An integrated picture of chronic pancreatitis derived by mapping variants in multiple disease genes onto pathogenic pathways.

Chronic pancreatitis (CP) is an etiologically and genetically heterogeneous inflammatory syndrome characterised by progressive damage to the exocrine and endocrine components of the pancreas [ 1]. The multigenic paradigm of CP has sparked research in recent years [ 2]. We aimed to expand the current knowledge of genetic susceptibility of pancreatitis in patients of Indian origin. By employing whole-exome sequencing in an Indian hospital cohort, we dissect the genetic landscape associated with CP or recurrent acute pancreatitis (RAP). Notably, all patients had at least one genetic variant identified in a pancreatitis-risk gene, and most had a co-occurrence of a second variant in an additional risk gene. Based on the presence of both acinar and ductal gene variants in individual patients, we propose a two-hit hypothesis where variants in proteins expressed in both acinar and ductal cells are critical for RAP/CP development.

Imbalance in the vWF - ADAMTS13 axis exists early in acute pancreatitis and predicts persistent organ failure and pancreatic necrosis-a prospective study.

BACKGROUND: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023). RESULTS: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]. CONCLUSION: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis.

Bile Culture May Guide Antibiotic Stewardship in Acute Bacterial Cholangitis.

BACKGROUND: Bile cultures are often sent with blood cultures in patients with acute bacterial cholangitis. AIMS: To assess the yield of blood and bile cultures in patients with cholangitis and the clinical utility of bile cultures in guiding therapy. METHODS: All patients diagnosed with cholangitis, based on the Tokyo 2013/2018 guidelines were recruited retrospectively over ten years. The clinical and investigation details were recorded. The results of bile and blood cultures including antibiotic sensitivity patterns were noted. The concordance of microorganisms grown in blood and bile cultures and their sensitivity pattern were assessed. RESULTS: A total of 1063 patients with cholangitis were included. Their mean age was 52.7 ± 14 years and 65.4% were males. Blood cultures were positive in 372 (35%) patients. Bile culture was performed in 384 patients with 84.4% being positive, which was significantly higher than the yield of blood culture (p < 0.001). Polymicrobial growth was more in bile (59.3%) than in blood cultures (13.5%, p < 0.001). E.coli, Klebsiella, Enterococcus and Pseudomonas were the four most common organisms isolated from both blood and bile. Extended spectrum betalactamase producing organisms were isolated in 57.7% and 58.8% of positive blood and bile cultures, respectively. Among 127 patients with both blood and bile cultures positive, complete or partial concordance of organisms was noted in about 90%. CONCLUSION: Bile and blood cultures have a similar microbial profile in most patients with cholangitis. As bile cultures have a significantly higher yield than blood cultures, they could effectively guide antimicrobial therapy, especially in those with negative blood cultures.

A Simple Pre-endoscopy Score for Predicting Risk of Malignancy in Patients with Dyspepsia: A 5-Year Prospective Study.

BACKGROUND: The guidelines for performing endoscopy in dyspeptic patients based on clinical parameters alone have shown variable performance, and there is a need for better prediction tools. AIM: We aimed to prospectively develop and validate a simple clinical-cum-laboratory test-based scoring model to identify dyspeptic patients with high risk of upper gastrointestinal malignancy (UGIM). METHODS: Adult patients with dyspeptic symptoms were prospectively recruited over 5 years. Clinical details including alarm features were recorded, and blood tests for hemoglobin and albumin were done before endoscopy. The presence of UGIM was the primary outcome. Risk factors for UGIM were assessed, and based on the OR of significant factors, a predictive scoring model was constructed. ROC curve was plotted to identify optimal cutoff score. The model was validated using bootstrapping technique. RESULTS: The study included 2324 patients (41.9 ± 12.8 years; 33.4% females). UGIM was noted in 6.8% patients. The final model had following five positive predictors for UGIM-age > 40 years (OR 3.3, score 1); albumin ≤ 3.5 g% (OR 3.4, score 1); Hb ≤ 11 g% (OR 3.3, score 1); alarm features (OR 5.98, score 2); recent onset of symptoms (OR 8.7, score 3). ROC curve had an impressive AUC of 0.9 (0.88-0.93), and a score of 2 had 92.5% sensitivity in predicting UGIM. Validation by bootstrapping showed zero bias, which further strengthened our model. CONCLUSION: This simple clinical-cum-laboratory test-based model performed very well in identifying dyspeptic patients at risk of UGIM. This can serve as a useful decision-making tool for referral for endoscopy.

