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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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).

Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial.

BACKGROUND: Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. METHODS: BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. RESULTS: Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. CONCLUSIONS: The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Liver transplantation for alcohol-related liver disease in the UK: revised UK Liver Advisory Group recommendations for referral.

Liver disease, of which liver cirrhosis is the most advanced stage, constitutes the fourth most common cause of life-years lost in men and women younger than 75 years in England, where mortality rates from liver disease have increased by 25% in the past decade. Alcohol consumption is the most common modifiable risk factor for disease progression in these individuals, but within the UK, there is substantial variation in the distribution, prevalence, and outcome of alcohol-related liver disease, and no equity of access to tertiary transplantation services. These revised recommendations were agreed by an expert panel convened by the UK Liver Advisory Group, with the purpose of providing consensus on referral for transplant assessment in patients with alcohol-related disease, and clarifying the terminology and definitions of alcohol use in liver injury. By standardising clinical management in these patients, it is hoped that there will be an improvement in the quality of care and better access to liver transplant assessment for patients with alcohol-related liver disease in the UK.

Multiparametric Magnetic Resonance Imaging, Autoimmune Hepatitis, and Prediction of Disease Activity.

Noninvasive monitoring of disease activity in autoimmune hepatitis (AIH) has potential advantages for patients for whom liver biopsy is invasive and with risk. We sought to understand the association of multiparametric magnetic resonance imaging (mpMRI) with clinical course of patients with AIH. We prospectively recruited 62 patients (median age, 55 years; 82% women) with clinically confirmed AIH. At recruitment, patients underwent mpMRI with LiverMultiScan alongside clinical investigations, which were repeated after 12-18 months. Associations between iron-corrected T1 (cT1) and other markers of disease were investigated at baseline and at follow-up. Discriminative performance of cT1, liver stiffness, and enhanced liver fibrosis (ELF) to identify those who failed to maintain remission over follow-up was investigated using the areas under the receiver operating characteristic curves (AUCs). Baseline cT1 correlated with alanine aminotransferase (Spearman's correlation coefficient [r S] = 0.28, P = 0.028), aspartate aminotransferase (r S = 0.26, P = 0.038), international normalized ratio (r S = 0.35 P = 0.005), Model for End-Stage Liver Disease (r S = 0.32, P = 0.020), ELF (r S = 0.29, P = 0.022), and liver stiffness r S = 0.51, P < 0.001). After excluding those not in remission at baseline (n = 12), 32% of the remainder failed to maintain remission during follow-up. Failure to maintain remission was associated with significant increases in cT1 over follow-up (AUC, 0.71; 95% confidence interval [CI], 0.52-0.90; P = 0.035) but not with changes in liver stiffness (AUC, 0.68; 95% CI, 0.49-0.87; P = 0.067) or ELF (AUC, 0.57; 95% CI, 0.37-0.78; P = 0.502). cT1 measured at baseline was a significant predictor of future loss of biochemical remission (AUC, 0.68; 95% CI, 0.53-0.83; P = 0.042); neither liver stiffness (AUC, 0.53; 95% CI, 0.34-0.71; P = 0.749) nor ELF (AUC, 0.52; 95% CI, 0.33-0.70; P = 0.843) were significant predictors of loss of biochemical remission. Conclusion: Noninvasive mpMRI has potential to contribute to risk stratification in patients with AIH.

Primary sclerosing cholangitis and the management of uncertainty and complexity.

Primary sclerosing cholangitis (PSC) is a rare chronic autoimmune disease with no effective therapy and a large unmet need for new treatments. Patients require significant healthcare resources over their lifetime with high rates of hospital admission, malignancy, liver transplantation and death. As a rare disease, expertise in management can be limited to large referral liver transplant programmes, and even then there is frequently variation in practice. In this case-based review, we aim to discuss common clinical dilemmas encountered by clinicians managing patients with PSC and address related competencies in the 2010 Gastroenterology Curriculum.

Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): A single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a progressive inflammatory liver disease characterised by relentless liver fibrosis and a high unmet need for new therapies. Preventing fibrosis represents an important area of interest in the development of vital new drugs. Vascular adhesion protein-1 (VAP-1) drives inflammation in liver disease, and provision of an antibody against VAP-1 blunts fibrosis in murine models of liver injury. METHODS AND ANALYSIS: BUTEO is a single-arm, two-stage, open-label, multi-centre, phase II clinical trial. Up to 59 patients will receive treatment with anti-VAP monoclonal antibody, BTT1023, over a 78-day treatment period. Adults with PSC and a serum alkaline phosphatase (ALP) of at least 1.5 times the upper limit of normal will be included. Our primary outcome measure is a reduction in ALP by >25% from baseline to Day 99. Secondary outcome measures include safety and tolerability, changes pre therapy/post therapy in circulating serum VAP-1 as well as imaging findings. The first patient participant was recruited on 08 September 2015. ETHICS AND DISSEMINATION: This protocol has been approved by the Research Ethics Committee (REC, reference 14/EM/1272). The first REC approval date was 06 January 2015 with three subsequent approved amendments. This article refers to protocol V3.0, dated 16 March 2016. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION: The trial is registered with the European Medicines agency (EudraCT: 2014-002393-37), the National Institute for Health Research (Portfolio ID: 18051) and ISRCTN: 11233255. The clinicaltrials.gov identifier is NCT02239211. Pre-results.

Preassessment Interview Improves the Efficacy and Safety of Bowel Preparation for Colonoscopy.

Aim. To determine whether preassessment improves bowel preparation quality and prevents renal deterioration for chronic kidney disease (CKD) patients. Methods. Data was collected prospectively starting in January 2011 for 12 months. Patients were divided according to the presence or absence of preassessment and stratified to one of three risk groups based on patient's comorbidities and identified risk factors for poor bowel preparation; group 1 had no risk factors, group 2 had 1 risk factor, and group 3 patients had 2 or more risk factors. The association between preassessment and bowel preparation quality was analyzed using binary logistic regression. Results. 1840 colonoscopies were carried out during the period. Total number analyzed was 1704. 404 patients were preassessed. Preassessment patients had significantly better bowel preparation across all groups (OR 1.605; p = 0.002). Group 3 patients were 52% more likely to have good bowel preparation (p = 0.04) if they had been preassessed. Eighty-eight patients were identified with an eGFR < 60 mL/min. There was a significant difference in the eGFR percentage change between patients with preassessment and those without (p = 0.006). Conclusions. Face-to-face preassessment appears to improve the quality of bowel preparation and aids in minimizing the risk of renal injury in patients with CKD.

The Pathogenesis of Autoimmune Liver Disease.

BACKGROUND: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. KEY MESSAGES: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. CONCLUSIONS: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.

The hidden endoscopic burden of sleeve gastrectomy and its comparison with Roux-en-Y gastric bypass.

BACKGROUND: This study aimed to assess the endoscopic burden of bariatric surgical procedures at our trust. This is an enhanced parallel study to "The Hidden Endoscopic burden of Roux-en-Y Gastric Bypass" published in Frontline Gastroenterology in 2013 incorporating the data for sleeve gastrectomy and comparison with Roux-en-Y gastric bypass (RYGB). METHODS: This is a retrospective study that included 211 patients undergoing sleeve gastrectomy over a 34-month period. We utilized previously collected data for the RYGB patient cohort which included 553 patients over a 29-month period. We searched our hospital endoscopic database for patients who underwent post-operative endoscopy for indications related to their surgery. RESULTS: 16.6% of the sleeve gastrectomy patients required post-operative endoscopy, of whom 11.4% underwent therapeutic procedures. This compares to 20.4% of the RYGB cohort of whom 50.4% needed therapeutic procedures (P<0.001). 1.9% of sleeve gastrectomy patients encountered a post-operative staple line leak and collectively required 29 endoscopic procedures. One patient also developed stricturing (0.47%) requiring 18 pneumatic dilatations. 11.4% of the RYGB cohort developed an anastomotic stricture requiring 57 balloon dilatation procedures. To date, these procedures have accumulated an equivalent cost of €159,898 in endoscopy tariffs, or €177 per RYGB and €373 per sleeve gastrectomy performed. CONCLUSIONS: Bariatric surgery can have significant implications in terms of patient morbidity and financial cost. Having a local bariatric surgery service increases the demand for endoscopic procedures in our hospital, both in investigating for and dealing with post-operative complications. Provision of extra resources and expertise needs to be taken into account.