Introduction

Bile acids serve as essential signaling molecules that regulate metabolic pathways, immune responses, and cellular proliferation through receptors such as TGR5 and S1PR2 (1). Notably, TGR5 deficiency exacerbates liver injury, while S1PR2 knockdown offers hepatoprotection (2,3).

Aims & Methods

This study examines the receptor-specific roles and interactions between TGR5 and S1PR2 in regulating cholangiocyte function under physiological and injury-related conditions. Intrahepatic biliary organoids were generated from murine liver tissue through microdissection and enzymatic dissociation, followed by morphological and phenotypic characterization. To enhance accessibility to apically expressed receptors, apical-out organoids (AOOs) were established under matrigel-free conditions using ultra-low attachment culture systems. Organoids were derived from wild-type, TGR5-knockout (TGR5⁻/⁻), S1PR2-knockout (S1PR2⁻/⁻), double-knockout (TGR5⁻/⁻S1PR2⁻/⁻), and S1PR2⁻/⁻ mice overexpressing TGR5 (S1PR2⁻/⁻/TGR5-tg). Organoids were stimulated for 6 hours with bile acids and receptor-specific agonists. Total RNA was subsequently extracted and processed for bulk RNA sequencing to evaluate global transcriptomic responses.

Results

Transcriptomic profiling revealed distinct gene expression patterns among knockout conditions compared to wild-type controls under non-stimulated conditions. Major histocompatibility complex class I (MHC-I) genes were significantly downregulated in TGR5⁻/⁻ organoids across multiple comparisons (TGR5⁻/⁻ vs. WT and double-knockout vs. WT), with consistent reductions in H2-Q1, H2-Q6, H2-Q10, H2-T5, H2-T7, and H2-T15 expression.
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Conclusion

These transcriptomic findings suggest a potential immunomodulatory role for TGR5 in the regulation of MHC-I gene expression in biliary epithelial cells under basal conditions. The consistent downregulation of MHC-I–related transcripts in TGR5-deficient organoids may indicate a role for this receptor in maintaining antigen presentation capacity in cholangiocytes. While these observations point toward a possible link between bile acid signaling and hepatic immune regulation, further validation is needed to confirm the functional consequences of altered MHC-I expression and to elucidate the underlying mechanisms.

References

1. Keitel V, Stindt J, Häussinger D. Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors. In: Fiorucci S, Distrutti E, editors. Bile Acids and Their Receptors. Cham: Springer International Publishing; 2019. p. 19-49.
2. Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut. 2016;65(3):487-501.
3. Wang Y, Aoki H, Yang J, Peng K, Liu R, Li X, et al. The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology. 2017;65(6):2005-18.

Introduction

Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease characterized by progressive destruction of small intrahepatic bile ducts, leading to cholestasis and end-stage liver disease. Liver transplantation (LT) remains the definitive treatment, with excellent long-term outcomes. However, a subset of patients experiences disease recurrence (rPBC), which may impact prognosis. Due to the rarity of the condition, risk factors for rPBC remain poorly defined.

Aims & Methods

This study aims to determine the prevalence of rPBC after LT and identify potential risk factors associated with recurrence. A systematic search was conducted in MEDLINE, Embase, and Cochrane CENTRAL using a predefined strategy. We included full-text studies reporting the number of PBC patients who developed rPBC post-LT. Abstracts and studies lacking clear data on prevalence or risk factors were excluded. Prevalence estimates were pooled using a two-step approach with logit transformation and generalized linear mixed models. Hazard ratios (HRs) and 95% confidence intervals (CIs) were synthesized using a random-effects model with restricted maximum likelihood estimation. All analyses were performed using R Studio.

