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

PLoS One. 2020 Feb 11;15(2):e0228737. doi: 10.1371/journal.pone.0228737. eCollection 2020.


Background: Higher alanine transaminase (ALT), indicating poor liver function, is positively associated with diabetes but inversely associated with body mass index (BMI) in Mendelian randomization (MR) studies, suggesting liver function affects muscle mass. To clarify, we assessed the associations of liver enzymes with muscle and fat mass observationally with two-sample MR as a validation.

Methods: In the population-representative "Children of 1997" birth cohort (n = 3,455), we used multivariable linear regression to assess the adjusted associations of ALT and alkaline phosphatase (ALP) at ~17.5 years with muscle mass and body fat percentage observationally. Genetic variants predicting ALT, ALP and gamma glutamyltransferase (GGT) were applied to fat-free and fat mass in the UK Biobank (n = ~331,000) to obtain unconfounded MR estimates.

Results: Observationally, ALT was positively associated with muscle mass (0.11 kg per IU/L, 95% confidence interval (CI) 0.10 to 0.12) and fat percentage (0.15% per IU/L, 95% CI 0.13 to 0.17). ALP was inversely associated with muscle mass (-0.03 kg per IU/L, 95% CI -0.04 to -0.02) and fat percentage (-0.02% per IU/L, 95% CI -0.03 to -0.01). Using MR, ALT was inversely associated with fat-free mass (-0.41 kg per 100% in concentration, 95% CI -0.64 to -0.19) and fat mass (-0.58 kg per 100% in concentration, 95% CI -0.85 to -0.30). ALP and GGT were unclearly associated with fat-free mass or fat mass.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alanine Transaminase / genetics
  • Alanine Transaminase / metabolism*
  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism*
  • Body Composition*
  • Body Mass Index
  • Cohort Studies
  • Female
  • Hand Strength
  • Humans
  • Linear Models
  • Liver / enzymology*
  • Male
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide
  • gamma-Glutamyltransferase / genetics
  • gamma-Glutamyltransferase / metabolism*


  • gamma-Glutamyltransferase
  • Alanine Transaminase
  • Alkaline Phosphatase