Blood, 1 May 2003, Vol. 101, No. 9, pp. 3358-3358
CONTROVERSY IN HEMATOLOGY
Rebuttal to Beutler
Richard S. Ajioka and
James P. Kushner
This is 1 of 4 items that constitute a section; for a listing of all the
items, see the May 1, 2003, table of contents.
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Article |
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 al2
and 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
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Footnotes |
Correspondence: From the Division of Hematology, Department of
Internal Medicine, University of Utah School of Medicine, Salt Lake
City, UT.
Submitted January 7, 2003; accepted January 8, 2003.
Reprints: James P. Kushner, Division of Hematology, 4C146
University of Utah School of Medicine, 30 North 1900 East, Salt Lake
City, UT 84132; e-mail: james.kushner{at}hsc.utah.edu.
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References |
1.
Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T.
Penetrance of 845G
A (C282Y) HFE hereditary haemochromatosis mutation in the USA.
Lancet.
2002;359:211-218[CrossRef][Medline]
[Order article via Infotrieve].
2.
Bulaj ZJ, Ajioka RS, Phillips JD, et al.
Disease-related conditions in relatives of patients with hemochromatosis.
N Engl J Med.
2000;343:1529-1535[Abstract/Free Full Text].
3.
Jackson HA, Carter K, Darke C, et al.
HFE mutations, iron deficiency and overload in 10,500 blood donors.
Br J Haematol.
2001;114:474-484[CrossRef][Medline]
[Order article via Infotrieve].
4.
Edwards CQ, Griffen LM, Goldgar D, et al.
Prevalence of hemochromatosis among 11,065 presumably healthy blood donors.
N Engl J Med.
1988;318:1355-1362[Abstract].
5.
Asberg A, Hveem K, Thorstensen K, et al.
Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.
Scand J Gastroenterol.
2001;36:1108-1115[CrossRef][Medline]
[Order article via Infotrieve].
6.
Willis G, Wimperis JZ, Smith KC, Fellows IW, Jennings BA.
Haemochromatosis gene C282Y homozygotes in an elderly male population.
Lancet.
1999;354:221-222[CrossRef][Medline]
[Order article via Infotrieve].
7.
Bathum L, Christiansen L, Nybo H, et al.
Association of mutations in the hemochromatosis gene with shorter life expectancy.
Arch Intern Med.
2001;161:2441-2444[Abstract/Free Full Text].
8.
Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP.
Clinical and biochemical abnormalities in people heterozygous for hemochromatosis.
New Engl J Med.
1996;335:1799-1805[Abstract/Free Full Text].
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