Publications by authors named "Keith D Lindor"

249 Publications

A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis.

Am J Gastroenterol 2021 May 4. Epub 2021 May 4.

Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany; Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium; Arizona State University, Phoenix, Arizona, USA; Liver Unit, Hospital Cli[Combining Acute Accent]nic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain; Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy; Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Introduction: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC.

Methods: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses.

Results: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively.

Discussion: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy.
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http://dx.doi.org/10.14309/ajg.0000000000001285DOI Listing
May 2021

Safety of fibrates in cholestatic liver diseases.

Liver Int 2021 Jun 18;41(6):1335-1343. Epub 2021 Mar 18.

Division of Gastroenterology and Hepatology, University of Miami, Miami, FL, USA.

Background And Aim: Off-label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases.

Methods: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases.

Results: A total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy.

Conclusions: Fibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC.
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http://dx.doi.org/10.1111/liv.14871DOI Listing
June 2021

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

Eur J Gastroenterol Hepatol 2020 Dec 14. Epub 2020 Dec 14.

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Background: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients.

Objective: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC.

Methods: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed.

Results: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value.

Conclusion: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.
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http://dx.doi.org/10.1097/MEG.0000000000002029DOI Listing
December 2020

Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

Clin J Gastroenterol 2021 Apr 24;14(2):684-689. Epub 2020 Nov 24.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.
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http://dx.doi.org/10.1007/s12328-020-01296-0DOI Listing
April 2021

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

J Clin Gastroenterol 2021 May-Jun 01;55(5):449-457

Division of Gastroenterology and Hepatology.

Goals: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC).

Background: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood.

Materials And Methods: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation.

Results: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78).

Conclusion: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.
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http://dx.doi.org/10.1097/MCG.0000000000001433DOI Listing
June 2020

Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis.

Hepatology 2021 May 19;73(5):1868-1881. Epub 2021 Apr 19.

Department of Radiology, Mayo Clinic, Rochester, MN.

Background And Aims: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection.

Approach And Results: This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re-examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5-year outcomes including overall survival (82% vs. 46%, log-rank P < 0.01) and recurrence-free survival following liver transplant (89% vs. 65%, log-rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01-0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01-0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed.

Conclusions: MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.
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http://dx.doi.org/10.1002/hep.31575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177077PMC
May 2021

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis.

Clin Gastroenterol Hepatol 2020 Aug 7. Epub 2020 Aug 7.

Bicocca Bioinformatics Biostatistics and Bioimaging Centre - B4, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC).

Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death.

Results: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score.

Conclusions: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation.
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http://dx.doi.org/10.1016/j.cgh.2020.08.006DOI Listing
August 2020

The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience.

J Gastroenterol 2020 Nov 8;55(11):1087-1097. Epub 2020 Aug 8.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA.

Background: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known.

Methods: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC).

Results: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11).

Conclusions: In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.
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http://dx.doi.org/10.1007/s00535-020-01714-7DOI Listing
November 2020

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

Scand J Gastroenterol 2020 Aug 7;55(8):941-950. Epub 2020 Jul 7.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.

Background: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV.

Methods: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline.

Results: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total  = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events.

Conclusion: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.
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http://dx.doi.org/10.1080/00365521.2020.1787501DOI Listing
August 2020

Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.

Am J Gastroenterol 2020 07;115(7):1066-1074

Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Introduction: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined.

Methods: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated.

Results: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN.

Discussion: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
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http://dx.doi.org/10.14309/ajg.0000000000000557DOI Listing
July 2020

An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort.

J Gastroenterol 2020 May 13;55(5):523-532. Epub 2020 Jan 13.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester, MN, 55905, USA.

Background: 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 41 years.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s00535-020-01663-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157157PMC
May 2020

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis.

Gut 2020 08 16;69(8):1502-1509. Epub 2019 Dec 16.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC.

Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database.

Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively.

Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance.
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http://dx.doi.org/10.1136/gutjnl-2019-319057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398464PMC
August 2020

Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response.

