Large Duct Primary Sclerosing Cholangitis Research Articles

Primary Sclerosing Cholangitis Limited to Intrahepatic Bile Ducts Has Distinctly Better Prognosis.

There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic). This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC. Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement. Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC. Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

DOP28 Yield of surveillance colonoscopy in patients with Primary Sclerosing Cholangitis

Abstract Background Patients with primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC), in particular in patients with concurrent diagnosis of inflammatory bowel disease (IBD). Therefore, strict surveillance colonoscopy in patients with PSC and PSC-IBD is recommended with consideration of random biopsies. The aim of this study was to assess the method and yield of surveillance colonoscopy in patients with PSC and PSC-IBD in routine practice in the Netherlands. Methods An observational cohort study was performed within the EpiPSC2 cohort in The Netherlands. Patients with a confirmed PSC diagnosis were included from January 2008 onwards. Data were collected retrospectively from the date of diagnosis until inclusion, and prospectively from that date forward. Patient demographics, PSC and IBD disease characteristics were collected at study inclusion and during annual follow-up. For this study, data collection was expanded retrospectively with colonoscopy and pathology reports. Outcomes were endoscopic surveillance technique, whether random or targeted biopsies were taken, if polypectomy was performed, dysplasia detection rate and type of dysplasia. Results The study population included 1,203 PSC patients, of whom 82.1% had large duct PSC, and 70.6% concomitant IBD (table 1). A total of 4,099 colonoscopies were performed in 759 individual patients, with a median of 4 colonoscopies per patient (IQR 2 – 8). The median follow-up duration was 11 years (IQR 12 – 17). In total, 11.5% (n=473) of colonoscopies were performed with chromo-endoscopy. Among the conducted colonoscopies, 2,543 included biopsies, 355 involved polypectomies, and 86 comprised both biopsies and polypectomies. Dysplasia was identified in 11.4% (341 out of 2,984) of the colonoscopies, including 14.1% indefinite for dysplasia (n=48), 75.1% low grade dysplasia (n=256), 7.6% high grade dysplasia (n=26), and 5.9% adenocarcinoma (n=20). The detection of dysplasia occurred through random biopsies in 89 colonoscopies (26.1%), targeted biopsies in 114 colonoscopies (33.4%) and polypectomy in 153 colonoscopies (44.9%) (figure 1). Dysplasia was observed in 195 (26%) individual patients, of whom 80.5% had PSC-IBD. Conclusion Our data highlights the importance of colonoscopic surveillance in PSC and PSC-IBD patients. Dysplasia was detected in over a quarter of patients undergoing surveillance colonoscopy. Notably, 26.1% of dysplasia cases were identified through random biopsies, emphasizing the importance of incorporating random biopsies into surveillance protocols for this specific patient population.

DOP14 Proctocolectomy is associated with improved transplant-free survival in patients with primary sclerosing cholangitis: results from a pooled collaborative international study

Abstract Background It is hypothesized that the gut-liver axis plays a pivotal role in the aetiology of primary sclerosing cholangitis (PSC). Colectomy before liver transplantation is associated with decreased rates of recurrent PSC.1 We previously observed that proctocolectomy with permanent ileostomy is associated with better transplant-free survival in a population-based Dutch cohort.2 The aim of the present study is to confirm the effect of colectomy on PSC disease course in an international context. Methods We conducted a retrospective analysis on the International PSC Registry (IPSCR), comprising patients from Finland, Norway, Sweden, and the Netherlands. Endpoints were defined as liver transplantation (LT) and PSC-related death (excluding colorectal carcinoma) and were censored in the first year after colectomy to allow for a delayed protective effect. Cox proportional hazards regression was performed, with correction for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, and inflammatory bowel disease (IBD) status (i.e. ulcerative colitis, Crohn’s disease or IBD unspecified). IBD status and colectomy status were included as time-dependent exposure variables, the latter stratified for extent and indication for colectomy. Results A total of 2595 patients were included, of which 1341 from the Netherlands, 560 from Finland, 528 from Norway, and 166 from Sweden. Of all patients 1900(73%) were diagnosed with IBD and 346(15%) had undergone a colectomy; 34(9%) hemi-, 91(26%) subtotal, and 172(50%) proctocolectomy with pouch and 65(19%) with ileostomy. During a total follow-up of 28,282 patient years, 848(33%) patients reached the endpoint LT or PSC-related death. Hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy (0.70(0.52-0.93)) compared to patients without colectomy with variation per country (Netherlands 0.82(0.56-1.19), Finland 0.52(0.24-1.13), Norway 0.59(0.31-1.03), Sweden 0.28(0.06-1.24)). This effect was less pronounced in case of a hemi- or subtotal colectomy (HR 0.84(059-1.20)). The effect was most pronounced in the proctocolectomy with permanent ileostomy group (HR 0.55(0.30-0.99)). Of the known risk factors only a concurrent IBD diagnosis had no significant effect on transplant-free survival. Conclusion Our extended data confirm that colectomy is associated with a decreased risk of liver transplantation and PSC-related death. An incremental effect was seen with the extent of the colectomy, with the most pronounced effect in the proctocolectomy group with permanent ileostomy. Our data support the putative role of the gut-liver axis in the disease course of PSC.

