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PubMed1993

Localization of expression of the cystic fibrosis gene in human pancreatic development.

Cystic fibrosis (CF) is a disease that affects the function of specialized epithelial cells within the lungs, gut, pancreas, sweat glands, and male genital ducts. Following the cloning of the CF gene, it is possible to examine tissue-specific expression of this gene. To investigate the onset of the CF disease process, expression of the CF gene in midtrimester human fetal tissues has been analyzed by in situ hybridization using antisense RNA probes. The major site of CF gene expression at this stage of development is in the pancreas. Within the pancreas, CF mRNA is seen to be largely restricted to the epithelium of intralobular and small interlobular ducts.

Cystic Fibrosis↗
PubMedDate not supplied

Pancreatic disease in children and young adults: evaluation with CT.

In children with pancreatic disease, computed tomography (CT) has a primary role in the evaluation of pancreatitis, trauma, and malignancy. At CT, pancreatic abnormalities may manifest as pancreatic enlargement (tumor, acute pancreatitis), pancreatic atrophy (cystic fibrosis, chronic pancreatitis), cystic lesions (pseudocysts, congenital simple cysts, autosomal dominant polycystic kidney disease, von Hippel-Lindau disease, cystic fibrosis, cystic neoplasms), or fatty replacement (cystic fibrosis, Shwachman-Diamond syndrome, history of steroid therapy, Cushing syndrome, Johanson-Blizzard syndrome, obesity). CT is the best modality for evaluation of pancreatitis, allowing detection of pancreatic abnormalities as well as abnormal extrapancreatic fluid collections. In children who have undergone blunt abdominal trauma, CT has been shown to be the best initial imaging study, being more sensitive than ultrasound for detection of pancreatic injury. In neoplastic conditions, CT demonstrates the extent of disease, enables characterization of the tissue components of the tumor, and allows accurate posttreatment follow-up. Although the various diseases of the pancreas may have overlapping appearances at CT, the correct diagnosis can often be made on the basis of the CT findings in combination with the clinical history, laboratory data, and the patient's age.

Adolescent↗
PubMed1990

Rationale for antioxidant therapy in pancreatitis and cystic fibrosis.

The overlapping features of the acquired diseases acute pancreatitis and chronic pancreatitis on the one hand, and of chronic pancreatitis and pancreatic involvement in the congenital condition cystic fibrosis on the other, suggest that the basic mechanism of pancreatic injury may be the same in each illness. We propose that pancreatic oxidant stress is the common denominator and, furthermore, that this is facilitated by a shortfall of micronutrient antioxidants in the face of heightened free radical activity through different sources. If so antioxidant supplements should alleviate symptoms. This deduction was supported by an exploratory dose-seeking study that spanned five years in 20 patients with recurrent (non-gall stone) acute or chronic pancreatitis and confirmed by a 20-week double-blind placebo-controlled crossover trial of the successful combination (daily doses of 600 micrograms organic selenium, 0.54 g vitamin C, 9000 IU B-carotene, 270 IU vitamin E and 2 g methionine) in a further 20 cases. A randomised trial of glutathione precursors, given intravenously for 24 hours after admission in patients with a first attack of acute pancreatitis, is in progress. Long-term trials of oral antioxidant formulas are planned in patients with cystic fibrosis.

Antioxidants↗
PubMed2003

Longitudinal follow-up of exocrine pancreatic function in pancreatic sufficient cystic fibrosis patients using the fecal elastase-1 test.

