The effect of liver enzymes on body composition: a Mendelian randomization study

Abstract

Background: Higher alanine transaminase (ALT) is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function may affect body composition. To clarify, we assessed the association of liver function with muscle and fat mass observationally with two-sample MR as a validation.Methods: In the population-representative "Children of 1997" birth cohort, we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) (IU/L) at ~17.5 years with muscle mass (kg) and body fat percentage (%). Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) (100% change in concentration) were applied to fat-free and fat mass (kg) in the UK Biobank (n=~331,000) to obtain unconfounded estimates using MR.Results: Observationally, ALT was positively associated with muscle mass (0.11, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (-0.03, 95% CI -0.04 to -0.02) and fat percentage (-0.02, 95% CI -0.03 to -0.01). Using MR, ALT was inversely associated with fat-free mass (-0.41, 95% CI -0.64 to -0.19) and fat mass (-0.58, 95% CI -0.85 to -0.30). ALP was not clearly associated with body composition. GGT was positively associated with fat-free (0.30, 95% CI 0.01 to 0.06) and fat mass (0.41, 95% CI 0.10 to 0.71).Conclusion: ALT reducing fat-free mass provides a possible pathway for the positive association of ALT with diabetes, and suggests a potential target of intervention.