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Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives
Open accessAbstract
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.
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“Murine erythroleukemia cells that overexpress ferritin H displayed lower levels of the labile iron pool and ROS (78).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [78]
In the citing paper
“Accumulating evidence shows that ferritin acts as an antioxidant protein (59, 60, 78, 159, 227, 243).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [78]
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“induction of ferritin mRNA was observed in mouse liver (303) and erythroid cells (78) treated with oxidative stress–inducing compounds.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [78]
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“overexpression or knockdown of ferritin expression in mammalian cells has proven the cytoprotective role of ferritin under prooxidative conditions (59, 60, 78, 159, 227, 243).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [78]
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Can Schistosoma japonicum infection cause liver cancer?
Jain, S. (2025) · Journal of Helminthology · doi:10.1017/s0022149x24000762 · Cited by 12
“Rare genetic and medical conditions including Wilson ’ s disease (Xu & Hajdu, 2008), Porphyria cutanea tarda (Baravelli et al., 2019), untreated hereditary hemochromatosis (Elmberg et al., 2003) among other issues are important risk factors in LC induction.”
Human genetic variation and the risk of hepatocellular carcinoma development
Ezzikouri, S., Benjelloun, S., & Pineau, P. (2013) · Hepatology International · doi:10.1007/s12072-013-9463-y · Cited by 11
“Hemochromatosis 20 [91]”
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Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients
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“Two of the CD patients with HH in the current study developed liver cancer, and this is consistent with our earlier study showing that HH patients are at a highly increased risk of liver cancer (standardized incidence ratio = 21) [3].”
BackgroundResultSelf-citationTrace Elements and Chemotherapy Sensitivity
Liu, Z., Yang, W., Long, G., & Wei, C. (2016) · Biological Trace Element Research · doi:10.1007/s12011-016-0667-6 · Cited by 11
“, hereditary hemochromatosis and Wilson’s disease), the accumulation of trace elements is related to the high incidence of HCC [20, 21].”
BackgroundTian, T., Xiao, F., Li, H., Ding, D., Wei, D., Hou, G., Zhao, L., Yang, Y., Yang, Y., & Zhou, W. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-4608 · Cited by 11
“Mutations in HFE and TMPRSS6 were reported to be associated with hereditary hemochromatosis (HH) (27,28), which is a risk factor for the development of liver carcinoma (29).”
BackgroundSurveillance for Hepatocellular Carcinoma
Chowdhury, R., & Satoskar, R. S. (2012) · Humana Press eBooks · doi:10.1007/978-1-61779-863-4_2 · Cited by 11
Recent Advancements in Known and Emerging Risk Factors of Hepatocellular Carcinoma
Hussain, M. M., Bi, F., Wang, J., Zhai, A., Li, F., & Hu, H. (2025) · Cancer Medicine · doi:10.1002/cam4.71330 · Cited by 11
Radiation-Induced Sarcoma After Heterotopic Ossification Prophylaxis
Rosenberg, D. M., Onderdonk, B. E., Majeed, N. K., Guzman, G., Farid, Y. R., Connell, P. P., & Son, C. H. (2019) · JBJS Case Connector · doi:10.2106/jbjs.cc.19.00146 · Cited by 10
Alpha-1 antitrypsin deficiency and primary liver cancers
Schneider, C. V., Decraecker, M., Bèaufrere, A., Payancé, A., Coilly, A., Schneider, K. M., Bioulac‐Sage, P., Blanc, J., Bail, B. L., Amintas, S., et al. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189290 · Cited by 9
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Screening for Hepatocellular Carcinoma
Lui, H.-F. (2011) · International Journal of Hepatology · doi:10.4061/2011/363151 · Cited by 9
Nilsson, R., & Liu, N. (2020) · Radiation Medicine and Protection · doi:10.1016/j.radmp.2020.11.003 · Cited by 9
Prevention of Hepatocellular Carcinoma
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Iron, Copper, and Selenium: Cancer's Thing for Redox BlingPreprint
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Diabetes and liver cancer risk: A stronger effect in Whites than Blacks?
Conway, R. B. N., Sudenga, S. L., McClain, D. A., & Blot, W. J. (2020) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107816 · Cited by 8
Is Schistosoma mansoni playing a part in liver carcinogenesis?
