KRAS mutation analysis by droplet digital PCR of duodenal juice from patients with MODY8 and other pancreatic diseases

Background Maturity-onset diabetes of the young type 8 (MODY8 or CEL-MODY) is an inherited pancreatic disease characterized by chronic inflammation of the pancreas and diabetes. It is not known whether MODY8 patients have increased risk for developing pancreatic cancer. We investigated KRAS mutation load in duodenal juice from MODY8 patients, comparing with other groups of pancreatic disease. Methods Droplet digital PCR (ddPCR) was used to detect KRAS codon 12/13/61 mutations in duodenal juice sampled from 11 MODY8 patients, nine healthy subjects and 100 patients clinically investigated due to suspected pancreatic disease. Results KRAS mutations were detected in 4/11 patients with MODY8 (36%), 1/9 healthy subjects (11%), 15/44 patients with chronic pancreatitis (CP, 34%), 3/5 patients with pancreatic ductal adenocarcinoma (PDAC, 60%), 3/20 patients with acute pancreatitis (15%), 0/13 patients with other pancreatic disorders and 2/18 patients with nonpancreatic gastrointestinal disease (11%). Of the 28 positive juice samples, 25 (89%) had low-abundance mutations in codons 12/13, with a variant allele frequency (VAF) less than 1%. KRAS-positive patients with MODY8 or CP had significantly lower VAFs than patients with PDAC (Mann-Whitney U test; p = 0.041). Although the overall mutation detection rate was higher for subjects ≥50 years old (26%) than for younger subjects (15%), the difference was not statistically significant. Conclusions KRAS mutations were detectable in duodenal juice from MODY8 patients, but with low abundance and at the same frequency as in CP patients. The discriminative value of the analysis with regard to other pancreatic disease was limited.publishedVersio

Diagnostic accuracy of transabdominal ultrasound in chronic pancreatitis

The performance of transabdominal ultrasound (US) in chronic pancreatitis (CP) following the advances in US technology made during recent decades has not been explored. Our aim in this prospective study was to evaluate the diagnostic accuracy of modern abdominal US compared with the Mayo score in CP. One hundred thirty-four patients referred for suspected CP were included in the study. Fifty-four patients were assigned the diagnosis CP. After inclusion, transabdominal US was performed. Ductal features (calculi, dilations and caliber variations, side-branch dilations and hyper-echoic duct wall margins) and parenchymal features (calcifications, cysts, hyper-echoic foci, stranding, lobulation and honeycombing) were recorded. Features were counted and scored according to a weighting system defined at the international consensus meeting in Rosemont, Illinois (Rosemont score). Diagnostic performance indices (95% confidence interval) of US were calculated: The unweighted count of features had a sensitivity of 0.69 (0.54–0.80) and specificity of 0.97 (0.90–1). The Rosemont score had a sensitivity of 0.81 (0.69–0.91) and specificity of 0.97 (0.90–1). Exocrine pancreatic failure was most pronounced in Rosemont groups I and II (p < 0.001). We conclude that using both unweighted and weighted scores, the diagnostic accuracy of modern transabdominal US is good. The extent of pancreatic changes detected by the method is correlated with exocrine pancreatic function.publishedVersio

Structural imaging findings are related to clinical complications in chronic pancreatitis

