title: Immune dysfunction in cirrhosis: Distinct cytokines phenotypes according to cirrhosis severity.
abstract: OBJECTIVE
  Cirrhosis associated immune dysfunction has been proposed to switch from a pro-inflammatory phenotype in stable cirrhosis to an immunodeficient one in patients with decompensated cirrhosis and acute-on-chronic liver failure. The aim of the present study was to compare serum cytokine levels between healthy patients, stable cirrhosis, and decompensated cirrhotic patients with and without development of acute-on-chronic liver failure (ACLF); and to explore whether any of the measured cytokines is associated with cirrhosis severity and prognosis in ACLF patients.
  
  
  METHODS
  Patients were enrolled from October 2013 to May 2014 in two hospitals located in Buenos Aires. Cirrhotic patients with an acute decompensating event were enrolled accordingly to the development of ACLF defined by the CANONIC study group. There were two control groups: healthy subjects (n=14) and stable cirrhotic patients (n=14). Demographic, clinical and biochemical data were obtained. Seventeen cytokines were measured using Bio-Plex Pro Human Cytokine 17-plex Assay.
  
  
  RESULTS
  Of the 49 decompensated cirrhotic patients enrolled, 18 (36.7%) developed ACLF. Leukocyte count, MELD score at admission, Clif-SOFA at admission and day 7 were significantly higher in the ACLF group (p=0.046, p<0.001, p<0.001, p<0.001 respectively) as well as short-term mortality (p<0.001) compared to stable and decompensated cirrhotic patients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhotic patients showed increased levels of pro-inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-α. Decompensated cirrhotic patients with the development of ACLF showed a significant decrease of IL-7, IL-10, IL-12, TNF-α, MCP-1 and IFN-γ, but a sustained response of IL-6 and IL-8. When evaluating cirrhosis severity, IL-6 and IL-8 correlated positively with MELD score, whereas only IL-6 correlated positively with Clif-SOFA score at day 7; IL-2 correlated negatively with Clif-SOFA at admission. In comparison with all scores, leukocyte count showed positive correlation and IFN-γ negative correlation with disease severity. When evaluating survival, only MELD and Clif-SOFA scores had a significant association with mortality.
  
  
  CONCLUSIONS
  Pro-inflammatory cytokines and chemo-attractant elements are increased in cirrhosis in comparison with healthy subjects, and display higher values concomitantly with cirrhosis progression. However, in acute-on-chronic liver failure an opposite cytokine pattern that can be resumed as a combination of immune paresis and excessive inflammatory response was observed. Several pro-inflammatory cytokines (IL-2, IL-6, IL-8 and IFN-γ) showed correlation with disease severity; their utility as prognostic biomarkers needs to be further studied.
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina. Electronic address: melidir@hotmail.com.
authors.forename: Melisa
authors.initials: M
authors.lastname: Dirchwolf
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo (INIGEM-CONICET), Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, 1120, Argentina.
authors.forename: Ariel
authors.initials: A
authors.lastname: Podhorzer
authors.affiliation: Sección de Hepatología, Hospital de Gastroenterología Dr. Carlos B. Udaondo, Buenos Aires 1280, Argentina.
authors.forename: Monica
authors.initials: M
authors.lastname: Marino
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Shulman
authors.affiliation: Sección de Hepatología, Hospital de Gastroenterología Dr. Carlos B. Udaondo, Buenos Aires 1280, Argentina.
authors.forename: Mariano
authors.initials: M
authors.lastname: Cartier
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Moira
authors.initials: M
authors.lastname: Zunino
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paz
authors.affiliation: Sección de Hepatología, Hospital de Gastroenterología Dr. Carlos B. Udaondo, Buenos Aires 1280, Argentina.
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.affiliation: Unidad de Bioquímica Clínica, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bocassi
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Gimenez
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Lucía
authors.initials: L
authors.lastname: Di Pietro
authors.affiliation: Sección de Hepatología, Hospital de Gastroenterología Dr. Carlos B. Udaondo, Buenos Aires 1280, Argentina.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Romero
authors.affiliation: Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
authors.forename: Hugo
authors.initials: H
authors.lastname: Fainboim
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo (INIGEM-CONICET), Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, 1120, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fainboim
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008103:Liver Cirrhosis / Q000097:blood* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012720:Severity of Illness Index; D016019:Survival Analysis; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Acute-on-chronic liver failure; Cirrhosis associated-immune dysfunction; Immune paresis; Systemic inflammation