Acute-on-Chronic Liver Failure: Pathogenesis and Diagnosis

Abstract

Acute-on-chronic liver failure (ACLF) is characterized by the acute deterioration in liver function in a patient with compensated or decompensated, but hitherto stable cirrhosis. It is precipitated by an acute event (e.g. bacterial infection, variceal hemorrhage or alcoholic hepatitis) and associated with failure of extrahepatic organs. The pathophysiology of ACLF is still poorly understood. However, data have been obtained in the context of bacterial infections which induce hyper-production of proinflammatory cytokines. This ‘cytokine storm’ plays a central role in the development of multi-organ failure. At the level of the microvasculature of vital organs proinflammatory cytokines activate endothelial cells by upregulating adhesion receptors and injure endothelial cells by inducing immune cells, and platelets to bind to endothelial cells. These cells release mediators such as proteases, oxidants, prostaglandins, and leukotrienes. These mediators injure endothelial cells, leading to increased permeability, vasodilation, and alteration of the procoagulant–anticoagulant balance. Cytokines also activate a procoagulant response and induce the inducible nitric oxide synthase, which produces nitric oxide, a potent vasodilator that worsens circulatory dysfunction. The diagnosis of ACLF is based on the recognition of: (a) an history of recent event that was the precipitating factor of ACLF; (b) systemic inflammation, (c) the rapid worsening of liver function, and (d) the development of at least one extrahepatic organ failure. Since the development of organ failures is associated with increased in-hospital mortality, any condition which could result in ACLF should be recognized at an early stage, in order to prevent the occurrence of organ failure.