Primary sclerosing cholangitis.

# Primary sclerosing cholangitis *The Lancet 2026* Seminar Primary sclerosing cholangitis Erik von Seth, Tom H Karlsen, Atsushi Tanaka, Cyriel Ponsioen, Annika Bergquist Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by biliary inflammation and Published Online fibrosis. Inflammatory bowel disease co-occurs in 50–80% of individuals with primary sclerosing cholangitis and there March 20, 2026 https://doi.org/10.1016/ is an increased risk for hepatobiliary and colorectal cancers. Primary sclerosing cholangitis presentation is highly S0140-6736(25)02582-6 variable but there is usually a slowly progressive fibrosis of the bile ducts with strictures, development of liver fibrosis Department of Upper and cirrhosis, and eventually a need for liver transplantation, after which primary sclerosing cholangitis can reoccur. Gastrointestinal Disease, Primary sclerosing cholangitis is diagnosed mostly at the asymptomatic stage but, as the disease advances, people Karolinska University Hospital, often have itching, fatigue, upper right abdominal pain, recurrent cholangitis, or complications related to portal Stockholm, Sweden hypertension. There are few treatment options and its exact cause and pathogenesis remain unclear. It is widely (E von Seth MD PhD, Prof A Bergquist MD PhD); Unit believed that both genetic and environmental factors are important, with the intestinal microbiome increasingly of Gastroenterology and recognised as crucial to disease development, progression, and outcomes. This Seminar explores the clinical features Nutrition, Karolinska of primary sclerosing cholangitis, summarises the current understanding of its pathogenesis, and gives insights into Institutet, Stockholm, Sweden (E von Seth, Prof A Bergquist); the challenges and opportunities in managing the disease. Clinic of Surgery and Specialized Medicine, Oslo Introduction Reported incidences range from less than 1∙0 to 1·6 University Hospital and Primary sclerosing cholangitis is a chronic progressive bile per 100 000 people and prevalences range from <1 to 32 University of Oslo, Oslo, duct disease characterised by inflammation and fibrosis, per 100 000 people.13–16 Primary sclerosing cholangitis is Norway (Prof T H Karlsen MD PhD); which results in multifocal biliary strictures and eventually more common in the northwestern hemisphere than the Department of Medicine, liver fibrosis and cirrhosis.1,2 The diagnosis is typically southern and eastern parts of the world.13–15,17–21 Variations Teikyo University School of made in the context of inflammatory bowel disease.3 in study methodologies contribute to discrepancies in Medicine, Tokyo, Japan (Prof A Tanaka MD PhD); Initially recognised in the mid-1960s,4,5 primary sclerosing reported incidence and prevalence across studies. Department of cholangitis gained wider recognition in the 1970s with the Co-occurrence with inflammatory bowel disease varies Gastroenterology & increased availability and use of endoscopic retrograde globally, with the strongest association in the northern Hepatology, Amsterdam cholangiography (ERC), the diagnostic standard at that hemisphere, which suggests that primary sclerosing University Medical Centers, Amsterdam, Netherlands time. In the 1980s, a diagnostic definition was established.6–8 cholangitis subtypes might exist that are distinct from the (Prof C Ponsioen MD PhD) Today, a typical cholangiogram with characteristic inflammatory bowel disease-associated form.22–24 In Correspondence to: strictures and associated beading of intrahepatic or Scandinavia, 76–88% of people with primary sclerosing Prof Annika Bergquist, extrahepatic ducts, done with MR cholangiography, along cholangitis are reported to have concomitant inflammatory Department of Upper with the exclusion of identifiable aetiologies for such bowel disease,25 whereas in southern Europe and Asia, Gastrointestinal Disease, Karolinska University Hospital, changes (secondary sclerosing cholangitis), remains one of inflammatory bowel disease coexists in 20–60%.3,14,20,26,27 Stockholm 14186, Sweden the most important hallmarks for diagnosing primary Variable colonoscopy practices might also aect the annika.bergquist@ki.se sclerosing cholangitis.9,10 reported prevalence of inflammatory bowel disease in The pathogenesis of primary sclerosing cholangitis is primary sclerosing cholangitis because colonoscopy with still poorly understood but it likely involves interactions biopsies is required to rule out inflammatory bowel between cholangiocytes, immune cells, and cells that disease.26 In a Japanese study, the prevalence of maintain the extracellular matrix, such as stellate cells inflammatory bowel disease rose from 37% to 61% when and portal myofibroblasts.11 Additionally, bile constituents only those who underwent colonoscopy were considered.26 and factors related to the gut microbiota and gut Conversely, primary sclerosing cholangitis is inflammation are likely involved.12 Eective treatments infrequent in people with inflammatory bowel disease, that halt disease progression and protect against with a pooled primary sclerosing cholangitis prevalence development of complications, such as liver cirrhosis, of 2·2% and the highest prevalence in subpopulations liver failure, and hepatobiliary cancer, are absent. Primary with extensive colitis (up to 11%).19 In addition, sclerosing cholangitis remains a challenging disease with substantial implications for individuals’ health and quality of life. Liver transplantation remains the primary Search strategy and selection criteria treatment option for advanced disease, emphasising the References for this Seminar were identified by searches of need for ongoing research and therapeutic advancements. MEDLINE, Current Contents, PubMed, and references from The aim of this Seminar is to provide an updated survey relevant articles using the search terms “primary sclerosing of our knowledge on primary sclerosing cholangitis, its cholangitis”, “cholangiocarcinoma”, and “inflammatory clinical management, and key future challenges. bowel disease” from July 7, 2000, to Jan 1, 2025. Abstracts and reports from meetings were included only when they Epidemiology related directly to previously published work. Only articles The incidence and prevalence of primary sclerosing published in English were included. cholangitis are low, with considerable global variation. www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 1 Seminar two studies using case-finding with proactive MR advanced disease and asymptomatic individuals can cholangiography in large groups with inflammatory exhibit substantial bile duct injury and liver fibrosis at bowel disease found radiological signs suggestive of diagnosis.17,31,38 When symptoms occur, they typically primary sclerosing cholangitis in 8–14% of include fatigue, itching, and intermittent or persistent individuals.17,28 right upper-quadrant abdominal pain.31,39 Fatigue is the The prevalence of inflammatory bowel disease is most common and debilitating symptom, substantially increasing globally.29 There are some data to suggest that aecting quality of life.39,40 Pruritus, ranging from mild primary sclerosing cholangitis follows the same trend,16 to severe, often worsens at night and can be localised but this increase might also be due to increased disease (eg, the palms, soles of the feet, and scalp) or generalised, recognition and MR cholangiography availability.1,13,14 It is leading to secondary skin damage. Biliary obstruction predicted that primary sclerosing cholangitis- and jaundice can indicate bile duct cancer, with up to inflammatory bowel disease will increase more than half of all primary sclerosing cholangitis-related inflammatory bowel disease30 and that a substantial rise cholangiocarcinomas detected at diagnosis or within the in primary sclerosing cholangitis globally is expected.16 first year.1,33,41 Chronic cholecystitis, gallstone formation, Primary sclerosing cholangitis is more common in men, and gallbladder polyps are common manifestations of with a male-to-female ratio typically around 2:1.31–33 This primary sclerosing cholangitis.42–46 Clinical signs of liver predominance seems less pronounced in low-prevalence failure or portal hypertension, such as ascites and areas.34,35 Primary sclerosing cholangitis occurs in all ages, variceal bleeding, are rare at initial presentation.31 with an incidence peak around age 40 years.1,31 In children, Associations with autoimmune diseases other than it also shows male predominance and a similar inflammatory bowel disease are present in about 25% of inflammatory bowel disease co-occurrence.36,37 patients and include type 1 diabetes, thyroid disease, rheumatoid arthritis, and coeliac disease.47 Clinical presentation Primary sclerosing cholangitis ranges from asym- Diagnosis ptomatic to severe