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/).

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.

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.

[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.

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.

[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.

[Photo-hemo-correction in the complex treatment of patients with obliterating atherosclerosis of the arteries of the lower limbs]. / Fotogemokorrektsiia v kompleksnom lechenii bol'nykh s obliteriruiushchim aterosklerozom arterii nizhnikh konechnostei.

Based on the assessment of clinical efficiency of the intravascular and percutaneous photomodification of blood with a helium-neon laser in 170 patients the authors have shown that it is expedient to include the photohemocorrection in the medical programs for the I-III degree ischemia.

Liquid pancreatic enzyme therapy for a patient with short bowel syndrome and chronic pancreatitis in a complicated case of Crohn's disease.

The case of a 45 year old female with multiple complications of Crohn's disease is reported. After multiple resections in the gastrointestinal tract she had been suffering from short bowel syndrome and severe malnutrition. With a special continuous gastric tube feeding system, she was able to maintain her weight for years. In the beginning of 1997 the enteral nutrition was not longer tolerated for an exacerbation of chronic pancreatitis. There was a weight loss, permanent pain and total parenteral nutrition had to be performed. In this situation a new liquid preparation of pancreatic enzymes which had been tested in the laboratory before, was used for continuous enzyme replacement via gastric tube. In combination with this enzyme preparation, enteral nutrition could successfully be started again.

The role of Wobe-Mugos in reducing acute sequele of radiation in head and neck cancers--a clinical phase-III randomized trial.

Oral enzymes act as a potent antiinflammatory, antiedematous agents thereby decreasing acute toxigenic effect of radiation and increasing compliance, quality of life of our patients. Fifty patients were randomized 25 allocated in enzyme and radiotherapy arm, 25 in radiotherapy alone. Pre RT and post RT biopsies were taken from both arms. In our study it was found that there was clinical, histopathological as well as statistical significant difference in both arms. The enzyme arm patients had mucostis of grade I in 76%, grade II in 12%, grade III in 8% while as 8% had grade I, 68% grade II, 24% had grade III in RT arm alone. In enzyme patients skin reactions of grade I in 72%, 20% had grade II, 8% had grade III. In control arm 12% had grade I, 76% had grade II, 8% had grade III skin reaction.

Proteinases reduce metastatic dissemination and increase survival time in C57Bl6 mice with the Lewis lung carcinoma.

The effect of combined proteolytic enzymes, administered by the rectal route, on the metastatic process and the time of survival in C57Bl6 mice with the Lewis lung carcinoma inoculated subcutaneously was investigated. In the control group, which received no enzyme treatment, 90% of animals died of the metastatic spread of cancer by day 18 after primary tumor extirpation. In Group A, which received the multi-enzyme solution from the time of primary tumor extirpation, 30% of mice died of disseminated cancer by day 25. In Group B, which was treated with the enzymes from 6 days before primary tumor extirpation, only 10% of animals showed the metastatic process by day 15. In Group C, which received the enzymes from 24 hours after intracutaneous tumor inoculation, no metastatic dissemination was discernible. In these three groups, the enzyme treatment was carried out throughout the study. None of the control animals survived for 100 days when the study was ended. The treated groups A, B and C showed survival rate 60%, 90% and 100% of animals, respectively, by 100 days.

Chronic pancreatitis: pathogenesis and management of pain.

Abdominal pain, excruciating and recurrent, is the dominant feature of chronic pancreatitis that initially brings most of the patients to the physician's attention. The pathogenesis of pancreatic pain is often multifactorial and explains why not all patients respond to the same mode of therapy. Increased intraductal pressure as a result of ductal stricture and/or calculi is the most frequent cause for pain in the large majority of patients with large duct disease. Interstitial hypertension, ongoing pancreatic ischemia, neuronal inflammation, and extra pancreatic complications may be the sole or additional factors in the pathogenesis of pain. The management of pain is difficult and requires a team approach. Internist, gastroenterologist, radiologist, surgeon, and a psychiatrist may have to work together to achieve maximum success. Drug and alcohol dependency needs vigorous management by a psychiatrist. Supportive therapy with a low-fat diet and antioxidant supplementation are helpful. When analgesic therapy fails, surgery may have to be considered much before a narcotic dependency develops. If at all of use, oral pancreatic enzyme therapy is suitable only in a selected group of patients--women with idiopathic pancreatitis. Endoscopic papillotomy, stent placement, and stone removal, although becoming popular, are under trial only and appear to be suitable in those with obstructive disease mostly localized to the head of the pancreas without much proximal disease. A patient with a dilated duct system is a good candidate for Puestow's pancreatico-jejunal anastamosis, which appears to be the best surgical procedure. Those with small duct diseases are difficult to be managed. Resective procedures and celiac ganglion blocking are suggested but not of much help.

