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PubMed1982

Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption.

The clinical presentation, courses, and sweat chloride values of 72 CF patients with normal fat absorption are described. In general, these patients had milder clinical symptoms and a lower mean sweat chloride value than their counterparts with steatorrhoea. Pulmonary function tests, including FEV1, FVC, FEF25%-75%, PaO2, and RV/TLC%, were significantly better in patients with normal fat absorption compared with both male and female patients who had steatorrhoea. The maintenance of better pulmonary function, coupled with the low mortality, suggests that patients without steatorrhoea have a better prognosis. This difference remains unexplained, but may be contributed to by nutritional, genetic, or pancreatic factors.

Adolescent↗
PubMed1998

Biochemical assessment of the nutritional status of cystic fibrosis patients treated with pancreatic enzyme extracts.

We examined the protein and fat nutritional status of 65 cystic fibrosis patients aged 4-26 y (x +/- SD: 11.2 +/- 5.6 y). Patients were treated with pancreatic enzyme extracts to improve nutrient absorption; in addition, most patients were supplemented with vitamins A and E. Results were compared with those in a control group of 39 subjects aged 5-29 y (x: 14.3 +/- 5.6 y) with no digestive diseases or nutritional deficiencies. Protein determination showed low albumin concentrations in 42% of the cystic fibrosis patients and decreased blood concentrations of retinol binding protein in 12% of the patients. Lipoprotein components were characterized by decreased cholesterol concentrations in 25% of the cystic fibrosis group. Also, mean concentrations of apolipoprotein A-I were significantly lower in the cystic fibrosis group than in control subjects. The results of fatty acid status, expressed in relative (%) and absolute (mg/L) values, showed concentrations of essential fatty acids, represented by linoleic and arachidonic acids, to be significantly decreased in cystic fibrosis patients; this decrease was markedly significant for fatty acid status expressed in absolute values, especially in the cholesteryl ester subfraction. Serum retinol and alpha-tocopherol concentrations were lowered by 8% and 46% in cystic fibrosis patients and control subjects, respectively: retinol, 1.80 +/- 0.50 and 2.37 +/- 0.60 micromol/L, P < 0.001, and alpha-tocopherol, 18.1 +/- 8.7 and 25.7 +/- 5.0 micromol/L, P < 0.001. In conclusion, despite regular treatment with pancreatic enzyme replacements, neither protein nor fat malnutrition in cystic fibrosis patients was completely corrected.

Adolescent↗
PubMed1994

Comparison of weight-based dosages of enteric-coated microtablet enzyme preparations in patients with cystic fibrosis.

Twenty-one stable hospitalized cystic fibrosis patients with malabsorption syndrome participated in an open-label crossover clinical trial to evaluate the efficacy of two-period dosing regimens of a pancreatic microtablet enzyme preparation in the treatment of steatorrhea. Standard dosing consisted of 500 U lipase/kg body weight/meal, 250 U lipase/kg body weight/snack; high dosing consisted of 1,500 U lipase/kg body weight/meal, 750 U lipase/kg body weight/snack. Doses were determined by units of lipase/kg body weight to provide dosing consistency among patients of varying size. Each patient was on a regular diet of approximately 100 g of fat per day. Two separate, 72-h stool collections were performed between markers. A significant difference in mean percentage fat absorbed between the standard dose and the high dose was found (86% versus 91%, p < 0.05). Subjects were then stratified into two groups, based on the grams of fecal fat eliminated (GFFE) as follows: Group 1 with < or = 7 GFFE/24 h on both dosages (n = 7) and Group 2 with > 7 GFFE/24 h on either dose (n = 14). A significant difference (p < 0.05) between Group 1 (96%) and Group 2 (88%) was noted in the percentage fat absorbed while on the high dose. Fat absorption improved from 81% to 88%, (p < 0.05) in Group 2. During the study period, the adverse reactions of constipation or elevated serum uric acid levels were not observed. The increased doses of pancreatic enzymes resulted in improved correction of steatorrhea.

Absorption↗
PubMed2005

Update on the evaluation of pancreatic exocrine status in cystic fibrosis.

