Introduction

The reported prevalence of early onset pancreatic cancer (EOPC), defined in this context as pancreatic cancer diagnosed in individuals under the age of 50, ranges from 4% to 18%. Its incidence has shown a significant increase compared to later onset pancreatic cancer (LOEP). However, there remains limited understanding regarding the extent of this escalation and which subgroups are predominantly affected. This study aims to characterize the clinical and epidemiological characteristics of EOPC in comparison to LOPC.

Aims & Methods

We conducted a retrospective analysis of consecutive pancreatic cancer (PC) patients with definitive histopathological diagnoses, treated at our institution between January 2018 and December 2023. This study aims to characterize the clinical and epidemiological characteristics of EOPC in comparison to LOPC.

Results

Among 223 patients with pancreatic cancer (PC), 37 (16.6%) had EOPC. The mean age of these patients was 37 ± 7 years (range: 18-50). No significant difference in terms of sex was found, with a male predominance in both groups (54.1% in EOPC vs. 55.9% in LOPC). Regarding risk factors, no significant difference was observed between the two groups for smoking, alcohol consumption, obesity, and diabetes. However, a significant increase in family history of pancreatic cancer was noted in the EOPC group (10.8% vs. 1.6%, OR: 3.7 [95% CI: 1.8 – 7.6], p=0.003). No significant difference was found between the two groups regarding tumor stage; cancer was resectable in 27% of cases in the EOPC group compared to 16.1% in the LOPC group (p=0.240). Regarding nutritional status, according to the Nutritional Risk Index (NRI), younger patients had a lower risk of severe malnutrition (18.9% vs. 39.8%, OR: 0.4 [95% confidence interval: 0.2 -0.9], p=0.01), and the mean albumin level was significantly higher in the EOPC group (36 ± 4 vs. 33 ± 5 g/L, p=0.016).

Conclusion

Our study not only highlights the substantial prevalence of EOPC, but also underscores the presence of distinct clinical and epidemiological differences compared to LOPC. Notable findings include a heightened familial predisposition, disparities in nutritional status. These insights emphasize the imperative for tailored screening and management strategies to effectively address the nuances of EOPC.

Clinical Case Summary

A female patient (born 1974) presented with chronic diarrhea (up to 16 times/day, including nocturnal episodes), bloating, periumbilical pain, fatigue, general weakness, and 10 kg weight loss. Since childhood, the patient had been under observation for chronic iron-deficiency anemia of unknown origin without prior gastrointestinal evaluation. Symptoms progressively worsened over two years due to the lack of therapeutic effect at the outpatient stage, leading to hospitalization in July 2022. Histology revealed total duodenal villous atrophy (celiac disease: Marsh 3C, Corazza-Villanacci B2; 30-40 IELs/100 epithelial cells) and lymphocytic microscopic colitis (MC) of the colon (60-70 IELs/100 epithelial cells). Other examinations (abdominal CT, enterography, stool analysis) were normal; labs showed mild iron-deficiency anemia, with protein markers within normal ranges. She was diagnosed with celiac disease combined with lymphocytic MC. A gluten-free diet, iron supplementation, and budesonide (9 mg/day for 3 months) were initiated, leading to clinical improvement. However, diarrhea recurred (up to 10 times/day) one month after stopping budesonide, despite adherence to the gluten-free diet. Duodenal histology improved (Marsh I, IELs ≤20/100 cells), confirming dietary effectiveness for celiac disease. Colonic histology showed ongoing lymphocytic MC activity (25-30 IELs/100 cells). The relapse was attributed to persistent MC. A prolonged regimen of budesonide (9 mg/day for 3 months, tapering to 6 mg/day for 6 months) was prescribed. This clinical case of celiac disease combined with lymphocytic MC demonstrates that significant improvement in small intestine structure can be achieved with a gluten-free diet and prolonged budesonide therapy. However, the recurrent diarrheal syndrome in this case was associated with the persistent course of MC. Literature emphasizes increased MC prevalence in celiac patients, reinforcing the need for timely recognition and combined therapy.

