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/).

Pancreatic exocrine insufficiency in patients with chronic heart failure and its possible association with appetite loss.

BACKGROUND: Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF. AIM: We attempted to detect the association between PEI and CHF-induced appetite. METHODS: Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study. RESULTS: The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels (r = 0.694, p < 0.001). Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 µg/g stool and SNAQ < 14. CONCLUSIONS: Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms.

[Correction of small bowel function as a new direction for treating patients with metabolic syndrome]. / Korrektsiia narushenii funktsional'nogo sostoianiia tonkoi kishki kak novoe napravlenie lecheniia bol'nykh s metabolicheskim sindromom.

AIM: To provide a rationale for and to evaluate the therapeutic efficiency of the combined use of pancreatic enzymes and actovegin in the combination therapy of patients with metabolic syndrome (MS) on the basis of comprehensive clinical and functional studies of the small bowel (SB). SUBJECTS AND METHODS: In the course of treatment, 120 patients with MS (verified using the diagnostic criteria elaborated by the All-Russian Research Society of Cardiology (2009)) underwent a comprehensive study of SB function: an isolated study of resorptive processes; evaluation of parietal and cavitary digestion, motor-evacuation function. The peripheral blood levels of gastrin, insulin, cortisol, thyroxine and thyrotropin were determined. RESULTS: The combined use of pancreatic enzymes and actovegin has a positive impact on the clinical and functional state of SB, which was manifested as restoration of its hydrolysis and absorption, as well as motor-evacuation function in the patients with MS. The treatment resulted in reductions in the levels of triglycerides from 2.85±0.34 to 1.53±0.18 mmol/l (p<0.01), total cholesterol from 6.08±0.16 to 5.19±0.21 mmol/l (p<0.05), and atherogenic factor from 5.21±0.28 to 2.93±0.34 (p<0.05). Posttreatment HOMA-IR decreased from 4.22±0.8 to 2.12±0.8. There were no substantial changes in insulin levels and insulin resistance index in the patients on standard therapy. CONCLUSION: The combined use of pancreatic enzymes and actovegin is pathogenetically sound in correcting SB dysfunctions and may be one of the most effective directions for the treatment of patients with MS.

Exocrine pancreas involvement in celiac disease: a review.

UNLABELLED: There are numerous studies in the literature regarding the involvement of intestinal as well as extra intestinal organs during the course of celiac disease, and there is accumulating evidence regarding the pancreatic changes caused by this pathology. METHOD: The literature on the relationship between celiac disease and pancreatic involvement has been extensively reviewed. RESULTS: Exocrine pancreatic involvement regards both the function and the morphology of the exocrine pancreas, and superimposed or more severe clinical changes seem to be related to the nutritional disturbances caused by celiac disease or by the disease itself. Patients with celiac disease may also develop a chronic pancreatitis more frequently than in general population both the intestinal and the extraintestinal manifestations of celiac disease. CONCLUSIONS: Fecal elastase 1-determination in celiacs may be useful in detecting and curing exocrine pancreatic insufficiency especially in patients with a new diagnosis of celiac disease or in those with refractory diarrhea. Few patents on pancreatic extracts are also briefly described.

[Nutritional therapy in acute pancreatitis]. / Ernährungstherapie bei akuter Pankreatitis.

Acute pancreatitis is a frequent clinical entity in the West. About 80% of patients with acute pancreatitis develop edematous pancreatitis, while 20% develop necrotizing pancreatitis: The latter is a potentially life-threatening disease. In this case, early enteral nutrition has been shown to improve the course of the disease. Usually, gastric enteral nutrition with a polymeric formula via a nasogastric tube is possible; only in a minority of patients is jejunal feeding necessary owing to the high gastric residual volume. An elemental formula is useful for patients with significant intestinal maldigestion. If enteral feeding is not feasible within 5-7 days, (additional) parenteral nutrition has to be considered. Individualized--primary enteral--nutritional support is an essential part of a multimodal therapy in severe acute pancreatitis and it improves clinical outcome.

Body image and cystic fibrosis: a critical review.

A slight frame and poor appetite are common among patients with cystic fibrosis (CF) yet healthy body weight has been related to a better prognosis. A review of studies exploring body image (BI) among adults and adolescents with CF was conducted. Seven electronic databases were searched for potential papers. They located 128 references, of which 24 were read in full and 12 included in the review. Accepted papers suggested females with CF had a better BI compared to males, but this could compromise survival, given their preference for a low body weight. Males may be more motivated to adhere to nutritional advice because they favor a larger form. Practitioners should broach the topic of BI at clinic appointments to ensure this does not have a detrimental impact on self-management, although more research is required to guide professionals in this task.

