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PubMed1995

Pancreatic pathology in non-insulin dependent diabetes (NIDDM).

NIDDM is a heterogeneous disease and subgroups of NIDDM include MODY (Maturity Onset Diabetes of the Young), Malnutrition-related diabetes (MRDM) and Fibrocalculus pancreatic diabetes (FCPD). Endocrine cell population is relatively unchanged in NIDDM: B-cells are reduced by up to 30% and A-cells increased by 10%. Islet amyloid is found in 96% of subjects occupying up to 80% of the islet associated with a reduction in B-cells. Amyloid formation is unlikely to cause diabetes but progressive accumulation increases the severity of the disease. Islet amyloid is formed from the islet amyloid polypeptide (IAPP), a normal constituent of B-cells, co-secreted with insulin. The causal factors for IAPP fibrillogenesis are unknown but abnormal synthesis or overproduction could be involved: stimulation of B-cell secretion in NIDDM by obesity, hyperglycaemia or suphonylurea therapy may promote amyloidosis and further aggravate islet pathology. A mutation of the glucokinase gene in MODY leads to diminished B-cell secretion but not amyloid formation. Diabetes and mutations of mitochondrial DNA is associated with poorly developed islet structure. Exocrine pancreatic size is reduced and there is evidence of sub-clinical chronic pancreatitis in NIDDM. In MRDM and FCPD, chronic pancreatitis and exocrine necrosis is associated with reduced insulin secretion. Unlike cystic fibrosis where islet amyloid is present in diabetic individuals, amyloid is absent from subjects with FCPD. Pathological changes in the exocrine and endocrine pancreas in NIDDM results from and contributes to the pathophysiology of insulin secretion in NIDDM.

Amyloid↗

PubMed2002

Genetics and pancreatic disease.

The recognition that variations in the DNA sequence of key genes predispose individuals to acute pancreatitis, chronic pancreatitis, and pancreatic cancer represents one of the greatest breakthroughs in pancreas research. This review highlights recent progress in understanding mutations in the cationic trypsinogen gene, the pancreatic secretory trypsin inhibitor gene, and the cystic fibrosis transmembrane conductance regulator gene with respect to pancreatitis. It also notes progress in the use of microarray technology, classification of chronic pancreatitis, and predisposition to pancreatic cancer.

Journal Article↗

PubMed1996

Combined islet-lung transplantation in a cystic fibrosis patient.

The prevalence of insulin-dependent diabetes mellitus (IDDM) in cystic fibrosis patients ranges from 2 to 8% and glucose intolerance up to 15%. In recent years, lung transplantation has helped to prolong life expectancy of cystic fibrosis patients and represents 10 to 30% of all indications for lung transplantation. The postoperative need for immunosuppressive therapy using diabetogenic agents has decompensatory effects on glucose regulation and will probably increase the number of insulin-dependent cystic fibrosis patients. We report the case of an insulin-dependent cystic fibrosis patient transplanted with a combined islet-lung allograft. The pre-transplantation C-peptide level was below 0.04 nmol/l and preoperative insulin requirement was some 100 U per day. A sequential bipulmonary lung transplantation was performed and, using the pancreas of the same donor, we isolated and purified the islets of Langerhans by a modified automated method. We obtained 232,200 islets equivalent, which were injected into the liver by portal embolization. The postoperative course was uncomplicated, the insulin requirement decreased to 50% of the preoperative need and the C-peptide value increased to normal values and remained with the normal range during a follow-up period of 15 months. In conclusion, we believe that, besides type I diabetic patients, insulin-dependent cystic fibrosis patients with a negative C-peptide value could also be good candidates for combined islet-lung allotransplantation.

Adult↗

PubMed2001

Glycoconjugate metabolism in a cystic fibrosis knockout mouse model.

