Sclerosing Cholangitis Research Articles

Transplantace jater pro cholestatická onemocnění

Summary: Cholestatic liver diseases are characterized by their progressive nature and limited conservative treatment options. Liver transplantation is the only effective method of treatment for the terminal stage. Before the era of liver transplantation, patients with cholestatic disease had a significantly reduced life expectancy. Liver transplantation is now indicated not only for patients with chronic liver failure or hepatobiliary malignancy, but also for those with reduced quality of life from cholestatic symptoms. Post-transplant care is particularly specific because of the presence of immune-associated diseases, such as inflammatory bowel disease in patients with primary sclerosing cholangitis. Recurrence of the underlying disease in the liver graft is a common long-term complication that can negatively affect graft survival and overall life expectancy. Despite the risk of recurrence, the long-term outcomes of liver transplantation for cholestatic disease are excellent, achieving longer survival compared to other transplant recipients. Key words: liver transplantation – primary sclerosing cholangitis – primary biliary cholangitis – secondary sclerosing cholangitis – liver sarcoidosis

Epidemiology of autoimmune liver disease in Korea: evidence from a nationwide real-world database

BackgroundAutoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are all immune-mediated chronic inflammatory liver diseases. Autoimmune liver diseases are rare, making identification and treatment difficult. To improve clinical outcomes and enhance patient quality of life, we performed an epidemiological study of autoimmune liver diseases based on real-world comprehensive data.ResultsWe used National Health Insurance Service claims data in Korea from 2005 to 2019. Patients were identified using the International Classification of Disease 10th Revision code, and rare intractable disease codes assigned according to the strict diagnostic criteria. In the AIH cohort, 8,572 (83.9%) were females and the mean age at diagnosis was 56.3 ± 14.3 years. PBC also showed female dominance (83.3%) and the mean age was 57.8 ± 12.6 years. Patients with PSC showed no sex predominance and had a mean age of 57.8 ± 21.5 years. During the study period, there were 10,212, 6,784, and 888 AIH, PBC, and PSC patients, respectively. The prevalence of AIH, PBC, and PSC in 2019 were 18.4, 11.8, and 1.5 per 100,000 population, while the corresponding incidences were 2.3, 1.4, and 0.3 per 100,000 population, respectively. Analysis of sex-age-standardized data showed that the annual prevalence of these diseases is increasing. The 10-year survival rates were 89.8%, 74.9%, and 73.4% for AIH, PBC, and PSC, respectively.ConclusionsThe number of patients with autoimmune liver disease in South Korea is increasing over time. Further research on autoimmune liver disease is needed to fulfill unmet clinical needs.

Serum Galectin-3 as a Non-Invasive Marker for Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a serious liver disease associated with inflammatory bowel disease (IBD). Galectin-3, an inflammatory and fibrotic molecule, has elevated circulating levels in patients with chronic liver disease and inflammatory bowel disease (IBD). This study aims to clarify whether galectin-3 can differentiate between patients with IBD, PSC, and PSC-IBD. Our study measured serum galectin-3 levels in 38 healthy controls, 55 patients with IBD, and 22 patients with PSC (11 patients had underlying IBD and 11 patients did not), alongside the urinary galectin-3 of these patients and 18 controls. Serum and urinary galectin-3 levels in IBD patients were comparable to those in controls. Among IBD patients, those with high fecal calprotectin, indicating severe disease, exhibited lower serum and elevated urinary galectin-3 levels compared to those with low calprotectin levels. Serum galectin-3 levels were inversely correlated with C-reactive protein levels. PSC patients displayed higher serum and urinary galectin-3 levels than IBD patients, with the highest serum levels observed in PSC patients with coexisting IBD. There was no correlation between serum and urinary galectin-3 levels and laboratory indicators of liver injury in both IBD and PSC patients. In conclusion, this study demonstrates that serum and urinary galectin-3 levels can distinguish IBD from PSC patients, and also reveals higher serum galectin-3 levels in PSC-IBD patients compared to those with isolated PSC.