References

1. Miehlke S., Guagnozzi D., Zabana Y., Tontini G.E., Kanstrup Fiehn A.M., Wildt S., Bohr J., Bonderup O., Bouma G., D’Amato M., Heiberg Engel P.J., Fernandez-Banares F., Macaigne G., Hjortswang H., Hultgren-Hörnquist E., Koulaouzidis A., Kupcinskas J., Landolfi S., Latella G., Lucendo A., Lyutakov I., Madisch A., Magro F., Marlicz W., Mihaly E., Munck L.K., Ostvik A.E., Patai Á.V., Penchev P., Skonieczna-Żydecka K., Verhaegh B., Münch A. European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905. Epub ahead of print. PMID: 33619914; PMCID: PMC8259259.

2. Calabrese C., Gionchetti P., Liguori G., Areni A., Fornarini G.S., Campieri M., Rizzello F. Clinical course of microscopic colitis in a single-center cohort study. J Crohns Colitis. 2011 Jun;5(3):218-21. doi: 10.1016/j.crohns.2011.01.004. Epub 2011 Feb 18. PMID: 21575884.

3. Microscopic Colitis: A Concise Review for Clinicians. June Tome MD, Amrit K. Kamboj MD, Darrell S. Pardi MD MS. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

4. Tome M.D., Kamboj A.K., Pardi D.S. Microscopic Colitis: A Concise Review for Clinicians. Mayo Clinic Proceedings. 2021;96(5):1212-1222. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

Introduction

Portal hypertension is a major complication of advanced chronic liver disease (ACLD) and is associated with gastro-oesophageal varices, a leading cause of morbidity and mortality. The British Society of Gastroenterology (BSG) recommends oesophagogastroduodenoscopy (OGD) for variceal screening in all patients with cirrhosis, which could result in a high volume of unnecessary procedures. Given increasing demands on NHS services and the need for cost-effective resource allocation, strategies to reduce unnecessary endoscopy are critical.
The Baveno VI and VII consensus workshops propose non-invasive criteria to optimise variceal screening. Baveno VI suggests that patients with a liver stiffness measurement (LSM) less than 20 kPa and a platelet count greater than 150×10⁹/L can safely avoid OGD. Baveno VII further refines this by recommending non-selective beta-blocker (NSBB) therapy in patients with clinically significant portal hypertension (CSPH), defined as LSM greater than 25 kPa, thereby eliminating the need for screening endoscopy in this group. For patients not clearly stratified by Baveno VI or VII criteria, splenic stiffness measurement (SSM) offers an additional non-invasive tool to refine risk assessment. Incorporating SSM in this intermediate-risk group may further reduce the need for OGD, with recent data showing a high negative predictive value for ​ruling out high-risk varices.

Aims & Methods

We aim to quantify the reduction in endoscopy burden achieved by applying Baveno VI and VII criteria in ACLD patients.
A retrospective analysis was conducted on 1,703 patients who underwent 1,802 FibroScans between January 1, 2024, and December 31, 2024. Patients were stratified based on LSM and platelet counts into the following categories:
1. BSG Criteria: All patients with LSM ≥10 kPa requiring OGD.
2. Baveno VI Criteria: Patients with LSM <20 kPa and platelet count ≥150×10⁹/L, for whom OGD could be safely avoided.
3. Baveno VII Criteria: Patients with CSPH (LSM ≥25 kPa) recommended for NSBB therapy without the need for screening OGD.
4. Patients requiring OGD: Those not meeting Baveno VI criteria and without CSPH.

