Elsevier

Cancer Epidemiology

Volume 40, February 2016, Pages 179-187
Cancer Epidemiology

Prospective association of liver function biomarkers with development of hepatobiliary cancers

https://doi.org/10.1016/j.canep.2016.01.002Get rights and content

Highlights

  • This is a case-control study nested in the multicentre prospective cohort.

  • Associations of 5 liver function biomarkers with hepatobiliary cancers were studied.

  • Positive associations were observed for liver but not biliary tract cancer risks.

Abstract

Introduction

Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers.

Methods

A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI).

Results

In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95%CI:2.72–6.59; OR(ALP) = 3.43, 95%CI:2.31–5.10;OR(AST) = 3.00, 95%CI:2.04-4.42; OR(ALT) = 2.69, 95%CI:1.89–3.84; OR(Bilirubin) = 2.25, 95%CI:1.58–3.20). Each liver enzyme (OR(GGT) = 4.98; 95%CI:1.75–14.17; OR(AST) = 3.10, 95%CI:1.04–9.30; OR(ALT) = 2.86, 95%CI:1.26–6.48, OR(ALP) = 2.31, 95%CI:1.10–4.86) but not bilirubin (OR(Bilirubin) = 1.46,95%CI:0.85–2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP) = 1.59, 95%CI:1.20–2.09).

Conclusion

This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.

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

References (37)

  • F.D. Mendes et al.

    Primary sclerosing cholangitis

    Clin. Liver Dis.

    (2004)
  • IARC, Estimated incidence mortality and 5-year prevalence. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx,...
  • A.I. Gomaa et al.

    Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis

    World J. Gastroenterol.

    (2008)
  • G.A. Michelotti et al.

    NAFLD, NASH and liver cancer

    Nat. Rev. Gastroenterol. Hepatol.

    (2013)
  • R. Jinjuvadia et al.

    The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis

    J. Clin. Gastroenterol.

    (2014)
  • E.G. Giannini et al.

    Liver enzyme alteration: a guide for clinicians

    CMAJ: Canadian Medical Association Journal = journal de l’Association medicale canadienne

    (2005)
  • C.H. Kim et al.

    Association of serum gamma-glutamyltransferase and alanine aminotransferase activities with risk of type 2 diabetes mellitus independent of fatty liver

    Diabetes Metab. Res. Rev.

    (2009)
  • M. Nannipieri et al.

    Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study

    Diabetes Care

    (2005)
  • Cited by (40)

    • Association between non-alcoholic fatty liver disease and the risk of biliary tract cancers: A South Korean nationwide cohort study

      2021, European Journal of Cancer
      Citation Excerpt :

      A few small case–control studies and only one population-based study have reported the association between NAFLD and the risk of cholangiocarcinoma. However, their results were inconsistent, with positive [8–12] or null associations [13–15]. Furthermore, no studies have assessed the association between NAFLD and the risk of gallbladder cancer.

    • Acute coumaphos organophosphate exposure in the domestic dogs: Its implication on haematology and liver functions

      2018, International Journal of Veterinary Science and Medicine
      Citation Excerpt :

      Although, hepatic congestion and hepatocellular necrosis were seen at post mortem examination in the affected animals, liver enzymes – ALT, AST, GGT and ALP values only showed marginal increases which were not statistically significant, but may require further appraisal in clinical diagnosis. This may not be unconnected with acute nature of the toxicity, because elevated plasma enzymes are common indicators of hepatitis, hepatocellular injuries and biliary obstruction, especially with ALT, AST and GGT [34,35], while ALP, though not specific, is more associated with skeletal muscle activities, bone resorption and remodeling. Acute Plasma ALP values could also increase in cases of intestinal mucosal damage and renal diseases such as nephrosis (as reported in the present study) and renal tubular acidosis [36,37].

    View all citing articles on Scopus
    1

    Deceased.

    View full text