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 two 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 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 (LPS) 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 two weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program.

Introduction to the Virtual Issue “Translational Studies in AUD: Liver Disease”

“…Moreover, the K18 M65:M30 ratio provides an estimate of the type of cell death (necrotic vs. apoptotic; Kramer et al., ). In this study (Kirpich et al., ), the K18 M65:M30 ratio was slightly >2 in patients with liver injury (based on elevated ALT levels) and was significantly higher than in subjects without liver damage, suggesting a necrosis was the predominant type of cell death in these patients. Of interest, there was relatively slow improvement in both K18 M65 and K18 M30, and levels of both the full‐length and caspase‐cleaved fragments were still significantly elevated after 8 days of abstinence.…”

“…Early diagnosis of the alcohol‐associated liver damage is important in order to reinforce the need for abstinence and to initiate drug/nutritional/therapy. In a study investigating a cohort of 48 otherwise healthy participants with AUD, but no clinical signs of ALD (34 males [M]/14 females [F]), an increase in plasma alanine aminotransferase (ALT) levels (normal range <40 U/l) as a marker of liver injury, was identified in a subset of patients (27M/6F; Kirpich et al., ). High ALT levels in these AUD patients were positively correlated with elevated levels of keratin 18 (K18) M65 ( r = 0.473, p = 0.005) and K18 M30 ( r = 0.357, p = 0.041).…”

“…Numerous clinical and experimental studies have shown that alcohol consumption (chronic and acute) impairs intestinal barrier integrity resulting in increased endotoxemia, a critical factor contributing to alcohol‐mediated liver disease (Szabo, ). Two studies recently published in ACER (Donnadieu‐Rigole et al., ; Kirpich et al., ) evaluated effects of alcohol withdrawal on gut permeability and endotoxemia in patients with AUD/ALD. Patients with mild ALD demonstrated a positive correlation between ALT (a marker of liver injury) and plasma lipopolysaccharide (LPS; a marker of endotoxemia) at admission to an alcohol treatment program (Kirpich et al., ).…”

“…Two studies recently published in ACER (Donnadieu‐Rigole et al., ; Kirpich et al., ) evaluated effects of alcohol withdrawal on gut permeability and endotoxemia in patients with AUD/ALD. Patients with mild ALD demonstrated a positive correlation between ALT (a marker of liver injury) and plasma lipopolysaccharide (LPS; a marker of endotoxemia) at admission to an alcohol treatment program (Kirpich et al., ). Elevated LPS levels significantly decreased by day 8 and persisted at those levels at day 15 of abstinence.…”

“…This virtual issue of Alcoholism: Clinical and Experimental Research ( ACER ) focuses on the interactions of AUD and alcohol‐associated liver disease. We cite important recent articles from ACER and a few selected companion papers from other journals that evaluate early diagnosis and mechanisms of alcohol‐associated liver disease (Kirpich et al., ; Samala et al., ), the role of alcohol withdrawal on the gut permeability and endotoxemia (Donnadieu‐Rigole et al., ; Kirpich et al., ), the impact of continued drinking on the gut‐liver axis in alcoholic liver disease (ALD; Bajaj et al., ), and methods of assessing drinking status in liver transplant recipients (Donnadieu‐Rigole et al., ; Fleming et al., ).…”