Noninvasive prognostic models, imaging, and elastography to predict clinical events in primary sclerosing cholangitis: A review.

Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.

A104 INVISIBLE COLONIC MALIGNANCY AND POSSIBLE IDIOSYNCRATIC DRUG-INDUCED LIVER INJURY FROM VEDOLIZUMAB IN A PATIENT WITH ULCERATIVE COLITIS, PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE HEPATITIS OVERLAP SYNDROME

Abstract Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Due to an increased risk of developing colorectal cancer, regular surveillance for dysplastic lesions via colonoscopy is recommended. Invisible dysplasia is the abnormal development of cells noted on pathology with no visible lesion seen during colonoscopy. Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease leading to progressive stricturing and fibrosis of the bile ducts. There is significant association between PSC and IBD, as up to 80% of patients with PSC having underlying IBD. Drug induced liver injury (DILI) is a common cause of acute liver failure in most Western countries. Most cases of DILI are self-limited, with resolution of laboratory and clinical findings after cessation of the offending agent. Purpose To describe a case of invisible colonic malignancy and possible idiosyncratic drug-induced liver injury from vedolizumab (VDZ) in a patient with ulcerative colitis (UC), PSC and autoimmune hepatitis (AIH) overlap syndrome. Method Patient consent was obtained. Information from electronic records was extracted, including admission notes and procedural reports. A literature review was performed using Pubmed. Result(s) A 32-year-old Caucasian female with UC on VDZ with PSC and AIH had multiple colonoscopies performed demonstrating multifocal low-grade dysplasia. However, she remained resistant to surgery. She presented to clinic with tea-coloured urine, fatigue, and scleral icterus. Investigations revealed conjugated hyperbilirubinemia with elevation in hepatocellular liver enzymes. Imaging was consistent with large duct PSC, and liver biopsy showed grade 2 chronic hepatitis raising the possibility of large bile duct obstruction. She underwent liver transplant assessment and VDZ was held. Her bilirubin and liver enzymes recovered. Given multiple colonoscopies showing multifocal dysplastic changes and the patient declining other biologics, she would ultimately undergo total proctocolectomy with end ileostomy. Pathology demonstrated mucinous adenocarcinoma with a signet ring component. Conclusion(s) Both mucinous adenocarcinoma and signet ring carcinoma are more aggressive malignancies associated with poor prognosis. Found more often in younger patients, they are often diagnosed in later stages with lymphovascular invasion. Here, there was no evidence of metastases in any of the 40 lymph nodes examined, which indicated more favourable prognosis. The mechanism by which VDZ potentially causes liver injury is unknown. Multiple therapies for PSC-AIH overlap and IBD were entertained as causative agents. However, significant improvement in clinical symptoms and serologic parameters following cessation of VDZ was temporally suggestive. This case simultaneously highlights the importance of both timely colectomy in IBD patients with high-risk features during surveillance and early recognition and cessation of potential causative medications which induce liver injury. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Adult Primary Sclerosing Cholangitis (PSC) subjects have worse biliary disease at diagnosis compared to pediatric PSC subjects

