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Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF)

Published:November 27, 2015DOI:https://doi.org/10.1016/j.jhep.2015.11.021

      Background & Aims

      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.

      Graphical abstract

      Keywords

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      References

        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144 (1437, e1421–e1429): 1426-1437
        • Jalan R.
        • Saliba F.
        • Pavesi M.
        • Amoros A.
        • Moreau R.
        • Gines P.
        • et al.
        Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
        J Hepatol. 2014; 61: 1038-1047
        • Jalan R.
        • Pavesi M.
        • Saliba F.
        • Amoros A.
        • Fernandez J.
        • Holland-Fischer P.
        • et al.
        The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure.
        J Hepatol. 2015; 62: 831-840
        • Boltjes A.
        • Movita D.
        • Boonstra A.
        • Woltman A.M.
        The role of Kupffer cells in hepatitis B and hepatitis C virus infections.
        J Hepatol. 2014; 61: 660-671
        • Baffy G.
        Kupffer cells in non-alcoholic fatty liver disease: the emerging view.
        J Hepatol. 2009; 51: 212-223
        • Steib C.J.
        Kupffer cell activation and portal hypertension.
        Gut. 2011; 60: 1307-1308
        • Jain L.
        • Sharma B.C.
        • Sharma P.
        • Srivastava S.
        • Agrawal A.
        • Sarin S.K.
        Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy.
        Dig Liver Dis. 2012; 44: 1027-1031
        • Romero-Gomez M.
        • Montagnese S.
        • Jalan R.
        Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
        J Hepatol. 2015; 62: 437-447
        • Butterworth R.F.
        The liver-brain axis in liver failure: neuroinflammation and encephalopathy.
        Nat Rev Gastroenterol Hepatol. 2013; 10: 522-528
        • Schnabl B.
        • Brenner D.A.
        Interactions between the intestinal microbiome and liver diseases.
        Gastroenterology. 2014; 146: 1513-1524
        • Pascual S.
        • Such J.
        • Esteban A.
        • Zapater P.
        • Casellas J.A.
        • Aparicio J.R.
        • et al.
        Intestinal permeability is increased in patients with advanced cirrhosis.
        Hepatogastroenterology. 2003; 50: 1482-1486
        • Fukui H.
        Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia.
        World J Hepatol. 2015; 7: 425-442
        • Fujimoto M.
        • Uemura M.
        • Nakatani Y.
        • Tsujita S.
        • Hoppo K.
        • Tamagawa T.
        • et al.
        Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance.
        Alcohol Clin Exp Res. 2000; 24: 48S-54S
        • Gandoura S.
        • Weiss E.
        • Rautou P.E.
        • Fasseu M.
        • Gustot T.
        • Lemoine F.
        • et al.
        Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis.
        J Hepatol. 2013; 58: 936-948
        • Kubes P.
        • Mehal W.Z.
        Sterile inflammation in the liver.
        Gastroenterology. 2012; 143: 1158-1172
        • Kristiansen M.
        • Graversen J.H.
        • Jacobsen C.
        • Sonne O.
        • Hoffman H.J.
        • Law S.K.
        • et al.
        Identification of the haemoglobin scavenger receptor.
        Nature. 2001; 409: 198-201
        • Moller H.J.
        • Aerts H.
        • Gronbaek H.
        • Peterslund N.A.
        • Hyltoft Petersen P.
        • Hornung N.
        • et al.
        Soluble CD163: a marker molecule for monocyte/macrophage activity in disease.
        Scand J Clin Lab Invest Suppl. 2002; 237: 29-33
        • Gronbaek H.
        • Sandahl T.D.
        • Mortensen C.
        • Vilstrup H.
        • Moller H.J.
        • Moller S.
        Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis.
        Aliment Pharmacol Ther. 2012; 36: 173-180
        • Holland-Fischer P.
        • Gronbaek H.
        • Sandahl T.D.
        • Moestrup S.K.
        • Riggio O.
        • Ridola L.
        • et al.
        Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS.
        Gut. 2011; 60: 1389-1393
        • Rode A.
        • Nicoll A.
        • Moller H.J.
        • Lim L.
        • Angus P.W.
        • Kronborg I.
        • et al.
        Hepatic macrophage activation predicts clinical decompensation in chronic liver disease.
        Gut. 2013; 62: 1231-1232
        • Kazankov K.
        • Barrera F.
        • Moller H.J.
        • Bibby B.M.
        • Vilstrup H.
        • George J.
        • et al.
        Soluble CD163, a macrophage activation marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C.
        Hepatology. 2014; 60: 521-530
        • Waidmann O.
        • Brunner F.
        • Herrmann E.
        • Zeuzem S.
        • Piiper A.
        • Kronenberger B.
        Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis.
        J Hepatol. 2013; 58: 956-961
        • Waidmann O.
        • Koberle V.
        • Bettinger D.
        • Trojan J.
        • Zeuzem S.
        • Schultheiss M.
        • et al.
        Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma.
        J Hepatol. 2013; 59: 769-779
        • Sandahl T.D.
        • Gronbaek H.
        • Moller H.J.
        • Stoy S.
        • Thomsen K.L.
        • Dige A.K.
        • et al.
        Hepatic macrophage activation and the LPS pathway in patients with alcoholic hepatitis: a prospective cohort study.