Results

Fifty-five studies met inclusion criteria, most conducted in Europe, followed by North America, Asia, and Australia; two studies were multi-continental. A total of 5,715 patients with PBC who underwent LT were included, with 9.98% being male. Reported prevalence of rPBC ranged from 0% to 50%, with a pooled prevalence of 15% (95% CI: 12%-19%). Significant risk factors for rPBC included younger age at LT (HR = 0.97, 95% CI: 0.96-0.98) and use of tacrolimus in maintenance immunosuppression (HR = 1.79, 95% CI: 1.09-2.95). Protective factors included cyclosporine-based maintenance immunosuppression (HR = 0.50, 95% CI: 0.28-0.87) and post-LT prophylactic use of ursodeoxycholic acid (HR = 0.42, 95% CI: 0.30-0.58). Donor age, donor-recipient sex mismatch, cold ischemia time, and use of tacrolimus, cyclosporine, or azathioprine in initial immunosuppression, as well as maintenance azathioprine or occurrence of acute cellular rejection, were not significantly associated with rPBC.

Conclusion

This is the largest meta-analysis to date evaluating rPBC, including 5,715 liver transplant recipients with PBC. The overall recurrence rate was 15%. Younger age at transplantation and tacrolimus-based immunosuppression were associated with higher recurrence risk, while cyclosporine and post-LT ursodeoxycholic acid appeared protective. These findings may inform risk stratification and guide post-transplant management in PBC. Prospective studies are needed to validate these associations and refine strategies to prevent rPBC.

Disclosure

RVM has received funding from PSC Support. GGLC has received a research grant from IPSEN.

Introduction

While early intervention with biologics improves clinical response in Crohn’s disease (CD), the optimal timing to reduce healthcare resource utilisation (HCRU) and direct costs remains unclear. This study examined the impact of biologic initiation on HCRU and direct costs over 5 years in adults recently diagnosed with CD in the US.

Aims & Methods

Adults with >2 non-ancillary outpatient claims (30 days apart) or 1 inpatient claim for CD (ICD-10: K50.x) from 1/1/2015 to 7/31/2024 were identified using Optum® Clinformatics® Data Mart. Patients with CD who started biologic treatment within 2 years of diagnosis (index date) and had continuous enrollment for 1 year pre- and 5 years post-index were stratified into early (<12 months) or late (>12-24 months) initiators. Due to skewed distributions, CD-related and non-CD-related costs at 5-year post-index were analysed using gamma log. Poisson or negative binomial (with zero-inflated models in some cases) were used to model HCRU. All models were adjusted for demographic and clinical characteristics at biologic initiation.

Results

Early initiators (EI) were significantly younger (mean[SD] age: 43.2[16.9] vs 48.0[16.6] years, p<0.001), predominantly male (50.6% vs 44.5%), had significantly higher commercial insurance (84.5% vs 77.2%, p=0.004) than late initiators (LI), and had similar Deyo Charlson comorbidity index scores (mean[SD]: 0.7[1.2] vs 0.7[1.3]). EI had significantly lower total mean medical costs ($63,761 vs $66,282), significantly lower IBD-related mean medical and pharmacy costs ($1074 vs $1494), as well as significantly lower mean pharmacy costs to treat depression ($28 vs $346), and anxiety ($38 vs $79) than LI (Table). Additionally, EI had fewer emergency visits (1.5 vs 1.6), fewer all-cause (4.2 vs 4.9 days), and CD-related hospitalisations days (3.9 vs 4.7 days) than LI. Other HCRUs and costs were similar between the two groups.

