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BACKGROUND: The duration of an endoscopic retrograde cholangiopancreatography (ERCP) is influenced by a multitude of factors. The aim of this study was to describe the factors influencing ERCP time and to create a tool for preintervention estimation of ERCP time. METHODS: Data from 74 248 ERCPs performed from 2010 to 2019 were extracted from the Swedish National Quality Registry (GallRiks) to identify variables predictive for ERCP time using linear regression analyses and root mean squared error (RMSE) as a loss function. Ten variables were combined to create an estimation tool for ERCP duration. The tool was externally validated using 9472 ERCPs from 2020 to 2021. RESULTS: Mean (SD) ERCP time was 36.8 (25.3) minutes. Indications with the strongest influence on ERCP time were primary sclerosing cholangitis and chronic pancreatitis. Hilar and intrahepatic biliary strictures and interventions on the pancreatic duct were the anatomic features that most strongly affected ERCP time. The procedure steps with most influence were intraductal endoscopy, lithotripsy, dilation, and papillectomy. Based on these results, we built and validated the SW: edish E: stimation of E: RCP T: ime (SWEET) tool, which is based on a 10-factor scoring system (e.g. 5 minutes for bile duct cannulation and 15 minutes for pancreatic duct cannulation) and predicted ERCP time with an average difference between actual and predicted duration of 17.5 minutes during external validation. CONCLUSIONS: Based on new insights into the factors affecting ERCP time, we created the SWEET tool, the first specific tool for preintervention estimation of ERCP time, which is easy-to-apply in everyday clinical practice, to guide efficient ERCP scheduling.
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Background & Aims: Primary sclerosing cholangitis (PSC) is a rare progressive liver disease associated with inflammatory bowel disease (IBD). It is usually diagnosed in adults but can also present in children. Data on long-term outcomes of pediatric PSC are limited. Our aim was to study the natural history of pediatric PSC in Sweden. Methods: This is a cohort study, including all children (<18 years), diagnosed with PSC between January 2000 and December 2015 at the Pediatric Liver Unit at Karolinska University Hospital, Stockholm. Patients were followed until liver transplantation, death or last date of follow-up (August 2021). Results: We identified 124 children with a median age of 14 (1.9-17.8) years at PSC diagnosis. Sixty percent were boys, 93% had IBD. Median follow-up time was 13 years (5.7-21.6). Overall event-free survival in the cohort was 91% (95% CI 0.84-0.95) at 5 years and 77% (95% CI 0.68-0.84) at 10 years after diagnosis. Autoimmune hepatitis (AIH) was present in 31% (n = 39). Portal hypertension developed in 13% (n = 16), biliary complications in 24% (n = 30), cholangiocarcinoma (CCA) in 0.8% (n = 1), while 13% (n = 16) underwent liver transplantation and three patients died. Transplant-free survival was 91% after 10 years. Individuals with a high SCOPE index at diagnosis had a 2.3-fold increased risk of requiring liver transplantation (hazard ratio 2.35, 95% CI 1.18-4.66, c-statistics = 0.70). Patients with an additional diagnosis of autoimmune hepatitis had slightly higher risk of reaching transplantation during follow-up (hazard ratio 2.85, 95% CI 1.06-7.67, p = 0.038). Conclusions: Children diagnosed with PSC have a good prognosis during the first decade after diagnosis. A high SCOPE index at diagnosis was associated with a less favorable outcome. Impact and implications: Data on long-term outcome in pediatric primary sclerosing cholangitis bridging over to adulthood is limited. There is a great need among children with primary sclerosing cholangitis and their parents for more knowledge about the natural history of this disease and what they can expect from the future. We hope that the data presented in this study may help counsel health professionals, young individuals and families affected by this disease.
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BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). METHODS AND ANALYSIS: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. ETHICS AND DISSEMINATION: Ethical approval has been granted by the East Midlands-Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. TRIAL REGISTRATION NUMBER: 1239.
