Normal liver enzymes do not indicate safety from alcohol-related liver disease: evidence from a Korean nationwide cohort

Abstract

OBJECTIVES: This study examined whether individuals with consistently normal liver enzyme levels are protected from alcohol-related liver disease and investigated whether heavy drinking increases liver disease risk independent of normal biomarker status. METHODS: We conducted a nationwide cohort study using Korean National Health Insurance Service data (2002-2019), including 19,035 participants aged >= 40 years who maintained normal liver enzyme levels (aspartate aminotransferase <= 40 & micro;/L, alanine aminotransferase <= 40 & micro;/L, gamma-glutamyl transferase <= 63 & micro;/L for men and <= 35 & micro;/L for women) across multiple examinations conducted between 2002 and 2008. Participants were categorized as abstainers (<= 1 time/mo), moderate drinkers (<= 2 times/wk), and heavy drinkers (>= 3 times/wk). Primary outcomes included incident liver disease identified using diagnostic codes. Cox proportional hazards models were used to estimate hazard ratios (HRs), with age-stratified analyses performed. RESULTS: Heavy drinkers demonstrated a significantly higher risk of liver disease than abstainers (HR, 1.73; 95% confidence interval [CI], 1.40 to 2.14), whereas moderate drinkers showed no significant association (HR, 1.06; 95% CI, 0.94 to 1.19). Consistent patterns emerged for middle-aged adults (40-69 years), with attenuated effects among participants aged >= 70 years. When alcoholic liver disease was analyzed specifically, both moderate (HR, 1.29; 95% CI, 1.05 to 1.58) and heavy drinkers (HR, 2.86; 95% CI, 2.09 to 3.91) exhibited significantly increased hazards. CONCLUSIONS: Despite normal liver enzyme levels, heavy alcohol consumption was associated with a significantly increased risk of liver disease. These findings challenge current reactive screening paradigms relying solely on biomarker abnormalities and support proactive alcohol counseling regardless of enzyme results. More sensitive strategies are needed for early detection of alcohol-related liver injury.