Novel Therapeutic Approaches in Treatment of Acute-on-Chronic Liver Failure

Abstract

Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.

Fig. 1

The overview of the disease progression model ( top ) and the pathogenesis of ACLF with the investigated treatment targets ( bottom ). The relevant studies to each treatment have been marked with * and placed inside brackets. ACLF, acute-on-chronic liver failure; FMT, fecal microbiota transplant; G-CSF, granulocyte–colony stimulating factor; HALPC, human allogenic liver-derived progenitor cells; RIPK, receptor-interacting protein kinase.

Fig. 2

Structure of albumin with its binding sites and the main compounds that bind to each one. * Cyst34 state can be assessed using HPLC and its inactivation is associated with mortality. ** Multimetal binding site can be assessed using cobalt-binding assay. *** SUDLOW binding sites can be assessed using electron paramagnetic resonance spectroscopy and their loss of function is associated with mortality. Albumin structure was modified and downloaded from RCSB PDB ( https://doi.org/10.2210/pdb1E78/pdb ) of PDB ID 1E78. ACLF, acute-on-chronic liver failure; HPLC, high performance liquid chromatography; RCSB PDB, Research Collaboratory for Structural Bioinformatics Protein Data Bank.

Fig. 3

Overview of modes of cell death in cirrhotic liver disease. Necroptosis and pyroptosis are the dominant forms of cell death in ACLF and TLR-4 and its downstream pathways play a key role in their activation. Intracellular LPS activates noncanonical inflammasomes resulting in CASP4/5 formation. Inactive GSDMD protein is then cleaved into its active form, GSDMD-N, which forms pores in the plasma membrane leading to pyroptotic cell death. Additionally, noncanonical inflammasomes activate NLRP3 (not shown in the figure) resulting in cleavage of pro-IL-1β and pro-IL-18 into their active forms. Formation of necrosome complex can be initiated by a variety of factors of which the activation of TNF receptor remains the principal trigger. TLR-4 activation can also directly activate RIPK3 thus triggering MLKL and pore formation in the cell membrane. The result of necroptotic or pyroptotic cell death is the release of cellular contents including DAMPs, cytokines, and chemokines, which further worsen the state of systemic inflammation. ACLF, acute-on-chronic liver failure; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain; CASP1, caspase-1; CASP4/5, caspase-4 or 5; DAMP, damage-associated molecular pattern; GSDMD, gasdermin D; IL, interleukin; LPS, lipopolysaccharide; MLKL, mixed linage kinase domain-like; NF-κB, nuclear factor κB; NLR, nucleotide-binding domain; NLRP, NOD-like receptor family; PYD, pyrin domain; RIPK, receptor-interacting protein kinase; TNF-α, tumor necrosis factor α; TLR-4, toll-like receptor-4.

Fig. 4

Suggested treatment algorithm for treatment of patients with ACLF grades 2 to 3. All four graphical figures in this review article were created with BioRender.com. ACLF, acute-on-chronic liver failure; CT CAP, computed tomography scan of chest, abdomen, and pelvis; LTx, liver transplantation; OF, organ failure; MDRO, multidrug-resistant organism.