Abstract
Background & Aims
Transjugular intrahepatic portosystemic shunt (TIPS) effectively treats complications of cirrhosis. Systemic inflammation (SI) is linked to acute-on-chronic liver failure (ACLF) and liver-related death. We aimed to assess the trajectory and clinical impact of SI parameters after TIPS implantation.
Methods
Consecutive patients undergoing elective implantation of covered TIPS for recurrent/refractory ascites or portal-hypertensive bleeding at the Medical University Vienna (NCT03409263; n = 58) and at the Hannover Medical School (NCT04801290, n = 51) were included. IL-6 was assessed at baseline (BL), 3 months (M3) and up to 6 (M6; Hannover cohort) or 9 months (M9; Vienna cohort) of follow-up; C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were assessed in the Vienna cohort only.
Results
In 109 patients (66.1% male, median age 57 years) receiving TIPS mainly (72.4%) by indication ascites the median BL IL-6 levels were 10.5 pg/ml; and 41.3% (n = 45/109) patients exhibiting IL-6 ≥14 pg/ml. From BL to M3, IL-6 decreased in 63.8% (n = 37/58; Vienna cohort) and in 68.6% (n = 35/51; Hannover cohort) of patients, respectively. Similar rates of decreases were observed also for CRP (in 62.1%) and for LBP (in 77.4%). A considerable IL-6 reduction (≥50% of baseline) was noted in 41 (37.6%) patients during follow-up. Competing risk regression in the combined cohort adjusted for age, albumin, and model for end-stage liver disease revealed that IL-6 decrease at M3 was an independently protective factor for the development of ACLF (adjusted subdistribution hazard ratio [asHR]: 0.26; 95% CI: 0.09–0.77; p = 0.016) and liver-related death (asHR: 0.26; 95% CI: 0.07–0.95; p = 0.042).
Conclusions
TIPS leads to a sustained reduction of SI and bacterial translocation in patients with decompensated cirrhosis. Decreasing IL-6 levels three months after TIPS implantation indicate a lower risk of ACLF and liver-related death in patients with cirrhosis.
Impact and implications:
Systemic inflammation is a major driver of disease progression in patients with decompensated advanced chronic liver disease (dACLD). This study demonstrates that systemic inflammation (i.e. interleukin-6 [IL-6]) effectively and sustainedly decreases after transjugular intrahepatic portosystemic shunt (TIPS) implantation. A decrease of IL-6 3 months after TIPS implantation is a protective factor for acute-on-chronic liver failure and liver-related death. Thus, our results suggest that TIPS reduces systemic inflammation in a clinically meaningful way.
Keywords: Transjugular intrahepatic portosystemic shunt, Systemic inflammation, Acute-on-chronic liver failure, Bacterial translocation
Graphical abstract
Highlights:
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IL-6 decreased after elective TIPS implantation in two distinct European cohorts of patients with cirrhosis.
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Decreased lipopolysaccharide-binding protein after TIPS implantation indicates decreased bacterial translocation.
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IL-6 decrease at 3 months after TIPS implantation is a protective factor for ACLF and liver-related death.
Introduction
Worldwide, advanced chronic liver disease (ACLD) is linked to significant morbidity and mortality.1,2 Patients’ prognosis worsens considerably after developing portal hypertension (PH)-related complications, such as variceal bleeding and ascites, marking the progression to the clinical stage of decompensated ACLD (dACLD).[3], [4], [5], [6]
With progressive severity of ACLD, there is a significant increase in parameters of systemic inflammation (SI) such as C-reactive protein (CRP) and IL-6, which is particularly relevant in patients with dACLD and ascites.5 This increase in the level of SI has been associated with bacterial translocation in patients with ACLD and PH.7 Closely linked to the gut–liver axis and SI8,9 is the acute-on-chronic liver failure (ACLF),6,10 a syndrome characterized by hepatic and extrahepatic organ failures.11,12
The implantation of transjugular intrahepatic portosystemic shunt (TIPS) is an important and effective treatment option for patients with dACLD as it ameliorates PH and related complications,4,13 thereby improving clinical outcomes.14 It has been demonstrated that TIPS decreases mortality in patients with severe variceal bleeding15,16 and with refractory or recurrent ascites.17,18
One previous study demonstrated that higher CRP levels at the time of TIPS implantation are linked to a higher prevalence of ACLF and mortality during follow-up.19 Moreover, another recent study showed that circulating levels of soluble urokinase plasminogen activator receptor as a marker of inflammatory activity at the time of TIPS implantation were associated with worse prognosis.20 However, data on the dynamics of inflammatory markers after TIPS implantation are lacking.
Thus, we aimed to (i) investigate the trajectories of SI parameters including CRP, IL-6, procalcitonin (PCT) and the bacterial translocation marker lipopolysaccharide-binding protein (LBP) after TIPS implantation, as well as (ii) the impact of the change in IL-6 (ΔIL-6) 3 months after TIPS on the development of ACLF and liver-related death during long-term follow-up.
Patients and methods
Study design
This study included consecutive adult patients with ACLD and available data on longitudinal levels of IL-6 undergoing elective implantation of covered TIPS for recurrent/refractory ascites or portal-hypertensive bleeding indication, who were included into two separate prospective registry studies at the Medical University of Vienna (NCT03409263; May 2018 to January 2024) and the Hannover Medical School (NCT04801290; September 2019 to February 2022). According to the designs of the registries, follow-up visits were scheduled at 3 months, 6 months (both cohorts) and 9 months (Vienna cohort) after TIPS implantation (i.e. baseline [BL]).
We excluded patients with vascular liver disease, hepatocellular carcinoma (HCC) or other active malignancy at the time of TIPS implantation, a history of liver transplantation (LT), patients undergoing early-TIPS or rescue-TIPS implantation, as well as patients with a follow-up <90 days after TIPS implantation or unavailable results on longitudinal IL-6 levels. Only adult patients (≥18 years) with evidence of cirrhosis were included.
Etiology of ACLD, sex, age, self-reported alcohol consumption, antiviral therapy, history of ascites, and variceal bleeding were prospectively evaluated. Information on development of ACLF, as well as LT and (liver-related) death during clinical follow-up was documented.
Laboratory values
BL laboratory values were assessed on the day before TIPS implantation. All laboratory tests of the Vienna cohort were conducted at the ISO-certified Department of Laboratory Medicine of the Medical University of Vienna. In Vienna the investigated markers were analyzed immediately after blood sampling. In Hannover, the blood samples for assessment of SI parameters were centrifuged for 10 min at 3,000 rpm immediately after collection. Subsequently, the supernatants were stored at -80 °C until the measurements were performed.
