Mutations in the HFE Gene and Their Interaction with Exogenous Risk Factors in Hepatocellular Carcinoma

doi:10.1006/bcmd.2001.0411

Blood Cells, Molecules, and Diseases

Volume 27, Issue 2, March 2001, Pages 505-511

https://doi.org/10.1006/bcmd.2001.0411 Get rights and content

Abstract

ABSTRACT

The possible role of iron in facilitating the development of liver cancer is still debated. The aims of this study were to define the prevalence of the mutations 845G → A and 187C → G (C282Y and H63D) in the HFE gene associated with hereditary hemochromatosis in Italian patients with hepatocellular carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carcinoma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinoma. None of the patients had a phenotype compatible with homozygous hereditary hemochromatosis. Interaction between HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepatitis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule out gender influence on patients' iron status by using the case-only approach specifically designed to estimate departure from multiplicative risk ratios under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6%, P < 0.03). At univariate analysis, iron overload was significantly associated with both HFE mutations (P < 0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P < 0.05). By multivariate analysis, a trend for an increased risk of being positive for hepatitis virus markers (OR 2.9, CI 95% 0.9–9.5) and of having been alcohol abusers (OR 3, CI 95% 0.7–14) was observed in patients heterozygous for the HFE mutations. These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.

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Does HFE Genotype Impact Macrophage Phenotype in Disease Process and Therapeutic Response?
2017, Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics
Iron is a critical cofactor involved in many important physiological processes throughout the human body. Therefore, mismanagement of iron can lead to numerous unfavorable effects, such as the generation of toxic reactive oxygen species during iron overload. Iron mismanagement is also a key component of multiple neurodegenerative diseases and cancer. One way in which iron overload occurs is through a mutation within the HFE, high iron, gene. However, the mechanism by which HFE effects these diseases has yet to be elucidated. In this review, we consider how the HFE genotype may influence the role of macrophages and microglia (the resident macrophage of the brain) in neurodegenerative disease and cancer. Macrophages appear to redistribute their iron to parenchymal cells when an HFE mutation is present, resulting in increased vulnerability to neurodegenerative diseases and cancer through macrophage mishandling of iron.
Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis
2012, Journal of Hepatology
Citation Excerpt :
The risk of HCC in patients with genetic haemochromatosis is well established, particularly in patients with overt cirrhosis [70]. Several teams have reported that the prevalence of HFE C282Y mutations was increased in patients with HCC [71,72]. However, other studies have failed to confirm these associations [73–75].
Liver carcinogenesis is a complex and multi-factorial process, in which both environmental and genetic features interfere and contribute to malignant transformation. Patients with cirrhosis are particularly exposed and justify periodical screenings in order to detect the early development of hepatocellular carcinoma (HCC). The risk of HCC is, however, not identical from one patient to another. The identification of host factors that may also play an important role in HCC development may improve our understanding of the implications of the various biological pathways involved in liver carcinogenesis; such progress may as well help refine the selection of patients who could benefit from specific preventative measures or could be given adapted screening policies. Numerous candidate-gene studies have reported associations between single nucleotide polymorphisms (SNPs) and the presence of HCC. Some of these publications unfortunately suffer from major methodological drawbacks because of their case–control, retrospective and monocentric aspect. Prospective cohort studies conducted in large homogeneous populations and comprising a sufficient number of events during follow-up may overcome these pitfalls, but require a long time to be conducted and are still scarce. More recently, the first Genome Wide Association studies (GWAs) have enabled the identification of unsuspected loci that may be involved in various steps implicated in liver tumourigenesis. Taken together, these studies highlight variants that modulate oxidative stress, iron metabolism, inflammatory and immune responses, DNA repair mechanisms or systems involved in cell-cycle regulation as genetic traits susceptible to modify the natural history of cirrhotic patients and partly explain the observed differences in the risk of HCC occurrence. However, large genetic epidemiology studies in the field of cancer diseases have suggested the limited ability of polymorphic traits, alone, to refine individual prognosis. The integration of various panels of genes into clinical scores may in the near future define a “genomic risk prediction” specific to liver cancer developed in cirrhotic patients.
Iron overload and HFE gene mutations in polish patients with liver cirrhosis
2011, Hepatobiliary and Pancreatic Diseases International
Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis.
Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes.
The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found.
Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.
EASL clinical practice guidelines for HFE hemochromatosis
2010, Journal of Hepatology
Citation Excerpt :
Subgroup analysis for gender specific prevalence and different etiologies were statistically underpowered. However, three studies in HCC reported a frequency of C282Y-homozygotes of 5.5–10% [101,102,106] and three further studies found an increased prevalence of C282Y heterozygosity [103,105,107]. Only one study [104] did not find an association between HCC and the C282Y-polymorphism.
Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFE-HC) is by far the most frequent and most well-defined inherited cause when considering epidemiological aspects and risks for iron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism [1]. Without therapeutic intervention, there is a risk that iron overload will occur, with the potential for tissue damage and disease. While a specific genetic test now allows for the diagnosis of HFE-HC, the uncertainty in defining cases and disease burden, as well as the low phenotypic penetrance of C282Y homozygosity poses a number of clinical problems in the management of patients with HC. This Clinical Practice Guideline will therefore, focus on HFE-HC, while rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a sub-type of ferroportin (FPN) mutations, on which limited and sparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC.
Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis
2010, Gastroenterologie Clinique et Biologique
Iron accumulation in the liver is considered to be a co-factor for progression of liver disease. Iron overload can enhance the effects of oxidative stress and influence the natural history of patients with cirrhosis, exposing them to a higher risk of hepatocellular carcinoma. The results of clinical studies designed to assess the impact of liver iron content on the risk of tumor development have remained controversial for some time. It is known that common factors can affect both liver iron overload and the risk of cancer, necessitating multivariate analyses of these features in large cohorts of cirrhotic patients. Furthermore, the causes and consequences of hepatic iron overload appear to depend on the cause of the underlying liver disease. Thus, the only solid evidence of a relationship between liver iron overload and event occurrence has come from longitudinal studies conducted in homogeneous cohorts of patients with cirrhosis. So far, the available data suggest that iron accumulation in the liver is an independent risk factor for hepatocellular carcinoma in patients with alcoholic cirrhosis and/or nonalcoholic hepatosteatosis, but not in those with viral hepatitis C cirrhosis.
L’accumulation de fer hépatique semble être un co-facteur impliqué dans la progression des lésions hépatiques en accentuant les effets du stress oxydant et pourrait influencer l’histoire naturelle des malades ayant une cirrhose constituée et exposés au risque de survenue du carcinome hépatocellulaire. Les études cliniques ayant évalué son influence sur le risque de développer une tumeur ont été controversées. Les facteurs influençant cette surcharge et le risque de survenue du cancer étant communs, l’analyse de ces différents facteurs nécessitait la réalisation d’analyses multivariées complexes dans des cohortes de grande ampleur. Par ailleurs, les causes et les conséquences de cette surcharge semblent dépendantes de la cause de la maladie hépatique sous-jacente, la cirrhose et le carcinome hépatocellulaire représentant des stades évolutifs communs à des maladies de cause et de physiopathologie différentes. Ainsi, seules les études longitudinales réalisées dans des cohortes de malades homogènes ont permis d’analyser les liens entre surcharge hépatique en fer et survenue d’évènements, suggérant notamment que cette surcharge serait un facteur de risque indépendant de survenue du carcinome hépatocellulaire chez les malades ayant une cirrhose alcoolique et/ou liée au syndrome métabolique, mais non chez les malades ayant une cirrhose virale C.
Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection
2009, Cancer Letters
Citation Excerpt :
HFE mutation seems to be associated with iron overload in patients with end-stage liver diseases and might accelerate hepatic fibrosis in patients with chronic hepatitis C infection [38]. However, results from small studies considering HFE mutations in HCC patients are conflicting, showing either no increased HCC risk [39] or a positive association of iron overload only in the presence of viral or alcohol induced liver damage or cirrhosis [40–42]. Hepatoblastoma is the most common childhood hepatic tumor [7].
The incidence of liver cancer is high in all low-resource regions of the world, with the exception of Northern Africa and Western Asia. The estimated worldwide number of new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries. Given the poor survival from this disease, the estimated number of deaths is similar to that of new cases.
Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, contamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is an important contributor to HCC burden in many low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations with low prevalence of HBV and HCV infection, and the association between tobacco smoking and HCC is now established. Diabetes is also related to an excess risk of HCC and the increased prevalence of overweight and obesity likely contributes to it.
The second most important type of liver cancer is cholangiocarcinoma, whose main known cause is infestation with the liver flukes, Opistorchis viverrini and Clonorchis sinensis, which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of liver cancer whose occurence is linked to occupational exposure to vinyl chloride.

