Mechanisms and implications of recompensation in cirrhosis

Abstract

Decompensated cirrhosis has long been considered the irreversible end stage of liver disease, characterised by further decompensating events until death or liver transplantation. However, the observed clinical improvements after effective antiviral treatments for HBV and HCV and after sustained alcohol abstinence have changed this paradigm, leading to the concept of "recompensation" of cirrhosis. Recompensation of cirrhosis was recently defined by Baveno VII as (i) cure of the primary liver disease aetiology; (ii) disappearance of signs of decompensation (ascites, encephalopathy and portal hypertensive bleeding) off therapy; and (iii) stable improvement of liver function tests (bilirubin, international normalised ratio and albumin). Achieving these recompensation criteria is linked to a significant survival benefit. However, apart from aetiological therapies, no interventions/treatments that facilitate recompensation are available, the molecular mechanisms underlying recompensation remain incompletely understood, and early predictors of recompensation are lacking. Moreover, current recompensation criteria are based on expert opinion and may be refined in the future. Herein, we review the available evidence on cirrhosis recompensation, provide guidance on the clinical management of recompensated patients and discuss future challenges related to cirrhosis recompensation.

Keywords: ascites; cirrhosis; hepatic encephalopathy; portal hypertension.

Fig. 1

Definition of recompensation. Recompensation requires the combination of aetiological cure, disappearance of signs of decompensation off therapy and improvement of liver function tests. The aetiological cure of liver disease includes alcohol abstinence, sustained virologic response for HCV and suppression of viral replication for HBV. Treatment and control of metabolic comorbidities such as obesity can favour recompensation. Lack of decompensation off therapy means no ascites without diuretics, no bouts of hepatic encephalopathy without lactulose/rifaximin, no episodes of portal hypertension-related bleeding for more than 12 months. Improvement of liver function tests include an increase in serum albumin and reductions in international normalised ratio and bilirubin.

Fig. 2

Schematic representation of mechanisms of cirrhosis progression and regression. The numbers refer to specific sites for action in order to promote/accelerate cirrhosis regression, and are listed according to their hierarchical relevance (acting on 1 and 2 is much more likely to achieve regression than acting on 9). 1) Aetiological therapy, safe lifestyle, no alcohol, management of co-factors; 2) decrease injury (decrease oxidative stress, necro-apoptosis); 3) restorative cellular mechanisms; 4) statins, enoxaparin, ASA?; 5) resmetirom, GLP-1 receptor agonists, PPARα agonists, FGF inhibitors; 6) restorative macrophages; 7) NSBBs/carvedilol; 8) NSBBs/rifaximin?/norfloxacin?; 9) treatment of specific complications: diuretics, SMTa/terlipressin, band ligation, lactulose, rifaximin. DAMPs, damage-associated molecular patterns; HSCs, hepatic stellate cells; KC, Kupffer cells; LSECs, liver sinusoidal endothelial cells; Mϕ, macrophages; NSBBs, non-selective beta blockers; PAMPs, pathogen-associated molecular patterns; PPAR, peroxisome proliferator-activated receptor-α; PSS, portal-systemic shunting; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.

Fig. 3

Structural and functional changes required for recompensation. After aetiological cure, hepatic and extrahepatic structural and functional changes are required to achieve recompensation. Improvement in synthetic liver function, a reduction in fibrosis septa thinning and a decrease in hepatic vascular/sinusoidal resistance are key mechanisms leading to a reduction in portal pressure. The reduction in portal pressure is expected to be associated with a restoration of cardiovascular alterations and the gut vascular barrier. Signs of portal hypertension such as splenomegaly/hypersplenism or portosystemic shunts are usually attenuated but may persist after recompensation. CSPH, clinically significant portal hypertension; LSECs, liver sinusoidal endothelial cells; MMPs, matrix metalloproteinases; SVR, sustained virological response.