disease with substantial morbidity.31 Primary sclerosing cholangitis is diagnosed by Asymptomatic individuals are often discovered cholangiographic changes at MR cholangiography after incidentally during evaluations for abnormal liver blood excluding secondary causes (table 1). A liver biopsy is not tests or through imaging studies done for other reasons. required unless needed to diagnose features of Importantly, the absence of symptoms does not exclude autoimmune hepatitis.10,48 Primary sclerosing cholangitis Diagnostic means Clinical advice at diagnosis or causes of disease Forms of primary sclerosing cholangitis Large-duct primary sclerosing cholangitis MR cholangiography–MRI Rule out secondary causes; check for associated diseases (inflammatory bowel disease) and rule out cholangiocarcinoma Small-duct primary sclerosing cholangitis Liver biopsy and MR cholangiography (normal) Histology is often unspecific; confirm that other typical diagnostic characteristics are present (inflammatory bowel disease required) and rule out other causes Primary sclerosing cholangitis with Antinuclear antibody, antismooth muscle antibody, Autoantibodies typical of autoimmune hepatitis and moderately elevated IgG features of autoimmune hepatitis antiliver kidney microsomal antibody, and antisoluble liver concentrations are common in large-duct primary sclerosing cholangitis without antigen–liver pancreas antibody; IgG; liver biopsy; MR autoimmune hepatitis; consider the risk of overdiagnosis and treatment side-effects cholangiography (normal or typical large-duct changes) Differential diagnosis IgG4-related cholangitis Use the HISORt criteria* Check IgG4 concentrations at diagnosis: mild elevation is common in advanced large- duct primary sclerosing cholangitis Cholangiocarcinoma CT, endoscopic ultrasound, and endoscopic retrograde ·· cholangiography with cytology and histology Genetic variants in ABCB4 Genetic testing Consider genetic testing in unclear cases with suspected small-duct primary sclerosing cholangitis Examples of secondary sclerosing cholangitis (not exhaustive) Bile duct injury History, imaging, and relevant serology Postoperative complications Choledocholithiasis History, imaging, and relevant serology Bile duct stones Infections History, imaging, and relevant serology HIV, recurrent bacterial infections, and liver fluke or ascaris infestation Ischaemic injury History, imaging, and relevant serology Critical illness and trauma Pancreatic disease History, imaging, and relevant serology Chronic pancreatitis and pancreatic cancer Congenital disease History, imaging, and relevant serology Choledochal cysts and biliary atresia *A diagnostic framework used in IgG4-related cholangitis (histology, imaging, serology, other organ involvement, and responsiveness to corticosteroids). Table 1: Diagnosis of primary and secondary sclerosing cholangitis, its variant forms, and differential diagnoses 2 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar exhibits a wide spectrum of severity and extent of biliary of 94%.50 Although MR cholangiography is sucient manifestations,49 with the large bile ducts being aected for diagnosis, a high-quality MRI with contrast in up to 90% of individuals.1,33 provides detailed information on bile duct thickness, liver parenchyma, and complications, like malignancy Large-duct primary sclerosing cholangitis and portal hypertension.51 Early and mild bile duct Typical cholangiographic changes show multifocal changes can be dicult to characterise and false- strictures and segmental dilatations of the bile ducts. positives can occur in cirrhosis of any aetiology.52,53 In MR cholangiography is the preferred imaging modality these cases, a liver biopsy could strengthen the for diagnosis10,48 with sensitivity of 86% and specificity diagnosis.10 A B Strictures and dilatations; cholangiocarcinoma C Symptoms and findings: High-grade stricture with Fatigue, itch, jaundice, prestenotic dilatation fevers or cholangitis, and abdominal pain D Right-sided predominance of colitis, © K. C. Toverud backwash ileitis, colorectal cancer or dysplasia, and spared rectum (few symptoms despite inflammation) Figure 1: Clinical characteristics of primary sclerosing cholangitis (A) The disease affects the biliary tree through inflammation and fibrosis, which results in multifocal biliary strictures and a high risk of cholangiocarcinoma.1,3,6–11,31 (B) When the disease progresses, high-grade strictures, often with prestenotic dilatation, can develop, leading to biliary obstruction and clinical symptoms.1,6,10,11,14,33,36 (C) Fatigue, itching, jaundice, bacterial cholangitis, and intermittent or persistent right upper-quadrant abdominal pain are common symptoms and signs in primary sclerosing cholangitis.31,36,39,40 Primary sclerosing cholangitis is associated with inflammatory bowel disease and 50–80% of affected individuals have concomitant inflammatory bowel disease. Primary sclerosing cholangitis inflammatory bowel disease shows distinct features from classic isolated inflammatory bowel disease, often with extensive colitis, a patchy inflammatory distribution that shows dominance of inflammation in the ascending colon, rectal sparing, and an increased risk of colorectal dysplasia compared with colitis without primary sclerosing cholangitis. (D) The inflammation almost always involves the colon and isolated ileal disease is rare.22–24,59–62 Reproduced with permission from Kari C Toverud. www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 3 Seminar There is variable interpretation of MR cholang iography features, such as bile duct loss, ductular reaction, a between radiologists and reporting standards are biliary pattern of interface activity, and chronic recommended.54 Invasive methods, such as ERC or cholestasis.49,63 Other cholangiopathies and genetic percutaneous transhepatic cholangiography, are usually disorders, such as ABCB4 mutations,64–67 can mimic restricted for interventions (ie, dilatation) or cytology these findings, necessitating careful evaluation, sampling on suspected neoplasia.55 Cholestasis, usually particularly in the absence of inflammatory bowel measured by alkaline phosphatase, is often present. disease.64,66,67 There is, however, a great variability of serum alkaline phosphatase concentrations in primary sclerosing Primary sclerosing cholangitis with features of cholangitis over time. Spontaneous normalisation of autoimmune hepatitis alkaline phosphatase is common and it is important to Features of autoimmune hepatitis occur in 4–7% of recognise that normal concentrations do not rule out adults1,33 and up to a third of children with primary primary sclerosing cholangitis.17,56,57 In one study, 40% of sclerosing cholangitis.36,37,68 Diagnosis of autoimmune newly diagnosed individuals had normalised alkaline hepatitis–primary sclerosing cholangitis generally requires phosphatase during a 10-year follow-up.58 A typical meeting autoimmune hepatitis criteria,69 cholangiographic clinical phenotype for a person with large-duct primary evidence of primary sclerosing cholangitis, and negative sclerosing cholangitis is shown in figure 1. antimitochondrial antibody with inflammatory bowel disease presence supporting the diagnosis. A positive Small-duct primary sclerosing cholangitis autoantibody testing (eg, antinuclear antibodies, smooth Small-duct primary sclerosing cholangitis accounts for muscle antibodies, and antisoluble liver antigen) and 4–9% of cases1,33 and is diagnosed when MR elevated alanine transferase or IgG suggest overlap, but cholangiography is normal but otherwise typical findings liver biopsy remains essential due to shared clinical and for primary sclerosing cholangitis are present, including histological features.69,70 Antineutrophil cytoplasmic histology showing typical primary sclerosing cholangitis antibody tests are not specific and are not diagnostic.71,72 A Cholangiographic changes B Cirrhosis Disease progression Symptoms and Fibro b sis io chemistry Liver stiffness Recurrence C Time (years) Preclinical Diagnosis Clinical events Liver transplant Post-transplant complications Figure 2: Natural history of primary sclerosing cholangitis (A) The disease is generally progressive, with cholangiographic changes becoming more extensive throughout disease course. (B) Assessing severity and prognosis is challenging due to the scarcity of widely validated biomarkers, but serum fibrosis tests and liver elastography are increasingly used. There is a long preclinical phase in the disease, which is often asymptomatic with normal or fluctuating liver blood tests. Disease progression is mostly very slow, with a median time to need for liver transplantation of approximately 18–21 years.1,2 (C) With time, there is increasing biliary and liver fibrosis and cholestasis, leading to a need for liver transplantation. After liver transplantation, primary sclerosing cholangitis can reoccur in up to 30% of individuals. Reproduced with permission from Kari C Toverud. 