Validation of an omega-3 substrate challenge absorption test as an indicator of global fat lipolysis.

INTRODUCTION: The coefficient of fat absorption (CFA) quantifies fat that remains in stool after digestion and is not a direct measure of lipolysis. CFA has been used to assess treatment of pancreatic insufficiency but does not correlate with pancreatic enzyme replacement therapy dose. We explored use of an omega-3 substrate absorption challenge test as a sensitive test of lipolysis and absorption. METHODS: We studied a novel microbially-derived lipase (SNSP003) employing an established surgical model commonly used to study the uptake of macronutrients, the exocrine pancreatic insufficient pig. Pigs were fed a high-fat diet and given a standardized omega-3 substrate challenge to test the effect of lipolysis on its absorption. Blood was drawn at 0, 1, 2, 4, 6, 8, 12, and 24 hours following the substrate challenge and was analyzed for omega-3 and total fat levels (c14:c24). SNSP003 was also compard to porcine pancrelipase. RESULTS: The absorption of omega-3 fats was significantly increased following administration of 40, 80 and 120 mg SNSP003 lipase by 51% (p = 0.02), 89%, (p = 0.001) and 64% (p = 0.01), respectively, compared to that observed when no lipase was administered to the pigs, with Tmax at 4 hours. The two highest SNSP003 doses were compared to porcine pancrelipase and no significant differences were observed. Both doses increased plasma total fatty acids (141% for the 80 mg dose (p = 0.001) and 133% for the 120 mg dose (p = 0.006), compared to no lipase) and no significant differences were observed between the SNSP003 lipase doses and porcine pancrelipase. CONCLUSION: The omega-3 substrate absorption challenge test differentiates among different doses of a novel microbially-derived lipase and correlates with global fat lipolysis and absorption in exocrine pancreatic insufficient pigs. No significant differences were observed between the two highest novel lipase doses and porcine pancrelipase. Studies in humans should be designed to support the evidence presented here that suggests the omega-3 substrate absorption challenge test has advantages over the coefficient of fat absorption test to study lipase activity.

Difference in Performance of EPI Pigs Fed Either Lipase-Predigested or Creon®-Supplemented Semielemental Diet.

Pancreatic enzyme replacement therapy (PERT) and fat predigestion are key in ensuring the optimal growth of patients with cystic fibrosis. Our study attempted to highlight differences between fat predigestion and conventional PERT on body composition of young pigs with exocrine pancreatic insufficiency (EPI). EPI and healthy pigs were fed with high-fat diet for six weeks. During the last two weeks of the study, all pigs received additional nocturnal alimentation with Peptamen AF (PAF) and were divided into three groups: H-healthy pigs receiving PAF; P-EPI pigs receiving PAF+PERT; and L-EPI pigs receiving PAF predigested with an immobilized microbial lipase. Additional nocturnal alimentation increased the body weight gain of EPI pigs with better efficacy in P pigs. Humerus length and area in pigs in groups L and P were lower than that observed in pigs in group H (p value 0.005-0.088). However, bone mineral density and strength were significantly higher in P and L as compared to that of H pigs (p value 0.0026-0.0739). The gut structure was improved in P pigs. The levels of neurospecific proteins measured in the brain were mainly affected in P and less in L pigs as compared to H pigs. The beneficial effects of the nocturnal feeding with the semielemental diet in the prevention of EPI pigs' growth/development retardation are differently modified by PERT or fat predigestion in terms of growth, bone properties, neurospecific protein distribution, and gut structure.

Pancrelipase with branched-chain amino acids for preventing nonalcoholic fatty liver disease after pancreaticoduodenectomy.

BACKGROUND: To investigate the efficacy of the early administration of pancreatic enzymes combined with an elemental diet of branched-chain amino acids (BCAA) for nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD). METHODS: Data were obtained for 122 consecutive patients who underwent PD. High-titer pancrelipase and a BCAA-rich solution was administered via a feeding tube beginning on postoperative day (POD) 4 (PB group: n = 31). Ninety-one patients who underwent PD prior to this treatment were included as a control group (n = 91). The radiological changes in the liver and pancreatic parenchyma related to NAFLD before and after PD were assessed on CT, and trends in liver function and nutritional status were evaluated over the 180-day post-PD period. RESULTS: Patient background factors, histopathology and operation-related variables were not significantly different between the two groups. Liver attenuation [56 HU (-13 to 73) vs. 61 (26 to 69), p = 0.015] and the liver-to-spleen attenuation ratio [1.12 (-0.38 to 1.48) vs. 1.24 (0.89 to 1.49), p = 0.018] were significantly decreased, and the pancreatic parenchyma was significantly thinner [17.9 mm (8.6-25.3) vs. 13.9 mm (2.5-23.2), p = 0.02] in the control group at 3 months after the operation. The alanine aminotransferase levels were also higher in the control group (p < 0.05, at POD 14, 30, 60 and 90), while the serum albumin (p < 0.05, at POD 30, 60 and 180) and total protein (p < 0.05, at POD 30, 60, 90 and 180) levels were significantly better in the PB group. CONCLUSIONS: Early supplementation of high-titer pancrelipase combined with a BCAA-rich elemental diet reduces the risk of NAFLD after PD.