The potential of volatile organic compounds to diagnose primary sclerosing cholangitis

IntroductionPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. PSC is a complex disease of largely unknown aetiology with a strong association with inflammatory bowel disease (IBD). Diagnosis, especially at early stage, is difficult and to date there is no diagnostic biomarker. The present study aimed to assess the diagnostic potential of Volatile Organic Compounds (VOCs) in exhaled breath to detect (early) PSC in an IBD population. MethodsBreath samples were obtained from 16 PSC, 47 PSC with IBD, and 53 IBD patients during outpatient clinic visit. Breath sampling was performed using the ReCIVA breath sampler and subsequently analysed by gas chromatography mass spectrometry. Random Forest modelling was performed to find discriminatory VOCs and create a predictive model that was tested using an independent test set. ResultsThe final model to discriminate PSC patients with or without IBD versus IBD only patients included twenty VOCs and achieved a sensitivity, specificity, and area under the receiver operating curve on the test set of 77%, 83%, and 0.84 respectively. Three VOCs (isoprene, 2-octanone and undecane) together correlated significantly to the Amsterdam-Oxford score for PSC disease prognosis. A sensitivity analysis showed stable results across early stage PSC including those with normal alkaline phosphatase levels, as well as further progressed PSC. ConclusionThe present study demonstrates that exhaled breath can distinguish PSC cases from IBD and has potential as a non-invasive clinical breath test for (early) PSC. Impact and ImplicationsPrimary Sclerosing Cholangitis (PSC) is a complex chronic liver disease, which ultimately results in cirrhosis, liver failure, and death. Detection especially in early disease can be challenging, and therefore therapy typically starts when there is already some irreversible damage. The current study shows that metabolites in exhaled breath, so called Volatile Organic Compounds, hold promise to non-invasively detect PSC also at early stages.

Coexistence of metabolic-associated fatty liver disease and autoimmune or toxic liver disease.

Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components of metabolic syndrome in FLD. MAFLD does not exclude coexistence of other liver disease, but impact of coexisting MAFLD is unclear. We investigated prevalence and characteristics of MAFLD in patients with biopsy-proven autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or toxic liver disease. Liver histopathology and clinical data from Helsinki University Hospital district (1.7 million inhabitants) between 2009 and 2019 were collected from patients with AIH, PBC, PSC, or toxic liver disease at the time of diagnosis. MAFLD was diagnosed as macrovesicular steatosis ≥5% together with obesity, type-2 diabetes, or signs of metabolic dysregulation. Of 648 patients included, steatosis was observed in 15.6% (n = 101), of which 94.1% (n = 95) was due to MAFLD. Prevalence of coexisting MAFLD in the four liver diseases varied between 12.4 and 18.2% (P = 0.483). Fibrosis was more severe in MAFLD among patients with toxic liver disease (P = 0.01). Histopathological characteristics otherwise showed similar distribution among MAFLD and non-FLD controls. Alcohol consumption was higher in MAFLD group among patients with AIH or PBC (P < 0.05 for both). In AIH, smoking was more common in patients with coexisting MAFLD (P = 0.034). Prevalence of coexisting MAFLD in other primary liver diseases is lower than reported in general population. Histopathology of MAFLD patients did not clearly differ from non-FLD ones. Alcohol and smoking were associated with MAFLD in AIH.

Imaging-based diagnosis of sarcopenia for transplant-free survival in primary sclerosing cholangitis

BackgroundImaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC.MethodsA total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause.ResultsOur study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141).ConclusionImaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.

Periportal macrophages protect against commensal-driven liver inflammation.

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammationat the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

Wits Transplant Unit Annual Report 2022: Adult and paediatric liver transplantation.

In 2022, the Wits Transplant Unit performed 57 liver transplants: 33/57 adult (58%) and 24/57 paediatric (42%) recipients. At the beginning of 2022, 28 candidates were on the adult waitlist. Forty-six candidates were added to the waitlist during the year. Sixty-five percent of waitlisted candidate were transplanted. Adult candidates remained on the waitlist for longer than previous years, with 52% of them waitlisted for less than one year before undergoing liver transplantation. There was a decrease in adult pretransplant mortality to 9% in 2021 from 25% in 2020. The most common aetiology in waitlist candidates was alcoholic steatohepatitis (ASH)/non-alcoholic steatohepatitis (NASH) (36%) and in recipients cholestatic (primary sclerosing cholangitis (PSC) and primary biliary sclerosis (PBC)) (40%). Most adult recipients received a deceased donor graft (79%). Unadjusted recipient one- and three-year survivals were 75% (95% confidence interval (CI) 65 - 83) and 74% (95% CI 65 - 81), respectively. In the paediatric population, the most common aetiologies for both pretransplant candidates and transplant recipients remained cholestatic disease and acute liver failure. There was a decrease in paediatric pretransplant mortality from 27% in 2017 to 6% in 2021. Unlike the adult cohort, most paediatric recipients received a living donor graft (79%). Unadjusted one-year and three-year survival rates were 85% (95% CI 75 - 92) and 68% (95% CI 56 - 77), respectively.

