Penetrance of haemochromatosis

Ryan and colleagues (Gut 2002;51:108–12) note that the expected homozygote frequency of 1 in 83 for the HFE C282Y mutation is not reflected in the number of patients with haemochromatosis seen in a clinical setting. Accordingly, they have studied family members of patients with haemochromatosis as a surrogate for population screening. As they point out, there are probably genes other than HFE that affect the expression of hereditary haemochromatosis, and such genes are likely to be overrepresented in the families of index cases. Thus the choice of relatives would tend to overestimate the prevalence of clinical manifestations of haemochromatosis. Yet their studies confirm others published within the past year^1–5 that suggest that the clinical penetrance of the homozygous state is so low that it cannot be detected, even in very large samples. Interestingly, Ryan et al seemed not to reach this conclusion, rather attributing symptoms such as fatigue, arthropathy, and impotence to the disease. But these are very common symptoms, and not only do they need to be ascertained from the target population before they have been told of their diagnosis, but also they must be compared with the prevalence of the same symptoms in those who are not homozygous for the C282Y mutation. It is notable in this respect, for example, that while Ryan et al found that 42.9% of “the expressing female cohort” complained of fatigue, a NHANES III study found that 43.4% of 14 235 women complained of extreme fatigue⁶; we found that 31.7% of women with wild-type HFE and 32.4% of women homozygous for the C282Y mutation complained of severe fatigue.¹

It seems to me remarkable that the authors of this and a number of studies cited above are reluctant to draw the obvious conclusion: the clinical penetrance of hereditary haemochromatosis is extremely low, so low that it has not been possible to detect it in very large population studies. For the past 20 years we have taught and have been taught that haemochromatosis is the most common disease of Northern Europeans. Until relatively recently I held this view.⁷ However, the interpretation of the data should not be moulded by preconceived ideas, and the controlled study of 41 000 individuals which we concluded recently¹ make the facts abundantly clear: the HFE mutation is common, the biochemical phenotype is common, but haemochromatosis is, in fact, a rare clinical disease.