PURPOSE OF REVIEW: Pancreatic functional status has a very strong effect on outcome in cystic fibrosis and pancreatic insufficiency requires lifelong treatment with pancreatic enzymes. Traditionally, clinical signs and symptoms have been used to decide who should be treated with pancreatic enzyme supplements; however, recent studies show that patients with cystic fibrosis are both undertreated and over-treated using this approach. This paper reviews recent progress in the development of noninvasive, indirect tests of pancreatic function for use as diagnostic tools for patients with cystic fibrosis. RECENT FINDINGS: Breath testing using C-labeled fat and measurement of several pancreatic enzymes in stool, such as chymotrypsin, lipase, and elastase have been explored as ways to define pancreatic functional status. Fecal elastase has good sensitivity, specificity, and positive and negative predictive value for defining severe pancreatic insufficiency in patients with cystic fibrosis and appears to be more useful than measurement of other fecal enzymes. Its role in milder pancreatic insufficiency and in disease states other than cystic fibrosis, such as chronic pancreatitis, is less clear. SUMMARY: Several new noninvasive, indirect tests of pancreatic function have been developed to aid in the definition of pancreatic functional status in patients with cystic fibrosis. An objective measure of pancreatic functional status should be obtained in all patients with cystic fibrosis, and the recent development of new screening tools such as fecal elastase makes this feasible.

Breath Tests↗
PubMed2006

Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients.

OBJECTIVES: Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. METHODS: We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. RESULTS: There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% +/- 24.9% and 17.8% +/- 13.6%, respectively, whereas the mean stool weight decreased by 517 +/- 362 g. CONCLUSIONS: TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

Adolescent↗
PubMed1995

Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression.

The most common mutation in the gene associated with cystic fibrosis (CF) causes deletion of phenylalanine at residue 508 (delta F508) of the gene product called CFTR. This mutation results in the synthesis of a variant CFTR protein that is defective in its ability to traffic to the plasma membrane. Because earlier studies showed delta F508-CFTR retains significant phosphorylation-regulated chloride (Cl-) channel activity, processes capable of restoring the mislocalized delta F508-CFTR to the correct cellular destination may have therapeutic benefit. Here we report one such process that involves overexpression of the mutant protein and appears to result in the escape of a small amount of delta F508-CFTR to the plasma membrane. In recombinant cells where expression of delta F508-CFTR is controlled by the metallothionein promoter, this effect can be brought about by treatment with sodium butyrate. Although cAMP-activated Cl- channel activity could also be detected in immortalized human airway epithelial cells homozygous for the delta F508 mutation at the single cell level, treatment with butyrate did not generate a measurable cAMP-stimulated Cl- current in polarized monolayers of primary CF airway epithelia. However, the observation that overexpression can effect the presence of recombinant delta F508-CFTR at the plasma membrane suggests that perhaps other butyrate-like compounds that are more potent and more specific for the promoter of the CF gene may be efficacious in alleviating the Cl- channel defect associated with CF.

Animals↗
PubMed2000

Clinical features associated with a delayed diagnosis of cystic fibrosis.

BACKGROUND: The majority of patients with cystic fibrosis (CF) are diagnosed in the first decade of life. In a small number of patients, the diagnosis is not made until later. OBJECTIVE: In this study, the clinical and genetic features of patients diagnosed after the age of 10 were examined. METHODS: All living patients in Northern Ireland diagnosed prior to 1983, when neonatal screening was introduced, were studied. A total of 103 patients were identified of whom 18 were diagnosed after the age of 10. The relationships between late diagnosis and clinical presentation, sputum microbiology, pancreatic sufficiency, nutritional status, genotype and distance from the regional CF centres was determined by multiple regression analysis. RESULTS: All 18 late-diagnosed patients had a sweat (chloride >70 mmol/l). Late diagnosis was significantly related to carriage of the R117H mutation (r(2) = 0.45) and pancreatic sufficiency (r(2) = 0.37). There was a weak relationship with pulmonary function (r(2) = 0.09). CONCLUSIONS: In Northern Ireland, late diagnosis in mainly associated with pancreatic function and carriage of the R117H mutation.

Adolescent↗
PubMed1980

Gastric emptying and lingual lipase activity in cystic fibrosis.

To identify gastric factors likely to contribute to fat maldigestion and malabsorption in cystic fibrosis (CF), gastric emptying time, secretion rate, and preduodenal lipolytic activity were studied. Gastric emptying of a liquid test meal and gastric acid secretion were determined in five CF teenagers with pancreatic insufficiency and in five healthy controls. During the first hr, the rate of gastric emptying exhibited a linear pattern in both CF patients and controls. Neither the emptying time nor the gastric secretion rate was different. Lingual lipase activity was measured in eight other CF patients with pancreatic insufficiency and in eight controls. Lipase activity was higher (P less than 0.05) in CF patients than in controls with values (mean +/- S.E.) of 34.48 +/- 11.59 and 12.65 +/- 5.60 mumole butyric acid min-1 ml-1, respectively. No correlation with age or body surface was observed. Intragastric lipolysis of a butterfat triglyceride test meal was fast in both groups, but more extensive (P less than 0.05) in CF patients than in controls. The data show that in CF with pancreatic insufficiency, gastric factors contributing to the first step of fat digestion are preserved. In fact, lingual lipase activity was found to be increased, and a more complete intragastric lipolysis was documented.