Cystic fibrosis knockout mice (cftr(-/-)) die prematurely of obstruction of the intestine which may result from accumulation of dehydrated glycoconjugate-containing mucus. We noted an increase in the specific activity of [(14)C]glucosamine-labeled high-molecular weight glycoconjugates, probably mucin, in the lumen of the intestine of cftr(-/-) (homozygous) mice compared to cftr(+/+) (wild-type) and cftr(+/-) (heterozygous) mice and a decrease in the turnover of glycoconjugates of several organs of the cftr(-/-) mice. No difference in the anionic composition of secreted intestinal glycoconjugates was detected and no difference in the amount of mucin 1 (Muc1) was found in the small intestine, colon, pancreas, and lungs of the different genotypes. In addition, the spleen of the cftr(-/-) mice was significantly smaller than that of control mice and the small intestine and colon were, respectively, longer and shorter compared to control mice. These results indicate modified glycoconjugate metabolism in cystic fibrosis knockout mice and morphologic changes to the spleen and intestine where the latter modifications are possibly related to the intestinal malabsorption associated with cystic fibrosis.

Animals↗

PubMed1986

Infection in patients with cystic fibrosis.

Cystic fibrosis is the most common lethal genetic disease of Caucasians. The disease affects the exocrine gland secretions throughout the body, and as a result, major pathologic changes develop in the pancreas and in the bronchi. Obstruction of the respiratory airways results in chronic infection, and in time, this leads to progressive deterioration of lung function. In the initial stages of the disease, usually during infancy, infection with Staphylococcus aureus plays an important role. Hemophilus influenzae infections are also common. As the disease progresses, infection with Pseudomonas aeruginosa develops. Exacerbation of bronchopulmonary infection is often initiated by respiratory viral or mycoplasmal infection, with superimposed S. aureus and P. aeruginosa infections contributing to the severity of the infection. Frequent courses of antibiotic therapy are usually required, and some patients may have to receive antibiotics continuously. Oral cephalosporins, ampicillin, and the combination of trimethoprim/sulfamethoxazole are commonly used for relatively mild infections. In the treatment of exacerbation of infection, intravenous penicillinase-resistant penicillins and anti-Pseudomonas antibiotics are the drugs of choice. For Pseudomonas infections, ticarcillin, carbenicillin, the ureidopenicillins, and the aminoglycosides are indicated. The combination of an anti-Pseudomonas penicillin and an aminoglycoside are most commonly used. Of the third-generation cephalosporins, ceftazidime appears to be the most efficacious. The quinolones (such as ciprofloxacin) are also active against P. aeruginosa, and preliminary studies of these drugs in patients with cystic fibrosis appear to indicate that they are as efficacious as the already available antibiotics. In many centers, Pseudomonas cepacia has emerged as a serious problem in patients with cystic fibrosis. This organism tends to develop resistance to multiple antibiotics. In some centers, infection with P. cepacia has been associated with a severe, frequently fatal, pneumonia.

Anti-Bacterial Agents↗

PubMed1977

Insulin and glucagon response to arginine infusion in cystic fibrosis.

The glucagon and insulin responses to intravenous arginine were studied in 17 children with cystic fibrosis and in 9 control children. It was found that the overall secretion of insulin was diminished; however, four of the CF children did have a normal output. The glucagon responses did not parallel those of insulin. The glucagon output varied in the CF children--seven had normal, four excessively high and six low output. Three of the four children with extremely high output had more severe disease and were below the third centile on the weight chart. These four had a fasting hypoglycaemia and also a very low glucose and insulin response. We have confirmed diminished insulin secretion in cystic fibrosis, but diminished glucagon secretion was only noted when some insulin secretion was preserved. The high levels of glucagon seen in the most insulin deficient subjects may be derived from extrapancreatic sources, or may be associated with 'stress' reaction in these patients who also had most severe pulmonary involvement. The data would be consistent with diminished glucagon and insulin secretion from the pancreas but as the disease progresses an excessive secretion of extra pancreatic glucagon results.

Arginine↗

PubMed1988

Efficacy of pancrease: crossover comparative study versus eurobiol in cystic fibrosis.

