Etiology Of Primary Sclerosing Cholangitis Research Articles

Genetic link between primary sclerosing cholangitis and thyroid dysfunction: a bidirectional two-sample Mendelian randomization study.

Observational studies have demonstrated an association between primary sclerosing cholangitis (PSC) and thyroid dysfunction (TD). However, the causal relationship between PSC and TD remains uncertain. The purpose of this study is to investigate the causal associations and specific direction between these two conditions. Gaining insight into the potential causal relationship between PSC and TD is valuable for elucidating the pathogenesis of PSC and for devising innovative approaches for the prevention and treatment of PSC and its associated complications. We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal association between PSC and TD, such as autoimmune thyroid disease (AITD), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), among others. PSC was the exposure variable, while TD was the outcome variable. To identify suitable instrumental variables (IVs), we utilized genome-wide association study (GWAS) datasets to select potential candidate single-nucleotide polymorphisms (SNPs). The primary statistical approach employed was the inverse-variance weighted (IVW) method, which was complemented by a series of sensitivity analyses to assess the robustness of the results by estimating heterogeneity and pleiotropy. We found that the causal associations between genetically predicted PSC and Graves' disease (GD), hyperthyroidism (IVW OR=1.230, 95%CI: 1.089-1.389, P=0.001; IVW OR=1.001, 95%CI: 1.000-1.002, P=0.000) were statistically significant. The reverse MR analysis indicated that genetic susceptibility to hyperthyroidism (P=0.000) and hypothyroidism (p=0.028) might be the risk of PSC. There was no statistically significant causal association observed between PSC and other TD (IVW P>0.05), with the exception of GD, hyperthyroidism, and hypothyroidism as determined through bidirectional two-sample analysis. To ensure the reliability of our findings, additional sensitivity analyses were conducted, including the leave-one-out (LOO) test, heterogeneity test, and pleiotropic test. In this study, we conducted an investigation into the causal association between PSC and TD. Our findings indicate that PSC significantly elevates the susceptibility to GD and hyperthyroidism from a statistical perspective. These results shed light on the etiology of PSC and have implications for the management of patients with PSC.

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

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

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic and/or extrahepatic bile ducts, leading to bile stasis, fibrosis, and ultimately to cirrhosis, and often requires liver transplantation (LT). PSC occurs more commonly in men, and is typically diagnosed between the ages of 30 and 40. Most cases occur in association with inflammatory bowel disease (IBD), which often precedes the development of PSC. PSC is usually diagnosed after detection of cholestasis during health evaluation or screening of patients with IBD. When symptomatic, the most common presenting symptoms are abdominal pain, pruritus, jaundice or fatigue. The etiology of PSC is poorly understood, but an increasing body of evidence supports the concept of cholangiocyte injury as a result of environmental exposure and an abnormal immune response in genetically susceptible individuals. PSC is a progressive disease, yet no effective medical therapy for halting disease progression has been identified. Management of PSC is mainly focused on treatment of symptoms and addressing complications. PSC can be complicated by bacterial cholangitis, dominant strictures (DSs), gallbladder polyps and adenocarcinoma, cholangiocarcinoma (CCA) and, in patients with IBD, colorectal malignancy. CCA is the most common malignancy in PSC with a cumulative lifetime risk of 10-20%, and accounts for a large proportion of mortality in PSC. LT is currently the only life-extending therapeutic approach for eligible patients with end-stage PSC, ultimately required in approximately 40% of patients. LT secondary to PSC has an excellent outcome compared to other LT indications, although the disease can recur and result in morbidity post-transplant.

Recurrence of primary sclerosing cholangitis after liver transplantation is associated with specific changes in the gut microbiome pretransplant - a pilot study.

