Rebuttal to Beutler

Dr Beutler has underestimated disease penetrance associated with the hemochromatosis homozygous genotype (HFE genotype Cys282Tyr/Cys282Tyr) for several reasons. First, there are flaws in the study done at the Kaiser-Permanente Health Appraisal Clinic,1 the results of which form the basis for Dr Beutler's conclusion that disease penetrance, in contrast to the iron phenotype manifest in the laboratory, is quite rare. The 2 most common findings in clinically evident hemochromatosis, namely hemochromatotic arthropathy and hepatic fibrosis and cirrhosis, were not directly evaluated. Arthropathy was evaluated with only a questionnaire in which Cys282Tyr homozygotes and control subjects were asked to report on the presence or absence of joint pain or stiffness and whether a diagnosis of any form of arthritis had been made in the past. More than 40% of control subjects responded affirmatively, a figure not different than in Cys282Tyr homozygotes. No radiographic evaluations were done in either group nor was any stratification done by age of the respondents. In contrast, Bulaj et al used radiographic examination of the metacarpal-phalangeal joints to determine the frequency of characteristic hemochromatotic arthropathy in 214 homozygotes identified without ascertainment bias.2 Radiographic evidence of hemochromatotic arthropathy was found in 40% of homozygous men with elevated ferritin values, and most of these men were older than 40 years.

The Kaiser-Permanente study found elevated aspartate aminotransferase values and elevated collagen IV values (a surrogate marker for hepatic fibrosis) more often in Cys282Tyr homozygotes than in controls, but the significance of this finding was minimized. No liver biopsies were done, even in Cys282Tyr homozygotes with the highest ferritin values. In contrast, Bulaj et al performed liver biopsies on nearly all male Cys282Tyr homozygotes and found evidence of fibrosis or cirrhosis in 27 (24%) of 113.2 Most of the abnormal liver biopsy samples were obtained from men older than 40 years with elevated ferritin values.

Second, Dr Beutler has presented a somewhat biased review of the literature to support his conclusion. A screening study of 10 566 English blood donors is cited in which none of 63 Cys282Tyr homozygotes identified showed clinical signs of iron overload.3 The ascertainment bias inherent in studying healthy blood donors is evident and the result duplicates an earlier study of healthy blood donors.4 In addition, our interpretation of the large population-based screening study done in Norway5 differs from that of Dr Beutler. Of the homozygous men identified, 8.5% had “at least moderate” fibrosis at liver biopsy. This represents a minimal estimate as 38% of the homozygous men identified were younger than 40 years, and only 129 of 193 clinically examined homozygous men with elevated ferritin values actually underwent liver biopsy.

Dr Beutler makes much of a study in which the frequency of Cys282Tyr homozygotes in elderly men was no different than the frequency of this genotype in younger men.6 Apparently death from hemochromatosis had not depleted the aged population of Cys282Tyr homozygotes. In contrast, a Danish study not cited by Dr Beutler found only half the expected number of elderly Cys282Tyr homozygotes and even noted an age-related reduction in the frequency of Cys282Tyr heterozygotes.7 

Finally, Dr Beutler feels that the report by Bulaj et al2and many other studies in which a substantial proportion of Cys282Tyr homozygotes were found to have organ damage from iron overload were flawed by the lack of appropriate controls. Dr Beutler seems to have dismissed these reports. In fact, controls have been studied for most of the pedigree-based reports, namely Cys282Tyr heterozygotes in whom complications of iron overload are extremely rare.8 

Our minimal estimate of the frequency of morbid complications associated with the Cys282Tyr homozygous genotype is 29% in men older than 40 years and 11% in women older than 50 years. This minimal estimate takes into account the possible effects of modifier loci that might influence disease penetrance.2