Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis

Abstract

Background & aims: Acute alcoholic hepatitis (AAH) is a major cause of liver-related morbidity and mortality; there are no good blood biomarkers for diagnosis or determining magnitude of cell death. Keratin 18 (KRT18, also called K18), found in epithelial cells, is released from hepatocytes upon death. We investigated whether level of K18 is a better marker of hepatocyte death than standard biomarkers and might be used to identify patients with AAH at risk for death within 90 days.

Methods: We analyzed data from 173 participants in a large trial performed at 4 medical centers. Participants with AAH were classified as severe (n = 57, model for end-stage liver disease [MELD] scores above 20) or moderate (n = 27, MELD scores from 12 to 19); 38 participants had alcohol use disorder with mild (n = 28) or no liver injury (n = 10); 34 participants had nonalcoholic steatohepatitis; and 17 participants were healthy (controls). We quantified serum levels of K18 using ELISAs and APOPTOSENSE kits.

Results: Serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the ratio of AST:ALT did not correlate with MELD scores. Patients with alcohol use disorder had higher serum levels of ALT than patients with severe AAH. Levels of K18M65 and K18M30 had statistically significant increases as liver disease worsened, as did the degree of necrosis (ratio of K18 M65:M30). The ratio of K18M65:ALT was increased in serum from patients with AAH compared with controls. Serum levels of K18 identified patients who died within 90 days with greater accuracy than commonly used static biomarkers.

Conclusions: There is a stronger association between serum level of keratin 18 and amount of hepatocyte death and liver disease severity than for other biomarkers (AST, ALT, and the AST:ALT ratio). The ratio of K18M65:M30 might be used as marker of mechanism of hepatocyte death, and the ratio of K18M65:ALT might be used to distinguish patients with AAH from patients with nonalcoholic steatohepatitis. Serum levels of K18 might be used to identify patients with severe AAH at risk for death. ClinicalTrials.gov identifier # NCT01922895 and NCT01809132.

Keywords: Hepatic; NASH; Predictive; Prognosis.

Conflict of interest statement

Disclosures/Conflicts of Interest: All authors declare no conflicts of interest.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:

Liver injury markers in alcohol use disorder (AUD) patients, moderate acute alcoholic hepatitis (AAH), and severe AAH. Fig.1a: Aspartate aminotransferase (AST) levels. Fig.1b: Alanine aminotransferase (ALT) levels. Fig.1c: AST:ALT ratio. Data are presented as mean ± standard deviation. *p

Figure 2:

K18 levels in alcohol use disorder (AUD) patients, moderate acute alcoholic hepatitis (AAH), and severe AAH. Fig. 2a: K18M65 levels. Solid line represents the upper limit of normal (−500u/l). The dotted line (2000 u/l) represents the level above which patients are classified as having AH based on criteria of Bissonnette and coworkers. Fig. 2b: K18M30 levels. Solid line represents the upper limit of normal (250u/l). Observed data, mean and standard deviation are presented. *p

Fig. 3:

K18M65:ALT and K18M30:ALT (postulated diagnostic biomarkers) across different groups. Fig. 3a: K18M65:ALT across all groups. Fig. 3b: K18M65:ALT in NASH vs. all AAH patients (moderate and severe). Fig. 3c: ROC curve for K18M65:ALT between NASH and AAH patients. Fig. 3d: Ratio of K18M30:ALT across all groups. Fig. 3e: K18M30:ALT in NASH vs. all AAH patients (moderate and severe). Fig. 3f: ROC for K18M30:ALT between NASH and AAH patients. Data are presented as mean ± SD. Statistical significance was set at p

Figure 4:

ROC curves for predicting 90-day mortality based on the K18 prognostic markers (K18M65, K18M30), four commonly used static biomarkers (DF, MELD, ABIC, GAHS). ROC curves for: K18M65 (Fig. 4a); K18M30 (Fig. 4b); DF (Fig. 4c); MELD (Fig. 4d); ABIC (Fig. 4e); GAHS (Fig. 4f).

Figure 5:

Kaplan-Meier (K-M) plots for predicting 90-day mortality based on K18 prognostic markers (K18M65, K18M30) and four commonly used static biomarkers (DF, MELD, ABIC, and GAHS). K-M plots for: K18M65 (Fig. 5a); K18M30 (Fig. 5b); DF (Fig. 5c); MELD (Fig. 5d); ABIC (Fig. 5e); GAHS (Fig. 5f).