Genetic Modulation of ALT Leads to Underestimation of Liver Injury in Male ALDH2*2 Drinkers.

Abstract

Background & aims: Serum alanine aminotransferase (ALT) is commonly used to detect hepatocellular injury. However, genetic and metabolic factors may modulate ALT levels. We focused on the potential impact of an in-activating mutation in aldehyde dehydrogenase 2 (ALDH2*2, rs671) polymorphism, prevalent among East Asians, on ALT levels and its interaction with alcohol consumption.

Methods: We analyzed Taiwan's Biobank data of 91,743 participants, 48.7% of whom were ALDH2*2 carriers, to assess the interaction between ALDH2 genotype, alcohol consumption and serum levels of liver enzymes. Mechanistic studies were conducted using ALDH2*2 knock-in (KI) mice exposed once to ethanol (1 g/kg), to evaluate ALT expression and serum levels, inflammation and liver injury. Integrative transcriptomic analyses, along with validation using publicly available datasets, were performed to identify transcriptional regulators of ALT.

Results: Male ALDH2*1/*2 drinkers exhibited a significantly lower serum ALT levels compared to ALDH2*1/*1 drinkers, despite higher gamma-glutamyl transferase levels (p < 0.001). Following acute ethanol administration to ALDH2*1/*2 mice, serum ALT elevation remained minimal despite comparable or greater accumulation of lipid oxidation product, 4-hydroxynonenal, enhanced MAPK activation, increased chemokine expression, and markedly aggravated histological necrosis relative to ethanol-treated wildtype mice. Notably, hepatic Alt1 mRNA and ALT protein expression were significantly reduced in ethanol-treated ALDH2*1/*2 mice. Integrated ChIP-seq analysis suggested that the transcription factor Hnf4a/HNF4A may regulate Alt1/ALT1 transcription. Validation using publicly available datasets confirmed reduced hepatic ALT1 expression in early inflammatory states and in patients with alcoholic hepatitis.

Conclusions: ALDH2 deficiency blunts serum ALT elevation following alcohol exposure by limiting hepatic ALT expression. These findings underscore the importance of considering ALDH2 genotype when interpreting serum ALT levels in male drinkers and provide a rationale for further investigation of genotype-informed ALT interpretation in East Asian populations.

Impact and implications: We found that serum ALT levels may underestimate liver injury in alcohol-consuming individuals carrying the ALDH2*2 (inactive) allele; genetic background and environmental factors may be considered when interpreting liver injury based on serum ALT, a commonly used clinical biomarker. Since previous studies have shown that ALDH2*2 carriers are at increased risk of alcohol-related liver disease, incorporating genotype-informed clinical strategies may improve early detection and clinical outcomes. These findings are particularly important for East Asian populations, where ALDH2*2 is common.

Clinical trial number: None.