Abstract Extraintestinal manifestations in inflammatory bowel disease (IBD) have been described with varying frequencies. The aim of this study was to estimate the prevalence of pancreatic duct abnormalities, exocrine and endocrine dysfunction, elevated pancreatic enzymes, hepato-biliary disease, coexisting cholangiographic and pancreatographic duct changes, and elevated serum levels of fibrosis markers in IBD, and to correlate the findings with clinical, endoscopic and histologic variables. From a local patient register, 237 patients were randomly selected and studied. Of these, 170 had ulcerative colitis (UC), 46 had Crohn's disease (CD), and 21 had indeterminate colitis (IC). A detailed history was obtained from medical records and in a face-to-face interview. The patients were screened with a para-aminobenzoic acid (PABA) test and, for pancreatic enzymes, liver function tests, serum aminoterminal propeptide of type III procollagen (PIIINP), and laminin. Further pancreatic evaluation included endoscopic retrograde cholangiopancreato-graphy (ERCP), ultrasound (US), secretin test, and glucagon C-peptide test. Further hepatobiliary evaluation consisted of ERCP, US, and liver biopsy. In IBD, the prevalence rates of pancreatic duct abnormalities and exocrine dysfunction were 8% and 4%, respectively. Parallel impairment of exocrine and endocrine functions was shown. Acute idiopathic pancreatitis may complicate IBD. About 7-17% presented with elevated pancreatic enzymes. Enzyme elevation was associated with extensive and histologically active disease and, in some cases, with primary sclerosing cholangitis (PSC). Abnormal liver test results were commoner in patients with CD than in patients with UC (30% versus 11%). The prevalence of PSC in IBD was 11%, which is higher than previously reported (3.7-7.5%). PSC was commoner in patients with CD than in patients with UC (17.4% versus 7.6%). About half of the PSC patients had concomitant pancreatic duct changes, and the prevalence of concurrent cholangiographic and pancreatographic duct changes in IBD was 4.6%. Both serum PIIINP and laminin were increased in IBD patients. This was not only seen in patients with hepatobiliary disease and PSC, but also in patients with pancreatic disease. In conclusion, pancreatic and hepatobiliary complications in IBD occur with high and similar frequencies in all IBD categories and are associated with each other. They are not clearly associated with the clinical course of IBD.

Inflammatory bowel disease (IBD) comprises diseases that are characterized by chronic or relapsing inflammation of the gastrointestinal tract. Primary sclerosing cholangitis (PSC) is an extraintestinal manifestation in IBD. Immunoreactivity against an autoantigen that is expressed both in the gastrointestinal tract and the biliary tract could be the link between these diseases. A possible source of such an antigen is goblet cells. Immunostainings of normal human tissues using IBD patient sera showed goblet cell immunoreactivity against goblet cells in all parts of the gastrointestinal tract. The most frequent immunostaining was found against goblet cells in the appendix against which 84% (42/50) of IBD patients compared to 8% (4/50) of healthy blood donors showed immunoreactivity. To identify the corresponding antigen we used three different approaches, investigation of immunoreactivity to different candidate proteins compared to IBD sera, immunoscreening of an appendiceal cDNA library, and immunoprecipitation of protein lysates from mucin producing cells followed by SDS-PAGE and 2D gel electrophoresis. These approaches led to the identification of several candidate autoantigens of which complement C3 is the most promising. A novel staining pattern with strong immunoreactivity to granules and the apical membrane of biliary epithelial cells was identified with 35% (12/34) of PSC sera compared to none of healthy controls (n=28). Screening of a cDNA library from normal human choledochus identified PDZ domain containing 1 (Pdzk1) and Glutathion S transferase theta 1 (GSTT1) as potential candidates. Pdzk1 is an interesting candidate which is expressed in the intestinal tract and bile ducts. GSTT1 antibodies were not specific for PSC and are thought to develop as an alloimmune response in patients with the GSTT1-null genotype. In conclusion, we have identified specific immunoreactivity to goblet cells and biliary epithelial cells using sera from patients with IBD and PSC respectively. We have also identified several potential autoantigens.

