Circulating liver enzymes and risks of chronic diseases and mortality in the prospective EPIC-Heidelberg case-cohort study

Abstract

Objectives: Elevated liver enzyme concentrations in blood are indicative of liver diseases and may provide an early signal for being at risk for other chronic diseases. Our study aimed to assess the relationships of alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate transaminase (AST) and the De Ritis ratio (AST/ALT) with incidence and mortality of cardiovascular diseases (CVD) and the four most common cancers, that is, breast, prostate, colorectal and lung.

Setting, participants and outcome measures: We analysed a case-cohort sample of the prospective European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort, including cancer (n=1632), cancer mortality (n=761), CVD (n=1070), CVD mortality (n=381) and a random subcohort (n=2739) with an average follow-up duration of 15.6 years. Concentrations of liver enzymes were measured in prediagnostic blood samples and Prentice-weighted Cox regression models were used to estimate HRs with 95% CIs.

Results: High ALP levels were associated with increased risk for lung cancer and all-cause mortality (highest vs lowest quartile, multivariable adjusted HR=2.39 (95% CI 1.30 to 4.39), HR=1.31 (95% CI 1.02 to 1.67)), high AST levels with all-cause mortality (HR=1.45 (95% CI 1.15 to 1.82)), and a high De Ritis ratio with prostate cancer risk, all-cause and cancer mortality (HR=1.61 (95% CI 1.10 to 2.36), HR=1.60 (95% CI 1.25 to 2.04), HR=1.67 (95% CI 1.26 to 2.23)). Using cut-points for liver enzyme levels above normal, we observed positive associations for all-cause mortality with ALP, GGT and AST, and assigning a combined risk score resulted in positive associations with all-cause and cause-specific mortality.

Conclusions: Measurements of serum liver enzymes, as routinely performed in health check-ups, may support the identification of individuals at increased risk for all-cause mortality. Further prospective studies are needed to verify our first results on individual cancers and on a combined risk score.

Keywords: EPIC; cancer; cardiovascular diseases; case-cohort; liver enzymes.

Figure 1

Spearman partial correlation of liver enzymes with covariates in the European Prospective Investigation into Cancer-Heidelberg subcohort (n=2739), adjusted for sex and age at blood donation. Red depicts positive correlation and blue depicts negative correlation; the darker the shade, the stronger the correlation. ALP, alkaline phosphatase; ALT, alanine aminotransferase; apo, apolipoprotein; AST, aspartate aminotransferase; CRP, C reactive protein; GGT, gamma-glutamyltransferase; HbA1c, glycosylated haemoglobin A1c; HDL, high-density lipoprotein; Lp(a), lipoprotein a; N, number of subjects; TG, triglycerides.