Insertion of a transjugular intrahepatic portosystemic shunt leads to sustained reversal of systemic inflammation in patients with decompensated liver cirrhosis

Abstract

Background/aims: Systemic Inflammation (SI) is considered a key mechanism in disease progression and development of complications in decompensated liver cirrhosis. SI is mainly driven by portal hypertension and bacterial translocation. Transjugular intrahepatic portosystemic shunt (TIPS) insertion represents an effective treatment for portal hypertension. This study aims to investigate the impact of TIPS insertion on SI and bacterial translocation.

Methods: We prospectively included 59 cirrhotic patients undergoing TIPS insertion. Blood samples were collected at TIPS insertion and follow-up (FU) 1, 3, 6, and 12 months thereafter. At all time points, we performed a comprehensive analysis of SI including 43 soluble inflammatory markers (SIMs), and surrogates of bacterial translocation (sCD14, sCD163). To investigate long-term kinetics of SI, C-reactive protein (CRP) and white blood cells (WBC) were retrospectively analyzed in a cohort of 177 patients up to 3 years after TIPS insertion.

Results: At TIPS insertion, 30/43 SIMs, sCD14, and sCD163 measured significantly higher in cirrhotic patients compared to healthy controls. By FU6 25 SIMs and sCD14 measured at significantly lower levels compared to baseline. Interestingly, in patients with TIPS indication of refractory ascites, IL-6 decreased to levels documented in earlier stages of cirrhosis. In long-term follow-up, CRP levels significantly decreased after TIPS insertion, which translated into lower mortality in Cox regression analysis (HR 0.968, p=0.042). Notably, patients with residual ascites post-TIPS showed significantly higher CRP and IL-6 levels across all follow-ups compared to patients with resolved ascites.

Conclusion: Decreasing portal hypertension via TIPS insertion leads to a significant attenuation of SI and bacterial translocation over time.

Keywords: Bacterial translocation; Liver cirrhosis; Portal hypertension; Systemic inflammation; Transjugular intrahepatic portosystemic shunt insertion.

Figure 1.

Selection algorithm for TIPS patients from Hannover Medical School. Shown is the selection algorithm for the TIPS patients included in the analysis of systemic inflammation based on CRP levels and WBC, as well as the subgroup of patients prospectively enrolled in the Hannover TIPS patient registry with detailed SIM analysis. TIPS, transjugular intrahepatic portosystemic shunt; CRP, C-reactive protein; WBC, white blood cells; SIM, soluble inflammatory marker.

Figure 2.

Comparison of SIM levels in the peripheral blood (A) of patients with decompensated liver cirrhosis compared to healthy controls and (B) in patients receiving a TIPS for RA compared to those receiving a TIPS for secondary prophylaxis of variceal bleeding and (C) in patients with a pre-TIPS PSG <16 mmHg compared to those with a pre-TIPS PSG ≥16mmHg. (A) n=5 healthy controls vs. n=58 baseline values of TIPS-patients; (B) n=45 TIPS indication RA vs. n=13 TIPS for variceal bleeding. (C) n=31 (PSG<16 mmHg) vs. n=26 (PSG≥16 mmHg); n=2 patients with missing PSG data were excluded. The color of the bar represents –log₁₀ (FDR)*(fold change between two groups). ^*FDR <0.05; ^**FDR <0.01. TIPS, transjugular intrahepatic portosystemic shunt; PSG: portosystemic gradient; SIM, soluble inflammatory marker.

Figure 3.

Course of systemic inflammation after TIPS insertion. (A) Heatmap shows SIMs with significant changes after TIPS insertion (FDR <0.05). Mixed effects model was used to assess the SIM changes after TIPS insertion with sample ID as random effect. The color of the bars represents the difference of the respective time point and baseline (FUX-BL). (B–G) shows courses of six representative SIMs. Wilcoxon signed rank test was used for comparisons. Whiskers visualize min to max. TIPS, transjugular intrahepatic portosystemic shunt; SIM, soluble inflammatory marker; BL, baseline; FU, follow-up.

Figure 4.

IL-6 levels before and after TIPS insertion in patients with TIPS indication refractory ascites and variceal bleeding. Shown is the course of IL-6 during 12-month follow-up after TIPS, stratified by TIPS indication (RA n=46 vs. VB n=13). Wilcoxon signed rank test was used for comparison. Whiskers show 95% CI with outliers as dots, the line within boxplots depicts the mean. IL-6, Interleukin 6; BL, baseline; FU, follow-up; RA, refractory ascites; VB, variceal bleeding; n.s., not statistically significant.

Figure 5.

Course of CRP levels and white blood cells (WBC) in the long-term follow-up after TIPS insertion. Shown is the course of CRP levels from (A) baseline to 6–12 months after TIPS insertion (n=98) and (B) 2 and 3 years after TIPS implantation (n=65) as well as the course of WBC from (C) baseline to 6–12 months after TIPS insertion (n=109) and (D) 2 and 3 years after TIPS (n=68). Patients were included in the 2-3-year analysis if at least one of these long-term follow-ups was available. P-values were obtained using the Wilcoxon signed-rank test. CRP, C-reactive protein; WBC, white blood cells.

Figure 6.

Course of sCD14 (A) and sCD163 (B) after TIPS insertion. Shown is the course of two surrogate markers of bacterial translocation, sCD14 (A) and sCD163 (B), at baseline and during follow-up after TIPS insertion. Whiskers show Maximum to Minimum, the line within boxplots depicts the mean. The grey dashed line on graphs indicates the mean level of respective sCD in healthy patients. sCD, soluble CD Receptor; BL, baseline; FU, follow-up; RA, refractory ascites; VB, variceal bleeding; n.s., not statistically significant.