These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Abstract Background The majority of patients with primary sclerosing cholangitis (PSC) have inflammatory bowel disease (IBD). This association has fostered several pathogenic hypotheses linking mucosal immunity to hepatobiliary inflammation. A putative therapeutic target along this axis centres on gut-derived IL-17 secretor cell subtypes, which are activated by interleukin (IL)23. Notably, emergent forms of IBD treatment host several anti-IL23 agents, however safety and efficacy data in PSC patients is limited. Methods We conducted a multi-centre study, evaluating treatment experiences with Ustekinumab (a dual anti-IL12/23 agent), Risankizumab, and Mirikizumab (anti-IL23 alone). Data was analysed to determine treatment impact on liver biochemistry; IBD response defined by serial Mayo colitis scores or faecal calprotectin (FCP) values; and treatment-emergent adverse events. Results Data was accrued across eight centres from 66 pts (Ustekinumab, 62; Risankizumab, 4 [n=1 escalated from Ustekinumab] and Mirikizumab, 1) with median treatment time of 9 months (IQR 5-24). The majority of patients were men (63%; n=42) with a median age at PSC diagnosis of 24y (IQR 17-36). The predominant PSC phenotype was large duct (73%; n=49), with two patients having cirrhosis, 13% (n=7) being transplant recipients, and 66% (n=44) having an IBD phenotype consistent with ulcerative colitis. At baseline, the median FCP and Mayo colitis scores were 810ug/L (IQR 369-1727; n=33/66) and 5 (IQR3-8; n=31/66), respectively. 60 patients were commenced on these agents as 2nd-4th line, after failure of prior biologic therapy. In all, IBD response was observed in 15% (n=8/52) at 6 months, 20% (n=7/35) at 12 months and 21% (n=4/19) at 24 months. Remission was achieved in 3 pts (4.5%) at 18 months. Among non-transplant patients, the median change in ALP from baseline to 6 months was not significant (ALP x upper limit of normal [ULN] 1.4 vs. 1.2; p=0.67), nor from baseline to 12 (ULN 1.1 vs. 1.1; p=0.161) or 24 months (ULN 1.6 vs. 1.0; p=0.074) (Figure 1). No significant differences in serum ALT or bilirubin were observed from baseline to 6, 12 or 24 months. Treatment was discontinued in 37% (n=25/67) due to lack of efficacy and in one patient due to an adverse event. Conclusion Anti-IL23 agents are safe and well-tolerated in PSC-IBD. However, IBD response and remission rates appear to dwarf those seen in IBD alone, with no significant effects on liver biochemistry.

Background & Aims: Senescence has been reported to have differential functions in cholangiocytes and hepatic stellate cells (HSCs) during human and murine cholestatic disease, being detrimental in biliary cells and anti-fibrotic in HSCs. Cholestatic liver disease is associated with loss of intestinal barrier function and changes in the microbiome, the mechanistic cause of which is undetermined. Methods: Intestinal samples were analysed from controls and patients with primary sclerosing cholangitis, as well as wild-type (WT) and p16-3MR transgenic mice. Cholestatic liver disease was induced by bile duct ligation (BDL) and DDC diet feeding. Fexaramine was used as an intestinal-restricted FXR agonist and antibiotics were given to eliminate the intestinal microbiome. Senescent cells were eliminated in p16-3MR mice with ganciclovir and in WT mice with the senolytic drug ABT-263. In vitro studies were done in intestinal CaCo-2 cells and organoids were generated from intestinal crypts isolated from mice. Results: Herein, we show increased senescence in intestinal epithelial cells (IECs) in patients with primary sclerosing cholangitis and in mice after BDL and DDC diet feeding. Intestinal senescence was increased in response to reduced exposure to bile acids and increased presence of lipopolysaccharide in vitro and in vivo during cholestatic liver disease. Senescence of IECs was associated with lower proliferation but increased intestinal stem cell activation, as supported by increased organoid growth from intestinal stem cells. Elimination of senescent cells with genetic and pharmacological approaches exacerbated liver injury and fibrosis during cholestatic liver disease, which was associated with increased IEC apoptosis and permeability. Conclusions: Senescence occurs in IECs during cholestatic disease and the elimination of senescent cells has a detrimental impact on the gut-liver axis. Our results point to cell-specific rather than systemic targeting of senescence as a therapeutic approach to treat cholestatic liver disease. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution. Here, Goode et al. build a T-cell eQTL map from primary sclerosing cholangitis and ulcerative colitis patients. Integrating eQTL and GWAS, they nominate effector genes at six genetic risk loci for primary sclerosing cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.