	Early initiator (EI) (N=1273)	Late initiator (LI) (N=290)	Adjusted P-value
Costs in US Dollars
Medical and pharmacy costs Medical costs Anxiety/depression outpatient costs Non-IBD pharmacy costs Opioid pharmacy costs Anti-depression pharmacy costs Anti-anxiety medication costs CD-related medical and pharmacy costs CD-related medical costs IBD-related medical and pharmacy costs	$290,491 (239,398) $63,761 (128,352) $11,492 (48,843) $225,657 (194,145) $170 (1697) $28 (393) $38 (476) $108,293 (116,124) $42,451 (70,935) $1,074 (5,567)	$298,162 (246,492) $66,282 (97,089) $12,203 (41,583) $230,385 (210,412) $189 (1285) $346 (4746) $79 (690) $100,574 (112,197) $45,547 (74,554) $1,494 (6,971)	0.794 0.0497 0.763 0.711 0.825 <.001 0.007 0.070 0.159 0.046
HCRU
Number of emergency department visits Number of outpatient visits Number of CD outpatient visits Number of CD-related emergency department visits Number of CD-related hospitalisations Number of IBD-related diagnostic procedures Number of CD-related management procedures Patients having pharmacy claim, n (%) Patients having IBD-related pharmacy, n (%) Patients having Extraintestinal manifestation, n (%) Days of hospitalisation Days of CD-related hospitalisations Length of hospitalisation in days	1.5 (4.1) 56.6 (49.8) 23.7 (19.2) 0.7 (2.3) 0.6 (1.2) 0.8 (1.0) 0.1 (0.3) 1240 (97.4%) 184 (14.5%) 58 (4.6%) 4.2 (10.4) 3.9 (9.5) 2.0 (3.8)	1.6 (4.0) 60.1 (53.6) 24.1 (19.9) 0.8 (2.3) 0.7 (1.4) 0.9 (1.0) 0.1 (0.3) 277 (95.5%) 33 (11.4%) 17 (5.9%) 4.9 (12.3) 4.7(12.2) 2.1 (4.5)	0.004 0.402 0.357 0.071 0.886 0.398 0.417 0.289 0.163 0.458 0.013 <.001 0.102
Data are presented as mean (SD=standard deviation) unless otherwise specified. CD, Crohn’s disease; IBD, inflammatory bowel disease

Conclusion

Early initiators of biologics had lower HCRU and reduced non-CD medication pharmacy costs at 5 years post-index compared to starting biologics after a year, potentially leading to overall cost savings and improving patient health outcomes.

Disclosure

Alyssa M. Parian: None to disclose
Deborah A. Fisher, Alan James Michael Brnabic, Nicholas Bires, Debbie Tinsley, Zbigniew Kadziola, Wai Man Maria Chan: employees and shareholders of Eli Lilly and Company

Introduction

Endoscopic Retrograde Cholangio-Pancreatography (ERCP) is performed to treat pathology within the biliary system. Patients undergoing this may be on systemic anticoagulation. ERCP is classed as a high-risk bleeding procedure within BSG guidelines. This would necessitate anticoagulation interruption to prevent bleeding. It is recognised however, that resumption of antiplatelets and anticoagulants is associated with improved survival and reduced incidence of thrombotic complications. Thus, all patients should have a clear anticoagulation plan.

Aims & Methods

Attendances for ERCP over a 6-month period were analysed. Of the 132 patients, 33 (25%) were taking either an antiplatelet, warfarin or a Direct Oral Anticoagulant (DOAC). Medical records were reviewed in relation to pre-procedure management of these medications, advice from the endoscopist regarding resumption and whether these medicines were managed appropriately thereafter.
Several interventions were then made; a change to the reporting software led to a prompt relating to antiplatelet/anticoagulant medications, an education campaign for post graduate doctors in training and medication guidance summaries visible in the endoscopy department.
A second 6-month review was then undertaken to evaluate if there had been any improvement in outcomes. In this time frame, 143 patients underwent ERCP of whom 27 (16.7%) were taking antithrombotic therapy.

Results

Results are in Table 1:

	Pre-Intervention	Post Intervention
Pre-procedure appropriate management	48.5%	70.9%
Documented advice on endoscopy report	10%	30%
Post procedure appropriate prescribing	36.3%	70%

One common error was holding of anticoagulation/antiplatelet medication from admission in anticipation of ERCP. This led to long periods off anticoagulation whilst awaiting ERCP.
Documented advice was given more frequently on Endoscopy reports in cases where the patient required further procedure.
It was challenging to analyse post procedural management for inpatients, as the quality of ward round documentation and discharge letters was variable.

