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Background and aim We sought to determine the association between alanine aminotransferase (ALT) in the normal range and mortality in the absence of liver dysfunction to better understand ALT’s clinical significance beyond liver injury and inflammation. Methods A cohort of 2,708 male and 3,461 female adults aged 20–75 years without liver dysfunction (ALT<30 in males & <19 in females, negative viral serologies, negative ultrasound-based steatosis, no excess alcohol consumption) from the National Health and Nutrition Examination Survey (NHANES)-III (1988–1994) were linked to the National Death Index through December 31, 2015. Serum ALT levels were categorized into sex-specific quartiles (Females: <9, 9–11, 11–14, ≥14 IU/L, Male: <12, 12–15, 15–20, ≥20 U/L). The primary outcome was all-cause mortality. Hazard ratios (HRs) were estimated, adjusting for covariates and accounting for the complex survey design. Results Relative to males in the lowest quartile (Q1), males in the highest quartile (Q4) had 44% decreased risk of all-cause mortality (aHR [95% CI]: 0.56 [0.42, 0.74]). Females in Q4 had 45% decreased risk of all-cause mortality (aHR [95% CI]: 0.55 [0.40, 0.77]). Males with BMI <25 kg/m2 in Q4 had significantly lower risk of all-cause mortality than Q1; however, this association did not exist in males with BMI ≥25 (BMI<25: 0.36 [0.20, 0.64], BMI≥25: 0.77 [0.49, 1.22]). Risk of all-cause mortality was lower in males ≥50 years than in males<50 (age≥50: 0.55 [0.39, 0.77], age<50: 0.81 [0.39, 1.69]). These age- and BMI-related differences were not seen in females. Conclusion ALT within the normal range was inversely associated with all-cause mortality in U.S. adults.

Objective To determine whether a low aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AST/ ALT ratio) is associated with insulin resistance among those without liver dysfunction. Methods In this cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2011-2016, we included 2747 (1434 male and 1313 nonpregnant female) adults ≥20 years without evidence of liver dysfunction (ALT<30 in male and <19 in female, negative viral serologies, no excess alcohol consumption, no elevated transferrin saturation, AST/ALT <2). Serum AST/ALT ratio was categorized into sex-specific quartiles (female: <1.12, 1.12-1.29, 1.29-1.47, ≥1.47 and male: <0.93, 0.93-1.09, 1.09-1.26, ≥1.26). The primary outcome was insulin resistance, as determined by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index score ≥3. Covariate-adjusted odds ratios (ORs) were estimated. Study analysis completed from 13 March 2020 to 21 April 2021. Results Among the 2747 individuals, 33% had insulin resistance. Those in the lowest quartile (Q1) of AST/ALT had 75% higher adjusted odds of insulin resistance compared to the highest quartile (Q4) [aOR (95% confidence interval (CI), 1.75 (1.20-2.57)]. This association was more pronounced in those with elevated BMI [Q1 vs. Q4;, BMI < 25: 0.66 (0.26-1.69); NAFLD per Fatty Liver Index ≥ 60: 2.04 (1.21-3.44), No NAFLD: 1.68 (0.94-3.01)]. Conclusion Lower AST/ALT ratio is associated with increased insulin resistance among those with healthy-range ALT, especially in those with BMI greater than or equal to 25 kg/m 2 .

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