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