IntroductionAdult Primary Sclerosing Cholangitis (PSC) subjects have worse outcomes compared to pediatric PSC subjects. The reasons for this observation are not completely understood. MethodsIn this single-center, retrospective (2005–17) study we compared clinical information, laboratory data, and previously published MRCP-based scores between 25 pediatric (0–18 years at diagnosis) and 45 adult (19 years and above) subjects with large duct PSC at the time of diagnosis. For each subject, radiologists determined MRCP-based parameters and scores after reviewing the MRCP images. ResultsThe median age at diagnosis for pediatric subjects was 14 years, while that of adult subjects was 39 years. At the time of diagnosis, adult subjects had a higher incidence of biliary complications like cholangitis and high-grade biliary stricture (27% vs. 6%, p = 0.003) and higher serum bilirubin (0.8 vs. 0.4 mg/dl, p = 0.01). MRCP analysis showed that adult subjects had a higher incidence of hilar lymph node enlargement (24.4% vs. 4%, p = 0.03) at diagnosis. Adult subjects had worse sum-IHD score (p = 0.003) and average-IHD score (p = 0.03). Age at diagnosis correlated with higher average-IHD (p = 0.002) and sum-IHD (p = 0.002) scores. Adult subjects had worse Anali score without contrast (p = 0.01) at diagnosis. MRCP-based extrahepatic duct parameters and scores were similar between groups. DiscussionAdult PSC subjects may have higher severity of disease at diagnosis compared to pediatric subjects. Future prospective cohort studies are required to confirm this hypothesis.

Natural history and prognosis of pediatric PSC with updates on management.

Natural history and prognosis of pediatric PSC with updates on management.

Evaluation of Tofacitinib in Primary Sclerosing Cholangitis and Associated Colitis: A Multicenter, Retrospective Study

Evaluation of Tofacitinib in Primary Sclerosing Cholangitis and Associated Colitis: A Multicenter, Retrospective Study

OP10 Proctocolectomy with permanent ileostomy is associated with better transplant-free survival in patients with primary sclerosing cholangitis: a retrospective cohort study

Abstract Background Inflammatory bowel disease (IBD) is the strongest known risk factor for primary sclerosing cholangitis (PSC) and seems associated with a worse prognosis. After liver transplantation, colectomy is associated with decreased rates of recurrent PSC and better graft survival.1 At the same time, the effect of colectomy on the disease course of PSC remains unclear.2 Available evidence depends either on small patient numbers, may be confounded by unobserved risk factors or colectomy was not considered as time-depending covariate. The aim of our study is to estimate the effect of colectomy on the disease course of PSC by taking time dependency and known risk factors into account. Methods We conducted a retrospective cohort study between January 1st 2008 and December 31st 2021 based on the Dutch population-based EpiPSC2 cohort. Transplant-free survival was defined as liver transplantation or PSC-related death (excluding colorectal carcinoma). The effect of colectomy was determined as time depending variable via Cox proportional hazards regression and was corrected for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, time depending IBD status (i.e. no IBD, ulcerative colitis (UC), Crohn’s disease (CD) or IBD Unspecified (IBD-U)), and tertiary centre inclusion. Effect of colectomy was stratified for extent (i.e. hemi-, subtotal, or proctocolectomy with pouch or ileostomy). Indication of colectomy (i.e. active disease, dysplasia and colorectal carcinoma or other) was also considered as predictor variable. Events in the first year after colectomy were censored due to a presumed delayed effect of colectomy on disease course. Results Of the 1341 patients included, 912(68%) were diagnosed with IBD and 187(14%) had undergone a colectomy. During a total follow-up of 14,393 patient years, 370(28%) patients underwent liver transplantation and 318(24%) patients died due to a PSC-related cause. Median transplant-free survival time was 20 years. Hazard ratio (HR) was significantly decreased in patients who had undergone proctocolectomy with ileostomy (HR 0.47(0.24-0.93)) compared to patients without colectomy. This effect was absent in the group with any other type of colectomy (HR 0.90(0.67-1.19)). Indication of colectomy had no apparent effect. Presence of UC, CD or IBD-U was not associated with a worse prognosis compared to absence of IBD (HR 0.99(0.81-1.21), HR 0.85(0.64-1.13), HR 0.75(0.43-1.29)). Conclusion Our data suggest that proctocolectomy with ileostomy confers protection for liver transplantation and PSC-related death. This points towards the putative pathophysiologic role of the colonic microbiota in PSC and may open avenues to a better understanding of the aetiology of PSC.

Primary sclerosing cholangitis-A long night's journey into day.