Abstract Biliary carcinoma, biliary fistula with occasional gallstone ileus and primary sclerosing cholangitis (PSC) are serious diseases and present specific diagnostic and therapeutic challenges. Stenting of biliary obstruction has also involved problems, but the reports are contradictory and partly limited. The aim of the present work was to evaluate and compare various imaging modalities in biliary diseases. The study also aimed to evaluate the usefulness of metallic stents in malignant biliary obstruction. The study population consisted of 210 patients with gallbladder carcinoma, bile duct carcinoma, biliary fistula, PSC or malignant biliary obstruction and eight control patients with various hepatobiliary diseases. The imaging findings of 80 patients with gallbladder carcinoma, 58 patients with bile duct carcinoma, and 16 patients with biliary fistula were reviewed. Nine patients with PSC underwent magnetic resonance cholangiography (MRC) and magnetic resonance imaging (MRI) of the liver, ultrasonography (US) of the liver and the bile ducts and endoscopic retrograde cholangiography (ERC). Eight control patients had had MRC and MRI of the liver and ERC. The medical records and radiographs of 39 patients with malignant biliary obstruction treated with percutaneously inserted metallic stents were also analysed. The stents included 48 Wallstents and seven Memotherm stents. In cases of gallbladder carcinoma, US visualised the primary tumour in 68 % and computed tomography (CT) in 57 % of the cases examined, but both methods were insufficient for accurate staging. In bile duct carcinoma, US revealed the primary tumour in 63 % and CT in 44 % of the cases examined. Both methods were sensitive in diagnosing peripheral intrahepatic cholangiocarcinoma, but inaccurate for more distal bile duct carcinoma or abdominal spread. The infiltrating type of gallbladder carcinoma and bile duct carcinoma were difficult to detect. US and CT were sensitive in revealing bile duct obstruction. The patients with biliary fistula and gallstone ileus had undergone various examinations with pathological, but not diagnostic results, and there was often a delay to diagnosis. Imaging did not reveal any of the ten spontaneous fistulas, but CT showed one of the five cases of gallstone ileus, and Gastrografin® meal revealed the single case of Bouveret's syndrome. Fistulography or cholangiography revealed all but one of the six iatrogenic fistulas. A nonvisualised or shrunken gallbladder at US should raise a suspicion of biliary enteric fistula in an appropriate clinical setting. MRC-MRI depicted the changes of PSC correctly in nine patients (radiologist 1) and in eight patients with one false positive finding (radiologist 2) in a blinded analysis. In the segmental comparison MRC missed especially bile duct dilatations. MRC was too pessimistic in the evaluation of the predictors of poor outcome. US detected features suggestive of PSC in eight patients (radiologist 3). US was unable to indicate the predictors of poor outcome. Of the patients with metallic stents in malignant biliary obstruction, 30 % had early and 66 % late complications, including stent obstructions, which occurred in 27 % of the patients at a mean of 4.4 months. The cause was mostly tumour ingrowth or overgrowth. The 25-week and 50-week patency rates were 71 % and 42 %. The patency rates of the patients with cholangiocarcinoma were significantly the lowest. There was also a tendency towards lower patency with less dilatation of the stents, an increasing number of the stents, longer strictures and hilar strictures. Many other complications were infectious. 31 % of the patients had late reinterventions.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with outcomes that include hepatobiliary malignancy and liver transplantation. The pathogenesis of PSC is incompletely understood and, as a result, few markers of disease progression have been identified. Vitamin D is associated with the development and treatment of multiple cancers as well as the progression of inflammatory bowel disease, making it a possible candidate as a biomarker associated with PSC outcomes. In this study, we retrospectively and prospectively collected complete laboratory results and outcome datapoints on 179 patients with PSC to determine the association between total 25(OH)-vitamin D levels, vitamin D supplementation, and both hepatobiliary malignancy and liver transplantation. Through survival analysis, we found that history of vitamin D supplementation was significantly associated with increased hepatobiliary malignancy-free and liver transplantation-free survival (p=0.025 and p=0.042, respectively). These results indicate that vitamin D is a promising factor associated with the progression of PSC to transplantation and malignancy. Future studies on this registry cohort as it increases in size and age may provide more conclusive data on the relationship between vitamin D and PSC.