Aliment Pharmacol Ther 2019 11 17;50(10):1127-1136. Epub 2019 Oct 17.

Toronto, Ontario, Canada.

Background: Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined.

Aim: To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models.

Results: There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage.

Conclusion: Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.
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http://dx.doi.org/10.1111/apt.15533DOI Listing
November 2019

Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series.

Am J Ther 2019 Aug 30. Epub 2019 Aug 30.

Arizona College of Osteopathic Medicine, Midwestern University, Downers Grove, IL.

Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD.

Areas Of Uncertainty: The etiopathogenesis of PSC remains an enigma.

Data Sources: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed.

Results: We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months.

Therapeutic Hypothesis: We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.
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http://dx.doi.org/10.1097/MJT.0000000000001065DOI Listing
August 2019

Factors Associated With Progression and Outcomes of Early Stage Primary Biliary Cholangitis.

Clin Gastroenterol Hepatol 2020 03 13;18(3):684-692.e6. Epub 2019 Aug 13.

Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, Thessaly University, Larissa, Greece.

Background & Aims: Patients usually receive a diagnosis of primary biliary cholangitis (PBC) at an early stage, based on biochemical analyses. We investigated the proportion of patients who progress to moderate or advanced PBC and factors associated with progression and patient survival.

Methods: We obtained data from 1615 patients (mean age, 55.4 y) with early stage PBC (based on their normal levels of albumin and bilirubin), collected at the time of initial evaluation or treatment, from the Global PBC Study Group database (comprising patients at 19 liver centers in North American and European countries). We collected data from health care evaluations on progression to moderate PBC (abnormal level of bilirubin or albumin) or advanced-stage PBC (abnormal level of both). The median follow-up time was 7.9 years. The composite end point was decompensation, hepatocellular carcinoma, liver transplantation, or death.

Results: Of the 1615 patients identified with early stage PBC, 904 developed moderate PBC and 201 developed advanced disease over the study period. The proportions of patients who transitioned to moderate PBC at 1, 3, and 5 years were 12.9%, 30.2%, and 45.8%. The proportions of these patients who then transitioned to advanced PBC at 1, 3, and 5 years later were 3.4%, 12.5%, and 16.0%, respectively. During the follow-up period, 236 patients had a clinical event. The proportions of patients with moderate PBC and event-free survival were 97.9%, 95.1%, and 91.5% at 1, 3, and 5 years, respectively, and the proportions of patients with advanced PBC and event-free survival were 90.6%, 71.2%, and 58.3% at 1, 3, and 5 years later, respectively. Variables associated with transition from early to moderate PBC included baseline levels of bilirubin, albumin, and alkaline phosphatase; aspartate to alanine aminotransferase ratio; platelet count; and treatment with ursodeoxycholic acid. Transitions from early to moderate PBC and from moderate to advanced PBC were associated with higher probabilities of a clinical event (time-dependent hazard ratios, 3.0; 95% CI, 2.0-4.5; and 4.6; 95% CI, 3.5-6.2).

Conclusions: Approximately half of patients with early stage PBC progress to a more severe stage within 5 years. Progression is associated with an increased risk of a clinical event, so surveillance is important for patients with early stage PBC.
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http://dx.doi.org/10.1016/j.cgh.2019.08.013DOI Listing
March 2020

AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review.

Clin Gastroenterol Hepatol 2019 11 12;17(12):2416-2422. Epub 2019 Jul 12.

Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; Arizona State University, Phoenix, Arizona.

Description: The purpose of this clinical practice update is to define key principles in the surveillance of hepatobiliary cancers including cholangiocarcinoma, gallbladder adenocarcinoma, and hepatocellular carcinoma in patients with primary sclerosing cholangitis (PSC).