Subject(s)
Cholangitis, Sclerosing , Research Design , Humans , Cholangitis, Sclerosing/therapy , Clinical Trials as Topic , Delphi Technique , Outcome Assessment, Health Care , Endpoint Determination , Systematic Reviews as TopicABSTRACT
BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel disease (IBD). However, there is limited overlap between IBD and PSC risk genes, but a stronger association between PSC and other autoimmune conditions. We aimed to assess the coexistence and familial association of autoimmune disorders in PSC, and the influence of autoimmune comorbidity on severe outcomes. APPROACH AND RESULTS: In a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives were evaluated. National registries provided data on diagnoses and outcomes (liver transplantation, hepatobiliary cancer, and liver-related death). The OR of autoimmune disease was estimated by logistic regression. The Fine and Gray competing risk regression estimated HRs for severe outcomes. The prevalence of non-IBD, non-autoimmune hepatitis, and autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77 (95% CI: 1.53-2.05). Highest odds were seen for celiac disease [OR: 4.36 (95% CI: 2.44-7.49)], sarcoidosis [OR: 2.74 (95% CI: 1.29-5.33)], diabetes type 1 [OR: 2.91 (95% CI: 2.05-4.05)], and autoimmune skin disease [OR: 2.15 (95% CI: 1.52-2.96)]. First-degree relatives of individuals with PSC had higher odds of developing IBD, autoimmune hepatitis, and any autoimmune disease than relatives of the comparators [OR: 3.25 (95% CI: 2.68-3.91); OR: 5.94 (95% CI: 2.82-12.02); OR: 1.34 (95% CI: 1.19-1.50)]. Autoimmune comorbidity in PSC was not associated with poorer outcomes [HR: 0.96 (95% CI: 0.71-1.28)]. CONCLUSIONS: Individuals with PSC and their first-degree relatives had higher odds of autoimmune disease compared to matched comparators. This finding provides validation for prior genetic discoveries at a phenotypic level. Autoimmune comorbidity did not impact severe outcomes.
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Background: Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. Methods: We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Findings: Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. Interpretation: We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040. Funding: This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.
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Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).
Subject(s)
Cholangitis, Sclerosing , Inflammatory Bowel Diseases , Humans , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/epidemiology , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/diagnosis , Liver , PhenotypeABSTRACT
BACKGROUND & AIMS: Chronic inflammation surrounding bile ducts contributes to the disease pathogenesis of most cholangiopathies. Poor efficacy of immunosuppression in these conditions suggests biliary-specific pathologic principles. Here we performed biliary niche specific functional interpretation of a causal mutation (CD100 K849T) of primary sclerosing cholangitis (PSC) to understand related pathogenic mechanisms. METHODS: Biopsy specimens of explanted livers and endoscopy-guided sampling were used to assess the CD100 expression by spatial transcriptomics, immune imaging, and high-dimensional flow cytometry. To model pathogenic cholangiocyte-immune cell interaction, splenocytes from mutation-specific mice were cocultured with cholangiocytes. Pathogenic pathways were pinpointed by RNA sequencing analysis of cocultured cells and cross-validated in patient materials. RESULTS: CD100 is mainly expressed by immune cells in the liver and shows a unique pattern around PSC bile ducts with RNA-level colocalization but poor detection at the protein level. This appears to be due to CD100 cleavage as soluble CD100 is increased. Immunophenotyping suggests biliary-infiltrating T cells as the major source of soluble CD100, which is further supported by reduced surface CD100 on T cells and increased metalloproteinases in cholangiocytes after coculturing. Pathogenic T cells that adhered to cholangiocytes up-regulated genes in the T-helper 17 cell differentiation pathway, and the CD100 mutation boosted this process. Consistently, T-helper 17 cells dominate biliary-resident CD4 T cells in patients. CONCLUSIONS: CD100 exerts its functional impact through cholangiocyte-immune cell cross talk and underscores an active, proinflammatory role of cholangiocytes that can be relevant to novel treatment approaches.
Subject(s)
Biliary Tract , Cholangitis, Sclerosing , Cholangitis , Humans , Animals , Mice , Liver/pathology , Bile Ducts/pathology , Biliary Tract/pathology , Epithelial Cells/pathology , Cell Differentiation , Cholangitis, Sclerosing/pathologyABSTRACT
Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.