Among patients in the Vienna cohort, IL-6 was measured via chemoluminescence-immunometric assay (Elecsys IL-6, Roche Diagnostics GmbH, Mannheim, Germany), while in the Hannover cohort, IL-6 was assessed using a multiplex immunoassay (Bio-Plex Pro Human Cytokine 48-Plex Screening Panel, Bio-Rad Laboratories, Inc., Hercules, CA, USA).
Inflammation parameters were longitudinally measured at pre-defined time points: before (BL) and 3 (M3) and 6 (M6) months after TIPS implantation in study centers. Moreover, inflammation parameters were assessed 9 (M9) months after TIPS implantation in the Vienna cohort. These included IL-6 (in pg/ml) in both cohorts, as well as CRP (in mg/dl), PCT (in ng/ml) and LBP (in μg/ml) in the Vienna cohort. In this study longitudinal IL-6 is defined as IL-6 available at BL and M3.
Outcomes and definitions of ACLF and liver-related death
The primary outcome was the impact of a decrease in IL-6 (ΔIL-6) after TIPS implantation on liver-related death. Secondary outcomes were the course of IL-6, CRP, PCT, and LBP, as well as the association of ΔIL-6 with the risk of ACLF and liver-related death.
ACLF was defined according to the EASL/CLIF (chronic liver failure) definition.10,21 Every death that was attributable to ACLD or occurring as a consequence of the patient’s underlying liver disease was considered to be liver related.
Statistical analysis
For categorical variables, the number (n) and proportion (%) of patients with the parameter of interest were indicated. Continuous data were reported as median with IQR. The D’Agostino & Pearson test and Shapiro–Wilk test were computed to test for normal distribution. For comparison of continuous non-normally distributed variables between two groups, the Mann–Whitney U test was computed. Pearson’s Χ2 test was used for group comparisons of categorical variables. For the assessment of non-normally distributed parameters over time with three or more time points, we utilized Friedman’s test. Spearman’s ρ was used for assessment of correlations. Graphically, the different parameters were plotted as boxplots depicting the median and IQR for each time point. The length of the whiskers was determined by Tukey’s method.
Fine and Gray competing risk regression models using the R package cmprsk22,23 (R Foundation for Statistical Computing, Vienna, Austria) were calculated to evaluate whether IL-6 levels before TIPS implantation and ΔIL-6 (before to 3 months after TIPS implantation) were associated with the risk of clinical events of interest. Apart from IL-6, well-established risk factors for inferior outcomes in ACLD (i.e. age, albumin and model for end-stage liver disease [MELD], serum creatinine, sodium) as well as sex were evaluated by univariate and multivariate analysis. Additional analyses corrected for portal pressure gradient (PPG) before and after TIPS were computed to investigate the prognostic impact of IL-6 decrease independently of PH severity. LT and non-liver-related death were considered as competing events in competing risk regression analysis. Only events that occurred after 90 days of follow-up were included in the analysis of changes of IL-6 on the outcome of patients with ACLD after TIPS implantation. For the analysis of the prognostic value of changes in IL-6, the cohorts were fused (‘combined cohort’) to increase the power of the analysis.
IBM SPSS 27.0 statistic software (IBM, Armonk, NY, USA), GraphPad Prism 8 (GraphPad Software, La Jolla, CA, USA) and R 4.2.1 (R Core Team, R Foundation for Statistical Computing) were used for statistical analyses. A two-sided p value of <0.05 was considered statistically significant.
Ethics
The study was approved by the ethics committee of both the Medical University of Vienna (EK 1943/2017) and the Hannover Medical School (No. 8498_BO_S_2019). It was performed according to the current version of the Helsinki Declaration. All patients included in the Vienna cohort were part of the AUTIPS Study (NCT03409263). Every included patient from Hannover was enrolled in the Hannover TIPS patient registry of Hannover Medical School (NCT04801290). All patients from both centers gave their written informed consent before study inclusion.
Results
Patient characteristics
Overall, 109 patients with male predominance (66.1%) and a median age of 57 years were included in the Vienna (n = 58) and in the Hannover cohort (n = 51). Details on the cohort building process are depicted in Fig. 1. Of all patients who were excluded because of insufficient clinical follow-up (<90 days), 10 (43.5%) died, one (4.3%) underwent LT and 12 (52.2%) were lost to follow-up. As detailed in Table S1, there were no significant differences in the main characteristics of patients included in the study and those who had to be excluded owing to a lack of longitudinally available IL-6 or clinical follow-up <90 days.
Fig. 1.
Patient flowchart.
ACLD, advanced chronic liver disease; IL-6 at M3, IL-6 at 3 months after TIPS implantation; TIPS, transjugular intrahepatic portosystemic shunt.
Table 1 presents the patient characteristics of the Vienna and Hannover cohorts, as well as the combined cohort. Of note, the two cohorts were comparable in terms of age, sex, TIPS indication, and PPG after TIPS implantation. Of note, 81.9% (n = 59/72) of patients with alcohol-related liver disease (ALD; including those with mixed etiology) were abstinent at the time of TIPS implantation. As detailed in Table S2, BL values of parameters of SI and bacterial translocation were not significantly different between patients with and without ALD. Most patients underwent TIPS implantation because of ascites (72.4%), while 21.1% had elective TIPS implantation for variceal bleeding, and 6.4% for both ascites and portal-hypertensive bleeding. In patients with bleeding indication, the median time from the last portal-hypertensive bleeding to TIPS implantation was 154 (IQR 97–259) days.
Table 1.
Patient characteristics at baseline and 3 months after TIPS implantation.