Adolescent↗
PubMed1997

Plasma concentrations of cholecystokinin and neurotensin in patients with cystic fibrosis.

BACKGROUND: Regulation of pancreatic exocrine secretion is controlled by vagovagal reflexes and hormones. A negative feedback control mechanism exists between the intraduodenal protease concentration and pancreatic enzyme secretion. In man cholecystokinin (CCK) is the major regulator of postprandial pancreatic enzyme secretion. There is a 50% reduction of meal-stimulated secretion by the specific CCK receptor antagonist loxiglumide, whereas atropine completely blocks postprandial secretion. Neurotensin is released postprandially by nerval reflexes and fat. It has been claimed that both hormones are increased in patients with pancreatic insufficiency. METHODS: We investigated CCK and neurotensin levels in patients with cystic fibrosis and pancreatic insufficiency. In 35 patients (2-24 years old) with cystic fibrosis with steatorrhea and in 15 patients (1.5-24 years old) with cystic fibrosis without pancreatic insufficiency pre- and post-prandial CCK and neurotensin plasma levels were measured 3 days after pancreatic enzyme therapy had been withdrawn. Nine patients (3-14 years old) who had no complaint of abdominal disease served as controls. RESULTS: Basal and postprandial CCK plasma levels did not differ statistically in the three groups, whereas basal and postprandial neurotensin levels were significantly increased in the cystic fibrosis groups. The severity of the disease had no effect on the neurotensin levels. CONCLUSIONS: Cystic fibrosis patients with severe pancreatic insufficiency did not have increased CCK plasma levels, suggesting that a CCK-mediated feedback mechanism of pancreatic enzyme secretion does not operate in our patients. In contrast, basal and postprandial neurotensin plasma levels were significantly increased in patients with cystic fibrosis but were independent of the severity of the pancreatic insufficiency.

Adolescent↗
PubMed1992

The origin of and subcellular mechanisms causing pancreatic bicarbonate secretion.

In recent years, there has been a rapid growth in knowledge about the subcellular mechanisms involved in pancreatic ductal secretion of bicarbonate. The mechanisms governing anion transport across the luminal membrane of duct cells have been well characterized. Evidence suggests that the cystic fibrosis transmembrane conductance regulator is a cyclic adenosine monophosphate-regulated Cl- conductance in the luminal membrane that plays a pivotal role in ductal bicarbonate secretion by recirculating the Cl- imported into duct cells through Cl(-)-HCO3- exchange. The mechanisms governing ion transfer across the basolateral plasma membrane of duct cells are less well defined. There is some evidence suggesting that secretin may cause exocytotic insertion of proton pumps into the basolateral plasma membrane. Once inserted into the plasma membrane, proton pumps could engage in primary active electrogenic H+ ion transport to interstitial tissue while secondary active HCO3- secretion occurs over the luminal membrane through Cl(-)-HCO3- exchangers coupled in parallel with the cystic fibrosis transmembrane conductance regulator. These and other subcellular phenomena related to ductal secretory function are reviewed.

Animals↗
PubMed2004

[Cystic fibrosis from the exocrine pancreatic point of view].

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder in Caucasians and is characterized by a wide variability of clinical expression. The vast majority of patients with CF have pancreatic insufficiency (PI) requiring exogenous pancreatic enzyme replacement therapy with meals. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein that functions as a chloride channel and is regulated by cAMP. CFTR gene mutations may be classified as severe or mild with respect to pancreatic function status. Patients homozygous for two severe mutations experience severe clinical presentation including PI. Patients carrying at least one mild mutation are considered to be pancreatic sufficient (PS) and carry an overall prognosis that is vastly superior to CF patients with PI. Thus mild mutations appear to be dominant, providing enough functional CFTR to avoid PI. Five general mechanisms have been proposed which describe how CFTR gene mutations influence CFTR-mediated chloride secretion. Classes 1, 2, and 3. that confer little or no chloride channel function, confer the PI phenotype. In contrast, classes 4 and 5 allow CFTR residual function, that are expected to confer the less severe PS phenotype. Recent advances in mutation detection technology and the demonstration of characteristic abnormalities in trans-epithelial potential difference measurements, have expanded the spectrum of diseases associated with the CFTR mutant genes, and paradoxically, in some ways complicated rather than simplified CF diagnosis. Until new diagnostic criteria is conclusively determined, CF diagnosis should be made on clinical rather than laboratory grounds.

Cystic Fibrosis↗