4 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar Differential diagnoses cases but is rarely eective outside definite IgG4-related Key dierential diagnoses are cholangiocarcinoma and cholangitis.78 IgG4-related cholangitis (table 1). Mild IgG4 elevation occurs in 10–15% of individuals with primary sclerosing Natural history cholangitis73–75 and must be distinguished from IgG4- Although the disease course is highly variable, primary related cholangitis, which shares similar biliary sclerosing cholangitis typically progresses over many strictures and symptoms.76 IgG4-related cholangitis years to severe liver disease or cholangiocarcinoma, diagnosis relies on clinical, biochemical, radiological, substantially aecting prognosis (figure 2).1,31,33 In For the PREsTo score see https:// and pathological criteria77 and dierentiation between it population-based cohorts, the median time to a combined rtools.mayo.edu/PRESTO_ and primary sclerosing cholangitis can be challenging. endpoint of death or liver transplantation has been calculator/ Using serum IgG4 concentrations more than 4 times estimated at between 18 and 21 years.1,2 Studies at referral For the Amsterdam–Oxford model see https://sorted.co/psc- higher than the upper limit of normal or using the centres, typically transplant centres, report a shorter calculator/ IgG4-to-IgG1 ratio with a cuto at 0·24 can increase the median transplant-free survival of 9–18 years, likely due For the UK-PSC Risk Score see diagnostic accuracy for IgG4-related cholangitis.73 to referral bias.31,38,79–83 Earlier diagnosis over the past http://www.uk-psc.com/ Corticosteroid treatment can be tested in equivocal two decades could have contributed to increased resources/the-uk-psc-risk-scores/ Description and references Clinical variables Age Younger age at diagnosis is associated with longer transplant-free survival31,33,38,79,89–93 Sex Female sex is a protective factor associated with lower risk of cholangiocarcinoma and longer transplant-free survival33 IBD No inflammatory bowel disease and no Crohn’s disease is associated with a longer transplant-free survival33 Primary sclerosing cholangitis phenotype Small-duct primary sclerosing cholangitis Associated with better prognosis and lower risk of cholangiocarcinoma; risk of progression to large-duct primary sclerosing cholangitis is frequent (23% over 7·4 years)33,84 Features of autoimmune hepatitis Concomitant features of autoimmune hepatitis in primary sclerosing cholangitis have a similar outcome to primary sclerosing cholangitis alone36,94 Alkaline phosphatase Elevated concentrations are associated with worse outcome; difficult to use due to fluctuations during the disease course10,48,57,58,90,95–98 Bilirubin Continuously elevated concentrations indicate worse prognosis but are usually applicable only in late-stage disease; normal or fluctuating values (eg, cholangitis or extrahepatic high-grade strictures) occur in early disease31,38,79,89–93,99 Measures of fibrosis Histology Associated with liver transplantation and liver-associated death; not used in clinical practice due to its invasiveness10,48,100–102 VCTE Liver stiffness measured by VCTE is strongly associated with fibrosis degree and clinical outcomes; cutoff values for risk stratification are still to be evaluated; values have been suggested for low-risk (<6·5 kPa) and high-risk (>9·9 kPa) clinical events; single increased values should be interpreted with caution due to high variability and put into clinical context103–106 MR elastography Liver stiffness measured by MR elastography is associated with fibrosis degree and clinical outcomes but is less evaluated and less available in clinical practice than VCTE107–109 Enhanced liver fibrosis test Serum test calculated from concentrations of TIMP-1, hyaluronic acid, and intact N-terminal PIIINP; is associated with liver fibrosis and transplant- free survival at 4–6 years; score >10·6 has been suggested to identify individuals at higher risk for liver transplantation or death; not widely available10,110–114 Imaging Spleen size >12 cm Associated with transplant and liver decompensation-free survival106,115 Anali score Risk score based on MRI and MR cholangiopancreatography with or without contrast; includes assessment of intrahepatic bile duct dilatation, hepatic dysmorphia, parenchymal enhancement, and portal hypertension; predicts adverse-free (hepatic decompensation), transplant-free survival3 2,116,117 DiStrict score MR cholangiopancreatography-based score of intrahepatic and extrahepatic bile duct strictures and dilatations; predicts risk of liver transplantation and liver-related death118 Primary sclerosing cholangitis-specific prognostic scores Revised Mayo score Used to estimate the overall survival probability over a time horizon of up to 4 years; based on factors that are affected in advanced disease and are applicable in in late-stage disease92 PREsTo Predicts hepatic decompensation (ie, encephalopathy, ascites, and variceal bleeding) within 5 years; risk score derived from nine variables: bilirubin, albumin, alkaline phosphatase, platelets, aspartate aminotransferase, haemoglobin, sodium, patient age, and disease duration90 Amsterdam–Oxford model Calculates the probability of transplant-free survival after 5, 10, and 15 years; based on seven clinical variables: age at diagnosis, primary sclerosing cholangitis phenotype (large duct or small duct), aspartate aminotransferase, alkaline phosphatase, bilirubin, albumin, and platelets89 UK-PSC Risk Score The short-term score estimates the 2-year transplant-free survival at diagnosis using bilirubin, albumin, haemoglobin, and platelets; 2 years after diagnosis, the long-term score can be applied (based on age at diagnosis, bilirubin, alkaline phosphatase, albumin, platelets, variceal haemorrhage, and presence of extrahepatic biliary disease at diagnosis) to estimate the transplant-free survival during the following 8 years91 VCTE=vibration-controlled transient elastography. Table 2: Risk factors for liver-related complications and mortality in individuals with primary sclerosing cholangitis www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 5 Seminar transplant-free survival numbers in the literature.2,30 with minimal alkaline phosphatase elevation or Small-duct primary sclerosing cholangitis might be an histological changes and near-normal MR early stage, with 23% of patients progressing to large- cholangiography findings. By contrast, middle-aged or duct involvement within approximately 7 years.84 The older individuals (particularly older than 60 years) with course of small-duct primary sclerosing cholangitis is large-duct primary sclerosing cholangitis and high-grade generally more benign than with large-duct involvement strictures have a substantially higher risk of and cholangiocarcinoma is rare.33,84 complications, especially for hepatobiliary malignancy.14 Asymptomatic individuals seem to have a more Accurate and individualised risk assessment and favourable prognosis than individuals with symptoms, information about disease progression and complications but once symptoms, severe cholestasis, and clinical are essential to avoid unnecessary psychological events occur, the progression of disease accelerates.31,79 distress.88 The pace of disease progression was shown in a prospective cohort of 512 individuals with primary Pathogenesis sclerosing cholangitis who were followed up with yearly The cause of primary sclerosing cholangitis is unknown MRI or MR cholangiography and for surveillance of and insights into pathophysiology have so far been hepatobiliary cancer.85 At baseline, with a median primary insucient to guide the development of eective sclerosing cholangitis duration of 7 years, 8% had severe therapies.11 Summarising research on the patho- bile duct changes with tight strictures seen on imaging. physiology of primary sclerosing cholangitis, the After 5 years of follow-up, 24% progressed to severe bile distinction between hypothesis-driven and hypothesis- duct changes and 10% had undergone liver transplantation free approaches oers diering insights (figure 3). or died.85 Other studies have shown that primary Since the identification of primary sclerosing sclerosing cholangitis is mostly stable over short periods cholangitis as a disease entity, its close relationship with (ie, 1–2 years).56 Before liver transplantation was inflammatory bowel disease has been thought to crucially introduced, most individuals died of liver-related involve biliary pathophysiology.4,120 However, the exact complications.86 Today, the most frequent cause of death mechanism of such a contribution remains unknown. in primary sclerosing cholangitis is