An open crossover study in patients with documented cystic fibrosis (CF) compared the efficacy and acceptability of Pancrease (Cilag, PC), consisting of pH-sensitive, enteric-coated microspheres, with those of Eurobiol, consisting of lyophilized total pancreas. Eleven patients, age 6-17 years, were hospitalized for study. A hypercaloric, normal fat diet as well as previous antibiotic, vitamin, and other CF therapy were maintained during the 2-week study period. During the first study week, eight patients were given four divided doses of either Pancrease, 8 capsules daily, and two patients were given Eurobiol, 2 bottles daily. One patient received six Pancrease capsules or 1.5 bottles of Eurobiol daily. Patients were switched to the alternate drug for the second study week. Stools were collected for analysis over the final 3 days of each week. Steatorrhea (mean +/- 1 SD) with Pancrease was 11.8 +/- 6.6 g/24 h and with Eurobiol was 17.9 +/- 11.7 g/24 h. The coefficient of lipid absorption was 74.1 +/- 13.3% for Pancrease and 58.6 +/- 22.5% for Eurobiol (p less than 0.02). The decrease in steatorrhea and increase in lipid absorption with Pancrease compared to Eurobiol were 33.9% and 26.5%, respectively. All patients considered the acceptability of Pancrease superior to that of Eurobiol. No adverse effects were seen with either drug.

Adolescent↗

PubMed1999

The duct cell in cystic fibrosis.

The pancreatic duct cell is central to the etiology of cystic fibrosis (CF) and is the site where pathology commences in utero. We have evaluated expression of the cystic fibrosis transmembrane conductance regulator gene (CFTR) through human development and shown it to be expressed from the early mid-trimester, with highest levels in the most distal portion of the developing duct system and in centroacinar cells. The precise cause of pancreatic destruction in CF is thought to be the obstruction of pancreatic ducts with inspissated secretions. We have shown that the MUC6 mucin is a significant component of the material that obstructs the ducts and that the MUC6 gene shows a very similar pattern of expression to that of CFTR in the developing pancreas. These observations provide a starting point for investigating how mutations in CFTR lead to obstruction of the pancreatic ducts in CF.

Cystic Fibrosis↗

PubMed1989

Cystic fibrosis associated islet changes may provide a basis for diabetes. An immunocytochemical and morphometrical study.

The pancreases of 23 patients (mean age 10.5 years, range 5-22) years dying of cystic fibrosis (CF) were evaluated at autopsy by routine histology and immunostaining for changes in their endocrine cell compartment. The severely altered pancreatic tissues showed end stage CF, with either a fibrotic pattern (CF-FIB, n = 14) or a lipoatrophic pattern (CF-LIP, n = 9) prevailing. In all specimens, irrespective of the dominating pattern, the islet system was affected by marked periinsular and intrainsular sclerosis. Quantitatively, the volume densities (relative tissue components) of the parenchymal, fibrotic, fatty and total endocrine compartments as well as the four islet cell types (B, A, D, PP) were determined by point counting. Compared with controls, the CF patients (including two patients with overt diabetes and glucose intolerance, respectively) had a significantly decreased insulin (B)-cell ratio (from 64.4 to 34%) with a concomitant rise in non-B-cells (A-cells: 23.2 to 35%; D-cells: 10.4 to 22%; PP-cells; 2 to 9%). Comparison of endocrine cell ratios in CF-FIB pancreases with CF-LIP pancreases revealed no significant differences. The reduction of approximately 50% of insulin cells in CF patients with advanced disease supports the concept that destruction of exocrine tissue with concomitant fibrous disorganization of islets gradually changes the proportional distribution of the endocrine cells in favor of the noninsulin cells. This slowly ongoing process probably provides the basis for islet dysfunction, i.e. diabetes, increasingly observed in final stage CF.

Adolescent↗

PubMed1992

Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis.

The impact of pre-diabetes on clinical status was retrospectively studied in 38 cystic fibrosis (CF) patients with diabetes mellitus (DM) and 38 non-diabetic CF patients (control patients), matched in pairs for age, sex, and chronic Pseudomonas aeruginosa lung infection. Quarterly parameters of CF clinical status were collected for 6 years prior to the diagnosis of DM in the index case. Compared to the control patients, decreases in body weight, body mass index (BMI), forced expiratory volume in 1s (FEV1), and forced vital capacity (FVC) and an increase in the daily intake of pancreatic enzyme capsules were found in the pre-diabetic patients. Statistically significant differences in body weight, BMI, FEV1, FVC, and intake of pancreatic enzyme capsules between pre-diabetic and control patients emerged 4, 4, 1.25, 3 and 4.5 years prior to the diagnosis of DM, respectively. The number of lung infections did not differ between the two groups of patients. Thus, when DM develops in CF patients, an insidious decline in overall clinical status is observed for years prior to its diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is presently unknown. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in CF.