Are Gender Differences Important for Autoimmune Liver Diseases?

Gender Medicine has had an enormous expansion over the last ten years. Autoimmune liver diseases include several conditions, i.e., autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and conditions involving the liver or biliary tree overlapping with AIH, as well as IgG4-related disease. However, little is known about the impact of sex in the pathogenesis and natural history of these conditions. The purpose of this review is to provide an update of the gender disparities among the autoimmune liver diseases by reviewing the data published from 1999 to 2023. The epidemiology of these diseases has been changing over the last years, due to the amelioration of knowledge in their diagnosis, pathogenesis, and treatment. The clinical data collected so far support the existence of sex differences in the natural history of autoimmune liver diseases. Notably, their history could be longer than that which is now known, with problems being initiated even at a pediatric age. Moreover, gender disparity has been observed during the onset of complications related to end-stage liver disease, including cancer incidence. However, there is still an important debate among researchers about the impact of sex and the pathogenesis of these conditions. With this review, we would like to emphasize the urgency of basic science and clinical research to increase our understanding of the sex differences in autoimmune liver diseases.

Quantitative MRCP and metrics of bile duct disease over time in patients with primary sclerosing cholangitis: A prospective study.

Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. Individuals with PSC were prospectively scanned using non-contrast MRCP. Quantitative metrics were calculated using MRCP+ post-processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371-day follow-up (range: 364-462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non-PSC liver disease. Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist-derived cholangiographic assessment (trial registration: ISRCTN39463479).

STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis.

Regulatory CD4+ T cells (Tregs) are pivotal for inhibition of autoimmunity. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology where contribution of Tregs is still unclear. Activation of the JAK-STAT pathway critically modifies functions of Tregs. In PSC, we studied activation of STAT proteins and Treg functions in response to cytokines. In 51 patients with PSC, 10 disease controls (chronic replicative hepatitis C), and 36 healthy controls we analyzed frequencies of Foxp3+CD25+CD127lowCD4+ Tregs, their expression of ectonucleotidase CD39, and cytokine-induced phosphorylation of STAT1, 3, 5, and 6 using phospho-flow cytometry. In parallel, we measured cytokines IFN-gamma, interleukin (IL)-6, IL-2, and IL-4 in serum via bead-based immunoassays. In patients with PSC, ex vivo frequencies of peripheral Tregs and their expression of CD39 were significantly reduced (p < .05 each). Furthermore, serum levels of IFN-gamma, IL-6, IL-2, and IL-4 were markedly higher in PSC (p < .05 each). Unlike activation of STAT1, STAT5, and STAT6, IL-6 induced increased phosphorylation of STAT3 in Tregs of PSC-patients (p = .0434). Finally, STAT3 activation in Tregs correlated with leukocyte counts. In PSC, we observed enhanced STAT3 responsiveness of CD4+ Tregs together with reduced CD39 expression probably reflecting inflammatory activity of the disease.

CsHscB Derived from a Liver Fluke Clonorchis sinensis Ameliorates Cholestatic Hepatic Fibrosis in a Mouse Model of Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammatory fibrosis usually involving the whole biliary tree. However, there are very limited treatment options to treat this disease. Our previous study found a lipid-protein rCsHscB from a liver fluke - Clonorchis sinensis, which had full capacities of immune regulation. Therefore, we investigated the role of rCsHscB in a mouse model of sclerosing cholangitis induced by xenobiotic 3,5- diethoxycarbonyl-1,4-dihydrocollidine (DDC) to explore whether this protein had potential therapeutic value for PSC. Mice were fed 0.1% DDC for 4 weeks and treated with CsHscB (30 μg/mouse, intraperitoneal injection, once every 3 days); the control group was given an equal amount of PBS or CsHscB under normal diet conditions. All the mice were sacrificed at 4 weeks for the evaluation of biliary proliferation, fibrosis, and inflammation. rCsHscB treatment attenuated DDC-induced liver congestion and enlargement and significantly decreased the upregulation of serum AST and ALT levels. The administration of rCsHscB to DDC-fed mice significantly decreased cholangiocyte proliferation and pro-inflammatory cytokine production compared to mice fed with DDC alone. Also, rCsHscB treatment showed a decreased expression of α-SMA in the liver and other markers of liver fibrosis (Masson staining, Hydroxyproline content, and collagen deposit). More interestingly, DDC-fed mice treated with rCsHscB showed a significant up-regulation of PPAR-γ expression, which was similar to control mice, indicating the involvement of PPAR-γ signaling in the protective action of rCsHscB. Overall, our data show that rCsHscB attenuates the progression of cholestatic fibrosis induced by DDC and supports the potential for manipulating the parasite-derived molecule to treat certain immune-mediated disorders.