Results

Liver stiffness distribution:
• <10 kPa: 1,534 patients
• 10–14.9 kPa: 136 patients
• 15–19.9 kPa: 44 patients
• 20–24.9 kPa: 31 patients
• ≥25 kPa: 57 patients
Impact of Adopting Baveno VI and VII:
• BSG Guidelines: 274 patients (LSM ≥10 kPa) would require OGD.
• Baveno VI: 149 patients (LSM <20 kPa, platelets ≥150) could avoid OGD.
• Baveno VII: 57 patients (LSM ≥25 kPa) would be managed with NSBB, avoiding OGD.
• Total Reduction: 206 out of 274 patients (~75%) could avoid OGD.

Conclusion

Adopting Baveno VI and VII criteria would significantly reduce the need for variceal screening endoscopy in ACLD patients. By applying these thresholds, up to 75% of OGDs could be avoided, optimising NHS resources and reducing patient burden. These findings support the routine use of non-invasive risk stratification in ACLD management.

References

1. Tripathi D, Stanley AJ, Hayes PC, et al. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680–1704. doi:10.1136/gutjnl-2015-309262
2. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–752. doi:10.1016/j.jhep.2015.05.022
3. de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959–974. doi:10.1016/j.jhep.2021.12.022

Introduction

Primary sclerosing cholangitis (PSC) is known to present characteristic cholangiographic findings; however, detailed observations using peroral cholangioscopy (POCS) have rarely been reported. We previously reported that POCS findings in PSC can be classified into three types: active (inflammatory), chronic (scarring), and tumorous (tumor-like). These findings may aid in the differential diagnosis of PSC and may be useful in predicting prognosis.

Aims & Methods

We aimed to analyze POCS findings in PSC in detail based on this classification and to clarify their characteristics by evaluating the frequency of each finding, their temporal changes, and comparisons with other biliary diseases.
We retrospectively reviewed 22 patients with PSC who underwent POCS between February 2018 and February 2023. For comparison, we included 19 cases of hepatolithiasis, 25 cases of cholangiocarcinoma, and 3 cases of IgG4-related sclerosing cholangitis (IgG4-SC). Twelve POCS findings were categorized into three types: active (mucosal erythema, ulcers, fibrous white exudates, irregular surface), chronic (longitudinal scarring, annular scarring, pseudodiverticula, stenosis), and tumorous (dilated vessels, tortuous vessels, friability, mass formation). In addition, we included “punched-out lesion (POL)” as an original finding. Each finding was graded on a 5-point scale (0–4) based on the extent or number of lesions, and scores were calculated for each type. We conducted three analyses: (1) correlation between cholangiographic and POCS findings in PSC, (2) temporal changes in POCS findings in PSC, and (3) comparison of POCS findings between PSC and other biliary diseases.

Results

In the first analysis, annular scarring (100%), stenosis (89%), POL (89%), and longitudinal scarring (86%) were frequently observed in PSC. Annular scarring was identified in all cases with a shaggy appearance on cholangiography, and stenosis were present in all ducts with band-like stricture. In ducts showing diverticulum-like outpouchings, longitudinal and annular scarring, pseudodiverticula, and POL were consistently seen, whereas other findings were absent. In the second analysis, active and tumorous scores varied over time even within the same case, whereas chronic scores remained stable or showed a progressive increase. A negative correlation was observed between active and chronic scores (p-value <0.001, r =-0.702). In the third analysis, chronic findings and POL were significantly more common in PSC compared to other diseases (p-value <0.001). Pseudodiverticula were seen exclusively in PSC, while dilated and tortuous vessels and friability were significantly more frequent in cholangiocarcinoma and IgG4-SC (p-value <0.001).

Conclusion

These findings suggest that the characteristic cholangiographic findings of PSC are mainly formed by chronic scarring. Diverticulum-like outpouchings reflect only fibrotic changes. Furthermore, the coexistence of inflammation and fibrosis, along with the time-dependent progression of fibrosis, is a unique feature of PSC, although active inflammation may obscure chronic findings. Finally, longitudinal scarring and POL were particularly prominent in PSC, and pseudodiverticula were highly specific to this disease, suggesting their usefulness in differential diagnosis. In conclusion, chronic findings on POCS are characteristic of PSC and may serve as a helpful tool in its diagnosis and differentiation from other biliary diseases.

