Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe

Therapeutic approaches for portal biliopathy: A systematic review

Portal biliopathy (PB) is defined as the presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC). The pathogenesis of PB is due to ab extrinseco compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC. Although asymptomatic biliary abnormalities can be frequently seen by magnetic resonance cholangiopancreatography in patients with PC (77%-100%), only a part of these (5%-38%) are symptomatic. Clinical presentation includes jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. In this subset of patients is required a specific treatment. Different therapeutic approaches aimed to diminish portal hypertension and treat biliary strictures are available. In order to decompress PC, surgical porto-systemic shunt or transjugular intrahepatic porto-systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches. Definitive treatment of PB often requires multiple and combined interventions both on vascular and biliary system. Liver transplantation can be considered in patients with secondary biliary cirrhosis, recurrent cholangitis or unsuccessful control of portal hypertension

Primary sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease (IBD). Medical treatment for PSC is still disappointing, whereas immunomodulators and biologics have been proven to be effective in IBD. AIMS: This study aimed to analyze (i) the natural history of patients with PSC with or without IBD and (ii) the long-term efficacy of biologics in patients with PSC and concomitant IBD or rheumatological disorders. PATIENTS AND METHODS: This study included 92 consecutive PSC patients, 50 (54.3%) men and 42 (45.7%) women, with a mean age of 32.0\ub114.3 years at diagnosis and a mean follow-up duration of 103.8\ub186 months. Forty-nine (53.3%) patients had associated IBD (38 ulcerative colitis, 10 Crohn's disease, one indeterminate colitis). RESULTS: No significant differences were found between PSC patients with and without associated IBD in terms of liver transplantation, cancer, and death rates. Cholangiocarcinoma was only identified among patients with PSC alone, whereas other cancers (hepatocellular carcinoma, colorectal, and gallbladder cancer) were found only in the group with associated IBD. Five PSC patients were treated with biologic agents: three with adalimumab and one with infliximab for IBD or for rheumatoid arthritis, and one patient with rituximab for rheumatoid arthritis. Adalimumab decreased alkaline phosphatase in two of three patients after 6 and 12 months, infliximab reduced \u3b3-glutamyltransferase after 6 and 12 months, but liver function tests tended to deteriorate thereafter. Cholangiography changes remained stable in all patients. CONCLUSION: Biologic agents may improve liver function tests in PSC patients, but may be associated with adverse events including deterioration of liver function

P.16.3 THE PROGNOSTIC ROLE OF MAGNETIC RESONANCE CHOLANGIOGRAPHY IN PSC

Background and aim: Magnetic resonance cholangiography (MRC) has became the diagnostic imaging modality of choice when PSC is suspected. The prognosis of this disease, however, is difficult to be determined, considering the survival variability due to the recurrence of complications and the loss of an effective medical therapy. The aim is to evaluate the prognostic role of MRC in patients with PSC. Material and methods: 35 consecutive patients with ERCP-proved PSC (21 males, 14 females; mean age 38 yrs, range 20\u201373 yrs) underwent MRC at different intervals during the follow-up. MRC images were acquired before and after Primovist\uae (hepato-specific contrast) administration. The prognostic value of MRC was assessed adapting the original validated Amsterdam classification adopted for ERCP. MRC imaging was scored from 1 (no abnormalities) to 5, based on the severity of biliary strictures and dilatations, both intra- and extrahepatic. The study analyzed the association between MRC score and: liver function tests, the Mayo risk score, the occurrence of clinical events (bacterial cholangitis, pancreatitis, cancer, major strictures requiring an endoscopic/surgical treatment), the contrast enhancement pattern. Results: The median follow-up was 94\ub176 months. According to the overall imaging score patients were divided in two groups:MRCstage3 (17 patients, 48.6%), MRC stage >3 (18 patients, 51.4%). Age at diagnosis was similar in the two groups (33 vs 29 years, p=n.s.). No significant association was observed between MRC score group and: the occurrence of bacterial cholangitis (17.6% vs 33.3%, p=n.s.), the development of pancreatitis/cancer/major strictures (29.4.6% vs 22.2%, p=n.s.), Mayo score at time of diagnosis (-0.53 vs -0.51, p=n.s.) and LFTs, except for ALT levels at 10 years from diagnosis (0.95 vs 2.56 xULN, p3 (35.3% vs 72.2%, p<0.05) Conclusions: MRC offers a good performance for prognostic purposes in PSC; in particular, a more severe MRC imaging, in term of biliary strictures and dilatations, indicates the concomitant functional exclusion of liver parenchymal areas. Therefore, the validation of this score is warranted in a larger cohort of PSC patients

