Epidemiology, Natural History, and Outcomes of Primary Sclerosing Cholangitis: A Systematic Review of Population-based Studies.

BACKGROUND & AIMS: The aim of this study was to quantify the global epidemiology of primary sclerosing cholangitis (PSC), alongside the incidence of liver transplantation, cancer, and death, through robust systematic review of population-based data. METHODS: We searched MEDLINE and EMBASE up to and including June 30, 2020 to identify population-based studies reporting the incidence and/or prevalence of PSC. Studies that did not report original data, or of exclusively pediatric-onset disease (diagnosis age <16 years) or exclusively PSC-associated with inflammatory bowel disease were excluded. RESULTS: Of 4922 published studies, 17 fulfilled inclusion criteria; 16 documenting incidence and 14 prevalence. The highest reported incidence of PSC was reported in Northern Europe (Finland, 1.58 and Norway, 1.3 per-100,000 population, respectively) and North America (Minnesota, 1.47); with the lowest being observed across the Mediterranean Basin (Italy, 0.1). Prevalence ranged from 31.7 in Finland and 23.99 in Minnesota, to 1.33 in Singapore and 0.0 in Alaska. Of studies reporting temporal occurrence, an increase in disease incidence was observed across North America and Northern Europe (4 studies), alongside an increase in prevalence over time (4 studies). The incidence and risks for clinical outcomes were presented by 9 of the included studies. Median transplant-free survival ranged from 9.7 (United States) to 20.6 years (Netherlands), with standardized mortality ratios of 2.5 and 4.2 compared with the control population. The standardized incidence of cholangiocarcinoma ranged from 235 (Finland) to 398 (Netherlands). CONCLUSIONS: Estimates of PSC incidence and prevalence vary, with most studies conducted in North America and Western Europe; the latter showing a steady increase in disease occurrence over time. Further research is needed to understand changes in disease epidemiology, including etiological drivers, the implications of rising case burden on health care policy, and better appreciation of PSC in the developing world.

Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Gut-homing lymphocytes that express the integrin α4ß7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4ß7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD. METHODS: We collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes. RESULTS: In the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation. CONCLUSIONS: In an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Efficacy and Safety of Cenicriviroc in Patients With Primary Sclerosing Cholangitis: PERSEUS Study.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease with no approved treatments. C-C chemokine receptor types 2 and 5 (CCR2/CCR5) play an important role in inflammation and fibrosis and are potential therapeutic targets for PSC. We evaluated the efficacy and safety of cenicriviroc (CVC), a dual antagonist of CCR2 and CCR5, for the treatment of PSC. This was a single-arm, open-label, exploratory study of CVC in adults with a clinical diagnosis of PSC, serum alkaline phosphatase (ALP) ≥1.5 times the upper limit of normal (ULN), with or without inflammatory bowel disease, across eight sites in the United States and Canada. The primary endpoint was percent change in ALP over 24 weeks; key secondary efficacy endpoints were proportion of participants who achieved ALP normalization and overall response (decrease to <1.5 times the ULN or 50% decrease). Of the 24 participants, 20 completed the study. The mean age was 43 years, 50% were female, and the mean body mass index was 25 kg/m2. From a median ALP baseline of 369 U/L (range: 173, 1,377 U/L), a median absolute reduction of 49.5 U/L (range: -460, 416 U/L) was achieved at week 24, corresponding to a median reduction of 18.0% (range: -46%, 89%). No participant achieved ALP normalization or a 50% decrease; 2 participants (10%) achieved a reduction in ALP to < 1.5 times the ULN, and 4 had ≥25% increase. Twenty participants (83.3%) reported at least one adverse event; most were mild to moderate in severity. The most frequent events were rash, fatigue, and dizziness. Conclusion: After 24 weeks of CVC treatment, adults with PSC achieved a modest reduction (median 18%) in the surrogate endpoint of ALP. CVC was well tolerated, and no new safety signals were observed. ClinicalTrials.gov identifier: NCT02653625.

Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches.

Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.

Practical strategies for pruritus management in the obeticholic acid-treated patient with PBC: proceedings from the 2018 expert panel.

