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 oxidemediated 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 functio