Liver Markers and Development of the Metabolic Syndrome

The Insulin Resistance Atherosclerosis Study

  1. Steven M. Haffner1
  1. 1Division of Clinical Epidemiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
  2. 2Leadership Sinai Centre for Diabetes, Mt. Sinai Hospital, Toronto, Ontario, Canada
  3. 3Department of Public Health Sciences, Wake Forest University School of Medicine, Winston Salem, North Carolina
  1. Address correspondence and reprint requests to Dr. Steven Haffner, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, Mail Code 7873, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: haffner{at}


Nonalcoholic fatty liver disease (NAFLD) is emerging as a component of the metabolic syndrome, although it is not known whether markers of NAFLD, including elevated concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALK), predict the development of metabolic syndrome. Our objective was to investigate the associations of elevated AST, ALT, and other liver markers, including C-reactive protein (CRP), with incident National Cholesterol Education Program–defined metabolic syndrome among 633 subjects in the Insulin Resistance Atherosclerosis Study who were free of metabolic syndrome at baseline. Insulin sensitivity (Si) and acute insulin response (AIR) were directly measured from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years. After 5.2 years, 127 individuals had developed metabolic syndrome. In separate logistic regression models adjusting for age, sex, ethnicity, clinic, and alcohol consumption, subjects in the upper quartiles of ALT, ALK, and CRP were at significantly increased risk of incident metabolic syndrome compared with those in the lowest quartile: ALT, odds ratio 2.50 (95% CI 1.38–4.51); ALK, 2.28 (1.24–4.20); and CRP, 1.33 (1.09–1.63). Subjects in the upper quartile of the AST-to-ALT ratio were at significantly reduced metabolic syndrome risk (0.40 [0.22–0.74]). After further adjustment for waist circumference, Si, AIR, and impaired glucose tolerance, the associations of ALT and the AST-to-ALT ratio with incident metabolic syndrome remained significant (ALT, 2.12 [1.10–4.09]; the AST-to-ALT ratio, 0.48 [0.25–0.95]). These associations were not modified by ethnicity or sex, and they remained significant after exclusion of former and heavy drinkers. In conclusion, NAFLD markers ALT and the AST-to-ALT ratio predict metabolic syndrome independently of potential confounding variables, including directly measured Si and AIR.

  • Received May 20, 2005.
  • Accepted August 4, 2005.
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