Prospective association of liver function biomarkers with development of hepatobiliary cancers
Introduction
Liver cancer is the sixth most commonly diagnosed cancer and the second leading cause of cancer death worldwide [1]. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is diagnosed at late stages and characterised by a poor prognosis [2]. Established HCC risk factors are chronic hepatitis B and C virus (HBV/HCV) infection, heavy alcohol drinking leading to liver cirrhosis, smoking and dietary aflatoxin exposure [3]. Important evidence from prospective studies also supports a role for diabetes and obesity-associated non-alcoholic fatty liver disease (NAFLD) as important HCC risk factors [4], [5]. The group of intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC; tumours of the gall bladder and extra-hepatic bile ducts) are anatomically related to HCC. They too are often diagnosed at late stages when prognosis is poor, also with little existing information about their key determinants [6].
Liver function biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used in clinical diagnosis of various disorders, including those related to liver function impairment and damage. Higher levels of specific combinations of these liver function biomarkers have been shown to be independently associated with NAFLD, liver cirrhosis, hepatitis infection, biliary obstruction [7] and diabetes risk [8], [9], which is itself also associated with increased risk of HCC [10]. Previous case-control studies have found that GGT, ALT and AST are increased in approximately 90% of diagnosed HCC cases while half of the cases also showed elevated liver-specific alkaline phosphatase (ALP) or bilirubin levels [11]. For bile duct cancers, the sparse available data suggest that approximately 70% of cases have elevated levels of ALP and GGT [12]. It is thus possible that alterations in liver function biomarkers occur during the early development of hepatobiliary cancers and may relate to some of the underlying mechanisms of tumour development at these sites. In a recent systematic review GGT but not ALT was associated with increased risk of overall and liver cancer but the geographical variations were observed for ALT [13]. Existing prospective observational studies investigating the association between liver function biomarkers and liver cancers have been mostly based on Asian populations [14], [15], and/or limited only to particular enzymes (either transaminases, ALT and AST, or GGT) [16], [17]. A cohort study based on a mostly hepatitis negative Taiwanese subjects measured only transaminases and found that both enzymes were good independent predictors for HCC development [16]. Other studies based on hepatitis infected Asian populations have found positive HCC risk associations with many liver enzymes, but not bilirubin [14], [15]. In a Swedish cohort, higher GGT levels were prospectively associated with increased risk for several cancer sites, including cancer in the liver, suggesting that this individual enzyme is not specific to disease in the liver and biliary tract [17]. However, there is currently little prospective data on this topic from additional Western populations where chronic hepatitis infections are less predominant while other HCC risk factors such as excessive alcohol intake, obesity or diabetes are common. Very little is known about possible associations with IHBC or GBTC, particularly from prospective cohort settings.
To address this, we aimed to evaluate associations between risk of HCC, IHBC and GBTC and five commonly measured liver function biomarkers (GGT, ALT, AST, ALP and bilirubin) using a nested case-control study within the large European Prospective Investigation into Cancer and Nutrition (EPIC) cohort,.
Section snippets
Study design
EPIC is a large multicentre prospective cohort study designed to investigate the association between diet, lifestyle and environmental factors and the incidence of various types of cancer and other chronic diseases. The rationale, study design and methods of recruitment are described in detail elsewhere [18], [19]. Briefly, diet and lifestyle data were collected from approximately 520,000 men and women aged 20–85 years enrolled between 1992 and 2000 in 23 centres throughout 10 European
Results
Selected baseline characteristics of cancer cases and their matched controls and correlations between variables are presented in Table 1 and Supplementary Tables 1 and 2. Supplementary Fig. 1 illustrates differences in biomarker levels between cases and controls over time. For the description see supplementary file.
Discussion
In this study, all of the measured liver enzymes (GGT, ALT, AST, ALP) and total bilirubin were shown to be positively associated with HCC risk. For IHBC, increases in the enzymes, but not bilirubin, were associated with higher risk. But for GBTC, which includes cancers of gallbladder and extra-hepatic bile ducts, only ALP showed a statistically significant association. Assessment of liver function markers can provide meaningful insight into the clinical condition of the liver, including
Conflict of interests
None
Specific author contributions:
The authors’ responsibilities were as follows- ER: is the overall PI of the EPIC study which is jointly coordinated from ICL and IARC; MJ, VF and MS: conceptualized, designed, obtained funding for and carried out the present research; MS: performed the statistical analysis; MS, VF and MJ: contributed to the writing of the manuscript and data interpretation. Contributing authors from each collaborating centres provided the original data and biological samples, information on the respective
Acknowledgements
Financial support: This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA) (grant number 2009-139; PI: M. Jenab). The coordination of EPIC is financially supported by the European Commission (DG-SANCO); and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Générale de l’Education Nationale; and Institut National de la Santé
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