Editorial: Redefining Decompensation in Cirrhosis—More Than an Academic Playground?

Of late, the characterization of disease stages in liver cirrhosis has undergone significant refinement. From division into 'compensated' and 'decompensated', the latter classifiable into 'first' and 'further', up to seven different stages have been established as prognostic models 1, 2. Beyond these progression-based views, a newer classification accounts for the dynamics of deterioration 3: Acute decompensation (AD) refers to the rapid onset of either grade 2–3 ascites, acute hepatic encephalopathy (HE), gastrointestinal bleeding, or bacterial infections, typically requiring hospitalization 3, 4. Non-acute decompensation (NAD), however, encompasses slowly developing ascites, low-grade HE, or jaundice, often managed in outpatient setting 3 (Figure 1). As the events defining AD are known precipitants of acute-on-chronic liver failure (ACLF) 4, AD unsurprisingly confers higher mortality than NAD, which nonetheless reduces survival compared to compensated cirrhosis 5-7. In the current study, Simonis et al. confirm the prognostic impact of this classification in a cohort of 505 patients, demonstrating a 12-month transplant-free mortality of 26% (AD) versus 11% (NAD) 5. Notably, hospitalization-admission per se (a criterion for AD in previous studies 6, 7) did not primarily determine prognosis but rather the rapidity of decompensation, reinforcing the clinical relevance of this classification and similarly prompting a revision of AD diagnostic criteria 5. All classifications aim to accurately stratify patients by disease stage, progression risk, and overall prognosis. However, these efforts must ultimately serve a more ambitious purpose—identifying stage-specific therapeutic windows and modifiable targets, preventing or even reversing stage progression. Regarding AD, systemic inflammation—generally recognized as a key driver of disease progression—has been proposed as the unifying mechanism of all AD events through a cascade acting in synergy with traditional factors (e.g., hyperammonaemia, portal hypertension), leading to multiorgan dysfunction up to ACLF 4, 8. Corroborating this, Simonis et al. found elevated C-reactive protein (CRP)-levels in AD patients 5, which is supported by a recent study by Verma and colleagues reporting significantly higher cytokine levels in this subgroup 7. Systemic inflammation might constitute a valuable therapeutic target, modifiable through treatment of underlying liver disease or reduction of portal hypertension. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) has emerged as the so far most potent tool, potentially even outnumbering the additional anti-inflammatory properties of non-selective beta-blockers (NSBB) 9, 10. Yet, identifying preemptive strategies to prevent progression to AD remains a critical objective. Interestingly, in NAD systemic inflammation seems to be less pertinent, with inflammatory profiles comparable to compensated cirrhosis 5-7. However, NAD-patients show evidence of cell death markers and elevated Insulin-like Growth-Factor-1 levels 7, all identifying patients at high progression risk to AD 7. Similarly, Simonis et al. found a predictive value of CRP in AD-patients, but not in those with NAD 5, 7. This suggests that, while systemic inflammation drives AD, cell death may be the key early event in cirrhosis patients developing NAD, thereby presenting a novel therapeutic target to halt disease progression. However, further studies should broaden our understanding of the underlying pathophysiological mechanisms; particularly the role of the gut–liver axis, possibly one source contributing to cell death, merits study. Ultimately, this should promote stage-specific therapeutic approaches—from etiological cure as the founding pillar of all therapeutic efforts to TIPS/NSBB, gut-microbiome-interventions/antibiotic-prophylaxis, or combinations thereof. Anja Tiede: writing – original draft, writing – review and editing, conceptualization, visualization. Benjamin Maasoumy: conceptualization, writing – original draft, writing – review and editing, supervision. Anja Tiede was supported by the 'KlinStrucMed' program of Hannover Medical School and by the 'Elser-Kröner-Fresenius-Stiftung'. Anja Tiede and Benjamin Maasoumy received funding from the MHHplus foundation. B.M.: Lecture and/or consultant fees from AbbVie, AstraZeneca, EWIMED, Fujirebio, Gilead, Luvos, Ipsen, Merz, MSD, Norgine, Roche, W.L. Gore & Associates. Research support from Altona, EWIMED, Fujirebio and Roche. This article is linked to Simonis et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70302 and https://doi.org/10.1111/apt.70344. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.