cholangiocarcinoma The concept of a leaky gut in primary sclerosing (32%), followed by liver failure (18%), transplant cholangitis with inflammatory bowel disease involves the complications (9%), and colorectal cancer (8%).1 propensity of bacteria or bacterial components to translocate to portal blood,121–123 thereby driving innate or Prognostic factors adaptive immune responses in the portal tracts. This Assessing disease stage and future prognosis is crucial process ultimately engages cholangiocytes which, in an for people with primary sclerosing cholangitis and their activated (ie, secretory senescent) form, actively physicians.39,87,88 However, the high risk of cancer at any contribute to the generation of peribiliary fibrosis via time during the disease course complicates prognosti- cross-talk with a range of proposed immune-related or cation and the development of reliable prognostic tools stromal cells.124,125 The onion skin multilayer appearance (table 2). Female sex, younger age at diagnosis, small-duct of fibrosis in primary sclerosing cholangitis supports an disease, large-duct disease limited to intrahepatic active role of cholangiocytes in stricture formation, but involvement, and absence of inflammatory bowel such a role might also result from luminal exposure to disease33,84,119 are associated with a favourable prognosis. bile or bile components, as well as dysregulated By contrast, elevated alkaline phosphatase and bilirubin protection against such exposures via deficits in the concen trations, advanced fibrosis assessed by vibration- protective mechanisms against bile acid toxicity (the controlled transient elastography or MR elastography, bicarbonate umbrella hypothesis).126 Various elements of advanced cholangiographic features, and increased these dierent hypotheses might all contribute spleen size are all linked to a higher risk of complications throughout primary sclerosing cholangitis development See Online for appendix (appendix).10,48,57,89–92,95,96 and include key regulators of bile acid homoeostasis, Providing an accurate long-term prognosis at the such as farnesoid X receptor (FXR), FGF19, peroxisome individual level in primary sclerosing cholangitis remains proliferator-activated receptors, and other nuclear bile challenging, especially in early disease, and remains acid receptors.127–131 one of the most important issues for people with primary Detailed analysis of the gut microbiota in primary sclerosing cholangitis.39 Currently, no specific prognostic sclerosing cholangitis has revealed numerous changes tools are recommended for individual use in clinical involving overall shifts in the microbial spectrum practice. Guidelines suggest using phenotypic features, (including a reduced diversity of microbes), with resulting standard biochemistry, liver elastography, and MRI or alterations in metabolic features, such as the production MR cholangiography for broader risk assessment.10,48 For of various microbial metabolites (eg, trimethylamine example, the risk of complications (eg, cholangio- N-oxide and vitamin B6) and a range of other molecules carcinoma) or need for liver transplantation is negligible potentially influencing immune function, biliary in young people (approximately younger than 20 years) homoeostasis, and cholangiocyte activation, or even 6 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar Hypothesis-driven research Hypothesis-free research Leakygut vitam Gu in t B si g , n e a x ls p ( o T s M om AO e, , etc) Microbiomeandm etabolom ics Microbial antigens Macrophages T cells Neutrophhils Lipopolysaccharides Pathobionts (Klebsiella, Veillonella, Th17-polarised Bacterial Cholangiocytes Enterococci, etc) naive T cells translocation and br ella Bic ri a c r h b o la n y a e t r e- cholangitis M Na a t s u t r c a e l l k ls iller cells m Th17 MAIT cells e a n l dt h e bic arb o b ci i na Tox te u C AA F EE T R X P B b ro i i l l t e e o a a n H C c c a i i l C d d t - e s O s d - 3 - C H O + 2 O TGR B ile an F d E V X o n D c R t t i R r h e a P c r e n a P u o r n d A l h a r d R F e t e i s G g P p o ; u X a F n t l R ; a i c ; to ; rs La d r d is g u e e c a t b se il L e iver disease an B ti C b R o , d T y C p R r , o a fi n l d ing M B c a e c l ( r l e o s g p , h A E a n p v g t s i e r i t g u s e e s in ) n – s Barr niS sci m el g oi ec- m u tl d nall al ita ps Neutrophils AAQQPP11 H 2 O TT cceellllss CD8+ effector Cross-talk 2 50 m T M h a e s m t o c c e e ry l l l l s s T cells MMaasstt cceellllss 150 B cells 50 NNeeuuttrroopphhiillss 1 23 456789111315171921 Chromosome Inflammatory Autoimmunity MMaaccrroopphhaaggeess bowel disease risk genes risk genes Primary sclerosing Onionskinfibrogenesis M S y t o e fi ll b at ro e b c l e a l s ls ts ©K.C.T c o h v o er la u n d g C i M tis I risk ge G n W e A s S,exome,andgeno meanalysis Figure 3: Important concepts on the pathophysiology of primary sclerosing cholangitis Important concepts are those of a leaky gut (based on the relationship with inflammatory bowel disease), toxic bile (related to potential deficits in protection against bile acids), and onion skin fibrosis (driven by cross-talk between cholangiocytes and immune cells and stromal cells involved in immune-mediated injury and the generation of peribiliary scarring). With the development of omics technologies over the past 25 years (eg, genomics and transcriptomics along with spatial information, metabolomics, and associated microbiome analysis) hypothesis-driven research in primary sclerosing cholangitis has been replaced and expanded by the application of hypothesis-free approaches. PPARs=peroxisome proliferator-activated receptors. MAIT=mucosal-associated invariant T cells. TMAO=trimethylamine N-oxide. GWAS=genome-wide association studies. Reproduced with permission from Kari C Toverud. www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 7 Seminar exerting overt toxic influences via exposure through the benefit from immunosuppression with prednisolone portal blood.12,132,133 Specific bacteria have also been and azathioprine.10 Careful follow-up with liver blood proposed to exert pathophysiological impact (so-called tests, IgG, liver stiness, and liver histology is warranted pathobionts), most consistently Klebsiella pneumoniae, to avoid overtreatment and side-eects. Enterococcus spp, and Veillonella spp.12,133–138 For pathobionts, only particular strains might be relevant—as shown for Symptom management K pneumoniae—for which only strains enabling gut Individuals with primary sclerosing cholangitis have a epithelial pore formation, and hence a leaky gut, were high symptom burden, including fatigue, itching, shown to reproduce liver pathology in mouse jaundice, bacterial cholangitis, and right upper-quadrant experiments.135 Biliary presence of these gut microbes abdominal pain (figure 1).39 In those with inflammatory might exacerbate injury once disease is established, as bowel disease, overlapping abdominal symptoms make it shown for Enterococci.139,140 dicult to distinguish their source. Fever warrants From a genetic perspective, primary sclerosing prompt evaluation for bacterial cholangitis and early cholangitis shows features common with inflammatory antibiotic initiation when necessary. Pruritus aects up bowel disease, but there is also considerable overlap of to 60% of people with primary sclerosing cholangitis and primary sclerosing cholangitis risk genes with those of is often under-recognised and inadequately treated. prototype autoimmune diseases, such as type 1 diabetes Antihistamines and cholestyramine are widely used, and multiple sclerosis.141 For genes involving Mendelian despite low ecacy.39 After excluding endoscopically forms of primary sclerosing cholangitis (eg, CD100), gene treatable biliary strictures and choledocholithiasis, function also points towards dysregulated immune standard therapy includes bezafibrate or rifampicin.10,161 responses as primary players in primary sclerosing New treatments for cholestatic itch, such as inhibitors of cholangitis pathogenesis.142 Given the absence of clinical ileal bile acid transporters and MAS-related G-protein- benefit from immunosuppressive drugs143 and recurrence coupled receptor antagonists, are being investigated but of primary sclerosing cholangitis during immuno- are not yet in clinical use (table 3).178–181 Many individuals suppression after liver transplantation,144,145 these with primary sclerosing cholangitis develop osteopenia or observations put forward a paradox of why, if primary osteoporosis, partly due to chronic cholestasis and related sclerosing cholangitis is an autoimmune disease, it is metabolic disturbances, including vitamin D deficiency refractory to such therapies. Ongoing exploration of the and impaired calcium absorption.182,183 Regular bone immune landscape in primary sclerosing cholangitis