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Multicenter Study
. 2021 Mar 1;12(3):e00315.
doi: 10.14309/ctg.0000000000000315.

Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis

Lars Bossen  1 , Mette Vesterhus  2   3   4 , Johannes R Hov  2   5   6   7 , Martti Färkkilä  8 , William M Rosenberg  9 , Holger J Møller  10 , Kirsten M Boberg  2   5   6   7 , Tom H Karlsen  2   5   6   7 , Henning Grønbæk  1
Affiliations
Multicenter Study

Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis

Lars Bossen et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC.

Methods: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison.

Results: Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients.

Discussion: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516).

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Conflict of interest statement

Guarantor of the article: Henning Grønbæk, MD, PhD.

Specific author contributions: Lars Bossen, MD and Mette Vesterhus, MD, PhD, contributed equally to this work. M.V., T.H.K. and H.G. conceived and designed the study. K.M.B., M.V., and J.R.H. collected the biological samples and clinical data. H.J.M. performed the laboratory analyses. W.R. contributed to the ELF test analyses. M.V. and L.B. performed statistical analyses. L.B., M.V., T.H.K., J.R.H., and H.G. contributed to the interpretation of the data. L.B. and M.V. drafted the manuscript. All authors reviewed the manuscript for critical content and approved the final version of the manuscript.

Financial support: None to report.

Potential competing interests: M.V. has received advisory board fees from Intercept. L.B. and H.G. have received an investigator-initiated research grant from Intercept. H.G. also received research grants from AbbVie, ADS AIPHIA Development Services AG, (Switzerland), ARLA Food for Health, and the NOVO Nordisk Foundation. W.M.R. is an inventor of the ELF test and has received research support and speaking fees from Siemens Healthineers. W.M.R. is a NIHR Senior Investigator and is supported by the UCLH NIHR BRC. J.R.H. has received advisory board fees from Novartis and Orkla Health, and research support from Biogen.

Figures

Figure 1.
Figure 1.
sCD163 and sMR distribution in 3 prespecified risk groups of Mayo score and ELF test. White boxes to the left are from the Oslo cohort, gray boxes to the right are from the Helsinki cohort. Mayo score is available in 64 patients in the Helsinki cohort, of whom only 2 had a Mayo score >2. ELF, enhanced liver fibrosis; sCD163, soluble CD163; sMR, soluble mannose receptor.
Figure 2.
Figure 2.
Cumulative death or LT in patients with low or high sCD163 (left) or sMR (right) in the combined cohort. Cutoffs for sCD163 (3.86 mg/L) and sMR (0.43 mg/L), respectively. The logrank test for equal survivor functions: sCD163, P < 0.001; sMR, P < 0.001. LT, liver transplantation; sCD163, soluble CD163; sMR, soluble mannose receptor.
Figure 3.
Figure 3.
AUC's for sCD163, sMR, ALP, ELF test, Mayo score, and AOM in patients with PSC in discriminating patients experiencing the composite endpoint (LT or death) or not. ALP, alkaline phosphatase; AOM, Amsterdam-Oxford model for primary sclerosing cholangitis; AUC, area under the receiver operating curve; ELF, enhanced liver fibrosis; PSC, primary sclerosing cholangitis; sCD163, soluble CD163; sMR, soluble mannose receptor.
See this image and copyright information in PMC

References

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