| Patient characteristics | Combined cohort (n = 109) | Vienna cohort (n = 58) | Hannover cohort (n = 51) | p value |
|---|---|---|---|---|
| Sex, male/female (% male) | 72/37 (66.1) | 39/19 (67.2) | 33/18 (64.7) | 0.780 |
| Age, years (IQR) | 57 (50–68) | 58 (50–68) | 56 (50–65) | 0.798 |
| Etiology | 0.769 | |||
| ALD, n (%) | 63 (57.8) | 36 (62.1) | 27 (52.9) | |
| Viral hepatitis, n (%) | 5 (4.6) | 2 (3.4) | 3 (5.9) | |
| Mixed etiology, n (%) | 9 (8.3) | 3 (5.2) | 6 (11.8) | |
| MASH, n (%) | 9 (8.3) | 4 (6.9) | 5 (9.8) | |
| Cryptogenic, n (%) | 7 (6.4) | 4 (6.9) | 3 (5.9) | |
| Other, n (%) | 16 (14.7) | 9 (15.5) | 7 (13.7) | |
| TIPS indication, n (%) | 0.836 | |||
| Ascites, n (%) | 79 (72.4) | 43 (74.1) | 36 (70.6) | |
| Variceal bleeding, n (%) | 23 (21.1) | 12 (20.7) | 11 (21.6) | |
| Both, n (%) | 7 (6.4) | 3 (5.2) | 4 (7.8) | |
| Child-Pugh stage | <0.001 | |||
| A, n (%) | 19 (17.4) | 9 (15.5) | 10 (19.6) | |
| B, n (%) | 66 (60.6) | 27 (46.6) | 39 (76.5) | |
| C, n (%) | 24 (22.0) | 22 (37.9) | 2 (3.9) | |
| MELD at BL, points (IQR) | 11 (9–13) | 11 (9–13) | 11 (9–14) | 0.763 |
| MELD at M3, points (IQR) | 12 (10–15) | 13 (11–16) | 12 (9–15) | 0.113 |
| Albumin at BL, g × dl-1 (IQR) | 34.2 (30.0–38.0) | 34.9 (32.8–38.4) | 32.0 (28.0–37.0) | 0.015 |
| Albumin at M3, g × dl-1 (IQR) | 34.5 (31.0–38.0) | 34.5 (32.0–38.3) | 34.0 (29.0–37.3) | 0.252 |
| Bilirubin at BL, mg × dl-1 (IQR) | 0.9 (0.6–1.4) | 1.0 (0.6–1.5) | 0.8 (0.5–1.4) | 0.318 |
| INR at BL, units (IQR) | 1.3 (1.1–1.4) | 1.3 (1.2–1.5) | 1.2 (1.1–1.3) | <0.001 |
| Creatinine at BL, mg × dl-1 (IQR) | 1.0 (0.8–1.3) | 0.9 (0.7–1.2) | 1.1 (0.9–1.6) | 0.001 |
| Sodium, mmol × L-1 (IQR) | 135 (133–138) | 135 (133–139) | 136 (132–137) | 0.415 |
| PPG before TIPS, mmHg (IQR)∗ | 16 (13–20) | 18 (15–22) | 15 (13–18) | 0.003 |
| PPG after TIPS, mmHg (IQR)† | 7 (5–8) | 7 (5–9) | 6 (4–8) | 0.057 |
| IL-6 at BL, pg × ml-1 (IQR) | 10.5 (4.2–24.6) | 22.1 (10.6–35.8) | 4.6 (2.8–9.7) | <0.001 |
| IL-6 at M3, pg × ml-1 (IQR) | 6.2 (2.6–17.5) | 13.6 (6.2–26.3) | 2.7 (1.5–5.3) | <0.001 |
| CRP at BL, mg × dl-1 (IQR) | 0.8 (0.3–1.7) | 0.7 (0.3–1.2) | 0.9 (0.3–2.2) | 0.190 |
ALD, alcohol-related liver disease; BL, baseline; CRP, C-reactive protein; IL-6, interleukin-6; INR, international normalized ratio; M3, 3 months after TIPS; MASH, metabolic dysfunction-associated steatohepatitis; MELD, model for end-stage liver disease; PPG, portal pressure gradient; TIPS, transjugular intrahepatic portosystemic shunt.
Continuous variables were compared by Mann–Whitney U test. Pearson’s Χ2 test or Fisher’s exact test, as appropriate, were used for group comparisons of categorical variables. Bold p values denote a statistically significant difference.
Available in 101 patients (Vienna: n = 50; Hannover: n = 51).
Available in 94 patients (Vienna: n = 44; Hannover: n = 50).
While the median MELD score in both cohorts was comparable at BL (Vienna: 11 vs. Hannover: 11; p = 0.763) and at M3 (Vienna: 13 vs. Hannover: 12; p = 0.113), the Vienna cohort included more patients with Child-Pugh stage C (Vienna: 37.9% vs. Hannover: 3.9%; p <0.001). Moreover, the median PPG before TIPS implantation (Vienna: 18 mmHg vs. Hannover: 15 mmHg; p = 0.003), as well as median levels of IL-6 at BL (Vienna: 22.1 pg/ml vs. Hannover: 4.6 pg/ml; p <0.001) and at M3 (Vienna: 13.6 pg/ml vs. Hannover: 2.7 pg/ml; p <0.001) were significantly higher in the Vienna cohort. Forty-five patients (41.3%) patients exhibited IL-6 ≥14 pg/ml. As detailed in Table S3, patients with portal-hypertensive bleeding indication had similar PPG as patients with ascites indication both before and after TIPS, but significantly lower levels of IL-6 (14.8 pg/ml vs. 4.2 pg/ml; p <0.001) and CRP at BL (1.0 mg/dl vs. 0.3 mg/dl; p = 0.003).
Changes of IL-6 at M3 after TIPS implantation (Vienna cohort and Hannover cohort)
In the Vienna cohort, there was a decrease in IL-6 from BL to M3 in 63.8% (n = 37/58) of patients with a median ΔIL-6 of -2.8 (IQR -21.4 to 3.6) pg/ml. Overall, the median IL-6 levels in the Vienna cohort decreased significantly at M3 as compared with BL (BL: 22.1 pg/ml vs. M3: 13.6 pg/ml; p = 0.029).
Similar results were obtained in the Hannover cohort with 68.6% (n = 35/51) of patients presenting decreased levels of IL-6 at M3 after TIPS implantation and a median ΔIL-6 of -1.6 (IQR -4.8 to 0.9) pg/ml. Again, the median IL-6 levels dropped significantly at M3 after TIPS implantation (BL: 4.6 pg/ml vs. M3: 2.7 pg/ml; p = 0.007).
Of note, the IL-6 levels of n = 20/58 (34.5%) patients in the Vienna cohort and of n = 21/51 (41.2%) patients in the Hannover cohort, were decreased by at least 50% at M3 after TIPS implantation.
Interestingly, ΔIL-6 did not correlate with PPG before TIPS (ρ = -0.02; p = 0.816), PPG after TIPS (ρ = 0.08; p = 0.473) or relative PPG change after TIPS (ρ = 0.09; p = 0.375). Moreover, ΔLBP did not correlate with relative PPG decrease after TIPS implantation (ρ = 0.17; p = 0.300), but showed a significant correlation with ΔIL-6 (ρ = 0.46; p <0.001).
Changes of other inflammatory parameters at M3 after TIPS implantation (Vienna cohort)
The analysis of additional parameters of SI assessed in the Vienna cohort yielded concordant results: CRP levels at M3 compared with BL were lowered in 62.1% (n = 36/58) of patients with a median ΔCRP of -0.1 (IQR -0.7 to 0.1) mg/dl. In 32.8% (n = 19/58) of patients, CRP had decreased by at least 50% at M3 and median CRP at M3 was significantly lower as compared with BL (BL: 0.7 mg/dl vs. M3: 0.4 mg/dl; p = 0.026).
