Quantitative magnetic resonance cholangiopancreatography metrics improve prognostication in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that is surrounded by much uncertainty. First of all, it is a rare disease, with reported prevalence between 0 and 31.7 per 100,000 individuals,1Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,2Barner-Rasmussen N. Pukkala E. Jussila A. et al.Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.Scand J Gastroenterol. 2020; 55: 74-81Crossref PubMed Scopus (31) Google Scholar and establishing a diagnosis can be difficult. The primary pathology is hidden deep in the liver, and there is no specific and easy noninvasive diagnostic test for PSC. Histologic features of fibrosing cholangiopathy are present in <20% of liver biopsy specimens obtained from patients with PSC and can also be seen in cases of secondary sclerosing cholangitis. Current US and European guidelines do not recommend liver biopsy for making a diagnosis of PSC except for suspected cases of small duct PSC and pediatric cases.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar In addition, biliary tract abnormalities can be found on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiography (ERC) in a wide array of conditions (see Supplementary Table 1). Furthermore, the course of PSC can be variable. Liver transplant–free survival ranges between 14.5 and 21.3 years in large cohorts.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar An important risk factor affecting survival is the development of cholangiocarcinoma (CCA). This has a cumulative incidence of approximately 20% at 20 years after diagnosis, but one third of CCA cases become manifest within 1 year after the diagnosis of PSC.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar Last but not least, the cause of PSC is still enigmatic, and consequently, there is no therapy that has been proven to modify disease progression. In recent years, there has been an upsurge of pilot studies and phase 2 clinical trials. Phase 2 and 3 trials are hampered by the lack of established surrogate endpoints for clinical outcome, the heterogeneity of the disease course, and the lack of clear definitions for many key clinical disease characteristics.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar While the available national and international clinical practice guidelines predominantly focus on clinical management, the International PSC Study Group (IPSCSG) has recognized that there is a vital need for clinical trials to use uniform definitions for the diagnosis of PSC and for assessing disease severity and outcomes.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar,8Chapman M.H. Thorburn D. Hirschfield G.M. et al.British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut. 2019; 68: 1356-1378Crossref PubMed Scopus (135) Google Scholar Therefore, the IPSCSG has commissioned a consensus process among its experts to issue a set of definitions to aid clinical trialists designing much needed clinical trials. To this end, an extensive consensus process was initiated, applying a hybrid between a Delphi process and a nominal group process, as was previously used by the IPSCSG and the European Crohn's and Colitis Organization.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar,9Dignass A. Eliakim R. Magro F. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.J Crohns Colitis. 2012; 6: 965-990Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar Where necessary, an additional survey was conducted among all IPSCSG members (see the Supplementary Methods for details). Results are presented as a comprehensive set of consensus statements (CSs) and diagnostic criteria for PSC. Although patients with PSC are increasingly diagnosed at earlier stages of disease based on asymptomatic serum liver enzyme abnormalities, at least 45% of patients PSC present with symptoms on either a constant or intermittent basis, which significantly reduces quality of life.10Broome U. Olsson R. Lööf L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Google Scholar Furthermore, more than 22% of asymptomatic patients may develop symptoms within 5 years. The most common clinical symptoms associated with PSC are fatigue; pruritus; right upper quadrant (RUQ) abdominal pain; and emotional distress, which may include anxiety and depression symptoms. Pruritus and abdominal pain can fluctuate dramatically, and this may be suddenly worsened because of the development of a biliary obstruction or acute bacterial cholangitis. Therefore, clinical evaluation with laboratory testing and imaging may be necessary in the event of the sudden appearance or worsening of symptoms. Emotional distress for many patients is attributable to chronic anxiety about the uncertain etiology of the disease, the lack of effective therapy, and the risk of malignancy, among others.11Ranieri V. Kennedy E. Walmsley M. et al.The Primary Sclerosing Cholangitis (PSC) Wellbeing study: understanding psychological distress in those living with PSC and those who support them.PLoS One. 2020; 15e0234624Crossref PubMed Scopus (10) Google Scholar The incorporation of clearly defined patient-reported symptoms into the design of clinical trials is both desirable from a patient-centered perspective and highly encouraged by regulatory agencies12Ponsioen C.Y. Lindor K.D. Mehta R. et al.Design and endpoints for clinical trials in primary sclerosing cholangitis.Hepatology. 2018; 68: 1174-1188Crossref PubMed Scopus (43) Google Scholar (Box 1, CS 1.1). Recently, 2 such tools have emerged. One patient-reported outcome (PRO) dedicated to PSC showed excellent reliability and was able to discern patients with cirrhosis and those with a history of depression.13Younossi Z.M. Afendy A. Stepanova M. et al.Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: the PSC PRO.Hepatology. 