Addition of second-line steroid sparing immunosuppressants like mycophenolate mofetil improves outcome of Immunoglobulin G4-related disease (IgG4-RD): a series from a tertiary care teaching hospital in South India.

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease. This disease may be associated with elevated serum and tissue IgG4 levels. Early treatment prevents fibrosis and organ damage. We retrospectively studied the clinicopathologic correlation and outcome of treatment in IgG4-RD. This single-center retrospective study was done using electronic records of patients subjected to assay of serum IgG4 levels in our laboratory by nephelometry. There were 473 patients with suspected IgG4-RD. Of them, 41 patients fulfilled comprehensive diagnostic criteria for IgG4-RD and 432 had diseases other than IgG4-RD. Clinical and histopathological data including tissue IgG4/IgG ratio, other relevant laboratory findings as well as management data of 41 patients with IgG4-RD were analyzed. There were 29 males and 12 females with mean age of 44.1 ± 2.19 years. Thirteen patients had definite, 19 had probable and 9 had possible IgG4-RD. Male predominance, multiple organ involvement and IgG4 responder Index were significantly higher in definite IgG4-RD as compared to probable and possible IgG4-RD. Serum IgG4 level was elevated in 37 patients (90.2%). Glucocorticoids were used in 35 patients (85.4%) and second-line immunosuppressive agent in 23 patients (65.7%). Of the 21 patients on follow-up, 19 (90.7%) had clinical improvement at the first follow-up visit. Nine (90%) out of the ten patients who were assessed by IgG4 responder index, also had shown improved score with treatment. Patients with IgG4-RD in our series showed favorable responses to treatment with glucocorticoids and addition of steroid sparing immunosuppressive agents (mainly mycophenolate mofetil) helped successful tapering of steroids, while maintaining the improvement.

Intermittent Directly Observed Therapy for Abdominal Tuberculosis: A Multicenter Randomized Controlled Trial Comparing 6 Months Versus 9 Months of Therapy.

BACKGROUND: The duration of treatment of gastrointestinal tuberculosis continues to be a matter of debate. The World Health Organization advocates intermittent directly observed short-course therapy (DOTs), but there is a lack of data of its efficacy in abdominal tuberculosis. We therefore conducted a multicenter randomized controlled trial to compare 6 months and 9 months of antituberculosis therapy using DOTs. METHODS: One hundred ninety-seven patients with abdominal tuberculosis (gastrointestinal, 154; peritoneal, 40; mixed, 3) were randomized to receive 6 months (n = 104) or 9 months (n = 93) of antituberculosis therapy using intermittent directly observed therapy. Patients were followed up 1 year after completion of treatment to assess recurrence. Patients were evaluated for primary endpoint (complete clinical response, partial response, and no response) and secondary endpoint (recurrence of the disease at the end of 1 year of follow-up). RESULTS: Baseline characteristics were similar between the 2 randomized groups. There was no difference between the 6-month group and 9-month group in the complete clinical response rate on per-protocol analysis (91.5% vs 90.8%; P = .88) or intent-to-treat analysis (75% vs 75.8%; P = .89). Only 1 patient in the 9-month group and no patients in the 6-month group had recurrence of disease. Side effects occurred in 21 (21.3%) and 16 (18.2%) patients in the 6-month and 9-month groups, respectively. CONCLUSIONS: There was no difference in efficacy of antituberculosis therapy delivered for either 6 months or 9 months in either gastrointestinal or peritoneal tuberculosis, confirming the efficacy of intermittent directly observed therapy. CLINICAL TRIALS REGISTRATION: NCT01124929.

Does COX1 gene polymorphism (A842G/C50T) influence peptic ulcer bleeding in Indian patients?.

This is a pilot study to test the hypothesis that polymorphisms that may be linked to cyclooxygenase production may affect the likelihood and the nature of bleeding in patients with ulcer disease. Of the two polymorphism that have previously been studied for links we chose the A842G polymorphims. Of the 50 patients with ulcer bleeding who were studied, 8 had a heterozygous polymorphisms and 42 had the normal configuration. On comparing these two groups. there were no significant differences in clinical presentation except that there was a tendency to have less gastric ulcers among those with the A842G/C50T polymorphism. Based on these studies we need to undertake a larger studies comparing these groups with those with ulcers without GI bleeding and those without ulcers

Comparison of the diagnostic yield of rapid versus non-rapid onsite evaluation in endoscopic ultrasound-guided fine-needle aspiration cytology of solid pancreatic lesions.

