Prospective association of liver function biomarkers with development of hepatobiliary cancers

M. Stepien, V. Fedirko, T. Duarte-Salles, P. Ferrari, H. Freisling, E. Trepo, A. Trichopoulou, C. Bamia, E. Weiderpass, A. Olsen, A. Tjonneland, K. Overvad, M. C. Boutron-Ruault, G. Fagherazzi, A. Racine, T. Kuhn, R. Kaaks, K. Aleksandrova, H. Boeing, P. LagiouV. Benetou, D. Trichopoulos, D. Palli, S. Grioni, R. Tumino, A. Naccarati, S. Panico, H. B. Bueno-de-Mesquita, P. H. Peeters, E. Lund, J. R. Quiros, O. C. Napoles, M. J. Sanchez, M. Dorronsoro, J. M. Huerta, E. Ardanaz, B. Ohlsson, K. Sjoberg, M. Werner, H. Nystrom, K. T. Khaw, T. J. Key, M. Gunter, A. Cross, E. Riboli, I. Romieu, M. Jenab

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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.


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).


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).


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.

Original languageUndefined/Unknown
Pages (from-to)179-87
Number of pages9
JournalCancer Epidemiology
Early online date11 Jan 2016
Publication statusPublished - Feb 2016

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