2018; 68: 155-165Crossref PubMed Scopus (21) Google Scholar A more recently developed tool to assess patient-reported symptoms, the Simple Cholestatic Complaints Score, was developed through digital surveys of patients and showed good criterion and construct validity and a very high test-retest reproducibility.14Munster K.N. Dijkgraaf M.G.W. Gennep S. et al.The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis.Liver Int. 2020; 40: 2758-2766Crossref PubMed Scopus (0) Google Scholar Further validation of these tools in larger and more diverse cohorts is needed.Box 1Consensus StatementsTabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab Tabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab A particular challenge in assessing clinical symptoms in patients with PSC is the frequent concurrence of inflammatory bowel disease (IBD), which itself can influence the clinical course of PSC and may also account for a significant proportion of symptoms, especially during periods of IBD exacerbations.15Cheung A.C. Patel H. Meza-Cardona J. et al.Factors that influence health-related quality of life in patients with primary sclerosing cholangitis.Dig Dis Sci. 2016; 61: 1692-1699Crossref PubMed Scopus (1) Google Scholar Existing tools, including the PSC PRO, do not specifically account for symptoms attributable to IBD. Although the Simple Cholestatic Complaints Score did not show a difference in PSC patient symptoms according to the presence or absence of IBD, a systematic evaluation of IBD symptoms in patients with PSC has not been performed, which can result in confounding findings. Therefore, assessment of PSC symptoms should be performed alongside specifically designed tools to detect symptoms from IBD in those with PSC-IBD or other relevant coexistent conditions (Box 1, CS 1.2) This is critically important for clinical trials that aim to use PRO measures as endpoints in PSC. Cholestatic serum liver tests are a characteristic, but nonspecific, feature of biliary disease irrespective of the nature of biliary involvement. Alkaline phosphatase (ALP) as the hallmark of cholestasis is elevated in the vast majority of patients with PSC.16Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.Hepatology. 2015; 61: 2080-2090Crossref PubMed Scopus (75) Google Scholar Previously, it was thought that to make a diagnosis of PSC, elevation of ALP, or gamma-glutamyl transpeptidase (gGT) in children (see the "Pediatric Primary Sclerosing Cholangitis" section) was a prerequisite. Recent studies have shown that elevated cholestatic serum parameters need not always be present. For more background, see the Supplementary Material. Aminotransferases are often moderately elevated, whereas at diagnosis, serum bilirubin and albumin levels are usually normal.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar Aminotransferase activity of more than 5 times the upper limit of normal (ULN) and a serum IgG of >2 × ULN should raise the suspicion of coexisting autoimmune hepatitis (AIH) and should trigger consideration of liver biopsy to identify histologic features that would support a diagnosis of AIH or PSC/AIH overlap, also called variant syndrome (Box 1, CS 2.1). This has management consequences, because patients with PSC/AIH commonly respond favorably to immunosuppressive medication such as corticoids and thiopurines, although not as well as patients with isolated AIH.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In contrast to primary biliary cholangitis (PBC) and AIH, there is no pattern of autoantibody reactivity in patients with PSC of relevance to diagnosis or treatment. Positive titers of autoantibodies are common in PSC, including antinuclear antibody (8%–77%), smooth muscle antibody (0%–83%), and atypical perinuclear antibody (26%–94%).18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar,19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar However, these are also frequently present in AIH, and perinuclear antineutrophil cytoplasmic antibodies can be found in ulcerative colitis (UC) in 41%–73% and in Crohn's disease in 6%–38%.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar, 19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar Serum IgG4 levels can be elevated in patients with PSC, but this has no validated bearing on diagnosis or disease severity (Box 1, CS 2.2). For distinction from IgG4-sclerosing cholangitis, see the Supplementary Material. Biliary imaging is integral to the diagnosis and classification of PSC. MRCP has been established as the noninvasive imaging of choice.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar Regarding the utility of magnetic resonance imaging (MRI) in PSC, the reader is referred to a recent publication from the IPSCSG Working Group on MRI in PSC.20Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus Google Scholar A of features are described in large duct PSC, including or within the and/or biliary of the intrahepatic ducts with of the biliary of the and changes not of PSC, and from causes of secondary sclerosing cholangitis in the absence of can be difficult. in the bile ducts on cholangiography are thought to be highly specific for PSC. in the common and common bile the are usually seen in disease and are reported in of cases in a large of C.Y. et al.Natural history of primary sclerosing cholangitis and prognostic of cholangiography in a 51: PubMed Scopus (0) Google Scholar small duct PSC cholangiography is normal is an in PSC. recent have reported on the history of small cohorts of small duct PSC patients to large duct PSC was described in and after a of years of in K. Eaton et resonance imaging features of primary sclerosing 2020; PubMed Scopus Google K.I. Bergquist A. H. et features and MRI progression of small duct primary sclerosing cholangitis J 2020; Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Box 1, CS was no with MRI findings and progression to large duct PSC in either in the bile ducts are a common and clinically relevant of the chronic inflammatory process that in the biliary in PSC. a of large duct PSC patients with the incidence of the development of can be to to approximately in patients with large duct A. P. et al.Development of bile duct in patients with primary sclerosing cholangitis with outcome after endoscopic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar extensive in the Supplementary the a of criteria that into the definition of a as in of is called a when it the criteria before MRCP or with of in or first-order intrahepatic not and worsening of cholestatic symptoms within 2 biliary or and/or of × ULN and recent for × P. et of in primary sclerosing cholangitis: outcome after Full Text Full Text PDF PubMed Scopus Google and/or within for × or of >2 × ULN no within is

