Impact on follow-up strategies in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival. METHODS We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality. RESULTS A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. CONCLUSIONS Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.Norwegian PSC Research Center German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) Integrated Research and Treatment Center - Transplantation 01EO0802 PopGen biobank NIH DK 8496

Expression of S-locus inhibitor gene (Sli) in various diploid potatoes

Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC.This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks.A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines

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

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis

Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02). Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.Peer reviewe

Management of post-operative pancreatic fistulas following Longmire–Traverso pylorus-preserving pancreatoduodenectomy by endoscopic vacuum-assisted closure therapy

Background!#!Pylorus-preserving pancreatoduodenectomy (PPPD) with pancreatogastrostomy is a standard surgical procedure for pancreatic head tumors, duodenal tumors and distal cholangiocarcinomas. Post-operative pancreatic fistulas (POPF) are a major complication causing relevant morbidity and mortality. Endoscopic vacuum therapy (EVT) has become a widely used method for the treatment of intestinal perforations and leakages. Here we report on a pilot single center series of 8 POPF cases specifically caused by dehiscences of the pancreatogastric anastomosis (PGD), successfully managed by EVT.!##!Methods!#!We included all patients with PGD after PPPD, who were treated with EVT between 07/2017 and 08/2020. For EVT a vacuum drainage film (EVT film) or open-pore polyurethane foam sponge (EVT sponge) was fixed to a 14Fr or 16Fr suction catheter and placed endoscopically within the PGD for intracavitary EVT with continuous suction between - 100 and - 150 mmHg. The EVT film/sponge was exchanged twice per week. EVT was discontinued when the PGD was sufficiently healed.!##!Results!#!PGD closure was achieved in 7 of 8 patients after a mean EVT time of 16 days (range 8-38) and 3 EVT film/sponge exchanges (range 1-9). One patient died on day 18 after PPPD from acute hemorrhagic shock, unlikely related to EVT, before effectiveness of EVT could be fully achieved. There were no adverse events directly attributable to EVT.!##!Conclusions!#!EVT could be an effective and safe addition to our therapeutic armamentarium in the management of POPF with PGD. Unless prospective comparative studies are available, EVT as minimally invasive therapeutic alternative should be considered individually by an interdisciplinary team involving endoscopists, surgeons and radiologists

Non-invasive assessment of liver fibrosis in autoimmune hepatitis: Diagnostic value of liver magnetic resonance parametric mapping including extracellular volume fraction

Purpose!#!Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that leads to severe fibrosis and cirrhosis. The aim of this study was to determine the diagnostic value of T1 and T2 mapping as well as extracellular volume fraction (ECV) for non-invasive assessment of liver fibrosis in AIH patients.!##!Methods!#!In this prospective study, 27 patients (age range: 19-77 years) with AIH underwent liver MRI. T1 and T2 relaxation times as well as ECV were quantified by mapping techniques. The presence of significant fibrosis (≥ F2) was defined as magnetic resonance elastography (MRE)-based liver stiffness ≥ 3.66 kPa. MRE was used as reference standard, against which the diagnostic performance of MRI-derived mapping parameters was tested. Diagnostic performance was compared by utilizing receiver-operating characteristic (ROC) analysis.!##!Results!#!MRE-based liver stiffness correlated with both, hepatic native T1 (r = 0.69; P &amp;lt; 0.001) as well as ECV (r = 0.80; P &amp;lt; 0.001). For the assessment of significant fibrosis, ECV yielded a sensitivity of 85.7% (95% confidence interval (CI): 60.1-96.0%) and a specificity of 84.6% (CI 60.1-96.0%); hepatic native T1 yielded a sensitivity of 85.7% (CI 60.1-96.0%); and a specificity of 76.9% (CI 49.7-91.8%). Diagnostic performance of hepatic ECV (area under the curve (AUC): 0.885), native hepatic T1 (AUC: 0.846) for assessment of significant fibrosis was similar compared to clinical fibrosis scores (APRI (AUC: 0.852), FIB-4 (AUC: 0.758), and AAR (0.654) (P &amp;gt; 0.05 for each comparison)).!##!Conclusion!#!Quantitative mapping parameters such as T1 and ECV can identify significant fibrosis in AIH patients. Future studies are needed to explore the value of parametric mapping for the evaluation of different disease stages