Background: The role of rapid on-site evaluation (ROSE) for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic lesions is debatable. In this study, we aimed to compare the diagnostic yield of ROSE vs. non-ROSE in solid pancreatic lesions. Methods: This retrospective single-center study included patients undergoing EUS-FNA of solid pancreatic lesions from 2019-2021. Patients with cystic lesions, those undergoing fine-needle core biopsy, those undergoing repeat procedures, and patients with non-diagnostic smears with less than 6-month follow up were excluded. The diagnostic yield, need for repeat procedures and number of passes required with and without ROSE were analyzed in these patients. Results: Of the 111 patients included, 56 underwent ROSE. The majority of lesions were malignant in both groups (79.6% ROSE vs. 75% non-ROSE). The diagnostic yield was 96.4% in the ROSE group and 94.5% in the non-ROSE group. Repeat samples were needed in 1 ROSE and 2 non-ROSE patients. The median number of passes made was significantly fewer in the ROSE group (3.5, interquartile range - 3,4) compared with the non-ROSE group (4, interquartile range - 3,5) P=0.01. However, the frequency of procedure-related complications was similar in both groups. Conclusion: The utilization of ROSE during EUS-FNA of solid pancreatic lesions does not affect the diagnostic yield or the need for repeat samples, but reduces the number of passes needed for acquiring samples.

Fibrosis in non-alcoholic fatty liver disease: correlation with simple blood indices and association with tumor necrosis factor-alpha polymorphisms.

AIM: The study was conducted with an aim to evaluate the clinico-pathological profile, the correlation of AST: ALT ratio and APRI with histological fibrosis, and the frequency of two specific polymorphisms (-238, -308) in the TNF alpha promoter region in patients with NAFLD. METHODS: The present study compared aspartate transaminase/alanine transaminase (AST/ALT) ratio and AST-to-platelet ratio index (APRI) with fibrosis score in 29 patients who underwent liver biopsy for NAFLD. Single nucleotide polymorphisms (SNP) in the tumor necrosis factor-alpha (TNF-alpha) promoter region at positions -308 and -238 were examined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: AST/ALT ratio correlated better than the APRI with liver fibrosis in patients with NAFLD (AUROC of 0.9 compared to 0.68). TNF-alpha promoter region SNPs were present in only a minority of patients, and did not correlate with fibrosis severity. CONCLUSIONS: AST/ALT ratio correlated well with liver fibrosis in Indian patients with NAFLD. The SNPs studied had no role in development of fibrosis in Indian patients with NAFLD.

Asymptomatic portal hypertension incidentally detected during upper gastrointestinal endoscopy.

Esophageal or gastric varices may be incidentally seen during endoscopy for dyspeptic or reflux symptoms. However, the frequency of their occurrence in these patients is unknown. Our center follows the scope and treat strategy for adult patients with dyspeptic or reflux symptoms and this provided us an opportunity to study this. Apart from providing an idea on the etiological spectrum, our data suggests that patients with incidentally detected varices have well preserved liver function which may provide a window for better management.

A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis.

Introduction: Hereditary pancreatitis (HP) is a rare debilitating disease with incompletely understood etio-pathophysiology. The reduced penetrance of genes such as PRSS1 associated with hereditary pancreatitis indicates a role for novel inherited factors. Methods: We performed whole-exome sequencing of three affected members of an Indian family (Father, Son, and Daughter) with chronic pancreatitis and compared variants with those seen in the unaffected mother. Results: We identified a novel frameshift mutation in exon 11 of TRPV6 (c.1474_1475delGT; p.V492Tfs*136), a calcium channel, in the patients. Functional characterization of this mutant TRPV6 following heterologous expression revealed that it was defective in calcium uptake. Induction of pancreatitis in mice induced Trpv6 expression, indicating that higher expression levels of the mutant protein and consequent dysregulation of calcium levels in patients with chronic pancreatitis could aggravate the disease. Discussion: We report a novel frameshift mutation in TRPV6 in an Indian family with HP that renders the mutant protein inactive. Our results emphasize the need to expand the list of genes used currently for evaluating patients with hereditary pancreatitis.

How Are Imaging Findings Associated with Exocrine Insufficiency in Idiopathic Chronic Pancreatitis?