Median levels of PCT were generally low at BL with a median of 0.1 (IQR 0.1–0.2) ng/ml. Still, we observed a decrease in PCT at M3 after TIPS implantation in 42.9% (n = 24/56) of patients with six patients (10.7%) exhibiting a PCT decrease of at least 50%.
Finally, LBP decreased in 77.4% (n = 41/53) of patients with a median ΔLBP of -2.4 (IQR -3.9 to -0.2) μg/ml. The median levels of LBP were significantly reduced at M3 compared with BL (BL: 8.5 μg/ml vs. M3: 5.8 μg/ml; p <0.001).
Trajectory of IL-6 and other inflammation parameters after TIPS implantation (Vienna cohort and Hannover cohort)
The course of inflammation parameters is shown in Fig. 2 and detailed in Table S5. Among patients with available IL-6 levels at every single time point (Vienna cohort: n = 38; Hannover cohort: n = 37), median IL-6 decreased throughout all time points in both the Vienna (from BL: 22.1 pg/ml to M9: 9.4 pg/ml; p = 0.035) and the Hannover cohort (from BL: 4.6 pg/ml to M6: 2.4 pg/ml; p = 0.002). Similarly, in the Vienna cohort there was a sustained decrease in CRP (longitudinally available in n = 41; from BL 0.7 mg/dl to M9 0.4; p = 0.008) and in LBP (longitudinally available in n = 30; from BL: 8.8 μg/ml to M9 6.2 μg/ml; p <0.001), while median levels of PCT remained unchanged (from BL: 0.1 ng/ml to M9: 0.1 ng/ml; p = 0.607).
Fig. 2.
Trajectory of plasma levels of parameters of systemic inflammation and bacterial translocation before and after TIPS placement.
Plasma levels of IL-6 in (A) the Vienna cohort and in (B) the Hannover cohort at baseline (BL), as well as 3 months (M3), 6 months (M6) and 9 months (in the Vienna cohort; M9) after TIPS implantation among patients with available interleukin-6 at every time point (nA = 38, nB = 37). (C, D) Plasma levels of C-reactive protein and lipopolysaccharide-binding protein, respectively, in the Vienna cohort at BL, M3, M6, and M9 among patients with available parameters at every time point (n = 41 and n = 30, respectively). Group comparison was conducted using Friedman’s test: (A) p = 0.035, (B) p = 0.002, (C) p = 0.008, (D) p <0.001. The boxplots depict the median and interquartile range for each time point. The length of the whiskers was determined by Tukey’s method.
Table 2 details the comparison of IL-6 (Vienna cohort and Hannover cohort), CRP, and LBP (Vienna cohort) at different time points as compared with BL. Importantly, the median values of parameters of SI and bacterial translocation decreased consistently and sustainedly, when over the subsequent time points as compared with BL. Moreover, Table S4 shows comparisons of these parameters between different time points compared with M3.
Table 2.
Comparison between plasma levels of IL-6, CRP, and LBP at baseline and at 3, 6 and 9 months after TIPS implantation.
| Vienna cohort | ||||
|---|---|---|---|---|
| Parameter | n | BL | M3 | p value |
| IL-6, pg × ml-1 (IQR) | 58 | 22.1 (10.6–35.8) | 13.6 (6.2–26.3) | 0.029 |
| n | BL | M6 | p value | |
| 49 | 19.9 (10.3–34.7) | 11.4 (6.2–27.4) | 0.359 | |
| n | BL | M9 | p value | |
| 38 | 22.1 (10.3–9.4) | 9.4 (5.7–23.4) | 0.139 | |
| Parameter | n | BL | M3 | p value |
| CRP, mg × dl-1 (IQR) | 58 | 0.7 (0.3–1.2) | 0.4 (0.2–1.2) | 0.026 |
| n | BL | M6 | p value | |
| 52 | 0.7 (0.3–1.2) | 0.5 (0.2–1.2) | 0.288 | |
| n | BL | M9 | p value | |
| 41 | 0.7 (0.3–1.2) | 0.4 (0.1–0.8) | 0.027 | |
| Parameter | n | BL | M3 | p value |
|
LBP, μg × ml-1(IQR) |
53 | 8.5 (6.3–10.6) | 5.8 (4.6–8.1) | <0.001 |
| n | BL | M6 | p value | |
| 43 | 8.5 (6.3–10.5) | 6.1 (4.5–8.3) | <0.001 | |
| n | BL | M9 | p value | |
| 30 |
8.8 (6.2–10.5) |
6.2 (4.2–7.4) |
<0.001 |
|
| Hannover cohort | ||||
| Parameter | n | BL | M3 | p value |
| IL-6, pg × ml-1(IQR) | 51 | 4.6 (2.8–9.7) | 2.7 (1.5–5.3) | 0.007 |
| n | BL | M6 | p value | |
| 37 | 4.6 (2.9–10.4) | 2.4 (1.3–5.8) | 0.006 | |
The number of patients with available values of the respective variable at BL and the time point of interest (M3, M6, or M9) was used for the single calculations. Wilcoxon test was computed for statistical analysis. Bold p values denote a statistically significant difference. BL, baseline; CRP, C-reactive protein; IL-6, interleukin 6; LBP, lipopolysaccharide-binding protein; M, months following TIPS insertion; TIPS, transjugular intrahepatic portosystemic shunt.
Follow-up and outcomes (combined cohort)
The median follow-up time was 538 (IQR 277–962) days. During the follow-up period 19.3% (n = 21/109) of patients developed ACLF, whereas 10.1% (n = 11/109) underwent LT. Overall, 21 (19.3%) patients died with 90.5% (n = 19/21) of deaths being liver related. Non-liver-related deaths included one patient who died as a result of necrotizing pancreatitis and one patient with structural heart disease who had a cardiac arrest.
Impact of ΔIL-6 on ACLF and liver-related death (combined cohort)
In the combined cohort, multivariable competing risk analysis adjusted for age, albumin at M3, and MELD at M3 revealed that ΔIL-6 at M3 after TIPS implantation was independently associated with subsequent ACLF (absolute standardized hazard ratio [asHR]: 1.01; 95% CI: 1.01–1.02; p <0.001, Table 3) and liver-related death (asHR: 1.02; 95% CI: 1.01–1.02; p <0.001).
Table 3.
