Introduction

Chronic pancreatitis (CP), influenced by both genetic and environmental factors, poses a significant health burden with its progressive nature. While excessive alcohol consumption is a prominent risk factor, non-alcoholic chronic pancreatitis (NACP) presents challenges due to less overt precipitating factors.

Aims & Methods

We aimed to assess the impact of rs7057398 and rs12688220 variants at the RIPPLY1-CLDN2-MORC4 locus and rare functionally deficient TRPV6 variants in NACP susceptibility.
Systematic search weas conducted on PubMed, Embase, and Web of Science databases on November 2, 2023, aiming to assess non-alcoholic acute recurrent pancreatitis (ARP) and CP cases, excluding conference abstracts and preprints. The protocol was prospectively registered (CRD42023438777). Utilizing a random-effect model with REML estimation, odds ratios (OR) with 95% confidence intervals (CI) were computed using the allelic model (rs7057398: C vs T; rs12688220: T vs C) for the total population and hemizygotes as well, the homozygote (rs7057398: CC vs TT; rs12688220: TT vs CC) and heterozygote model (rs7057398: CT vs TT; rs12688220: TC vs CC). Minor allele frequnecy (MAF) was calculated for both variants. In the analysis of functionally deficient rare TRPV6 variants were collectively pooled and compared to cases without mutations affecting TRPV6 function, calculating OR with 95% CI. Subgroup analysis, stratified by age, set the threshold for early-onset CP at 30 years in all cases. Statistical heterogeneity was evaluated using Chi² tests and I² values. Due to limited study numbers, funnel plots and Egger’s test were deemed inappropriate. Risk of bias was assessed using the Joanna Briggs Institute's tool.

Results

Six studies were included in the quantitative analyses for SNPs rs7057398 and rs12688220. MAF for rs7057398 was 0.49 (CI 0.31 to 0.67) in cases and 0.38 (CI 0.27 to 0.50) in controls. For rs12688220, MAF was 0.46 (CI 0.27 to 0.67) in cases compared to 0.35 (CI 0.24 to 0.47) in controls. MAF was notably higher in Indian and Asian studies compared to European cohorts. Both risk alleles were significantly associated with NACP in homozygotes, heterozygotes and hemizygotes, respectively (see Table). In the allelic model, minor allele carriers displayed significantly increased odds for NACP for rs7057398 (OR 1.54, CI 1.17 to 2.01, p=0.009) and rs12688220 (OR 1.64, CI: 1.10 to 2.45, p=0.025). Limited data was available on early-onset cases, therefore definitive conclusions cannot be drawn. Functionally deficient TRPV6 variants were associated with a 35-fold increased odds of developing NACP compared to individuals without these variants (OR = 35.32, CI 20.72 to 60.22, across 4 cohorts, 2236 cases and 2748 controls). Risk of bias was generally jugded to be high in the included studies.

Conclusion

Our meta-analysis highlights the significant association of variants rs7057398 and rs12688220 of the RIPPLY1-CLDN2-MORC4 locus, along with functionally deficient TRPV6 variants, with NACP. These findings emphasize the importance of genetic screening for identifying individuals at risk of NACP and inform personalized intervention strategies.

Introduction

Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. Activated pancreatic stellate cells (PSCs) are the main effector cells of pancreatic fibrosis. The purpose of this study was to investigate the function of E2F1-HDAC1 complex in the activation of PSCs, evaluate the role of HDAC1 inhibitor Cedaramine during pancreatic fibrosis, and explore the molecular regulated mechanism between E2F1-HDAC1 complex and PIWIL1/mTOR signaling pathway.

Aims & Methods

When inducing pancreatic fibrosis in C57BL/6 mice, 20% L-arginine (250 mg/100g) was injected intraperitoneally twice a week, with an interval of 1 hour, lasting for 8 weeks, and then PSCs were isolated. Use RNA interference (RNAi) constructed by lentivirus and vectors constructed based on over-expression vectors to knock out and over-express E2F1 and HDAC1 Protein. In order to explore the effects of E2F1-HDAC1 complex on PSC activation and EMC secretion, western blotting and IHC staining were used respectively. To explore transcriptional molecular mechanism between E2F1-HDAC1 complex and PIWIL1, luciferase reporter assay, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) were applied. Hematoxylin-eosin, Masson and Sirius red staining were used to analyze the effect of E2F1-HDAC1 complex and HDAC1 inhibitor Cedaramine on histological changes and collagen deposition.