Effects of pancreatic enzyme preparations on erythrocyte glutathione peroxidase activities and plasma selenium concentrations in cystic fibrosis.

To substitute for exocrine pancreatic insufficiency, patients with cystic fibrosis (CF) take pancreatic enzymes (PE) originating from porcine pancreas. Five different pancreatic enzyme preparations used by our patients contained 0.5-1.4 microg selenium per g tablet. In patients taking PE in doses that were gradually increased to improve fat absorption during a 48-month period, the effects of PE dose on erythrocyte selenium-dependent glutathione peroxidase (SeGSH-Px) activities and plasma selenium concentrations were studied. At baseline, erythrocyte SeGSH-Px activities were significantly lower in patients (p=.01), while plasma selenium concentrations did not differ between patients and healthy subjects. When PE dose and, consequently, selenium intake from PE was increased, erythrocyte SeGSH-Px activities (p < .001) and plasma selenium concentrations (p=.02) increased. Changes in SeGSH-Px activities during the initial 8 months correlated with those in selenium intake from PE (r=0.67, p < .001). Plasma selenium concentrations plateaued at 12 months and erythrocyte SeGSH-Px activities did so at 36 months, when patients had reached SeGSH-Px activities similar to those of healthy subjects. At 48 months, patients took an average lipase dose of 17400 U x kg(-1) x d(-1) and selenium dose from PE of 0.53 microg x kg(-1) x d(-1). We conclude that selenium content of PE preparations has a significant effect on SeGSH-Px activity in patients with CF. This form of selenium supply needs to be taken into account when selenium supplements are given to patients with CF.

[Conservative medical treatment of chronic pancreatitis]. / Die medizinisch-konservative Behandlung der chronischen Pankreatitis.

The conservative medical treatment of chronic pancreatitis entails dealing prevalently with exocrine and endocrine insufficiency, diet and pain. As steatorrhoea can cause malabsorption, it is advisable to reduce first the fat content of the diet and secondly to prescribe, where necessary, pancreatic enzymes. Several factors can lead to a poor therapeutic enzyme effect. Attention should be given to the pharmacological properties of the enzyme-preparation and to the secretion of acid in the stomach. An endocrine insufficiency is more difficult to treat compared to a classical diabetes mellitus, for lack of endocrine regulatory mechanisms. Pain is the consequence of several pathophysiological processes. Before initiating analgetic treatment, a minimal diagnostic program should be completed allowing the exclusion of those primary causes of pain which require an alternative approach such as interventional endoscopy or surgery.

Mismatch of duodenal deliveries of dietary fat and pancreatin from enterically coated microspheres.

Gastric emptying of dietary fat is affected by both chemical and physical factors; but when ingested as a free oil or an aqueous emulsion, fat may empty most rapidly immediately after the meal. In contrast, gastric transit of 1- to 3-mm spheres (like those of enterically coated pancreatins) is known to vary inversely with sphere diameter; and spheres leave the stomach initially slowly, if their diameter is > or = 1.6 mm. Our objective was to determine whether 2-mm microspheres of Pancrease would empty much more slowly than free or emulsified oil and whether 1.2-mm microspheres of Creon would empty as fast as free oil. We used a gamma camera to track the concurrent gastric emptying of 123I-labeled oil and 113mIn-labeled spheres of Pancrease or Creon in pancreatic-insufficient subjects with cystic fibrosis who ingested 20 g of free oil in spaghetti meals or 20 g of oil emulsified in a milk meal. We found that either type of oil emptied rapidly initially but slowed later, whereas either dosage form emptied slowly initially but rapidly later. Unexpectedly, the smaller spheres of Creon emptied about the same as Pancrease did after the spaghetti meal. For example, 50% of oil but < 25% of either dosage form had left the stomach by 90 min after the meals. Both dosage forms were lipophilic, forming aggregates in vitro. We concluded that the gastric emptying of either dosage form frequently lagged behind the emptying of oil from ordinary meals. We speculated that the similar transits of the 1.2-mm Creon and the 2-mm Pancrease resulted from aggregation of these microspheres in the presence of free oil.

High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.

BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.