aim of this study was to investigate whether erythroid iron uptake is directly affected by HFE mutations. DESIGN AND METHODS: Iron status and erythropoiesis was investigated in sixty, asymptomatic HFE C282Y homozygotes. Reverse transcription-polymerase chain reaction, flow cytometry and immunocytochemistry were employed to investigate the HFE expression profile of normal peripheral blood, nucleated erythroid cells and several cultured cell lines. RESULTS: The HFE C282Y homozygous subjects showed subtle erythropoietic changes with raised transferrin saturation and reticulocyte counts and low-normal serum transferrin receptor levels, but normal erythrocyte count and mean cell volume. HFE mRNA was detected in macrophages and monocytes and HFE protein was detected in granulocytes and at low levels in monocytes. Cultured primary human erythroid colonies did not express HFE mRNA or protein. INTERPRETATION AND CONCLUSIONS: There is evidence that HFE C282Y homozygotes display increased plasma iron turnover and increased erythropoiesis, despite there being no evidence that HFE is expressed in erythroid colonies with a normal HFE genotype. It is likely that HFE mutations do not directly alter erythroid iron handling, but alter the supply of iron to the erythroid tissues.

Screening for hereditary haemochromatosis within families and beyond.

Screening programmes for haemochromatosis that include follow-up identification of relatives are claimed to be cost effective. We assessed uptake of screening by first-degree relatives of two groups of index cases: people homozygous for the C282Y mutation ascertained by genetic screening of blood donors; and patients presenting clinically with haemochro matosis. Only 40 (24%) of 165 relatives of blood donors had been tested. By contrast, testing uptake in 121 relatives of patients diagnosed clinically was more than double that (53%), despite unstructured provision of genetic information. A substantial number of untested relatives had undiagnosed iron overload. Overall efficacy of population screening for haemochromatosis is undermined by these observations.

Hereditary haemochromatosis: only 1% of adult HFEC282Y homozygotes in South Wales have a clinical diagnosis of iron overload.

In northern Europe, about 90% of patients with hereditary haemochromatosis (HH) are homozygous for a single mutation (C282Y) of the HFEgene and approximately 1 in 150 people in the general population carries this genotype. However, the clinical significance of HFE mutations remains uncertain, as is the proportion of people homozygous for C282Y who will develop clinical symptoms leading to a diagnosis of HH. A systematic review of patients with HH over a 2-year period within a defined UK region has revealed that only 1.2% of adult C282Y homozygotes have been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% has more than 4 g iron (the diagnostic threshold for iron overload).