Acute-on-chronic liver failure: far to go-a review

Abstract

Acute-on-chronic liver failure (ACLF) has been recognized as a severe clinical syndrome based on the acute deterioration of chronic liver disease and is characterized by organ failure and high short-term mortality. Heterogeneous definitions and diagnostic criteria for the clinical condition have been proposed in different geographic regions due to the differences in aetiologies and precipitating events. Several predictive and prognostic scores have been developed and validated to guide clinical management. The specific pathophysiology of ACLF remains uncertain and is mainly associated with an intense systemic inflammatory response and immune-metabolism disorder based on current evidence. For ACLF patients, standardization of the treatment paradigm is required for different disease stages that may provide targeted treatment strategies for individual needs.

Keywords: Acute-on-chronic liver failure; Clinical management; Immune-metabolism disorder; Organ failure; Prognosis; Systemic inflammatory response.

Fig. 1

Pathophysiology of ACLF. Chronic liver diseases related to alcohol and HBV under precipitating events (bacterial infection and HBV reactivation) induce a dramatic immune-inflammatory response and metabolism disorder and eventually develop into multiple organ failures. The systemic inflammatory response plays an important role in the development of ALD-ACLF. The released PAMPs and DAMPs from bacteria and necrotic cells activate immune cells and result in the increased release of inflammatory mediators and even a cytokine storm. Activation of the innate-immune system and exhaustion of the adaptive immune system are the core mechanisms of HBV-ACLF. Alterations in metabolic pathways regulate glycolysis, proteolysis and lipolysis in the context of immune-inflammatory disorder and liver failure. Glucose is used to rapidly produce ATP through glycolysis and enters the pentose phosphate pathway and glucuronic acid pathway, whereas mitochondrial oxidative phosphorylation is suppressed; mitochondrial β-oxidation of fatty acids is inhibited; and increased generation and accumulation of amino acids are metabolized through specific metabolic pathways. ACLF, acute-on-chronic liver failure; ATP, adenosine triphosphate; HBV, hepatitis B virus; CoA, coenzyme A; DAMPs, damage-associated molecular patterns; ETC, electron transport chain; HMGB1, high mobility group box 1; IL, interleukin; LPS, lipopolysaccharide; MDSC, myeloid-derived suppressor cell; m-TOR, mammalian target of rapamycin; NETs, neutrophil extracellular traps; NO, nitric oxide; PAMPs, pathogen-associated molecular patterns; PPAR, peroxisome proliferator-activated receptors; PRRs, pattern-recognition receptors; ROS, reactive oxygen species; TCA, tricarboxylic acid; TNF-α, tumour necrosis factor-α

Fig. 2

Schematic diagram showing a paradigm for ACLF management. In the chronic liver disease stage, standardization of management protocols for the treatment of precipitating events is needed to close the “switch” of acute deterioration. Once patients develop to the acutely decompensated stage, different populations could be diagnosed using different criteria depending on the phenotype specificity of ACLF. Non-ACLF patients should be predicted the risk of progression to ACLF to prevent the onset of ACLF with intense intervention, while ACLF patients should be assessed for different prognostic stratifications by scores. Patients with ACLF who can derive a high survival benefit from LT by evaluation should be prioritized for liver transplantation, making efficient use of the limited donor organs and reducing the risk of futile transplantation. ACLF, acute-on-chronic liver failure; ALD, alcohol-related liver disease; HBV, hepatitis B virus; CLIF-C ACLFs, chronic liver failure consortium ACLF score; COSSH, Chinese Group on the Study of Severe Hepatitis B; COSSH- ACLF IIs, COSSH- ACLF II score; COSSH-onset-ACLFs, COSSH-onset-ACLF score; G-CSF, granulocyte colony-stimulating; SDC, stable decompensated cirrhosis; UDC, unstable decompensated cirrhosis