18q deletion in a cystic fibrosis infant, increased morbidity and challenge for correct treatment choices: a case report.

Cystic Fibrosis (CF) is the most frequent recessive disease of Caucasian patients. Association with other diseases or syndromes has previously been reported. Co-morbidity may be a challenge for clinicians, who have to face more severe problems. We have described a CF infant, F508del homozygote, diagnosed by neonatal screening, who also had a chromosome 18q terminal deletion [del (18)(q22-qter)]. Some clinical features of the 18q deletion: e.g., cardiopathy, gastro-oesophageal reflux and severe muscular hypotonia, worsened the CF clinical picture and his quality of life, with repeated pulmonary exacerbations and failure to thrive in the first six months of life. The treatment strategy was chosen following an accurate multi-disciplinary team study of overlapping chromosome syndrome and CF symptoms. The use of a gastrostomy device for enteral nutrition together with a new device (Ez-PAP) for chest physiotherapy led to normal growth, a notably reduced hospitalization rate and improved quality of life. This case shows how co-morbidities worsening the clinical course of a "complicated patient" can be faced thanks to unconventional therapies that represent a challenge for clinicians.

Effect of liquid pancreatic enzymes on the assimilation of fat in different liquid formula diets.

BACKGROUND: In some diseases, patients require high-calorie tube feeding with standard enteral formulas usually administered via temporal feeding tubes. One frequent pathophysiological condition in a relevant number of these patients is exocrine pancreatic insufficiency. Patients unable to swallow capsules might benefit from a liquid pancreatic enzyme (LPE) preparation. METHODS: LPEs were prepared and mixed with different commercially available formula diets produced for enteral feeding. Lipolysis was then measured by fatty acid titration. RESULTS: Complete lipolysis by liquid enzyme preparations was observed in diverse formula diets. Fat assimilation was even complete when LPE had been prepared 3.5 hours before the experiments, showing that the enzymes had been stable up to that time. CONCLUSIONS: The use of LPEs seems to be a good therapeutic option in patients with exocrine pancreatic insufficiency and the need for permanent high-calorie enteral feeding. Pharmaceutical companies should therefore be further encouraged to develop and distribute liquid enzyme preparations.

Pancreatic enzyme therapy for pancreatic exocrine insufficiency.

Pancreatic exocrine insufficiency with steatorrhea is a major consequence of pancreatic diseases (eg, chronic pancreatitis, cystic fibrosis, severe acute necrotizing pancreatitis, pancreatic cancer), extrapancreatic diseases such as celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resection. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. Therapy for pancreatic exocrine insufficiency is based on the oral administration of pancreatic enzymes aiming at providing the duodenal lumen with sufficient active lipase at the time of gastric emptying of nutrients. Administration of enzymes in the form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. Nevertheless, such factors as 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.

[Conservative treatment of chronic pancreatitis]. / Chronische Pankreatitis: Konservative Therapie.

Chronic pancreatitis represents an inflammatory disease of the pancreas with progressive fibrotic destruction of the gland. The disease is characterized by abdominal pain, exocrine and endocrine insufficiency. Morphological alterations of the pancreas and signs of exocrine and endocrine insufficiency are difficult to detect early in the course of the disease. The conservative treatment of chronic pancreatitis aims at (1) control of abdominal pain, (2) replacing lost exocrine function, (3) treatment of endocrine insufficiency, (4) prevention of weight loss or achievement of weight gain, (5) limiting progression and complications of the disease, and finally (6) psychiatric and social advice with special emphasis on the treatment of chronic alcohol abuse. The patient must be counselled about the importance of abstinence from alcohol. Abdominal pain is controlled with strict analgetic medication using a step-by-step approach in increasing the dosage. Exocrine insufficiency is treated with a diet of several small meals per day and supplementation of pancreatic enzymes. Endocrine insufficiency is treated with insulin.

Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study.

