Preventive Effect of High-Dose Digestive Enzyme Management on Development of Nonalcoholic Fatty Liver Disease after Pancreaticoduodenectomy: A Randomized Controlled Clinical Trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a complication of pancreaticoduodenectomy (PD). We conducted a randomized clinical trial to determine if high-dose digestive enzymes prevented the development of NAFLD after PD. STUDY DESIGN: This parallel-group, nonblinded, multicenter study enrolled patients undergoing elective PD at Shinshu University School of Medicine, from June 2011 to April 2017. Patients were randomly assigned to receive normal-dose (Excelase: 3.0 g/day [Meiji Seika Pharma Holdings Co, Ltd]) or high-dose digestive enzyme treatment (Excelase: 3.0 g/day; Pancreatin [Tokyo Chemical Industry Co Ltd]: 3.0 g/day; Berizym [Kyowa Pharmaceutical Industry Co Ltd]: 3.0 g/day; and Toughmac-E [Ono Pharmaceutical Co, Ltd]: 3.0 g/day) within 1 week after surgery. Because patients in the control group switched interventions upon receiving a diagnosis of NAFLD, intention-to-treat analysis was used. The primary endpoint was incidence of NAFLD within 1 year, and the secondary endpoints were the incidences of NAFLD at 1, 3, 6, and 12 months and the rate of improvement in NAFLD with high-dose transfer in the control group. The secondary analysis comprised assessment of risk factors for the development of NAFLD. RESULTS: Eighty-four patients were randomly assigned (42 per group), 80 of whom were finally analyzed (39 normal-dose, 41 high-dose). The incidence of NAFLD was significantly lower in the high-dose (8 of 41) compared with the normal-dose (25 of 39) patients (p < 0.001). Multivariate analysis identified normal-dose (odds ratio [OR] 14.65, p < 0.001), total protein ≤ 6.5g/dL (OR 9.01, p = 0.018), pre-albumin ≤ 22.0 mg/dL (OR 7.71, p = 0.018), and pancreatic function diagnostic test ≤ 70% (OR 6.66, p = 0.009) as independent risk factors. There were no adverse effects. The model was accurate (c-index = 0.92) and reliable (Hosmer-Lemeshow test p = 0.32). CONCLUSIONS: High-dose administration of digestive enzymes significantly reduced the onset of NAFLD after PD compared with normal-dose administration. Registration number: UMIN000005595 (http://www.umin.ac.jp/ctr/).

Two cases of agenesis of the dorsal pancreas and a review of the literature.

BACKGROUND: Agenesis of the dorsal pancreas (ADP) is a very rare disease with no specific symptoms, and the pathogenesis is not clear. Some patients will be accompanied by other diseases, such as pancreatic tumor or pancreatitis. But most cases are very atypical and difficult to distinguish. Some syndromes of pancreatic exocrine insufficiency are common in patients with ADP. Here, we report two cases of ADP and summarize the clinical features, diagnosis, and treatment of ADP. CASE PRESENTATION: Case A is a 65-year-old Chinese woman who presented with abdominal pain accompanied by nausea, bloating and acid reflux. The enhanced abdominal CT scan found nothing meaningful except the absence of the body and tail of the pancreas. The diagnosis was considered as gastrointestinal dysfunction cause by exocrine pancreatic insufficiency and recovered after symptomatic treatment. Case B is a 61-year-old Chinese woman who presented with abdominal pain accompanied by fever, vomiting and bloating. The abdominal CT showed multiple stones in the gallbladder, and the body and tail of the patient's pancreas were absent. She was diagnosed with cholelithiasis and recovered after laparoscopic cholecystectomy. CONCLUSION: Agenesis of the dorsal pancreas (ADP) is a rare congenital disease with an unclear pathogenesis that presents multiple symptoms. It should be considered when the patients have non-specific, persistent and unexplained symptoms such as bloating or uncontrolled blood sugar. Imaging examination is helpful for diagnosis. And it does not require surgical intervention unless it accompanies other diseases, EPI need to be considered when the non-specific gastrointestinal symptoms appear.

