Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis

• Published in: Journal of hepatology Vol. 63; no. 5; pp. 1272 - 1284
• Main Authors: Bernardi, Mauro, Moreau, Richard, Angeli, Paolo, Schnabl, Bernd, Arroyo, Vicente
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2015
• Subjects: Animals; Arteries - physiopathology; Ascites; Bacterial translocation; Cardiovascular dysfunction; Cirrhosis; Cytokines - metabolism; Gastroenterology and Hepatology; Humans; Inflammation - complications; Inflammation - metabolism; Inflammation - physiopathology; Liver Cirrhosis - complications; Liver Failure - etiology; Liver Failure - metabolism; Liver Failure - physiopathology; Peripheral arterial vasodilation hypothesis; Pro-inflammatory cytokines; Renal dysfunction; Systemic inflammation; Vasodilation - physiology; plasma renin activity; ACLF; GTP; toll-like receptors; systemic inflammation hypothesis; HRS; TNF; CX3CL1; TLR(s); mesenteric lymph nodes; C-RP; K ATP; PAMPs; nitric oxide synthase; nitric oxide; IL; HSP; relative adrenal insufficiency; guanosine 5′ monophosphate; carbon monoxide; GMP; acute-on-chronic liver failure; BH4; adenosine triphosphate-sensitive potassium channels; Cirrhosis; pathogen-associated molecular patterns; NOS; SIH; receptor tyrosine kinases; hepatorenal syndrome; ROS; IPVD; VEGFs; acute kidney injury; peripheral arterial vasodilation hypothesis; lipopolysaccharide; Ascites; Systemic inflammation; PICD; NO; tetrahydrobiopterin; PAVH; PRRs; Renal dysfunction; plasma C-reactive protein; vascular endothelial growth factors; heat shock protein; HPS; LPS; DAMPs; BT; reactive oxygen species; hepatic encephalopathy; danger-associated molecular patterns; SNS; bacterial translocation; interleukin; AKI; MLNs; SBP; hepatopulmonary syndrome; sympathetic nervous system; fractaline chemokine; guanosine 5′ triphosphate; CO; RTKs; paracentesis-induced circulatory dysfunction; ECM; pattern recognition receptors; tumor necrosis factor; intrapulmonary vasodilatation; Cardiovascular dysfunction; Pro-inflammatory cytokines; RAI; spontaneous bacterial peritonitis; HE; PRA; extracellular matrix; Peripheral arterial vasodilation hypothesis; Bacterial translocation; KATP
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2015.07.004

Summary The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.