Correspondence |
Haemochromatosis and non-hepatic malignancy
Sir,We thank Dr Das for his interest in our recent review.1 He highlights the high risk of non-hepatic malignancies in hereditary haemochromatosis (HH).2 While the increased prevalence of hepatocellular cancer in HH is not in debate, controversy does surround the rate of non-hepatic malignancy in HH.
Some studies that suggested a higher incidence were limited in design or clearly defined outcome measures. In one study of 71 patients with HH, an 8.4% rate of non-hepatic cancer was noted in 7 years (only six cases) of follow-up, with no claim made as to statistical significance.3 In a study quoted by Dr Das, Nelson et al.4 showed a statistically significant increased risk of gastric and colorectal cancer, but their primary endpoints included many different types of cancer, some showing no increased risk compared to controls. Further, in the study by Fracanzani et al.,5 which showed a relative risk of 1.8, suggesting a definite trend towards an increased risk, the results did not reach statistical significance (95%CI 0.8–4). There were 20 cases of non-hepatic malignancy in this study, with nine in the control group, but the increased numbers were in the colon, bladder and lung, organs not known to accumulate excess iron in HH.
Since increased iron stores alone have not been shown to be pre-malignant in recent studies, it has been suggested that interplay between genetic factors in HH could be implicated in the development of malignancy.
A recently published study compared the frequencies of HFE C282Y and H63D alleles and associated odds ratios in 100 consecutive unrelated White adults with malignancy to those in 318 controls in a community-based oncology practice.6 The frequencies of the C282Y and H63D alleles were similar to those in the general population, leading investigators to conclude that C282Y and H63D were not associated with an increased cancer risk. The odds ratios did suggest, however, that the development of specific types of malignancy may relate to the inheritance of the HFE gene. In a population-based study of 1847 heterozygous individuals and their 5973 first-degree relatives, patients with HH had a 20-fold increased risk of liver cancers, but with an almost unaltered risk of all other cancers (95%CI 1–1.4), including gastrointestinal cancers. The overall risk of cancer in first-degree relatives did not appear to be increased.7
That non-HFE genetic factors may interfere with the risk of developing cancers suggests exciting implications for basic science research. For example, polymorphisms of tumour necrosis factor affect the expression and severity of liver damage in patients with HH, with a lower prevalence of cirrhosis noted in patients with TNF-
polymorphisms than in those without8.
Iron overload may be carcinogenic. On the basis of the current evidence, however, the risk of non-hepatic malignancy in HH cannot unequivocally be stated to be higher than in matched controls. There is a clear need of further information from more and better-designed studies that incorporate careful follow-up of identified HH patients and matched controls.
The association of extra-hepatic malignancy in HH is intriguing, raising as many questions as it seems to answer. We commend Dr Das on the splendid service he has set up at his hospital, and believe that it is the work of similarly dedicated clinicians that will form the basis of the much-needed evidence to unravel this mystery.
Wythenshawe Hospital South Manchester University Hospital Manchester email: jklimdi{at}doctors.org.uk
References
1. Limdi JK, Crampton JR. Hereditary haemochromatosis. Q J Med 2004; 97:315–24.
2. Das D. Cancer and hereditary haemochromatosis. Q J Med 2004; 97:698–9.
3. Tiniakos G, Williams R. Cirrhotic process, liver cell carcinoma and extra hepatic malignant tumors in idiopathic haemochromatosis. Study of 71 patients treated with venesection therapy. Appl Pathol 1988; 6:128–38.[Medline]
4. Nelson RL, Davis FG, Persky V, Becker E. Risk of neoplastic and other diseases among people with heterozygosity for hereditary hemochromatosis. Cancer 1995; 76:875–9.[CrossRef][Web of Science][Medline]
5. Fracanzani AL, Conte D, Fraquelli M, Taioli E, Mattioli M, Losco A, Fargion S. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 2001; 33:647–51.[CrossRef][Web of Science][Medline]
6. Barton JC, Bertoli LF, Acton RT. HFE C282Y and H63D in adults with malignancies in a community medical oncology practice. BMC Cancer 2004; 4:6.[Medline]
7. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003; 125:1733–41.[CrossRef][Web of Science][Medline]
8. Fargion S, Valenti L, Dongiovanni P, Scaccabarozzi A, Fracanzani AL, Taioli E, Mattioli M, Sampietro M, Fiorelli G. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood 2001; 97:3707–12.
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