From random to precise: updated colon cancer screening and surveillance for inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). The pathogenesis of CRC in IBD differs from sporadic cancer, with the burden of inflammation being an important contributing factor. Other risk factors for developing CRC in patients with Crohn's disease (CD) or ulcerative colitis (UC) includes a family history of CRC, personal history of dysplasia, history of strictures, or primary sclerosing cholangitis (PSC). Dysplasia is the precursor of cancer and ensuring effective surveillance strategies is vital for early detection and intervention. In the past, dysplasia detection relied on random biopsies, but recent studies have shown that, with the adaptation of high-definition white light endoscopy (HD-WLE), dye sprayed chromoendoscopy (DCE) and virtual chromoendoscopy (VCE), dysplasia detection has improved. While there exists a certain degree of consensus amongst experts regarding the management of dysplasia, it is important to implement a personalized approach to each patient's care. Our review focuses on advancements in the past two decades, specifically highlighting the modifications that have been implemented since the SCENIC guidelines. It also explores future directions, including the potential implementation of stool studies as a non-invasive tool for surveillance and the emerging role of artificial intelligence (AI) in dysplasia detection.

Serum vitamins and homocysteine levels in autoimmune liver disease: A systematic review and meta-analysis.

Vitamins and homocysteine (Hcy) are involved in liver metabolism and related to the pathogenesis of autoimmune liver disease (AILD), but consensus is lacking. This study aims to systematically summarize relevant evidence to clarify the association of serum vitamins and Hcy levels with AILD. The English and Chinese literature was searched until August 29, 2023. Studies were included if they were observational studies of investigating serum vitamins and Hcy levels in patients with AILD and their healthy comparisons. Quality assessment was performed by using the Newcastle-Ottawa Scale, and a meta-analysis was conducted using ReviewManager 5.3. The protocol was registered in the international prospective register of systematic reviews (PROSPERO), with registration number CRD42023455367. A total of 25 case-control studies comprising 3487 patients (1673 patients and 1814 healthy controls) were included for analysis. There were 548 autoimmune hepatitis (AIH) cases, 1106 primary biliary cholangitis (PBC) cases, and 19 primary sclerosing cholangitis (PSC) cases. We found that serum A and E were decreased in both AIH and PBC/PSC; but vitamin C was reduced only in patients with PBC, not AIH. In addition, decreased content of 25(OH)D3 was found in both AIH and PBC. However, levels of 25(OH)D did not differ between the patients and controls, and were independent of disease types and the country. Only one study that met the inclusion criteria reported vitamin B6, B9, B12, and Hcy changes, and found that vitamin B6 and B9 were significantly decreased in patients with PBC, while serum vitamin B12 and Hcy levels were significantly elevated in them. One eligible study each confirmed a reduction in plasma vitamin K1 and 1,25(OH)2D3 in patients with PBC. Most vitamins are deficient in AILD, so appropriate vitamin supplementation should be necessary. Further studies with larger sample sizes are needed to validate these findings.

De Novo Inflammatory Bowel Disease after Liver Transplantation: Eleven Years' Experience in Shiraz, Iran

Background: Colon inflammation may occur after solid and liquid organ transplantations at a rate higher than in the general population. Objectives: This study aimed to investigate the incidence of de novo inflammatory bowel disease (IBD) and assess some risk factors after Orthotopic Liver Transplantation (OLT) in liver transplant patients in Shiraz, Iran. Methods: The sample study comprised patients (n = 1702) who had received liver transplants between 2001 and 2012 at the Shiraz liver transplant center. The data were obtained from patient records, which included information on their medical history, colonoscopy reports, family history of IBD, and other risk factors. The study evaluated the status of inflammatory bowel disease (IBD) among patients who had undergone liver transplantations due to Autoimmune Hepatitis (AIH) group, Primary Sclerosing Cholangitis (PSC), and other liver transplant patients. Additionally, case groups were formed, comprising AIH patients (n1 = 10) and other patients with IBD (n2 = 10), and were compared with transplant patients without IBD as the control group (n1 = 21, n2 = 21). Results: Out of the total 1702 patients, 254 (14.92%) had AIH, 211 (12.40%) had PSC, and 1237 (72.68%) had other outcomes. The mean of leukocyte counts (P-value = 0.73), types of immunosuppressant medications, and serum levels of cyclosporine (P-value = 0.77) and tacrolimus (P-value = 0.27) did not show any significant differences between the case and control groups. However, it was observed that IBD developed earlier in patients with AIH compared to other patients (20.1 ± 2.23 vs 53.9 ± 4.42 months). Conclusions: The incidence of IBD after liver transplantation was higher compared to the general population, and it occurred earlier in patients who underwent transplantation for AIH and other groups.