Qualitative magnetic resonance cholangiopancreatography (MRCP) scoring models in primary sclerosing cholangitis (PSC) are hampered by interobserver variability and evidence for quantitative MRCP has so far been limited by cohort sizes, follow-up time and lack of validation. This study aimed to validate the prognostic value of quantitative MRCP metrics in PSC in a large multicentre cohort. Retrospective, cross-sectional, clinical and quantified MRCP data by MRCP+ were collected from a non-transplant and transplant centre and randomised (1:1 ratio) into a derivation and validation set. Transplant-free survival, a composite of liver transplantation and PSC-related mortality (excluding colorectal carcinoma), was the primary endpoint. Least absolute shrinkage and selection operator analysis with manual guidance was used to compose a risk classifier. Prognostic performance and risk stratification were expressed by C-statistic and hazard ratios (HRs), and were validated in the validation set. A total of 224 patients were included with a median 6.8 years (Q1,Q3: 4.5, 9.8) of follow-up from MRCP onwards. Analysis identified number of strictures, proportion of 3-5 mm diameter ducts, years from diagnosis to MRCP and centre type as prognostic. The derived risk classifier showed a C-statistic of 0.72 (95% confidence interval [CI]: 0.60-0.81) and stratified effectively, with high-risk patients having threefold higher HR than low-risk patients (HR, 3.2; 95% CI: 1.6-6.4; P = 0.001) in the validation set. This study confirms the prognostic value of quantitative MRCP (number of strictures and proportion of 3-5 mm diameter ducts) on long-term transplant-free survival in PSC and warrants further study on incorporating quantitative MRCP metrics into existing prognostic risk models.

