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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Alcohol-Dependent Subjects; Endotoxemia; Mild Alcoholic Liver Disease.

Fig. 1

Plasma ALT and AST levels in a cohort of alcohol-dependent individuals at the beginning of alcohol detoxification program. (A) Based on initial ALT levels, patients were divided into two groups: Group 1 (ALT < 40 U/L, n=15) and Group 2 (ALT ≥ 40 U/L, n=33). (B) AST levels in Group 1 and Group 2 paralleled ALT levels. (C) The AST/ALT ratio. (D-F) Sex differences between Groups 1 and 2 in ALT, AST levels, and AST/ALT ratio. The data are expressed as means ± SEM, * p < 0.05. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Fig. 2

Plasma levels of liver injury markers in alcohol dependent subjects during alcohol detoxification program. (A) CK18 M65, (B) CK18 M30, (C) CK18 M65:M30 ratio, and (D) L-FABP. Analysis of variables was performed at the onset (baseline), day 8, and day 15 of the program. The data are expressed as means ± SEM, * p < 0.05. CK18, Cytokeratin 18; L-FABP, liver fatty acid-binding protein.

Fig. 3

Plasma cytokine levels in alcohol dependent patients during alcohol detoxification program. (A) TNF-α, and (B) PAI-1 levels. Analysis of variables was performed at the onset (baseline), day 8 , and day 15 of the program. The data are expressed as means ± SEM, * p < 0.05. PAI-1, Plasminogen activator inhibitor type 1; TNF-α, tumor necrosis factor alpha

Fig. 4

Plasma markers of endotoxemia in alcohol dependent subjects during alcohol detoxification program. (A) LPS levels were increased in patients with liver injury (Group 2) compared to patients without liver damage (Group 1). (B) LPS levels were positively correlated with ALT levels at T1 in Group 2 males. (C) Flagellin levels were significantly increased at T1 in patients with liver injury compared to individuals without liver damage. Analysis of variables was performed at the onset (baseline), day 8, and day 15 of the program. The data are expressed as means ± SEM, * p < 0.05. Correlation analysis was performed at the onset of detoxification therapy. ALT, alanine aminotransferase; LPS, lipopolysaccharides.