Introduction

Chronic pancreatitis is a progressive inflammatory disease characterized by irreversible damage to the pancreas. The etiology of the disease is heterogenous and includes alcohol abuse, smoking, genetic risk factors and autoimmune diseases. Several clinical classification and severity scoring systems have been proposed, but none have been globally accepted or reached broad clinical use. Identifying patients at a higher risk of death is crucial for improving patient care and management.

Aims & Methods

This study aimed to develop a prediction model based on promoter hypermethylation of specific genes and clinical factors to differentiate patients with chronic pancreatitis who are at a higher risk of mortality. Clinical variables such as age, sex, smoking status, alcohol consumption, exocrine insufficiency, and endocrine insufficiency, as well as the methylation status of 16 genes, were analyzed using a backward stepwise Cox regression model. The methylation status was determined by a specialized bisulfite based PCR technique. The final model's performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), and used to determine a risk score for each patients. The “cutpt” package in Stata was used to determine an optimal cut-off, in order to stratify patients into low and high-risk groups. Kaplan-Meier survival curves, and cox regression, and AUC were used to determine the accuracy of the risk groups.

Results

Ninety-seven patients with chronic pancreatitis were included in the study. The final prediction model included age, sex, exocrine insufficiency, endocrine insufficiency, and the methylation status of 5 genes: SFRP2, HIC1, MLH1, RASSF1A, and CDKN2B. The AUC of the model was 0.84, indicating high reliability. The model was superior to a model including only clinical variables (AUC = 0.76), indicating added value of the methylation markers. The optimal cut-off value for the risk score was 7.76. According to this, 67 patients were in the low-risk group, and 30 in the high-risk group. The 5-year survival in the high-risk group was 53% compared to 94% in the low-risk group. Being in the high-risk group was significantly associated with an increased HR of death of 10.2 (95% CI; 4.9-21.1), demonstrating the model's strong prognostic value.

Conclusion

The developed prediction model, which combines clinical factors and gene promoter hypermethylation status, could be a valuable tool for identifying patients with chronic pancreatitis who are at a higher risk of death. This study serves as proof-of-concept of the unexplored potential of methylation analysis in cell-free DNA in chronic pancreatitis. This model can potentially enhance patient care by enabling targeted interventions and monitoring for high-risk individuals, ultimately improving their prognosis and quality of life.

Disclosure

S.D.H., P.H.M., O.T.-U., and H.B.K. declare that they have a patent on a diagnostic panel including the promoter hypermethylation status of 8 genes. Application No. 16161073.8 – 1403 Pancreatic Cancer methylation Markers (18.03.2016)

Introduction

Low Phospholipid-Associated Cholelithiasis (LPAC) syndrome is a rare disorder caused by mutations in the ABCB4 phospholipid transporter, found in biliary canaliculi. These mutations lead to a deficiency in phospholipids and the subsequent precipitation of cholesterol crystals within the small intrahepatic bile ducts. LPAC syndrome can be diagnosed following the emergence of biliary symptoms or through familial screening. The objective of our study is to characterize the epidemiological, clinical, and paraclinical data of patients monitored for LPAC syndrome in our institution and to assess therapeutic responses and outcomes.

Aims & Methods

We collected data from all patients diagnosed with LPAC syndrome at our institution. Diagnosis was established based on the presence of at least two of the following criteria: (1) age at onset of biliary symptoms ≤40 years; (2) presence of hyperechoic intrahepatic foci ("comet tails" or micro-spots); (3) recurrence of biliary symptoms post-cholecystectomy.

Results

10 patients were included. The Average age at diagnosis was 33,6 years, with symptoms typically beginning around age 30. The sex ratio was 2/8 (M/F).a family history of biliary lithiasis and cholecystectomy before the age of 40 were found in 70% of cases . None of the female patients had a history of pregnancy-related cholestasis. 70% of the patients had undergone cholecystectomy prior to their LPAC diagnosis, with recurrence of biliary symptoms before age 40 in all these patients. Clinical presentations upon admission included symptomatic gallstone disease in 5 cases, acute cholangitis due to main bile duct stones in 4 cases, and acute lithiasic pancreatitis in 1 case. Hepatobiliary ultrasound was performed in all patients, revealing comet tail signs in 50% of cases, hyperechoic intrahepatic spots in 20% of cases, and intrahepatic stones in 50% of cases. Biochemical tests showed hyperbilirubinemia in 30% of cases, elevated Gamma-GT and alkaline phosphatase in 80% of cases, and hepatocellular damage in 40% of cases. A mutation in the ABCB4 gene was found in 2-patients.8 patients benefit from An Ursodeoxycholic Acid (UDCA) dosage averaging 11mg/kg, experiencing significant clinical and biological improvements.