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BACKGROUND AND AIMS: Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS: We performed a case-control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model. RESULTS: Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%-5.7%), 1.7% (0.9%-3.1%), 3.1% (1.9%-4.8%) and of T2D 14.8% (11.1%-19.5%), 18.1% (14.6%-22.2%), 6.3% (2.8%-13.3%) in patients with AIH, PBC and PSC, respectively. CONCLUSIONS: Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.
Subject(s)
Autoimmune Diseases , Cholangitis, Sclerosing , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Hepatitis, Autoimmune , Liver Cirrhosis, Biliary , Liver Diseases , Humans , Liver Cirrhosis, Biliary/epidemiology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Case-Control Studies , Propensity Score , Liver Diseases/epidemiology , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Hepatitis, Autoimmune/complications , Hepatitis, Autoimmune/epidemiology , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/epidemiologyABSTRACT
Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases affecting the liver which is a key metabolic organ that ensures glucose homeostasis. It is well known that patients with other chronic liver diseases such as cirrhosis and nonalcoholic fatty liver disease (NAFLD) display glucose disturbances like insulin resistance and have an increased risk of diabetes. Previous evidence on glucose disturbances in patients with autoimmune liver disease is scarce but does point towards a potentially increased risk of type 1 diabetes and type 2 diabetes. The underlying mechanisms are unknown but may reflect genetic predisposition, concurrent NAFLD and or cirrhosis development, and treatment (steroid) related impairment of glucose homeostasis. Therefore, increased awareness and surveillance of diabetes development in patients with autoimmune liver disease may be important. Overall, detection and treatment of diabetes generally follow the usual diabetes guidelines; however, in patients with advanced liver cirrhosis, HbA1c may not be a reliable marker of average glucose levels, and treatment with insulin is generally recommended. In addition, it has recently been suggested that sodium-glucose cotransporter 2 inhibitors may be beneficial in treating refractory ascites. Further research on diabetes risk in autoimmune liver disease is warranted.
Subject(s)
Autoimmune Diseases , Cholangitis, Sclerosing , Diabetes Mellitus, Type 2 , Hepatitis, Autoimmune , Liver Cirrhosis, Biliary , Liver Diseases , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/complications , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Liver Cirrhosis, Biliary/etiology , Cholangitis, Sclerosing/complications , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Liver Diseases/etiology , Autoimmune Diseases/complications , Autoimmune Diseases/diagnosis , Autoimmune Diseases/drug therapy , Hepatitis, Autoimmune/complications , Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/drug therapy , Chronic Disease , Liver Cirrhosis/complications , Glucose , LiverABSTRACT
BACKGROUND: Management and follow-up strategies for primary sclerosing cholangitis (PSC) vary. The aim of the present study was to assess patient-reported quality of care to identify the most important areas for improvement. METHODS: Data were collected via an online survey hosted on the EU Survey platform in 11 languages between October 2021 and January 2022. Questions were asked about the disease, symptoms, treatment, investigations and quality of care. RESULTS: In total, 798 nontransplanted people with PSC from 33 countries responded. Eighty-six per cent of respondents reported having had at least one symptom. Twenty-four per cent had never undergone an elastography, and 8% had not had a colonoscopy. Nearly half (49%) had never undergone a bone density scan. Ursodeoxycholic acid (UDCA) was used in 90-93% in France, Netherlands and Germany, and 49-50% in the United Kingdom and Sweden. Itch was common (60%), and 50% of those had received any medication. Antihistamines were taken by 27%, cholestyramine by 21%, rifampicin by 13% and bezafibrate by 6.5%. Forty-one per cent had been offered participation in a clinical trial or research. The majority (91%) reported that they were confident with their care although half of the individuals reported the need for more information on disease prognosis and diet. CONCLUSION: Symptom burden in PSC is high, and the most important areas of improvement are disease monitoring with more widespread use of elastography, bone density scan and appropriate treatment for itch. Personalised prognostic information should be offered to all individuals with PSC and include information on how they can improve their health.
Subject(s)
Cholangitis, Sclerosing , Humans , Cholangitis, Sclerosing/diagnosis , Ursodeoxycholic Acid/therapeutic use , Prognosis , Pruritus/drug therapy , Patient Reported Outcome Measures , Quality of Health CareABSTRACT
BACKGROUND AND AIMS: We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). METHODS: We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. RESULTS: In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. CONCLUSIONS: Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. IMPACT AND IMPLICATIONS: We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.
