Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis.

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.

The Role of Immunoglobulin G4 in Outcomes of Primary Sclerosing Cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting bile ducts which eventually develops into liver cirrhosis and liver failure. The aim of this study was to investigate serum IgG subclass distribution in patients with PSC and its possible association with PSC outcomes. PATIENTS AND METHODS: We performed a retrospective analysis of 181 patients who had been diagnosed with PSC between January 1970 and December 2015 and followed at our outpatient clinic. Their demographic, immunological, and clinical characteristics were recorded and analyzed. RESULTS: This study included 181 patients with PSC (120 males, 61 females). There was no association between IgGs and the development of autoimmune hepatitis, cirrhosis, cholangiocarcinoma, liver transplantation, inflammatory bowel disease, and colectomy. Patients with elevated IgG4 had statistically significant higher rates of cholangitis (p = 0.02) and endoscopic retrograde cholangiopancreatography (ERCP) (p = 0.009). High IgG4 values were observed in nine patients who underwent ERCP. In these nine patients, on average, IgG4 was evaluated 5 years after ERCP (min 3 days, max 11 years). Subanalysis considering only IgG4 values evaluated before ERCP showed no significant difference but remains significant if we consider IgG4 values after ERCP. CONCLUSION: Elevated IgG4 in our study showed a possible association with higher rates of cholangitis and ERCP among patients with primary sclerosing cholangitis. It seems that IgGs may be a useful tool for the prediction of outcomes in patients with PSC. A prospective study is necessary, especially to study the trends of IgGs values during disease as well as the role of possible seroconversion.

Immunoglobulin G subtypes-1 and 2 differentiate immunoglobulin G4-associated sclerosing cholangitis from primary sclerosing cholangitis.

BACKGROUND: Autoimmune pancreatitis is a special form of chronic pancreatitis with strong lymphocytic infiltration and two histopathological distinct subtypes, a lymphoplasmacytic sclerosing pancreatitis and idiopathic duct centric pancreatitis. Immunoglobulin G4-associated cholangitis may be present at the time of autoimmune pancreatitis type 1 diagnosis or occur later over the course of the disease. Immunoglobulin G4 is considered reliable but not an ideal marker for diagnosis of autoimmune pancreatitis type 1 with reported sensitivity between 71-81%. It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis as the treatment and prognosis of the two diseases are totally different. It was the aim of the study to find a marker for immunoglobulin G4-associated cholangitis that would distinguish it from primary sclerosing cholangitis. PATIENTS AND METHODS: We performed a retrospective analysis of patients with autoimmune pancreatitis at our outpatient clinic. Patients from the primary sclerosing cholangitis registry were taken as a control group. Blood samples for the measurement of immunoglobulin subclasses were analysed at the time of diagnosis. RESULTS: Patients with autoimmune pancreatitis and immunoglobulin G4-associated cholangitis had higher values of immunoglobulin G2 when compared to autoimmune pancreatitis alone or primary sclerosing cholangitis with a high specificity (97%) and high positive predictive value (91%). In patients with normal or low immunoglobulin G2 or immunoglobulin G4, a high level of immunoglobulin G1 indicated primary sclerosing cholangitis. CONCLUSION: Immunoglobulin G1 and immunoglobulin G2 can distinguish patients with immunoglobulin G4-associated cholangitis from those with primary sclerosing cholangitis.

Inter-reader agreement of interpretation of radiological course of bile duct changes between serial follow-up magnetic resonance imaging/3D magnetic resonance cholangiopancreatography of patients with primary sclerosing cholangitis.

