Primary sclerosing cholangitis €“ a comprehensive sclerosing...

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  • Key point

    PSC is by formal definition arare disease, yet the inci-dence is currently risingdue to unknown changes inenvironmental exposures.



    Keywords: Primary sclerosingcholangitis; IgG4-associatedcholangitis; Cholangiocarcinoma.

    Received 4 March 2017; received inrevised form 15 July 2017; accepted22 July 2017

    1Norwegian PSC Research Center,Department of TransplantationMedicine, Division of Surgery,Inflammatory Medicine and Trans-plantation, Oslo University HospitalRikshospitalet, Oslo, Norway;2Institute of Clinical Medicine,University of Oslo, Norway;3Research Institute of InternalMedicine, Division of Surgery,Inflammatory Medicine and Trans-plantation, Oslo University HospitalRikshospitalet, Oslo, Norway;4UCL Institute for Liver and Diges-tive Health, Division of Medicine,University College London, UK;5Sheila Sherlock Liver Centre, RoyalFree London NHS Foundation Trust,London, UK;6National Centre for Ultrasound inGastroenterology, HaukelandUniversity Hospital, Bergen, Norway

    Primary sclerosing cholangitis a comprehensive review

    Tom H. Karlsen1,2,3,, Trine Folseraas1,3, Douglas Thorburn4,5, Mette Vesterhus1,6


    Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi-focal bile ductstrictures and progressive liver disease. Inflammatory bowel disease is usually present andthere is a high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimatelyrequire liver transplantation, after which disease recurrence may occur. With limited thera-peutic options and a lack of proven surveillance strategies, patients currently have significantunmet needs. In the present seminar, we provide a comprehensive review of the status of thefield. We emphasise developments related to patient stratification and disease behaviour, andprovide an overview of management options from a practical, patient-centered perspective.We survey advances made in the understanding of PSC pathogenesis and summarise the ongo-ing efforts to develop an effective therapy based on these insights. 2017 European Association for the Study of the Liver. Published by Elsevier B.V. This is anopen access article under the CC BY-NC-ND license (


    Primary sclerosing cholangitis (PSC) is a chronicliver disease where inflammation and fibrosis leadto multifocal biliary strictures. The close associa-tion with inflammatory bowel disease (IBD) is ahallmark of the condition, with IBD present in themajority of patients (Fig. 1).1,2

    Until the mid-1960s, most published articleswere case reports.3 The broad implementation ofendoscopic retrograde cholangiography (ERC)throughout the 1970s led to increasing recognitionof the condition and in 1980, three landmarkpapers from the US, the UK and Norway establisheda clinical definition.46 Subsequently, the associa-tion of PSC with cholangiocarcinoma (CCA),7 colo-nic neoplasia8 and the sub-phenotypes of small-duct PSC,9 PSC with high immunoglobulin 4(IgG4) levels,10,11 and autoimmune hepatitis over-lap syndrome12,13 have been described. Diseaseprogression and end-stage liver disease are inevita-ble in most patients,14 and in 1983 liver transplan-tation was established as the only curativetreatment option.15 PSC recurrence after livertransplantation in some patients was noted a fewyears later.16

    The pathogenesis of PSC is unknown, but a num-ber of mechanistic theories have been proposed.The concentric fibrosis around the bile ducts inPSC (Fig. 2) is found in a variety of conditions andlikely represents a common final pathway for

    Journal of Hepatology 2017 vol. 67 j 12

    chronic bile duct injury of any cause (Box 1). Defectsin mechanisms protecting against bile acid toxicityhave been proposed as key players in PSC develop-ment.1719 The relationship with IBD has alsoinspired several avenues of research.20 Passive leak-age of pro-inflammatory microbial components tothe portal circulation and the possibility of an anti-genic trigger of microbial origin were for many yearsthe predominant theories.21,22 Recruitment of gut-derived T cells to the liver or an insult resulting fromdisturbances in the gut microbiota have also beenproposed.23,24

    We aim to describe the current understanding ofPSC, emphasising recent developments in patho-physiology and clinical management.