Impact of the change in IL-6 from baseline to month 3 and decrease of IL-6 levels at 3 months after TIPS implantation on the risk of (i) ACLF and (ii) liver-related death at 2 years of follow-up.
| Parameter of interest |
Multivariate (adjusted) analysis |
|||||
|---|---|---|---|---|---|---|
| ΔIL-6 model |
IL-6 decrease model |
|||||
| (i) ACLF | asHR | 95% CI | p value | asHR | 95% CI | p value |
| ΔIL-6, pg × ml-1 | 1.01 | 1.01–1.02 | <0.001 | |||
| IL-6 decrease at M3, yes | 0.26 | 0.09–0.77 | 0.016 | |||
| Age, years | 1.04 | 0.99–1.10 | 0.140 | 1.04 | 0.99–1.09 | 0.089 |
| M3 MELD score, points | 1.22 | 1.08–1.37 | 0.011 | 1.20 | 1.07–1.33 | 0.001 |
| M3 albumin, g × L-1 | 0.94 | 0.84–1.04 | 0.240 | 0.97 | 0.86–1.08 | 0.550 |
| (ii) liver-related death | asHR | 95% CI | p value | asHR | 95% CI | p value |
| ΔIL-6, pg × ml-1 | 1.02 | 1.01–1.02 | <0.001 | |||
| IL-6 decrease at M3, yes | 0.26 | 0.07–0.95 | 0.042 | |||
| Age, years | 1.01 | 0.98–1.04 | 0.580 | 1.02 | 0.99–1.05 | 0.200 |
| M3 MELD score, points | 1.27 | 1.11–1.46 | <0.001 | 1.26 | 1.14–1.39 | <0.001 |
| M3 albumin, g × L-1 | 0.98 | 0.86–1.13 | 0.810 | 1.02 | 0.90–1.16 | 0.760 |
Multivariate Fine and Gray competing risk regression models in the combined cohort are shown. Liver transplantation and non-liver-related death were considered as competing risks. Bold p values denote a statistically significant difference. ACLF, acute-on-chronic liver failure; asHR, absolute standardized hazard ratio; IL-6, interleukin 6; M, months following transjugular intrahepatic portosystemic shunt insertion; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt.
Impact of IL-6 decrease at M3 on liver-related outcomes (combined cohort)
Next, we dichotomized the overall cohort into one subgroup of patients who exhibited a decrease of IL-6 at M3 after TIPS implantation compared with BL (n = 72) and those who did not (n = 37).
As demonstrated in Fig. 3 and Table S6, patients with IL-6 decrease at M3 had a significantly lower cumulative incidence of ACLF (IL-6 decrease: 12.2% vs. no IL-6 decrease: 34.1%; p = 0.004) and liver-related death (IL-6 decrease: 8.6% vs. no IL-6 decrease: 30.3%; p = 0.007) at 2 years of follow-up.
Fig. 3.
Cumulative incidence of ACLF and liver-related death stratified by IL-6 at 3 months after TIPS.
Cumulative incidence of (A) ACLF and (B) liver-related death stratified by decrease/no decrease of IL-6 at 3 months after TIPS implantation (M3). Liver transplantation and non-liver-related death were considered as competing risks. Cumulative incidences were compared via Gray’s test: (A) p = 0.004, (B) p = 0.007. ACLF, acute-on-chronic liver failure; TIPS, transjugular intrahepatic portosystemic shunt.
Importantly, as depicted in Table 3, competing risk regression adjusted for the same cofactors showed that an IL-6 decrease at M3 after TIPS implantation was an independent protective factor concerning the development of ACLF (asHR: 0.26; 95% CI: 0.09–0.77; p = 0.016) and liver-related death (asHR: 0.26; 95% CI: 0.07–0.95; p = 0.042). Notably, IL-6 decrease at M3 after TIPS implantation also was independently linked to liver-related death when corrected for PPG before (asHR: 0.30; 95% CI: 0.11–0.88; p = 0.028), as well as PPG after TIPS implantation (asHR: 0.33; 95% CI: 0.11–0.97; p = 0.045).
Characteristics of patients with decreased IL-6 at M3 (combined cohort)
Of note, as detailed in Table 4, patients with and without IL-6 decrease at M3 after TIPS implantation did not differ significantly in relevant BL parameters such as sex, age, etiology of cirrhosis, MELD or Child-Pugh stage, as well as albumin at BL and PPG before TIPS implantation. However, there were numerically more patients with TIPS implantation because of ascites among patients with IL-6 decrease at M3 (75.0% vs. no IL-6 decrease: 67.6%; p = 0.186). Moreover, patients with IL-6 decrease at M3 after TIPS implantation tended to have a lower median PPG after TIPS implantation (6 mmHg vs. no IL-6 decrease: 7 mmHg; p = 0.094).
Table 4.
Patient characteristics and clinical outcomes of patients with and without IL-6 decrease 3 months after TIPS implantation.
| Patient characteristics | IL-6 decrease (n = 72) | No IL-6 decrease (n = 37) | p value |
|---|---|---|---|
| Sex, male/female (% male) | 47/25 (65.3) | 25/12 (67.6) | 0.811 |
| Age, years (IQR) | 57 (51–65) | 60 (48–69) | 0.739 |
| Etiology | 0.427 | ||
| ALD, n (%) | 44 (61.1) | 19 (51.4) | |
| Viral hepatitis, n (%) | 4 (5.6) | 1 (2.7) | |
| Mixed etiology, n (%) | 7 (9.7) | 2 (5.4) | |
| MASH, n (%) | 6 (8.3) | 3 (8.1) | |
| Cryptogenic, n (%) | 3 (4.2) | 4 (10.8) | |
| Other, n (%) | 8 (11.1) | 8 (21.6) | |
| TIPS indication, n (%) | 0.186 | ||
| Ascites, n (%) | 54 (75.0) | 25 (67.6) | |
| Variceal bleeding, n (%) | 12 (16.7) | 11 (29.7) | |
| Both, n (%) | 6 (8.3) | 1 (2.7) | |
| Child-Pugh stage | 0.735 | ||
| A, n (%) | 13 (18.1) | 9 (24.3) | |
| B, n (%) | 43 (59.7) | 20 (54.1) | |
| C, n (%) | 16 (22.2) | 8 (21.6) | |
| MELD at BL, points (IQR) | 11 (9–13) | 10 (9–14) | 0.724 |
| MELD at M3, points (IQR) | 12 (10–15) | 13 (11–15) | 0.113 |
| Albumin at BL, g × dl-1 (IQR) | 33.8 (29.5–37.0) | 34.8 (30.6–38.1) | 0.494 |
| Bilirubin at BL, mg × dl-1 (IQR) | 0.8 (0.5–1.5) | 1.0 (0.6–1.3) | 0.770 |
| INR at BL, units (IQR) | 1.3 (1.1–1.4) | 1.3 (1.1–1.4) | 0.626 |
| Creatinine at BL, mg × dl-1 (IQR) | 1.0 (0.8–1.2) | 1.0 (0.8–1.4) | 0.336 |
| Sodium, mmol × L-1 (IQR) | 135 (133-138) | 135 (133–138) | 0.981 |
| PPG before TIPS, mmHg (IQR) | 16 (13–19) | 16 (14-20) | 0.543 |
| PPG after TIPS, mmHg (IQR) | 6 (5–8) | 7 (6–9) | 0.094 |
| IL-6 at BL, pg × ml-1 (IQR) | 10.9 (4.3–29.4) | 10.3 (2.1–20.8) | 0.062 |
| IL-6 at M3, pg × ml-1 (IQR) | 5.0 (2.0–12.0) | 13.5 (5.1–30.8) | <0.001 |
| CRP at BL, mg × dl-1 (IQR) | 1.0 (0.3–2.2) | 0.6 (0.3–1.2) | 0.077 |
| Follow-up time, days (IQR) | 601 (275–1073) | 421 (275–736) | 0.273 |
| ACLF, n (%) | 9 (12.5) | 12 (32.4) | 0.013 |
| Liver transplantation, n (%) | 7 (9.7) | 4 (10.8) | 0.858 |
| Death, n (%) | 11 (15.3) | 10 (27.0) | 0.141 |
| Liver-related death, n (%) | 9 (12.5) | 10 (27.0) | 0.058 |
ALD, alcohol-related liver disease; BL, baseline; CRP, C-reactive protein; IL-6, interleukin-6; INR, international normalized ratio; MASH, metabolic dysfunction-associated steatohepatitis; MELD, model for end-stage liver disease; PPG, portal pressure gradient; TIPS, transjugular intrahepatic portosystemic shunt. Continuous variables were compared by Mann–Whitney U test. Pearson’s Χ2 test or Fisher’s exact test, as appropriate, were used for group comparisons of categorical variables. Bold p values denote a statistically significant difference.