Objectives: Interpretation of MRI/MRCP in primary sclerosing cholangitis (PSC) at a single time point has low inter-reader agreement. Agreement of interpretation of the dynamic course of duct changes in follow-up MRI/MRCP is of clinical importance but remains unknown. Our aims are therefore to assess the inter-reader agreement of interpretation of the course of duct changes in PSC and investigate if elimination of 3 D MRCP affects inter-reader agreement.Materials and Methods: We studied 40 consecutive PSC-patients who underwent two liver MRI/MRCPs at two time points. Two readers independently evaluated the course of duct changes between the two time points in two imaging sets, one with and one without 3 D MRCP. The intraclass correlation coefficient (ICC) was calculated for evaluation of inter-reader and intra-reader agreement between the two time points and two imaging sets accordingly.Results: Inter-reader agreement of the interpretation of the course of duct changes between the two time points was poor (ICC up to 0.224). Elimination of 3 D MRCP neither improved inter-reader agreement which was again poor (ICC up to 0.26) nor did it change considerably the way readers interpret the course of ducts changes (ICC for intra-reader agreement between 0.809 and 0.978).Conclusions: Inter-reader agreement of the interpretation of radiological course of duct changes is poor in serial follow-up MRI/MRCP of PSC-patients. Elimination of 3 D MRCP does not increase inter-reader agreement but maintains an excellent intra-reader agreement for the interpretation of the dynamic course of bile duct changes.Key pointsInter-reader agreement of interpretation of radiological course of bile duct changes between serial follow-up MRI/MRCP examinations of patients with PSC is poor.Absence of 3D MRCP does not affect considerably the way readers interpret the radiological course of bile ducts changes.When MRCP is absent or of low quality, utilization of other sequences seems to be helpful as an alternative for bile duct evaluation.

Prevalence of Viremic hepatitis C, hepatitis B, and HIV infection, and vaccination status among prisoners in Stockholm County.

BACKGROUND: Identification and knowledge of settings with high prevalence of hepatitis C virus (HCV) infection is important when aiming for elimination of HCV. The primary aim of this study was to estimate the prevalence of viremic HCV infection among Swedish prisoners. Secondary aims were to estimate the prevalence of hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV), and the proportion who have received hepatitis B virus (HBV) vaccination. METHODS: A cross-sectional study of all incarcerated persons (n = 667) at all prisons (n = 9) in Stockholm County was conducted. All prisoners are routinely offered opt-in screening for HCV antibodies (anti-HCV), HCV RNA, HBsAg, anti-HBs, anti-HBc and HIV Ag/Ab at prison in Sweden. Data on the results of these tests and the number of received HBV vaccine doses were collected from the prison medical records. The parameters of HCV RNA, anti-HCV, and occurrence of testing for HCV were analysed in multiple logistic regression models in relation to age, sex and prison security class. RESULTS: The median age was 35 (IQR 26-44) years, and 93.4% were men. Seventy-one percent (n = 471) had been tested for anti-HCV, 70% (n = 465) for HBsAg and 71% (n = 471) for HIV. The prevalence of anti-HCV, HCV RNA, HBsAg and HIV Ag/Ab was 17.0, 11.5, 1.9, and 0.2%, respectively among tested persons. The proportion of prisoners who had received full HBV vaccination was 40.6% (n = 271) among all study subjects. CONCLUSIONS: The prevalence of viremic HCV infection among Swedish prisoners in Stockholm County was 11.5%, which is high in comparison to the general population. Therefore, when aiming for the WHO goal of HCV elimination, prisons could suit as a platform for identification and treatment of HCV infection. There is a need to increase testing for blood-borne viruses and to improve vaccination coverage against HBV in Swedish prisons.

No Superiority of Stents vs Balloon Dilatation for Dominant Strictures in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917.

Optimizing the detection of biliary dysplasia in primary sclerosing cholangitis before liver transplantation.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) have increased risk of cholangiocarcinoma (CCA). We evaluated pre-transplant work-up in PSC patients, to search for the most effective strategy for the detection of biliary dysplasia or early CCA. METHODS: Two hundred and twenty five consecutive PSC patients undergoing liver transplantation (LTx) in Sweden between 1999 and 2013 were studied. Patients with CCA or dysplasia in the explanted liver were compared with those with benign histopathology. Measures of test performance were calculated for patients having brush cytology on one endoscopic retrograde cholangiopancreaticography (ERCP) occasion, for those having repeated examinations with or without cholangioscopy, and for fluorescence in situ hybridization (FISH). Survival after LTx was analyzed. RESULTS: Brush cytology on a single ERCP occasion had moderate sensitivity (57%) and high specificity (94%) for the detection of CCA/high grade dysplasia (HGD) in the explanted liver. The corresponding sensitivity and specificity for FISH were 84% and 90%, respectively. Utilizing repeated ERCP and brush cytology to confirm the initial finding improved sensitivity to 82%. Using single operator cholangioscopy (SOC) for targeted examination at the second ERCP improved sensitivity (100%) and specificity (97%) significantly. Mortality rate in patients with incidentally discovered CCA (n = 16) in the explanted liver was significantly higher than in patients with HGD or benign histopathology (HR 16.0; 95% CI, 5.6-45.4; p < .001). CONCLUSIONS: Repeated brush cytology especially when combined with targeted examination under SOC guidance is superior to single brush examinations. This strategy improves the detection of malignancy in PSC and is of importance for selection of patients for LTx.

