Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction

Abstract

Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure(s). The pathomechanisms involved in decompensation and disease progression are still not well understood, and as specific disease-modifying treatments do not exist, research to identify novel therapeutic targets is of the utmost importance. This review amalgamates the latest knowledge on disease mechanisms that lead to tissue injury and extrahepatic organ failure - such as systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes - and marries these with the classical paradigms of acute decompensation to form a single paradigm. With this detailed breakdown of pathomechanisms, we identify areas for future research. Novel disease-modifying strategies that break the vicious cycle are urgently required to improve patient outcomes.

Keywords: ACLF; Acute-on-chronic liver failure; Ascites; Cirrhosis; DAMP; Hepatic encephalopathy; Organ failure; PAMP; Tissue injury; Variceal bleeding.

Fig. 1.. Cardiocirculatory alteration in decompensated cirrhosis.

The thickness of the lines and arrows is proportional to the relevance of the pathophysiological mechanisms and clinical consequences. AKI, acute kidney injury; AVP, arginine-vasopressin; CO, carbon monoxide; DAMPs, danger-associated molecular patterns; ECS, endocannabinoids; HPS, hepatopulmonary syndrome; HRS, hepatorenal syndrome; NO, nitric oxide; PAMPs, pathogen-associated molecular patterns; PGI2; prostacyclin; RAA, renin-angiotensin-aldosterone system; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNS, sympathetic nervous system. *Hepatic encephalopathy is not only caused by microvascular dysfunction but also by inflammation, hyperammonaemia and other factors.

Fig. 2.. Inflammatory processes of severe liver disease.

The underlying liver disease and the consequent effects on the gut microbiome are two major triggers of inflammation in a decompensated liver. Increased gut permeability linked to changes in the gut microbiome and portal hypertension result in high levels of PAMPs in the blood. High levels of LPS and other PAMPs from the leaky gut are then delivered to the liver via the portal vein. PAMPs and DAMPs in the liver that in turn are sensed by TLRs trigger inflammasome activation in KCs, hepatocytes and/or monocyte-derived pro-inflammatory macrophages. The persistent influx of PAMPs and DAMPs from the leaky gut and underlying disease results in a sustained inflammatory response that compromises the anti-inflammatory response. Additionally, the tissue microenvironment of the disease state (indicated by the red arrows) drives macrophage polarisation toward the M1 pro-inflammatory phenotype. While decreased polarisation of M2 macrophages results in insufficient anti-inflammatory cytokines and phagocytosis of activated neutrophils, processes that regulate inflammation in the healthy state. AIM2, absent in melanoma 2 protein; DAMPs, damaged-associated molecular patterns; HMGB1, high mobility group box protein 1; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; KC, Kupffer cell; LPS, lipopolysaccharide; M1, pro-inflammatory monocyte-derived macrophage; M2, anti-inflammatory monocyte-derived macrophage; MCP-1, monocyte chemotractant protein 1; NASH, non-alcoholic steatohepatitis; NET, neutrophil extracellular trap; NLR, NOD-like receptor; PAMPs, pathogen-associated molecular patterns; TGF-β, transforming growth factor-β; TLR, Toll-like receptor; TNFa, tumour necrosis factor-α.

Fig. 3.. Metabolic alterations in decompensated cirrhosis.

(A) In decompensated cirrhosis and ACLF, systemic inflammation increases energy consumption and mitochondria become dysfunctional. ATP production in peripheral organs declines in favour of less effective glycolysis and ROS production leading to cell and tissue injury. In order to cope with increased energy demands lipolysis and proteolysis are accelerated, increasing circulating lipids and amino acids. Lipids act as immune stimulants further aggravating systemic inflammation. Glutaminase is central in generating ammonia from amino acids that arise from proteolysis and intestinal translocation. Hyperammonaemia leads to mitochondrial dysfunction and tissue injury, aggravates skeletal muscle loss, and impairs neutrophil function, facilitating secondary infections which aggravate systemic inflammation. (B) Under normal conditions immune cells obtain most of their energy (about 36 ATPs per molecule of glucose) from the citric acid cycle (TCA or Krebs cycle) and OXPHOS, which take place in the matrix and the inner membrane, respectively, of the mitochondria. The TCA cycle produces NADH and FADH₂, which initiate OXPHOS for ATP synthesis through the ETC. (C) Once activated, immune cells dampen OXPHOS and shift ATP production to aerobic glycolysis. The metabolic reprogramming of activated immune cells also implies the induction of the pentose phosphate pathway, which branches from glycolysis at the first committed step and use nutrients to generate nucleotides and NADPH. Aerobic glycolysis, which ultimately produces lactate, is less efficient than OXPHOS in energy production and only generates 2 ATPs per glucose molecule. Impaired OXPHOS in activated immune cells might also result in the leaking of electrons at the ETC, leading to enhanced production of ROS. α-KG, α-ketoglutarate; ETC, electron transport chain; G6P, glucose-6-phosphate; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Fig. 4.. The pathophysiological paradigm of decompensated cirrhosis.

Disease progression from compensated cirrhosis to acute decompensation and acute-on-chronic liver failure is characterised by the development of cirrhosis-related complications (bacterial infections, variceal bleeding, ascites and HE) and tissue injury leading to extrahepatic organ injury. The transition from compensation to decompensation is dominated by cardiocirculatory dysfunction, whereas organ failure relates mainly back to metabolic alterations with microvascular dysfunction and reduced organ perfusion representing one potential link between both. Systemic inflammation initiated by precipitating events, as well as PAMP and DAMP release, becomes a superior modulator of disease processes but also directly induces tissue injury. Feedback mechanisms perpetuate systemic inflammation and culminate in a pathomechanistic spiral. DAMP, damage-associated molecular pattern; HE, hepatic encephalopathy; PAMP, pathogen-associated molecular pattern.