BACKGROUND: Oral pancreatic enzyme supplements should be properly administered in order to ensure an adequate gastric mixing with the food and simultaneous gastric emptying with the chyme. AIM: To evaluate, in a prospective, randomized, open, comparative, three-way, crossover study, the effect of the administration schedule on the efficacy of oral pancreatic enzymes for the treatment of exocrine pancreatic insufficiency. METHODS: Twenty-four consecutive chronic pancreatitis patients with maldigestion secondary to exocrine pancreatic insufficiency were treated with 40 000 U lipase in the form of capsules containing enteric-coated mini-microspheres. Capsules were taken just before meals (schedule A), just after meals (schedule B) or distributed along with meals (schedule C) for three consecutive 1-week crossover periods in a randomized order. Fat digestion before and during the three treatment periods was evaluated by an optimized mixed (13)C-triglyceride breath test. RESULTS: Before therapy, the (13)CO(2) recovery in the breath test was 23.8 +/- 15.8% (normal >58.0%). During therapy, the (13)CO(2) recovery tended to be higher when capsules were taken along with meals ((13)CO(2) recovery 61.4 +/- 21.4%) or just after meals ((13)CO(2) recovery 60.6 +/- 21.8%) than when taken just before meals ((13)CO(2) recovery 53.9 +/- 20.3%). The percentage of patients who normalized fat digestion under therapy was 50, 54 and 63% with schedules A, B and C respectively. CONCLUSIONS: The efficacy of pancreatic enzyme supplements for the treatment of exocrine pancreatic insufficiency may be optimized by administration during or after meals.

[Diagnosis and therapy of chronic pancreatitis]. / Diagnostik und Therapie der chronischen Pankreatitis.

Chronic pancreatitis is characterized by recurrent or persisting pain. As the exocrine pancreatic insufficiency occurs early in the progression of the disease, the endocrine function may persist intact. Imaging procedures and pancreatic function tests are used to make a diagnosis. Therapy consists of pain reduction, which might require endoscopic or surgical intervention. Treatment of exocrine and endocrine pancreatic insufficiency is based on diet and substitution of pancreatic enzymes, minerals and vitamins, as well as insulin.

Pancreatic enzyme supplement improves dysmotility in chronic pancreatitis patients.

BACKGROUND AND AIMS: Impaired gallbladder contraction and rapid gastric emptying in patients with chronic pancreatitis may be the result of depleted pancreatic exocrine function. The authors tested whether oral pancreatic enzymes can improve the dysmotility or not. METHODS: Study subjects consisted of 15 patients with chronic pancreatitis and 18 healthy controls. The gastric emptying time and gallbladder contraction were studied. All patients were initially studied using a test meal without pancreatic enzymes, followed on separate days by a test meal with a single and a triple dose of pancreatic enzymes. Blood samples were taken before and 2 h after the test meal to determine the pancreatic polypeptide levels. RESULTS: In patients with chronic pancreatitis, gallbladder contraction at 15 min after the meal was impaired. The gastric emptying time was faster and the ratio of pre- to postprandial pancreatic polypeptide levels was enhanced. A single dose and a triple dose of oral enzymes further improved the gastric emptying time and the pancreatic polypeptide ration, but did not improve the gallbladder contraction rate at 15 min. CONCLUSIONS: It was demonstrated that the oral pancreatic enzymes improved the gastric dysmotility, confirming the previous findings that suggested the depleted pancreatic enzyme output caused the dysmotility.

Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes.

UNLABELLED: Despite treatment with supra-physiological doses of pancreatic enzyme supplements, residual steatorrhoea is a common problem in patients with cystic fibrosis (CF) and pancreatic insufficiency. Strategies to enhance the activity of pancreatic enzymes include decreasing duodenal acidity. The aim of this study was to evaluate the effect of omeprazole (Losec), a proton-pump inhibitor, on fat absorption in CF patients with residual steatorrhoea despite high dose pancreatic enzyme supplements (> or =10,000 U lipase/kg per day). A random cross-over design was chosen. Fat digestion was evaluated with and without omeprazole by means of chemical fat measurements in 3-day stool collections together with 3-day weighed food records for calculation of fat absorption. The results of 15 patients (3 girls and 12 boys) with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5-15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000-22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5-16.5 g/day) to 5.5 g (quartiles 4.9-8.1 g/day) (P<0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81-89%) without versus 94% (quartiles 90-96%) with omeprazole (P<0.001). CONCLUSION: Omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution.

Alpha amylase is a major allergenic component in occupational asthma patients caused by porcine pancreatic extract.

