14.2 No data

Figure 12.11 Map showing frequencies of the C282Y mutation in Europe. Data are derived from a meta analysis involving over 10 000 people in 63 European populations. Grey scale shows density percentages. High frequencies of C282Y are found in areas with populations of high Celtic descent. Reprinted from Lucotte and Dieterlen (2003), copyright 2003, with permission from Elsevier.

approximately 2000 years ago (Fig. 12.11). The mutation was then passed on and spread by population migration with heterozygote advantage postulated for the individual based on relative protection from iron deficiency and possibly infectious disease. Approximately five people out of every 1000 northern Europeans are now homozygous for p.C282Y. The p.H63D mutation is older, with a higher prevalence and worldwide distribution.

For those individuals homozygous for p.C282Y, a number of biochemical and clinical sequelae may result, culminating in the most severe forms of iron overload (Fig. 12.12) (Pietrangelo 2004). The initial biochemical phase is characterized by slow progressive plasma iron overload, whose effects are rarely manifested before adult hood. This can be accelerated by high dietary iron or attenuated by active iron use or loss. The second phase involves progressive iron accumulation in parenchymal tissues before the final stage of organ damage. This is more frequent in men, typically with cirrhotic involvement of the liver, but also potentially causing endocrine problems such as diabetes, cardiac arrhythmias and heart failure, and destructive arthritis of the joints. Screening for HFE haemochromatosis is clinically a very attractive option as therapeutic phlebotomy is safe and effective, reducing morbidity and mortality associated with the disease if instituted early. Further insights into the apparently low penetrance of p.C282Y are, however, required to facilitate this. Why should severe haemochromatosis

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