Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers

Abstract

The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute-on-chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis-associated immune dysfunction (CAID). Gut-derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF.Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.

Keywords: CIRRHOSIS; CLINICAL DECISION MAKING; LIVER FAILURE.

Figure 1

Biomarkers, endpoints and other tools biomarker classification proposed by the Food and Drug Administration. We included some examples adapted to ACLF to demonstrate how each biomarker clarifies and describes their hierarchical relationships, connections and dependencies. ACLF, acute-on-chronic liver failure; AD, acute decompensation; AKI, acute kidney injury; CLIF, chronic liver failure; HRS, hepatorenal syndrome; NGAL, neutrophil gelatinase-associated lipocalin; PREDICT, predicting acute-on-chronic liver failure in cirrhosis.

Figure 2

An overview of the main therapeutic approaches in patients with cirrhosis to prevent decompensation and progression to acute-on-chronic liver failure. Created with BioRender.com with publication licence. TLR-4, toll-like receptor 4.

Figure 3

Key landmark clinical trials in cirrhosis in patients with compensated cirrhosis and clinically significant portal hypertension (A) and in patients with decompensated cirrhosis (B). (A) Illustrates recently published phase 2a/b and 3 clinical trials in patients with compensated cirrhosis and clinically significant portal hypertension with the outcome of improved decompensation-free survival. These include trials of non-specific beta blockers, rifaximin-α, statins, testosterone, granulocyte colony-stimulating factor (GCSF)/autologous CD133 stem cell therapy and faecal microbiota transplantation (FMT). The trials highlighted in green bars are positive, light red bars negative and in grey bars are still recruiting or await reporting. (B) Illustrates recently published phase 2a/b and 3 clinical trials in patients with decompensated cirrhosis with the main outcome of survival. These include trials of human albumin solution, midodrine, simvastatin, cotrimoxazole, GCSF and GCSF in combination with growth hormone/erythropoietin. HVPG, hepatic venous pressure gradient; SAEs, serious adverse events; SBP, spontaneous bacterial peritonitis; SMT, standard medical therapy. Created with BioRender.com with publication licence.

Figure 4

Novel targets and therapies for acute-on-chronic liver failure. The Figure illustrates novel targets and therapies that are in early development and/or phases 1 and 2 trials for acute-on-chronic liver failure. G-CSF, granulocyte colony-stimulating factor; RIPK, receptor interacting protein kinase; TLR, toll-like receptor. Created with BioRender.com with publication licence.