Methods: The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age. BEST PRACTICE ADVICE 2: Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months BEST PRACTICE ADVICE 3: Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC. BEST PRACTICE ADVICE 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture. BEST PRACTICE ADVICE 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma. BEST PRACTICE ADVICE 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20. BEST PRACTICE ADVICE 7: The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm. BEST PRACTICE ADVICE 8: Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
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http://dx.doi.org/10.1016/j.cgh.2019.07.011DOI Listing
November 2019

Cancer risk, screening and surveillance in primary sclerosing cholangitis.

Minerva Gastroenterol Dietol 2019 Sep 19;65(3):214-228. Epub 2019 Jun 19.

Office of University Provost, Arizona State University, Phoenix, AZ, USA.

Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory condition mainly of the large bile ducts, affecting predominantly young men, and is associated with the presence of inflammatory bowel disease. There is no known cure for PSC, which progresses to cirrhosis or death over 10-20 years. Hepatobiliary malignancy, especially cholangiocarcinoma, is a feared complication associated with poor overall survival. Screening and surveillance appear to improve overall outcomes. To capture as many relevant studies, broad search criteria were employed within the PubMed database. Given the high prevalence of IBD and its own associations with the development of malignancy two separate search strategies were employed. Results were filtered by English language. The first search identified the risks, epidemiological factors and surveillance strategies for patients with PSC at risk for developing malignancy. MeSH terms included: cholangitis, sclerosing, digestive system neoplasms, liver neoplasms, biliary tract neoplasms, cholangiocarcinoma, gallbladder neoplasms, colonic neoplasms, rectal neoplasms, or pancreatic neoplasms, risk factors, risk, surveillance, epidemiology and screen. The second included inflammatory bowel diseases, Crohn's, or colitis, and assessed for additional malignancies such as lymphoma and skin neoplasms. A total of 288 results returned with 21 duplicates; 267 remaining abstracts were assessed for relevance for inclusion by the authors. Patients with PSC show significantly higher than average risk for the development of hepatobiliary and colonic malignancies including cholangiocarcinoma, gallbladder carcinoma and colorectal carcinoma. Yearly ultrasound surveillance followed with more definitive cross-sectional imaging is prudent to arrive in a timely diagnosis of carcinoma, reducing morbidity and mortality.
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http://dx.doi.org/10.23736/S1121-421X.19.02586-8DOI Listing
September 2019

Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study.

Scand J Gastroenterol 2019 May 26;54(5):633-639. Epub 2019 May 26.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA.

To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC). PSC is a chronic cholestatic liver disorder for which there is no established medical therapy. Preclinical data suggest curcumin may have a beneficial effect in PSC. Subjects with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal (ULN) received curcumin 750 mg orally twice daily for 12 weeks in an open-label pilot study. The primary composite endpoint was proportion of subjects who had a reduction of SAP to less than 1.5 times ULN or a 40% reduction in SAP between baseline and week 12. Secondary endpoints included changes in serum aspartate aminotransferase, total bilirubin, Mayo PSC risk score and self-reported health questionnaires. Two-hundred and fifty-eight patients with PSC were screened and 15 subjects were enrolled and all completed 12 weeks of therapy. The most common reason for subject exclusion was SAP less than 1.5 times the ULN ( = 98). Curcumin did not result in a significant median (interquartile range) change in SAP times the ULN [3.43 (2.10-4.32) to 2.46 (1.89-4.41),  = .36], and only 20% (3/15) subjects achieved the primary endpoint. Similarly, there was no significant change in the secondary endpoints. There were no serious adverse events reported. While curcumin was well tolerated, it was not associated with significant improvements in cholestasis or symptoms. Moreover, this study also illustrates that a low SAP is common among those with PSC. PSC: Primary sclerosing cholangitis; IBD: inflammatory bowel disease; CCA: cholangiocarcinoma; SAP: serum alkaline phosphatase; ULN: upper limit of normal; UDCA: ursodeoxycholic acid; CRP: c-reactive protein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; FIS: fatigue impact scale; AE: adverse events; PREsTo: PSC risk estimate tool; IQR: interquartile range; ELF: enhanced liver fibrosis.
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http://dx.doi.org/10.1080/00365521.2019.1611917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895452PMC
May 2019

Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis.