Background & Aims: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. Methods: We performed bulk RNA-sequencing of monocytes and T(H)1, T(H)17, T-REG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. Results: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; T(H)1 and T(H)17 cells are activated in all PBC cases but better regulated in responders; and T-REG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of T(H)1 cells, and activation of T-REG cells are interrelated and more prominent in responders. Conclusions: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response.

Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 personsJournal of HepatologyVol. 79Issue 2PreviewThe prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. Full-Text PDF We read with interest the systematic review and meta-analysis by Le et al. which demonstrates the rapidly increasing worldwide incidence of non-alcoholic fatty liver disease (NAFLD) likely associated with the obesity epidemic.[1]Le MH Le DM Baez TC Wu Y Ito T Lee EY Global incidence of non-alcoholic fatty liver disease: a systematic review and meta-analysis of 63 studies and 1,201,807 persons.J Hepatol. 2023; 79: 287-295Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Recently, we have demonstrated that NAFLD is the second most common cause of liver disease in patients admitted to hospital with decompensated cirrhosis in the UK (14.4% of admissions).[2]The Trainee Collaborative for Research and Audit in Hepatology UKRegional variation in characteristics of patients with decompensated cirrhosis admitted to hospitals in the UK.Lancet Gastroenterol Hepatol. 2023; 8: 604-606Abstract Full Text Full Text PDF Scopus (2) Google Scholar We strongly agree that targeted public health interventions to reduce the incidence and prevalence of NAFLD combined with optimal outpatient management strategies are needed to mitigate against NAFLD-related complications.[3]McPherson S Armstrong MJ Cobbold JF Corless L Anstee QM Aspinall RJ et al.Quality standards for the management of non-alcoholic fatty liver disease (NAFLD): consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology NAFLD Special Interest Group.Lancet Gastroenterol Hepatol. 2022; 7: 755-769Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar However, efforts to better characterise and stratify this cohort are similarly required. Utilising more robust phenotypic data should allow for the development of NAFLD-specific risk prediction models and may encourage implementation of precision approaches to improve overall patient outcomes. We analysed data from a UK multicentre, retrospective observational cohort study, including patients admitted to hospitals with decompensated cirrhosis in November 2019[4]The Trainee Collaborative for Research and Audit in Hepatology UKAdmission care bundles for decompensated cirrhosis are poorly utilised across the UK: results from a multi-centre retrospective study.Clin Med (Lond). 2023; 23: 193-200Crossref PubMed Scopus (4) Google Scholar (Table S1 provides regional submission data). We compared admissions for patients with NAFLD to the rest of the predominately alcohol-related liver disease (ARLD) cohort. Details of methods and statistical analyses are presented in the supplementary materials. The NAFLD cohort were significantly older (69.0 (IQR 62.3-77.0) vs. 55.5 (IQR 47.0-65.0), p <0.0001∗) and less likely to be male (50.6% vs. 63.5%, p = 0.001∗) (Table 1A). Whilst we note Le et al. demonstrated a higher incidence of NAFLD amongst male patients, this may reflect previous findings that mortality is comparable across male and female patients with NAFLD, reflecting a similar prevalence of advanced disease.[5]Simon T.G. Roelstraete B. Khalili H. Hagström H. Ludvigsson J.F. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort.Gut. 2021; 70: 1375-1382Crossref PubMed Scopus (248) Google Scholar No differences were demonstrated in the proportion of admissions with a previous history of decompensation or known liver disease, or a history of hepatocellular carcinoma (HCC) between cohorts. Patients admitted with NAFLD were significantly less likely to regularly consume alcohol (18.0% vs. 61.8%, p <0.0001∗) than the rest of the predominant ARLD cohort (Table 1A). However, alcohol consumption has been shown to be underreported in previous cohorts of NAFLD and markers of alcohol use may have highlighted individual’s regularly consuming alcohol above recommended limits.