African American race does not confer an increased risk of clinical events in patients with primary sclerosing cholangitis.

BACKGROUND: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. METHODS: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. RESULTS: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. CONCLUSIONS: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

Sarcopenic visceral obesity is associated with increased post-liver transplant mortality in acutely ill patients with cirrhosis.

"Sarcopenic obesity" refers to a condition of low muscle mass in the context of obesity, though may be difficult to assess in patients with cirrhosis who are acutely ill. We aimed to define sarcopenic visceral obesity (SVO) using CT-based skeletal muscle index (SMI) and visceral-to-subcutaneous adipose tissue ratio (VSR) to examine its association with post-transplant mortality. We analyzed 116 adult inpatients with cirrhosis who were urgently listed and transplanted between 1/2005 and 12/2017 at 4 North American transplant centers. SVO was defined as patients with sarcopenia (SMI <50 cm2 /m2 in men and <39 cm2 /m2 in women) and visceral obesity (VSR ≥ 1.54 in men and ≥1.37 in women). The percentage who met criteria for sarcopenia, visceral obesity, and SVO were 45%, 42%, and 20%, respectively. Cumulative rates of post-transplant mortality were higher in patients with SVO compared to patients with sarcopenia or visceral obesity alone at 36 months (39% vs. 14% vs. 8%) [logrank p = .01]. In univariable regression, SVO was associated with post-transplant mortality (HR 2.92, 95%CI 1.04-8.23) and remained significant after adjusting for age, sex, diabetes, encephalopathy, hepatocellular carcinoma, and MELD-Na (HR 3.50, 95%CI 1.10-11.15). In conclusion, SVO is associated with increased post-transplant mortality in acutely ill patients with cirrhosis.

Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score.

BACKGROUND AND AIMS: The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). APPROACH AND RESULTS: Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87. CONCLUSIONS: After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

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.

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.

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

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.

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis.

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.

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

Goals: To assess if curcumin improves markers of cholestasis among subjects with primary sclerosing cholangitis (PSC). Background: 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. Study: 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. Results: 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 (n = 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), p = .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. Conclusion: 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. Abbreviations 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.

Poor performance of psoas muscle index for identification of patients with higher waitlist mortality risk in cirrhosis.

BACKGROUND: Sarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality. METHODS: We evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3 months of listing, we determined SMI and PMI expressed by cm2 /m2 . Low SMI was defined as SMI <39 cm2 /m2 in women and <50 cm2 /m2 in men as published by us earlier. Cut-offs for PMI to predict mortality were established using a receiver-operating characteristic analysis. Mortality predictors were determined using competing-risk analysis with reported results as subdistribution hazard ratios (sHRs). RESULTS: Of 353 waitlist candidates, 68% were men, mean age 56 ± 9 years, and Model for End-stage Liver Disease of 16 ± 8 points. Low SMI was present more frequently in men than women (51 vs. 36%, P = 0.02). Moderately strong correlation between SMI and PMI was observed (r > 0.7, P < 0.001). Low PMI (males < 5.1 cm2 /m2 ; females < 4.3 cm2 /m2 ) yielded poor and moderate concordance with low SMI in men and women, respectively (Kappa coefficient 0.31 and 0.63). SMI (39 ± 9 vs. 43 ± 7 cm2 /m2 ; P = 0.009) and PMI (4.4 ± 1.3 vs. 5.2 ± 1.1 cm2 /m2 ; P = 0.001) were lower in women who died and/or were delisted (compared with non-deceased patients) whereas men who died and/or were delisted had only lower SMI (47 ± 7 vs. 51 ± 9 cm2 /m2 ; P = 0.003), but not PMI compared with non-deceased patients. In women, both SMI (sHR 0.94, P = 0.048) and PMI (sHR 0.58, P = 0.002) were predictors of mortality, while in men, SMI was significant (sHR 0.95, P = 0.001) and PMI showed a trend to be (sHR 0.85, P = 0.09) associated with mortality. Overall, 104 patients (29%) were misclassified between SMI and PMI categories. Using PMI cut-offs, 66% and 28% of low SMI men and women, who have a higher risk of mortality, were incorrectly classified as low risk. CONCLUSIONS: Skeletal muscle index is a more complete and robust measurement than PMI, especially in men with cirrhosis. Low PMI identifies an incomplete subset of patients at increased risk of mortality indicated by low SMI. Given the poor performance of PMI, SMI should not be substituted by PMI.

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

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.

Current Status of Liver Transplantation for Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease diagnosed with elevated alkaline phosphatase in the presence of antimitochondrial antibody. With the introduction and widespread use of ursodeoxycholic acid the proportion of PBC patients undergoing liver transplant (LT) has decreased. However, up to 40% of patients are ursodeoxycholic acid nonresponders and require second-line treatment or progress to end-stage liver disease requiring LT. Several scoring systems have been developed and validated to assess treatment response and transplant-free survival in patients. Although PBC is a favorable indication for LT, recurrence of PBC may occur and requires biopsy for diagnosis.

Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow-up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19-9, and alpha-fetoprotein). The primary endpoints were HBCa recurrence, HBCa-related death, and all-cause mortality. Overall survival was assessed by the Kaplan-Meier survival method; HBCa-related survival was assessed using competing risk regression. Tests of significance were two-tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow-up was 712 and 283 person-years pre- and post-HBCa diagnosis, respectively. Seventy-eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty-one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5-year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5-year probability of experiencing an HBCa-related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no-surveillance group. CONCLUSION: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351).

Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications.

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.

Emerging treatments for primary sclerosing cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease that can progress to end-stage liver disease, cirrhosis and cholangiocarcinoma. PSC is an uncommon and highly heterogeneous disease, associated with inflammatory bowel disease and a complex pathophysiology. To date, no medical therapies have proved effective. The only available treatment for end-stage PSC is liver transplant, but recurrence is a significant complication. Areas covered: This review will explore previously tested treatments, discuss current treatment strategies and present viewpoints about future emerging therapies in PSC. We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: The development of new therapies in PSC has been challenging. However, with greater awareness of the disease nowadays, new insights into the disease may help in the design of future therapeutic agents in PSC and ultimately in effective therapies.

The Microbiome and Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC.

Pseudocirrhosis: A Case Series and Literature Review.

Pseudocirrhosis describes morphological changes of the liver that closely mimic cirrhosis, without the typical histopathological changes seen in cirrhosis. It most commonly occurs in patients with metastatic breast cancer, although it has been reported in other malignancies as well. Like in cirrhosis, portal hypertension is often seen in patients with pseudocirrhosis. Pseudocirrhosis is a rare but important complication of metastatic cancer. In this case series and literature review, we describe 6 patients with hormone-receptor-positive metastatic breast cancer. We report the significant morbidity associated with pseudocirrhosis in the course of treatment in patients with metastatic breast cancer.

Gastric lap-band infection due to Mycobacterium abscessus presenting as new-onset ascites in a cirrhotic patient.

Nontuberculous mycobacteria are ubiquitous environmental organisms that are infrequently implicated as pathogens. Peritoneal infection with nontuberculous mycobacteria is rare and published reports are most commonly associated with peritoneal dialysis. This study describes a case of a 41-year-old woman with cirrhosis who had Mycobacterium abscessus peritonitis and an abdominal abscess resulting from infection of a remotely placed gastric band (Lap-Band; Apollo Endosurgery, Inc).

Emerging drugs for the treatment of Primary Biliary Cholangitis.

INTRODUCTION: Primary biliary cholangitis (PBC) is an autoimmune chronic disease of the liver that can progress to cirrhosis and hepatocellular carcinoma. It affects approximately 1 in 4,000 with a 10:1 female to male ratio. The diagnosis of PBC can be made based on serum antimitochondrial antibodies (AMA) in a patient with abnormally high serum alkaline phosphatase after ruling out other causes of cholestasis and biliary obstruction. Genome-wide association studies have revealed several human leukocyte antigen (HLA) and non-HLA risk loci in PBC, and complex environmental-host immunogenetic interactions are believed to underlie the etiopathogenesis of the disease. Fatigue and pruritus are the most common and often problematic symptoms; although often mild, these can be severe and life-alternating in a subset of patients. Ursodeoxycholic acid (UDCA) is the only drug approved by the United States Food and Drug Administration for the treatment of PBC. Clinical trials have shown that UDCA significantly improves transplant-free survival. However, nearly 40% of PBC patients do not respond adequately to PBC and are at higher risk for serious complications when compared to PBC patients with complete response to UDCA. AREAS COVERED: Here we provide a detailed discussion regarding novel therapeutic agents and potential areas for further investigation in PBC-related research. EXPERT OPINION: Results of ongoing clinical trials and emerging treatment paradigms for PBC will likely further improve medical management of this disorder in the near future.

Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

UNLABELLED:  Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. MATERIAL AND METHODS: This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. RESULTS: Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. CONCLUSIONS: Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Advances in primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic, progressive cholangiopathy that frequently affects men and is associated with inflammatory bowel disease. Although the cause of the disease is still debated, a genetic association and link to immune-mediated disease triggered by environmental factors are thought to contribute. The disease can present as isolated imaging abnormalities, biochemical changes, cholangiocarcinoma, or end-stage complications such as cirrhosis. Symptoms of primary sclerosing cholangitis include fatigue, jaundice, pruritus, or steatorrhoea. Differentiation of primary sclerosing cholangitis can be challenging because other chronic cholangiopathies can present similarly; however, the distinction is necessary to optimise disease surveillance. Management involves assessment for comorbid inflammatory bowel disease and exclusion of other associated cholangiopathic disorders. Patients with primary sclerosing cholangitis have a poor prognosis; progression to liver cirrhosis is common, and an increased risk of hepatobiliary and colorectal cancers is present in those with inflammatory bowel disease. Although much research involves locating an active therapy that can alter the disease course, the only available treatment is liver transplantation, and risk for disease recurrence remains. Use of ursodeoxycholic acid can improve alkaline phosphatase and bilirubin concentrations but does not alter the disease course. In this Review, we summarise aetiological theories, provide an update on hepatobiliary malignancies that require surveillance, and discuss exciting areas of investigation for potential treatment.