mineral density monitoring and supplementation of using high-throughput technologies, such as single-cell calcium and vitamin D are recommended, especially for analysis, spatial transcriptomics and other spatial omics those on corticosteroids.10 (eg, proteomics and metabolomics), B-cell and T-cell receptor profiling, and antibody profiling is likely to shed Emerging therapies light on this paradox and potential factors involved in the Although drugs targeting cholestasis might benefit people multicellular cross-talk driving primary sclerosing with primary sclerosing cholangitis, immunom odulators cholangitis development.146–151 Candidate-driving factors in remain ineective, despite the presumed autoimmune primary sclerosing cholangitis potentially refractory to involvement in pathogenesis. A promising agent is immune-targeted interventions include gut microbial norucholic acid, an ursodeoxycholic acid analogue with a factors, viral factors, and changes to bile composition, shortened side-chain, which significantly reduced alkaline thus linking the various proposed concepts of primary phosphatase in a phase 2 trial.162 Norucholic acid induces sclerosing cholangitis development. bicarbonate-rich hypercholeresis, protects cholangiocytes, and might exert anti-inflam matory eects. In a phase 3 Management trial published in 2025, norucholic acid was superior to Medical treatment placebo for the composite endpoint of partial alkaline Currently, no drug is approved to improve the long-term phosphate normalisation (<1·5 times higher than the prognosis of primary sclerosing cholangitis.129 upper limit of normal) and no histological worsening Ursodeoxycholic acid, a hydrophilic bile acid used (15·1% vs 4·2%).163 The response rate for norucholic acid globally with varying practice,39,152 improves cholestasis was higher without concomitant ursodeoxycholic acid and lowers alkaline phosphatase,153,154 but has scarce (23·4%) than with it (12·7%); it also achieved sustained evidence for better clinical outcomes.155–159 Recommended liver enzyme reduction and was well tolerated. doses are 13–20 mg/kg and higher doses (28–30 mg/kg) Other drugs tested include FXR agonists (obeticholic might be harmful.160 A practical approach is to treat those acid and cilofexor),167,184 peroxisome proliferator-activated with elevated alkaline phosphatase, symptoms, or both, receptor agonists,168,185 statins,158,169 biologics, and inflam- continuing only if concentrations normalise and matory pathway blocking agents.145,170,186–188 Given primary symptoms improve. Individuals with primary sclerosing sclerosing cholangitis-associated dysbiosis, microbiota cholangitis and definite features of autoimmune modulation has been attempted via antibiotic treatments hepatitis, with interface hepatitis on histology, might and faecal microbiota transplantation, but without 8 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar proven long-term benefits.189 Vancomycin can lower trials.10,48 Drugs that are currently being investigated are alkaline phosphatase190–192 but safety concerns, such as summarised in table 3.171,173,193 Future trials in primary antibiotic multiresistance, limit its use and guidelines sclerosing cholangitis should account for variable advise against routine prescription outside clinical geographical, ethnic, and genetic backgrounds. Description or mechanism of action Study descriptor Primary endpoint Status Outcome Ursodeoxycholic acid derivatives Norucholic acid Homologue of ursodeoxycholic acid with a Phase 2 RCT (N=161) Change in ALP at week 12 Completed162 Significant reduction of shortened side-chain; induces bicarbonate- ALP; no safety concerns rich hypercholeresis, protects cholangiocytes, and has direct anti-inflammatory and immunomodulatory effects Norucholic acid Homologue of ursodeoxycholic acid with a Phase 3 RCT (N=302) Prevention of disease progression Completed163 Significantly superior to shortened side-chain; induces bicarbonate- by stable histology and placebo: 15·1% vs 4·2% rich hypercholeresis, protects cholangiocytes, ALP <1·5 × ULN at 2 years reached primary endpoint; and has direct anti-inflammatory and well tolerated immunomodulatory effects Berberine ursodeoxychlolate Ionic salt of berberine and ursodeoxycholic Phase 2 RCT (N=55) Change in ALP at week 6 Completed164 Significant reduction of (HTD1801) acid; improves lipid metabolism and reduces ALP; no safety concerns inflammation FXR agonists Obeticholic acid Steroidal FXR agonist Phase 2 RCT (N=76) Change in ALP at week 24 Completed165 No significant reduction of ALP; frequent side-effects (pruritus) Cilofexor Inhibits bile acid synthesis and promotes Phase 3 RCT (N=160) Proportion of patients with Terminated166 Terminated early: low choleresis; reduces inflammation and fibrosis histological progression of liver probability (6·8%) of fibrosis achieving primary endpoint FGF-19 NGM282 (Aldafermin) Non-tumourigenic analogue of FGF-19; Phase 2 RCT (N=62) Change in ALP at week 12 Completed167 No significant reduction of inhibits bile acid synthesis by inhibiting ALP; no safety concerns CYP7A1 in the liver and reduces inflammation and fibrosis PPAR agonists Bezafibrate (pan-PPAR/PXR PPAR-agonist signal through specific Phase 3 RCT (N=104) ALP <1·5 × ULN and a reduction of Recruiting NA agonist) intranuclear receptors to control diverse ≥15%; bilirubin ≤ULN; no increase metabolic processes, including lipid and bile in liver stiffness acid metabolism Seladelpar (PPAR-δ agonist) PPAR-agonist signal through specific Phase 2 RCT (N=100) Change in ALP at week 24 Terminated NA intranuclear receptors to control diverse metabolic processes, including lipid and bile acid metabolism Elafibranor (PPAR-α/δd agonist) PPAR-agonist signal through specific Phase 2 RCT (N=68) Treatment-emergent adverse Completed168 35·3–57·7% dose- intranuclear receptors to control diverse events dependent reduction of metabolic processes, including lipid and bile ALP; no safety concerns acid metabolism Statins Simvastatin Reduces the production of cholesterol, has Phase 3 RCT (N=560) Time-to-death, liver Recruiting169 NA pleiotropic effects, improves endothelial transplantation listing, variceal function, and reduces inflammation bleeding, or the development of hepatobiliary cancer Biologics and inflammatory pathway blocking agents VAP-1 antibody VAP-1 blockade Phase 2 observational Change in ALP at day 99 Completed170 No significant reduction of study (N=23) ALP; no safety concerns Cenicriviroc Dual antagonist of CCR2 and CCR5 Phase 2 observational Change in ALP over 24 weeks Completed171 No significant reduction of study (N=24) ALP; no safety concerns CM-101 CCL24 blockade Phase 2 RCT (N=68) Treatment-emergent adverse Completed172 Significant reduction in events liver stiffness measurement in moderate and advanced fibrosis; no safety concerns Aspirin Acetylsalicylic acid Phase 3 RCT (N=968) Occurrence of primary sclerosing Recruiting NA cholangitis-related cancers and need for liver transplantation (Table 3 continues on next page) www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 9 Seminar Description or mechanism of action Study descriptor Primary endpoint Status Outcome (Continued from previous page) Antifibrotic agents Simtuzumab Monoclonal antibody against LOXL2 Phase 2 RCT (N=234) Change in hepatic collagen Completed56 No significant reductions in content on liver biopsy at week 96 Ishak fibrosis stage; no safety concerns Bexotegrast (PLN-74809) Dual-selective inhibitor of αβand αβ Phase 2 RCT (N=121) Treatment-emergent adverse Completed173 No safety concerns v 6 v 1 integrins events Microbial manipulations Vancomycin Oral glycopeptide antibiotics Phase 3 RCT (N=102) Change in ALP at 6 months Active, not NA recruiting Faecal microbiota Restores gut microbiota diversity Phase 2 RCT (N=58) Change in ALP at week 48 Recruiting174 NA transplantation Other compounds Pyridoxin Vitamin B6 restores deficiency to improve Phase 2 RCT Change in ALP at week 12 Recruiting NA metabolic and immune functions Curcumin Naturally occurring compound with anti- Phase 1/2 open-label, Change in ALP at week 12 Completed175 No significant reduction of inflammatory effects single-arm study ALP; no safety concerns (N=15) Vidofludimus Calcium Dihydroorotate dehydrogenase inhibitor Phase 2 open-label, Change in ALP at week 6 months Completed176 No significant reduction of single-arm study ALP; no safety concerns (N=18) HK-660S β-Lapachone, anti-inflammatory and Phase 2 RCT (N=21) Change in ALP at week 12, Completed177 No significant reduction of antifibrotic effects improvements in primary ALP; no safety concerns sclerosing cholangitis severity (MR cholangiography with the Anali score) Treatment for itch Bezafibrate (included primary Pan-PPAR Phase 3 RCT (N=76) ≥50% reduction of pruritus (visual Completed161 Bezafibrate superior to sclerosing