[6]Staufer K Huber-Shonauer U Strebinger G Pimingstorfer P Suesse S Scherzer TM et al.Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease.J Hepatol. 2022; 77: 918-930Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Admissions for patients with NAFLD were predominantly related to the management of ascites (40.9% vs. 32.1%, p = 0.02∗) or encephalopathy (25.6% vs. 15.8%, p = 0.002∗), and less likely to be for jaundice (2.8% vs. 17.2%, p <0.0001∗) (Table 1A). Ascites is associated with the highest risk of readmission for patients with NAFLD.[7]Paik JM Eberly KE Kabbara K Harring M Younossi Y Henry L et al.Non-alcoholic fatty liver disease is associated with greater risk of 30-day hospital readmission in the United States (U.S.).Ann Hepatol. 2023; 28: 101108Crossref PubMed Scopus (2) Google Scholar Patient-centred elective outpatient paracentesis provision is therefore a requisite component of modern hepatology services. Recently, data has implicated the premature onset of encephalopathy in NAFLD, while the association of hyperammonaemia with deleterious outcomes is also well-described.[8]Thomsen KL Eriksen PL Kerbert AJC De Chiara F Jalan R Vilstrup H Role of ammonia in NAFLD: an unusual suspect.JHEP Reports. 2023; 5: 100780Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar A high index of suspicion for encephalopathy is required in this cohort, in addition to a low threshold in initiating therapies for hyperammonaemia. The reduction in the proportion of patients admitted with jaundice likely reflects the cohort of patients from the predominately ARLD cohort presenting with alcohol-related hepatitis.Table 1Characterising UK NAFLD admissions.A) VariableNNAFLD, n = 176NAlternate aetiology of liver disease, n = 1,048p valueAge17669.0 (62.3-77.0)1,04855.5 (47.0-65.0)<0.0001∗Male sex17689 (50.6%)1,048665 (63.5%)0.001∗Current alcohol use12222 (18.0%)813502 (61.8%)<0.0001∗Previously known liver disease176151 (85.8%)1,048890 (84.9%)0.82Previous known decompensation176116 (65.9%)1,048706 (67.4%)0.73Known HCC17610 (5.7%)1,04854 (5.2%)0.72Reason for admission Ascites17672 (40.9%)1,048336 (32.1%)0.02∗ Encephalopathy17645 (25.6%)1,048166 (15.8%)0.002∗ Gastrointestinal bleeding17619 (10.8%)1,048161 (15.4%)0.13 Jaundice1765 (2.8%)1,048180 (17.2%)<0.0001∗ Sepsis17610 (5.7%)1,04869 (6.6%)0.74Prognostic scores MELD score14713.0 (11.0-18.0)95517.0 (12.0-21.0)<0.0001∗ UKELD score14753.0 (51.0-60.0)95557.0 (52.0-62.0)<0.0001∗ Child-Pugh score1398.0 (7.0-10.0)9329.0 (8.0-11.0)0.0005∗Post 24-hour care Managed by a specialist176125 (71.0%)1,048776 (74.1%)0.41 Predominately managed on a specialist ward17693 (52.8%)1,043597 (57.2%)0.29 Critical care admission during stay1769 (5.1%)1,048123 (11.7%)0.008∗ Transfer to another centre1765 (2.8%)1,04819 (1.8%)0.37 Admission mortality17127 (15.8%)1,029160 (15.6%)0.91 Length of stay1427.0 (4.0-13.0)8597.00 (3.0-13.0)0.60B) VariableNSurvivors, n = 144NNon-survivors, n = 27p valueAge14469.0 (62.0-76.0)2773.0 (65.0-78.0)0.17Male sex14472 (50.0%)2715 (55.6%)0.68Current alcohol use10220 (19.6%)172 (11.8%)0.74Previously known liver disease144125 (86.8%)2722 (81.5%)0.54Previous known decompensation14496 (66.7%)2717 (63.0%)0.83Known HCC1448 (5.6%)272 (7.4%)0.66Reason for admission Ascites14459 (41.0%)2711 (40.7%)>0.9999 Encephalopathy14438 (26.4%)275 (18.5%)0.47 Gastrointestinal bleeding14416 (11.1%)272 (7.4%)0.74 Jaundice1444 (2.8%)271 (3.7%)0.58 Sepsis14410 (6.9%)270 (0.0%)0.37Prognostic scores MELD score11913.0 (10.0-17.0)2321.0 (15.0-27.0)<0.0001∗ UKELD score11953.0 (50.0-57.0)2359.0 (54.0-61.0)0.0001∗ Child-Pugh score1138.0 (7.0-9.0)2210.0 (8.8-11.0)0.0002∗Post 24-hour care Managed by a specialist144100 (69.4%)2721 (77.8%)0.49 Predominately managed on a specialist ward14478 (54.2%)2712 (44.4%)0.40 Critical care admission during stay1445 (3.5%)274 (14.8%)0.04A) Comparison of admissions for patients with NAFLD compared to patients with alternate aetiologies of liver