Incidence of Secondary Sclerosing Cholangitis in Hospitalized Long COVID-19 Patients: A Retrospective Single Center Study.

SARS-CoV-2 infection and associated COVID-19 disease can lead to critical illness with a risk of developing a multiple organ failure. Subsequently, this may lead to various pathological sequelae, such as secondary sclerosing cholangitis after surviving COVID-19 (SSC-COVID). The aim is to retrospectively analyze a cohort of hospitalized patients with first-wave (February 2020-June 2020) SARS-CoV-2 infection and persisting unclear cholangiopathy to determine the incidence of SSC-COVID and its risk factors. A total of 249 patients were hospitalized at the university hospital in Tübingen, Germany, with SARS-CoV-2 infection during the first wave of the pandemic. Of these, 35.3% (88/249) required intensive care treatment; 16.5% (41/249) of them died due to the complications of COVID-19; 30.8% (64/208) of surviving patients could be followed up und were retrospectively analyzed at our center. The incidence of confirmed SSC-COVID was 7.8% (5/64). All SSC-COVID patients had an ICU stay >20 days, for invasive ventilation, positioning treatment, vasopressor treatment, but possible risk factors for SSC were not significant due to the small number of patients. SSC-COVID is an emerging disease in post-COVID patients with a high incidence in our single-center cohort. SSC-COVID should be considered as a differential diagnosis, if unclear cholangiopathy or cholestasis persists after SARS-CoV-2 infection.

Autoimmune Liver Diseases and Rheumatoid Arthritis-Is There an Etiopathogenic Link?

Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.

Association between gut microbiota and autoimmune cholestatic liver disease, a Mendelian randomization study.

Previous studies have suggested that the gut microbiota (GM) is closely associated with the development of autoimmune cholestatic liver disease (ACLD), but limitations, such as the presence of confounding factors, have resulted in a causal relationship between the gut microbiota and autoimmune cholestatic liver disease that remains uncertain. Thus, we used two-sample Mendelian randomization as a research method to explore the causal relationship between the two. Pooled statistics of gut microbiota from a meta-analysis of genome-wide association studies conducted by the MiBioGen consortium were used as an instrumental variable for exposure factors. The Pooled statistics for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were obtained from the R9 version of the FinnGen database (https://r9.finngen.fi/). Inverse-variance Weighted (IVW), cML-MA, MR-Egger regression, Weighted median (WME), Weighted mode (WM), and Simple mode (SM) were used to detect the association between intestinal flora and the causal relationship between intestinal flora and ACLD, in which IVW method was dominant, was assessed based on the effect indicator dominance ratio (odds ratio, OR) and 95% confidence interval (CI). Sensitivity analysis, heterogeneity test, gene pleiotropy test, MR pleiotropy residual sum and outlier test (MR-PRESSO) were combined to verify the stability and reliability of the results. Reverse Mendelian randomization analysis was performed on gut microbiota and found to be causally associated with ACLD. The IVW results showed that the relative abundance of the genus Clostridium innocuum group, genus Butyricicoccus, and genus Erysipelatoclostridium was negatively correlated with the risk of PBC, that is, increased abundance reduced the risk of PBC and was a protective, and the relative abundance of the genus Eubacterium hallii was positively correlated with the risk of PSC, which is a risk factor for PSC. Family Clostridiaceae1 and family Lachnospiraceae were negatively correlated with the risk of PSC, which is a protective factor for PSC. This study found a causal relationship between gut microbiota and ACLD. This may provide valuable insights into gut microbiota-mediated pathogenesis of ACLD. It is necessary to conduct a large-sample randomized controlled trial (RCT) at a later stage to validate the associated role of the relevant gut microbiota in the risk of ACLD development and to explore the associated mechanisms.

