Melisa Dirchwolf1, Ariel Podhorzer2, Monica Marino3, Carolina Shulman4, Mariano Cartier3, Moira Zunino4, Silvia Paz4, Alberto Muñoz3, Andrea Bocassi5, Juan Gimenez4, Lucía Di Pietro4, Gustavo Romero3, Hugo Fainboim4, Leonardo Fainboim2. 1. Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina. Electronic address: melidir@hotmail.com. 2. Instituto de Inmunología, Genética y Metabolismo (INIGEM-CONICET), Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, 1120, Argentina. 3. Sección de Hepatología, Hospital de Gastroenterología Dr. Carlos B. Udaondo, Buenos Aires 1280, Argentina. 4. Hepatopatías Infecciosas, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina. 5. Unidad de Bioquímica Clínica, Hospital Francisco J. Muñiz, Buenos Aires 1282, Argentina.
Abstract
BACKGROUND/ OBJECTIVES: 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.
BACKGROUND/ OBJECTIVES: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 cirrhoticpatients 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. Cirrhoticpatients 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 cirrhoticpatients (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 cirrhoticpatients 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 cirrhoticpatients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhoticpatients showed increased levels of pro-inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-α. Decompensated cirrhoticpatients 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: Pratik Sinha; Kevin L Delucchi; Yue Chen; Hanjing Zhuo; Jason Abbott; Chunxue Wang; Nancy Wickersham; J Brennan McNeil; Alejandra Jauregui; Serena Ke; Kathryn Vessel; Antonio Gomez; Carolyn M Hendrickson; Kirsten N Kangelaris; Aartik Sarma; Aleksandra Leligdowicz; Kathleen D Liu; Michael A Matthay; Lorraine B Ware; Carolyn S Calfee Journal: Thorax Date: 2021-07-12 Impact factor: 9.139