Discussion
In this study conducted in two large European liver centers we demonstrate a significant decrease IL-6 and CRP, representative of SI, following TIPS implantation in patients with dACLD. This decrease was preserved during follow-up at all observed time points (at 3, 6, and 9 months after BL), indicating that TIPS implantation leads to a sustained amelioration of SI, which was pronounced before TIPS implantation in most patients. Moreover, we found similar results regarding the course of LBP post TIPS, which suggests a reduction of bacterial translocation as pathomechanistic explanation for the amelioration of SI. Although this in line with another recently published study,24 our data establishes dynamics of IL-6 after TIPS implantation as a risk factor for clinical outcomes. Importantly, ΔIL-6 (as a metric variable) as well as any IL-6 decrease (as a dichotomic variable) at M3 after TIPS implantation proved to be independently associated with ACLF and liver-related death in our study, underscoring the clinical relevance of our findings. Our results postulate that the effectiveness of TIPS to improve clinical outcomes are partly caused by reducing bacterial translocation and subsequently ameliorating SI in patients with dACLD. Indeed, SI is a well-accepted driver of disease progression in the setting of dACLD.5,21,25,26 Relevantly, conditions associated with particularly high levels of SI such as bacterial infections and alcoholic hepatitis, have been identified as the main precipitating factors of ACLF in patients with dACLD.27 Notably, patients remaining with high IL-6 after TIPS require closer monitoring as they are at particularly high risk for clinical events.
Generally, the state of increased SI in dACLD is closely associated with the gut–liver axis,7 as signal molecules derived from the gut, as well as pathogen-associated molecular patterns and damage-associated molecular patterns reach the liver via the portal venous blood stream.28 Consecutively, there is a shift in the balance of pro-inflammatory and anti-inflammatory cytokines in patients with ACLD,29 which results in the development of a pro-inflammatory phenotype in patients with dACLD, which is characterized by immune cell activation and pro-inflammatory mediators such as CRP and inflammatory cytokines such as IL-6.30,31 Accompanied by immunological changes, subsumed by the term cirrhosis-associated immune dysfunction,32 this eventually leads to the development of clinical complications including bacterial infections, ACLF and eventually liver-related death.33
As bacterial translocation, a central factor for the development of progressive SI in patients with dACLD, is closely tied to PH,9 TIPS implantation may be an effective treatment by reducing PPG and thereby also improving bacterial translocation. LBP is an important endotoxin-binding protein in humans34 and is well-established as a marker for bacterial translocation in ACLD.35 Indeed, our study demonstrates markedly lower levels of LBP throughout M9 after TIPS implantation. Importantly, LBP was decreased in 77.4% of patients in the Vienna cohort at M3, indicating an early improvement of bacterial translocation in the majority of patients following TIPS implantation. Thus, the decrease of portal pressure may be a key factor for the reduction of SI and bacterial translocation after TIPS implantation, which is supported by the finding that ΔIL-6 correlated significantly with ΔLBP. Interestingly, changes in PPG after TIPS implantation were not linked to ΔIL-6 or ΔLBP. Because of the exploratory design of our study, the reason for this cannot be inferred from our data and further research is required to fully elucidate the relationship between dynamics of PH and parameters of SI and bacterial translocation after TIPS implantation.
Furthermore, we observed a significant and sustained decrease of key inflammatory parameters including IL-6 and CRP in most patients included in this study after TIPS implantation. Although several studies have reported that increased levels of inflammatory parameters at the time of TIPS implantation are associated with detrimental outcomes,19,20 the dynamics of these inflammatory parameters with reduction following TIPS implantation represent an important novel finding. Indeed, it has been described that TIPS implantation is beneficial in patients with (lower grade) ACLF, reducing mortality in this patient group.36 Our study adds novel mechanistic insights for this association, as it demonstrates that by reducing levels of SI, TIPS implantation prevents ACLF and liver-related death in patients with dACLD who undergo elective TIPS implantation. As a consequence, TIPS implantation may be seen viewed as a therapeutic approach that alters the natural history in patients with dACLD,2 as it attenuates bacterial translocation and ameliorates SI as two key drivers of liver disease progression. Importantly, our study demonstrates that any decrease of IL-6 3 months after TIPS implantation is associated with significantly improved outcomes in terms of ACLF and liver-related death, proposing an easy-to-use and intuitive cutoff of a parameter that is readily available in clinical practice. Patients who do not exhibit decreased IL-6 levels 3 months after TIPS implantation represent a cohort at continued risk for liver-related clinical outcomes who should be followed-up closely.
