With great pleasure we read the editorial by Georg Semmler, Lorenz Balcar and Mathias Mandorfer on our manuscript “TIPS insertion leads to a sustained reversal of systemic inflammation in patients with decompensated liver cirrhosis” [1]. Their editorial provides an excellent and comprehensive overview of systemic inflammation in the context of liver cirrhosis [2].

We appreciate the highlighting of the relevance of our findings, which were enhanced by the presentation of results from our recent publication focusing on IL-6, lipopolysaccharide binding protein (LBP) and post-transjugular intrahepatic portosystemic shunt (TIPS) outcome [3]. Particularly the decrease of LBP provides valuable additional mechanistic insights into the suggested improvement of bacterial translocation. Regarding the limitations of these studies, we agree that the investigation of the predictive values of certain inflammatory patterns or singular trajectories remain of interest for larger patient cohorts.

However, both studies notably underscore the prognostic importance of a decrease in systemic inflammation, highlighting the enduring need to therapeutically target systemic inflammation. In light of our novel data, TIPS insertion seems to be more effective than all previously presented interventions, e.g., non-selective beta-blockers (NSBB) or antibiotic co-medication, which have individually shown anti-inflammatory effects in decompensated cirrhosis [4-6]. In the post-TIPS setting, however, we detected no significant effects of rifaximin and norfloxacin in our study. Similarly, recent data from our center indicate that no meaningful additional anti-inflammatory effect of NSBB can be expected if portal pressure is sufficiently lowered by TIPS insertion. Importantly, NSBB after TIPS were also not associated with an improved outcome [7]. Thus, we hypothesize that the recently confirmed anti-inflammatory effects of TIPS may outnumber the effects seen by NSBB or any other currently available treatment option.

Furthermore, TIPS insertion may even lead to a reversal of liver disease stage. D’Amico and colleagues introduced up to seven prognostically relevant stages of liver disease, which were recently shown to be characterized by an almost exponentially increasing level of systemic inflammation upon progressing to the final stage 6, refractory ascites [8,9]. While TIPS is a well-known treatment for refractory ascites [10], thus improving the visible, phenotypical stage of liver disease, the present studies reveal for the first time a sustained inflammatory downregulation and thus partial reversal of liver stage disease as characterized by inflammatory markers [1,3]. The markedly elevated levels of IL-6 in patients with refractory ascites decrease to levels observed in lower stages of cirrhosis, equaling those of patients without ascites at 6 months after TIPS intervention [1]. Importantly, this enhances the understanding of mechanisms through which TIPS insertion leads to improved survival and reduced rates of cirrhosis-associated complications – and lastly, recompensation [11-13]. In this regard, TIPS insertion may be able to “turn back the clock” of liver disease, both phenotypically and on the inflammatory level (Fig. 1).

Furthermore, Semmler and colleagues aptly described an “uncoupling” of portal hypertension and systemic inflammation in the progression of decompensated liver cirrhosis, which can be observed from stage 4 onwards in the classification of D’Amico et al. Henceforth, only systemic inflammation, but not the portal pressure gradient, increases significantly across subsequent stages (Fig. 1) [8,9]. However, our data indicate that this uncoupling in the higher liver disease stages does not necessarily mean that patients will not benefit from a portal pressure reduction. This is also very well in line with the majority of recent data published on the survival benefits of NSBB in patients classifiable as the most advanced stage 6, e.g., with refractory ascites and even in the setting of acute-on-chronic liver failure (ACLF) and spontaneous bacterial peritonitis, as well as the reported superior survival associated with preemptive TIPS insertion in patients with ACLF due to variceal bleeding [14-17]. We certainly agree with Semmler and colleagues that there seems to be a point of no return, beyond which systemic inflammation cannot be targeted by portal pressure reduction anymore. However, this particular juncture in the disease trajectory still needs to be better defined [18,19].

In light of the scarcity of donor organs and thus, liver transplantation, future studies may also address the question whether immunomodulatory drugs may be a possible therapeutic approach in the setting beyond the aforementioned juncture. Until then, the prognostic implications of an amelioration of systemic inflammation after TIPS insertion may serve as an important addition towards the progressive shifting toward earlier consideration of treatment with TIPS in patients with cirrhosis.