The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis

J Hepatol. 2021 Mar;74(3):670-685. doi: 10.1016/j.jhep.2020.11.048. Epub 2020 Dec 7.


Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.

Keywords: ACLF; Acute-on-chronic liver failure; Bacterial infections; Metabolism; Pre-ACLF; Stable decompensated cirrhosis; Systemic inflammation; Unstable decompensated cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acute-On-Chronic Liver Failure / etiology*
  • Ascites / etiology*
  • Esophageal and Gastric Varices / etiology
  • Gastrointestinal Hemorrhage / etiology*
  • Hepatic Encephalopathy / etiology*
  • Humans
  • Hypertension, Portal / etiology
  • Inflammation / complications
  • Inflammation / metabolism
  • Liver Cirrhosis / complications*
  • Liver Cirrhosis / metabolism
  • Multiple Organ Failure / etiology*