Porcine pancreatic extracts (PPE) are composed of alpha-amylase and lipase, which are common components of digestive enzymes. They have been known to cause occupational asthma in exposed workers in pharmaceutical and baking industries, as well as in a laboratory technician, but there has been no report of PPE-induced occupational asthma in medical personnel and their IgE binding components to each component. Four asthmatic subjects showing positive results on PPE-bronchoprovocation testing were enrolled. All of them were nurses working in a university hospital. Their job included grinding and mixing PPE powder for admitted patients. Serum-specific IgE antibodies to PPE, alpha-amylase, and lipase were measured by enzyme linked immunosorbent assay (ELISA). To confirm specificity of IgE binding and cross-allergenicity among the three extracts, ELISA inhibition tests were performed. In order to characterize allergenic components within these three extracts, SDS-PAGE and IgE immunoblot analysis were done. Specific IgE antibodies to PPE, alpha-amylase, and lipase were detectable by ELISA in all study subjects. An alpha-amylase ELISA inhibition test showed significant inhibitions by amylase and PPE, and minimal inhibition by lipase. However, a lipase ELISA inhibition test showed significant inhibitions by alpha-amylase and PPE with a lesser degree of inhibition by lipase. Furthermore, IgE immunoblot analysis showed one IgE binding component (55 kDa) within PPE, six components (55 kDa, 43 kDa, 41 kDa, 32 kDa, 31 kDa, 29 kDa) within alpha-amylase and two components (31 kDa, 29 kDa) within lipase extracts. Thesefindings suggest that inhalation of PPE powder can induce IgE-mediated bronchoconstriction in exposed nurses. Alpha-amylase is a major allergenic component within PPE.

A pancreatic extract-enriched diet improves the nutritional status of aged rats.

Correction of the malnourished state, particularly common and severe in elderly people, is often unsuccessful. To improve the efficiency of realimentation, we evaluated the nutritional effect of a pancreatic extract (PE)-enriched diet in malnourished aged rats. Sprague-Dawley male rats were randomly assigned to 6 groups as follows: 1 group of control rats had free access to the diet for 12 wk (C group) and 5 groups were 50% food restricted for the same period. One food-restricted group was then killed (R group) and the 4 remaining groups were refed for 1 wk using a standard diet enriched either with two different doses of a pancreatic extract (2.4 or 4.8 g/d in PE1 and PE2 groups, respectively) or with an isonitrogenous casein hydrolysate (CH1 and CH2 groups, respectively). Profound alterations induced by food restriction (FR) were moderately corrected by refeeding, except nitrogen balance, which was reestablished in rats refed all diets (P: < 0.01 vs. R). Supplementation of the food ration with a pancreatic extract clearly improved recovery. Indeed, body weight gain, both jejunal and ileal trophicity [jejunum: total height, PE2: 849 +/- 45 microm vs. CH2: 768 +/- 17 microm (P: < 0.05); protein content, PE2: 69.9 +/- 5.7 mg vs. CH2: 56.4 +/- 4.8 mg (P: < 0.01)] and nonspecific immune response in terms of H2O2 production by polymorphonuclear neutrophils and tumor necrosis factor alpha (TNF-alpha) by macrophages (PE2, 20.7 +/- 4.7 vs. CH2, 8.7 +/- 2.3, P: < 0.05) were improved in rats fed PE2. A pancreatic extract could improve the efficiency of realimentation in malnourished aged rats.

Local transrectal enzymatic treatment for chronic nonbacterial prostatitis and prostatodynia: initial clinical experience.

We report our initial clinical experience with local transrectal application of enzymatic treatment for chronic nonbacterial prostatitis and prostatodynia in 20 patients. Using a specially designed symptom score for evaluation of subjective treatment parameters, a statistically significant improvement of symptoms was found in the areas of pain, micturition, and recreational activities. No statistically significant differences were noted in laboratory values before and after treatment. Minimal local side effects were seen in only one patient. A favorable clinical response was noted in 75% of patients, whereas the remaining 25% showed only moderate improvement of symptoms. No patient experienced complete treatment failure.

[Application of systemic enzyme therapy in combined treatment of patients with pulmonary cancer and malignant thymoma]. / Zastosuvannia systemnoï enzymoterapiï v kombinovanomu likuvanni khvorykh na rak leheni ta zloiakisnu tymomu.

The systemic enzymotherapy using Wobe-Mugos E in the combined treatment of 32 patients with pulmonary cancer and of 21 patients with malignant thymoma was applied. After the chemotherapy and radiotherapy conduction the reduction of the postoperative septic-purulent complications, the pneumofibrosis occurrence prophylaxis was noted.