Our study also has limitations. Firstly, the somewhat limited sample size in both the Vienna and Hannover cohort has to be mentioned, as it could decrease particularly the power of outcome analyses. To account for this, we decided to pool the two cohorts into a combined cohort for the analysis of the impact of dynamics of IL-6 on clinical outcomes of patients with dACLD following TIPS implantation. Still, the results obtained in the competing risk regression models require further validation. Secondly, not all parameters were available at all time points, which was as a result of organizational problems during the COVID-19 pandemic.37 Thirdly, different assays were used for the analysis of IL-6 in the Vienna and in the Hannover cohort, which differed regarding limits of quantification and may explain the overall different absolute levels of IL-6 detected in the Hannover and in the Vienna cohort. However, by investigating not absolute levels of IL-6 at BL and M3, but rather the trajectory of relative IL-6 levels between these time points (ΔIL-6 and the presence/absence of IL-6 decrease), we accounted for this limitation and demonstrated that any decrease of IL-6 at M3 represents a protective factor regarding the development of ACLF and liver-related death. Furthermore, we did not assess laboratory markers of alcohol consumption. However, this study included a clinically stable cohort of patients with dACLD undergoing elective TIPS implantation, with the majority showing abstinence at the time of TIPS implantation. Notably, we included patients with elective TIPS implantation because of ascites or variceal bleeding. The impact of SI parameter dynamics on clinical outcomes may vary between these patient cohorts. Unfortunately, owing to the limited sample size, this point cannot be answered by our data and further research is needed to determine this. Lastly, we excluded patients with pre-emptive TIPS and rescue-TIPS implantation and thus cannot comment on the prognostic value of IL-6 in these patients, however, the usually very high BL IL-6 levels in these settings would limit drawing conclusions from further dynamics.
In conclusion, by exploring the trajectories of IL-6, CRP, and LBP at different time points after TIPS implantation, we demonstrate amelioration of SI potentially mediated by reduced bacterial translocation as early as M3 after TIPS implantation. Moreover, this amelioration/attenuation of SI and bacterial translocation was sustained at all subsequent time points after TIPS implantation. Importantly, any decrease of IL-6 at M3 after TIPS implantation represented a protective factor regarding ACLF and liver-related death independently of age and liver function. Monitoring IL-6 decrease 3 months after TIPS implantation may thus be used as a valuable risk stratification tool in patients after TIPS implantation.
Abbreviations
ACLD, advanced chronic liver disease; ACLF, acute-on-chronic liver failure; ALD, alcohol-related liver disease; asHR, absolute standardized hazard ratio; BL, baseline; CRP, C-reactive protein; dACLD, decompensated ACLD; HCC, hepatocellular carcinoma; LBP, lipopolysaccharide-binding protein; LT, liver transplantation; M3, 3 months after TIPS implantation; M6, 6 months after TIPS implantation; M9, 9 months after TIPS implantation; MELD, model for end-stage liver disease; PCT, procalcitonin; PH, portal hypertension; PPG, portal pressure gradient; SI, systemic inflammation; TIPS, transjugular intrahepatic portosystemic shunt.
Financial support
Clinical Research Group MOTION, Medical University of Vienna, Vienna, Austria – a project funded by the Clinical Research Groups Programme of the Ludwig Boltzmann Gesellschaft (Grant No.: LBG_KFG_22_32) with funds from the Fonds Zukunft Österreich. AT, LS, and HR were supported by the ‘KlinStrucMed’ programme of Hannover Medical School and by the ‘Elser-Kröner-Fresenius-Stiftung’.
Authors’ contributions
Research design: AK, LH. Data acquisition: AK, AT, PH, TM-B, LS, HR, LR, MS, MM, BM, TR, LH). Data analysis: AK, LH. Data interpretation: all authors. Drafted the manuscript: AK, TR, LH. Critical revision of manuscript: AT, PH, JK, TM-B, LS, HR, LR, ND, GK, MT, MM, CF, BM.
Data availability statement
The data are available upon reasonable request to the corresponding author.
Conflicts of interest
The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: AK, AT, PH, JK, TM, LS, HR, LR, ND, GK, CF, BM, and LH declare no conflicts of interest. MT received research grants, travel grants, speaker fees, and advised for Gilead Sciences; received consultancy fees from AbbVie, Albireo, Agomab, BiomX, Boehringer Ingelheim, Chemomab, Falk, GlaxoSmithKline, Genfit, Hightide, Intercept, Ipsen, Jannsen, Mirum, MSD, Novartis, Pliant, Regulus, Siemens and Shire; research funding from Albireo, Alnylam, Cymabay, Falk, Intercept, MSD, Takeda, and UltraGenyx; travel grants from AbbVie, Falk, Intercept and Jannsen; speaker fees from Albireo, BMS, Falk, Intercept, Ipsen, MSD, and Madrigal; the Medical Universities of Graz and Vienna have filed patents on medical use of norUDCA and MT is listed as co-inventor. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, Takeda, and W.L. Gore & Associates and received travel support from AbbVie and Gilead. TR served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W.L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W.L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead, and Roche. BM reports lecture and/or consultant fees from AbbVie, Astella, BMS, Falk, Fujirebio, Gilead, Luvos, MSD, Norgine, Roche, and W.L. Gore & Associates. He received research support from Altona, EWIMED, Fujirebio, and Roche.
Please refer to the accompanying ICMJE disclosure forms for further details.
Footnotes
Author names in bold designate shared co-first authorship
Given their role as Associate Editor, Mattias Mandorfer had no involvement in the peer-review of this article and had no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to the Co-Editor Virginia Hernández-Gea.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhepr.2024.101308.