Treatment of Severe Protein Malnutrition After Bariatric Surgery.

BACKGROUND: Severe protein malnutrition, with a serum albumin < 25 g/L, is one of the complications that may develop after bariatric surgery. It is associated with increased morbidity and mortality and requires timely diagnosis and appropriate treatment to prevent rapid clinical deterioration. However, evidence-based recommendations for a specific treatment approach are currently not available. The present study describes the efficacy of a newly developed treatment regimen for post-bariatric patients presenting with severe hypoalbuminemia. METHODS: A single-centre, retrospective analysis of eleven post-bariatric patients presenting with severe hypoalbuminemia, treated with continuous 24 h nasal-jejunal tube feeding of a medium chain triglyceride (MCT) formulation in combination with pancreatic enzyme supplementation every 3 h. RESULTS: Duration of tube feeding ranged from 25 to 156 days (median 64 days) and pancreatic enzyme was supplemented for 22-195 days (median 75 days). An increase in serum albumin levels of 5 g/L and 10 g/L was achieved after a median period of 20 (range 6-26 days) and 36 days (range 21-57 days), respectively. Albumin levels were > 35 g/L after a median period of 58 days (range 44-171 days). CONCLUSION: In this case series, a continuous 24-h nasal-jejunal MCT tube feed combined with frequent pancreatic enzyme supplementation was effective in all patients presenting with severe post-bariatric hypoalbuminemia and was not associated with adverse effects.

Cellulase, Coca-Cola®, pancreatin and ursodeoxycholic acid in the dissolution of gastric bezoars: why not all together?

Two cases of a chemical dissolution of gastric phytobezoars are presented. The novel approach of that management is the pharmacological mixture than completely made disappear the bezoars in patients fated to surgery removal.

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.

BACKGROUND: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT01587534.

[Duodenal dystrophy: An interdisciplinary problem].

Duodenal dystrophy (DD) is the pathological change in the wall of the duodenum, which is caused by chronic inflammation in its ectopic pancreatic tissue. The most common complications of DD are acute or chronic pancreatitis and impaired duodenal patency, which along with severe pain are an indication for surgical treatment. Pancreaticoduodenal resection is recognized as the operation of choice. The paper describes a clinical case demonstrating the efficiency and safety of minimally invasive (laparoscopic) surgical technologies in this category of patients. Resectional interventions of this volume are also shown to be accompanied by the development of pancreatic insufficiency that necessitates continuous enzyme replacement therapy.

Nutrition Management of Cystic Fibrosis in the 21st Century.

Despite significant advancements made in life expectancy over the past century, cystic fibrosis remains a life-threatening genetic disease that affects the gastrointestinal tract, and it has significant impact on the nutrition status of those with the disease. Nutrition management includes a high-calorie/high-fat diet, pancreatic enzyme replacement therapy, vitamin and mineral replacement, and enteral support as needed. As patients are living longer, clinicians may encounter patients with cystic fibrosis in obstetrician offices, endocrine clinics, or hospital settings, owing to lung transplantation or for treatment for distal intestinal obstruction syndrome.

Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery. AIM: To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9-15 capsules/day) over placebo in treating PEI after pancreatic resection. METHODS: A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9-15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova). RESULTS: All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. -4.2% (-12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE. CONCLUSIONS: This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).

Exocrine pancreatic insufficiency following esophagectomy.