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Diagnosis and Management of Primary Sclerosing Cholangitis

Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. Individuals with PSC were prospectively scanned using non-contrast MRCP. Quantitative metrics were calculated using MRCP+ post-processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371-day follow-up (range: 364-462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non-PSC liver disease. Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist-derived cholangiographic assessment (trial registration: ISRCTN39463479).

NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A nebulous matter

A quantitative MRCP-derived score for medium-term outcome prediction in primary sclerosing cholangitis.

Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI‐MRCP) in primary sclerosing cholangitis (PSC) is currently based on qualitative assessment and has high interobserver variability. We investigated the utility and performance of quantitative metrics derived from a three‐dimensional biliary analysis tool in adult patients with PSC. MRI‐MRCP, blood‐based biomarkers, and FibroScan were prospectively performed in 80 participants with large‐duct PSC and 20 healthy participants. Quantitative analysis was performed using MRCP+ (Perspectum Ltd., United Kingdom), and qualitative reads were performed by radiologists. Inter‐reader agreements were compared. Patients were classified into high risk or low risk for disease progression, using Mayo risk score (MRS), Amsterdam‐Oxford model (AOM), upper limit of normal (ULN) alkaline phosphatase (ALP), disease distribution, and presence of dominant stricture. Performance of noninvasive tools was assessed using binomial logistic regressions and receiver operating characteristic curve analyses. Quantitative biliary metrics performed well to distinguish abnormal from normal bile ducts (P < 0.0001). Interobserver agreements for MRCP+ dilatation metrics (intraclass correlation coefficient, 0.90‐0.96) were superior to modified Amsterdam intrahepatic stricture severity score (κ = 0.74) and Anali score (κ = 0.38). MRCP+ intrahepatic dilatation severity showed excellent performance to classify patients into high‐risk and low‐risk groups, using predictors of disease severity as the reference (MRS, P < 0.0001; AOM, P = 0.0017; 2.2 × ULN ALP, P = 0.0007; 1.5 × ULN ALP, P = 0.0225; extrahepatic disease, P = 0.0331; dominant stricture, P = 0.0019). MRCP+ intrahepatic dilatation severity was an independent predictor of MRS >0 (odds ratio, 31.3; P = 0.035) in the multivariate analysis. Conclusion: Intrahepatic biliary dilatation severity calculated using MRCP+ is elevated in patients with high‐risk PSC and may be used as an adjunct for risk stratification in PSC. This exploratory study has provided the groundwork for examining the utility of novel quantitative biliary metrics in multicenter studies.

Primary Sclerosing Cholangitis (PSC) is a rare, progressive liver disease characterized by bile duct inflammation and fibrosis, often diagnosed using Magnetic Resonance Cholangiopancreatography (MRCP). The complexity of MRCP interpretation necessitates advanced tools like deep learning (DL) and machine learning (ML) to enhance diagnostic accuracy and prognostic prediction. This systematic review evaluates the application of DL and ML in MRCP-based PSC diagnosis and management. To synthesize evidence on the feasibility, accuracy, and clinical utility of DL and ML in MRCP for PSC, focusing on diagnostic performance, disease progression prediction, and clinical decision-making support. A systematic review was conducted following PRISMA guidelines, searching PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to June 2025. Studies applying DL or ML to MRCP for PSC diagnosis or management were included, with outcomes focusing on diagnostic accuracy (sensitivity, specificity, AUC) and predictive performance. Quality was assessed using the QUADAS-2 tool, and data were synthesized narratively due to heterogeneity. A total of Six studies (n = 1840 patients) were included, utilizing convolutional neural networks (CNNs), MRCP + software, and algebraic topology-based ML. Diagnostic accuracy was high, with sensitivities of 80.0 %–95.0 % and specificities of 80.0 %–90.9 % for PSC detection, often outperforming radiologists. Prognostic models achieved AUROCs of 0.80–0.86 for predicting hepatobiliary complications, liver transplantation, or hepatic decompensation, surpassing traditional scores (e.g., Anali, Mayo). Clinical utility included early PSC and cholangiocarcinoma detection and risk stratification. Limitations included retrospective designs, small sample sizes, and lack of external validation. DL and ML applied to MRCP show promise in enhancing PSC diagnosis and prognosis, with high accuracy and potential to reduce interobserver variability. However, methodological limitations and validation challenges necessitate prospective, multicenter studies to ensure generalizability and clinical adoption.

