title: Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study.
abstract: Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62).
  
  
  
  We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919).
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Elisabeth M G
authors.initials: EM
authors.lastname: de Vries
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: de Krijger
authors.affiliation: Helsinki University and Helsinki University Hospital, Department of Gastroenterology, Helsinki, Finland.
authors.forename: Martti
authors.initials: M
authors.lastname: Färkkilä
authors.affiliation: Department of Pathology, Helsinki University and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.affiliation: National Institute for Health Research, Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: National Institute for Health Research, Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Ytting
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ben
authors.initials: B
authors.lastname: Vainer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Henk R van
authors.initials: HR
authors.lastname: Buuren
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maren H
authors.initials: MH
authors.lastname: Harms
authors.affiliation: Department of Hepatology, AP-HP, Hôpital Saint-Antoine, Sorbonne Universités, University Pierre and Marie Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chazouilleres
authors.affiliation: Department of Pathology, AP-HP, Hôpital Saint-Antoine, Sorbonne Universités, University Pierre and Marie Curie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.affiliation: Department of Hepatology, AP-HP, Hôpital Saint-Antoine, Sorbonne Universités, University Pierre and Marie Curie, Paris, France.
authors.forename: Astrid D
authors.initials: AD
authors.lastname: Kemgang
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Chapman
authors.affiliation: Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, United Kingdom.|Ludwig Institute for Cancer Research, Oxford, United Kingdom.
authors.forename: Lai Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Williamson
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Annette S H
authors.initials: AS
authors.lastname: Gouw
authors.affiliation: Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Paradis
authors.affiliation: Institut Universitaire de Pathologie-IUP, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: National Institute for Health Research, Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom.|Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hübscher
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D015209:Cholangitis, Sclerosing / Q000401:mortality* / Q000473:pathology* / Q000601:surgery; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D038622:Internationality; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation / Q000379:methods / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D015588:Observer Variation; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome