Exocrine Pancreatic Insufficiency Therapy Research Articles

Pancreatic-like enzymes of microbial origin restore growth and normalize lipid absorption in a pig model with exocrine pancreatic insufficiency.

IntroductionThe standard therapy for exocrine pancreatic insufficiency (EPI) is porcine-derived pancreatic enzyme replacement therapy (PERT). In the present study we tested a new approach with a mixture of pancreatic-like enzymes of microbial origin (PLEM) in a 1-week efficacy study in EPI pigs. In addition to the conventionally used coefficient of fat and nitrogen absorption (CFA and CNA), parameters that more accurately reflect the nutritional and health status, such as changes in the lipemic index (LI), plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels, and somatic growth, were determined.Material and methodsA PLEM dose containing 120 000 active lipase units, 80 000 active protease units and 12 000 active amylase units (all from Sigma, St. Louis, MO) was given as a powder, twice daily with a meal (40 g fat/meal) to 8 EPI pigs for 7 days. Ten healthy pigs were used as a comparator.ResultsThe PLEM enhanced fat and protein digestion, and reversed growth impairment in EPI pigs. With treatment, CFA and CNA increased by 59% and 43% (p < 0.05), respectively. Although fat and protein absorption were lower than in the comparator, the postprandial blood lipid profile was normal as in healthy pigs. The mucosal thickness significantly increased by 27%, 50% and 26%, in the proximal, middle, and distal jejunum (p < 0.05) with treatment and resembled that of healthy animals.ConclusionsPancreatic-like enzymes of microbial origin supported somatic growth and normalized the postprandial lipid profile. As a measure of efficacy, postprandial LI, TG and NEFA are viable endpoints to be explored in human trials.

Novel ciliate lipases for enzyme replacement during exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency caused by inflammation or pancreatic tumors results in nutrient malfunction by a lack of digestive enzymes and neutralization compounds. Despite satisfactory clinical results with current enzyme therapies, a normalization of fat absorption in patients is rare. An individualized therapy is required that includes high dosage of enzymatic units, usage of enteric coating, and addition of gastric proton pump inhibitors. The key goal to improve this therapy is to identify digestive enzymes with high activity and stability in the gastrointestinal tract. We cloned and analyzed three novel ciliate lipases derived from Tetrahymena thermophila. Using highly precise pH-STAT-titration and colorimetric methods, we determined stability and lipolytic activity under physiological conditions in comparison with commercially available porcine and fungal digestive enzyme preparations. We measured from pH 2.0 to 9.0, with different bile salts concentrations, and substrates such as olive oil and fat derived from pig diet. Ciliate lipases CL-120, CL-130, and CL-230 showed activities up to 220-fold higher than Creon, pancreatin standard, and rizolipase Nortase within a pH range from pH 2.0 to 9.0. They are highly active in the presence of bile salts and complex pig diet substrate, and more stable after incubation in human gastric juice compared with porcine pancreatic lipase and rizolipase. The newly cloned and characterized lipases fulfilled all requirements for high activity under physiological conditions. These novel enzymes are therefore promising candidates for an improved enzyme replacement therapy for exocrine pancreatic insufficiency.

Online CME Participation by Gastroenterologists Improves Management of Exocrine Pancreatic Insufficiency

Introduction: Management of exocrine pancreatic insufficiency (EPI) can be challenging for gastroenterologists. This study assessed the effect of online continuing medical education (CME) on clinical decision-making among participating gastroenterologists compared to non-participating matched peers. Methods: The American Gastroenterological Association Institute and Medscape, LLC identified performance gaps in management of EPI. An enduring online video-based CME expert roundtable discussion was hosted on Medscape from February 28th, 2013. Clinical case vignettes with assessment questions were administered to CME participants following the CME activity and final data for outcomes was collected by May 30th, 2013. A control group of non-participants that matched the participants' characteristics (e.g., specialty, number of EPI patients treated) was randomly selected and administered the same set of questions. The difference in responses to survey questions between the two groups were analyzed using chi-square tests (P < .05), and educational effect size was calculated using Cohen's d formula, which represented the degree of nonoverlap in answers between the CME participants and non-participants. Results: Gastroenterologist CME participants (n=100) were 37.2% more likely to make evidence-based practice choices than non-participants (n=100) (moderate educational effect size of d=0.58) in the following areas: - 28% more participants ordered a fecal elastase test to confirm EPI (75% participants vs 47% non-participants, P<0.001). - 12% more participants ruled out small bowel bacteria overgrowth in poor responders to enzyme replacement therapy (90% participants vs 78% non-participants, P=.02). - 16% more participants ordered a Vitamin D level for a patient with a history of diarrhea due to EPI (93% participants vs 77% non-participants, P=.002). - 12% more participants accurately counselled patients beginning EPI therapy (88% participants vs 76% non-participants, P=.03). - Most participants (88%) and non-participants (90%) recognized that efficacy of pancreatic enzyme supplementation is influenced by timing of consumption. Conclusion: CME participation in an online video roundtable discussion impacted clinical decisionmaking in gastroenterologists treating EPI, which may translate to improved outcomes in patients. Future education should focus on testing to confirm EPI and patient-clinician communication on treatment adherence and disease management.

Chronic Pancreatitis and Persistent Steatorrhea: What Is the Correct Dose of Enzymes?

Exocrine pancreatic insufficiency with steatorrhea is a major consequence of chronic pancreatitis. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. Nutritional counseling and oral pancreatic enzyme replacement are the basis for the therapy for exocrine pancreatic insufficiency. Aim of enzyme therapy is not only to avoid symptoms but also to normalize digestion. With this aim, oral administration of pancreatic enzymes in the form of enteric-coated minimicrospheres is the therapy of choice. This enzyme preparation avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. Despite that, factors like an acidic intestinal pH and bacterial overgrowth may prevent normalization of fat digestion even in compliant patients. The present article reviews the current evidence on therapy of exocrine pancreatic insufficiency in chronic pancreatitis patients, with special attention to different potential endpoints to select the optimal enzyme dose for individual patients.

Pancreatic Insufficiency in Adult Celiac Disease: Do Patients Require Long-Term Enzyme Supplementation?

Celiac disease is associated with exocrine pancreatic insufficiency. We previously reported that in 30% (20/66) of adult celiac patients with current or persistent diarrhea the underlying cause was exocrine pancreatic insufficiency. Of these 20 patients, 19 initially improved on pancreatic supplementation. To date, there are no published longitudinal studies. The 20 patients who had initially received therapy for exocrine pancreatic insufficiency were prospectively followed-up for 4 years. Gastrointestinal symptoms, dietary adherence, celiac antibody status, and dose of enzyme supplementation were recorded. Fecal elastase-1 (Fel-1) was repeated to reassess exocrine pancreatic function. In the study, 19/20 patients were reviewed, as one had died (mean age 59.7 years, 7 males). The mean duration of celiac disease was 13.2 years. Eleven out of nineteen were still taking enzyme supplementation at a mean dose of 45,000 units of lipase per day. Only 1/11 reported no symptomatic benefit and 8/19 patients had discontinued supplementation because their diarrhea had improved. In the whole group there was a significant increase in Fel-1 levels over time, with median values of 90 μg/g at 0 months, 212 μg/g at 6 months, and 365 μg/g at follow-up (45-66 months)(p < 0.0001). Fecal elastase-1 is useful in identifying exocrine pancreatic insufficiency in adult celiac patients with diarrhea. Our longitudinal data suggests that pancreatic enzyme supplementation could be discontinued in a substantial proportion of patients as symptoms improve.

Adenovirus-mediated transfer of human lipase complementary DNA to the gallbladder

Background/Aims: Despite many improvements in current therapy, exocrine pancreatic insufficiency remains a significant problem in cystic fibrosis. To establish a new therapy for exocrine pancreatic insufficiency, the feasibility of transferring the human pancreatic lipase complementary DNA to the gallbladder as a possible target using a recombinant adenovirus vector was evaluated. Methods: The adenovirus vector AdCMV.Lip was constructed using the cytomegalovirus immediate early promoter to drive the human pancreatic lipase complementary DNA. In vitro infection of the human gallbladder epithelial cell line HS-181 and ex vivo infection of the sheep gallbladder with AdRSV.β-gal (an adenovirus vector containing the Escherichia coli lacZ [(β-galactosidase] gene) or AdCMV.Lip were evaluated. Results: The supernatant from AdCMV.Lip-infected HS-181 showed the secretion of active lipase for at least 2 weeks in vitro. The epithelium of gallbladder infected with AdRSV.β-gal ex vivo showed the expression of the β galactosidase. The fluid from the gallbladder lumen infected with AdCMV.Lip showed the increased lipase activity.Conclusions: These observations show that an adenovirus vector can transfer a human pancreatic enzyme in vitro and ex vivo, suggesting the feasibility of in vivo gene therapy for exocrine pancreatic insufficiency in cystic fibrosis.

Enzyme Replacement Therapy for Exocrine Pancreatic Insufficiency in Man

Enzyme Replacement Therapy for Exocrine Pancreatic Insufficiency in Man