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.

The platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure

“…This supports previous reports of the neutrophil 'function' enhancing role of TNF-α 61 , including phagocytosis, which then plays a fundament role in halting liver damage and driving hepatic recovery in acute liver injury 16,62 . Neutrophils thus mediate liver healing after APAP induced liver injury 51 with defective neutrophil function resulting in poor outcomes [63][64][65] . This has direct relevance to the clinic where enhancing neutrophil numbers and function using granulocyte-colony stimulating factor (G-CSF) improves survival in patients with acute liver failure 66 and severe alcoholic hepatitis 67 .…”

Antimicrobial resistance in chronic liver disease

“…Furthermore, standard microbiological techniques are still unable to identify clinically relevant infection-causing organisms, compounding the difficulties around narrowing the drug spectrum, and identifying sensitivity patterns. Specific biomarkers to aid in either the earlier detection of infection or to guide de-escalation of antimicrobial therapy in cirrhosis are currently difficult to recommend, with none to date being of satisfactory value by way of representativeness and severity of infection, accuracy or reproducibility [15,19]. Whilst examples such as C-reactive protein, procalcitonin, lipopolysaccharide-binding protein and soluble CD14 are well established acute-phase proteins that have been investigated in several experimental and mechanistic contexts in cirrhosis, their utility in decision making in the acute clinical setting remains controversial and requires further evaluation.…”

“…There are multiple potential avenues for systemic immunomodulation in CLD, many of which are at an early phase of investigation [76,77]. Should these strategies have the desired effect of improving cirrhosis-associated immune dysfunction (CAID) [15,78] and heightening the cirrhotic patient's barrier to infection, this would require less exposure to antimicrobial therapy and, therefore, reduce the risk of developing AMR in the first instance.…”

“…Restricting the inappropriate use of antibiotics-the cornerstone of approaches to reduce MDR-is particularly difficult in CLD patients, with their known increased susceptibility to infection as a result of excessive intestinal microbial translocation [13,14] and deranged immune function [15]. Acute bacterial infections are often the immediate cause of death, associated with a 400% increase in mortality in hospitalised patients, and a post-infection mortality rate of 28% and 63% at 1 month and at 1 year, respectively [16,17].…”

Effect of L‑carnitine on health‑related quality of life in patients with liver cirrhosis

“…L-carnitine regulates the cellular process of generating energy by transferring acyl groups from the cytoplasm to the mitochondrial matrix for β-oxidation ( 6 ). L-carnitine deficiency has been demonstrated to reduce the availability of energy in the liver and is associated with impairments in various aspects of energy metabolism, including utilization and accumulation of carbohydrate and lipids in liver cirrhosis ( 7 , 8 ). Several studies have described the ability of L-carnitine to reduce serum ammonia concentration in clinical trials ( 9 , 10 ).…”