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Hereditary hemochromatosis (HHC) is a recessive genetic disorder in which inappropriately high levels of iron are absorbed in the gut, causing excessive iron storage in organs such as the liver. Without treatment, hepatic cirrhosis and other serious conditions including diabetes, cardiomyopathy and arthritis may occur from the age of around 40 onwards. Routine venesection (blood-letting) to maintain appropriate serum iron levels is a simple yet effective means by which to prevent these complications.The majority of people with hereditary haemochromatosis are homozygous for the C282Y mutation in the HFE (haemochromatosis) gene. In the UK, C282Y homozygotes comprise over 90% of affected individuals, and 1 in 150 of the general population; the disease shows relatively low penetrance, and many homozygotes never develop clinical symptoms. Early diagnosis and pre-symptomatic treatment can prevent all potential complications of hemochromatosis, but there is no way of identifying which individuals with the mutation are likely to develop symptoms. Population screening for HHC has been proposed in the UK, due to the high prevalence of the mutant allele coupled with the low cost and high efficacy of early diagnosis and treatment compared with that for late stage diagnosis. However, opponents cite the low penetrance and unpredictablity of the clinical genotype as arguments against population based screening.

A publication in the Lancet reports on an assessment of the uptake of screening by first-degree relatives of two groups, C282Y homozygotes identified by genetic screening of blood donors, and patients presenting clinically with haemochromatosis [McCune et al., 2003, Lancet 362, 1897-98]. They found that whilst 53% of relatives of haemochromatosis patients had previously been screened, only 24% of the relatives of non-symptomatic blood donors had been tested. The authors conclude that the absence of a relative affected by clinically apparent haemochromatosis apparently reduced motivation for relatives to avail themselves of screening, despite the provision of information about the disease and the risk to family members. They note that: “the possibility of a muted response from high-risk family members has not been considered in the debate about population screening”.

Following interview, 99% of relatives of the non-symptomatic C282Y homozygotes opted to be tested for the mutation, leading to the identification of 25 C282Y homozygotes of which ten showed raised serum iron levels. All previously untested relatives of the clinical proband C282Y homozygotes asked to be tested, and 34 were found to be C282Y homozygotes; 20 of these had raised serum iron levels. The authors note that the original uptake of screening by the relatives of clinical cases, whilst substantially higher than that by the relatives of blood donors, is nevertheless unsatisfactory, and point to the success of their proactive approach to offering counselling and testing in raising uptake. They conclude that previous calculations that have claimed screening for HHCis cost effective have assumed a much greater rate of uptake by relatives than was observed in this study. Although a proactive approach can substantially improve uptake, this has associated cost implications that would need to be taken into account in any calculation of cost-benefit. Moreover, given the relatively low uptake of screening among even relatives of individuals diagnosed with clinical haemochromatosis, the probable degree of compliance in population screening programmes (and hence their efficacy) is called into question.

Comment: This study makes an important contribution to the debate over optimal strategies for HHC population screening. Clearly, there is scope for considerable improvement of uptake in the context of cascade (familial) screening of the relatives of clinical patients, and it seems that active recruitment, counselling and the provision of detailed information can facilitate such an improvement. Although an approach such as this is obviously desirable, it would necessitate a substantial input of resources. However, the economic implications of undiagnosed C282Y homozygotes who may go on to develop clinical disease must also be taken into consideration.