Screening for hemochromatosis—Should we do the last test first?

Hemochromatosis is the most common genetic disease affecting Canadians, yet it is underdiagnosed and considered by many physicians to be rare. Since the discovery of the gene for hemochromatosis (HFE),[1] a genetic blood test for the C282Y mutation of the HFE gene has become widely available. More than 90% of typical hemochromatosis patients are homozygotes for the C282Y mutation. A population screening study in London, Ontario of 5211 voluntary blood donors has demonstrated a prevalence of 1 in 327 for C282Y homozygotes.[2] However, considerable debate has arisen about the risks and benefits of widespread genetic screening and the utility of screening for iron overload (phenotypic testing) as compared to genetic testing[3] (see the Table).

As described in Dr Samuel Krikler's article in this issue of the BCMJ, a screening study of 1905 adult men from Vancouver were tested for hemochromatosis by serial measurements of transferrin saturation, ferritin, and genetic testing. The study detected only two C282Y homozygotes, yet 71 patients with a variety of other conditions and genetic variations were detected with this screening strategy. Do these 71 patients have significant iron overload requiring treatment, or are they merely a manifestation of the lack of specificity of the transferrin saturation as a screening test? Furthermore, is there a benefit (or risk) to detecting these additional conditions by a population screening project for hemochromatosis? The proposed advantages of phenotypic screening for hemochromatosis are that it will detect all types of iron overload or deficiency and focus on those that may require phlebotomy therapy. However, it also detects a large number of patients that may have abnormal transferrin saturation and/or ferritin but do not have iron overload. Non-HFE related iron overload has been a rare condition at our medical centre, representing only 3% of significant iron overload cases. It has been overestimated in many previous studies in which the search for a secondary cause of iron overload has often been incomplete. Another argument in favor of phenotypic screening has been the low cost of the phenotypic screening test. The transferrin saturation has been estimated to be as low as $5. The cost of the genetic testing can be as low as $20, and should not be compared with charges in American centres of US$175. The cost implications of population screening have been estimated to be cost-effective under a range of assumptions, but the clinical expression of the disease may have been overestimated in previous studies.[4,5]

If hemochromatosis is so common, why did this Vancouver study detect only two cases? The patient sample contained 60% white people, so it would have been expected that three to four homozygotes would have been detected. The small sample size may have been contributory, but another explanation is that a C282Y homozygote may have a normal transferrin saturation and/or ferritin. The non-expressing homozygote has been estimated to range from 5% to 50% of cases and is particularly common in women. At our centre, the prevalence of a C282Y homozygote having a transferrin saturation <55% and a ferritin >300 ug/L was approximately 3%. Is there any advantage to detecting a non-expressing homozygote by genetic testing? In young patients, they may develop iron overload at a later age, so early detection would alert them to annual ferritin determination or a plan to be a regular voluntary blood donor. Pedigree studies of non-expressing homozygotes have identified iron-loaded siblings. There has been concern about genetic discrimination in the identification of non-expressing homozygotes or in the identification of a neonate by genetic testing. In Canada, there have been discussions with medical directors of insurance companies (Canadian Life and Health Insurance Association Annual Meeting 2001) about insurance ratings based on hemochromatosis genetic tests. Most insurance physicians have stated that ratings will not be based solely on genetic tests, and that C282Y homozygotes will be requested to provide more medical information about iron overload or organ damage. Many physicians see early diagnosis and treatment as an advantage to insurance companies and not a detriment to the client. Neonatal testing has been discouraged because of the uncertainty surrounding discrimination, the lack of informed consent of the neonate, and the long follow-up period before problems may develop. However, recent surveys presented at the Bioiron 2001 conference in Cairns, Australia showed that 97% of parents surveyed in Canberra approved of neonatal genetic testing for hemochromatosis (M. Bassett, personal communication, August 2001), and a study has been done in France in which 2275 neonates have already been tested (J. Rochette, personal communication, August 2001). In this study, pedigrees were extensively investigated from neonates back to the grandparents (reverse cascade screening) and a high yield of new homozygotes was detected. The authors concluded that this is a highly efficient method of detecting hemochromatosis in their population. The immediate advantage over an adult screening program is that a national system is in place to obtain and process neonatal blood samples for phenylketonuria and hypothyroidism, which are much less common than hemochromatosis but have immediate consequences in the untreated neonate.

So if we have a simple genetic test that detects 97% of cases, why not apply that test as the first test rather than investigate all of the other cases with phenotypic abnormalities? Should we be doing the last test first? Genetic screening in the workplace is beginning in Melbourne, and in this study, C282Y homozygotes and compound heterozygotes will be treated based on a subsequent serum ferritin test. Acceptance of the program remains to be determined. A large multicentre, multi-ethnic screening study using transferrin saturation, ferritin, and genetic testing sponsored by the NIH has begun (the HEIRS study) which will screen 100,000 people (including 20,000 Canadians in London and Toronto). This study has an extensive psychosocial component that will address many of the unresolved issues surrounding genetic testing for hemochromatosis. Preliminary studies in London have not demonstrated adverse psychosocial consequences of genetic testing for hemochromatosis.[6] This study may lead to recommendations surrounding national screening for hemochromatosis in the United States and Canada. In the meantime, many public health authorities are still unconvinced that there is a need for screening for hemochromatosis given the low morbidity and mortality that has been documented from hospital records and death certificates.[7] The screening of 65,238 Norwegians demonstrated a high prevalence of C282Y homozygotes but a low morbidity, and most discovered cases were asymptomatic.[8] A recent study from San Diego has shown that the prevalence of signs and symptoms attributed to hemochromatosis is similar to a matched control population with normal genetic tests.[5]

The natural history of untreated disease is highly variable, and this natural history will not be determined by the screening studies, which study patients at one point in time. In our community, an awareness of hemochromatosis that has been generated by the HEIRS study has already led to family physicians doing transferrin saturation measurements in white adults. It is unlikely that the present screening studies will result in a national screening program in Canada. A screening program based on genetic testing first may be seen as discriminatory to the evolving multi-ethnic population of Canada. Perhaps the greatest benefit of these population screening studies will be an increasing awareness by physicians and patients of hemochromatosis, leading to a preventive health strategy for high-risk groups. The highest risk group is young white males. They can be simply screened with a transferrin saturation; if transferrin is elevated above 50%, a genetic test for the C282Y mutation of the HFE gene is recommended.

Population screening strategies for hemochromatosis.

Competing interests

Dr Adams is the chief medical adviser to the Canadian Hemochromatosis Society.

Paul C. Adams, MD

Dr Adams, a gastroenterologist, is a professor of medicine at the London Health Sciences Centre, University of Western Ontario, London, Ontario and a principal investigator of the Hemochromatosis and Iron Overload Screening Study (HEIRS).