cholangitis, primary analogue scale) at day 21 placebo: 41% vs 11% biliary cholangitis, and reached endpoint secondary sclerosing cholangitis) Maralixibat IBAT inhibitors interrupt the enterohepatic Phase 2 open-label, Treatment-emergent adverse Completed178 Treatment-emergent circulation of bile acids and reduce the bile single-arm study events, change in bile acids at adverse event in 85%; itch acid pool through inhibition of the apical (N=27) week 14 and change in pruritus improved in 8–70%, most sodium-dependent bile acid transporter in (secondary endpoint) in severe pruritus the terminal ileum Ritivixibat (A3907) IBAT inhibitors interrupt the enterohepatic Phase 2 open-label, Treatment-emergent adverse Recruiting NA circulation of bile acids and reduce the bile single-arm study events acid pool through inhibition of the apical sodium-dependent bile acid transporter in the terminal ileum Volixibat IBAT inhibitors interrupt the enterohepatic Phase 2 RCT Mean change in daily itch NRS for Recruiting NA circulation of bile acids and reduce the bile 28 weeks acid pool through inhibition of the apical sodium-dependent bile acid transporter in the terminal ileum EP547 (included primary MRGPRX4 inverse agonist; blocking Phase 2 RCT Change in worst itch NRS for 6 Completed NA sclerosing cholangitis and pruritogenic activity prevents the activation weeks primary biliary cholangitis) of MRGPRX4 and subsequent itch sensation More recently published studies were included when relevant. ALP=alkaline phosphatase. FXR=farnesoid X receptor. IBAT=ileal bile acid transporter. NA=not assessable. NRS=Numeric Rating Scale. PPAR=peroxisome proliferator-activated receptor. RCT=randomised controlled trial. ULN=upper limit of normal. *According to ClinicalTrials.gov (accessed Dec 25, 2024). Table 3: Overview of key clinical trials for potential medical therapies in primary sclerosing cholangitis Endoscopic treatment assumption that it might delay disease progression. It is ERC is generally used in primary sclerosing cholangitis to not clear which individuals will benefit from biliary treat symptoms caused by severe bile duct strictures, such intervention in terms of symptom relief and long-term as bacterial cholangitis, pruritus, and jaundice; diagnose outcomes. cholangiocellular dysplasia and cholangioc arcinoma; and Guidelines define strictures by MR cholangiography dilate asymptomatic high-grade strictures on the morphology and symptoms.10,48 MR cholangiography is 10 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar used to assess severity and location before intervention, early-stage hilar cholangiocarcinoma and high-grade whereas ERC is recommended for relevant strictures in biliary dysplasia) and in trials for liver transplantation in the common bile duct or hepatic ducts, defined as a cholangiocarcinoma.210,211 Although cholangiocarcinoma greater than 75% reduction in duct diameter (with or is associated with a high recurrence rate following liver without upstream dilatation), with obstructive symptoms transplantation,212–214 the integration of neoadjuvant or cholestatic blood tests.55 Since it is only possible to chemoradiation in rigorously selected patients has establish if a stricture is causing symptoms or shown improved outcomes.215 Under such protocols, biochemical cholestasis after treatment, an ERC expert 5-year overall survival rates approaching 65% have been panel from the International Primary Sclerosing reported.210,215–217 Cholangitis Study Group classified strictures as possible Timing of liver transplantation in primary sclerosing dominant on MR cholangiography and definite dominant cholangitis is complex due to the disease’s unpredictable when symptoms, cholestasis, or both improve after progression, high risk of cholangiocarcinoma, and therapeutic ERC.49 Individuals with cirrhosis are less variable symptom burden.10,48,218 Symptoms that severely likely to respond to bile duct dilatation than those impact quality of life (eg, recurrent bacterial cholangitis without.194 In bacterial cholangitis, biliary decompression and severe itch) can occur despite preserved liver is crucial in patients with an underlying high-grade function and Model for End-Stage Liver Disease (MELD)- stricture. based criteria might not adequately capture the severity Dilatation of asymptomatic strictures is widely of disease-related morbidity in these individuals. Access practised but its benefit is unclear. Observational data to transplantation is further influenced by organ suggest that individuals with primary sclerosing availability and regional listing policies. cholangitis included in scheduled ERC surveillance Post-transplant outcomes for people with primary programmes have better transplant-free survival than sclerosing cholangitis are similar to other indications, those treated on an on-demand basis (17·8 years with 5-year survival rates of 82–92% and 10-year survival vs 11·1 years).195,196 However, robust evidence for the rates of 73–81%.219 Living donor liver transplantation ecacy of such proactive interventional strategies is yields similar results to deceased donor liver insucient. The preferred initial therapy method for bile transplantation in countries in Europe and North duct dilatation is single balloon dilatation on the basis of America.220,221 In Japan, where living related donors results from the randomised DILSTENT trial.197 Balloon predominate, the survival rate is 83% at 5 years and 68% dilatation and short-term stenting (<2 weeks) had similar at 10 years post-transplantation.219,222 success (50% at 3 months) and recurrence-free intervals Re-transplantation is sometimes needed: graft 5-year (26 weeks vs 34 weeks), but adverse events were more survival rates are 71–85% and 10-year survival rates frequent with stenting (45%) than balloon dilatation are 58–66%.223 Recurrence of primary sclerosing (7%).197 Stricture recurrence within 1 year is common, cholangitis is a leading cause of graft loss that aects leading some centres to repeat balloon dilation until 20–30% of recipients, regardless of donor type.10 cholangiographic resolution.195,196 Limited pilot data Diagnosing recurrent primary sclerosing cholangitis indicate that applying fully-covered metal stents might requires typical cholangiographic findings and often improve treatment eect and patency of extrahepatic histological evidence at least 90 days post-transplant, dominant strictures.196 There are currently no drug- after exclusion of hepatic ischaemia, chronic ductopenic eluting stents available for biliary applications. rejection, anastomotic strictures, and donor–recipient ERC in primary sclerosing cholangitis has a notable risk blood type incompatibility.224 Risk factors for recurrent of complications, mainly post-ERC pancreatitis (2–8%) primary sclerosing cholangitis include active and bacterial cholangitis (2–7%), making prophylactic anti- inflammatory bowel disease, older donor age, higher biotics mandatory.10,198–209 Decisions regarding endoscopic MELD scores, and acute cellular rejection.225 Colectomy therapy are ideally made within a multidisciplinary team before liver transplantation might reduce the risk of involving hepatologists, abdominal radiologists, and recurrent primary sclerosing cholangitis.225 endoscopists. The intervention should be chosen by experienced endoscopists, selecting the most appropriate Primary sclerosing cholangitis-associated technique based on the individual’s condition. hepatobiliary cancer Hepatobiliary malignancies are the leading cause of Liver transplantation increased mortality in primary sclerosing cholangitis, Liver transplantation is the only curative treatment for with elevated risks of cholangiocarcinoma, gallbladder primary sclerosing cholangitis and is typically indicated cancer, and hepatocellular carcinoma, with cholangio- in patients with decompensated cirrhosis, intractable carcinoma being the most prevalent.1,33,41,44,45,83 Up to bacterial cholangitis, refractory pruritus or jaundice, and 50% of all patients with cholangiocarcinoma are early stage of cholangiocarcinoma (biliary dysplasia).10,48 diagnosed within the first year following a primary Overt cholangiocarcinoma is generally a contraindication sclerosing cholangitis diagnosis. Cholangiocarcinoma for liver transplantation, with some exceptions (eg, aects 2% of people with a new primary sclerosing www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 11 Seminar cholangitis diagnosis1,2,33,41,81 and probably reflects sclerosing cholangitis are so far scarce.242–244 The serum previously undetected primary sclerosing cholangitis. tumour marker CA 19–9 is widely used, despite its Being older than 50 years and the presence of high-grade limitations:248–251 concentrations can rise due to cholestasis or progressive biliary strictures are associated with a and bacterial