Abstract 1626: Clonal expansion in bile duct associated with chronic inflammation

Abstract Introduction: Chronic inflammation has been implicated in cancer development in many tissues and has recently been associated with promoted clonal expansion in non-cancer tissues. Primary sclerosing cholangitis (PSC) is a chronic progressive disease of unknown etiology affecting the bile ducts and has been associated with a substantially increased risk of cholangiocarcinoma. Clonal dynamics in the normal bile duct and PSC epithelium remains poorly understood because of the limited accessibility to normal/inflamed bile ducts. In this study, we established a method to detect somatic mutations accumulated in the bile duct epithelium and investigated a mutation rate in normal bile duct cells and clonal expansion in PSC epithelium. Methods: We established single cell-derived organoids from bile, which were subjected to whole genome sequencing to measure the age-related mutation rate in normal epithelial cell in the bile ducts. We next established organoids from multiple sites in perihilar bile ducts and collected epithelial samples from intrahepatic bile ducts obtained by laser-capture microdissection (LCM) from patients with PSC who underwent total hepatectomy for liver transplantation, for which we performed whole exome sequencing to investigate clonal expansion in PSC-involved bile ducts. Results: In total, 14 single cell-derived organoid lines were established from 2 patients with PSC and 3 control individuals. Based on the whole genome sequencing of those organoids, the number of mutations found in non-PSC bile duct epithelium increases with age at an annual mutation rate of 34.3 mutations per genome per year, which did not substantially differ from the rate in the PSC epithelium, suggesting that the inflammatory process in PSC hardly affected the mutations in PSC epithelium. To further investigate clonal expansion in the PSC epithelium, a total of 120 bulk organoid samples from perihilar bile ducts in 3 PSC patients and 111 LCM samples from intrahepatic bile ducts in 4 PSC patients were analyzed. In perihilar bile duct-derived organoids, we detected a median of 13 [1-30] somatic mutations per exome in samples derived from perihilar bile ducts and 20 [5-41] mutations per exome in those from intrahepatic LCM samples. Most mutations were detected in a single sample but some mutation clusters were shared by adjacent samples, which expanded in an area as large as 13 mm in length. Expanded clones harbored mutations in known cancer-driver genes, such as ARID1A and KRAS, which were enriched in segmental bile ducts, suggesting their role in the clonal expansion. Conclusions: Here, we established the method to detect somatic mutations accumulated in the normal/inflamed bile duct epithelium using an organoid-based analysis of clonal somatic mutations. Our results revealed clonal expansion existing in PSC epithelium and open up a way to the better understanding of carcinogenesis in the bile duct. Citation Format: Hirona Maeda, Nobuyuki Kakiuchi, Takashi Ito, Eri Ogawa, Masahiro Shiokawa, Norimitsu Uza, Hiroko Tanaka, Yasuhito Nannya, Hideki Makishima, Yuzo Kodama, Etsuro Hatano, Satoru Miyano, Seishi Ogawa. Clonal expansion in bile duct associated with chronic inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1626.

Primary Sclerosing Cholangitis: Gender Effects in Valencia's Low-Prevalence Region.

Recent studies point out to epidemiological changes in primary sclerosing cholangitis (PSC). Our aims were to determine in PSC patients followed in several centers in a Mediterranean geographic area: (i) changes in baseline features and (ii) effect of gender on clinical course. Retrospective multicenter study of PSC patients treated in 8 hospitals in a Mediterranean area between 2000 and 2021. Charts were reviewed compiling demographic, clinical, radiological, and histological variables. Cohort of 112 PSC patients included, 42% women, 70% diagnosed after 2010. Women were increasingly diagnosed in recent cohorts. The median time from diagnosis to the combined endpoint liver transplantation (Lt) and/or death was 6.9years. Asthenia at diagnosis (p = 0.009) was associated with lower transplant-free survival, while diagnosis before 2005 was associated with greater LT-free survival (p < 0.001). By Cox regression, LT-free survival was not influenced by age, sex, or cirrhosis at the time of diagnosis. Women were found to have less jaundice at diagnosis (2 vs 14%; p = 0.013), higher prevalence of ANA antibodies (43.9 vs 15.7%; p = 0.003), and lower GGT levels at diagnosis (GGT 123 vs 209U/L; p = 0.014) than men. In an area traditionally considered to have low prevalence, the prevalence of affected women surpasses expectations based on existing literature. There appear to be gender-related variations in the presentation of the condition, highlighting the need for confirmation through larger-scale studies.