SummaryPrimary sclerosing cholangitis (PSC) is a common indication for liver transplantation (LT). Up to 25% of patients experience recurrence of PSC (rPSC) after LT, which is associated with significant morbidity and mortality. To date, it is not possible to predict which patients are at risk for rPSC. The aetiology of PSC is complex and is speculated to involve translocation of intestinal bacteria to the liver, because of its frequent co‐occurrence with inflammatory bowel diseases (IBD). Here, we investigate whether the mucosal intestinal microbiome of PSC patients (n = 97) at time of first LT can identify those patients who will develop rPSC. 16S gene sequencing of bacterial DNA isolated from formalin‐fixed paraffin‐embedded biopsies showed that PSC patients with Crohn’s disease (n = 15) have a reduced microbial diversity and that inflammation of the mucosa is associated with beta‐diversity changes and feature differences. No differences in alpha‐ or beta diversity were observed between patients with rPSC (n = 14) and without rPSC (n = 83). However, many over‐represented bacterial features were detected in patients with rPSC, while surprisingly, those without recurrence of disease were characterized by an increased presence of the Gammaproteobacteria Shigella. This pilot study warrants further investigation into bacterial differences between rPSC and non‐rPSC patients.

Bile microbiota in primary sclerosing cholangitis: Impact on disease progression and development of biliary dysplasia

ObjectiveThe etiopathogenesis and risk for development of biliary neoplasia in primary sclerosing cholangitis (PSC) are largely unknown. Microbes or their metabolites have been suggested to play a role. To explore this potential microbial involvement, we evaluated the differences in biliary microbiota in PSC patients at an early disease stage without previous endoscopic retrograde cholangiography (ERC) examinations, advanced disease stage, and with biliary dysplasia or cholangiocarcinoma.DesignBile samples from the common bile duct were collected from 46 controls and 80 patients with PSC during ERC (37 with early disease, 32 with advanced disease, and 11 with biliary dysplasia). DNA isolation, amplification, and Illumina MiSeq sequencing were performed for the V1-V3 regions of the bacterial 16S rRNA gene.ResultsThe most common phyla found were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Actinobacteria. The most common families were Prevotellaceae, Streptococcaceae, Veillonellaceae, Fusobacteriaceae, and Pasteurellaceae, and the most common genera were Prevotella, Streptococcus, Veillonella, Fusobacterium, and Haemophilus. The bacterial communities of non-PSC subjects and early stage PSC patients were similar. Alpha diversity was lower in patients with biliary dysplasia/cholangiocarcinoma than in other groups. An increase in Streptococcus abundance was positively correlated with the number of ERC examinations. Streptococcus abundance was also positively correlated with an increase in disease severity, even after controlling for the number of ERC examinations.ConclusionsOur findings suggest that the aetiology of PSC is not associated with changes in bile microbial communities, but the genus Streptococcus may play a pathogenic role in the progression of the disease.

The Microbiome and Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC.

WS16.6 Is primary sclerosing cholangitis (PSC) a cystic fibrosis-related disorder? Electrophysiological testing and full sequencing of the CFTR gene

Objectives PSC and Cystic Fibrosis related liver disease (CFLD) have features in common: chronic inflammation and bile duct damage with similar cholangiographic findings. There is controversy if PSC is related to CFTR dysfunction. The aim of this study is to determine whether PSC is associated with mutations in the cftr gene and abnormalities in CFTR function assays. Methods Patients with PSC were referred for Nasal Potential Difference (NPD) measurement, sweat chloride concentration and complete cftr sequencing of the full coding sequence by NGS (new generation sequencing-PGM life technology). Results 32 patients aged 46±13 yrs (IBD in 17) were examined. Cftr sequencing showed 6 patients with cftr mutations on one allele and 19 with polymorphisms in the cftr gene. 28 patients had normal NPD results (Basal NPD −14.6±4.9, response to amiloride 9.2±4.7, response to Cl − free + isoproterenol −11.1±5.7 mV), sweat chloride 43±19 mmol/L and 4 patients had abnormal NPD results (Basal NPD −21.1±8.6, response to amiloride 15.7±7.4, response to Cl − free + isoproterenol −1.1±4.4 mV); sweat chloride was 69, 54, 65 and 44 mmol/L. Of note, one of these patients is infertile; one patient has chronic pancreatitis. Two patients with abnormal NPD carried W1282X/5T mutation and the 2620–26A Conclusion 4 patients out of 32 (12.5%) with PSC have been found to have some features of CFTR related disorder and 18.75% carry cftr mutations and 50% have polymorphisms of the cftr gene. This study will improve our understanding of the etiology of PSC and its relationship to cftr dysfunction.