Background/objectives: Structural pancreatic changes and complications related to chronic pancreatitis are well described, but little is known about their relationship. We aimed to explore the associations between pancreatic morphology and clinical complications in a large chronic pancreatitis cohort. Methods: The Scandinavian Baltic Pancreatic Club database collects registrations on patients with definite or probable chronic pancreatitis according to the M-ANNHEIM diagnostic criteria. In this cross-sectional study, we used multivariate logistic regression analyses to evaluate whether imaging-based structural pancreatic changes were associated with common clinical complications. We adjusted for sex, age, disease duration, current alcohol abuse and current smoking. Results: We included 742 patients with a mean age of 55 years. Among these, 68% were males, 69% had pancreatic exocrine insufficiency, 35% had diabetes, 12% were underweighted and 68% reported abdominal pain. Main pancreatic duct obstruction, severe (i.e. more than 14) calcifications, pancreatic atrophy and parenchymal changes throughout the entire pancreas (continuous organ involvement) were positively associated with pancreatic exocrine insufficiency. Continuous organ involvement and pseudocysts were positively and negatively associated with diabetes, respectively. Pancreatic atrophy and severe calcifications were positively associated with underweight, and severe calcifications were negatively associated with pain. Conclusions: This study shows independent associations between distinct structural changes on pancreatic imaging and clinical complications in chronic pancreatitis. Pancreatic atrophy, severe calcifications and continuous organ involvement may be of particular clinical relevance, and these findings should motivate monitoring of pancreatic function and nutritional status.publishedVersio

Pancreatic enzyme treatment in chronic pancreatitis : Quality of management and adherence to guidelines–A cross-sectional observational study

Objectives: Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence-based guidelines treatment of CP. Patients and methods: Patients with definitive or probable CP according to M-ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase <200 μg/g was defined as a marker for PEI. Enzyme replacement therapy of 100,000 lipase units or more was defined as adequate treatment. Results: We included 1006 patients from 8 centers in five countries. Sixty-four percent of the patients were correctly treated. Twenty-five per cent of PEI patients were not taking enzymes at all, and 20% of PEI patients were undertreated with insufficient PERT doses according to the guidelines. Fourteen percent of patients with sufficient pancreatic function were receiving enzymes despite normal exocrine pancreatic function. There were center differences. Current smoking was associated with lack of treatment and alcohol abuse was associated with under-treatment. There were no associations between “no treatment” or “under-treatment” for underweight or vitamin D deficiency. Conclusion: In our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence.publishedVersionPeer reviewe

Pancreatic exocrine insufficiency in diabetes is associated with autonomic dysfunction

Objectives: Pancreatic exocrine insufficiency (PEI) is prevalent in diabetes. Pathophysiological theories imply autoimmune destruction, lack of trophic effects of insulin or impaired neuronal stimulation, but the relationship between PEI and autonomic dysfunction is largely unknown. In a pilot study, we aimed to investigate if patients with diabetes and PEI had impaired autonomic function. Methods: We measured faecal elastase in 59 patients with type 1 or 2 diabetes, using a cut-off-value <200 μg/g to define PEI. Based on faecal elastase results, patients were stratified into matched case (n = 8) and control groups (n = 13). We used heart rate variability, baroreflex sensitivity and orthostatic hypotension tests to assess autonomic dysfunction. Results: All baroreflex sensitivity parameters were reduced in cases with PEI compared with controls (all p < .05). The heart rate variability parameters root mean square of successive RR interval differences (p = .05) and high frequency (p = .04) were also reduced. We found no difference in orthostatic hypotension between the groups. Conclusions: In this first-of-its-kind study, we found that diabetes patients with PEI had reduced autonomic function compared with matched controls. Although numbers are small, results support the hypothesis that autonomic dysfunction could be a contributor to PEI in diabetes.publishedVersio

Ultrasound echo-intensity predicts severe Pancreatic affection in cystic fibrosis patients

Background: Pancreatic destruction affects the majority of patients with cystic fibrosis. We aimed to relate ultrasound findings to exocrine pancreatic function and cystic fibrosis genotype. Methods: Patients with cystic fibrosis and a matched group of healthy controls were included. We performed transabdominal ultrasound, and recorded echo intensities of the pancreas and parenchymal characteristics according to endoscopic ultrasound based Rosemont criteria. Results: We included 39 patients and 29 healthy controls. The cystic fibrosis patients were grouped according to exocrine pancreatic function; Cystic fibrosis, insufficient (n = 20) and sufficient (n = 19). Echo intensity measures and visual score demonstrated hyper-echogenicity in the pancreas insufficient group compared to the pancreas sufficient groups (p<0.001). Ductal and parenchymal changes were not prevalent in any of the groups. Conclusion: The hyper-echoic pancreas was the most frequent ultrasonographic finding in exocrine pancreas insufficient cystic fibrosis patients. Pancreatic echo levels correlated to pancreatic phenotype