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

Background & AimsPeople with primary sclerosing cholangitis (PSC) have a variable and often progressive disease course that is associated with biliary and parenchymal changes. These changes are typically assessed by magnetic resonance imaging (MRI), including qualitative assessment of magnetic resonance cholangiopancreatography (MRCP). Our aim was to study the association of novel objective quantitative MRCP metrics with prognostic scores and patient outcomes. MethodsWe performed a retrospective study including 77 individuals with large-duct PSC with baseline MRCP images, which were postprocessed to obtain quantitative measures of bile ducts using MRCP+™. The participants’ ANALI scores, liver stiffness by vibration-controlled transient elastography, and biochemical indices were collected at baseline. Adverse outcome-free survival was measured as the absence of decompensated cirrhosis, liver transplantation (LT), or liver-related death over a 12-year period. The prognostic value of MRCP+-derived metrics was assessed by Cox regression modelling. ResultsDuring a total of 386 patients-years, 16 cases of decompensation, 2 LTs, and 5 liver-related deaths were recorded. At baseline, around 50% of the patients were classified as being at risk of developing disease complications. MRCP+ metrics, particularly those describing the severity of bile duct dilatations, were correlated with all prognostic factors. Univariate analysis showed that MRCP+ metrics representing duct diameter, dilatations, and the percentage of ducts with strictures and/or dilatations were associated with survival. In a multivariable-adjusted analysis, the median duct diameter was significantly associated with survival (hazard ratio 10.9, 95% CI 1.3–90.3). ConclusionsMRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival. Lay summaryIn this study, we assessed in people with primary sclerosing cholangitis (PSC) the association of novel objective quantitative MRCP metrics automatically provided by a software tool (MRCP+) with prognostic scores and patient outcomes. We observed that MRCP+ metrics in people with PSC correlate with biochemical, elastographic, and radiological prognostic scores and are predictive of adverse outcome-free survival.

Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC

Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277-468 U/L) and 417 U/L (IQR, 196-801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n= 5], other adverse events [n= 5], subject decision/investigator discretion [n= 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median,-8.3% [IQR,-25.9% to 11.0%]; P= .066), GGT (-29.8% [IQR,-42.3% to-13.9%]; P < .001), alanine aminotransaminase (ALT) (-29.8% [IQR,-43.7% to-6.6%]; P= .002), and aspartate aminotransaminase (AST) (-16.7% [IQR,-35.3% to 1.0%]; P= .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P= .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (-29.8% [IQR,-64.3% to-8.5%]; P= .001). In subjects with detectable serum BAs at BL (n= 40), BAs decreased-23.9% (IQR,-44.4% to-0.6%; P= .006) at week 48 (n= 28) and-25.7% (IQR,-35.9% to 53.7%; P= .91) at week 96 (n= 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30,-17.3% [IQR,-39.3% to 8.8%]; P= .018; CK18 M65,-43.5% [IQR,-54.9% to 15.3%]; P= .096). At week 96, a small, but statistically significant absolute increase of 0.15 units inEnhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P=.028). In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. gov identifier: NCT02943460.

Prevalence of inflammatory bowel disease in patients with primary sclerosing cholangitis: A systematic review and meta-analysis.

Previous studies have established an association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC). The disease burden of IBD in PSC patients was not well estimated. The study aimed to quantify the pooled prevalence of IBD in PSC and to investigate whether subtypes of PSC and sex influence the prevalence of IBD. PubMed, Embase, and Web of Science were searched through November 2021 for studies reporting data on IBD among PSC patients. The outcomes were the prevalence of IBD in patients with PSC, as well as the association (odds ratio [OR]) of IBD in PSC according to subtype and sex. Based on the analysis of 25 studies, the prevalence of IBD in patients with PSC was 71.1% (95% CI 68.2-75.1%), most commonly in UC (55.9%, 95% CI 52.5-59.3%). The pooled prevalence of IBD was 76.9% in Australia (95% CI 71.2-82.6%, 1 study), 75.9% (95% CI 69.5-82.3%, 4 studies) in North America, 70.9% (95% CI 65.8-76.0%, 17 studies) in Europe and 67.0% (95% CI 57.9-76.0%, 2 studies) in Asia. Male PSC patients had a higher prevalence of IBD (OR 1.67, 95% CI 1.52-1.83) and UC (OR 2.02, 95% CI 1.56-2.63) and a lower prevalence of CD (OR 0.77, 95% CI 0.67-0.88) than female patients. Large duct PSC patients had a higher prevalence of IBD (OR 2.57, 95% CI 2.03-3.25) and UC (OR 4.51, 95% CI 1.22-16.71) than small duct PSC patients. The study provided the first pooled estimates of the burden of IBD in patients with PSC and could be used as the basis for risk stratification of PSC patients.

Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study

Background and aimsLittle is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population.MethodsWe conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers.ResultsA total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2–15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival.ConclusionIn this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

S2491 Small Duct Primary Sclerosing Cholangitis: An Atypical Presentation

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic progressive disease of the liver and biliary tract causing cholestasis, fibrosis, and strictures in intra and extrahepatic bile ducts. Patients are often asymptomatic, but as the disease progress, complications occur and include: recurrent cholangitis, portal hypertension, cirrhosis of the biliary tract, end-stage liver disease, and hepatobiliary malignancies, namely cholangiocarcinoma. Within the entity of PSC, there are two distinct variants: small duct PSC and large duct PSC. Here we present a case of small duct PSC presenting atypically with chronic portal vein thrombosis and a hilar mass. CASE DESCRIPTION/METHODS: 36- year old Pakistani man presented with right upper quadrant abdominal pain, jaundice, and fever. He reported a history of chronic abdominal pain and recurrent jaundice, as well as chronic portal vein thrombosis (PVT) since childhood. The patient was recently hospitalized in another institute for the same complaint for which he had a Computerized tomography (CT) of the abdomen that revealed marked splenomegaly together with evidence of portal vein occlusion with cavernous transformation as well as Intrahepatic biliary ductal dilation with a transition in the common hepatic duct and a hilar mass. The patient underwent endoscopic retrograde cholangiography (ERC) with biopsies obtained through cholangioscopy that were unremarkable. Liver biopsy showed findings consistent with primary sclerosing cholangitis with acute cholangitis and changes secondary to portal vein thrombosis. DISCUSSION: Primary sclerosing cholangitis is a chronic, incurable disease in which the liver and biliary tract become fibrosed, and strictures form in the intra and extrahepatic biliary ducts causing obstruction, portal hypertension, and eventual liver cirrhosis necessitating a liver transplant. MRC is the most frequently used diagnostic tool due to its high specificity and sensitivity. Although ERC is more sensitive, there are added risks and complications (i.e., pancreatitis and bacterial cholangitis) with this technique. When ERC is performed, findings typically include multifocal short annular strictures, which create a "beaded" pattern. Although most patients are shown to have intra and extrahepatic bile duct involvement, a small subset presents with only intra or extrahepatic bile duct involvement. Only a few small duct PSC cases were reported in the literature, and it rarely presents with an inflammatory mass as well as PVT, as in our case.Figure 1.: Portal fibrosis with mild to focal moderate ductular reaction, accompanied by neutrophils.Figure 2.: A Coronal contrast-enhanced CT image through the abdomen shows intrahepatic beading (red arrow) with intervening sites of alternating strictures, mildly dilated, and normal ducts. There is compensatory hypertrophy of the right lobe and caudate lobe of the liver (green arrows).Figure 3.: A Coronal MRCP Image through the liver shows multiple multifocal diffuse intrahepatic and extrahepatic strictures (red arrows) and severely dilated intrahepatic ducts (blue arrows), with a branching-tree appearance. There is extrahepatic beading with intervening sites of a normal, narrow stricture (long red arrow), and mildly dilated extrahepatic ducts (yellow arrow).

Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis

Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression. We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week96. Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints). In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.

Clinical features and MRI progression of small duct primary sclerosing cholangitis (PSC)

PurposeFirst, to evaluate and describe the clinical and MRI progression of patients with small duct primary sclerosing cholangitis (sdPSC), and second, to look for MRI features associated with disease progression to large duct PSC. Method16 patients (7 female, 9 male; median age 27 years) with diagnosis of sdPSC and available MR imaging were included in this retrospective dual-center study. Liver function tests (LFTs) and imaging was reviewed in consensus by two radiologists at baseline and follow-up, and compared by means of non-parametric tests, with p < 0.05 deemed significant. ResultsAt baseline and follow-up patients had a cholestatic liver profile with elevated LFTs. Progressive liver deformity, heterogeneous enhancement and hilar lymphadenopathy were common findings. In 9 patients follow-up MRI was available with a mean interval between imaging of 10.6 years (range 3.6−15.3 years). 5 patients (55.5 %) developed cholangiographic changes diagnostic of large duct PSC. No correlation was observed between MRI findings or LFTs at baseline and the endpoint of developing PSC typical cholangiographic changes at follow-up imaging (p > 0.05). ConclusionsMore than half of sdPSC patients developed cholangiographic changes, supporting that sdPSC may be an early stage of large duct PSC rather than an entity of its own. Larger studies are needed to address the value of MRI for prediction of sdPSC disease progression.

