Impact of portal hypertension on epithelial cell death markers in patients with decompensated liver cirrhosis

Introduction Portal hypertension (PH) drives decompensating events in patients with liver cirrhosis. Epithelial cell death markers m30 and m65 have been shown to predict outcome in patients with liver cirrhosis and alcoholic liver disease. While m30 is considered to reflect apoptosis, m65 is considered to reflect overall cell death. We hypothesize that PH increases hepatocellular injury which is reflected by increased serum levels of epithelial cell death markers.

Aims To analyze the role of PH on markers of epithelial cell death and their capacity to predict outcome of patients with refractory ascites undergoing transjugular intrahepatic portosystemic shunt (TIPS) implantation.

Methods 66 patients with cirrhosis undergoing TIPS-placement were included in this prospective observational study. Peripheral blood samples were drawn from the cubital vein pre-TIPS and at early (1-3 months) and late (6-12 months) follow-up post-TIPS. Hepatic and portal venous blood was sampled during the TIPS-procedure. 20 patients with compensated liver cirrhosis were recruited as controls. M30/m65 were measured using a commercially available ELISA kit. A multivariable Cox proportional hazards model to identify predictors of six months transplant-free survival (composite of liver transplantation and death) was carried out including age, sex, baseline m30/m65 values and baseline MELD and FIPS score as variables.

Results Patients with decompensated cirrhosis pre-TIPS displayed higher levels of m30 and m65 than patients with compensated liver cirrhosis ([Table 1]). Both markers of epithelial cell death increased in a step-wise fashion according to the Child-Pugh stage. Only m65 but not m30 was elevated in the hepatic and portal vein as compared to the cubital vein. Following correction of PH by TIPS implantation and recompensation, both markers decreased over time, reaching levels comparable to patients with compensated cirrhosis. Within multivariable analysis, we found no relevant influence on six-month survival for pre-TIPS baseline levels of m30 and m65 ([Table 2]).

Table 1 Baseline and follow-up values of epithelial cell death markers in patients with compensated (control) and decompensated cirrhosis undergoing TIPS-placement.

Parameter	Compensated (n=20)	Decompensated (pre-TIPS, n=66)	Early follow-up (n=43) 34 (27, 45) days post-TIPS	Late follow-up (n=32) 190 (147, 259) days post-TIPS
m30 [U/l]	142.5 (103.5, 230.0)	195.2 (156.2, 300.6)*	187.0 (133.4, 249.7)	144.1 (108.0, 190.4+
Δm30 [U/l]			−10.6 (−67.9, 37.1)	−48.4 (−100.7, 2.0)
Δm30% [U/l]			−4.8 (−33.4, 15.3)	−24.5 (−42.0, 1.4)
m65 [U/l]	291.1 (239.9, 468.8)	582.4 (444.3, 885.0)**	520.7 (395.4, 726.6)	415.5 (271.2, 546.4)++
Δm65 [U/l]			−51.1 (−150.0, 64.1)	−159.3 (−393.4, −48.8)
Δm65% [U/l]			−9.6 (−23.7, 17.2)	−30.0 (−47.5, −10.3)

Data are shown as median values with the 0.25- and 0.75-quartile. A group-wise comparison between patients with compensated and decompensated liver cirrhosis was carried out using a Mann-Whitney-U-Test (*=p-value<0.05;**=p-value<0.01). Longitudinal measurement repetitions in patients with decompensated cirrhosis pre-TIPS and at early and late follow-up were analyzed with the Friedman test (⁺=p-value<0.05; ⁺⁺⁺=p-value<0.01).; Abbreviations: TIPS, transjugular intrahepatic portosystemic shunt.

Table 2 Multivariable Cox proportional hazards model to identify predictors for the composite endpoint death and liver transplantation at 6 months.

Predictors	Hazard ratio	95%-confidence interval	p-value
Age	1.02	0.97 – 1.07	0.401
Sex	0.41	0.16 – 1.04	0.060
Baseline MELD score (log scale)	1.35	0.22 – 8.36	0.749
Baseline FIPS score	1.60	0.63 – 4.01	0.321
Baseline m30 (log scale)	1.43	0.57 – 3.60	0.451
Baseline m65 (log scale)	0.67	0.21 – 2.11	0.493

None of the variables that entered the model had a relevant influence on 6-months survival.; Abbreviations: MELD, model for end-stage liver disease; FIPS, Freiburg Index of post-TIPS survival.

Conclusions Portal hypertension is a possible driver of hepatic cell death in patients with decompensated cirrhosis, as its correction also leads to a reversal of markers of epithelial cell death. Baseline m30/m65 values do not seem to influence six months survival which suggests that TIPS-placement overcomes the unfavorable spontaneous prognosis otherwise indicated by elevated baseline m30/65 levels.

Publication History

Article published online:
28 August 2023