Current research on the treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a progressive disease of the liver characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts, leading to fibrosis and ultimately liver failure, cirrhosis and an increased risk of malignancy. The etiology of PSC is unclear. It is often associated with the inflammatory bowel diseases (IBD), particularly Ulcerative Colitis (UC); up to 75% of PSC patients have UC. PSC is more prevalent in men than in women. Ursodeoxycholic acid (UDCA) has been extensively studied in PSC in randomized clinical trials but failed to show a positive impact on the natural course of the disease. Currently, there is no effective medical therapy for PSC, and the majority of patients will eventually require liver transplantation. PSC is one of the leading indications for liver transplantation. In this paper, we review the current research on the potential therapeutic agents for the treatment of PSC.

944 PHENOTYPIC AND FUNCTIONAL PLASTICITY OF CD4posCD25highCD127pos AND CD4posCD25highCD127neg T CELLS IN AUTOIMMUNE HEPATITIS

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by progressive inflammation, fibrosis and destruction of the bile ducts. The aetiology of PSC remains enigmatic although lymphocytic infiltration in areas of portal damage suggests an autoimmune mediated disease. CD28 is an important T cell co-stimulatory molecule and CD28− T cells have been reported as being involved in several autoimmune diseases. CD28− T cells are able to produce high amounts of IFNg, resist to apoptosis and show enhanced cytolytic activity. Given this we sought to further characterise CD28− T cells in PSC. Methods: Immunohistochemistry was used to localise CD4 and CD8 subsets in human liver tissue. Liver-infiltrating mononuclear cells (LIMCs) and peripheral blood mononuclear cells (PBMCs) were isolated from normal individuals and patients with PSC. Flow cytometry was used to determine the frequency and phenotypic characteristics of CD4 and CD8 T cells in association with CD28 expression. Results: Immunohistochemical analysis revealed high CD4 and CD8 T cell infiltration in the portal areas of human PSC liver, which was much higher when compared to normal donor livers (n = 5). CD4+ and CD8+ T cells in peripheral blood of PSC patients were present at equal frequencies (ratio of CD4:CD8 1:1) whereas in PSC LIMCs an increased frequency of CD8 T cells was observed (ratio 1:1.5). CD4+CD28− T cells were present at a frequency of 5% in normal peripheral blood, 10% in PSC patients’ peripheral blood and 52% in human PSC liver. 50% of the CD8+ T cells in normal peripheral blood were CD28−. In PSC patients, in both peripheral blood and liver the frequency of CD8+CD28− T cells was 75% and 71% respectively. Conclusions: Our results show a 5-fold increase in the frequency of CD4+CD28− T cells in human PSC liver when compared to PSC patients’ peripheral blood, and an increased frequency of CD8+CD28− T cells in both peripheral blood and liver of PSC patients. Our data suggest that CD28− T cells may be involved in the pathogenesis of PSC.