METABOLIC SYNDROME INDUCES A MORE RAPID PROGRESSION OF FIBROSIS IN PRIMARY BILIARY CIRRHOSIS IN EARLY STAGE

Background and aim: Metabolic syndrome (MS) is a comorbidity, possibly associated to PBC, which increases the risk of cardiovascular events. Transient elastography (TE) is a useful tool for assessing liver fibrosis in PBC, but its performance in longitudinal studies is still scanty. Aim: To assess liver fibrosis progression in patients with PBC (associated or not to MS) using TE after a 2-year interval from the initial diagnosis (histologically confirmed in all patients). Material and methods: Patients and method: A total of consecutive 80 patients with PBC (19 of whom having MS) underwent a prospective TE analysis at baseline and after 2-year interval. The median follow up was 25 months, (range 21\u201327 months). All patients were treated with UDCA (15 mg/kg/day). MS was defined MS according to the American Heart Association criteria and these patient underwent to specific therapy for MS. Statistical comparison between liver stiffness was conducted usingWilcoxon test. Pearson coefficient of correlation (r) was calculated to analyse the relation between liver stiffness and Mayo score. Results: A significant overall progression of mean liver stiffness (LS) was observed in patients with PBC (8.9\ub15.5 kPa vs 10.2\ub17.6 kPa, p=0.0071). No significant difference was observed in fibrosis progression in early histological stage (stage 1) at diagnosis ( 1.4\ub12.2 kPa, p=0.07), but a significant increase was observed for patient with moderate to advanced fibrosis (stage 2-3-4) ( 1.3\ub14.8 kPa, p=0.04). No significant difference was observed in the progression of liver stiffness between patients with and without MS ( 1.6\ub15.8 kPa vs 1.2\ub14.1 kPa, p=ns). Subgrouping patients according to the histological stage at diagnosis, a significant increase of liver stiffness was observed in stage 2 patients with MS respect to that without MS (p=0.02). Transient elastography positively correlated with Mayo score at diagnosis and after two year of follow-up (r0= 0.35, p<0.05 and r1=0.42, p<0.05). Conclusions: Overall PBC patients treated with UDCA demonstrate a significant progression in LS after 2-year of follow up, especially in the group with moderate to advanced fibrosis at diagnosis. A significant increase on LS was observed in patients with MS and stage 2

Thyroid Dysfunction in Primary Biliary Cholangitis: A Comparative Study at Two European Centers

OBJECTIVES: Primary biliary cholangitis (PBC) is often associated with other autoimmune diseases, but little is known about the influence of thyroid disease (TD) on the natural history of PBC. Our aim is to analyze the association between PBC and TD, and the latter's impact on the natural history of PBC at two European centers. METHODS: The study involved 921 PBC patients enrolled between 1975 and 2015 in Padova (376 patients) and Barcelona (545 patients), with a mean follow-up of 126.9±91.7 months. Data were recorded on patients' histological stage at diagnosis, biochemical data, associated extrahepatic autoimmune conditions, and clinical events, including hepatic decompensation. RESULTS: A total of 150 patients (16.3%) had TD, including 94 patients (10.2%) with Hashimoto's thyroiditis; 15 (1.6%) with Graves' disease; 22 (2.4%) with multinodular goiter; 7 (0.8%) with thyroid cancer; and 12 (1.3%) with other thyroid conditions. The prevalence of different types of TD was similar in Padova and Barcelona, except for Graves' disease and thyroid cancer, which were more frequent in the Padova cohort (15.7 vs. 5.0%, and 8.6 vs. 1.3%, respectively, P<0.05). Overall, there were no differences between PBC patients with and without TD in terms of their histological stage at diagnosis, hepatic decompensation events, occurrence of HCC, or liver transplantation rate. The presence of associated TD was not associated with lower survival for PBC patients in either cohort. CONCLUSIONS: TDs, and autoimmune TD like Hashimoto's thyroiditis in particular, are often associated with PBC, but the presence of TD does not influence the rate of hepatic complications or the natural history of PBC