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

Background & AimsActivation 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.MethodsEighty-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.ResultsWe 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)).ConclusionsThe 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.

White blood cell count (WCC), sCD163, and sMR levels in patients in the different study groups: Group 1: Liver cirrhosis, no ascites and no ACLF; Group 2: Liver cirrhosis with ascites/subrogates but no ACLF; Group 3: ACLF-I, Group 4: ACLF-II; Group 5: ACLF-III.We observed a stepwise increase in WCC, sCD163 and sMR with increasing disease severity, and both sCD163 and sMR were independently associated with short and long-term mortality. Addition of sCD163 and sMR to the original CLIF-C ACLF and CLIF-C AD 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)).93