Surgical and Medical Treatment of Pyloric and Duodenal Pythiosis in a Dog.

A 5 yr old, male, neutered mixed-breed dog was referred for persistent vomiting 2 wk following a pyloric biopsy for a pyloric outflow obstruction. Histopathology at the time of initial surgery was suggestive of pythiosis. Following referral, the dog underwent radical surgical treatment with a Billroth II procedure, partial pancreatectomy, and cholecystoduodenostomy. Histopathology and serology confirmed the diagnosis of pythiosis and medical treatment consisting of itraconazole and terbinafine was started postoperatively. Serology titers were checked again at 8, 12, and 24 wk postoperatively revealing a positive response to treatment and no reoccurrence of pythiosis. Since surgery, the patient experienced waxing and waning elevations of liver values and laparoscopic liver biopsies 10 mo postoperatively revealed hepatic cirrhosis with fibrosis, bile duct hyperplasia, and chronic inflammation. This report documents successful treatment of pyloric/duodenal pythiosis and the long-term (17 mo) consequences associated with the Billroth II, partial pancreatectomy, and biliary rerouting in the dog.

Delayed small bowel transit in children with cystic fibrosis and pancreatic insufficiency.

OBJECTIVE: Gastrointestinal disturbances are common in people with cystic fibrosis (CF); however, motility studies in this population have yielded inconsistent results. This study examined gastric emptying (GE) and small bowel transit (SBT) time in children with CF and pancreatic insufficiency compared with a healthy adult reference group. METHODS: Participants consumed an 8-ounce liquid test meal (approximately 550 calories, 32 g of fat) labeled with 300 µCi 99m technetium (Tc) sulfur colloid. Subjects with CF received a standard dose of pancreatic enzymes before consuming the test meal. GE and SBT were measured using a standard nuclear medicine scan. GE was determined after correcting for 99mTc decay in both anterior and posterior images. SBT was determined by following the movement of the tracer from the stomach to the cecum. The percentage arrival of total small bowel activity at the terminal ileum and cecum/ascending colon at 6 hours was used as an index of SBT. A 1-way analysis of covariance was performed for comparisons between groups after adjustment for age, sex, and body mass index. RESULTS: Subjects with CF (n = 16) had similar GE compared with the healthy reference group (n = 12); however, subjects with CF had significantly prolonged SBT time. At 6 hours, 37.2% ± 25.4% (95% CI 23.7-50.7) of the tracer reached the terminal ileum and colon compared with 68.6% ± 13.1% (95% CI 60.2-76.9) for the reference group (P < 0.001). After controlling for sex, age, and body mass index, this difference remained statistically significant (F = 12.06, adjusted R = 0.44, P < 0.002). CONCLUSIONS: Children with CF and pancreatic insufficiency had unaltered GE but delayed SBT time when taking pancreatic enzymes.

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.

Efficacy of lower than standard doses of pancreatic enzyme supplementation therapy during acid inhibition in patients with pancreatic exocrine insufficiency.

GOAL: To compare, during strong acid inhibition with omeprazole, the effect of 2 different doses of an enteric-coated pancreatic enzyme preparation on fecal fat excretion and abdominal symptoms in patients with exocrine insufficiency due to chronic pancreatitis (CP). BACKGROUND: Treatment with pancreatic enzymes reduces fecal fat excretion in patients with CP but is rather unsuccessful due to irreversible lipase inactivation at pH below 4. STUDY: Sixteen patients with CP (3 women, 13 men; age 53+/-3 y) participated in this randomized double blind 2-way cross over study. Fecal fat excretion and fat intake were measured and abdominal symptoms (visual analog scales) were scored during a 2 weeks control period, during omeprazole 60 mg+pancreatic enzymes 10,000 Fédération Internationale Pharmaceutique IU lipase tid (treatment A) for 2 weeks and during omeprazole 60 mg+pancreatic enzymes, 20,000 Fédération Internationale Pharmaceutique IU lipase tid (treatment B) for 2 weeks. RESULTS: During acid inhibition with enzyme supplementation fecal fat excretion was significantly (P<0.01) reduced compared with control: 18+/-7 and 18+/-5 g/24 h versus 36+/-8 g/24 h for treatment A, B, and control, respectively. Abdominal symptom score and general well being improved significantly (P<0.05) during treatments A and B versus control. No differences in fat excretion or symptoms scores between treatments A and B were observed. CONCLUSIONS: During strong acid inhibition, lower than recommended oral doses of pancreatic enzymes are therapeutically effective with respect to fat absorption and symptom reduction.