Primary sclerosing cholangitis (PSC) is a rare inflammatory chronic liver disease that causes damage to the intra- and or extrahepatic bile ducts leading to cholestasis. As the disease proceeds the development of cirrhosis and eventually liver failure occurs. This study aims to determine the role of IgG subclasses in the prognosis of PSC and its outcome. A retrospective analysis was performed of 183 patients followed at the Department of Upper Abdominal Diseases at the Karolinska University Hospital. Factors that were analysed were sex, age at PSC diagnosis, total IgG values, IgG subclasses values and events of autoimmune hepatitis (AIH), inflammatory bowel disease (IBD), colectomy, cirrhosis, cholangitis, endoscopic retrograde cholangiopancreatography (ERCP), liver transplantation and cholangiocarcinoma. This study showed that high IgG4 levels were associated with a higher incidence of cirrhosis, liver transplantation, cholangitis and ERCP, while low IgG4 levels were associated with a prior IBD diagnosis. In conclusion, elevated IgG4 levels were associated with a higher occurrence of cirrhosis, cholangitis, ERCP and liver transplantation. It seems that IgG4 could be of importance for outcome prediction in PSC.

Primary sclerosing cholangitis (PSC) is a rare chronic liver disease characterized by inflammation and fibrosis of the biliary ducts, resulting in cholestasis and eventually liver failure. No effective treatment is currently available and most patients ultimately require liver transplantation in order to survive. The underlying mechanisms of the disease is poorly understood but a range of hypotheses exist, many of which recognize and grapple with PSC's close relationship with inflammatory bowel disease. Most agree genetics is involved, predisposing for an imbalance in 1) bile acid metabolism, 2) immune response and/or 3) gut microbiota. This literature study aims to describe and elucidate recent progress in the field of pharmacotherapy, as it relates to PSC and our current understanding of the disease. Covered in this study is a total of seven randomized, controlled trials, published between 2015-2022, and available through the medical database/search engine PubMed. Endpoints of particular note are ALP and ELF. ALP, or alkaline phosphatase, is an enzyme found in the liver. Rising levels of ALP in the blood stream is indicative of liver damage. ELF, or Enhanced Liver Fibrosis, is a blood test measuring markers of fibrosis, useful in assessing and staging fibrosis in chronic liver disease. Drugs included in this literature study are aldafermin, cilofexor, fenofibrate, norUrsodeoxicholic acid, obeticholic acid, simtuzumab and vancomycin. With the exception of aldafermin and simtuzumab, all showed promise as ALP reducing agents, in general lowering levels with 15-40 percent. In the case of fenofibrate, a reduction of 65 percent was observed. Of the drugs measured against ELF, only aldafermin produced a statistically significant reduction in fibrosis markers. At the time being it is not entirely clear what to make of the results, due to uncertainties surrounding ALP as a prognostic marker. To what extent ALP predicts transplantation free survival is still a matter of debate. Although considerable efforts have been made to further our understanding of PSC, much is yet to be solved. With regards to pharmacotherapy, the field is experiencing somewhat of a renaissance, showcased by the dozen on-going randomized, controlled trials on a plethora of potential PSC substances. Thus, the search for an effective therapy against PSC goes on.

Background: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3− mediated signaling. Aims: The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status. Methods: In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients. Results: The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49/437; p = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; p < 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3− PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3−) PSC patients. Conclusion: MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC.

Inflammatory bowel disease (IBD) represents a group of multifactorial illnesses with increasing incidence worldwide. Crohn's disease (CD) and ulcerative colitis (UC) are the two most thoroughly defined phenotypes of IBD. IBD associated with primary sclerosing cholangitis (PSC) - a progressive biliary disease leading to cirrhosis and liver failure - is considered as specific IBD phenotype (also referred to as 'PSC - IBD') due to its clinical and pathophysiological characteristics. The aim of the experimental part of this thesis was to define specific features of PSC - IBD in the key areas of IBD pathogenesis. These are: microbiota composition, gut - barrier failure, genetic predisposition and aberrant cellular and antibody immune response. Furthermore, the other goals were to describe relation of IBD status and activity to liver transplantation (LTx) and carcinogenesis based on thorough analysis of clinical data in patients under surveillance at the liver transplantation unit. Using the next-generation parallel sequencing technology, we discovered specific bacterial and mycobial features of gut microbiota composition in PSC - IBD which significantly differed from UC and healthy controls recruited from Czech general population. Moreover, we identified numerous seral biomarkers distinguishing CD, UC...