Recompensation of Liver Cirrhosis by TIPS Reduces Epithelial Cell Death Markers, Translating Into Improved Clinical Outcome

Abstract

Background and aims: Portal hypertension is the main pathophysiological driver of decompensation in patients with liver cirrhosis. Epithelial cell death markers, m30 and m65, correlate with hepatic injury and predict outcomes across various stages of liver disease. We aim (i) to evaluate whether portal hypertension itself contributes to liver outcome-relevant epithelial injury, and (ii) to analyse the capacity of m30/m65 to predict outcome in patients receiving a transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites.

Methods: Sixty-six patients undergoing TIPS placement for refractory ascites and 20 patients with compensated cirrhosis as controls were prospectively enrolled in this monocentric cohort study. Epithelial cell death markers were analysed pre-TIPS, as well as 1-3 and 6-9 months post-TIPS. The capacity of baseline levels of m30/m65 in predicting six-month transplant-free survival rates was analysed by multivariable Cox proportional hazards regression.

Results: Levels of m30 and m65 were higher in patients with decompensated cirrhosis (pre-TIPS) compared with compensated cirrhosis (controls). Following correction of portal hypertension by TIPS and recompensation, both markers decreased over time, reaching levels comparable to patients with compensated cirrhosis. On multivariable analysis, pre-TIPS baseline levels of m30 and m65 were not predictive for six-month survival.

Conclusion: Correction of portal hypertension via TIPS reduces levels of epithelial cell death markers, indicating that portal hypertension is a driver of outcome-relevant, hepatic cell death in patients with decompensated cirrhosis. Baseline m30/m65 values do not affect six-month survival rates, which suggests that TIPS placement overcomes the unfavourable spontaneous prognosis otherwise indicated by elevated baseline m30/65 levels.

Keywords: ACLF; DAMPs; acute‐on chronic liver failure; m30; m65; portal hypertension; transjugular intrahepatic portosystemic shunt.

FIGURE 1

Epithelial cell death markers m30/m65 in patients with compensated and decompensated cirrhosis pre‐TIPS (A+B) and stratified according to the Child–Pugh stage (C+D). Both m30 (A) and m65 (B) levels were higher in patients with decompensated (n = 66) compared to compensated (n = 20) liver cirrhosis (p = 0.016 and < 0.001, respectively, Mann–Whitney‐U test), and showed a stepwise increase when stratified according to the Child–Pugh stage (panel C, D; CPS A: n = 18, CPS B: n = 53, CPS C: n = 15). Data are shown as violin plots depicting the median (solid line) and the 0.25‐ and 0.75 quartile (dotted lines). CPS, Child–Pugh score; TIPS, transjugular intrahepatic portosystemic shunt.

FIGURE 2

Evolvement of epithelial cell death markers m30 (A) and m65 (B) during early and late follow‐up a median 35 and 190 days after TIPS placement and stratified according to patients with ascites control (C, D) and persistent ascites (E, F) at early follow‐up. Both m30 and m65 values showed a relevant decrease over time, returning to values comparable to patients with compensated liver cirrhosis (A, B, p = 0.01 for m30 and < 0.001 for m65, Friedman‐Test). When stratified into patients with a response and nonresponse defined as having ascites requiring paracentesis at early follow‐up, levels of m30 and m65 only decreased in patients with a response (C, D) but remained similar in patients with a nonresponse (E, F). For the separate analysis of responders and nonresponders, patients that showed a secondary response after TIPS dilatation were also classified as nonresponders for presenting with ascites requiring paracentesis at the time of blood sampling. Number of patients at each assessment: Pre‐TIPS n = 66, early follow‐up n = 40, late follow‐up n = 32. Responders: n = 28; nonresponders n = 12. Panel A and B depict violin plots with the median (solid line) and the 0.25‐ and 0.75‐quartile (dotted lines).