Gut-liver axis in Primary sclerosing cholangitis

La cholangite sclérosante primitive (CSP) est une maladie rare, de cause inconnue, caractérisée par des lésions fibro-inflammatoires des voies biliaires. La CSP est fréquemment associée aux maladies inflammatoires chroniques de l’intestin (MICI). Il est admis que les MICI résultent d’une rupture de l’équilibre entre le microbiote intestinal et le système immunitaire. Il est possible que les mêmes mécanismes interviennent dans la CSP. Le modèle animal le plus communément utilisé pour étudier la CSP, la souris Mdr2-/- ne développe pas spontanément de colite, cependant une colite expérimentale peut être induite par le dextran sulfate de sodium (DSS). Premièrement, nous avons réalisé une étude clinique visant à analyser le microbiote intestinal des patients atteints de CSP. Nos résultats montrent que les patients atteints de CSP présentent une dysbiose bactérienne et fongique, avec une rupture du réseau de corrélations entre bactéries et champignons. Deuxièmement, nous avons réalisé une étude préclinique visant à développer un modèle animal de CSP-MICI (souris Mdr2 -/- avec colite induite par DSS) afin d’évaluer l’impact de la maladie colique sur l’atteinte hépatique, et inversement. Nos résultats montrent que la colite induite chez la souris Mdr2-/- est plus sévère que chez la souris sauvage. Cependant la colite améliore les lésions fibro-inflammatoires hépatiques de la souris Mdr2-/-. Ce travail montre pour la première fois l’importance du microbiote fongique intestinal dans la dysbiose associée à la CSP, ainsi que la complexité des interactions entre le foie et l’intestin au cours de cette pathologie.Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of unknown etiology, which is characterized by fibro-inflammatory lesions of bile ducts. PSC is frequently associated with inflammatory bowel disease (IBD). Previous data have shown that IBD results from an imbalance of gut microbiota and immune system equilibrium. Such a mechanism can contribute to PSC pathogenesis. The most widely used animal model for the study of PSC, Mdr2-/- mice, do not spontaneously develop IBD. However, experimental colitis can be induced by administration of dextran sulphate sodium (DSS). First, we performed a clinical study to analyze gut microbiota in PSC patients. Our results show that PSC patients displayed not only a bacterial but also a fungal gut dysbiosis, characterized by a strong disruption in bacteria-fungi correlation network. Second, we performed an experimental study to develop an animal model of PSC-IBD (Mdr2-/- mouse with colitis induced by DSS) to assess the impact of colitis and liver disease on each other. Our results show that the induced colitis is more severe in Mdr2-/- mice than in wild type mice, whereas colitis improved fibro-inflammatory lesions in liver of Mdr2-/- mice. This work shows for the first time the importance of the fungal gut microbiota in PSC associated dysbiosis, as well as the complexity of interactions in the gut-liver axis in this disease

Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis

International audiencePatients with primary sclerosing cholangitis (PSC) were previously shown to display a bacterial gut dysbiosis but fungal microbiota has never been examined in these patients. The aim of this study was to assess the fungal gut microbiota in patients with PSC

Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French–Spanish experience

International audienceBACKGROUND & AIMS: In patients with primary sclerosing cholangitis (PSC), ursodeoxycholic acid (UDCA) treatment improves serum liver tests and surrogate markers of prognosis but has no proven effect on survival. Additional therapies are obviously needed. Fibrates, PPAR agonists with anti-cholestatic properties, have a beneficial effect in primary biliary cholangitis. The aim of this study was to evaluate the safety and efficacy of fibrates in PSC patients.METHODS: Retrospectively, we investigated PSC patients treated with fibrates (fenofibrate 200mg/day or bezafibrate 400mg/day) for at least 6 months in addition to UDCA, after an incomplete biochemical response (alkaline phosphatase [ALP] ≥1.5×upper limit of normal) to UDCA. Changes in biochemical parameters and clinical features were assessed.RESULTS: Twenty patients were included (fourteen from Paris and six from Barcelona): median age 43.8 years, median liver stiffness 11kPa (≥F3). Upon treatment with fibrates (median duration of 1.56 years), liver tests significantly improved, including a reduction of ALP levels by 41% and pruritus significantly decreased. No serious adverse event attributable to fibrates occurred. Discontinuation of fibrates was followed by a clear rebound of ALP. Despite biochemical improvement, liver stiffness significantly increased.CONCLUSIONS: Combining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC

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, shortterm 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.Peer reviewe

Simple Magnetic Resonance Scores Associate With Outcomes of Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) has a variable, often progressive course. Magnetic resonance cholangiography (MRC) is used in diagnosis of PSC. Magnetic resonance risk scoring systems, called Anali without and with gadolinium, are used to predict disease progression, determined by radiologic factors. We aimed to assess the prognostic value of Anali scores in patients with PSC and validate our findings in a separate cohort. METHODS We performed a retrospective study of patients with large-duct PSC (internal cohort, 119 patients in France and external cohort, 119 patients in Canada, Italy, and United Kingdom). All the first-available MRC results were reviewed by 2 radiologists and the Anali scores were calculated: Anali without gadolinium= (1x dilatation of intrahepatic bile ducts) + (2x dysmorphy) + (1x portal hypertension); Anali with gadolinium= (1x dysmorphy) + (1x parenchymal enhancement heterogeneity). The primary endpoint was survival without liver transplantation or cirrhosis decompensation. The prognostic value of Anali scores was assessed by Cox regression modeling. RESULTS During a total of 549 patient-years for the internal cohort and 497 patient-years for the external cohort, we recorded 2 and 8 liver transplantations, 4 and 3 liver-related deaths, 26 and 25 cirrhosis decompensations, respectively. In the univariate analysis, factors associated with survival without liver transplantation or cirrhosis decompensation in the internal cohort were: serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and albumin and Anali scores. Anali scores without and with gadolinium identified patients survival without liver transplantation or cirrhosis decompensation with a c-statistic of 0.89 (95% CI, 0.84-0.95) and 0.75 (95% CI, 0.64-0.87), respectively. Independent prognostic factors identified by multivariate analysis were Anali scores and bilirubinemia. The prognostic value of Anali scores was confirmed in the external cohort. CONCLUSIONS In internal and external cohorts, we found that Anali scores, determined from MRC, associate with outcomes of patients with PSCs. These scores might be used as prognostic factors

First Wave of COVID-19 in French Patients with Cystic Fibrosis

International audienceViral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs; 1 had negative RT-PCR but typical COVID-19 signs on a CT scan; and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9–60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) > 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely. View Full-Tex

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis

Objectives: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value. Methods: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 7 dilatation of intrahepatic bile ducts) + (2 7 dysmorphy) + (1 7 portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models. Results: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (\u3c1 = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively. Discussion: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC

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.status: publishe

Validation of the Prognostic Value of Histologic Scoring Systems in Primary Sclerosing Cholangitis:An international cohort study

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSCrelated death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (k = 0.56) and substantial for Nakanuma component fibrosis (k = 0.67), Ishak stage (k = 0.64), and Ludwig stage (k = 0.62). Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value