Alternative strategies to appropriate diagnosis need testing

EDITOR—The contributions by Seamark and Hutchinson on the role of testing for and treatment of hereditary haemochromatosis highlight important issues about this disease and more generally about the clinical application of new genetic discoveries.1 Uncertainties about the definition of disease are highlighted—should it be based on genotype, abnormal biochemistry, or symptoms, and, consequently, at what point does a predisposition to disease become genuine disease? This is a reflection more generally of the genetics of disease predisposition and the management of disease risk. Inevitably if we treat the risk of a disease—be it by venesection for raised concentrations of ferritin or with tamoxifen in women with a family history of breast cancer—only a proportion of patients will benefit and some will be harmed.2

We should be cautious about developing screening strategies for hereditary haemochromatosis for the general population. Proponents of population screening argue that it is common (based on a genetic definition of disease) and that prospective cohort studies show that early treatment results in normal life expectancy.3 For ethical reasons there will probably never be evidence from randomised controlled trials of venesection compared with watchful waiting in people with raised concentrations of ferritin. There is, however, sufficient uncertainty about expression of disease in C282Y homozygotes in the general population, and the role of gene/gene and gene/environment interaction in determining penetrance to postpone population …