Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis.
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).



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).



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®) test and Mayo risk score proved to be stronger predictors of transplant-free survival.



Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC.



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.
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
Mette
M
Vesterhus
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Anders
A
Holm
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
Johannes Roksund
JR
Hov
Bioinformatics Core Facility, Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
Ståle
S
Nygård
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
Erik
E
Schrumpf
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
Espen
E
Melum
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Liv Wenche
LW
Thorbjørnsen
Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway.
Vemund
V
Paulsen
Institute of Clinical Medicine, University of Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway.
Knut
K
Lundin
Calpro, Oslo, Norway.
Inge
I
Dale
National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Odd Helge
OH
Gilja
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
Serge J L B
SJLB
Zweers
The Institute of Clinical Epidemiology and Molecular Biology (EpiGen), Campus Ahus, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Morten
M
Vatn
Department of Surgery, NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands.
Frank G
FG
Schaap
Department of Surgery, NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands.
Peter L M
PLM
Jansen
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Thor
T
Ueland
K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, University of Oslo, Oslo, Norway; Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
Helge
H
Røsjø
Institute of Clinical Medicine, University of Oslo, Norway; Division of Medicine, Department of Gastroenterology, Oslo University Hospital, Oslo, Norway.
Bjørn
B
Moum
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Cyriel Y
CY
Ponsioen
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway.
Kirsten Muri
KM
Boberg
Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
Martti
M
Färkkilä
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway. Electronic address: t.h.karlsen@medisin.uio.no.
Tom H
TH
Karlsen
K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway; Dept. of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Fridtjof
F
Lund-Johansen
D000293:Adolescent; D000328:Adult; D000368:Aged; D001646:Bile / Q000378:metabolism; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism*; D016022:Case-Control Studies; D015209:Cholangitis, Sclerosing / Q000097:blood* / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000097:blood / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009664:Norway; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D040081:Protein Array Analysis; D055815:Young Adult
D015415:Biomarkers; C508606:CXCL8 protein, human; D016209:Interleukin-8
Biomarker; Calprotectin; IL-8; PSC; Prognosis