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

Abstract

ObjectivesElevated 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 measuresWe 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.ResultsHigh 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.ConclusionsMeasurements 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.

Circulating liver function markers and colorectal cancer risk: A prospective cohort study in the UK Biobank

“…An inverse association of ALT with risk of overall cancer 10 or mortality has been reported in prior studies 30,44,45 . The EPIC‐Heidelberg case‐cohort study, the only existing study that examined AST in relation to CRC risk, reported no associations 11 . However, the EPIC‐Heidelberg study had a small number of CRC (n = 256) and the participants had much higher levels of liver enzymes than ours, which may have explained the null findings, based on our observation that the inverse association between liver function markers and CRC weakened at the higher end of the biomarker levels.…”

“…As for GGT, previous studies reported inconsistent but mostly positive associations with overall cancer risk, [11][12][13][14]46,47 and some also reported a positive association with CRC risk in men, 12 in current alcohol drinkers 13 and for colon cancer. 14 However, participants in those studies had much higher levels of GGT and most observed a higher disease risk in the highest category only.…”

“…However, systematic evaluation of liver function markers in relation to CRC risk remains lacking. Discrepant findings have been reported in prior studies that examined a few selected liver function markers only in relation to CRC risk 10‐19 . Moreover, these studies are limited by the relatively small sample size (most with <500 CRC cases) and inadequate control for confounding by general and visceral adiposity and lifestyle factors.…”

“…Discrepant findings have been reported in prior studies that examined a few selected liver function markers only in relation to CRC risk. [10][11][12][13][14][15][16][17][18][19] Moreover, these studies are limited by the relatively small sample size (most with <500 CRC cases) and inadequate control for confounding by general and visceral adiposity and lifestyle factors. In addition, none of these studies have yet examined the associations according to tumor subsites, despite the evidence that the gut-microbiota-liver axis may be of particular importance to proximal colon cancers compared to distal CRCs.…”

Liver status and outcomes in patients without previous known liver disease receiving anticoagulant therapy for venous thromboembolism

“…The evaluation of liver enzymes in patients without liver diseases has become an emerging topic of research, most likely due to progressive aging of the population, increasing use of hepatotoxic drugs and better knowledge of non-alcoholic fatty liver disease [ 1 – 3 ]. Elevated liver enzymes in asymptomatic people has been associated with an increased risk for cardiovascular diseases or death, [ 4 – 8 ] and an increased incidence of venous thromboembolism (VTE) in one study [ 9 ]. Moreover, liver fibrosis is an important prognostic factor in patients with a number of liver disorders [ 10 – 14 ].…”