Aim The aim is to study the association between imaging findings in chronic pancreatitis and fecal elastase 1 (FE1) in patients with idiopathic chronic pancreatitis (ICP). Methods In this retrospective study on a prospectively maintained database of patients with ICP, a radiologist blinded to clinical and laboratory findings reviewed CT and/or MRI. Findings were documented according to recommendations of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer, October 2018. Low FE1 (<100 µg elastase/g) was considered diagnostic of pancreatic exocrine insufficiency (PEI). Association between imaging findings and FE1 was studied. Results In total, 70 patients (M: F = 37:33) with ICP with mean age of 24.2 (SD 6.5) years, range 10 to 37 years and mean disease duration of 5.6 (SD 4.6) years, range 0 to 20 years were included. Mean FE level was 82.5 (SD 120.1), range 5 to 501 µg elastase/g. Mean main pancreatic duct (MPD) caliber was 7 (SD 4) mm, range 3 to 21 mm and mean pancreatic parenchymal thickness (PPT) was 13.7 (SD 5.5) mm, range 5 to 27 mm. There was a significant association between FE1 and MPD size, PPT, type of pancreatic calcification; presence of intraductal stones, side branch dilatation on magnetic resonance cholangiopancreatography and extent of pancreatic involvement ( p <0.05). In total, 79%, 86%, and 78% with moderate to severe MPD dilatation, pancreatic atrophy, and side branch dilatation had low FE1, respectively. But nearly half of those with no or mild structural abnormality on imaging had low FE1. Conclusion Significant association between FE1 and specific imaging findings demonstrates its potential as a marker of exocrine insufficiency and disease severity in chronic pancreatitis. But imaging and FE1 are complementary rather than supplementary.

Comprehensive evaluation of patterns of hypoglycemia unawareness (HUA) and glycemic variability (GV) in patients with fibrocalculous pancreatic diabetes (FCPD): A cross-sectional study from South India.

OBJECTIVES: Hypoglycemia unawareness (HUA) in patients with FCPD is common with an unclear etiology. We evaluated the prevalence, characteristics of HUA, glycemic variability (GV), its possible association with pancreatic glucagon secretion & cardiac autonomic function in patients with FCPD. METHODS: A two-week ambulatory glucose profile (AGP) and cardiac autonomic function test was done in patients with FCPD (n = 60), and categorized into UNAWARE (n = 44) and AWARE (n = 16) groups based on the Hypoglycemia Unawareness Index (HUI) score. Glycaemic variability was assessed from the AGP data using Easy GV 9.0.2 software. A subset of patients from both the groups (n = 11) underwent a mixed-meal challenge test and were compared with healthy individuals (controls; n = 11). RESULTS: HUA was evidenced in 73% (44/60) of patients with FCPD. Significant hypoglycemia, nocturnal hypoglycemia, duration of hypoglycemia and poor cardiac autonomic functions (p = 0.01) were prominent in the UNAWARE group. The overall GV was greater in the UNAWARE group. In the UNAWARE group, significantly reduced fasting and post prandial glucagon levels negatively correlated with HUI (r = -0.74, p < 0.05) and GV-hypoglycemia indices (p < 0.05) In contrast, significantly higher post prandial glucagon levels in the AWARE group positively correlated with post prandial hyperglycemia (r = 0.61, p < 0.05). CONCLUSION: Heterogeneity in patterns of glucagon secretion were significantly associated with HUA and GV. Reduced glucagon levels contribute to greater risks of HUA, nocturnal hypoglycemia and greater GV, while hyperglucagonemia predisposes to postprandial hyperglycemia and hypoglycemia awareness in patients with FCPD.

Exocrine Pancreatic Insufficiency Following Gastric Resectional Surgery-is Routine Pancreatic Enzyme Replacement Therapy Necessary?