Weight loss following esophagectomy is a management challenge for all patients. It is multifactorial with contributing factors including loss of gastric reservoir, rapid small bowel transit, malabsorption, and adjuvant chemotherapy. The development of a postoperative malabsorption syndrome, as a result of exocrine pancreatic insufficiency (EPI), is recognized in a subgroup of patients following gastrectomy. This has not previously been documented following esophageal resection. EPI can result in symptoms of flatulence, diarrhea, steatorrhea, vitamin deficiencies, and weight loss. It therefore has the potential to pose a significant level of morbidity in postoperative patients. There is some evidence that patients with proven EPI (fecal elastase-1 < 200 µg/g) may benefit from a trial of pancreatic enzyme replacement therapy (PERT). We observed symptoms compatible with EPI in a subgroup of patients following esophagectomy. We hypothesized that this was contributing to malabsorption and malnutrition in these patients. To investigate this, fecal elastase-1 was measured in postoperative patients, and in those with proven EPI, a trial of PERT was commenced in combination with specialist dietary education. At routine postoperative follow-up, which included assessment by a specialist dietitian, those patients with symptoms suggestive of malabsorption were given the opportunity to have their fecal elastase-1 measured. PERT was then offered to patients with fecal elastase-1 less than 200 µg/g (EPI) as well as those in the 200-500 µg/g range (mild EPI) with more severe symptoms. Fecal elastase-1 was measured in 63 patients between June 2009 and January 2011 at a median of 4 months (range 1-42) following surgery. Ten patients had fecal elastase-1 less than 200 µg/g, and all had failed to maintain preoperative weight. All accepted a trial of PERT. Nine (90%) had symptomatic improvement, and seven (70%) increased their weight. Thirty-nine patients had a fecal elastase-1 in the 200-500 µg/g range. Twelve were given a trial of PERT based on level of symptoms, five (42%) reported an improvement in symptoms, but only two (17%) gained weight. Our early results support the observation that EPI is a factor contributing to postoperative morbidity in patients recovering from esophagectomy and that these patients can benefit from a trial of PERT. Our study has limitations, and a formal trial is required to evaluate the impact of EPI and PERT following esophagectomy. Currently, our practice is to measure fecal elastase-1 in any patient with unexplained weight loss or symptoms of malabsorption. In patients with proven EPI or those who are symptomatic with mild EPI, a trial of PERT should be offered and symptoms reassessed.

Adherence to pancreatic enzyme supplementation in adolescents with cystic fibrosis.

PURPOSE: Levels of adherence to pancreatic enzyme supplementation were investigated in Atlantic Canada adolescents with cystic fibrosis (CF). METHODS: Participants were recruited from CF clinics at the Izaak Walton Killam Health Centre in Halifax, Nova Scotia, and the Janeway Children's Health & Rehabilitation Centre in St. John's, Newfoundland and Labrador. Self-report questionnaires were mailed to potential participants (n=51) by clinic staff and completed surveys (n=9) were mailed to the principal investigator. RESULTS: Nine adolescents (mean age 15.2 ± 1.9 years) participated in the study. The adherence survey indicated that the majority perceived themselves to be adherent to taking enzymes with meals (67%), but only 44% perceived themselves to be adherent to taking enzymes with snacks. Recorded amounts of enzymes, taken over three days, indicated that 67% of participants were actually adherent to taking enzymes with meals and 56% with snacks. Including those who correctly predicted non-adherence, 56% and 44% of participants accurately predicted their adherence to taking enzymes with meals and snacks, respectively. CONCLUSIONS: Adherence rates in the literature vary because of differences in definition and measurement. In the CF population, adherence has been shown to have a positive effect on quality of life. Results for this small group of patients suggest that Atlantic Canada adolescents with CF are able to estimate correctly their adherence to taking pancreatic enzymes, but definite conclusions cannot be made because of the small number of respondents.

Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it?

Pancreatic exocrine insufficiency with steatorrhea is a major consequence of pancreatic diseases (e.g. chronic pancreatitis, cystic fibrosis, severe acute necrotizing pancreatitis, pancreatic cancer), extrapancreatic diseases like celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resections. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. Therapy of pancreatic exocrine insufficiency is based on the oral administration of pancreatic enzymes aiming at providing the duodenal lumen with sufficient amount of active lipase at the time of gastric emptying of nutrients. Administration of enzymes in form of enteric-coated minimicrospheres 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 critically reviews current therapeutic approaches to pancreatic exocrine insufficiency.

A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis.

OBJECTIVE: At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted. RESEARCH DESIGN AND METHODS: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required. MAIN OUTCOME MEASURES: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study. RESULTS: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old). CONCLUSIONS: No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.