Results

In LV-E2F1 and LV-HDAC1 group, the level of α-SMA, Col I and Col III were significantly increased compared with si-E2F1 and si-HDAC1 group. However, the expression of PIWIL1, desmin and p-mTOR were reduced in LV-E2F1 and LV-HDAC1 group. Meanwhile, E2F1-HDAC1 complex directly binded to the PIWIL1 promoter and then activated its transcription. In addition, as fibrosis aggravated over time, the levels of E2F1 and HDAC1 significantly increased. HDAC1 inhibitor Cedaramine can significantly improve collagen deposition in pancreatic fibrosis.

Conclusion

Our findings suggest that E2F1-HDAC1 complex targets PIWIL1 to regulate pancreatic stellate cell activation. HDAC1 inhibitor Cedaramine could become a potential drug in the treatment of pancreatic fibrosis.

Disclosure

This work was supported by grants from the Fund for Fostering Young Scholars of Peking University Health Science Center (BMU2021PY010), National Natural Science Foundation of China (No. 82002461), Beijing Municipal Hospital Management Center "Youth" Talent Plan (QML20231104) and Medjaden Academy and Research Foundation for Young Scientists (MJR20211110).

Introduction

Primary Biliary cholangitis (PBC) is a cholestatic condition caused by autoimmune damage of the biliary channels and potentially Precipitating biliary liver cirrhosis and ESLD. The National PBC audit highlighted the nationwide variability in diagnosing and managing PBC (1). The BSG guideline-recommended standard dosing of UDCA (13–15 mg/kg/ day) and prompt liver transplant assessment when indicated (2). Additionally, it endorsed early detection of cirrhosis with related screening to establish and treat hepatocellular carcinoma and oesophageal varices early and it supports adequate control of symptoms such as fatigue or itching which can be challenging (1,2).

Aims & Methods

We obtained medical records from our Electronic Prescription and Medication Administration (EPMA) team for all PBC patients on UDCA between May 2021 and May 2023. A total of 141 patients were identified; 45 and 12 patients were excluded as duplicate and incomplete records, respectively. Only 84 patients were included in this retrospective analysis all with confirmed PBC as defined by the BSG and BASL. Mostly Females (84%) with a mean age of 56.5 years old (35:78). Data were collected from clinic letters and medical records regarding UDCA dose per body weight, symptoms control, refer to liver transplantation, FibroScan and Variceal/HCC screening when liver cirrhosis is a concern.

Results

Our audit revealed that only 78% of the patients were on ideal dosing of UDCA as per documented body weight, additionally, no clear symptoms scoring (fatigue, itching, joint pain, etc) was used. However, in the 19 patients with established biliary cirrhosis on fibroScan, there was good compliance with HCC screening (84%) and oesophageal varices screening (78.9%).
Additionally, only 7 patients were referred for liver transplant assessment or discussed with the tertiary center (see Table 1 for details).

Conclusion

More compliance with the recommended dose of UDCA in our patient is needed to achieve clinical outcomes and normalization of liver functions. there was great compliance with variceal and HCC screens in cirrhotic patients However we also advised prompt early referrals for liver transplant assessment. Furthermore, documentation and scoring of extrahepatic symptoms should be improved.

References

1) Burke, Laura et al. “The National Audit of Primary Biliary Cholangitis (PBC) in the United Kingdom: Defining the Audit Dataset and Data Collection System.” Cureus vol. 14,6 e25609. 2 Jun. 2022, doi:10.7759/cureus.25609.
2) Hirschfield, Gideon M et al. “The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines.” Gut vol. 67,9 (2018): 1568-1594. doi:10.1136/gutjnl-2017-315259.