    Epidemiology and demographics

    PSC conforms to the definition of a rare disease,affecting less than 200,000 individuals in the USand less than 5 per 10,000 inhabitants in the EU(with fewer than 250,000 individuals affected acrossthe EU). Epidemiological studies of PSC, althoughhampered by the lack of an ICD10 code,25 report aprevalence rate of around 1 per 10,000 and an inci-dence rate in Northern Europe and the US ofbetween 0.4 and 2.0 per 100,000 per year.26,27 There


  • Corresponding author. Address:Department of TransplantationMedicine, Division of Surgery,Inflammatory Medicine andTransplantation, Oslo UniversityHospital Rikshospitalet, Postboks4950 Nydalen, N-0424 Oslo, Nor-way. Tel.: +47 2307 3616; fax: +472307 3928.E-mail address: (T.H. Karlsen).



    Multifocal bile ductstrictures and dilatations

    Pancolitis withright-sided


    Backwash ileitis


    Rectal sparing

    CMI K. C. Toverud CMI

    Fig. 1. Macroscopic bowel and bile duct pathology in primary sclerosing cholangitis (PSC). PSC is a chronic liver disease whereinflammation and fibrosis lead to multifocal biliary strictures. The close association with inflammatory bowel disease (IBD) is ahallmark of the condition, with IBD affecting about two-thirds of patients overall. Colonic involvement is most often classified asulcerative colitis, but sometimes it is interpreted as Crohns or indeterminate colitis. Despite the frequently mild symptoms, there isusually pancolitis. Often a right-sided predominance, subtle ileal inflammation (backwash ileitis) and rectal sparing are seen. PSC isassociated with a considerable risk of gastrointestinal malignancies, mainly cholangiocarcinoma and colorectal cancer. Printed withpermission from Kari C. Toverud.


    is a geographic gradient towards the South and theEast, with studies in Spain, Singapore and Japanreporting approximately 10-fold lower prevalencerates, i.e. at 0.022, 0.13 and 0.095 per 10,000,respectively.28 Childhood-centric assessments havefound incidence rates of 0.23 and 0.2 per 100,000per year.29,30 Several studies indicate the incidence

    Journal o

    of PSC is increasing.3134 Whilst this may be partlyattributable to the application of magnetic reso-nance cholangiography (MRC) rather than ERC, theclinical features of newly diagnosed patients appearstable over time,34 which indicates an earlier diag-nosis may not explain the increase. A similarincrease has been seen in most autoimmune and

    f Hepatology 2017 vol. 67 j 12981323 1299

    mailto:t.h.karlsen@ medisin.uio.nomailto:t.h.karlsen@

  • Seminar

    Environmental factors












    A. Stricture

    C. Cholangio-carcinoma

    B. Cirrhosis



    Antibody ANCA

    Genetically alteredimmunefunction

    T cellT cell

    T cellT cell



    B cellB cell







    C. Tove

    rud CM


    Genetic factors

    Liver homing



    TLR Gut leakage

    Gut homing





    Portal myo-fibroblasts

    Environmental fact

    Genetic factors


    Fig. 2. Integrated overview of the pathophysiology of primary sclerosing cholangitis (PSC). Clockwise, the figure illustrates the development from (1) initiating factors(upper right piece) to (6) liver-related complications (upper left piece). (1) There have been considerable advances in understanding the genetics of PSC, with more than 20susceptibility genes now identified (Table 1). The combined impact of genetic susceptibility factors on overall PSC liability is currently less than 10%, and even accounting forfuture gene discoveries, environmental risk likely accounts for more than 50%. (2) The relationship between the gut and the liver affection in PSC is not clear. Early theorieswere concernedwith the possible leakage of pro-inflammatory bacterial products (e.g. lipopolysaccharides, LPS) whichwould engage innate immune responses (e.g. by toll-like receptor signalling). The strong human leukocyte antigen (HLA) associations found in genetic studies however claim a strong involvement of adaptive immune responses,by determiningwhich antigens can be presented to the T cell receptor (TCR). Gut derived antigens are potential triggers of these responses, and activated T cellsmaymigrate toboth the liver and gut following clonal expansion because of the overlapping adhesion molecule profiles of gut and liver endothelia (i.e. mucosal vascular address in celladhesion molecule 1 [MadCAM-1] and vascular cell adhesion molecule 1 [VCAM-1] expression along with Chemokine C-C motif ligand 25 [CCL25] secretion).249

    Anti-neutrophil cytoplasmic antibodies (ANCA) are frequently observed in PSC,250 and may reflect B cell responses to antigens of gut origin.22 (3) Bile is toxic,251 and itscomposition is shaped by involvement of gut-microbial