BACKGROUND: A progressive decline in pancreatic function is possible in cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. The secretin-cholecystokinin test is invasive and not acceptable as a repeatable procedure for children. Steatorrhea, conversely, has low sensitivity. Therefore, the aim of the present study was to evaluate the usefulness of the noninvasive fecal elastase-1 (E1) test for the longitudinal assessment of exocrine pancreatic function (EPF) in pancreatic-sufficient (PS) CF patients. METHODS: One hundred eighty-four CF patients were included in the study. In all subjects, E1 concentrations and fecal fat excretion were measured. PS patients were followed for 5 years. RESULTS: At the beginning of the study, 35 (19.0%) CF patients were PS, and 32 (17.4%) had normal E1 concentrations. Longitudinal measurements of E1 concentrations in PS patients with CF demonstrated stable enzyme output in 27 and gradual decrease in 8. The decrease was rapid in five infant patients and gradual in three older patients. The decrease of E1 concentrations preceded the appearance of steatorrhea in all eight subjects. CONCLUSIONS: The decline of EPF in patients with CF appears more frequently during the first months and years of life. However, late PS to pancreatic-insufficient (PI) conversion is also possible. The appearance of maldigestion is preceded by the decrease of fecal E1 concentration. Thus, the fecal E1 test is a helpful screening tool for the longitudinal assessment of declining EPF in PS patients with CF to demonstrate pancreatic deterioration. In suspected patients, fecal fat excretion should be assessed.

Adolescent↗
PubMed2005

A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice.

BACKGROUND & AIMS: Cystic fibrosis transmembrane regulator (CFTR) gene mutations are associated with pancreatic insufficiency and pancreatitis. Chronic pancreatitis, including cystic fibrosis-related disease, may exist as a continuum between acute and chronic disease and may manifest as recurrent pain. We hypothesized that cftr(m1UNC) (-/-) mice, which have no evidence of chronic pancreatitis, are susceptible to developing acute pancreatitis. METHODS: We used a cerulein hyperstimulation model of acute pancreatitis and measured histological changes, tissue edema, neutrophil infiltration, inflammatory mediators' mRNA expression, apoptosis markers, and pancreatic trypsin and serum lipase activities. Additionally, we quantitated in vivo pancreatic secretion and pancreatic digestive enzymes. RESULTS: Multiple proinflammatory cytokine genes were constitutively overexpressed in cftr (-/-) pancreas compared with wild-type mice. During acute pancreatitis, cftr (-/-) mice developed more severe acute pancreatitis than wild-type, as indicated by greater pancreatic edema, neutrophil infiltration, mRNA expression of multiple inflammatory mediators, and less apoptotic cell death. In contrast to wild-type mice, cftr (-/-) mice had blunted increases in pancreatic trypsin and serum lipase activities, but similar percentages of pancreatic trypsinogen activation. Finally, cftr (-/-) mice had less in vivo pancreatic secretion in response to cholecystokinin octapeptide and reduced pancreatic digestive enzyme protein and mRNA levels, thus suggesting mild pancreatic insufficiency. CONCLUSIONS: A baseline proinflammatory state and an antiapoptotic phenotype may sensitize cftr (-/-) mice to developing more severe acute pancreatitis with an exuberant pancreatic inflammatory response. Cftr (-/-) mice have mild pancreatic insufficiency, which partially explains the blunted increase of pancreatic and serum digestive enzymes during acute pancreatitis. These findings may explain the susceptibility to acute pancreatitis in persons with classic and nonclassic cystic fibrosis.

Acute Disease↗
PubMed2001

Cholesterol esterase activities in commercial pancreatic enzyme preparations and implications for use in pancreatic insufficient cystic fibrosis.

BACKGROUND: Although clinical symptoms in pancreatic insufficiency are often dramatically improved by pancreatic preparations, these often fail to normalize biochemical indicators of malabsorption. It seemed relevant, therefore, to investigate the amounts of cholesterol esterase in these preparations and, using in-vitro methods, some of the activities of this enzyme. The enzyme is just as physiologically important as lipase in accomplishing lipid digestion and absorption. METHODS: Cholesterol esterase was assayed in commercial pancreatic extract preparations, lyophilized pig pancreas and human duodenal fluid. The in-vitro activities of the enzyme were also investigated on single and mixed dietary substrates. RESULTS: Other than Creon, the commercial preparations showed negligible cholesterol esterase activities, whereas considerable activities were found in pancreatic tissue and duodenal fluids. In-vitro, pig cholesterol esterase was confirmed to be dependent on 3-hydroxy bile salt concentration for hydrolysis and synthesis and that the rate for hydrolysis greatly exceeds that of synthesis in normal concentrations of bile salts. However, with mixed lipid substrates, no bile salt concentration was found at which hydrolysis or synthesis predominates. CONCLUSIONS: When pancreatic or hepato-biliary function is compromised, optimum lipid hydrolysis may not be achieved in therapeutic use, and the pig enzyme may perform differently to the human enzyme. In-vivo trials may reveal whether augmentation of the commercial products with this enzyme would be worthwhile.

