Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients.

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH), and examines its association with disease severity, and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in severe (MELD≥20) AAH patients compared to non-severe AAH (MELD≤19), or non-alcohol-consuming controls, suggesting that urine HPMA is a novel non-invasive biomarker in severe AAH. The association between HPMA and MELD in AAH patients was nonlinear. In non-severe patients, there was a positive trend, although not significant, while in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with CK18-M30 (adjusted R2 =0.812, p=0.016) and CK18-M65 (adjusted R2 =0.670, p=0.048); similarly HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 =0.875, p=0.007) and CK18-M65 (adjusted R2 =0.831, p=0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 =0.777, p=0.022) or TNFα (adjusted R2 =0.677, p=0.046). In severe AAH patients, IL-1β, IL-8 and TNFα are the predominant proinflammatory cytokines that interact with HPMA, and play important mediating roles in influencing the extent/pattern of liver cell death.