Gastroenterology

Gastroenterology

Volume 125, Issue 6, December 2003, Pages 1733-1741
Gastroenterology

Clinical-liver, pancreas, and biliary tract
Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives

https://doi.org/10.1053/j.gastro.2003.09.035Get rights and content

Abstract

Background & Aims: Iron overload may be carcinogenic. Patients with hereditary hemochromatosis (HH) are reportedly at a 20–200-fold risk of intrahepatic cancer, but the reported risks for nonhepatobiliary cancers are conflicting. The risk of cancer in heterozygous individuals (estimated allele frequency, 1/10 to 1/20) is unknown. This study aimed to better assess these risks. Methods: We performed a population-based cohort study of 1847 Swedish patients with HH and 5973 of their first-degree relatives using nationwide, population-based health and census registers. We used standardized incidence ratios (SIRs) as relative risk. Results: With 62 liver cancers and 128 nonhepatobiliary cancers, patients with HH were at a 20-fold risk of liver cancer (SIR, 21; 95% confidence interval [CI], 16–22) but an almost unaltered risk of all other cancers (SIR, 1.2; 95% CI, 1.0–1.4), including nonelevated risks for several gastrointestinal tract cancers. At 10 years of follow-up, the absolute risk of liver cancer was 6% among men and 1.5% among women. With 21 liver cancers and 508 nonhepatobiliary cancers, first-degree relatives were at an unaltered risk of extrahepatic cancer (SIR, 1.0; 95% CI, 0.9–1.1, including unelevated risks for gastrointestinal cancers) but at a modest and historic increased risk of hepatobiliary cancer (SIR, 1.5; 95% CI, 1.0–2.4), the histopathologic spectrum of which differed from the patients. Conclusions: Patients (particularly men) with HH are at increased risk for hepatocellular cancer, although the magnitude of the risk is lower than previous estimates. Overall cancer risk in first-degree relatives does not seem to be increased.

Section snippets

Patients

The cohort of patients with HH was assembled from 3 sources (Figure 1).

  • 1.

    In Sweden, virtually all inpatient care is public and referral to the hospital is based on county of residence rather than socioeconomic factors. The population-based Swedish Inpatient Register contains information on all inpatient care since 1964 (nationwide since 1987). About 99% of all hospitalizations are included.25 In this register, all individuals older than 15 years and discharged with a diagnosis of HH (coded

Patients

In total, 1847 patients were followed up for 12,398 person-years. During follow-up, 190 cancers were registered, corresponding to an SIR of 1.7 (95% CI, 1.5–2.0; Table 2). The relative risks for selected gastrointestinal cancers (cancers of the esophagus [SIR, 0; 95% CI, 0.0–3.2; n = 0), stomach [SIR, 0.3; 95% CI, 0.0–1.5; n = 1], pancreas [SIR, 1.0; 95% CI, 0.2–3.0; n = 3], and colon-rectum [SIR, 1.3; 95% CI, 0.7–2.0; n = 17]) and for the combined group of nonhepatobiliary cancers were not

Discussion

In this study, the hitherto largest population-based follow-up study of patients with HH and their first-degree relatives, we confirm the existence of an elevated risk of primary liver (hepatocellular) cancer among patients with HH. Among the first-degree relatives, we observed only a marginally increased and historic occurrence of liver cancer, the histopathologic spectrum of which differed from that of the patients. Furthermore, our study provided little support for the proposed increased

References (39)

  • A.M Jouanolle et al.

    Haemochromatosis and HLA-H

    Nat Genet

    (1996)
  • C.Q Edwards et al.

    Prevalence of hemochromatosis among 11,065 presumably healthy blood donors

    N Engl J Med

    (1988)
  • E Ryan et al.

    Underdiagnosis of hereditary haemochromatosislack of presentation or penetration?

    Gut

    (2002)
  • E.H Hanson et al.

    HFE gene and hereditary hemochromatosis: a HuGE review. Human genome epidemiology

    Am J Epidemiol

    (2001)
  • C Niederau et al.

    Survival and causes of death in cirrhotic and noncirrhotic patients with primary hemochromatosis

    N Engl J Med

    (1985)
  • Q Yang et al.

    Hemochromatosis-associated mortality in the United States from 1979 to 1992an analysis of multiple-cause mortality data

    Ann Intern Med

    (1998)
  • R.A Bradbear et al.

    Cohort study of internal malignancy in genetic hemochromatosis and other chronic non-alcoholic liver diseases

    J Natl Cancer Inst

    (1985)
  • A.W Hsing et al.

    Cancer risk following primary hemochromatosisa population-based cohort study in Denmark

    Int J Cancer

    (1995)
  • G Tiniakos et al.

    Cirrhotic process, liver cell carcinoma and extrahepatic malignant tumors in idiopathic haemochromatosis

    Appl Pathol

    (1988)
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    Supported by grant 00 1247 from the Swedish Cancer Society.

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