Absorption↗
PubMed1979

[Determination of the ribonuclease activity of the duodenal contents of children as a test in the differential diagnosis of cystic fibrosis and pancreatic exocrine insufficiency].

Ribonuclease activity was determined in the duodenal contents of healthy children, in children with cystic fibrosis and with pancreatic exocrine insufficiency. Assays were made at 7.0, in 0.05 M buffer without and with 0.35 M NaCl. The ratio of activity in 0.35 M NaCl to that in buffer alone was found to be 2.4 +/- 1.3 for children with cystic fibrosis as compared with 12 +/- 5 for the control group and children with pancreatic exocrine insufficiency.

Amylases↗
PubMed1995

Cystic fibrosis and pancreatic cancer cells synthesize and secrete MUC1 type mucin gene product.

The purpose of this study was to determine the biochemical and molecular characteristics of mucin synthesized by cystic fibrosis cells (CFPAC-1), a pancreatic cancer cell line derived from a patient with cystic fibrosis, and pancreatic cancer (SW-1990) cell lines. High molecular weight glycoproteins (HMG) were quantified by [3H]-glucosamine labeling and chromatography on sepharose CL-4B. Mucin gene expression was determined by using cDNA probes for 2 distinct intestinal mucins (MUC2 and MUC3) and one stomach mucin (MUC1). The specific mucin core epitopes were confirmed by immunoblots using antibodies that recognize T, Tn, sialosyl Tn, MUC1, MUC2, and MUC3. The results of these experiments demonstrate that CFPAC-1 cells contained 1.25 fold and 1.4 fold more HMG in the membrane and cytosolic fractions, however, secreted 4-fold more HMG into the medium compared to SW-1990 cells. The HMG of SW-1990 was found to be mucinous in nature and not proteoglycans, as it was not susceptible to hyalurinidase, heparinase and chondroitinase ABC. The HMG of CFPAC-1 was also predominantly (80%) mucinous but with small amounts of proteoglycans. mRNA and immunoblot analysis suggest that these CFPAC-1 and SW-1990 cells predominantly express MUC1 apomucin, small amounts of MUC2 apomucin, and no MUC3. Pulse chase labeling and immunoprecipitation of MUC1 type mucin using the 139H2 monoclonal antibody demonstrated that different sizes of mucin gene product were present in both cell lines, corresponding to the known length polymorphism of this mucin. Both T and Tn antigens were significantly higher in CFPAC-1 and SW-1990 cells as compared to sialosyl Tn antigen. These findings were associated with the increased activities of polypeptidyl N-acetylgalactosaminyl transferase and b1,3-galactosyltransferase. These investigations demonstrate for the first time that cystic fibrosis cells (CFPAC-1) secrete and synthesize high amounts of mucin which is associated with high levels of MUC1 mRNA, low levels of MUC2 mRNA and non detectable MUC3 mRNA.

Amino Acid Sequence↗
PubMed1983

Architecture of human pancreas: implications for early changes in pancreatic disease.

An increased proportion of ductulelike structures, sometimes dilated, occurs in association with pancreatic adenocarcinoma, chronic pancreatitis, cystic fibrosis, and pancreatic ectasia associated with conditions such as uremia. This frequently is interpreted as ductular proliferation, implying origin in ductal elements. Recent animal studies have provided an altered view of pancreatic architecture that is consistent with acinar dedifferentiation leading to the ductulelike structures, or tubular complexes. The architecture of pancreas from organ donors was studied by light and scanning electron microscopy and by wax reconstruction of serial sections. It is concluded that the zymogen granule-containing cells of normal human exocrine pancreas are arranged as branching tubules that vary in diameter and curve acutely. The tubules frequently end blindly to form acinar structures; less frequently they anastomose. This arrangement is consistent with the interpretation that tubular complexes associated with pancreatic disease result from dedifferentiative changes in acinar cells. Tubular complexes may reflect a defect or defects common to pancreatic disease rather than ductular proliferation specific to each one.

