Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients

Abstract

Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal ≤ 13 µmol/L (Group 1 (Gr.1); n = 80), and elevated > 13 µmol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27; Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1β (IL-1β)), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)); 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-β, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients; AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-β, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.

Folic Acid Homeostasis and Its Pathways Related to Hepatic Oxidation in Adolescent Rats Exposed to Binge Drinking

“…It has been demonstrated for the first time that BD exposure during adolescence, as in chronic alcoholic patients, leads to HHcy [ 44 ]. Alterations in hepatic Hcy metabolism are reflected by altered levels of circulating plasma Hcy concentrations, and this is correlated with diverse pathologies, such as vascular dysfunction, neurodegenerative disorders and of course, hepatic injury, including those generated by EtOH consumption [ 45 ].…”

“…It is probable that BD-EtOH exposure contributes to increased serum Hcy levels by altering, as in Chr-EtOH exposition, the methionine cycle and transsulfuration pathway by increasing S-adenosylhomocysteine (SAH) and decreasing hepatic S-adenosylmethionine (SAM), as well as decreasing γ-GCS, leading to lower GSH synthesis. These effects of EtOH are attributed to the ROS generated, and they are exacerbated by a lack of hepatic FA that serves as a cofactor in these pathways [ 44 , 51 ]. Both situations have been detected in BD adolescent rats.…”

Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis

“…The development of ALD has been reported with chronic and heavy alcohol drinking in several studies [ 15 , 16 ]. Public health studies by the World Health Organization report an overall increase in consumption of alcohol worldwide and in the United States.…”

“…No AUD patient exhibited any clinical evidence of advanced ALD. Several of our studies further detail the information on admission, exclusion and inclusion, and detox treatment [ 15 , 39 , 40 , 41 ]. Patients were screened during the first three days of admission, in which they were decided to be part of the SOC group or to be eligible for randomization in studies.…”

Illustration of a Novel Gut-Brain Axis of Alcohol Withdrawal, Withdrawal-Associated Depression, Craving and Alcohol-Severity Index in Alcohol Use Disorder Patients

“…Subjects were diagnosed with alcohol use disorder according to DSM-IV, based on the alcohol dependence module of the SCID I-interview, and alcohol withdrawal for either of the two eligibility criteria: (1) clinically manifest significant alcohol withdrawal symptoms, with or without detectable blood alcohol concentrations (BACs); or (2) in the absence of the above, current intoxication above 0.1 g/dl BAC, self-reported history of continuous alcohol intake for more than the past one month, as well as self-reported previous episodes of significantly distressful alcohol withdrawal symptoms. More information on patient participation and enrollment can be obtained in previous publications 17,31,32 .…”