Liver cirrhosis and immune dysfunction

Abstract

Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.

Keywords: acute-on-chronic liver failure (ACLF); cirrhosis-associated immune dysfunction (CAID); compensated and decompensated cirrhosis; immune paralysis; inflammation.

Graphical Abstract

Fig. 1.

Progression of cirrhosis-associated immune dysfunction during deterioration of cirrhosis. Cirrhosis-associated immune dysfunction worsens with more-severe systemic inflammation and immune deficiency, while cirrhosis progresses from compensated to decompensated stages to ACLF. Worsening of cirrhosis-associated immune dysfunction is expressed by increasing acute-phase proteins, such as CRP; increasing inflammatory cytokines, i.e. TNF, IL6, IL8, MCP1 (CCL2), MIP1B (CCL4), IP-10 (CXCL10) and GCSF; increasing anti-inflammatory cytokines, including IL10 and IL1RN; decreased phagocytosis and increased oxidative burst by neutrophils; decreased phagocytosis and superoxide production by monocytes, and increased monocytic HLA-DR expression and ex vivo TNF production in decompensated cirrhosis, which are decreased in ACLF. Created with a license from Biorender.com.

Fig. 2.

Targets to ameliorate cirrhosis and cirrhosis-associated immune dysfunction. Dysbiosis and bacterial translocation, aberrant circulating blood factors and immune cell abnormalities contribute to the pathogenesis and deterioration of cirrhosis and cirrhosis-associated immune dysfunction. Dysbiosis, intestinal inflammation and bacterial translocation can be reduced by antibiotics (e.g. norfloxacin) and fecal microbiota transplant. Yaq-001, a novel carbon absorbent that can absorb LPS and inflammatory cytokines, and TAK-242, an inhibitor of the important LPS receptor TLR4, are currently being evaluated in clinical studies for their use in cirrhosis and ACLF. Elevated circulating factors in the blood, including LPS and other microbial products, prostaglandins, reactive oxygen species (ROS), cytokines and catecholamines, worsen systemic inflammation and cirrhosis. Administration of albumin ameliorates inflammation and cirrhosis by binding these mediators. Liver dialysis devices and plasma exchange strategies remove noxious agents. Cyclooxygenase inhibitors reduce prostaglandin levels and beta-blockers attenuate the effects of catecholamines, improving systemic inflammation and the liver phenotype. Hematopoietic and mesenchymal stem cells as well as a variety of immune cells are markedly decreased and the immune cells do not function properly, worsening systemic inflammation. Administration of GCSF has shown promise in some studies, however it did not show a benefit in others. Infusions with stem cells and progenitor cells have shown beneficial immunomodulatory effects and improved outcome in cirrhosis and ACLF. Thrombopoietin receptor agonists are currently being investigated in clinical studies to improve thrombocytopenia in patients with ACLF. Created with a license from Biorender.com.