disease. B) Comparison of NAFLD admissions resulting in patient survival with those that did not. Non-normally continuous data were analysed using Mann-Whitney U tests and presented as median (IQR). Categorical data were analysed using Fisher’s exact tests and presented as number (%). ∗Statistical significance set as per Benjamini-Hochberg procedure with a false discovery rate of 0.05.HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; UKELD, UK end-stage liver disease. Open table in a new tab A) Comparison of admissions for patients with NAFLD compared to patients with alternate aetiologies of liver disease. B) Comparison of NAFLD admissions resulting in patient survival with those that did not. Non-normally continuous data were analysed using Mann-Whitney U tests and presented as median (IQR). Categorical data were analysed using Fisher’s exact tests and presented as number (%). ∗Statistical significance set as per Benjamini-Hochberg procedure with a false discovery rate of 0.05. HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; UKELD, UK end-stage liver disease. Following admission, no differences were noted between cohorts in the proportion of patients managed by a specialist Gastroenterologist/Hepatologist on specialist wards, or in patients transferred to specialist centres. No differences were demonstrated between patient cohorts for mortality during admission (15.8% vs. 15.6%, p = 0.91) despite admissions with NAFLD having significantly lower prognostic scores and being less likely to access critical care (5.1% vs. 11.7%, p = 0.008∗) (Table 1A). Whilst this may reflect the older age of this cohort and concomitant comorbidity, previous concerns have been raised regarding limited access to critical care for patients with ARLD with stigma amongst healthcare professionals suggested as a potential barrier for this cohort.[9]Mitchison H. Saksena S. Hudson M. NCEPOD and alcohol-related liver disease, what are the views of those who deliver the service? A survey of consultants and trainees in North Eastern England.J R Coll Physicians Edinb. 2018; 48: 293-298Crossref PubMed Google Scholar Understanding potential barriers to patients with NAFLD accessing critical care is required to optimise management. Admissions for patients with NAFLD were not more likely to result in mortality after adjustment for age, critical care admission or MELD score (adjusted odds ratio 1.16; 95% CI 0.65-2.00; Fig. S1). Whilst comparisons between non-survivors and survivors are likely underpowered, conventional prognostic models discriminated admission survival (Table 1B). However, no prognostic scores significantly outperformed other models (p = 0.41), with no model achieving an AUC of greater than 0.8 (Fig. S2). After exclusion of admissions resulting in mortality or critical care admission, length of stay was no different to the rest of the cohort (Table 1A). Limitations of these analyses are discussed in the supplementary materials and include the retrospective design, coverage of only a single month, incomplete coverage of the UK with potential selection bias, lack of data regarding comorbidities and the subjective nature of aetiology assignment. Whilst accepting these limitations, this study is representative of a large, real-world cohort. With the likely increased incidence of patients being admitted to hospital with decompensated NAFLD, further work to understand how to optimally manage this cohort are necessary. This cohort is older, often more co-morbid and will likely require a tailored approach to their care. Understanding barriers to providing best care, including access to critical care, is essential when developing the hepatology services of the future. We are grateful for the funding support provided by Guts-UK. We are grateful for the support and endorsement from the British Society of Gastroenterology, British Association for the Study of the Liver, Scottish Society of Gastroenterology and the Welsh Association for Gastroenterology and Endoscopy. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the supplementary data to this article. 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APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA.