J Hepatol 2019 08 11;71(2):357-365. Epub 2019 Apr 11.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address:

Background & Aims: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC.

Methods: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW).

Results: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001).

Conclusion: The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC.

Lay Summary: In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.
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http://dx.doi.org/10.1016/j.jhep.2019.04.001DOI Listing
August 2019

Current and promising therapy for primary biliary cholangitis.

Expert Opin Pharmacother 2019 06 22;20(9):1161-1167. Epub 2019 Apr 22.

a Mayo Clinic , Division of Gastroenterology and Hepatology , Rochester , MN , USA.

Introduction: Primary biliary cholangitis is a chronic, cholestatic liver disease that may progress to cirrhosis with complications of end-stage liver disease. Approved treatment options include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) but novel therapies are being investigated.

Areas Covered: In this review, the authors describe the current pharmacotherapy for the treatment of primary biliary cholangitis (PBC) and for management of side effects such as pruritus and fatigue based on the currently available literature.

Expert Opinion: Patients diagnosed with PBC should be offered treatment with UDCA at 13-15 mg/kg per day if liver enzymes are elevated. If they do not meet the defined criteria of response, adjunctive therapy should be considered. This may include OCA at 5 mg per day for patients without cirrhosis or investigational therapy. Management of the most common side effects, pruritus, and fatigue, is nuanced and includes lifestyle modifications as well as pharmacological approaches. Several tools such as the Mayo Risk Score and GLOBE are available for prognostic modeling. Ultimately, patients with PBC may end up requiring liver transplantation and referral to a transplant center may also be needed.
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http://dx.doi.org/10.1080/14656566.2019.1601701DOI Listing
June 2019

Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies.

World J Gastroenterol 2019 Feb;25(6):659-671

Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.
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http://dx.doi.org/10.3748/wjg.v25.i6.659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378537PMC
February 2019

Machine Learning-based Development and Validation of a Scoring System for Screening High-Risk Esophageal Varices.

Clin Gastroenterol Hepatol 2019 08 29;17(9):1894-1901.e1. Epub 2019 Jan 29.

Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, California. Electronic address:

Background & Aims: Many patients with cirrhosis who undergo esophagogastroduodenoscopy (EGD) screening for esophageal varices (EVs) are found to have no or only small EVs. Endoscopic screening for EVs is therefore a potentially deferrable procedure that increases patient risk and healthcare cost. We developed and validated a scoring system, based on readily-available data, to reliably identify patients with EVs that need treatment.

Methods: We collected data from 238 patients with cirrhosis undergoing screening EGD from January 2016 through December 2017 at 3 separate hospitals in Los Angeles (training cohort). We abstracted data on patient sex, age, race/ethnicity, platelet counts, and levels of hemoglobin, serum sodium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, international normalized ratio, albumin, urea nitrogen, and creatinine. We also included etiology of cirrhosis, presence of ascites, and presence of hepatic encephalopathy. We used a random forest algorithm to identify factors significantly associated with the presence of EVs and varices needing treatment (VNT) and calculated area under the receiver operating characteristic curve (AUROC). We called the resulting formula the EVendo score. We tested the accuracy of EVendo in a prospective study of 109 patients undergoing screening EGDs at the same medical centers from January 2018 through December 2018 (validation cohort).

Results: We developed an algorithm that identified patients with EVs and VNT based on international normalized ratio, level of aspartate aminotransferase, platelet counts, urea nitrogen, hemoglobin, and presence of ascites. The EVendo score identified patients with EVs in the training set with an AUROC of 0.84, patients with EVs in the validation set with and AUROC of 0.82, and EVs in patients with cirrhosis Child-Turcotte-Pugh class A (n = 235) with an AUROC of 0.81. The score identified patients with VNT in the training set with an AUROC of 0.74, VNT in the validation set with and AUROC of 0.75, and VNT in patients with cirrhosis Child-Turcotte-Pugh class A with and AUROC of 0.75. An EVendo score below 3.90 would have spared 30.5% patients from EGDs, missing only 2.8% of VNT. The same cutoff would have spared 40.0% of patients with Child-Turcotte-Pugh class A cirrhosis from EGDs, missing only 1.1% of VNT.