References

T Fujisawa, M Ushio, S Takahashi, et al., Role of Peroral Cholangioscopy in the Diagnosis of Primary Sclerosing Cholangitis. Diagnostics (Basel), 2020. 10(5).
T Itoi, T Kamisawa, Y Igarashi, et al., The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis. J Gastroenterol, 2013. 48(4): p. 504-14.
T H Karlsen, T Folseraas, D Thorburn, et al., Primary sclerosing cholangitis - a comprehensive review. J Hepatol, 2017. 67(6): p. 1298-1323.
T Nakazawa, K Notohara, S Tazuma, et al., The 2016 diagnostic criteria for primary sclerosing cholangitis. J Gastroenterol, 2017. 52(7): p. 838-844.
T Nakazawa, H Ohara, H Sano, et al., Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc, 2004. 60(6): p. 937-44.
H Isayama, S Tazuma, N Kokudo, et al., Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol, 2018. 53(9): p. 1006-1034.
W L Campbell, M S Peterson, M P Federle, et al., Using CT and cholangiography to diagnose biliary tract carcinoma complicating primary sclerosing cholangitis. AJR Am J Roentgenol, 2001. 177(5): p. 1095-100.

Introduction

Current therapeutic strategies for inflammatory bowel disease (IBD) remain limited, with clinical efficacy often falling short of expectations. Post-translational modifications play a pivotal role in IBD pathogenesis. This study aims to elucidate the functional significance of ubiquitination in IBD development and progression.

Aims & Methods

By analyzing colon RNA sequencing (RNA-seq) data from healthy and dextran sulfate sodium (DSS)-induced colitis mice, combined with RNA-seq datasets from healthy individuals and ulcerative colitis (UC) patients, we identified differential RNA expression levels of ATDC between healthy and inflammatory groups. Single-cell RNA sequencing (scRNA-seq) analysis further pinpointed the primary cell types exhibiting ATDC expression discrepancies. These findings were validated through immunohistochemistry, immunofluorescence, and western blot. Co-immunoprecipitation (Co-IP) assays and molecular docking simulations were employed to confirm and model the interaction between ATDC and PRMT5 in vitro. The role of ATDC in IBD pathogenesis was investigated using an ATDC-knockout (ATDC-KO) murine DSS model, with flow cytometry analyses delineating its impact on immune status.

Results

RNA-seq analysis revealed elevated ATDC mRNA levels in DSS-treated mice and UC patient intestinal tissues. scRNA-seq data indicated ATDC upregulation predominantly in the intestinal epithelial cells of UC patients. Protein-level upregulation of ATDC was further confirmed in both DSS mice and UC patient specimens. Lipopolysaccharide stimulation increased ATDC expression in Caco2 cells. Overexpression of ATDC in Caco2 cells, coupled with mass spectrometry, identified ATDC-PRMT5 binding, which was corroborated by Co-IP assays and molecular docking simulations. ATDC overexpression downregulated PRMT5 protein (but not mRNA) levels. In DSS models, PRMT5 expression was reduced compared to healthy controls; however, ATDC-KO mice exhibited PRMT5 upregulation and exacerbated colitis severity. Flow cytometry demonstrated an elevated Th17 cell proportion in ATDC-KO DSS mice relative to wild-type counterparts.

Conclusion

This study is the first to demonstrate the protective role of ATDC in colitis. ATDC attenuates colonic inflammation by promoting the degradation of PRMT5, thereby suppressing Th17 cell-mediated immune responses. Enhancing ATDC activity may represent a novel therapeutic strategy for mitigating colitis progression.