945 PHENOTYPIC CHARACTERISATION OF CD4 EFFECTOR IMMUNE RESPONSES IN CHILDHOOD AUTOIMMUNE LIVER DISEASE

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by progressive inflammation, fibrosis and destruction of the bile ducts. The aetiology of PSC remains enigmatic although lymphocytic infiltration in areas of portal damage suggests an autoimmune mediated disease. CD28 is an important T cell co-stimulatory molecule and CD28− T cells have been reported as being involved in several autoimmune diseases. CD28− T cells are able to produce high amounts of IFNg, resist to apoptosis and show enhanced cytolytic activity. Given this we sought to further characterise CD28− T cells in PSC. Methods: Immunohistochemistry was used to localise CD4 and CD8 subsets in human liver tissue. Liver-infiltrating mononuclear cells (LIMCs) and peripheral blood mononuclear cells (PBMCs) were isolated from normal individuals and patients with PSC. Flow cytometry was used to determine the frequency and phenotypic characteristics of CD4 and CD8 T cells in association with CD28 expression. Results: Immunohistochemical analysis revealed high CD4 and CD8 T cell infiltration in the portal areas of human PSC liver, which was much higher when compared to normal donor livers (n = 5). CD4+ and CD8+ T cells in peripheral blood of PSC patients were present at equal frequencies (ratio of CD4:CD8 1:1) whereas in PSC LIMCs an increased frequency of CD8 T cells was observed (ratio 1:1.5). CD4+CD28− T cells were present at a frequency of 5% in normal peripheral blood, 10% in PSC patients’ peripheral blood and 52% in human PSC liver. 50% of the CD8+ T cells in normal peripheral blood were CD28−. In PSC patients, in both peripheral blood and liver the frequency of CD8+CD28− T cells was 75% and 71% respectively. Conclusions: Our results show a 5-fold increase in the frequency of CD4+CD28− T cells in human PSC liver when compared to PSC patients’ peripheral blood, and an increased frequency of CD8+CD28− T cells in both peripheral blood and liver of PSC patients. Our data suggest that CD28− T cells may be involved in the pathogenesis of PSC.

Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease leading to fibrotic biliary strictures and liver cirrhosis. The patient population is heterogeneous with regard to disease progression and the presence of co-morbidities, complicating the practical handling of patients as well as studies of pathogenetic mechanisms. The aetiology of PSC is unknown, but the recent findings of several robust susceptibility genes emphasise the importance of genetic risk factors. There is no effective medical treatment available to delay the disease progression, but endoscopic therapy of biliary stenoses may be indicated. Follow-up of patients includes management of the inflammatory bowel disease that is found in the majority of cases along with investigations aimed at the early detection of cholangiocarcinoma and colorectal cancer, which also occur at increased frequencies. In the present review, we aim to summarise the present knowledge of PSC with a particular emphasis on the possible basis of disease variability.

Increased Risk of Primary Sclerosing Cholangitis and Ulcerative Colitis in First-Degree Relatives of Patients With Primary Sclerosing Cholangitis

The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

Current Treatments of Primary Sclerosing Cholangitis

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic disease characterized by hepatic inflammation and obliterative fibrosis, resulting in both intra- and extra-hepatic bile duct strictures. End-stage liver disease and bile duct carcinoma represent frequent complications. Incidence and prevalence of PSC in USA have been recently estimated as 0.9 per 100,000 person-years, and 1-6 per 100,000 person-years, respectively. Major diagnostic criteria include the presence of multifocal strictures, beadings of bile ducts, and compatible biochemical profile, once excluded secondary causes of cholangitis. Since the aetiology of PSC remains poorly defined, medical therapy is currently limited to symptom improvement and prolonged survival. Ursodeoxycholic acid (UDCA), corticosteroids and immunosuppressants have been proposed alone or in combination to improve the clinical outcome. In selected cases, surgical or endoscopic procedures need to be considered. Orthotopic liver transplantation (OLT) is at the moment the only definitive approach although disease relapse has been reported. In this article the state of the art in PSC treatment and future promises in this field are reviewed.

Steroid-Responsive (Autoimmune?) Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation, fibrosis and destruction of the intrahepatic and extrahepatic bile ducts (1). Although the natural history of PSC is variable, it is almost always progressive and leads to cirrhosis and liver failure (2‐5). The etiology of PSC is unknown, and there is no effective medical treatment. We report on all patients who first presented to us between January 1999 and December 2001 with confirmed sclerosing cholangitis of a highly inflammatory nature. Six such patients presented in this time-period out of 80 patients with PSC. All six of these patients improved dramatically in response to glucocorticoid treatment. Biochemical tests of liver function normalized in five patients and improved greatly in the sixth, cholangiograms improved in those who had cholangiograms before and after treatment and symptoms resolved in all six. The response of these patients to immunosuppressive therapy suggests that their sclerosing cholangitis may be of autoimmune etiology. Based on this experience, we suggest that PSC may be a syndrome with different etiologies, rather than one discrete disease, and that our patients have an autoimmune variant. That sclerosing cholangitis may be a family of diseases with different etiologies would explain the disparate results found in the PSC literature concerning the efficacy of medical treatments.