Conclusion

Further education to junior staff around utility of BSG anticoagulation guidelines greatly improved pre and post procedure management and thus forms a cornerstone to improve care. Further education to more senior staff may also improve decision rationale and medication advice in ward round documentation and discharge paperwork. Human factors also need to be considered; limited advice is likely related to high endoscopy workload pressures, with sub analysis showing that advice is improved when further intervention is required or in higher risk settings, illustrating that antithrombotic decisions are considered by the endoscopist. Improved documentation at procedure with the support of upgrades to reporting software will enhance post procedure care and consequently reduce demands on the service.​

References

Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline updateVeitch AM, Radaelli F, Alikhan R, et al. Gut 2021;70:1611–1628
UEG poster: Improving documented advice regarding anticoagulants and antiplatelets in acute upper gastrointestinal bleeds. Authors: Dr Emily Creed, Dr Vanessa Theis, Dr Katie Clark, Dr Sweekriti Gurung, Dr Abdullah Motam and Dr Gregor Farrell Bins.

Introduction

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related death. Most colorectal cancers arise from benign polyps, especially dysplastic adenomas. Colonoscopy with polypectomy is the gold standard for preventing cancer by interrupting the adenoma-carcinoma sequence. This has led to the development of various techniques and devices for improved prevention and treatment. Hot snare endoscopic mucosal resection (HS-EMR), which combines submucosal injections with electrocautery, is commonly used for excising various colorectal polyps. However, it carries risks of diathermy-related complications, such as perforation, and bleeding. To address these issues, cold snare endoscopic mucosal resection (CS-EMR) has been proposed as an alternative. Concerns about residual adenoma/recurrence have been raised with CS-EMR. Therefore, we conducted this meta-analysis to compare the two techniques.

Aims & Methods

We searched electronic databases, including MEDLINE via PubMed, Scopus, Web of Science, and Cochrane, without restrictions on publication date or language. We included RCTs comparing CS-EMR and HS-EMR for colorectal polyp resection. Primary outcomes included the incidence of delayed bleeding and residual/recurrent adenoma (RRA).

Results

On Nov 5, 2024, our literature search across electronic databases retrieved a total of 1,888 records. Following a meticulous screening process, six studies met the eligibility criteria encompassing 1,449 patients and 1,947 polyps. Regarding safety, the overall effect estimates regarding delayed bleeding showed statistically significant results favoring CS-EMR group [OR 0.31, 95 % CI (0.12–0.76), P = 0.01] with no heterogeneity (P = 0.40; I² = 0 %). However, statistical superiority for CS-EMR could not be detected regarding early bleeding [OR 0.78, 95 % CI (0.31–1.97), P = 0.60]. Only two studies reported data on delayed perforation, showing a numerical difference favoring CS-EMR; however, statistical significance could not be obtained [OR 0.26, 95 % CI (0.03–2.41), P = 0.24]. Regarding efficacy, the overall effect estimates regarding complete resection and RRA did not favor either of the groups [OR 0.62, 95 % CI (0.25–1.53), P = 0.30], [OR 2.81, 95 % CI (0.43–18.47), P = 0.28] respectively.

Conclusion

Evidence obtained from this meta-analysis suggests that CS-EMR offers superior safety compared to HS-EMR for colorectal polyp resection. Current evidence remains limited due to the small number of studies included. Therefore, further high-quality randomized controlled trials with larger sample sizes are needed.

References

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

• Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329(27):1977–81.

• Facciorusso A, Del Prete V, Antonino M, Buccino VR, Muscatiello N. Efficacy of endoscopic polypectomy techniques for colorectal polyps: a systematic review and network meta-analysis. Gastrointest Endosc. 2020;91(4):733–745.e9.

• Pohl H, Srivastava A, Bensen SP, Anderson P, Rothstein RI, Gordon SR, et al. Incomplete polyp resection during colonoscopy—results of the complete adenoma resection (CARE) study. Gastroenterology. 2013;144(1):74–80.e1.

• Tutticci N, Hewett DG. Cold snare polypectomy: A safe, effective technique for sessile polyps. Gastrointest Endosc Clin N Am. 2015;25(2):291–301.

• Kawamura T, Takeuchi Y, Asawa S, Yokota I, Matsuno T, Omori T, et al. A comparison of cold and hot snare polypectomy for small colorectal polyps: a randomized controlled trial. Am J Gastroenterol. 2018;113(3):403–411.