Hemochromatosis: the Irony of Population Screening

H emochromatosis is not a new condition, having been well described in the 19th century. However, since the discovery of the hemochromatosis gene (HFE) in 1996 (1), there has been an explosion of publications on all aspects of the disease, including pathogenesis, genotypephenotype correlations, and population screening. Population screening based on phenotype (elevated transferrin saturation and/or ferritin) was studied throughout the 1980s and a high prevalence was found in populations of northern European ancestry. The Norwegian study by AÊ sberg et al. is built on a strong foundation of phenotypic studies (2–4) which included serial testing of transferrin saturation, serum ferritin, liver biopsy, and clinical judgement. The problem with phenotypic testing was the lack of speci city of the iron tests, particularly in the setting of in ammation or liver disease. The genetic test for hemochromatosis (C282Y mutation of the HFE gene) allowed for a new con rmatory test to diagnose hemochromatosis in patients with elevated iron tests. Economic models predicted the cost effectiveness of population screening for hemochromatosis (5) and large screening studies have begun in Europe, the United States, Canada, and other countries. AÊ sberg et al. have completed the largest screening study to date, with 65,238 Norwegians attending health appraisal clinics being offered initial screening by transferrin saturation and con rmatory genetic testing. The study found that 95% of their clinical cases of hemochromatosis de ned by a single experienced clinician had HFE mutations. There were 179 of 272 eligible patients who proceeded to liver biopsy. In this sample, 3.7% of the men who underwent biopsy and none of the women had cirrhosis. This is relevant, since cirrhosis is the major clinical factor affecting long-term survival. This prevalence of cirrhosis is higher than several other large screening studies in which no cirrhotics were found, but few patients underwent liver biopsy. Does a screening study need to result in 179 liver biopsies? Although liver biopsy is well accepted by gastroenterologists in the setting of possible hemochromatosis, it is not well accepted by haematologists, geneticists, and public heath physicians. Since development of the genetic test, liver biopsy has shifted from a diagnostic test to a prognostic test in C282Y homozygotes. It remains a useful diagnostic test in non-C282Y homozygotes. Previous studies have demonstrated that cirrhosis is rare in the C282Y homozygote with a serum ferritin <1000 mg/L and a normal AST, which may have included many cases in this study (6). The information gathered in this study will be a valuable resource, but this may be the last screening study in which liver biopsy was so commonly performed. Since genetic testing was only done selectively, we do not know the number of C282Y homozygotes with normal iron tests in this study. Estimates of non-expressing homozygotes have ranged from 5% to 50% and are higher in women than in men (7). Since the prevalence found in this study approximates the expected prevalence in men, it seems unlikely that a large sample of non-expressing cases were missed. The observation of decreased clinical expression in women is consistent with previous studies. Initial genotyping would detect all C282Y homozygotes at the risk of creating disease in the non-expressing cases (labeling, stigmatization, genetic discrimination). In fact, the strategy used in this study of selective genetic testing in persons with abnormal iron tests is the preferred approach from consensus conferences (8). The use of genetic testing earlier in the strategy, for example, after the  rst elevated transferrin saturation and on the same sample may have been a more ef cient strategy than multiple patient visits. Despite sampling a wide age range, the iron abnormalities, symptoms, and liver biopsy  ndings would be considered mild compared to any series of referred patients. A question of great interest that remains unanswered is what would have happened to these cases had they not been detected in this screening study. Progressive iron overload and cirrhosis are not inevitable outcomes and an increasing number of untreated cases have been reported without progressive iron overload. It seems unlikely that a randomized trial of treatment versus no treatment will occur. Epidemiological projects like the Busselton study in Western Australia have provided some information on the natural history of untreated C282Y homozygotes (9). Another approach that may answer some of these questions would be a case control study on a historical collection of blood samples. This has recently been reported in the study of the natural history of hepatitis C (10). And so the irony of population screening for hemochromatosis is that with modern advances in diagnostic testing they have found a high prevalence but a low morbidity. This is in contrast to screening programs for diseases with a low prevalence but high morbidity, such as phenylketonuria. The observations from this study are consistent with the clinical judgement of many physicians who continue to believe that hemochromatosis is a rare disease. Is the screening of 65,238 cases to  nd 4 cirrhotics justi ed? We would need to know how many cases of cirrhosis were prevented to be sure. For many years, the economic model makers have claimed that we needed a large clinical study to verify their many inherent assumptions. Now, even after such a study, the authors seem uncertain about the recommendations for the future, but what EDITORIAL