Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated
cirrhosis and is characterised by the presence of one or more organ failures, intense systemic
inflammation, peripheral blood
lymphopenia, and a high risk of death without
liver transplantation within 28 days. Herein, we propose the hypothesis that intense systemic
inflammation may lead to organ failures through five different non-mutually exclusive mechanisms. First,
pathogen-associated molecular patterns and inflammatory mediators (i.e.
cytokines and
lipid mediators) stimulate the production of the
vasorelaxant nitric oxide in the walls of splanchnic arterioles, leading to enhanced splanchnic and systemic vasodilation which, in turn, induces enhanced activity of endogenous
vasoconstrictor systems causing renal vasoconstriction and
acute kidney injury. Second, neutrophils that reach the systemic circulation are prone to adhere to the vascular endothelium.
Cytokines and
lipid mediators act on the endothelium in microvessels of vital organs, an effect that favours the migration of neutrophils (and probably other leukocytes) to surrounding tissues where neutrophils can cause tissue damage and thereby contribute to organ failure. Third,
cytokines and
lipid mediators promote the formation of microthrombi that impair microcirculation and tissue oxygenation. Fourth, acute
inflammation stimulates intense peripheral catabolism of
amino acids whose products may be metabotoxins that contribute to
hepatic encephalopathy. Fifth, acute inflammatory responses, which include the production of a broad variety of biomolecules (
proteins and
lipids), and an increase in biomass (i.e., granulopoiesis requiring de novo
nucleotide synthesis), among others, are energetically expensive processes that require large amounts of nutrients. Therefore, immunity competes with other maintenance programmes for energy. The brain stem integrates the energy demand of each organ system, with immunity considered a top priority. The brain stem may "decide" to make a trade-off which involves the induction of a dormancy programme that permits the shutdown of mitochondrial respiration and oxidative phosphorylation in peripheral organs. In the context of acutely decompensated
cirrhosis, the consequence of a shutdown of mitochondrial respiration and
ATP production would be a dramatic decrease in organ function.