title: Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF).
abstract: OBJECTIVE
  Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study.
  
  
  METHODS
  Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion.
  
  
  RESULTS
  We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)).
  
  
  CONCLUSIONS
  The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: Henngroe@rm.dk.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Rødgaard-Hansen
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Niels Kristian
authors.initials: NK
authors.lastname: Aagaard
authors.affiliation: The EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus & Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: The EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Liver Unit, Hospital Clinic de Barcelona, Unviersity of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Solà
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Domenicali
authors.affiliation: Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piano
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Holger Jon
authors.initials: HJ
authors.lastname: Møller
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000276:immunology / Q000401:mortality*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood; D015415:Biomarkers; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000032:analysis; D008103:Liver Cirrhosis / Q000276:immunology / Q000401:mortality*; D008262:Macrophage Activation; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000032:analysis; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000032:analysis / Q000097:blood; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface
keywords: Acute-on-chronic liver failure; Biomarker; CD163; Cirrhosis; Cirrhosis complications; Macrophages; Mannose receptor; Prognosis