Background: Identifying high-grade strictures (HGS) in patients with primary sclerosing cholangitis (PSC) relies upon subjective assessments of magnetic resonance cholangiopancreatography (MRCP). Quantitative MRCP (MRCP+) provides objective evaluation of MRCP examinations, which may help make these assessments more consistent and improve patient management and selection for intervention. We evaluated the impact of MRCP+ on clinicians’ confidence in diagnosing HGS in patients with PSC. Methods: Three expert abdominal radiologists independently assessed 28 patients with PSC. Radiological reads of MRCPs were performed twice, in a random order, three weeks apart, then a third time with MRCP+. HGS presence was recorded on semi-quantitative confidence scales. The cases where readers definitively agreed on presence/absence of HGS were used to assess inter- and intra-reader agreement and confidence. Results: When using MRCP alone, high intra-reader agreement was observed in identifying HGS within both intra- and extrahepatic ducts (64.3% and 70.8%, respectively), while inter-reader agreement was significantly lower for intrahepatic ducts (42.9%) than extrahepatic ducts (66.1%) (p &lt; 0.01). Using MRCP+ in the third read significantly improved inter-reader agreement for intrahepatic HGS detection to 67.9% versus baseline reads (p = 0.02) and was comparable with extrahepatic ducts. Reader confidence tended to increase when supplemented with MRCP+, and inter-reader variability decreased. MRCP+ metrics had good performance in identifying HGS in both extra-hepatic (AUC:0.85) and intra-hepatic ducts (AUC:0.75). Conclusions: MRCP evaluation supported by quantitative metrics tended to increase individual reader confidence and reduce inter-reader variability for detecting HGS. Our results indicate that MRCP+ might help standardize MRCP assessment and subsequent management for patients with PSC.

Contemporary primary sclerosing cholangitis (PSC) population-based cohorts describing the epidemiology, natural history, and long-term fluctuations in serum alkaline phosphatase (SAP) and their prognostic relevance are lacking. Therefore, we investigated the incidence and natural history of PSC and quantified SAP fluctuations among those with PSC in Olmsted County, Minnesota over the last 41years. The Rochester Epidemiology Project was used to identify 56 subjects diagnosed with PSC between 1976 and 2017 in Olmsted County. The primary endpoint (n = 19) included liver transplantation, hepatic decompensation, and cholangiocarcinoma. The age- and sex-adjusted incidence of PSC (per 100,000 person years) nearly doubled from 2001 to 2017 compared to 1976-2000 (1.47; 95% CI 0.99-1.96 versus 0.79; 95% CI 0.42-1.16, p = 0.02). This increase paralleled a rise in patients with markers of a milder phenotype at the time of diagnosis: normal SAP (26.32% versus 0%, p < 0.01) and lower Mayo PSC risk score [0.36 (-0.57 to 1.55) versus -0.50 (-1.25 to 0.35), p = 0.03]. Intra-individual SAP fluctuates with a median coefficient of variation of 36.20%. SAP normalization and dropping below 1.5 × upper limit of normal (ULN) occurs at a rate of 5% and 10% per year, respectively. SAP less than 1.5 × ULN was associated with a lower risk of PSC-related complications (hazard ratio 0.11; 95% CI 0.03-0.42). The patients with PSC are increasingly being diagnosed with a milder phenotype. While a lower SAP is associated with improved outcomes, the high intra-individual variation of SAP levels calls into question the practice of using a single SAP value as a surrogate endpoint in clinical trials.