cholangitis, both of which are frequent higher risk of cholangiocarcinoma, whereas a lower risk events in primary sclerosing cholangitis, and false low is seen in patients with small-duct primary sclerosing values are observed due to genetic variations in the FUT2 cholangitis and in children.33,37,84,226,227 Following the first and FUT3 genes.252–254 Persistently elevated CA 19–9 year after primary sclerosing cholangitis diagnosis, the without bacterial cholangitis strengthens a suspicion of reported annual cholangiocarcinoma incidence cholangiocarcinoma. Research on better tumour markers is 0·4–1·5%.1,33,41,85,228–230 The risk of gallbladder cancer is in serum and bile is ongoing but slow due to the rarity of approximately 0·11% per year, but increases substantially primary sclerosing cholangitis and primary sclerosing if gall bladder polyps are present.44–46 The risk of cholangitis-associated cholangiocarcinoma.255,256 hepatocellular carcinoma is low and restricted to individuals older than 50 years who have developed Surveillance for early detection of hepatobiliary cirrhosis.231,232 malignancy Cholangiocarcinoma in primary sclerosing cholangitis The prognosis of cholangiocarcinoma is poor, with a develops through a low-to-high-grade dysplasia mean survival of 6–18 months41,257–259 depending on carcinoma sequence233 and detection of biliary dysplasia tumour type, stage, and liver function.258 Early detection indicates a high risk of concurrent malignancy.234 is crucial for curative treatment with surgical resection or Malignant transformation should be suspected with liver transplantation10,48 and therefore warrants early rapid symptom progression, worsening of cholestasis, diagnosis and consequently monitoring for early cancer advancing strictures on imaging, or biliary dysplasia.235 detection. Regular surveillance with imaging (MRI, MR Special attention and diagnostic investigation should be cholangiography, or ultrasound every 6–12 months) with given to those with newly diagnosed primary sclerosing or without measurement of CA 19–9 is therefore cholangitis and high-grade strictures.10,48 Distinguishing recommended by guidelines10,48 and widely implemented, dysplasia and early cholangiocarcinoma from benign despite limited evidence.152 Evidence on optimal imaging primary sclerosing cholangitis progression is challenging modality and frequency is scarce and practices vary due to biliary inflammation, bacterial cholangitis, and globally.257 The frequency and type of imaging should be previous instrumentation procedures (eg, ERC), which individualised and guided by disease severity and cause reactive epithelial changes that are endoscopically progression. Ultrasound is commonly used for the early dicult to distinguish from dysplasia in cytology and detection of gallbladder polyps and of gallbladder cancer biopsies.236 In one study, among individuals transplanted and hepatocellular carcinoma in patients with cirrhosis. for biliary dysplasia to prevent cholangiocarcinoma, By contrast, MRI and MR cholangiography oer superior 42% of individuals with preoperative low-grade dysplasia diagnostic accuracy for identifying early cholangio- and 24% with high-grade dysplasia had neither dysplasia carcinoma lesions.239 CA 19–9 is not helpful as a and cholangiocarcinoma in the explanted liver.237 surveillance marker due to its limited sensitivity and specificity.249,251,253,254,260 Retrospective studies indicate that Diagnosis of cholangiocarcinoma in primary sclerosing surveillance improves transplant-free survival; however cholangitis their results are aected by selection bias and lead-time Multiphasic and contrast-enhanced CT or MRI are bias.59,257,261,262 A potential benefit of regular imaging is the preferred for cancer diagnostics,10,48,238 but all imaging detection of asymptomatic, treatable, benign high-grade techniques have limited sensitivity and specificity in strictures. Dilatation of these strictures with ERC could early cholangiocarcinoma in primary sclerosing lead to improved liver function. This suggestion is cholangitis.10 Perihilar cholangiocarcinoma criteria (mass supported by data from a few centres in which ERC is or periductal thickening) have a high specificity of 98% done regularly and is reported to be associated with a but low sensitivity of 58%.54,239 ERC with brush cytology favourable outcome.195,196 Regular imaging for primary diagnoses cholangiocarcinoma with a specificity of 97% sclerosing cholangitis monitoring is reasonable and but has poor sensitivity (7–43%).240 Sensitivity improves often requested by individuals with primary sclerosing with molecular diagnostics and cholangioscopy using cholangitis, even though its prognostic value and cost- targeted biopsies, although these are less eective in eectiveness still need to be established. primary sclerosing cholangitis than in non-primary sclerosing cholangitis strictures.241–247 Fluorescence in situ Inflammatory bowel disease hybridisation analysis increases sensitivity to 68% but Primary sclerosing cholangitis is associated with lowers specificity to 70%.241 Next-generation sequencing inflammatory bowel disease, of which 76% is ulcerative increases diagnostic accuracy in individuals with colitis, 17% is Crohn’s disease, and 8% is unspecified.59–61 suspicious cholangiocarcinoma without underlying A diagnosis of inflammatory bowel disease in primary primary sclerosing cholangitis, but data in primary sclerosing cholangitis requires colonoscopy with biopsies 12 www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 Seminar because endoscopic signs of inflammation might be outcomes, although most data are retrospective.145,186 In unobtrusive.263 A cross sectional study comparing colon addition, oral vancomycin therapy shows promise. inflammation in people with primary sclerosing A meta-analysis of 21 open-label studies involving cholangitis with and without inflammatory bowel disease 290 individuals, many being children, reported clinical and in people with inflammatory bowel disease alone response or remission in nearly half of the treated found that most individuals with primary sclerosing patients.271 Of note, vancomycin-resistant Enterococci cholangitis without clinically manifest inflammatory developed in 8·7% of these patients. The European bowel disease showed immune cell infiltration and Society for Paediatric Gastroenterology Hepatology and increased IL17A and IFNG expression in intestinal Nutrition recommend cautious use in children due to biopsies.264 This finding underscores the need for insucient long-term data.272 Prospective, randomised colonoscopy with biopsies to rule out inflammatory controlled trials are needed to establish optimal dosing, bowel disease and raises the question of whether primary treatment duration, ecacy, and long-term safety of sclerosing cholangitis without gut inflammation even vancomycin. Observational studies show ambiguous exists. outcomes on the relevance of colectomy,273–275 but pooled The primary sclerosing cholangitis inflammatory international data (32 236 patient-years) indicate that bowel disease phenotype appears distinct from classic proctocolectomy with permanent ileostomy is associated isolated inflammatory bowel disease. It is characterised with a reduced risk of liver transplantation or primary by overlapping signs of ulcerative colitis and Crohn’s sclerosing cholangitis-related death with a hazard ratio disease, extensive colitis, patchy inflammatory of 0·41 (95% CI 0·24–0·71) compared with no colectomy.276 distribution with dominance of inflammation in ascending colon, and an increased risk of colorectal Pregnancy dysplasia compared with colitis without primary Individuals with primary sclerosing cholangitis are often sclerosing cholangitis.22–24,59–62 The inflammation always of childbearing age, which raises questions regarding involves the colon and isolated ileal disease is pregnancy risks. In early-stage primary sclerosing rare (2–5%).23,24 Reports on backwash ileitis in primary cholangitis without advanced fibrosis, pregnancy is sclerosing cholangitis inflammatory bowel disease are generally well tolerated with favourable outcomes.277 inconsistent, likely due to diering definitions.263,265–267 Maternal primary sclerosing cholangitis has been linked Only two of five studies on rectal sparing in this disease to an increased risk of preterm birth and caesarean found significant dierences in its prevalence.28 delivery, but not with elevated risks of stillbirth, neonatal Consequently, neither feature is widely accepted as death, or congenital anomalies.278 About a third of distinct features of the inflammatory bowel disease patients report a worsening of primary sclerosing phenotype in primary sclerosing cholangitis.67 cholangitis-related symptoms during pregnancy.279 Some studies suggest that primary sclerosing