Introduction

Primary sclerosing cholangitis (PSC) is a major type of autoimmune cholestatic liver disease with unknown etiology, characterized by cholestasis, abnormal biliary epithelial homeostasis, biliary tract fibrosis and consequently liver dysfunction^1,2. Notably, PSC further elevates the risk of developing cholangiocarcinoma³. Investigating the underlying causal factors could contribute to the development of novel therapeutic strategies, thereby mitigating the burden on public health systems imposed by these conditions.
Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases. The toxicity of bile acids is associated with the severity of cholestatic diseases^4,5. Among all BA components, hydrophobic BAs such as chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)⁶ are considered the main toxic components to the bile duct epithelium and hepatocytes. Besides, glycochenodeoxycholic acid (GCDCA) has been used to model BA toxicity both in vivo and in vitro⁷. The clinical usefulness of plasma BA in cholestatic diseases was studied via BA profiling in cholangitis cohorts, and the clinical utility was analysed^4,8. Nevertheless, no large-scale epidemiology studies have identified the causal relationship between individual components of BA and the pathogenesis of cholangitis, especially the sequence between changes in BA composition and disease onset.
In this study, we extracted summary statistics of 32 plasma BA components from the largest metabolome GWAS dataset to date⁹ as exposures and performed two-sample MR using 2 datasets of PSC as outcomes, followed by reverse MR, to assess the causal relationship between BAs and the pathogenesis of this disease.

Aims & Methods

We aimed to identify causal bile acid components on PSC using mendelian randomization. Summary statistics for primary sclerosing cholangitis were retrieved from European Bioinformatics Institute and FinnGen Consortium, and plasma bile acid components data were obtained from European Bioinformatics Institute. BA profiles of PSC patients by GC-MS were retrieved from published researches. Statistical analyses used the inverse variance weighted(IVW), weighted median(WM), maximum likelihood(ML) and MR-Egger algorithm, followed by various sensitivity analyses and reliability evaluation.

Results

Plasma level of glycochenodeoxycholate glucuronide(GCDCG) is negatively correlated with primary sclerosing cholangitis (IVW: OR=-0.12, p=0.0269 in EBI dataset, OR=-0.38, p=0.0299 in FinnGen dataset). No reverse causal effect was identified(IVW: p=0.7067 in EBI dataset, p=0.5158 in FinnGen dataset). GCDCG was decreased in bile of patients with PSC compared with healthy controls (logFC=-2.09, p=0.010).

Conclusion

Our findings provide evidence regarding the risk of primary sclerosing cholangitis for individuals with low level of plasma glycochenodeoxycholate glucuronide, and targeting the transformation of glycochenodeoxycholate into its glucuronide may be a novel therapeutic strategy to primary sclerosing cholangitis.

References

1. Dyson JK, Beuers U, Jones DEJ, et al. Primary sclerosing cholangitis. Lancet 2018;391(10139):2547-2559.
2. Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2023;21(8):2076-2087.
3. Tham EKJ, Lim RY, Koh B, et al. Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis. Clin Gastroenterol Hepatol 2024.
4. Mousa OY, Juran BD, McCauley BM, et al. Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation. Hepatology 2021;74(1):281-295.
5. Perreault M, Białek A, Trottier J, et al. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction. PLoS One 2013;8(11):e80994.
6. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999;159(22):2647-58.
7. Du Y, Khandekar G, Llewellyn J, et al. A Bile Duct-on-a-Chip With Organ-Level Functions. Hepatology 2020;71(4):1350-1363.
8. Tietz-Bogert PS, Kim M, Cheung A, et al. Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis. International Journal of Molecular Sciences 2018;19(10):3188.
9. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nature Genetics 2023;55(1):44-53.

Introduction

Pain is the hallmark and most disabling symptom of chronic calcific pancreatitis (CCP), often severe and significantly impairing patients' quality of life. Its pathophysiology involves increased intraductal pressure, chronic inflammation, and neuropathic changes.

Aims & Methods

This study aimed to assess the prevalence of pain in CCP and to identify factors associated with its occurrence and severity.
This was a retrospective analytical study including patients followed for CCP. We collected data on disease duration, etiology, clinical manifestations, complications, analgesic treatments (AT), and symptom evolution under treatment. Pain intensity and impact on quality of life were assessed using the Izbicki Score (IS), which categorizes pain as mild (0–20), moderate (21–40), severe (41–60), or very severe (>60). Incomplete records that prevented IS calculation were excluded. Data were entered and analyzed using SPSS software, with statistical significance set at p < 0.05.

Results

We included 22 patients (14 men and 8 women), with a mean age of 55.6 years [27–80 years]. The most common symptoms were epigastric pain (n=18), weight loss (n=13), and chronic diarrhea (n=6). The mean delay between symptom onset and diagnosis was 25 months [1–120 months]. Etiologies included hyperparathyroidism (n=6), alcohol use (n=2), pancreas divisum (n=2), autoimmune causes (n=2), and were undetermined in 10 cases. The IS ranged from 0 to 93.75, with a mean of 40.22. Eight patients had an IS >40. Morphine was required in four cases; paracetamol was prescribed for 12 patients, and tramadol for two. Endoscopic treatment was indicated in three cases, while one patient underwent a Wirsungojejunostomy.
In univariate analysis, alcohol consumption was significantly associated with the occurrence of epigastric pain (p=0.01). Smoking and alcohol use were both linked to a higher IS (>50) (p=0.04). Smoking cessation was associated with a better analgesic response (p=0.04). Morphine use was significantly more frequent among alcoholic patients (p=0.01), and their treatment response was often unfavorable (p=0.02).

Conclusion

In our cohort, 80% of patients with CCP experienced pain, which was severe to very severe in nearly half the cases. Pain intensity was significantly associated with tobacco and alcohol consumption, while cessation improved treatment response. These findings underscore the importance of therapeutic education focused on smoking and alcohol cessation, in addition to analgesic management, to slow disease progression and improve pain control.

Introduction

HBV infection is a critical global health issue and the leading cause of cirrhosis and hepatocellular carcinoma (HCC) with its mechanisms still not fully understood. Despite existing several HCC biomarkers, challenges such as low sensitivity and tumor heterogeneity hinder early detection, highlighting the need for further exploration of mechanisms and new diagnostic markers.

Aims & Methods

In this study, we conducted an integrated multi-omics study of HCC GWAS, TCGA-LIHC, GTEx, and HPA data, in order to identify pathogenic genes and serum markers for HBV-associated HCC. The expression of candidate genes or serum markers were then evaluated in HCC liver tissues or serum. In vitro and in vivo cellular functional experiments were performed to determine their roles in tumor progression.

Results

Our findings revealed that the ATF6B-APOC2-CD36 axis derived growth and metastasis in HBV-associated HCC. Mechanistically, HBV induced ATF6B expression via the endoplasmic reticulum stress pathway. Then ATF6B bound to the APOC2 promoter region, thereby enhancing APOC2 expression. APOC2 further interacted with CD36 to activate the Wnt/β-catenin signaling pathway, promote EMT and consequently facilitate the growth and metastasis of liver cancer. Moreover, serum APOC2 significantly increased in HBV-related HCC patients and when combined with PIVKA-II shown high diagnostic value for AFP-negative HBV-related HCC.

Conclusion

Our findings demonstrated that the ATF6B-APOC2-CD36 axis contributes to HCC progression and serum APOC2 offers diagnostic potential for AFP-negative HBV-related HCC patients. These findings may advance molecular understanding, early diagnosis, and treatment of HBV-related HCC.