Jain, S. (2024) · Journal of Helminthology · doi:10.1017/s0022149x24000506 · Cited by 9
“…non-alcoholic steatohepatitis (Dhamija et al. 2019), exposure to hepa-tocarcinogen Aflatoxin B1 (Hamid et al. 2013), rare medical conditions like Wilson ’ s disease (Xu and Hajdu 2008), Porphyria cutanea tarda (Baravelli et al. 2019), and untreated hereditary hemochromatosis (Elmberg et al. 2003).”
Allameh, A., Hüttmann, N., Charlebois, E., Katsarou, A., Gu, W., Gkouvatsos, K., Pasini, E., Bhat, M., Minić, Z., Berezovski, M. V., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03108-2 · Cited by 9
Puzzling out iron complications in cancer drug resistance
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Insights in Molecular Therapies for Hepatocellular Carcinoma
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Adenoviral gene therapy in hepatocellular carcinoma: a review
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Hemochromatosis Gene Status as a Risk Factor for Barrett’s Esophagus
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“First, several studies suggest that conditions which increase the total body iron stores may increase the risk of both hepatic and non-hepatic malignancies [5–10].”
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“Cancer risk in patients with HH has been well studied, with a 20‐fold increased risk of HCC and minimal increased risk of all other cancers[26]; the risk for cancer in HH following LT is not well described.”
BackgroundCheng, A., & Al-Samkari, H. T. (2024) · Blood Advances · doi:10.1182/bloodadvances.2024013666 · Cited by 6
“23,24 This may re fl ect (1) inadequate power of our study population to detect a signi fi cant correlation, especially given the overall low prevalence of malignancy in the studied population; (2) a primarily young adult population with underrepresentation of older patients who are at highest risk…”
BackgroundHepatic Pathobiology of Iron Overload
Ruddell, R. G., & Ramm, G. A. (2011) · Humana Press eBooks · doi:10.1007/978-1-60327-485-2_18 · Cited by 7
Hereditäre Hämochromatose, Alpha-1-Antitrypsin-Mangel und Morbus Wilson
Zhou, H. J., & Hp, F. (2007) · Der Pathologe · doi:10.1007/s00292-007-0954-2 · Cited by 6
Genetic variants underlying precancerous conditions of hepatocellular carcinoma
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“130 131 Moreover, even in the absence of cirrhosis, patients with HFE-associated HH have an increased risk of HCC, further suggesting a carcinogenic role for hepatic iron deposition, primarily mediated by DNA damage and lipid peroxidation induced by iron-driven oxidative stress.”
Rugh, A. B. (2012) · Palgrave Macmillan US eBooks · doi:10.1057/9781137012883_1 · Cited by 6
Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis
Jarvik, G. P., Wang, X., Fontanillas, P., Kim, E., Chanprasert, S., GORDON, A. S., Bastarache, L. A., Kowdley, K. V., Harrison, T. A., Rosenthal, E. A., et al. (2020) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2020.100010 · Cited by 5
“The association of clinical HH and CRC has not been studied in large samples, but one smaller study of 1,847 individuals with HH and 5,973 of their first-degree relatives found no association.(17) The reported HFE genotype association with CRC is based on small sample sizes and has not been incorporated into clinical…”
Metadata
- Authors
- Elmberg, M., Hultcrantz, R., Ekbom, A., Brandt, L., Olsson, S., Olsson, R., Lindgren, S., Lööf, L., Stål, P., Wallerstedt, S., Almer, S., Sandberg-Gertzén, H., & Askling, J.
- Affiliations
- Karolinska University Hospital (SE)
- Sahlgrenska University Hospital (SE)
- Uppsala University Hospital (SE)
- Linköping University Hospital (SE)
- Corresponding author
- Elmberg, Maria
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 125
- Issue
- 6
- Pages
- 1733-1741
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2165680505
- Cited by
- 273
- References
- 41
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 14 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 14 · 2019: 12 · 2018: 8 · 2017: 11 · 2016: 11 · 2015: 8 · 2014: 15 · 2013: 19 · 2012: 17
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Cancerfonden
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- hereditary hemochromatosis, cancer risk, iron overload, hepatocellular carcinoma, liver cancer, gastrointestinal cancer, first-degree relatives, heterozygous carriers, familial cancer risk
- MeSH terms
- Hemochromatosis Protein, Adolescent, Adult, Aged, Aged, 80 and over, Female, Hemochromatosis, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Membrane Proteins, Middle Aged, Mutation, Risk, Histocompatibility Antigens Class I
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