Quantitative magnetic resonance cholangiopancreatography metrics are associated with disease severity and outcomes in people with primary sclerosing cholangitis

Magnetic resonance cholangiopancreatography (MRCP) is used in the diagnosis and management of primary sclerosing cholangitis (PSC). However, MRCP is subjective, and guidelines state that there is insufficient evidence to recommend MRCP as a prognostic tool. EASL-PSC guidelines have identified quantitative MRCP (MRCP+) as having promising utility for risk assessment and prediction of clinical outcomes. We conducted a systematic review to determine the clinical utility of MRCP+ metrics for the management of patients with PSC. We systematically searched PubMed and MEDLINE for cohort studies reporting on MRCP+ metrics associated with risk prediction, clinical outcomes, and disease progression published between January 2019 and May 2024. Studies reporting on adults with diagnosed PSC with paired MRCP were selected. There were no limitations on the type of study (retrospective/prospective). Studies reporting on only qualitative assessment of MRCP were excluded. Six manuscripts with 512 subjects met the study criteria. For risk prediction and disease progression, 4 articles reported 21 unique MRCP+ metrics, which were significantly associated with the Amsterdam-Oxford model and the MAYO risk score. MRCP+ metrics had AUC ranging 0.65 to 0.87 and hazard ratios ranging 0.96 to 17.79 for the prediction of adverse outcomes, including liver transplantation, death, hepatic decompensation, biliary complications, and cholangiocarcinoma. Associations between biochemical markers of liver function (alkaline phosphatase, bilirubin, aspartate aminotransferase, gamma glutamyl transferase, and albumin) ranged -0.42≤ R ≤0.48. MRCP+ metrics have clinical utility to support patient management alongside addressing key gaps, including standardising MRCP assessment, early detection of disease, and quantification of risk.

EASL Clinical Practice Guidelines: Management of cholestatic liver diseases

Magnetic resonance cholangiopancreatography (MRCP) is a less-invasive alternative to endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis of primary sclerosing cholangitis (PSC). This study evaluated the diagnostic accuracy of MRCP in PSC compared with ERCP, and assessed the diagnostic accuracy of different T2w sequences. 95 patients (69 PSC, 26 controls) were evaluated using both ERCP and MRCP. Exclusion criteria included secondary sclerosing cholangitis and contraindications to MRCP. The diagnosis of PSC was confirmed in 69 patients based on ERCP as the reference gold standard. MRCP was performed using a 1.5 Tesla MR unit, using breath hold, coronal and transverse half-Fourier acquisition single-shot turbo spin-echo (HASTE), coronal-oblique, fat-suppressed half-Fourier rapid acquisition with relaxation enhancement (RARE), and coronal-oblique, fat-suppressed, multisection, thin-section HASTE (TS-HASTE) sequences. The MRCP morphological criteria of PSC were evaluated and compared with ERCP. The sensitivity, specificity, and diagnostic accuracy were 86%, 77%, and 83%, respectively, using the MRCP-RARE sequence, and increased further to 93%, 77%, and 88%, respectively, by the inclusion of follow-up MRCP in 52 patients, performed at 6-12-month intervals. HASTE and TS-HASTE sequences showed significantly lower diagnostic accuracy but provided additional morphologic information. MRCP can diagnose PSC but has difficulties in early PSC and in cirrhosis, and in the differentiation of cholangiocarcinoma, Caroli's disease, and secondary sclerosing cholangitis. A positive MRCP would negate some diagnostic ERCP studies but a negative MRCP would not obviate the need for ERCP.