Plasma choline depletion is associated with decreased peripheral blood leukocyte acetylcholine in children with cystic fibrosis.

BACKGROUND: Choline is an important constituent of acetylcholine. Choline is needed for acetylcholine in the nonneuronal acetylcholine system that includes epithelial cells of the lung and intestine, endothelial cells, and immune cells. Plasma free choline concentrations are low in children with cystic fibrosis (CF), but the implications for acetylcholine are unknown. OBJECTIVE: We determined the relation between plasma free choline and related metabolites and leukocyte acetylcholine in children with CF and in a control group of healthy children without CF. DESIGN: This was a cross-sectional study in 34 children with CF who were pancreatic insufficient and taking pancreatic enzyme-replacement therapy and in 16 healthy children. Plasma free choline, betaine, dimethylglycine, methionine, homocysteine, and leukocyte acetylcholine concentrations were quantified by using isotope-dilution HPLC-tandem mass spectrometry. RESULTS: Mean (±SE) plasma free choline was 9.30 ± 0.37 and 6.54 ± 0.38 µmol/L (P < 0.05) and leukocyte acetylcholine was 1.21 ± 0.016 and 0.077 ± 0.011 pmol leukocyte acetylcholine/10(6) cells (P < 0.05) in control children and children with CF, respectively. Leukocyte acetylcholine was positively correlated with plasma free choline concentration in children with CF (r = 0.412, P < 0.05) but not in control children. Plasma betaine, dimethylglycine, and methionine concentrations were also lower in children with CF than in control children (P < 0.05). CONCLUSIONS: A low free choline and methyl status in children with CF is associated with reduced acetylcholine in leukocytes. Whether these changes are explained by a mutation in the CF transmembrane conductance regulator or disturbances in choline metabolism and the implications for immune cell dysfunction in CF are unknown. This trial was registered at clinicaltrials.gov as NCT01150136.

[Peculiarities of diabetes mellitus course in chronic pancreatitis].

In order to identify features of the course pancreatic diabetes and discussion of the principles of conservative therapy were examined 66 patients with CP in age of 30 to 65 years (55 men, 11 women). Among them in 22 cases disease was followed with formation of calcification of pancreas, 13 - pancreatic cysts, and 5 revealed pseudo tumor form of CP, 10 patients had clinical and laboratory evidence of diabetes. Concerning CP complicated course were performed 14 resection and 11 draining operations on the pancreas. Based on clinical, instrumental and laboratory data was made the diagnosis of CP. Exocrine pancreatic function was assessed on the results of the breath test, using 13C-trioktanaine, which is applied for exocrine pancreatic function in vivo test. The content of C-peptide was investigated by enzyme-linked immunosorbent assay (ELISA). The data indicate pancreatic exocrine function decrease in patients with CP with complications and without complications in compare with the norm of 44% (24,3 +/- 1,7, 26,6 +/- 1,3%, respectively) according to the breath test. Significant decrease of the cumulative output tags based on the test data of patients with CP and pancreatic calcification, diabetes mellitus, after resection surgery with CP complications, and there were significant differences in compare with a group of patients with CP without complications (p = 0.5). The level of C-peptide in these groups of patients decreased significantly in compare with a group of patients with CP without complications, and patients with CP and Diabetes was reduced to 0,11 +/- 0,02 ng/ml, at a rate range of 0.7-1.9 ng/ml, ie below the minimum values of norm. Obtained a direct correlation between the level of C-peptide and indicators breath test in patients after resection HP (r = 0,84, p = 0,03). Antibodies to insulin in the whole group of studied patients CPs were negative, which proves the specific type of Diabetes at HP. Antibodies to insulin can be detected only at diabetes type 1. In 7 patients with CP and CD detected calcification, 5 patients performed resection surgery, 3 patients had calcification and conducted the pancreas resection. Thus, we can conclude that in patients with CP and formation of pancreas calcification, pancreas resections may predict the development of diabetes.

[Effect of enzyme supportive therapy of the Ermital' on a quality of life of patients with chronic pancreatitis].

