Liver Enzyme Levels Are Associated With Metabolic Syndrome and Predict All-Cause and Cardiovascular Mortality in a High-Risk Population: The Strong Heart Family Study

Introduction: Non-alcoholic fatty liver disease has been associated with an increased risk of cardiovascular disease (CVD). Levels of the circulating hepatic enzymes aspartate amino transferase (AST) and alanine amino transferase (ALT) are used as non-invasive biomarkers of liver fat and fibrosis. A number of studies have investigated the potential for these biomarkers of liver function, as well as their ratio AST/ALT, to predict CVD risk, with equivocal results. We hypothesized that these measurements might be important biomarkers of CVD in American Indians (AI) who experience high rates of both liver disease and type 2 diabetes-related CVD. Methods: The Strong Heart Family Study (SHFS) is a population-based family study of heart disease and its risk factors in AI. Participants (n=2760) were recruited from 12 tribes located within 3 geographical regions in Arizona, North/South Dakota, and Oklahoma. Circulating biomarkers and metabolic measures were assessed during a clinic visit in 2001-2003. Participants were followed for morbidity and mortality events until the end of 2016. Median follow-up time was 14.5 years. Results: In this study, 59.8% were female, mean (± standard deviation) age was 40.8 ±17.2 years, mean BMI was 31.3 ± 7.5 kg/m 2 , 19% had type 2 diabetes (T2D), 32.6% were hypertensive, and 36.1% were current smokers. In univariate analyses, higher ALT and AST levels (IU/L) were associated with all components of the metabolic syndrome (MS), i.e., increased waist circumference, triglycerides, blood pressure, fasting glucose, and decreased HDL-C; all p<0.01. Among diabetes-free participants, those with MS (n=790, as defined by NCEP ATP III criteria) had higher ALT (37.0 ± 0.6 IU/L vs. 29.4 ± 0.6 IU/L, p<0.01) and AST (28.5 ± 0.5 IU/L vs. 24.5 ± 0.5 IU/L, p<0.01) than those who were free of MS (n=1419). In a Cox proportional-hazards model, ALT, AST and the AST/ALT ratio were significantly associated with all-cause mortality (n= 439 deaths), when controlling for age, sex, smoking status, hypertension and T2D. Hazards ratios (95% confidence interval) associated with ALT, AST, and ALT/AST ratio were 1.02 (1.01, 1.03), 1.03 (1.02, 1.04), and 1.2 (1.1, 1.3) respectively. In a separate model, AST and AST/ALT ratio were significantly associated with CVD mortality (n=120), and respective hazard ratios were 1.03 (1.01, 1.05) and 1.2 (1.01, 1.43). Parallel trends for associations between these liver biomarkers and incident CVD events (n=272) were not statistically significant though the hazard ratio related to AST/ALT ratio was 1.12 (0.97, 1.3). Conclusions: In American Indians of the SHFS, liver function biomarkers are significantly associated with metabolic syndrome and its components, and predict all-cause and cardiovascular mortality, suggesting that common mechanisms impact MS-related CVD risk factors and liver disease biomarker levels in this high-risk population.