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^☆: Grant support: Murst ex 40% 2000, Ricerca Finalizzata IRCCS 1998, Ricerca Finalizzata ISS 1999 (30/12/92 No. 502): “Storia naturale, terapia e prevenzione delle epatopatie acute e croniche.”

^☆☆: Abbreviations used: HH, hereditary hemochromatosis; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; LIC, liver iron concentration; OR, odds ratio; CI, confidence intervals; RR, relative risk.

^★: Communicated by E. Beutler, M.D., 02/20/01

^f3: Correspondence and reprint requests to: Silvia Fargion, Dipartimento di Medicina Interna, Università di Milano, Ospedale Maggiore IRCCS, Pad Granelli, Via F Sforza 35, Milan, Italy. Fax: 39-2-55180241. E-mail: [email protected].

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Regular ArticleMutations in the HFE Gene and Their Interaction with Exogenous Risk Factors in Hepatocellular Carcinoma☆,☆☆,★

Abstract

J. Hepatol.

Gastroenterology

Hepatology

J. Hepatol.

J. Hepatol.

Gastroenterology

J. Hepatol.

Blood Cells Mol. Dis.

Lancet

J. Hepatol.

Gastroenterology

Gastroenterology

Am. J. Gastroenterol.

Primary iron overload

The role of iron in cancer

Eur. J. Cancer Prevent.

Survival and causes of death in cirrhotic and non-cirrhotic patients with primary hemochromatosis

N. Engl. J. Med.

Regular Article
Mutations in the HFE Gene and Their Interaction with Exogenous Risk Factors in Hepatocellular Carcinoma☆,☆☆,★