Conclusion

LPAC syndrome is a rare pathology in our series, predominantly affecting young, non-overweight women with personal and family history of early biliary stones occurrence . Treatment with Ursodeoxycholic Acid (UDCA) controlled symptoms in the majority of cases.

Clinical Case Summary

We report the case of 20 year old female patient with Crohn's disease who was shifted to Combo therapy (Infliximab + Azathioprine) for failing to reach mucosal healing on Conventional treatment. Quantiferon test, virology panel and a CT chest were negative prior to therapy. After one year of treatment she presented with high grade fever, weight loss, and abdominal pain. COVID-19 PCR and CT chest were negative. However, quantiferon test was positive. CTE abdomen showed marked thickening and stricture in the ileocecal area. Colonoscopy (Video available) was done to obtain biopsies; serpiginous ulcers with narrowing were noted. Histopathological assessment showed heavy Inflammatory cells with no more specification. A gene Xpert PCR on the tissue biopsy was positive for MTB. Given the septic state of the patient biological therapy was held for the duration of her treatment. She started Anti-TB and improved as the fever subsided and she gained weight. Colonoscopy was re-attempted after 4 months of treatment to confirm resolution (Video available). An impassable fibrotic stricture was noted the biopsy forceps could however be introduced and biopsies were obtained. Gene Xpert test was negative. The patient was started on Ustekinumab monotherapy with good response.
TB infection in patients on Anti-TNF therapy is a well-recognized potential side-effect of these drugs. To the best of our knowledge, this is the first reported case of Ileocecal TB on top of Crohn’s disease. A major challenge was weighing how much of the active inflammation shown in the endoscopy, biopsy and imaging was due to TB infection and how much was because of Crohn's disease activity. The time to re-initiate therapy was difficult given that the patient's bad general condition before starting antimicrobial treatment. While recommendations suggest starting immunosuppressives after 8 weeks of treatment in active tuberculosis, the evidence support this in pulmonary rather than extrapulmonary tuberculosis.

Introduction

Inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic inflammation of the intestines. This is accompanied by oxidative stress, which plays an important role in the pathophysiology of IBD. Oxidative stress-related biomarkers can serve as potential biomarkers for disease activity monitoring. Systemic free thiols (FT) are found to accurately reflect oxidative stress brought on by inflammation and have shown promise as a biomarker for inflammatory disease activity in IBD. However, the clinical significance of this marker warrants validation. This prospective diagnostic study aimed to compare FT to other validated biomarkers and investigate the link between FT and endoscopic disease activity in patients with IBD.

Aims & Methods

An interim analysis was conducted in 52 patients. FT were measured using a colorimetric detection method. Clinical disease activity was quantified by the Harvey-Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC. Biochemical disease activity was determined by measuring blood C-reactive protein [CRP] and fecal calprotectin [fCal] levels. Endoscopic disease activity was quantified with the Mayo endoscopic sub score for UC and the Simple Endoscopic Score (SES-CD) for CD. Serum FT levels were assessed for correlations with disease activity parameters using linear and logistic regression analyses. Discriminative capacity of FT as biomarker was assessed by calculating receiver operating characteristics (ROC) statistics.

Results

Serum FT levels demonstrated a significant inverse correlation with clinical parameters, such as the HBI (r=-0.53, p<0.05). Additionally, other inflammatory biomarkers, including CRP, exhibited a negative correlation with serum FT levels (r=-0.43, p<0.05), which were decreased in patients with active IBD . Discrimination between clinically quiescent (HBI<5) and active disease based on serum FT levels was accurate (AUC=0.80, p=0.02) with a value numerically higher than that of fCal (AUC=0.55, p=0.83). Serum FT levels did not significantly differ between biochemically quiescent and active disease based on CRP (AUC=0.69, p=0.20). Both endoscopic scores demonstrated a tendency toward negative associations with serum FT levels. Patients with moderate and severe disease activity had lower FT levels compared to those with mild disease activity (estimated marginal means [EMM] 497.2 vs 529.5 µM, p=0.43) and 447.1 vs 529.5µM , p=0.06, respectively).

Conclusion

The interim analysis of this study indicates that plasma FT levels inversely correlate with IBD activity and may surpass traditional markers like fCal in detecting disease states. Plasma FT demonstrates potential as a sensitive biomarker for both clinical and endoscopic disease activity in IBD. Further patient inclusion and longitudinal data are essential to validate FT's utility fully. Continued research could establish FT as a key tool for personalized treatment strategies, improving patient outcomes in IBD management.

Disclosure

S. Geertsema, A.R. Bourgonje., H. van Goor, G. Dijkstra, and K.N. Faber are supported by a research grant from Janssen Research & Development LLC. A.R. Bourgonje received speaker fees from AbbVie. G. Dijkstra received research grants from Royal DSM, Takeda, and Janssen Pharmaceuticals and speaker fees from AbbVie, Pfizer, Takeda, and Janssen Pharmaceuticals.