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Alcohol‐associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol‐associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)‐derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA‐derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End‐Stage Liver Disease score

Bile acids (BAs) play important functions in the development of alcohol‐associated liver disease (ALD). In the current study, urine BA concentrations in 38 patients with well‐described alcohol‐associated hepatitis (AH) as characterized by Model for End‐Stage Liver Disease (MELD), 8 patients with alcohol‐use disorder (AUD), and 19 healthy controls (HCs) were analyzed using liquid chromatography–mass spectrometry. Forty‐three BAs were identified, and 22 BAs had significant changes in their abundance levels in patients with AH. The potential associations of clinical data were compared to candidate BAs in this pilot proof‐of‐concept study. MELD score showed positive correlations with several conjugated BAs and negative correlations with certain unconjugated BAs; taurine‐conjugated chenodeoxycholic acid (CDCA) and MELD score showed the highest association. Cholic acid, CDCA, and apocholic acid had nonsignificant abundance changes in patients with nonsevere ALD compared to HCs but were significantly increased in those with severe AH. Receiver operating characteristic analysis showed that the differences in these three compounds were sufficiently large to distinguish severe AH from nonsevere ALD. Notably, the abundance levels of primary BAs were significantly increased while most of the secondary BAs were markedly decreased in AH compared to AUD. Most importantly, the amount of total BAs and the ratio of primary to secondary BAs increased while the ratio of unconjugated to conjugated BAs decreased as disease severity increased. Conclusion: Abundance changes of specific BAs are closely correlated with the severity of AH in this pilot study. Urine BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage ALD and may have prognostic value in AH morbidity.

Bacterial infection is frequently observed in patients with alcoholic liver disease (ALD). We examined a possible role of Porphyromonas gingivalis in the development/progression and severity of disease in patients with acute alcoholic hepatitis (AAH). Plasma specimens from 47 patients with AAH (16 moderate, Model for End‐Stage Liver Disease [MELD] score <20]; 31 severe, MELD score >20) and 22 healthy controls (HCs) were collected. Clinical, drinking history (lifetime drinking history [LTDH]), and demographic data were collected. Antibody tests for immunoglobulin (Ig) G, IgM, and IgA against two P. gingivalis strains were performed. Between‐group comparisons and within‐group association analyses were carried out. Patients with severe AAH showed significantly higher plasma levels of IgG, IgA, and IgM against two P. gingivalis strains (W83 and 33277) compared to HCs. Patients with moderate AAH also had significantly elevated anti‐P. gingivalis IgA concentrations for both strains compared to HCs. Male patients with moderate AAH showed a significant inverse association in LTDH and anti‐P. gingivalis IgM. The aspartate aminotransferase:alanine aminotransferase ratio was positively associated with IgM of both strains in male patients with moderate AAH. Female patients with severe AAH showed a significant association between MELD scores and W83 IgM. Conclusion: Antibody response to P. gingivalis in AAH is elevated. Significantly elevated plasma anti‐P. gingivalis IgG, IgA, and IgM in severe AAH provide preliminary data that P. gingivalis could be a novel risk factor in the development/severity of AAH. Antibody response to P. gingivalis in acute alcoholic hepatitis is elevated. Significantly elevated plasma anti‐P. gingivalis IgG, IgA and IgM in severe acute alcoholic hepatitis provide preliminary data that P. gingivalis could be a novel risk factor in the development/severity of AAH. [ABSTRACT FROM AUTHOR]

Background: Alcohol-associated hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury and could potentially be used for mortality prediction., Methods: EDTA plasma samples were collected from patients with AH (n = 62); Model for End-Stage Liver Disease score defined AH severity as moderate (12-20; n = 28) and severe (>20; n = 34). The peptidome data were collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition, and protease involvement. Machine-learning methods were used to develop mortality predictors., Results: Analysis of plasma peptides from patients with AH and healthy controls identified over 1600 significant peptide features corresponding to 130 proteins. These were enriched for extracellular matrix fragments in AH samples, likely related to the turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes was dominated by changes in peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Causal graphical modeling identified 3 peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over the Model for End-Stage Liver Disease score and were used to create a clinically applicable mortality prediction assay., Conclusions: A signature based on plasma peptidome is a novel, noninvasive method for prognosis stratification in patients with AH. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)