Potential therapies for acute-on-chronic liver failure

Abstract

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

FIGURE 1

Mechanism of action of novel therapies for ACLF. Therapeutic approaches include targeting gut bacterial translocation and the microbiome, liver inflammation, cell death and regeneration, circulating immune cells and extracorporeal liver support. Dysbiosis in ACLF results in increased translocation of bacterial components and these PAMPs activate innate immune cells and thereby contribute to systemic inflammation. Antibiotics, NSBBs, engineered bacteria, FMT and phage therapy aim to improve dysbiosis and reduce bacterial translocation. Hepatocytes are injured by PAMPs and DAMPs and the resulting local inflammatory response. IL‐1 inhibitors and TLR4 inhibitors decrease this inflammation. RIPK1 inhibitors inhibit cell death and NKG2D, TRAIL, KCTD9 and CXCR2 inhibitors aim to reduce innate immune cell‐mediated hepatocyte death. IL‐22 and G‐CSF promote hepatic regeneration. Systemic inflammation and immune dysfunction contribute to organ failures and development of bacterial infections respectively. TLR7/8 agonists, IL‐33, PD1/TIM3 inhibitors, Poly(IC), MERTK/AXL inhibitors, LPA and glutamine synthetase inhibitors reduce circulating immunosuppressive responses. Extra‐corporeal liver support can be divided into artificial, such as Dialive or plasma exchange, and artificial, such as mesenchymal stem cells or organoids. Artificial support devices remove circulating toxins. Cellular therapies promote hepatic regeneration. ALP, alkaline phosphatase; AXL, anexelekto; DAMP, danger‐associated molecular pattern; FMT, faecal microbiota transplantation; G‐CSF, granulocyte colony‐stimulating factor; IL, interleukin; LPA, lysophosphatidic acid; LPS, lipopolysaccharide; MERTK, Mer tyrosine kinase; MPO, myeloperoxidase; NSBBs, non‐selective beta blockers; NKG2D, natural killer cell group 2D; PAMP, pathogen‐associated molecular pattern; PD1, programmed cell death protein 1; PD‐L1, programmed death ligand 1; TIM3, T cell immunoglobulin and mucin domain‐containing protein 3; TLR, Toll‐like receptor; TRAIL, tumour necrosis factor‐related apoptosis‐inducing ligand.