Adolescent↗

PubMed1995

Direct double antibody sandwich immunoassay of mucin M1 epitopes in human mucus secreting pancreatic cell lines.

A direct sandwich enzyme immunoassay using two monoclonal antibodies was developed in order to quantify mucin M1 antigens produced by two pancreatic adenocarcinoma cell lines: CAPAN-1 and CFPAC-1. As a solid phase, the wells of a microtiter plate were coated with a first monoclonal antibody, 1-13 M1 and the biotinylated monoclonal conjugate 9-13 M1 was used as the second antibody. The assay was optimized with streptavidin-peroxidase. The detection limit of the assay is 1.6 ng/ml. This ELISA is highly specific, sensitive, reproducible and quickly performed. It will permit the comparison of mucin exocytosis by the two cell lines in response to secretagogue agents and may help in the study of the pathogenesis of mucus hypersecretion such as cystic fibrosis.

Antibodies, Monoclonal↗

PubMed2005

Pancreatic enzyme therapy and clinical outcomes in patients with cystic fibrosis.

OBJECTIVE: To assess the relationship between pancreatic enzyme therapy (PET) and the clinical outcomes of growth, abdominal pain, constipation, gassiness, and number of stools in cystic fibrosis (CF). STUDY DESIGN: Patients (n = 1215) >4 weeks of age from 33 Cystic Fibrosis Foundation accredited sites who had a sweat chloride >60 mmol/L or two CF-causing mutations were enrolled using a proportionate sampling strategy in a nonblinded study. Patients submitted a stool sample and completed a questionnaire. The study coordinator also completed a questionnaire for each patient. Enzyme dosing and growth, abdominal pain, gassiness, constipation, and number of stools were compared. RESULTS: Of the 1215 enrolled patients, 1131 (93.1%) were prescribed PET. Only 14.9% had pancreatic function assessed before enrolling in this study. Stool elastase-1 analysis identified 1074 (89%) patients as pancreatic insufficient (PI). There was no association between PET and the outcomes: growth, abdominal pain, gassiness, constipation, and number of stools. CONCLUSION: PET dose is not correlated with growth or gastrointestinal symptoms. More sensitive outcome measures of the effectiveness of PET in patients with CF are needed to guide treatment of PI.

Abdominal Pain↗

PubMed1985

Enzyme immunoassay for pancreatic lipase: comparison with turbidimetric method in pancreatic diseases.

We report the results of the analytical and clinical evaluation of a specific enzyme immunoassay for determination of human pancreatic lipase, in comparison with a turbidimetric method, in pancreatic pathology. Under standardized conditions of incubation time and temperature we found intraassay coefficient of variation (CV) of 1.3, 3.2, 2.1% at means = 18.7, 43.7, 224 micrograms/L and interassay CV of 2.8, 4.6, 3.0% at means = 19, 42.6, 230 micrograms/L, respectively. In general, a good correlation (r = 0.97) was found between lipase determined as a protein or through its catalytic activity. No significant correlation (r = 0.38) was observed with samples containing low concentration of lipase (up to 18 micrograms/L). We conclude that the turbidimetric method is reliable for routine determinations in the diagnosis of acute pancreatic pathology. However, the better sensitivity of the immunochemical assay should provide additional information for monitoring pancreatic insufficiency.

Acute Disease↗

PubMed1996

Neuropathy and vasculopathy in colonic strictures from children with cystic fibrosis.