BACKGROUND AND AIMS: This article provides expert guidance on the management of pruritus symptoms in patients receiving obeticholic acid (OCA) as treatment for primary biliary cholangitis (PBC). PBC is a chronic, autoimmune cholestatic liver disease that affects intrahepatic bile ducts. If not adequately treated, PBC can lead to cholestasis and end-stage liver disease, which may require transplant. Timely treatment is therefore vital to patient health. Pruritus is a common symptom in patients with PBC. Additionally, the use of OCA to treat PBC can contribute to increased pruritus severity in some patients, adding to patient discomfort, decreasing patient quality of life (QoL), and potentially affecting patient adherence to OCA treatment. METHODS: In May 2018, a group of physician experts from the fields of gastroenterology, hepatology, and psychiatry met to discuss the management of pruritus in OCA-treated patients with PBC. Recognizing the importance of optimizing treatment for PBC, these experts developed recommendations for managing pruritus symptoms in the OCA-treated PBC patient based on their experience in clinical practice. RESULTS: These recommendations include a comprehensive list of management strategies (including over-the-counter, prescription, and alternative therapies), guidance on titration of OCA to minimize pruritus severity, and an algorithm that outlines a practical approach to follow up with patients receiving OCA, to better assess and manage pruritus symptoms. CONCLUSIONS: Pruritus associated with OCA therapy is dose dependent and often manageable, and with the proper education and tools, most pruritus cases can be effectively managed to minimize treatment discontinuation.

Diagnosis and classification of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and that is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. It is progressive in most patients and leads to cirrhosis. It is a rare disease, mostly affecting people of northern European descent, males greater than females. The diagnosis is best established by contrast cholangiography, which reveals a characteristic picture of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance. Inflammatory bowel disease (IBD) is present in ~75% of the patients with PSC, mostly ulcerative colitis (~85% of the cases). In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps and cancer, and hepatic osteodystrophy. The etiology of PSC is not clear, but studies are ongoing. The median survival without liver transplantation is 12 to 15 years after diagnosis. Currently there are no effective treatments except liver transplantation. Immunosuppressive medications have not been shown to be effective but antibiotics and anti-fibrotic agents seem promising.

A Rare Case of Icteric Acute Hepatitis C Infection Acquired Through Intranasal Methamphetamine Use.

Most patients with acute hepatitis C (HCV) infections are asymptomatic, while 15% present with jaundice. Intranasal drug use can uncommonly transmit HCV via contaminated instruments and nasal epithelial breakdown. Given a 15% prevalence of HCV infection in chronic methamphetamine users, recognition of potential transmission routes is important to target prevention and screening efforts in this population.

Patient tolerability of bowel preparation is associated with polyp detection rate during colonoscopy.

BACKGROUND & AIMS: A number of factors have been identified that influence the yield of screening colonoscopy. The perceived tolerability of bowel preparation has not been studied as a predictor of quality outcomes in colonoscopy. We aimed to characterize the association between patient-perceived tolerability of bowel preparation and polyp detection during colonoscopy. METHODS: We performed a cross-sectional cohort study of 413 consecutive adult patients presenting for outpatient colonoscopy at two outpatient endoscopy centers at our institution. We developed a standardized questionnaire to assess the patient's experience with bowel preparation. Bowel preparation quality was measured using the validated Ottawa scale and colonoscopic findings were recorded for each patient. The primary outcome was polyp detection and the secondary outcome was the quality of bowel preparation. RESULTS: Patient-reported clarity of effluent during bowel preparation correlated poorly with Ottawa score during colonoscopy, ĸ=0.15. Female gender was an independent risk factor for a poorly tolerated bowel prep (OR 3.93, 95% CI 2.30 - 6.72, p<0.001). Report of a poorly tolerated bowel prep was independently associated with the primary outcome, polyp detection (OR 0.39, 95% CI 0.18 - 0.84, p=0.02) and also with the secondary outcome, lower quality bowel preparation (OR 2.39, 95% CI 1.17 - 4.9, p=0.02). CONCLUSIONS: A patient-perceived negative experience with bowel preparation independently predicted both a lower quality bowel preparation and a lower rate of polyp of detection. Assessment of the tolerability of bowel preparation before colonoscopy may be a clinically useful predictor of quality outcomes during colonoscopy.

Esophageal adenocarcinoma in a 40-year-old man with cystic fibrosis: coincidence or not?

OBJECTIVE: To report a case of esophageal cancer in an adult patient with cystic fibrosis (CF) and review the relationship between these 2 diseases. CASE REPORT: A 40-year-old man with CF presented with worsening epigastric pain, weight loss, and upper gastrointestinal (GI) bleeding. Endoscopy revealed innumerable masses in the distal esophagus. The workup revealed esophageal adenocarcinoma metastatic to the liver and the lungs. DISCUSSION: Abnormal mucous secretions in CF patients impair the innate GI mucosal barriers. The incidence of both gastroesophageal reflux disease and GI malignancies is higher in patients with CF. Patients with CF now survive long enough to potentially experience the consequences of long-term acid exposure, including esophagitis, Barrett esophagus, and esophageal cancer. CONCLUSION: Our case report adds to a small but growing body of evidence that CF is a significant risk factor for GI malignancies, including esophageal adenocarcinoma. Controlled studies are needed to determine whether a causal relationship truly exists.