Conclusions: We algorithmically developed a formula, called the EVendo score, that can be used to predict EVs and VNT based on readily available data in patients with cirrhosis. This score could help patients at low risk for VNT avoid unnecessary EGDs.
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http://dx.doi.org/10.1016/j.cgh.2019.01.025DOI Listing
August 2019

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

J Hepatol 2019 03 6;70(3):348-350. Epub 2019 Jan 6.

Professor of Medicine and Senior Advisor to the Provost, College of Health Solutions, Arizona State University, Phoenix, AZ, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2018.12.006DOI Listing
March 2019

Effects of Age and Sex of Response to Ursodeoxycholic Acid and Transplant-free Survival in Patients With Primary Biliary Cholangitis.

Clin Gastroenterol Hepatol 2019 09 4;17(10):2076-2084.e2. Epub 2019 Jan 4.

Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Primary biliary cholangitis (PBC) predominantly affects middle-aged women; there are few data on disease phenotypes and outcomes of PBC in men and younger patients. We investigated whether differences in sex and/or age at the start of ursodeoxycholic acid (UDCA) treatment are associated with response to therapy, based on biochemical markers, or differences in transplant-free survival.

Methods: We performed a longitudinal retrospective study of 4355 adults in the Global PBC Study cohort, collected from 17 centers across Europe and North America. Patients received a diagnosis of PBC from 1961 through 2014. We evaluated the effects of sex and age on response to UDCA treatment (based on GLOBE score) and transplant-free survival using logistic regression and Cox regression analyses, respectively.

Results: Male patients were older at the start of treatment (58.3±12.1 years vs 54.3±11.6 years for women; P<.0001) and had higher levels of bilirubin and lower circulating platelet counts (P<.0001). Younger patients (45 years or younger) had increased serum levels of transaminases than older patients (older than 45 years). Patients older than 45 years at time of treatment initiation had increased odds of a biochemical response to UDCA therapy, based on GLOBE score, compared to younger patients. The greatest odds of response to UDCA were observed in patients older than 65 years (odds ratio compared to younger patients 45 years or younger, 5.48; 95% CI, 3.92-7.67; P<.0001). Risk of liver transplant or death (compared to a general population matched for age, sex, and birth year) decreased significantly with advancing age: hazard ratio for patients 35 years or younger, 14.59 (95% CI, 9.66-22.02) vs hazard ratio for patients older than 65 years, 1.39 (95% CI, 1.23-1.57) (P<.0001). On multivariable analysis, sex was not independently associated with response or transplant-free survival.

Conclusion: In longitudinal analysis of 4355 adults in the Global PBC Study, we associated patient age, but not sex, with response to UDCA treatment and transplant-free survival. Younger age at time of treatment initiation is associated with increased risk of treatment failure, liver transplant, and death.
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http://dx.doi.org/10.1016/j.cgh.2018.12.028DOI Listing
September 2019

Antimitochondrial Antibody-Negative Primary Biliary Cholangitis: Is It Really the Same Disease?

Clin Liver Dis 2018 08;22(3):589-601

Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA; Office of the Provost, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA. Electronic address:

Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a term reserved for patients with clinical and histopathological findings consistent with PBC but without positive AMA. There does not seem to be a natural progression from AMA negativity to positivity. Antinuclear and antismooth muscle antibodies are frequently found in the absence of histologic autoimmune hepatitis features. The disease course may be more severe than AMA-positive. Response to standard therapy for PBC and autoimmune hepatitis varies. Nevertheless, there is insufficient evidence to suggest AMA-negative PBC is different enough to warrant classification as a separate disease from AMA-positive PBC.
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http://dx.doi.org/10.1016/j.cld.2018.03.009DOI Listing
August 2018

Primary sclerosing cholangitis in children versus adults: lessons for the clinic.