cholangitis inflammatory bowel disease activity generally Quality of life and the patient voice runs a milder course compared with isolated Patient involvement and attention to quality of life in inflammatory bowel disease, but others do not.263,265,266 people with primary sclerosing cholangitis are This disparity might be because people with primary increasing.39,280,281 This attention includes the sclerosing cholangitis are often considered in clinical implementation of people-first language to reduce remission with no or few symptoms, despite ongoing stigma of disease282 (ie, people with primary sclerosing right-sided endoscopic inflammatory activity.268,269 cholangitis instead of primary sclerosing cholangitis Primary sclerosing cholangitis inflammatory bowel patients), as applied in this Seminar. Disease burden in disease also significantly increases the risk of colorectal primary sclerosing cholangitis is substantial, with a neoplasia. A meta-analysis from 2016 comprising of shortfall of quality of life and quality-adjusted life-years 16 studies reported an odds ratio of colonic dysplasia or (QALYs) as disease progresses.283 Quality of life is cancer of 3·24 (95% CI 2·14–4·90) in comparison to influenced not only by liver disease and symptoms but inflammatory bowel disease alone.270 In primary also by inflammatory bowel disease, cancer risk, and the sclerosing cholangitis-associated ulcerative colitis, fact that primary sclerosing cholangitis often aects neoplasia can occur much earlier than in ulcerative young individuals during key life stages, such as family colitis only, making annual colonoscopy for dysplasia planning and career development. surveillance from primary sclerosing cholangitis Quality of life in primary sclerosing cholangitis has diagnosis strongly recommended.10,48,55,61 been assessed using generic tools (eg, SF-36 and IBD-Q) The relationship between colonic inflammation and and pruritus scales (eg, the Numerical Rating Scale),284–286 primary sclerosing cholangitis progression constitutes an which benefit from widespread validation and regulatory important research topic.12 No convincing evidence shows acceptance. Since this generic approach leaves several that inflammatory bowel disease treatment with gaps for many primary sclerosing cholangitis-related mesalazine, azathioprine, infliximab, adalimumab, or issues, an interview-based, comprehensive quality-of-life vedolizumab improves primary sclerosing cholangitis assessment form specifically designed for people with www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 13 Seminar primary sclerosing cholangitis is currently in 6 Chapman RW, Arborgh BA, Rhodes JM, et al. Primary sclerosing development.287 Finally, targeting implementation in cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 1980; 21: 870–77. clinical trials, symptom-scoring forms for cholestasis- 7 Schrumpf E, Elgjo K, Fausa O, Gjone E, Kolmannskog F, Ritland S. related itch (the Simple Cholestatic Complaints Sclerosing cholangitis in ulcerative colitis. Scand J Gastroenterol Score288–290), abdominal pain and fatigue,287,291 and a 1980; 15: 689–97. 8 Wiesner RH, LaRusso NF. Clinicopathologic features of the patient-reported definition of bacterial cholangitis49,129 are syndrome of primary sclerosing cholangitis. Gastroenterology 1980; also in progress and are expected to become secondary or 79: 200–06. even coprimary endpoints once they are validated and 9 Bowlus CL, Lim JK, Lindor KD. AGA Clinical Practice Update on surveillance for hepatobiliary cancers in patients with primary approved by regulatory authorities. sclerosing cholangitis: expert review. Clin Gastroenterol Hepatol 2019; 17: 2416–22. Future directions 10 European Association for the Study of the Liver. EASL Clinical Despite its rarity, primary sclerosing cholangitis remains Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77: 761–806. a significant health problem through high medical costs, 11 Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary cancer-related mortality, and loss of QALYs.1,283 Key sclerosing cholangitis – a comprehensive review. J Hepatol 2017; research priorities include early diagnosis of primary 67: 1298–323. 12 Hov JR, Karlsen TH. The microbiota and the gut–liver axis in sclerosing cholangitis and cholangiocarcinoma detection, primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; identification of valid surrogate endpoints for clinical 20: 135–54. trials, and elucidation of pathophysiology to discover 13 Mehta TI, Weissman S, Fung BM, Sotiriadis J, Lindor KD, Tabibian JH. Global incidence, prevalence and features of primary potential drug targets.10 Increasing numbers of clinical sclerosing cholangitis: a systematic review and meta-analysis. trials with promising early-phase results indicate an Liver Int 2021; 41: 2418–26. imminent shift in the clinical management of primary 14 Trivedi PJ, Bowlus CL, Yimam KK, Razavi H, Estes C. Epidemiology, natural history, and outcomes of primary sclerosing sclerosing cholangitis from therapeutic nihilism and cholangitis: a systematic review of population-based studies. observational strategies towards eective interventions Clin Gastroenterol Hepatol 2022; 20: 1687–700. and proactive complication management to slow disease 15 Cooper J, Markovinovic A, Coward S, et al. Incidence and progression, reduce mortality, and minimise symptom prevalence of primary sclerosing cholangitis: a meta-analysis of population-based studies. Inflamm Bowel Dis 2024; 30: 2019–26. burden in people with primary sclerosing cholangitis.129 16 Olfatifar M, Rajabnia M, Sadeghi A, et al. The epidemiological Contributors trends and projected future of primary sclerosing cholangitis by AB and EvS drafted the initial outline of the manuscript and all authors 2040: an updated meta-analysis and modeling study. PLoS One 2025; 20: e0322479. discussed and agreed on the final outline. AB finalised the manuscript, which was approved by all authors. THK, AB, and EvS drafted all figures. 17 Lunder AK, Hov JR, Borthne A, et al. Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in All authors did the literature search, critically reviewed and edited the patients with long-term inflammatory bowel disease. manuscript, and were responsible for writing parts of the manuscript. Gastroenterology 2016; 151: 660–69. Declaration of interests 18 Tanaka A, Takikawa H. Geoepidemiology of primary sclerosing EvS has received speaker’s fees from Ipsen. THK has received cholangitis: a critical review. J Autoimmun 2013; 46: 35–40. consultancy fees from Gilead, MSD, Boehringer Ingelheim, Falk 19 Barberio B, Massimi D, Cazzagon N, Zingone F, Ford AC, Pharma, and Rectify Pharma. AT has received a research grant from the Savarino EV. Prevalence of primary sclerosing cholangitis in Ministry of Health, Labor, and Welfare of Japan; consulting fees from EA patients with inflammatory bowel disease: a systematic review and Pharma, GSK, Kowa Company, Mirum, and Ipsen; honoraria for lectures meta-analysis. Gastroenterology 2021; 161: 1865–77. and presentations from AbbVie and Gilead Sciences, support for travel 20 Xu X, Meng T, Shi L, et al. Prevalence and clinical profiles of from GSK and Kowa Company; and serves on advisory boards for GSK, primary sclerosing cholangitis in China: data from electronic medical records and systematic literature retrieval. J Autoimmun EA Pharma, Kowa Company, Mirum, and Ipsen. CP has received grants 2024; 147: 103264. from Perspectum, NGM, and Takeda and consulting fees from 21 Leung KK, Li W, Hansen B, et al. Primary sclerosing cholangitis- Chemomab. AB has received consultancy fees from Astra and Ipsen; inflammatory bowel disease: epidemiology, mortality, and impact of speaker’s fees from Ipsen; and serves on the advisory board for Ipsen. diagnostic sequence. JHEP Rep Innov Hepatol 2024; 7: 101272. Acknowledgments 22 Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique We thank Kari C Toverud for her help in developing the figures. form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54: 91–96. References 23 Boonstra K, van Erpecum KJ, van Nieuwkerk KM, et al. Primary 1 Boonstra K, Weersma RK, van Erpecum KJ, et al, and the sclerosing cholangitis is associated with a distinct phenotype of EpiPSCPBC Study Group. Population-based epidemiology, inflammatory bowel disease. Inflamm Bowel Dis 2012; 18: 2270–76. malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013; 58: 2045–55. 24 de Vries AB, Janse M, Blokzijl H, Weersma RK. 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Liver Int 2023; 43: 639–48. www.thelancet.com Published online March 20, 2026 https://doi.org/10.1016/S0140-6736(25)02582-6 21 --- [PDF原文](https://sci-net.xyz/storage/7461664/65a0b40995ad9169cfb874a749561038f70bd8d76a0decbf5dd5138bfd0bc866/Primary-sclerosing-cholangitis.pdf) DOI: 10.1016/S0140-6736(25)02582-6