Liver Injury and Endotoxemia in Male and Female Alcohol‐Dependent Individuals Admitted to an Alcohol Treatment Program

Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol‐induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex‐related differences in these parameters in alcohol‐dependent individuals admitted to an alcohol treatment program. A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. Sixty‐nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor‐alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. The study documented the association of mild alcohol‐induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program. The study demonstrated that mild alcohol‐induced liver injury (alcohol‐dependent individuals with slightly elevated ALT [Group 2] versus normal ALT [Group1]) was associated with endotoxemia, which improved with 2 weeks of abstinence. Liver damage and endotoxemia were greater in females than males, although they had fewer drinks/day and shorter lifetime duration of heavy drinking. The study provides further evidence for the role of the gut:liver axis in the development of ALD and a rationale for LPS‐targeted therapies for early ALD.