Adolescent↗
PubMed2002

Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis.

BACKGROUND & AIMS: Pancreatitis is known to occur in some patients with cystic fibrosis (CF), but the prevalence, natural history, and genotypic basis are unclear. We examined a well-defined cohort of patients with CF to answer these questions. METHODS: Patients with CF were identified from a computerized database (1966-1996). Chart audit identified all patients with CF and pancreatitis. RESULTS: Among 1075 patients with CF, 937 (87%) were pancreatic insufficient at diagnosis, 28 (3%) were pancreatic sufficient but developed pancreatic insufficiency after diagnosis, and 110 (10%) have remained pancreatic sufficient. No patients with pancreatic insufficiency developed pancreatitis. Nineteen patients (17.3%) with pancreatic sufficiency experienced one or more attacks of pancreatitis. The mean age at diagnosis of pancreatitis was 22.7 +/- 10.3 years (range, 10-35 years), and pancreatitis was recognized before the diagnosis of CF in 6 patients (32%). The diagnosis of CF in pancreatic-sufficient patients, with and without pancreatitis, was established at a significantly older age than in those with pancreatic insufficiency (P < 0.0001). Genotyped patients with pancreatic insufficiency carried 2 severe mutant alleles. All genotyped patients with pancreatic sufficiency and pancreatitis carried at least one mild mutation. No specific genotype was predictive of pancreatitis. CONCLUSIONS: Patients with CF with pancreatic sufficiency carry at least one mild mutant allele and are at a significant risk of developing pancreatitis. Symptoms of pancreatitis may precede the diagnosis of CF. Pancreatitis is associated with an otherwise mild CF phenotype.

Adult↗
PubMed1985

Effect of cimetidine on enzyme inactivation, bile acid precipitation, and lipid solubilisation in pancreatic steatorrhoea due to cystic fibrosis.

In pancreatic steatorrhoea, both pH-dependent bile acid precipitation and enzyme inactivation may limit the efficacy of pancreatic enzyme supplements and both may be preventable by addition of cimetidine. To separate these effects we compared postprandial jejunal aspirate from eight adults with steatorrhoea due to cystic fibrosis on three randomised treatment regimens (pancreatin, cimetidine, and both together). We also compared the results with those of previous studies of patients on no treatment, and of healthy subjects. On pancreatin 60% of the test meal entered the jejunum at pH less than 5 compared with 17% in health. Lipase concentration and lipolysis increased over the values on no treatment (14.2 vs 4.4 U/l, p less than 0.01; 16% vs 11%, p less than 0.02) but bile acid precipitation was not reduced (38% vs 27%, NS), and aqueous-phase lipid concentration decreased (6.7 vs 8.6 mM/l, p less than 0.05). On cimetidine, bile acid precipitation fell (19% vs 38%, p less than 0.05); although lipase concentration and lipolysis were lower than on pancreatin (4.8 U/l vs 14.2 U/l, p less than 0.01; 9% vs 16%, p less than 0.01) lipid solubilisation increased (8.8 vs 6.7 mM/l, p less than 0.05). On the combination, there was a marked improvement (p less than 0.02) in lipid solubilisation (18.3 mM/l), reflecting the improvement both in lipase (38.4 U/l) and lipolysis (24%), and in bile acid precipitation (5.6%). We conclude that the efficacy of pancreatin is limited by pH-dependent bile acid precipitation in addition to enzyme inactivation. The action of cimetidine in improving the efficacy of pancreatin depends on prevention of both these effects.

Adolescent↗
PubMedDate not supplied

[Concentration of plasma beta-carotene in cystic fibrosis children with pancreatic insufficiency].

Patients with cystic fibrosis (CF) have significantly decreased plasma concentrations of antioxidant vitamins which is considered to result both from fat malabsorption and from chronic pulmonary infection. The aim of this study was to investigate levels of vitamin A and beta-carotene in plasma of CF subjects with pancreatic exocrine insufficiency. In thirty CF patients mean plasma concentrations of vitamin A (1.17 micromol/l) was lower by 30% and that of beta-carotene (1.3 micromol/l) by 60% than in healthy children. Vitamin A level was positively correlated with beta-carotene (r=0.67; p<0.001). Ratios of beta-carotene to total cholesterol and cholesterol of LDL (low density lipoprotein) were 40% lower than in the control group. We conclude that in our CF patients the concentration of beta-carotene does not seem to be sufficient to inhibit lipid peroxidation especially of LDL fraction.

