Causes and Consequences of Innate Immune Dysfunction in Cirrhosis

Abstract

Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.

Keywords: ascites; decompensated chirrosis; infection; innate immnuity; monocyte.

Figure 1

Features of innate immune deficiency in advanced cirrhosis. Host and microbial inflammatory mediators resulting from liver injury and gut bacterial translocation initially activate innate immune cells, contributing to inflammation and the development, and progression of liver cirrhosis. Chronic stimulation progressively perturbs innate immune sensing and surveillance functions, contributing to infection risk in patients with decompensated cirrhosis. Genetic and environmental factors also contribute to immune dysfunction. The features of cellular and humoral innate immune deficiency commonly identified in cohorts of patients with advanced cirrhosis are summarized. DAMP, Damage Associated Molecular Pattern; PAMP, Pathogen Associated Molecular Pattern; PRR, Pattern Recognition Receptor; PPI, Proton Pump Inhibitor; MBL, Mannose Binding Lectin; TLR, Toll-like receptor.