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Abstract Details
The Systemic Inflammation Hypothesis: Towards a New Paradigm of Acute Decompensation and Multiorgan Failure in Cirrhosis
J Hepatol. 2020 Dec 7;S0168-8278(20)33836-8. doi: 10.1016/j.jhep.2020.11.048.Online ahead of print.
Vicente Arroyo1, Paolo Angeli2, Richard Moreau3, Rajiv Jalan4, Joan Claria5, Jonel Trebicka6, Javier Fernández5, Thierry Gustot7, Paolo Caraceni8, Mauro Bernardi8, investigators from the EASL-CLIF Consortium, Grifols Chair; European Foundation for the Study of Chronic Liver Failure (EFClif)
Author information
1European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain. Electronic address: vicente.arroyo@efclif.com.
2European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; University of Padova, Padova, Italy.
3European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Service d'Hépatologie, APHP, Hôpital Beaujon, Clichy, France; Université de Paris, INSERM, CNRS, Centre de Recherche sur l'Inflammation (CRI), U1149, ERL 8252, F-75018 Paris, France.
4European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.
5European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain.
6European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; JW Goethe University, Frankfurt, Germany.
7European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; C.U.B. Erasme, Bruxelles, Belgium.
8European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; University of Bologna, Bologna, Italy.
Abstract
Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy (HE) and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left-ventricular dysfunction, HE to hyperammonemia, and variceal hemorrhage 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 functions 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. This cascade of events may therefore have deleterious effects on organ function. 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 prioritization 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 subsequent impairment in organ functions.