Correspondence

Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis

N Engl J Med 2008; 358:2293-2295May 22, 2008

Article

To the Editor:

The report by Allen et al. (Jan. 17 issue)1 on iron-overload–related disease in patients with HFE hereditary hemochromatosis states that among men, the clinical penetrance among HFE C282Y homozygotes was 28.4%. Our study showed that only about 2% of male C282Y homozygotes had full-blown clinical disease.2 We are disappointed that the authors still suggest that our results were biased because we excluded patients with a prior diagnosis of hemochromatosis, even after we showed them that the results were unaltered without this exclusion.3 Moreover, contrary to their assertion, all our patients were examined by a physician.

In reality, when examined side by side, our data are quite similar (Table 1Table 1Characteristics of Male HFE C282Y Homozygotes.) and resemble those in two other larger studies.4,5 The apparently high penetrance in the study by Allen et al. results from applying very liberal criteria in defining clinical disease. For example, the vague category of “diagnosis by a physician owing to symptoms associated with hereditary hemochromatosis” could well include patients with commonplace symptoms such as fatigue, which are then attributed, without proof, to iron overload.

Moreover, bias that increases symptoms attributed to hemochromatosis is introduced by not correcting for nonhomozygotes who have the same symptoms.

Jill Waalen, M.D., M.P.H.
Ernest Beutler, M.D.
Scripps Research Institute, La Jolla, CA 92037
beutler@scripps.edu

5 References

1. 1

   Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358:221-230
   Full Text | Web of Science | Medline

2. 2

   Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of the 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211-218
   CrossRef | Web of Science | Medline

3. 3

   Beutler E, Felitti VJ, Koziol JA, Gelbart T. Clinical haemochromatosis in HFE mutation carriers. Lancet 2002;360:413-414
   CrossRef | Web of Science

4. 4

   Asberg A, Hveem K, Kruger O, Bjerve KS. Persons with screening-detected haemochromatosis: as healthy as the general population? Scand J Gastroenterol 2002;37:719-724
   CrossRef | Web of Science | Medline

5. 5

   Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352:1769-1778
   Full Text | Web of Science | Medline

To the Editor:

The question concerning the penetrance of homozygous HFE C282Y alleles, addressed in the report by Allen at al. and other reports,1,2 has been confused with expressivity, the variability of the penetrant trait. The proportion of C282Y homozygotes with evidence of the trait of hepatic dysfunction is separate from the degree of severity of that dysfunction. Few would disagree that the abnormal biochemical, clinical, and histopathological findings among homozygotes are on a continuum of hepatic stress responses, with dysfunction and tissue destruction probably representing progressive hepatic injury. The question for clinicians is whether these findings lead to excess morbidity or mortality. In this study, the number of heterozygotes was lower than predicted if they were in Hardy–Weinberg equilibrium; is there an age-related depletion of C282Y homozygotes? Allen et al. report no hepatic insufficiency or overall excess mortality associated with homozygosity. Are these findings owing to the very high rate and amount of blood donations or venesections that the authors report among homozygotes, or do they reflect a relatively benign natural history for C282Y homozygosity?

Hugh Young Rienhoff, Jr., M.D.
Laguna Honda Hospital, San Francisco, CA 94116
hyrjr@yahoo.com

2 References

1. 1

   Ajioka RS, Kushner JP. Clinical consequences of iron overload in hemachromatosis homozygotes. Blood 2003;101:3351-3354
   CrossRef | Web of Science | Medline

2. 2

   Beutler ER. Rebuttal to Ajioka and Kushner. Blood 2003;101:3354-3357
   CrossRef | Web of Science

Author/Editor Response

Waalen and Beutler highlight the point that in C282Y homozygotes, the definition of clinical disease (“clinical penetrance”) continues to be keenly debated. They confuse “serious disease” with iron-overload–related disease. In our study, the C282Y homozygous men with documented iron overload were significantly more likely to have objective disease associated with hereditary hemochromatosis (21 of 27 men, 78%) than the C282Y homozygous men without evidence of iron overload (2 of 15, 13%; P<0.001).

Our estimate of the prevalence of iron-overload–related disease among homozygotes was based on a reduced list of hemochromatosis-associated signs and symptoms and included only objective measures of disease (including examination by a physician who was unaware of the HFE genotype and liver biopsy, neither of which were performed by Beutler and colleagues), in addition to the presence of iron overload as defined by Whitlock et al.1 Our study showed a significantly higher prevalence of histologic liver damage than that reported by Beutler and colleagues (in 14 of 74 men vs. 1 of 75, P<0.001), although our estimate is conservative, since not all homozygotes consented to undergo liver biopsy. The observed proportion of C282Y homozygotes with these objective disease symptoms remains an unbiased estimate of the population prevalence, even though these same symptoms were less prevalent among nonhomozygotes in our sample.

Although according to our definition of iron-overload–related disease, we included the 12 symptomatic homozygotes in whom the diagnosis was made by a physician, all but 5 of them had other symptoms of hereditary hemochromatosis that would have independently met the study criteria for disease related to iron overload. Furthermore, of 10 male homozygotes with varying levels of iron overload but without symptoms in whom the diagnosis was made during the study period because of elevated iron values, cascade screening, or other reasons, 9 underwent therapeutic venesection to prevent progression to disease.

In response to Rienhoff, we cannot be sure that there was not an age-related depletion of homozygotes before the study. Although we are certain of the genotype of the 203 homozygotes after confirmatory testing, we may have underestimated the proportion of C282Y heterozygotes in our cohort of 31,192 participants because of technical challenges of genotyping stored samples. The high rate of blood donation among our study participants may have abrogated the degree of iron loading found in C282Y homozygotes.

Katrina J. Allen, M.D., Ph.D.
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia
katie.allen@rch.org.au

Lyle Gurrin, Ph.D.
University of Melbourne, Parkville, VIC 3152, Australia

Lawrie Powell, M.D., Ph.D.
Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia

1 References

1. 1

   Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145:209-223
   Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Giada Sebastiani, Kostas Pantopoulos. (2011) Disorders associated with systemic or local iron overload: from pathophysiology to clinical practice. Metallomics 3:10, 971
   CrossRef

2. 2

   Lyle C. Gurrin, Nicholas J. Osborne, Clare C. Constantine, Christine E. McLaren, Dallas R. English, Dorota M. Gertig, Martin B. Delatycki, Melissa C. Southey, John L. Hopper, Graham G. Giles, Gregory J. Anderson, John K. Olynyk, Laurie W. Powell, Katrina J. Allen. (2008) The Natural History of Serum Iron Indices for HFE C282Y Homozygosity Associated With Hereditary Hemochromatosis. Gastroenterology 135:6, 1945-1952
   CrossRef