TY - JOUR
T1 - Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis
AU - Vesterhus, Mette
AU - Holm, Anders
AU - Hov, Johannes Roksund
AU - Nygard, Stale
AU - Schrumpf, Erik
AU - Melum, Espen
AU - Thorbjornsen, Liv Wenche
AU - Paulsen, Vemund
AU - Lundin, Knut
AU - Dale, Inge
AU - Gilja, Odd Helge
AU - Zweers, Serge J. L. B.
AU - Vatn, Morten
AU - Schaap, Frank G.
AU - Jansen, Peter L. M.
AU - Ueland, Thor
AU - Rosjo, Helge
AU - Moum, Bjorn
AU - Ponsioen, Cyriel Y.
AU - Boberg, Kirsten Muri
AU - Farkkila, Martti
AU - Karlsen, Tom H.
AU - Lund-Johansen, Fridtjof
PY - 2017/6
Y1 - 2017/6
N2 - Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC).Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992-2006] and n = 138 [2008-2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100).Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p <0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p <0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF (R)) test and Mayo risk score proved to be stronger predictors of transplant-free survival.Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.Lay summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
AB - Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC).Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n = 167 [1992-2006] and n = 138 [2008-2012]), inflammatory bowel disease (n = 96) and healthy controls (n = 100).Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p <0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p <0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF (R)) test and Mayo risk score proved to be stronger predictors of transplant-free survival.Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.Lay summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KW - PSC
KW - Biomarker
KW - Prognosis
KW - Calprotectin
KW - IL-8
KW - NATURAL-HISTORY
KW - POPULATION
KW - MANAGEMENT
KW - INTERLEUKIN-8
KW - CALPROTECTIN
KW - DIAGNOSIS
KW - MODEL
U2 - 10.1016/j.jhep.2017.01.019
DO - 10.1016/j.jhep.2017.01.019
M3 - Article
C2 - 28161472
SN - 0168-8278
VL - 66
SP - 1214
EP - 1222
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -