Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure

The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.