Subject(s)
Cholangitis, Sclerosing , Inflammatory Bowel Diseases , Vitamin B 6 Deficiency , Humans , Vitamin B 6 Deficiency/complications , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/surgery , Cross-Sectional Studies , Vitamin B 6 , Inflammatory Bowel Diseases/complications , LiverABSTRACT
BACKGROUND: Primary Sclerosing Cholangitis (PSC) is a hepatobiliary disease closely related to ulcerative colitis (UC). In PSC patients, colectomy has been linked to improved prognosis, especially following liver transplantation. This suggests an involvement of the gut-liver axis in PSC etiology. OBJECTIVE: We aimed to investigate the association between colectomy and the risk of future PSC in an epidemiological setting. METHOD: Through nationwide registers, we identified all adults diagnosed with UC in Sweden 1990-2018 and retrieved information on PSC diagnosis and colectomy. Within the UC cohort (n = 61,993 patients), we matched 5577 patients with colectomy to 15,078 without colectomy. Matching criteria were sex, age at UC onset (±5 years), year of UC onset (±3 years), and proctitis at the time of colectomy. Incidence rates of PSC per 1000-person year were calculated, and the Cox proportional hazard regression model estimated hazard ratios (HRs) for PSC until 31 December 2019. RESULTS: During the follow-up, 190 (3.4%) colectomized UC patients and 450 (3.0%) UC comparators developed PSC, yielding incidence rates of 2.6 and 2.4 per 1000 person-years (HR 1.07 [95% CI 0.90-1.28]). The cumulative incidence of colectomy decreased remarkably over calendar periods, but the cumulative incidence of PSC remained unchanged. The risk of developing PSC in colectomized versus comparators changed over time (HR 0.68 [95% CI; 0.48-0.96] in 1990-97 and HR 2.10 [95% CI; 1.37-3.24] in 2011-18). CONCLUSIONS: In UC patients, colectomy was not associated with a decreased risk of subsequent PSC. The observed differences in the risk of PSC development over calendar periods are likely due to changes in PSC-diagnosis and UC-treatment.
Subject(s)
Cholangitis, Sclerosing , Colitis, Ulcerative , Adult , Humans , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/surgery , Cholangitis, Sclerosing/diagnosis , Cholangitis, Sclerosing/epidemiology , Cholangitis, Sclerosing/surgery , Colectomy/adverse effects , Prognosis , Proportional Hazards ModelsABSTRACT
Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.
Subject(s)
Cholangitis, Sclerosing , Genome-Wide Association Study , Humans , Phenotype , Interferon Regulatory Factors/genetics , Polymorphism, Single NucleotideABSTRACT
BACKGROUND & AIMS: The evidence for hepatobiliary tumour surveillance in patients with primary sclerosing cholangitis (PSC) is scarce. In this study, we aimed to prospectively evaluate cholangiocarcinoma (CCA) surveillance with yearly MRI with cholangiopancreatography (MRI/MRCP) in a nationwide cohort. METHODS: In total, 512 patients with PSC from 11 Swedish hospitals were recruited. The study protocol included yearly clinical follow-ups, liver function tests and contrast-enhanced MRI/MRCP and carbohydrate antigen (CA) 19-9. Patients with severe/progressive bile duct changes on MRI/MRCP were further investigated with endoscopic retrograde cholangiopancreatography. Patients were followed for 5 years or until a diagnosis of CCA, liver transplantation (LT) and/or death. Risk factors associated with CCA were analysed with Cox regression. RESULTS: Eleven patients (2%) were diagnosed with CCA, and two (0.5%) with high-grade bile duct dysplasia. Severe/progressive bile duct changes on MRI/MRCP were detected in 122 patients (24%), of whom 10% had an underlying malignancy. The primary indication for LT (n = 54) was biliary dysplasia in nine patients (17%) and end-stage liver disease in 45 patients (83%), of whom three patients (7%) had unexpected malignancy in the explants. The median survival for patients with CCA was 13 months (3-22 months). Time to diagnosis of high-grade dysplasia and/or hepatobiliary malignancy was significantly associated with severe/progressive bile duct changes on MRI/MRCP (hazard ratio 10.50; 95% CI 2.49-44.31) and increased levels of CA19-9 (hazard ratio 1.00; 95% CI 1.00-1.01). CONCLUSION: In an unselected cohort of patients with PSC, yearly CA19-9 and MRI/MRCP surveillance followed by ERCP was ineffective in detecting cancer early enough to support long-term survival. Given the low occurrence of CCA, studies on