Shallu Midha

Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations.

Objective To study the genetic predisposition, phenotype and prognosis of idiopathic chronic pancreatitis (CP). Design Prospective observational and case–control study. Setting Tertiary care academic centre. Patients Consecutive patients with CP. Interventions Detailed mutational analysis was done for the cationic trypsinogen, SPINK1 and CFTR genes with single-strand conformational polymorphism or restricted fragment length polymorphism, and sequencing. Clinical and disease characteristics of idiopathic versus alcoholic CP, and early onset versus late onset idiopathic CP were compared. Response to multimodality treatment (medical, endoscopic and/or surgical) and prognosis were analysed. Main outcome measures Genetic mutations, phenotypic characterisation and prognosis of idiopathic CP. Results Of the 411 patients with CP, 242 had idiopathic aetiology (age 27.50±11.85 years; 154 men). Malnutrition and cassava were not risk factors. SPINK1 N34S mutation was present in 42% of patients with idiopathic CP (vs 4% controls, p<0.001) and 17% of patients with alcoholic CP (p=0.016 compared with controls). In the CFTR gene, nine patients with idiopathic CP had mutations and 41 patients had polymorphisms (50% vs 10% controls, p<0.001). Diabetes developed in 35.53% of patients with idiopathic CP. About 85% of patients had significant pain relief with therapy. The probability of surviving for 35 years after onset of idiopathic CP was 83%. The typical features of tropical calcific pancreatitis were seen only in 5.8% of patients. Conclusion Strong genetic susceptibility due to SPINK1 and CFTR gene mutations, and comparative phenotype of idiopathic CP in India suggest that the term ‘tropical calcific pancreatitis’ is a misnomer.

Dietary Counseling Versus Dietary Supplements for Malnutrition in Chronic Pancreatitis: A Randomized Controlled Trial

BACKGROUND & AIMS Up to 50% of patients with chronic pancreatitis (CP) are malnourished. There are limited data on the role of dietary intervention in improving the nutritional status of such patients. The aim was to compare the efficacy of medium chain triglyceride (MCT)-enriched commercial dietary supplements with dietary counseling for homemade food in the management of malnutrition in patients with CP. METHODS In a randomized controlled trial, consecutive undernourished patients with CP (body mass index [BMI] <18.5 kg/m(2)) at a tertiary care hospital were randomized to receive either dietary counseling for regular homemade food or commercial MCT-enriched dietary supplements for a period of 3 months to compensate for the dietary calorie deficit. All patients received standard management for CP including pancreatic enzyme supplements. Primary outcome measure was improvement in BMI. RESULTS Sixty malnourished patients with CP were randomized to counseling group (n = 29; mean age, 32 +/- 10 years; male, 83%) and supplementation group (n = 31; mean age, 28 +/- 10 years; male, 84%). BMI increased in both the counseling group and supplementation group (17.2 +/- 1.7 vs 18.1 +/- 1.8 kg/m(2), P = .001; 16.7 +/- 1.6 vs 18.2 +/- 1.6 kg/m(2), P = .001). There were similar improvements in triceps skinfold thickness, dietary intake, fecal fat, and pain score during a period of 3 months in both groups. There was, however, no significant difference between the counseling and supplementation groups with regard to any of the outcome measures. CONCLUSIONS Dietary counseling for a balanced homemade diet is as good as commercial food supplements in improving malnutrition in patients with CP.

Cause and effect relationship of malnutrition with idiopathic chronic pancreatitis: Prospective case–control study

Background and Aim:  Patients with chronic pancreatitis are often malnourished. The role of malnutrition in the pathogenesis of chronic pancreatitis is unclear. The aim of the present article was to study prospectively the cause and effect relationship of malnutrition with idiopathic chronic pancreatitis in a case–control study.

Modifiable and non-modifiable risk factors for pancreatic cancer: A review

Pancreatic ductal adenocarcinoma is associated with a poor prognosis and a high case-fatality rate. The reasons for poor prognosis are low rates of curative resection due to local infiltration and distant metastasis. To increase survival rates of patients with pancreatic cancer, early detection through surveillance and screening is important. However, screening could only be cost-effective in high-risk populations. Identification of significant risk factors therefore assumes significance. Risk factors could be non-modifiable or modifiable. Non-modifiable risk factors include increasing age, familial cancer syndromes, Afro-American race, hereditary and other forms of chronic pancreatitis, diabetes, and non-O blood group. Important modifiable risk factors include smoking, obesity, dietary factors such as non-vegetarian diet, and toxins. Preventive strategies at the population level and an effective screening program targeted at high-risk people may help in prevention and early detection of pancreatic ductal adenocarcinoma.

Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer.

