Sports Science (A+ work, No plagarism, Quality Work)

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THE LANCET • Vol 360 • August 3, 2002 • www.thelancet.com 411

CORRESPONDENCE

Clinical haemochromatosis in HFE mutation carriers Sir—Ernest Beutler and co-workers (Jan 19, p 211)1 calculate that fewer than 1% of C282Y homozygotes develop frank clinical haemochro- matosis, a penetrance much lower than previously thought. We believe their conclusion is flawed. The prevalence of symptomatic haemochromatosis is not the same as the penetrance of the C282Y/C282Y genotype.

Penetrance is the proportion of people who have the genotype that develops the phenotype. Definition of the phenotype is central. Four stages are recognised in haemochromatosis; end-organ damage and severe fibrosis or cirrhosis define stage 4.

In Beutler and co-workers’ study, only three of 119 patients had serum ferritin higher than 1000 �g/L and raised aspartate aminotransferase; only one had bronzed diabetes. This number would underestimate the proportion of people with the C282Y/C282Y genotype who had stage 4 disease, and their data suggest that the proportion of patients with stage 2–3 is more than 1% (stage 1 is genetic predisposition without phenotypic abnormality).

Stage 4 liver disease can be predicted by measurement of serum ferritin, aspartate aminotransferase, and pres- ence of hepatomegaly. Beutler and co- workers misquote Guyarder’s conclu- sion2 as saying that only haemochro- matosis patients with serum ferritin concentrations of more than 1000 �g/L and with raised aspartate aminotrans- ferase concentrations develop severe liver fibrosis. Guyarder and colleagues noted that 30 of 68 patients with serum ferritin higher than 1000 �g/L and normal aspartate aminotransferase had severe hepatic fibrosis.

No information on hepatic fibrosis is available from Beutler and co-workers’ study. However, 57% of patients had raised serum transferrin saturation, and 65% raised serum ferritin. 30% had been previously diagnosed with haemochromatosis. Most (28 of 45) of these patients were excluded from the analysis of symptoms, lowering the estimate of penetrance based on symptoms. If an agreed definition of phenotype3 is used, Beutler and co- workers’ study suggests a penetrance much higher than 1%, perhaps as high as 50% if based on serum transferrin saturation.

We have found screening of liver clinic referrals with serum transferrin saturation to be a reliable predictor of haemochromatosis (figure). This approach identified 11 C282Y homo- zygous over a 3-year period, of whom nine had phenotypic haemochro- matosis.4 On screening of people with late-onset diabetes mellitus, undiagnosed C282Y homozygosity is five times as common as in controls.5

All eight homozygotes detected had phenotypic haemochromatosis with cirrhosis (four with hepatocellular carcinoma).

Beutler and co-workers note no loss of C282Y homozygotes from the population with increasing age, and conclude that this supports low penetrance. However, they took no account of demographic changes in southern California in the past few decades. Immigration of younger Hispanic and Asian populations, in which there is a lower prevalence of C282Y homozygosity, would have a confounding effect by diluting the prevalence in younger age- groups.

Population screening for the mutation in the hereditary haemo- chromatosis (HFE) protein is controversial since the penetrance of the HFE mutation is unclear. We believe Beutler and co-workers underestimate the penetrance. Based on liver-biopsy findings of screen- detected homozygotes, the penetrance of the HFE mutation is far higher than they suggest. *A Poullis, S J Moodie, J D Maxwell St George’s Hospital and Medical School, London SW17 0RE, UK (e-mail: [email protected])

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: 211–18.

2 Guyarder D, Jacquelinet C, Moirand R, et al. Non-invasive prediction of fibrosis in C282Y homozygous haemochromatosis. Gastroenterology 1998; 115: 929–36.

Asthma in exercising children exposed to ozone Sir—In their report of asthma in exercising children and exposure to ozone, Rob McConnell and colleagues (Feb 2, p 386)1 conclude that the incidence of new asthma diagnoses is associated with heavy exercise in communities living in areas with high ambient ozone concentrations. They claim that these conditions, air pollution, and outdoor exercise might contribute to development of asthma in children.

McConnell and colleagues do not take into account the playing of sports inside compared with outside—ozone concentrations probably differ. Further- more, patterns of time and activity outdoors show degree of ambient ozone exposure.2 We would like to know whether inclusion of these time and activity patterns alter the results.

McConnell and colleagues attribute the effect on incidence of asthma only to ozone, despite particulate matter also having a significant effect with higher numbers of sports. Sarnat and colleagues3 have reported that effects of ozone could be related to the effects of particulate matter.

Asthma is recognised as a major public-health problem. One goal of asthma management, according to the Global Initiative for Asthma guidelines, is to improve quality of life of asthmatic patients doing sports and other activities. Even if pollution is a concern, I am unsure that McConnell and colleagues’ conclusion really helps as a preventive strategy. They do not take into account other possibly more important sources of pollution, such as passive smoking for young children, and active smoking in teenagers. It is impractical to keep children inside and allow no or little outdoor exercise in areas with high ozone levels. *C Raherison, L Filleul *Laboratoire Santé Travail Environnement, Institut de Santé Publique, d’Epidémiologie et de Développement, Université Bordeaux 2, 33076 Bordeaux, France; Service Des Maladies Respiratoires, Hopital du Haut-Lévèque, Bordeaux; and Institut de Veille Sanitaire, Bordeaux (e-mail: [email protected])

1 McConnell R, Berhane K, Gilliland F, et al. Asthma in exercising children exposed to ozone: a cohort study. Lancet 2002; 359: 386–91.

2 Kunzli N, Kelly T, Balmes J, Tager IB. Reproducibility of retrospective assessment of outdoor time-activity patterns as an individual determinant of long-term ambient ozone exposure. Int J Epidemiol 1997; 26: 1258–71.

3 Sarnat JA, Schwartz J, Catalano PJ, Suh HH. Gaseous pollutants in particulate matter epidemiology: confounders or surrogates? Environ Health Perspect 2001; 109: 1053–61.

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