individualised strategies for follow-up and improved diagnostic methods for PSC-related CCA are warranted. IMPACT AND IMPLICATIONS: A prospective nationwide 5-year study was conducted to evaluate yearly cholangiocarcinoma surveillance using MRI and CA19-9 in patients with primary sclerosing cholangitis. Only 2% of the patients were diagnosed with cholangiocarcinoma during follow-up and their prognosis remained poor despite surveillance. This surveillance strategy failed to detect cancer early enough to support long-term survival. Therefore, individualised strategies and improved diagnostic methods will be required to improve the early detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Cholangitis, Sclerosing , Humans , Cholangitis, Sclerosing/diagnosis , CA-19-9 Antigen , Prospective Studies , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/pathology , Bile Ducts, Intrahepatic/pathologyABSTRACT
BACKGROUND & AIMS: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. METHODS: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. RESULTS: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. CONCLUSIONS: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Cholangitis, Sclerosing , Humans , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/diagnostic imaging , Retrospective Studies , Follow-Up Studies , Cholangiocarcinoma/diagnosis , Cholangiopancreatography, Endoscopic Retrograde , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/diagnosisSubject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Cholangitis, Sclerosing , Humans , Cholangitis, Sclerosing/diagnosis , Cholangitis, Sclerosing/therapy , Cholangitis, Sclerosing/pathology , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/therapy , Cholangiocarcinoma/pathology , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/therapy , Bile Duct Neoplasms/pathologyABSTRACT
Background & Aims: Magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis and follow-up of individuals with primary sclerosing cholangitis (PSC). The aim of our study is to develop an MRCP-score based on cholangiographic findings previously associated with outcomes and assess its reproducibility and prognostic value in PSC. Methods: The score (DiStrict score) was developed based on the extent and severity of cholangiographic changes of intrahepatic and extrahepatic bile ducts (range 0-8) on 3D-MRCP. In this retrospective, multicentre study, three pairs of radiologists with different levels of expertise from three tertiary centres applied the score independently. MRCP examinations of 220 consecutive individuals with PSC from a prospectively collected PSC-cohort, with median follow-up of 7.4 years, were reviewed. Inter-reader and intrareader agreements were assessed via intraclass correlation coefficient (ICC). After consensus, the prognostic value of the score was assessed using Cox-regression and outcome-free survival rates were assessed via Kaplan-Meier estimates. Harrell's C-statistic was calculated. Results: Forty patients developed outcomes (liver transplantation or liver-related death). Inter-reader agreement between experienced radiologists was good (ICC 0.82; 95% CI 0.74-0.87, and ICC 0.81; 95% CI 0.70-0.87, respectively) and better than the agreement for the pair of experienced/less-experienced radiologists (ICC 0.48; 95% CI 0.05-0.72). Agreement between radiologists from the three centres was good (ICC 0.76; 95% CI 0.57-0.89). Intrareader agreement was good to excellent (ICC 0.85-0.93). Harrell's C was 0.78. Patients with a DiStrict score of 5-8 had 8.2-fold higher risk (hazard ratio 8.2; 95% CI 2.97-22.65) of developing outcomes, and significantly worse survival (p <0.001), compared to those with a DiStrict score of 1-4. Conclusions: The novel DiStrict score is reproducible and strongly associated with outcomes, indicating its prognostic value for individuals with PSC in clinical practice. Impact and implications: The diagnosis of primary sclerosing cholangitis (PSC) is based on magnetic resonance cholangiopancreatography (MRCP). However, the role of MRCP in the prognostication of PSC is still unclear. We developed a novel, simple, and reproducible risk-score, based on MRCP findings, that showed a strong association with prognosis in individuals with PSC (DiStrict score). This score can be easily used in clinical practice and thus has the potential to be useful in clinical trials and in patient counselling and management.