The data on exocrine pancreatic insufficiency (EPI) following gastric resectional surgery is variable, ranging from 26% to as high as 100%. This study aimed to document symptomatic EPI following gastric resectional surgery and to objectively document EPI, by fecal elastase (FE) testing. This was a cross-sectional study among patients undergoing gastric resection for adenocarcinoma of the stomach, at the Upper Gastrointestinal Surgical Unit at the Christian Medical College Hospital, Vellore, India. A detailed questionnaire was administered to the patients in the postoperative period, to evaluate clinical symptoms of EPI. Further, study participants were tested for FE pre- and postoperatively. Of the 60 patients in this study, the postoperative questionnaire administered to all patients during follow up. None showed symptoms suggestive of EPI. Pre- and post-operative FE testing were feasible in 27 of the 60 patients, which showed a 33% incidence of EPI. None of the patients had clinical symptoms of EPI, following gastric resectional surgery, on short-term follow-up. However, more than a third of the patients tested developed asymptomatic EPI after gastric resectional surgery, based on FE testing. This may be explained by the fact that in the early postoperative period, EPI following gastric resectional surgery perhaps has a mild, subclinical presentation. Therefore routine pancreatic supplementation after gastric resectional surgery may not be necessary. However, one needs to carefully look for worsening of symptoms of EPI on long-term follow-up, which may necessitate appropriate investigations followed by pancreatic enzyme replacement therapy.

Prevalence of serological markers of hepatitis B in inflammatory bowel disease - Experience from a tertiary care centre in South India.

Inflammatory bowel disease patients are at risk of hepatitis B infection. Data on this prevalence from South Asia are limited. We conducted a prospective study comprising of 76 inflammatory bowel disease patients between October 2013 and August 2014. Prevalence of hepatitis B surface antigen in inflammatory bowel disease, ulcerative colitis and Crohn's disease patients were 2.6%, 2.4% and 3% respectively and that of markers of hepatitis B exposure (hepatitis B surface antigen /hepatitis B core antibody) were 11.8%, 14.3% and 9.1% respectively. Risk factors found significantly more common in those positive for viral markers compared to those negative were age, non-inflammatory bowel disease related surgery and hospital admission. Only 7(9.2%) had completed hepatitis B vaccination. There is a need to create awareness among physicians regarding the importance of hepatitis B screening and vaccination in inflammatory bowel disease patients.

Acoustic radiation force impulse imaging of pancreas in patients with early onset idiopathic recurrent acute pancreatitis.

BACKGROUND AND AIMS: Patients with recurrent acute pancreatitis (RAP) may progress to chronic pancreatitis (CP). A critical step in this progression is the development of fibrosis. Elastography has been used to assess degree of fibrosis by measurement of shear wave velocity (SWV). The aim of this study was to measure the stiffness of pancreas as a surrogate for pancreatic fibrosis in patients with RAP and compare it with a group of individuals without any history of pancreatic disorders. MATERIAL AND METHODS: Using acoustic radiation force impulse (ARFI) imaging SWV was calculated in 31 patients with idiopathic RAP having disease onset ≤30 years. A control group of 31 individuals with no history pancreatic disorder and no features of CP on endosonography was selected for comparison. ARFI imaging was done by a single radiologist who was blinded to the cases and controls RESULTS:: Mean age of patients with RAP was 24.8 (SD 9.86) years, disease duration was 3.45 (interquartile range 1-5) years, mean number of episodes 4.9 (SD 2.72). There was a significant difference in SWV between patients (1.27 ± 0.50 m/s) and controls (1.00 ± 0.17 m/s) (P = 0.001)). There was a positive correlation between SWV and number of pain episodes (P = 0.026) and negative correlation with BMI (P = 0.002). CONCLUSION: SWV was high in patients with RAP indicating a stiff pancreas. The stiffness increases with the number of episodes of pancreatitis.

Self-expanding metal stent in esophageal perforations and anastomotic leaks.

BACKGROUND AND AIMS: Placement of self-expanding metal stents (SEMS) has emerged as a minimally invasive treatment option for esophageal perforation and leaks. The aim of our study was to assess the role of SEMS for the management of benign esophageal diseases such as perforations and anastomotic leaks. METHODS: All patients (n = 26) who underwent SEMS placement for esophageal perforation and anastomotic leaks between May 2012 and February 2019 were included. Data were analyzed in relation to the indications, type of stent used, complications, and outcomes. RESULTS: Indications for stent placement included anastomotic leaks 65% (n = 17) and perforations 35% (n = 9). Fully covered SEMS (FCSEMS) was placed in 25 patients, and in 1, partially covered SEMS (PCSEMS) was placed. Stent placement was successful in all the patients (n = 26). Four patients did not report for follow-up after stenting. Among the patients on follow-up, 91% (20/22) had healing of the mucosal defect. Stent-related complications were seen in 5 (23%) patients and included stent migration [3], reactive hyperplasia [1] and stricture [1]. CONCLUSION: Covered stent placement for a duration of 8 weeks is technically safe and clinically effective as a first-line procedure for bridging and healing benign esophageal perforation and leaks.