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.

isolated ileal disease. In those without IBD, 142 (28%) patients had not had a colonoscopy and biopsies to exclude diagnosis. Among those with colitis without previous colectomy (n=743), 580 (78.1%) underwent annual colonoscopic surveillance; 30 (5.2%) with dye spray, 230 (39.7%) with biopsies and dye spray, and 252 (43.4%) with protocol biopsies alone. Conclusion There is unwarranted variation in the care of patients with PSC in the UK. In particular relating to risk stratification, exclusion of colitis and surveillance for biliary tract and colonic cancer. The lack of uniformity in clinical practice highlights the need for better education of clinicians about PSC management and the potential role of clinical networks for rare liver diseases within the UK

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

BACKGROUND:Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice. METHODS:Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA. FINDINGS:Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level. INTERPRETATION:This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians. FUNDING:Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing.

Introduction The increased risk of colorectal cancer in patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) justifies an enhanced surveillance strategy with annual colonoscopy and dye spray or protocol biopsies. As symptoms are frequently mild in PSC-IBD colitis can be missed unless colonoscopy and biopsies are undertaken at diagnosis of PSC. We audited the colitis surveillance against audit standards published in the BSG and UK PSC guidelines. Methods All UK PSC investigators were invited (March 2019-Jan 2021) to complete an electronic questionnaire encompassing demographics, diagnosis and bowel cancer surveillance data on each patient with PSC under the care of their service. Results 1,795 patients across 30 centres (liver units n=1548, general gastroenterology units n=247) were included. Median age at diagnosis was 51 years and 56.4% were men. Concurrent IBD was present in 1264 patients (70.4%) with 256 (20.3%) having had a colectomy. Where classified, colitis was present in 924/939 (98.4%) patients whereas isolated ileal disease was present in 15/939 patients. Pancolitis (Montreal classification E3) was the commonest disease distribution (673/939, 71.7%). Most patients with IBD were followed up by an IBD specialist (n=616, 48.7%), 266 (21.1%) were followed by a general gastroenterologist, 236 (18.7%) by a hepatologist, whereas 15 (1.2%) patients were followed in a joint IBD/Hepatology clinic. Among those with colitis without previous colectomy (n=743), 580 (78.1%) underwent annual colonoscopic surveillance; 30 (5.2%) with dye spray, 230 (39.7%) with biopsies and dye spray, and 252 (43.4%) with protocol biopsies alone. Of those without documented IBD diagnosis, only 303/507 (59.7%) had this excluded by colonoscopy and biopsies. Age<40 was associated with poorer compliance with colonoscopy surveillance. (P=0.023). Conclusions IBD screening and colonic cancer surveillance is suboptimal in this large UK cohort of patients with PSC. This highlights the need for awareness of PSC-IBD management to address this unwarranted variation in care of people with PSC in the UK.

Introduction Primary sclerosing cholangitis (PSC) is a rare disorder and as such clinical care can be heterogeneous. We audited PSC management across the UK against audit standards set by the British Society of Gastroenterology (BSG). Method All UK PSC investigators were invited to complete an electronic questionnaire on the PSC patient cohort encompassing demographics, diagnosis, bowel and biliary tract cancer surveillance, and risk stratification data (March 2019 - Jan 2021). Results 1,795 patients across 30 centres (liver units n = 1548, general gastroenterology units n = 247) were included. Median age at diagnosis was 51 years and 56.4% were men. Magnetic resonance cholangiography (MRCP) was performed as a diagnostic investigation in 1616 patients (90.0%) and 777 (43.3%) had a liver biopsy. Most were monitored by a hepatologist (n = 1610, 89.7%). 931 patients (51.9%) received non-licensed therapy with Ursodeoxycholic acid. 785 patients (43.7%) had not undergone disease staging or risk stratification within the last 2 years; where performed, it was most commonly by transient elastography (n = 645, 78.7%). Surveillance for biliary tract cancer was not undertaken in 515 patients (28.7%); when performed, it was most commonly by ultrasound (US) (n = 568, 47.1%) or alternating MRCP/US (n = 429, n = 35.6%). Ca 19 - 9 was utilised in 730 patients. Concurrent IBD was present in 1264 patients (70.4%) with 256 (20.3%) having had a colectomy. Where classified, pancolitis (Montreal classification E3) was the commonest disease distribution (673/939, 71.7%) with 1.6% (n = 15) having isolated ileal disease. In those without IBD, 142 (28%) patients had not had a colonoscopy and biopsies to exclude diagnosis. Among those with colitis without previous colectomy (n=743), 580 (78.1%) underwent annual colonoscopic surveillance; 30 (5.2%) with dye spray, 230 (39.7%) with biopsies and dye spray, and 252 (43.4%) with protocol biopsies alone. Conclusion There is unwarranted variation in the care of patients with PSC in the UK. In particular relating to risk stratification, exclusion of colitis and surveillance for biliary tract and colonic cancer. The lack of uniformity in clinical practice highlights the need for better education of clinicians about PSC management and the potential role of clinical networks for rare liver diseases within the UK.