Antioxidants↗
PubMed1996

[Acute pancreatitis in cystic fibrosis].

Cystic fibrosis is the most prevalent hereditary disease in the Caucasian race. It is a multisystemic alteration that affects the quality and quantitative properties of exocrine secretions. The pancreas develops a progressive atrophy causing steatorrhoea and nutritive deficiencies. Acute pancreatitis is an unusual complication. The pancreatic atrophy prevents the inflammatory response. Published series suggest that pancreatitis in 0.5%, including patients without pancreatic insufficiency. We present two cases with cystic fibrosis, with and without pancreatic insufficiency, who developed acute pancreatitis.

Acute Disease↗
PubMed2001

Analysis of exocrine pancreatic function in cystic fibrosis: one mild CFTR mutation does not exclude pancreatic insufficiency.

BACKGROUND: Cystic fibrosis (CF) is the most common cause of exocrine pancreatic insufficiency in childhood. The aim of the present study is to evaluate the correlation between genotype and exocrine pancreatic insufficiency in CF patients. The special emphasis was put on the analysis of mild CFTR mutations. DESIGN: The study comprised 394 CF patients and 105 healthy subjects (HS). Elastase-1 concentrations were measured in all subjects. RESULTS: Severe pancreatic insufficiency was associated with the presence of two CFTR gene mutations (DeltaF508, N1303K, CFTR dele 2,3 (21kb), G542X, 1717-1G-A, R533X, W1282X, 621GT, 2183AAG, R560T, 2184insA and DeltaI507, G551D, 895T) and mild insufficiency with the presence of at least one mutation (R117H, 3171insC, A155P2, 138insL, 296 + 1G-A, E92GK, E217G, 2789 + 5G-A. 3849 + 1kbC-T/3849 + 1kbC-T) genotype resulted in high elastase-1-values. However, in case of patients with genotype DeltaF508/3849 + 10kbC-T, 1717-1GA/3849 + 10kbC-T as well as with DeltaF508/R334W, both high and low elastase-1 concentrations were found. Low E1 values were found in a patient with DeltaF508/R347P genotype. CONCLUSION: Patients who carry two 'severe' mutations develop pancreatic insufficiency, whereas those who carry at least one 'mild' usually remain pancreatic sufficient. However, the presence of one mild mutation does not exclude pancreatic insufficiency.

Adult↗
PubMed1985

Linoleic acid absorption from lipid supplements in patients with cystic fibrosis with pancreatic insufficiency and in control subjects.

To determine the relative role of malabsorption as the cause of decreased linoleic acid in blood and tissue lipids of patients with cystic fibrosis (CF) and pancreatic insufficiency, the increase in plasma linoleic acid was determined after ingestion of various lipid supplements. CF patients with documented pancreatic insufficiency and normal control subjects were given each of four different lipid supplements on separate days (a minimum of 3 days apart). The supplements were commercial safflower oil, Microlipid, Captex 810D, and Captex 810B. Fasting subjects consumed 36 g of lipid in a milk shake containing 15 g of protein and 45 g of carbohydrate. Plasma samples obtained at 0, 2, 4, 6, and 8 h after the meal showed that CF patients absorbed linoleic acid from all of the lipid preparations tested when administered with their regular dose of pancreatic enzyme supplement. The mean maximal increase in percent plasma linoleic acid in CF patients was not different from controls after ingestion of safflower oil, Microlipid, and Captex 810B. With Captex 810D the CF patients had a significantly higher increase in percent plasma linoleic acid than controls, 6.75% vs. 2.27%, respectively, at 2 h (p less than 0.01), and 11.10% vs. 4.65% at 8 h (p less than 0.01). The CF patients also appeared to absorb the Captex products faster than controls, suggesting that presence of medium chain length fatty acids in these structured lipids facilitated their utilization by CF patients. The results indicate that malabsorption alone cannot account for the inadequate or marginal essential fatty acid status of CF patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