        Am J Gastroenterol. 2014; 109: 1749-1756
        • Rodgaard-Hansen S.
        • Rafique A.
        • Christensen P.A.
        • Maniecki M.B.
        • Sandahl T.D.
        • Nexo E.
        • et al.
        A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness.
        Clin Chem Lab Med. 2014; 52: 453-461
        • Andersen E.S.
        • Rodgaard-Hansen S.
        • Moessner B.
        • Christensen P.B.
        • Moller H.J.
        • Weis N.
        Macrophage-related serum biomarkers soluble CD163 (sCD163) and soluble mannose receptor (sMR) to differentiate mild liver fibrosis from cirrhosis in patients with chronic hepatitis C: a pilot study.
        Eur J Clin Microbiol Infect Dis. 2014; 33: 117-122
        • Rodgaard-Hansen S.
        • Rafique A.
        • Weis N.
        • Wejse C.
        • Nielsen H.
        • Pedersen S.S.
        • et al.
        Increased concentrations of the soluble mannose receptor in serum from patients with pneumococcal bacteraemia, and prediction of survival.
        Infect Dis (Lond). 2015; 47: 203-208
        • Moller H.J.
        Soluble CD163.
        Scand J Clin Lab Invest. 2012; 72: 1-13
        • Moller H.J.
        • Hald K.
        • Moestrup S.K.
        Characterization of an enzyme-linked immunosorbent assay for soluble CD163.
        Scand J Clin Lab Invest. 2002; 62: 293-299
        • Wolbers M.
        • Koller M.T.
        • Witteman J.C.
        • Steyerberg E.W.
        Prognostic models with competing risks: methods and application to coronary risk prediction.
        Epidemiology. 2009; 20: 555-561
        • Lee F.Y.
        • Lu R.H.
        • Tsai Y.T.
        • Lin H.C.
        • Hou M.C.
        • Li C.P.
        • et al.
        Plasma interleukin-6 levels in patients with cirrhosis. Relationship to endotoxemia, tumor necrosis factor-alpha, and hyperdynamic circulation.
        Scand J Gastroenterol. 1996; 31: 500-505
        • Byl B.
        • Roucloux I.
        • Crusiaux A.
        • Dupont E.
        • Deviere J.
        Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients.
        Gastroenterology. 1993; 104: 1492-1497
        • Moller H.J.
        • Gronbaek H.
        • Schiodt F.V.
        • Holland-Fischer P.
        • Schilsky M.
        • Munoz S.
        • et al.
        Soluble CD163 from activated macrophages predicts mortality in acute liver failure.
        J Hepatol. 2007; 47: 671-676
        • Kazankov K.
        • Tordjman J.
        • Moller H.J.
        • Vilstrup H.
        • Poitou C.
        • Bedossa P.
        • et al.
        The macrophage activation marker sCD163 is independently associated with NAFLD severity in morbid obesity and reduced by bariatric surgery.
        J Gastroenterol Hepatol. 2015; 30: 1293-1300
        • Kazankov K.
        • Moller H.J.
        • Bibby B.M.
        • Vilstrup H.
        • George J.
        • Gronbaek H.
        Reply: To PMID 24623375.
        Hepatology. 2015; 61: 735-736
        • Etzerodt A.
        • Maniecki M.B.
        • Moller K.
        • Moller H.J.
        • Moestrup S.K.
        Tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163.
        J Leukoc Biol. 2010; 88: 1201-1205
        • Moller H.J.
        • Moestrup S.K.
        • Weis N.
        • Wejse C.
        • Nielsen H.
        • Pedersen S.S.
        • et al.
        Macrophage serum markers in pneumococcal bacteremia: prediction of survival by soluble CD163.
        Crit Care Med. 2006; 34: 2561-2566
        • Kjaergaard A.G.
        • Rodgaard-Hansen S.
        • Dige A.
        • Krog J.
        • Moller H.J.
        • Tonnesen E.
        Monocyte expression and soluble levels of the haemoglobin receptor (CD163/sCD163) and the mannose receptor (MR/sMR) in septic and critically ill non-septic ICU patients.
        PLoS One. 2014; 9: e92331
        • Thomsen K.L.
        • Hebbard L.
        • Glavind E.
        • Clouston A.
        • Vilstrup H.
        • George J.
        • et al.
        Non-alcoholic steatohepatitis weakens the acute phase response to endotoxin in rats.
        Liver Int. 2014; 34: 1584-1592
        • Wiest R.
        • Das S.
        • Cadelina G.
        • Garcia-Tsao G.
        • Milstien S.
        • Groszmann R.J.
        Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
        J Clin Invest. 1999; 104: 1223-1233
        • Wiest R.
        • Cadelina G.
        • Milstien S.
        • McCuskey R.S.
        • Garcia-Tsao G.
        • Groszmann R.J.
        Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats.
        Hepatology. 2003; 38: 1508-1515
        • Martinez-Pomares L.
        The mannose receptor.
        J Leukoc Biol. 2012; 92: 1177-1186
        • Taylor P.R.
        • Martinez-Pomares L.
        • Stacey M.
        • Lin H.H.
        • Brown G.D.
        • Gordon S.
        Macrophage receptors and immune recognition.
        Annu Rev Immunol. 2005; 23: 901-944
        • Martinez-Pomares L.
        • Mahoney J.A.
        • Kaposzta R.
        • Linehan S.A.
        • Stahl P.D.
        • Gordon S.
        A functional soluble form of the murine mannose receptor is produced by macrophages in vitro and is present in mouse serum.
        J Biol Chem. 1998; 273: 23376-23380
        • Jordens R.
        • Thompson A.
        • Amons R.
        • Koning F.
        Human dendritic cells shed a functional, soluble form of the mannose receptor.
        Int Immunol. 1999; 11: 1775-1780