Colonic strictures are rare in patients who have cystic fibrosis, but recently have developed in those who have been treated with delayed-release high-dose pancreatic enzyme supplements. Colonic strictures from eight such pediatric patients showed neural abnormalities consisting of ganglion cell hyperplasia and ectopia, and intermyenteric plexus hyperplasia. Cholinergic and adrenergic stains of mucosal nerve fibers were more prominent in histological sections of the cystic fibrosis strictures than in sections from colons of children without cystic fibrosis. The mean grade of staining with acetylcholinesterase in the lamina propria of the strictured cystic fibrosis colons was 2.38 +/- 1.25, compared with .93 +/- .93 (P < .055) in bowels from children without cystic fibrosis. The mean grade for tyrosine hydroxylase staining in the lamina propria was 2 +/- .97 in the strictures and was .79 +/- .81 (P < .05) in the bowels of children who did not have cystic fibrosis. Vasoactive intestinal peptide staining in bowels from children with cystic fibrosis with and without stricture did not differ significantly from that of children without cystic fibrosis. Vasculopathy consisting of fibrointimal hyperplasia in submucosal veins and mesenteric arteries was found only in colonic strictures owing to cystic fibrosis. Colonic strictures in patients with cystic fibrosis who received high-dose pancreatic enzyme supplements contain ganglion cell abnormalities, and mucosal cholinergic and adrenergic activity may be increased in these strictures. The stricture vasculopathy may be drug-related and/or related to increased catecholamine activity.

Acetylcholinesterase↗

PubMed1977

False negative meconium test results in screening for cystic fibrosis.

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Cystic Fibrosis↗

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↗

PubMed1995

Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface.

Chronic colonization and infection of the lung with Pseudomonas aeruginosa is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. We found that polarized CF bronchial and pancreatic epithelia bound P. aeruginosa in a reversible and dose-dependent manner. There was significantly greater binding to CF bronchial and pancreatic cells than to their matched pairs rescued with the wild-type CF transmembrane conductance regulator. Bound P. aeruginosa were easily displaced by unlabeled P. aeruginosa but not by Escherichia coli, an organism that does not cause significant pulmonary disease in CF. In contrast, Staphylococcus aureus, a frequent pathogen in CF, could effectively displace bound P. aeruginosa from its receptor. We found undersialylation of apical proteins and a higher concentration of asialoganglioside 1 (aGM1) in apical membranes of CF compared with rescued epithelia. Incubation of P. aeruginosa with aGM1 reduced its binding, as did treatment of the epithelia with the tetrasaccharide moiety of this ganglioside (Gal beta 1-3GalNAc beta 1-4Gal beta 1-4Glc). Finally, an antibody to aGM1 effectively displaced P. aeruginosa from its binding site and blocked binding of S. aureus to CF cells but not to rescued cells. These results show that the tetrasaccharide of aGM1 is a receptor for P. aeruginosa and S. aureus and that its increased abundance in the apical membrane of CF epithelia makes it a likely contributor to the pathogenesis of bacterial infections in the CF lung.

Bacterial Adhesion↗

PubMed1999

13C and H2 breath tests to study extent and site of starch digestion in children with cystic fibrosis.

BACKGROUND: Starch is an important source of energy for children with cystic fibrosis, but little is known about their capacity to digest it. METHODS: A 13C breath test was used to measure starch digestion and oxidation in 16 children with cystic fibrosis (median [range] age, 7.9 [4-15] years; 7 girls, 9 boys) and 5 normal healthy control subjects (median age, 8.3 [7-13] years; 3 girls, 2 boys). A test meal of 13C flour and lactulose was consumed and breath samples were obtained half-hourly thereafter for 6 hours to measure 13C enrichment by isotope ratio mass spectrometry and H2 by electrochemistry. The test was repeated on 10 children with cystic fibrosis when they were taking pancreatic supplements. RESULTS: The median (range) cumulative percentage 13C dose recovery (cPDR), was 35% (18-52%) in control subjects, 18% (9-33%) in children with cystic fibrosis without enzymes, and 29% (22-51%) in those with pancreatic supplements. cPDR differed significantly between healthy control subjects and children with cystic fibrosis without enzymes (p = 0.01) and between children with cystic fibrosis with and without enzymes (p < 0.0001), but there was no difference between control subjects and children with cystic fibrosis taking enzymes (p = 0.5). Eight children with cystic fibrosis had a cPDR within control range, and in six there was a second peak in 13CO2 enrichment coincident with an increase in H2. CONCLUSIONS: Starch digestion and oxidation are diminished in children with cystic fibrosis, but pancreatic enzymes restored them to near normal levels. A second peak in 13CO2 enrichment, suggestive of colonic starch fermentation was absent in healthy children, but present in some children with cystic fibrosis and abolished by pancreatic enzymes.

Adolescent↗