Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study

Abstract

BackgroundInterleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far.MethodsThis is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications.ResultsA total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 ± 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P < 0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P < 0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular (≤18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with reduced overall survival were high CRP (≥2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258, CI (0.077 to 0.862)), model of end stage liver disease (MELD) score ≥20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 0.955, CI (0.922 to 0.989)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)).ConclusionsIn patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis.

Interleukin-22 serum levels are a negative prognostic indicator in patients with hepatocellular carcinoma

“…Concurring with other studies originating from Europe, 5,6 we recently defined a serum IL-22 concentration of 18 pg/mL as the threshold, discriminating normal from elevated systemic levels of this cytokine. 4 In agreement with our previous data, we found herein also in HCC patients that elevated IL-22 levels (>18 pg/mL, R&D Systems, Quantikine) were significantly associated with shorter overall survival (OS) (P 5 0.035, hazard ratio [HR] 0.491, 95% confidence interval [CI] 0.254-0.950) (Fig. 1).…”

“…3 We have recently found an association between disease severity as well as overall survival with IL-22 serum levels in patients with advanced liver cirrhosis. 4 In light of the emerging key role of IL-22 in hepatocellular carcinoma (HCC), 3 we assessed serum IL-22 levels in a cohort of 156 HCC patients (79.5% males) with mainly alcoholic and hepatitis C virus (HCV)-related liver disease. Concurring with other studies originating from Europe, 5,6 we recently defined a serum IL-22 concentration of 18 pg/mL as the threshold, discriminating normal from elevated systemic levels of this cytokine.…”

Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases

“…Studies of the molecular processes underlying fibrosis in the liver have suggested that IL-22 can reduce fibrosis by inducing apoptosis of the HSCs through activation of the STAT3, p53 and SOCS3 (suppressor of cytokine signaling 3) pathways [76]. Human cases of hepatic cirrhosis have been found to express enhanced (upregulated) levels of IL-22, which has been correlated with the development of hepatorenal syndrome, ascites and reduced survival [77]. Because IL-22 has the capacity to reduce hepatic fibrosis, its upregulated level has been proposed as a predictive biomarker for assessing prognosis of hepatic cirrhosis cases in clinic [78].…”

How Does Interleukin-22 Mediate Liver Regeneration and Prevent Injury and Fibrosis?

“…However, a number of studies have previously described a raised level of IL-22 in sera as well as in hepatocytes. A positive correlation was found between the severity of liver disease and level of IL-22 in cirrhotic patients or hepatitis B virus (HBV) patients [28, 43, 51]. In some ailments, IL-22 may lead to inflammation.…”