Diagnostic accuracy of a short endoscopic secretin test in patients with cystic fibrosis

Objective: Short endoscopic secretin tests for exocrine pancreatic function are not properly evaluated in cystic fibrosis (CF). Methods: Patients with CF and healthy controls (HCs) underwent endoscopic collection of duodenal juice between 30 and 45 minutes after secretin stimulation. Duodenal juice was analyzed for HCO3- concentration and pancreatic enzyme activities. Stool was analyzed for fecal elastase. Results: Thirty-one patients with CF and 25 HCs were tested. Patients were classified as exocrine pancreatic sufficient (n = 13) or insufficient (n = 18). Both bicarbonate concentrations and enzyme activities in duodenal juice differentiated patients with CFI from patients with CFS and HC (P < 0.001). The population displays strong correlation between severe CF genotype in both alleles and pancreatic insufficient phenotype (P < 0.001). Conclusions: Pancreatic exocrine insufficient CF patients could be differentiated from exocrine sufficient patients and HCs using short endoscopic secretin test

Automated spectrophotometric bicarbonate analysis in duodenal juice compared to the back titration method

AbstractObjectivesWe have recently evaluated a short endoscopic secretin test for exocrine pancreatic function. Bicarbonate concentration in duodenal juice is an important parameter in this test. Measurement of bicarbonate by back titration as the gold standard method is time consuming, expensive and technically difficult, thus a simplified method is warranted. We aimed to evaluate an automated spectrophotometric method in samples spanning the effective range of bicarbonate concentrations in duodenal juice. We also evaluated if freezing of samples before analyses would affect its results.MethodsPatients routinely examined with short endoscopic secretin test suspected to have decreased pancreatic function of various reasons were included. Bicarbonate in duodenal juice was quantified by back titration and automatic spectrophotometry. Both fresh and thawed samples were analysed spectrophotometrically.Results177 samples from 71 patients were analysed. Correlation coefficient of all measurements was r = 0.98 (p < 0.001). Correlation coefficient of fresh versus frozen samples conducted with automatic spectrophotometry (n = 25): r = 0.96 (p < 0.001)ConclusionsThe measurement of bicarbonate in fresh and thawed samples by automatic spectrophotometrical analysis correlates excellent with the back titration gold standard. This is a major simplification of direct pancreas function testing, and allows a wider distribution of bicarbonate testing in duodenal juice. Extreme values for Bicarbonate concentration achieved by the autoanalyser method have to be interpreted with caution

Pancreatic exocrine insufficiency in diabetes is associated with autonomic dysfunction

Objectives: Pancreatic exocrine insufficiency (PEI) is prevalent in diabetes. Pathophysiological theories imply autoimmune destruction, lack of trophic effects of insulin or impaired neuronal stimulation, but the relationship between PEI and autonomic dysfunction is largely unknown. In a pilot study, we aimed to investigate if patients with diabetes and PEI had impaired autonomic function. Methods: We measured faecal elastase in 59 patients with type 1 or 2 diabetes, using a cut-off-value <200 μg/g to define PEI. Based on faecal elastase results, patients were stratified into matched case (n = 8) and control groups (n = 13). We used heart rate variability, baroreflex sensitivity and orthostatic hypotension tests to assess autonomic dysfunction. Results: All baroreflex sensitivity parameters were reduced in cases with PEI compared with controls (all p < .05). The heart rate variability parameters root mean square of successive RR interval differences (p = .05) and high frequency (p = .04) were also reduced. We found no difference in orthostatic hypotension between the groups. Conclusions: In this first-of-its-kind study, we found that diabetes patients with PEI had reduced autonomic function compared with matched controls. Although numbers are small, results support the hypothesis that autonomic dysfunction could be a contributor to PEI in diabetes