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.

The value of thioredoxin family proteins and proliferation markers in dysplastic and malignant gallbladders in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Patients with primary sclerosing cholangitis (PSC) have an increased risk for biliary and gallbladder malignancy and markers of early malignancy in PSC are lacking. The aims were to evaluate biomarkers to look for premalignancy/malignancy. METHODS: All available gallbladder specimens (n = 53) in patients with PSC at Karolinska University Hospital between 1985 and 2006 were reviewed. Immunohistochemical staining for p53, Ki-67, Cyclin D1 and the thioredoxin family redox proteins; Thioredoxin reductase 1 (TrxR1), isoform-TrxR1-v.2.3.5, Thioredoxin (Trx1) and Glutaredoxin1 (Grx1) was performed on tissues from patients with carcinoma (n = 6), dysplasia (n = 7) and non-cancerous gallbladder epithelium (n = 6). RESULTS: Dysplasia and carcinoma were found in 16/53 (30%) cases. Inflammation and fibrosis of the gallbladder wall were more common in tissue with gallbladder dysplasia/carcinoma than in benign tissue 12/25 (48%) versus 4/28 (12%) (p < 0.01) and in 13/21 (62%) versus 3/32 (9%) (p < 0.0001), respectively. Immunoreactivity for p53, Ki67, Cyclin D1 was detected in significantly more cases of dysplasia/carcinoma of the gallbladder than in non-cancerous epithelium. 2/19 (11%) of the samples were positive in non-cancerous epithelium versus 7/17 (41%) in dysplasia/carcinoma (p < 0.05) for TrxR1-v.2.3.5. Grx1 was down regulated; more specifically 15/19 (79%) positive cases in non-cancerous epithelium versus 7/17 (41%) in dysplasia/carcinoma. CONCLUSION: PSC patients have a frequency of gallbladder dysplasia/carcinoma of 30% in operative specimens. The overexpression of TrxR1-v2,3,5 and down regulation of Grx1 in dysplastic gallbladder epithelium suggest that these proteins should be further evaluated as possible future immunohistochemical markers in the early diagnosis of biliary malignancy in PSC.

Pancreatic duct changes are not associated with early signs of chronic pancreatitis at magnetic resonance imaging (MRI) in patients with primary sclerosing cholangitis.

OBJECTIVE: The association between chronic pancreatitis (CP) and primary sclerosing cholangitis (PSC) has been reported previously. The aims of the present study were to evaluate the presence of early pancreatic abnormalities and duct changes, using MRCP/MRI in PSC and to evaluate possible risk factors for these changes and their clinical importance. MATERIALS AND METHODS: One hundred and three patients with PSC were identified among all MRI liver/pancreas referrals in 2001-2005. MRCP was used to grade pancreatic duct changes in three groups: grade 0 (normal), grade 1 (mild) and grade 2 (severe). For detection of early MRI signs of CP, the pancreas-spleen signal intensity ratio (SIR), the arterial and early venous phase ratio (A/PV ratio) and the age-related size of the pancreas were evaluated. RESULTS: Pancreatic duct changes were found in 24% of the PSC patients. The pancreatic duct changes were associated with extrahepatic biliary involvement and long duration of PSC but not associated with pancreas-spleen SIR, A/PV ratio, pancreas size, previous post-ERCP or acute pancreatitis. Severe pancreatic duct changes were significantly associated to abdominal pain. Clinically significant CP was seen in one PSC patient (1%). CONCLUSIONS: Pancreatic duct changes are associated with extrahepatic bile duct strictures and not with the early MRI signs of CP. Therefore, pancreatic duct changes seem to be part of the spectrum of PSC and should not be defined as CP. Pancreatic duct changes are of limited clinical importance but may contribute to abdominal pain in PSC.