Magnetic resonance imaging features of small-duct primary sclerosing cholangitis.

To evaluate the biliary tree and hepatic parenchymal findings on magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) in small-duct primary sclerosing cholangitis (SD-PSC). Thirty-nine patients with biopsy-proven primary sclerosing cholangitis (PSC) without any bile duct abnormality on MRCP (n = 15) or ERCP (n = 24) at the time of diagnosis were identified. Follow-up MRCP was available in 36/39 patients (12/15 Baseline MRCP group and 24 Baseline ERCP group). Two radiologists in consensus assessed the MRI/MRCP findings. The baseline MRI/MRCP of 15 SD-PSC patients was compared with MRI/MRCP of 15 normal healthy potential liver donors (Control group). Comparisons were made between SD-PSC patients and the Control group, and between baseline and follow-up MRI/MRCP findings in the SD-PSC patients. In the 15 Baseline MRCP SD-PSC subjects, the biliary tree was normal with a trend of larger bile ducts compared to the Control group. Periductal enhancement (arterial phase: 70%, 7/10; delayed phase: 90%, 9/10), heterogeneous parenchymal signal on T2-weighted (53%, 8/15) and post contrast-enhanced images (70%, 7/10), and enlarged periportal lymph nodes (73%, 11/15) were frequently present in patients with SD-PSC. Eight (33%) of 24 SD-PSC patients who had normal MRCP at baseline MRCP or initial follow-up MRCP after normal baseline ERCP showed large-duct PSC (LD-PSC) features on follow-up and the 10-year cumulative incidence for progression to LD-PSC rate was 8.5%. SD-PSC patients have a normal biliary tree but frequently have peribiliary enhancement, abnormal parenchymal signal intensity, and periportal lymphadenopathy. One-third shows progression to LD-PSC on follow-up.

2797 Fenofibrate and PSC: A Case Series From a Single Center Liver Registry

INTRODUCTION: Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with no current effective therapy. Ursodeoxycholic acid (UDCA) is often used, however it does not slow disease progression despite improvement in serum alkaline phosphatase (ALP). Fenofibrate (FF) improves cholestasis in patients with primary biliary cholangitis (PBC). We present a retrospective single-center case series of Fenofibrate in PSC patients. METHODS: Methods: Patients were identified within a Liver Registry with large-duct PSC on FF. Overlap cases with PBC or autoimmune hepatitis were excluded. The mean age at diagnosis was 39.7 ± 19.2 years; 4 were males, 5 Caucasian and 2 Hispanic. Five had inflammatory bowel disease, five had intra/extrahepatic disease and two had intrahepatic disease. All patients received UDCA. FF was added 5-396 months post diagnosis. RESULTS: Mean ALP pre-FF was 654 U/L ± 646 and after 4-6 months improved by a mean of 176 ± 263.4 U/L; 4/7 patients had ALP reduction with FF and 3 achieved a normal ALP level (Figure 1). MRI post FF was available in five patients; 3 had worsening of strictures after 6-12 months of FF while 2/5 were stable). ERCP was performed for stricture management on 4 patients and 2 required repeat ERCP. One patient developed cirrhosis; no patients developed ascites, encephalopathy, cholangiocarcinoma or hepatocellular carcinoma. One patient had a transplant evaluation for refractory pruritus. Of four with pruritus pre-FF, 1; one had moderate improvement. Of 6 patients with fatigue, 3 had persistence post-FF and 1 had new fatigue. Of 3 patients who had cholangitis pre-FF, 2 had recurrent episodes post-FF. No patients developed myopathy or acute kidney injury. FF was discontinued in one patient due to lack of ALP improvement at 6 months. Amsterdam-Oxford Risk Score (Figure 2) was calculated at time of FF, 4-6 months after FF, and at 1- and 2- years for those with data beyond 6 months. Among the 4 patients with ALP improvement, there was mild improvement in the risk score (not sustained beyond 2 years in 3 patients). CONCLUSION: Conclusion: This case series suggests a potential use for FF in the treatment of PSC. However, despite reduction in ALP, fatigue, pruritus, and recurrent cholangitis persisted and FF did not improve strictures, similar to UDCA studies in PSC. Future aims of this study involve examining elastography data pre- and post-FF. The role of FF in PSC treatment should be examined in larger, longitudinal studies.