Ranitidine and omeprazole as adjuvant therapy to pancrelipase to improve fat absorption in patients with cystic fibrosis.

BACKGROUND: Inadequate treatment of pancreatic insufficiency in patients with cystic fibrosis (CF) causes malabsorption of nutrients with significant sequelae. The objective of this study was to measure the effect of acid suppressant therapy on fat absorption in patients with CF who received a pH-sensitive, enteric-coated microtablet enzyme product. METHODS: A double-blind, placebo-controlled crossover study of 12 children and 10 adults with pancreatic insufficient CF was performed. All subjects were receiving pancrelipase therapy (Pancrease MT10 and MT16; Ortho-McNeil, Springhouse, PA, U.S.A.) and for the study also received either placebo or ranitidine (Zantac; Glaxo-Wellcome, Research Triangle Park, NC U.S.A.) 5 mg/kg or 10 mg/kg daily. The adult subjects also received omeprazole therapy (Prilosec; AstraZeneca/Merck, Wilmington, DE, U.S.A.), 20 mg daily, as adjuvant therapy to pancreatic enzymes. Serial 3-day fat-balance studies were performed in the Clinical Research Center. The data were analyzed using individual paired t tests that compared each treatment with placebo and two repeated-measures, general linear model F tests. RESULTS: The linear model for all subjects showed no overall adjuvant drug effect on fat absorption, P = 0.32. A second linear model F test analysis of adult subjects, comparing all four drug treatments (placebo, ranitidine 5 and 10 mg/kg daily and omeprazole), also showed no difference in fat absorption, P = 0.15. Paired t test subgroup analysis of the adults showed an improvement of 4.97% (P = 0.003) in mean fat absorption comparing low-dose ranitidine to placebo. All other t test analyses showed no significant change in fat absorption between placebo and acid suppressant treatment. There was marked intersubject and intrasubject variability in fat absorption. CONCLUSIONS: No overall significant improvement in fat absorption could be demonstrated with adjuvant therapy. Fat absorption measured by 3-day fat-balance studies varied greatly even when comparing the same subject for placebo and baseline treatments, despite identical dietary fat and enzyme intakes. The large variability limited our ability to test for a difference in fat absorption and has significant implication for the use of this test, considered the gold standard, for determining enzyme dosage adequacy.

Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen.

OBJECTIVE: To prospectively evaluate the biochemical status of vitamins A, D, and E in children with cystic fibrosis (CF). SUBJECTS: A total of 127 infants identified by the Colorado CF newborn screening program. DESIGN: Vitamin status (serum retinol, 25-hydroxy vitamin D, ratio of alpha-tocopherol/total lipids) and serum albumin were assessed at diagnosis (4 to 8 weeks), ages 6 months, 12 months, and yearly thereafter, to age 10 years. RESULTS: Deficiency of 1 or more vitamins was present in 44 (45.8%) of 96 patients at age 4 to 8 weeks as follows: vitamin A 29.0%, vitamin D 22.5%, and vitamin E 22.8%. Of these patients with initial deficiency, the percent that was deficient at 1 or more subsequent time points, despite supplementation, was vitamin A 11.1%, vitamin D 12.5%, and vitamin E 57.1%. Of the initial patients with vitamin sufficiency, the percent who became deficient at any time during the 10-year period was as follows: vitamin A 4.5%, vitamin D 14.4%, and vitamin E 11.8%. The percent of patients deficient for 1 or more vitamins ranged from 4% to 45% for any given year. CONCLUSIONS: Despite supplementation with standard multivitamins and pancreatic enzymes, the sporadic occurrence of fat-soluble vitamin deficiency and persistent deficiency is relatively common. Frequent and serial monitoring of the serum concentrations of these vitamins is therefore essential in children with CF.

Assessment of the effectiveness of drug therapies on nutritional status in the elderly: "concerning a randomised, double-blind clinical study of the activity of pancreatic extracts and a placebo during the renutrition of elderly subjects suffering from protein caloric undernutrition".

AIMS: to study, versus placebo, the value of administering pancreatic extracts in elderly subjects suffering from denutrition. METHODS: 52 subjects over 70 years of age, living in the Toulouse region of France, were included in this study. Each subject was required to present with an impaired nutritional status of their food intake, anthropometric and laboratory markers. RESULTS: among the 52 patients included in the study, 26 received the placebo and 26 received a pancreatic extract (Créon 12,000). 88% of these patients were women and 12% were men, the mean age of patients was 87+/-6 years. The groups were comparable at entry into the study. Nutritional intake increased in the two groups. There was a non-significant increase in body weight in the treated group when compared with the placebo group. DISCUSSION: we think that in the future, it would be preferable to conduct studies in convalescent subjects, reducing the frequency of nutritional assessments (food intake on D0 and D90, to reduce interference with the patient's habits.