References

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Introduction

A male patient in his twenties presented with clinical aspects of primary sclerosing cholangitis (PSC), chronic cholestatic liver disease, and hypothyroidism. PSC is a rare, chronic cholestatic liver disease characterized by biliary strictures and peribiliary fibrosis (1). Susceptible loci were identified in GWAS but the correlation between genetic background and disease pathogenesis needs further investigation (2). In the index patient we identified a heterozygote candidate variant in the ABCC6 gene (c.2279G>A, p.(Arg760Gln)). Dysfunctional ABCC6 was described to cause ABCB11 and ABCG5/G8 genes overexpression, leading to imbalanced bile composition resulting in gallstone formation and cholestasis (3). ABCC6 variants were previously described in cases with low phospholipid-associated cholelithiasis (LPAC) and intrahepatic cholestasis of pregnancy (ICP)(4-6) . Subsequently, we aimed to investigate rare variants in ABCC6 gene in whole exome sequencing (WES) results from patients with suspected cholestatic liver disease.

Aims & Methods

Variant evaluation and annotation analysis was carried out on WES data, with focus on loss of function and missense variants, presenting allele frequency (AF) of ≤1% based on gnomAD database (https://gnomad.broadinstitute.org). Variants were filtered to include only those in genes relevant to the patients’ clinical phenotype. For each rare variant, a comprehensive in silico assessment was performed using tools such as REVEL, AlphaMissense, EVE, SIFT, and MetaLR to evaluate potential pathogenicity. Filtered were prioritized and interpreted using ACMG-AMP guidelines. This systematic approach ensured a clinically meaningful and evidence-based evaluation of the identified variants.

Results

Nine different rare heterozygote variants were identified in fifteen samples of 247 WES results. Among these, the missense variants c.179G>A, p.(Arg60Gln) and c.3139C>T, p.(Arg1047Cys) were found in two LPAC patients. Additionally, the c.1171A>G, p.(Arg391Gly) variant was observed in two related cases: a mother with ICP and her child with elevated gamma-glutamyl transferase (GGT) levels and jaundice. Moreover, this variant was also detected in another patient with elevated transaminases. c.3871G>A, p.(Ala1291Thr) and c.955A>G, p.(Ile319Val) were seen in patients with ICP and cholestasis, respectively. Three other variants were also identified in patients with liver disease of unknown etiology (c.1540G>A, p.(Val514Ile) and c.2707G>C, p.(Glu903Gln) and c.4397G>A, p.CYS1466Tyr). Additionally one splicing variant (c.37-1G>A, p,?) was also detected in a patient with cholangiocarcinoma (CCA). All variants were observed in heterozygote state and classified as variants of uncertain significance (VUS).

Conclusion

An in-depth analysis of WES data led to the identification of several potentially disease-relevant variants in the ABCC6 gene. These variants may play a contributory role in the observed hepatic phenotypes, suggesting a broader functional involvement of ABCC6 beyond its well-established association with pseudoxanthoma elasticum (PXE). Our findings highlight the importance of integrating genetic data with detailed clinical phenotyping to enhance understanding of genotype–phenotype correlations and reveal novel roles for known genes in atypical or organ-specific presentations.

References

1. Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 2021;75(3):634-46.
2. Goode EC, Fachal L, Panousis N, Moutsianas L, McIntyre RE, Bai BYH, et al. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun. 2024;15(1):9594.
3. Ibold B, Faust I, Tiemann J, Gorgels T, Bergen AAB, Knabbe C, et al. Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues. Lipids Health Dis. 2019;18(1):2.
4. Liu X, Lai H, Xin S, Li Z, Zeng X, Nie L, et al. Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study. BMC Pregnancy Childbirth. 2021;21(1):110.
5. Liu X, Zheng J, Xin S, Zeng Y, Wu X, Zeng X, et al. Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy. Front Genet. 2022;13:941027.
6. Romeo M, Dallio M, Federico A. Is it time to reconsider the MRP6 role in bile secretion and LPAC genetic signature? J Hepatol. 2023;79(4):e152-e4.

Disclosure

The authors declare that they have no conflict of interest.