Introduction

Abdominal pain is a prominent symptom in acute pancreatitis (AP) and has been linked to disease severity.

Aims & Methods

We aimed to examine associations between pain intensity and the outcome of AP and the discriminatory ability of pain intensity to predict these outcomes. For this, we conducted a post-hoc analysis using data from the PAINAP database of patients admitted with AP across 118 centres in 27 countries. Based on the pain intensity on admission using a numeric rating scale (NRS) of 0 to 10, patients were categorised as having no/mild (NRS 0-3), moderate (NRS 4-6) or severe pain (NRS 7-10). Demographic details and AP outcomes were compared across these three groups, and associations were explored using multivariable regression analyses. Finally, the influence of pain intensity on the probability of AP outcomes was assessed by calculating AUC-ROCs, sensitivity, specificity, positive/negative predictive values, and likelihood ratios.

Results

We included 1,727 patients, of whom 183 (11%) reported no/mild pain, 503 (29%) moderate pain, and 1,041 (60%) severe pain. Severe pain was associated with more severe AP (OR 1.66 (95% confidence interval (95%CI), 1.09-2.52), P=0.02), renal failure (OR 3.04 (95%CI, 1.35-6.87) and pancreatic necrosis (OR 2.37 (95%CI, 1.22-4.59), P=0.01) compared to no/mild pain. Severe pain had a low discriminatory ability for predicting outcomes of AP, with AUC-ROCs ranging from 0.53 to 0.61.The sensitivity was moderate for all outcomes, with the highest value (81% (95%CI, 72-88)) for renal failure. The specificity was lower across all outcomes, ranging from 41 to 42%. Positive predictive values were low (9-30%), whereas negative predictive values were higher (77-97%).The highest negative predictive value was observed for renal failure. Pain intensity (cutoff NRS ≥ 7) did not affect the post-test probability of outcomes compared to pre-test probability, suggesting that pain intensity alone is insufficient for evaluating prognosis in AP.

Conclusion

Pain intensity was associated with worse outcomes in AP, but the discriminatory performance of pain intensity for predicting AP outcomes was poor. Future research is warranted to refine the assessment of AP pain and clarify the underlying mechanisms. A more comprehensive understanding of pain in AP could improve its prognostic value, guide more personalised treatment strategies, and optimise pain management.

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.

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

Advanced fibrosis is the primary prognostic determinant in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Current estimates suggest that more than 25% of adults worldwide are affected by MASLD, and it is expected to become the leading cause of liver transplants in the future [1]. Current non-invasive tools like Fibrosis-4 (FIB-4) lack optimal balance between sensitivity and specificity. We aimed to develop and compare two ML models: Extreme Gradient Boosting (XGBoost) and logistic regression to predict advanced fibrosis using routinely available clinical data, with liver stiffness measurement via transient elastography as the reference standard.

Aims & Methods

We used data from NHANES 2017-2018. Adults with valid liver stiffness measurement from transient elastography were included. Advanced fibrosis was defined as liver stiffness >=8.2 kPa. Input features included AST, ALT, platelet count, BMI, triglycerides, glucose, and diabetes status. A total of 2,625 participants were included. Data were split 80:20 into training and testing sets respectively using stratified sampling to preserve fibrosis prevalence (~9%). To address class imbalance, the XGBoost model was trained using a weighted loss function. Logistic regression was used as a baseline comparator. Classification thresholds were optimized using Youden's Index to determine the best trade-off between over- and under-classification of fibrosis. Model performance was evaluated using AUROC, accuracy, sensitivity, and specificity.

Results

Both models demonstrated good discriminatory performance. The XGB model achieved an AUROC of 0.73, with sensitivity of 78.9%, specificity of 61.2%, and accuracy of 77.3%. While logistic regression yielded a slightly higher AUROC of 0.77, greater specificity (81.6%), and lower sensitivity (60.7%) and accuracy (62.7%).

Conclusion

Both ML models using simple clinical and biochemical inputs demonstrated reasonable performance in detecting advanced fibrosis among patients with MASLD. The XGBoost model provided a more balanced profile with improved sensitivity, while logistic regression offered better specificity. To address class imbalance (~9% prevalence), XGBoost used a weighted loss function, and both models were calibrated using Youden's Index to optimize classification thresholds. Limitations include reliance on a non-invasive fibrosis surrogate (transient elastography), and lack of external validation. Future work should validate these models in prospective cohorts and explore integration into digital clinical tools.

References

[1] McTeer, M., Applegate, D., Mesenbrink, P., Ratziu, V., Schattenberg, J. M., Bugianesi, E., Geier, A., Romero Gomez, M., Dufour, J. F., Ekstedt, M., Francque, S., Yki-Jarvinen, H., Allison, M., Valenti, L., Miele, L., Pavlides, M., Cobbold, J., Papatheodoridis, G., Holleboom, A. G., Tiniakos, D., … LITMUS Consortium investigators (2024). Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information. PloS one, 19(2), e0299487. https://doi.org/10.1371/journal.pone.0299487
[2] Satapathy, S. K., Bernstein, D. E., & Roth, N. C. (2022). Liver transplantation in patients with non-alcoholic steatohepatitis and alcohol-related liver disease: the dust is yet to settle. Translational gastroenterology and hepatology, 7, 23. https://doi.org/10.21037/tgh-2020-15

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

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.