Objective To study if chronic pancreatitis (CP) is a risk factor for pancreatic cancer. Methods Through a cohort and a case-control study design, CP and other important risk factors including smoking, diabetes, alcohol, obesity, and genetic mutations were studied for their association with pancreatic cancer. Results In the cohort study, 402 patients with CP were included. During 3967.74 person-years of exposure, 5 of the 402 patients (4 idiopathic CP, 1 hereditary CP) developed pancreatic cancer after 16.60 ± 3.51 years of CP. The standardized incidence ratio was 121. In the case-control study, 249 pancreatic cancer patients and 1000 healthy controls were included. Of the 249 patients with pancreatic cancer, 24 had underlying idiopathic CP, and none had alcoholic pancreatitis. SPINK1 gene mutation was present in 16 of 26 patients with idiopathic CP who had pancreatic cancer. Multivariable analysis showed CP (odds ratio [OR], 97.67; 95% confidence interval [CI], 12.69–751.36), diabetes (>4 years duration) (OR, 3.05; 95% CI, 1.79–5.18), smoking (OR, 1.93; 95% CI, 1.38–2.69) as significant risk factors for pancreatic cancer. The population attributable risk was 9.41, 9.06, and 9.50 for diabetes, CP, and smoking, respectively. Conclusions Genetically determined CP but not alcoholic CP is a strong risk factor for pancreatic cancer.

Long‐term pain relief with optimized medical treatment including antioxidants and step‐up interventional therapy in patients with chronic pancreatitis

Abdominal pain is difficult to treat in patients with chronic pancreatitis (CP). Medical therapy including antioxidants has been shown to relieve pain of CP in the short‐term. Our aim was to study the long‐term results of optimized medical and interventional therapy for pain relief in patients with CP with a step‐up approach.

Leptin and its correlation with exocrine and endocrine pancreatic function in idiopathic chronic pancreatitis: implications for pathophysiology.

Objectives: Leptin alters pancreatic exocrine and &bgr;-cell secretion in animal studies. We hypothesized that leptin might be important in the pathogenesis of idiopathic chronic pancreatitis (ICP) and/or the development of diabetes in ICP. Methods: Fifty patients with ICP (25 with diabetes, 25 without diabetes) and 25 healthy controls were included in a prospective, case-control study. Fasting plasma leptin concentration was measured by enzyme-linked immunosorbent assay. Exocrine and endocrine pancreatic functions were assessed by fecal chymotrypsin and serum C-peptide, respectively. Anthropometric parameters and body fat mass (FM) were measured. Results: Patients with ICP (mean age, 30 years; 33 men) had significantly lower body mass index (19.5 ± 2.6 kg/m2) and FM (10.6 ± 4.2 kg) as compared with controls (body mass index, 21.7 ± 4.1 kg/m2; FM, 19.0 ± 16.6 kg; P < 0.01). Fecal chymotrypsin (median, 5.2 [range, 0.3-42.6] U/kg) and C-peptide (median, 1.7 [range, 0.2-9.5] ng/mL) were significantly lower in patients than in controls (12.9 [range, 2.5-33.0] U/kg and 3.5 [range, 0.3-10.3] ng/mL; P < 0.01). Plasma leptin concentration was slightly lower but statistically insignificant in patients with ICP (median, 4.0 [range, 2.0-62.5] ng/mL) as compared with controls (median, 5.0 [range, 2.0-63.0] ng/mL). Patients with and those without diabetes were also comparable with regard to their leptin concentration, pancreatic functions, and anthropometric parameters. Conclusions: Leptin does not seem to have a pathophysiological role in either ICP or the development of diabetes in ICP.

Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis

BACKGROUND Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP. METHODS Consecutive patients with AP were included in a prospective cohort study at a tertiary care center. Serum levels of IL-6, TNF-α, IL-10, MCP-1, GM-CSF and IL-1β were measured at day 3 of onset of AP. Variables such as age, co-morbidity, etiology, SIRS, and cytokines were modeled to predict severe AP by multivariable regression analysis. Genotyping was done to correlate IL-6, TNF-α and MCP-1 gene polymorphisms with cytokine levels. RESULTS Of 236 patients with AP, 115 patients admitted within 7 days of onset formed the study group. 37 of the 115 (32%) patients developed organ failure. Independent predictors of organ failure were persistent SIRS (OR 34; 95% CI: 7.2-159) and day 3 serum IL-6 of >160 pg/ml (OR 16.1; 95% CI:1.8-142). IL-6 gene (-174 G/C) GG genotype was associated with significantly higher levels of IL-6 compared to CC/CG genotype. Serum IL-6 >160 pg/ml increased the positive predictive value of persistent SIRS from 56% to 85% and specificity from 64% to 95% for predicting OF without compromising its sensitivity and negative predictive value. CONCLUSION Serum IL-6 of >160 ng/ml added significantly to the predictive value of SIRS for severe AP.