Gallbladder emptying in patients with primary sclerosing cholangitis.

AIM: To assess gallbladder emptying and its association with cholecystitis and abdominal pain in patients with primary sclerosing cholangitis (PSC). METHODS: Twenty patients with PSC and ten healthy subjects were investigated. Gallbladder fasting volume, ejection fraction and residual volume after ingestion of a test meal were compared in patients with PSC and healthy controls using magnetic resonance imaging. Symptoms, thickness and contrast enhancement of the gallbladder wall and the presence of cystic duct strictures were also assessed. RESULTS: Median fasting gallbladder volume in patients with PSC [67 (19-348) mL] was twice that in healthy controls [32 (16-55) mL] (P < 0.05). The median postprandial gallbladder volume in patients with PSC was significantly larger than that in healthy controls (P < 0.05). There was no difference in ejection fraction, gallbladder emptying volume or mean thickness of the gallbladder wall between PSC patients and controls. Contrast enhancement of the gallbladder wall in PSC patients was higher than that in controls; (69% +/- 32%) and (42% +/- 21%) (P < 0.05). No significant association was found between the gallbladder volumes and occurrence of abdominal pain in patients and controls. CONCLUSION: Patients with PSC have increased fasting gallbladder volume. Gallbladder Mucosal dysfunction secondary to chronic cholecystitis, may be a possible mechanism for increased gallbladder.

Gallbladder disease in patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: Gallbladder abnormalities may be part of the spectrum in primary sclerosing cholangitis (PSC). The aim of the present study was to evaluate the occurrence and prognostic importance of gallbladder abnormalities in patients with PSC. METHODS: Presence of gallbladder abnormalities was assessed in 286 patients with PSC treated at the Liver Unit, Karolinska University Hospital, Huddinge, between 1970 and 2005. RESULTS: One or more gallbladder abnormalities were found in 41% of the patients. Gallstones were found in 25% and cholecystitis in 25%. Cholecystitis among patients with extrahepatic involvement of PSC (30% (65/214)) was significantly higher than among those with intrahepatic involvement (9% (6/70)) (P<0.0001). A gallbladder mass lesion with a mean size of 21 (+/-9) mm (S.D.) was found in 18 (6%) patients, in 56% (10/18) of whom it constituted gallbladder carcinoma. In 9 patients without a gallbladder mass lesion, histological re-evaluation disclosed epithelial dysplasia of the gallbladder. CONCLUSIONS: Gallbladder disease is common in patients with PSC. Dysplasia and carcinoma are commonly found in gallbladder epithelium, suggesting that regular examination of the gallbladder in PSC patients could be of value for early detection of a gallbladder mass lesion. Cholecystectomy is recommended when such a lesion is detected, regardless of its size.

Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden.

OBJECTIVE: The use of magnetic resonance cholangiopancreaticography (MRCP) as a non-invasive diagnostic tool for primary sclerosing cholangitis (PSC), together with increased clinical awareness of the disease, has led to earlier diagnosis. The aim of this study was to investigate the clinical presentation of PSC including its association with inflammatory bowel disease (IBD) and the development of cholangiocarcinoma at one centre over an observation period of 20 years. MATERIAL AND METHODS: All patients with well-defined PSC, diagnosed after 16 years of age and treated at Huddinge University Hospital between 1984 and 2004, were included in the study (n=246). PSC and IBD characteristics were retrieved from the patients' medical records. The patients were subdivided according to the date of diagnosis: 185 PSC patients diagnosed before 30 October 1998 were compared with 61 patients diagnosed after that date. RESULTS: Patients diagnosed after 1998 were significantly older at diagnosis (mean age 41 versus 37 years) and presented fewer symptoms (47% versus 63%) as well as a lower frequency of coexisting IBD (69% versus 82%). In the whole group, women had significantly more symptoms than men, particularly pruritus (p<0.05). CONCLUSIONS: The clinical spectrum of PSC in Sweden has changed over the past 20 years; today, PSC patients are older at diagnosis and associated IBD is less frequent.