Expert Rev Gastroenterol Hepatol 2018 Oct 1;12(10):1025-1032. Epub 2018 Oct 1.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.

Introduction: Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder that presents with multifocal biliary strictures. PSC has a variable course but often leads to progressive liver disease, and most patients will eventually require liver transplantation. PSC has a strong association with inflammatory bowel disease and autoimmune liver disease. Areas covered: The objective of this article is to compare and contrast the clinical features and natural history of PSC in children to adults. We performed a PubMed search of the English literature using keywords 'primary sclerosing cholangitis', 'PSC', 'children', and 'pediatric.' Expert commentary: While certain features of PSC are similar in the pediatric and adult population, there are unique features of pediatric PSC. More longitudinal studies are needed to better understand the natural history of pediatric PSC. It is conceivable that treatment for PSC that will alter the course of disease may become available in the future.
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http://dx.doi.org/10.1080/17474124.2018.1521719DOI Listing
October 2018

Primary Sclerosing Cholangitis, Part 2: Cancer Risk, Prevention, and Surveillance.

Gastroenterol Hepatol (N Y) 2018 Jul;14(7):427-432

Dr Tabibian is an associate professor at the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy and resident research director in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California.

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, progressive cholangiopathy. In a clinically significant proportion of patients, the disease course of PSC is punctuated by carcinogenesis, namely cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and/or colorectal carcinoma. Indeed, malignancy is arguably the most consequential sequela and the cause of nearly 50% of deaths in patients with PSC. This statistic is multifactorial, relating partly to the premalignant nature of PSC, challenges in diagnosis due to obscuration of cancer by the inflammation and fibrosis inherent to PSC, and the unpredictability of which type of cancer will develop in PSC and when. Here, in the second of a 2-part series, we review cancer risk, prevention, and surveillance in patients with PSC. We also discuss potential cancer surveillance strategies in PSC and, where evidence is limited, make pragmatic recommendations based on current data and expert opinion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111497PMC
July 2018

Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases.

Hepatology 2019 01 6;69(1):394-419. Epub 2018 Nov 6.

University of Texas Southwestern Medical Center, Dallas, TX.

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http://dx.doi.org/10.1002/hep.30145DOI Listing
January 2019

Dominant strictures in primary sclerosing cholangitis: A multicenter survey of clinical definitions and practices.

Hepatol Commun 2018 Jul 4;2(7):836-844. Epub 2018 May 4.

Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale AZ.

Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC-associated DSs. We conducted an anonymous, 23-question, survey-based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow-up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence-based consensus, and increase adherence to societal guidelines. ( 2018;2:836-844).
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http://dx.doi.org/10.1002/hep4.1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049068PMC
July 2018

Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment.

Gastroenterol Hepatol (N Y) 2018 May;14(5):293-304

Dr Tabibian is an associate professor in the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California. Dr Ali is a research fellow in the Division of Gastroenterology and Hepatology at Mayo Clinic in Phoenix, Arizona. Dr Lindor is a professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic and senior advisor to the provost at Arizona State University in Phoenix, Arizona.

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy that can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The course of PSC is often complicated by portal hypertension, symptoms of cholestasis, and recurrent bacterial cholangitis, among other conditions, with a consequent decrease in survival (median, approximately 20 years) and quality of life. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Despite its rarity, PSC is the fifth leading indication for liver transplantation (LT) in the United States. Although the only intervention known to extend survival of patients with PSC, LT is costly and invasive, and recurrent PSC affects approximately 30% of LT recipients. Over the past several years, owing in part to progress in the understanding of PSC, novel pharmacotherapeutics have been developed, some of which are currently in the PSC clinical trial pipeline. Here, in the first of a 2-part series, we provide a review and update of the epidemiology, etiopathogenesis, clinical features, and treatment of PSC. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034608PMC
May 2018