The purpose of the study was to evaluate the quality of life in patients with chronic pancreatitis with the presence of complications treated conservatively and surgical treatment. With the help of a questionnaire MOS SF-36 were asked 80 patients with CP, of whom 15 patients were after the operation, the PDR, 10 patients underwent draining operations, 15 patients had a history of pancreatic necrosis, in 20 patients with CP were characterized by complications (cyst calcification, kalkulez, pseudotumoral form of HP, diabetes) and surgical interventions were not performed in 20 CPs proceeded without complications. Were obtained significant differences on all scales of the questionnaire with the control group all CP patients. Assessment of coping with pain in long-terms after various operations was revealed significantly better results and got rid of persistent pain in patients with a complicated course, who underwent surgery. 23 CP patients with a complicated course, as enzyme replacement therapy received in ermital dose of 20,000 IU lipase 3-4 times a day for 3 weeks. The assessment of quality of life before and after therapy with ermital. The intensity of pain significant changes in the groups received. On the other hand the improvement in general health, physical and social functioning.

Properties of different pancreatin preparations used in pancreatic exocrine insufficiency.

BACKGROUND: Pancreatic enzyme preparations are a life-saving substitution for a pivotal physiological function of the entire organism that is impaired in chronic pancreatitis, cystic fibrosis and other diseases with exocrine pancreatic insufficiency. Pancreatic enzyme preparations, generically called pancreatin, are not alike. Rather, they present a broad variety of pancreatin composition. AIM: The properties of a set of commercially available pancreatin preparations were investigated in light of the physiological tasks such enzymes must fulfill during the normal digestive process. METHODS: Measurements of size, surface, acid resistance, release of enzymes, pharmacokinetics and batch consistency were undertaken. RESULTS: Although all pancreatin preparations contain the declared lipase units and are acid-stable, a wide variation was observed in the particle size (pyloric passage), specific surface area and release kinetics of lipase activity at pH 6 (duodenum). CONCLUSION: At present, available pancreatin preparations vary widely with respect to investigated parameters, which may have consequences for facilitating optimal digestion.

Pancreatic enzyme pharmacotherapy.

Supplemental pancreatic enzyme preparations are provided to patients with conditions of pancreatic exocrine deficiency such as chronic pancreatitis and cystic fibrosis. These patients frequently experience steatorrhea, which occurs from inadequate fat absorption. The delivery of sufficient enzyme concentrations into the duodenal lumen simultaneously with meals can reduce nutrient malabsorption, improve the symptoms of steatorrhea, and in some cases alleviate the pain associated with chronic pancreatitis. Current clinical practices dictate administration of lipase 25,000-40,000 units/meal by using pH-sensitive pancrelipase microspheres, along with dosage increases, compliance checks, and differential diagnosis in cases of treatment failure. Despite the large number of specialty enzyme replacements available commercially, many patients remain dissatisfied with standard therapy, and future developments are needed to optimize treatment in these individuals.

An elemental diet controls inflammation in indomethacin-induced small bowel disease in rats: the role of low dietary fat and the elimination of dietary proteins.

Elemental diets (EDs) are effective in treating Crohn's disease. We hypothesize that low dietary fat and amino acids used as the sole nitrogen source are the major contributors for the success of EDs. We examined the influences of the addition of dietary fat and protein to an ED using an indomethacin-induced inflammation model in rat small intestine. In the ED-fed rats, the intestinal damage score was decreased compared with that in the standard chow group with decreasing intestinal permeability. By supplementing an ED with soybean oil (SO), intestinal permeability was increased to a level similar to that of the standard chow group. For this group, the intestinal damage score also increased compared with that of the ED group but did not reach the levels observed in the standard chow group. The addition of dietary proteins (using heat-denatured pancreatin) resulted in intestinal damage scores that were significantly higher than those of the ED+SO-fed group. The dietary protein increased the intestinal damage score. These results suggest that EDs control inflammation by decreasing intestinal permeability and the elimination of dietary proteins.