Supplementary data
The following are the supplementary data to this article:
References
- 1.Sepanlou S.G., Safiri S., Bisignano C., et al. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5:245–266. doi: 10.1016/S2468-1253(19)30349-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.D'Amico G., Garcia-Tsao G., Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217–231. doi: 10.1016/j.jhep.2005.10.013. [DOI] [PubMed] [Google Scholar]
- 3.de Franchis R., Bosch J., Garcia-Tsao G., et al. Baveno VII – renewing consensus in portal hypertension. J Hepatol. 2022;76:959–974. doi: 10.1016/j.jhep.2021.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mandorfer M., Aigner E., Cejna M., et al. Austrian consensus on the diagnosis and management of portal hypertension in advanced chronic liver disease (Billroth IV) Wien Klin Wochenschr. 2023;135(Suppl. 3):493–523. doi: 10.1007/s00508-023-02229-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Costa D., Simbrunner B., Jachs M., et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J Hepatol. 2021;74:819–828. doi: 10.1016/j.jhep.2020.10.004. [DOI] [PubMed] [Google Scholar]
- 6.D'Amico G., Morabito A., D'Amico M., et al. Clinical states of cirrhosis and competing risks. J Hepatol. 2018;68:563–576. doi: 10.1016/j.jhep.2017.10.020. [DOI] [PubMed] [Google Scholar]
- 7.Simbrunner B., Mandorfer M., Trauner M., et al. Gut-liver axis signaling in portal hypertension. World J Gastroenterol. 2019;25:5897–5917. doi: 10.3748/wjg.v25.i39.5897. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Trebicka J., Fernandez J., Papp M., et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol. 2020;73:842–854. doi: 10.1016/j.jhep.2020.06.013. [DOI] [PubMed] [Google Scholar]
- 9.Trebicka J., Reiberger T., Laleman W. Gut-liver axis links portal hypertension to acute-on-chronic liver failure. Visc Med. 2018;34:270–275. doi: 10.1159/000490262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Moreau R., Jalan R., Gines P., et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–1437.e1–9. doi: 10.1053/j.gastro.2013.02.042. [DOI] [PubMed] [Google Scholar]
- 11.Jalan R., Saliba F., Pavesi M., et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014;61:1038–1047. doi: 10.1016/j.jhep.2014.06.012. [DOI] [PubMed] [Google Scholar]
- 12.Balcar L., Semmler G., Pomej K., et al. Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute-on-chronic liver failure. United Eur Gastroenterol J. 2021;9:427–437. doi: 10.1002/ueg2.12089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Bucsics T., Lampichler K., Vierziger C., et al. Covered transjugular intrahepatic portosystemic shunt improves hypersplenism-associated cytopenia in cirrhosis. Dig Dis Sci. 2022;67:5693–5703. doi: 10.1007/s10620-022-07443-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Larrue H., D'Amico G., Olivas P., et al. TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis. J Hepatol. 2023;79:692–703. doi: 10.1016/j.jhep.2023.04.028. [DOI] [PubMed] [Google Scholar]
- 15.García-Pagán J.C., Caca K., Bureau C., et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370–2379. doi: 10.1056/NEJMoa0910102. [DOI] [PubMed] [Google Scholar]
- 16.Bucsics T., Schoder M., Goeschl N., et al. Re-bleeding rates and survival after early transjugular intrahepatic portosystemic shunt (TIPS) in clinical practice. Dig Liver Dis. 2017;49:1360–1367. doi: 10.1016/j.dld.2017.08.002. [DOI] [PubMed] [Google Scholar]
- 17.Bureau C., Thabut D., Oberti F., et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology. 2017;152:157–163. doi: 10.1053/j.gastro.2016.09.016. [DOI] [PubMed] [Google Scholar]
- 18.Bucsics T., Hoffman S., Grünberger J., et al. ePTFE-TIPS vs repetitive LVP plus albumin for the treatment of refractory ascites in patients with cirrhosis. Liver Int. 2018;38:1036–1044. doi: 10.1111/liv.13615. [DOI] [PubMed] [Google Scholar]
- 19.Jansen C., Möller P., Meyer C., et al. Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality. Hepatology. 2018;67:1472–1484. doi: 10.1002/hep.29612. [DOI] [PubMed] [Google Scholar]
- 20.Loosen S.H., Benz F., Mohr R., et al. Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS. JHEP Rep. 2024;6 doi: 10.1016/j.jhepr.2024.101054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hartl L., Simbrunner B., Jachs M., et al. Lower free triiodothyronine (fT3) levels in cirrhosis are linked to systemic inflammation, higher risk of acute-on-chronic liver failure, and mortality. JHEP Rep. 2024;6 doi: 10.1016/j.jhepr.2023.100954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Fine J.P., Gray R.J. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509. [Google Scholar]
- 23.Jachs M., Hartl L., Schaufler D., et al. Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes. Gut. 2021;70:1758–1767. doi: 10.1136/gutjnl-2020-322712. [DOI] [PubMed] [Google Scholar]
- 24.Tiede A., Stockhoff L., Liu Z., et al. TIPS insertion leads to sustained reversal of systemic inflammation in patients with decompensated liver cirrhosis. Clin Mol Hepatol. 2024 doi: 10.3350/cmh.2024.0587. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Taru V., Szabo G., Mehal W., et al. Inflammasomes in chronic liver disease: hepatic injury, fibrosis progression and systemic inflammation. J Hepatol. 2024;81:895–910. doi: 10.1016/j.jhep.2024.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Simbrunner B., Villesen I.F., Königshofer P., et al. Systemic inflammation is linked to liver fibrogenesis in patients with advanced chronic liver disease. Liver Int. 2022;42:2501–2512. doi: 10.1111/liv.15365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Trebicka J., Fernandez J., Papp M., et al. PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis. J Hepatol. 2021;74:1097–1108. doi: 10.1016/j.jhep.2020.11.019. [DOI] [PubMed] [Google Scholar]
- 28.Racanelli V., Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl. 1):S54–S62. doi: 10.1002/hep.21060. [DOI] [PubMed] [Google Scholar]
- 29.Tilg H., Diehl A.M. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med. 2000;343:1467–1476. doi: 10.1056/NEJM200011163432007. [DOI] [PubMed] [Google Scholar]
- 30.Clària J., Stauber R.E., Coenraad M.J., et al. Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure. Hepatology. 2016;64:1249–1264. doi: 10.1002/hep.28740. [DOI] [PubMed] [Google Scholar]
- 31.Waidmann O., Brunner F., Herrmann E., et al. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis. J Hepatol. 2013;58:956–961. doi: 10.1016/j.jhep.2013.01.005. [DOI] [PubMed] [Google Scholar]
- 32.Albillos A., Martin-Mateos R., Van der Merwe S., et al. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol. 2022;19:112–134. doi: 10.1038/s41575-021-00520-7. [DOI] [PubMed] [Google Scholar]
- 33.Hartl L., Simbrunner B., Jachs M., et al. An impaired pituitary-adrenal signalling axis in stable cirrhosis is linked to worse prognosis. JHEP Rep. 2023;5 doi: 10.1016/j.jhepr.2023.100789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Schumann R.R., Latz E. Lipopolysaccharide-binding protein. Chem Immunol. 2000;74:42–60. doi: 10.1159/000058760. [DOI] [PubMed] [Google Scholar]
- 35.Alexopoulou A., Agiasotelli D., Vasilieva L.E., et al. Bacterial translocation markers in liver cirrhosis. Ann Gastroenterol. 2017;30:486–497. doi: 10.20524/aog.2017.0178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Trebicka J., Gu W., Ibáñez-Samaniego L., et al. Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS. J Hepatol. 2020;73:1082–1091. doi: 10.1016/j.jhep.2020.04.024. [DOI] [PubMed] [Google Scholar]
- 37.Hartl L., Semmler G., Hofer B.S., et al. COVID-19-related downscaling of in-hospital liver care decreased patient satisfaction and increased liver-related mortality. Hepatol Commun. 2021;5:1660–1675. doi: 10.1002/hep4.1758. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Data Availability Statement
The data are available upon reasonable request to the corresponding author.