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PubMed1999

[Gastrointestinal complications of adult patients with cystic fibrosis].

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. The primary cellular defect, the reduced expression of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to a chloride secretory defect, is present in all epithelial cells of endodermal and mesodermal origin and has been described in sweat glands, the airway epithelium and the small intestine, the colon and rectum, including the pancreas. In the upper GI-tract the most troublesome complaints and symptoms originating from the esophagus are peptic esophagitis or esophageal varices. In the small intestinal wall, the clinical expression of CF largely depends on the decreased secretion of fluid and chloride ions and the sticky mucous covering the enterocytes. Although CFTR expression in the colon is lower, the large intestine may be the site of several serious complications such as rectal prolapse, distal intestinal obstruction (DIOS), and intussusception. In recent years an increase in colonic strictures after the use of high-dose pancreatic enzymes, has been increasingly reported. CF has also been reported to be increasingly associated with a number of hepatic and/or biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. Plugging of intrahepatic bile ducts with inspissated secretions is thought to play a major role in the pathogenesis. It has been estimated that about 15% of cystic fibrosis patients reveal serum liver enzyme abnormalities, but prevalence of liver involvement is likely to be higher. Oral bile acid therapy is promising, but its long-term benefits in terms of survival and prevention of major complications by liver cirrhosis remain to be established. Pancreatic dysfunction in cystic fibrosis (CF) is characterized by an insufficient pancreatic exocrine function. However, 10-15% of CF patients have pancreatic sufficiency and this status is genetically determined by one or two "mild" mutations in the CFTR.

Adult↗
PubMed1999

A PDZ-interacting domain in CFTR is an apical membrane polarization signal.

Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to the apical plasma membrane of epithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. However, the motifs that localize CFTR to the apical membrane are unknown. We report that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) comprise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 COOH-terminal amino acids, including the PDZ-interacting domain, is mispolarized to the lateral membrane. We also demonstrate that CFTR binds to ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50), an apical membrane PDZ domain-containing protein. We propose that COOH-terminal deletions of CFTR, which represent about 10% of CFTR mutations, result in defective vectorial chloride transport, partly by altering the polarized distribution of CFTR in epithelial cells. Moreover, our data demonstrate that PDZ-interacting domains and PDZ domain-containing proteins play a key role in the apical polarization of ion channels in epithelial cells.

Amino Acid Sequence↗
PubMed1985

Problems in the treatment of malabsorption in CF.

Several factors play a role in the cause of malabsorption in CF. Besides the enzyme deficiency in the secretion of the exocrine pancreas, decreased bile-salt concentration in the gut may also be an important factor in the fat malabsorption. The contribution to the fat absorption by other lipases, such as lingual lipase and gastric lipase, remains to be proved. The therapeutic measures are only partly effective because of the breakdown of swallowed enzymes by gastric acid. Some improvement is reached by using a new acid-resistant coating for the enzyme supplement. Newly developed and essential for its success is the application of small coated particles to prevent retention in the stomach, and the easy breakdown of the coating in an alkaline solution. The treatment of the bile salt deficiency has not been successful until now. A trial with additional Tween 80, with the option of supplementing the detergent activity which was found to be successful in Crohn disease, was without marked success.

Bicarbonates↗
PubMed2005

[Cystic fibrosis--the most frequent life-shortening autosomal recessive disease].

Cystic Fibrosis (CF) is one of the most frequent genetic diseases in the white populations of Europe and North America. Its clinical manifestations are highly variable, ranging from a characteristic life-shortening pathology of the lungs and the pancreas in classical CF to symptoms mainly restricted to male sterility in patients with congenital bilateral aplasia of the vasa deferentia (CBAVD). The genetic basis of CF is mutations in both copies of the CFTR gene, which codes for an ion channel. Even though one single mutation, deltaF508, is responsible for two-thirds of all mutated CFTR alleles, a total of over 1000 CFTR mutations have been described, whose relative frequencies vary between different ethnic groups, and whose biochemical consequences are correlated to the clinical manifestations of the disease. Since 4% of white Europeans and North Americans are healthy heterozygous carriers of CF, the molecular diagnosis of this disease, offered in the context of genetic counselling by a specialist in human genetics, is of great importance.

Alleles↗
PubMedDate not supplied

Isolated idiopathic chronic pancreatitis associated with a compound heterozygosity for two mutations of the CFTR gene.

We report the case of a patient suffering from idiopathic chronic pancreatitis (ICP) and compound heterozygous for mutations G542X and S1235R of the cystic fibrosis transmembrane regulator (CFTR) gene. The patient had normal sweat test and no other clinical sign usually linked with a typical or moderate pathology (bronchiectasis, nasal polyposis, congenital absence of the vas deferens) of the CFTR gene. G542X is a severe mutation, which is usually found in classical cystic fibrosis when associated with other severe mutations. S1235R is a quite rare abnormality recently reported as being potentially pathogenic when combined in trans with a second CF mutation. Our case is quite similar to the only other six patients in the literature in whom only the pancreas is affected and who bear a rare mutation with moderate effect. The history and the clinical features of our patient indicate an unambiguous isolated ICP in which the presence of the S1235R mutation--in trans with regard to G542X--is likely responsible for the ICP phenotype. This case could throw light on some of the as yet poorly known abnormalities of the CFTR gene in the ICP phenotype.

Adult↗
PubMed2000

Advances in nutritional management of chronic pancreatitis.

Nutrition has an important role in the management of chronic pancreatitis (CP), with two main goals for treatment of patients. The first goal is to provide optimal nutrition support and the second is to decrease pain by minimizing stimulation of the exocrine pancreas. Because cholecystokinin (CCK) stimulates secretion from the exocrine pancreas, one approach is to decrease CCK levels through modulation of diet. If postprandial pain is a limiting factor, alternative enteral therapies that minimally stimulate the pancreas may be beneficial. Nutritional counseling, antioxidants, and pancreatic enzymes may play a role in effective management of CP as well. In addition, because idiopathic CP is associated with cystic fibrosis gene mutations, therapies directed toward cystic fibrosis may also benefit these patients.

Chronic Disease↗
PubMed2004

The molecular basis of pancreatic fibrosis: common stromal gene expression in chronic pancreatitis and pancreatic adenocarcinoma.

OBJECTIVES: Tissue desmoplasia occurs in a number of disease states, but its molecular basis is poorly understood. To determine which genes are overexpressed in cells contained within the desmoplastic stroma of pancreatic adenocarcinoma and chronic pancreatitis, we undertook genetic profiling of microdissected tissue samples of pancreatic adenocarcinoma, chronic pancreatitis, normal pancreas, and pancreatic cancer cell lines. We observed that samples of both pancreatic adenocarcinoma and chronic pancreatitis showed elevated expression of many shared genes compared with the normal pancreas. We hypothesized that these common genes likely important in stromal production and/or function could be identified using a strategy that involved comparisons between pancreatic adenocarcinoma, chronic pancreatitis, normal pancreas, and pancreatic cancer cell lines. METHODS: We performed oligonucleotide microarray analysis of 6800 different genes expressed in 10 samples of pancreatic adenocarcinoma, 5 samples of normal pancreas, 5 samples of chronic pancreatitis, and 7 pancreatic cancer cell lines. Microarray findings were validated with RT-PCR, and immunohistochemistry was used to verify protein localization to the stromal compartment of both pancreatic cancer and chronic pancreatitis. RESULTS: We employed a deductive comparison whereby genes expressed in the normal pancreas and pancreatic cancer cell lines were selectively eliminated from those expressed in common by pancreatic adenocarcinoma and chronic pancreatitis. This strategy identified 107 genes predicted to be expressed within cells of the stromal compartment of both pancreatic adenocarcinoma and chronic pancreatitis. CONCLUSIONS: These genes are likely important factors in epithelial-stromal signaling in pancreatic desmoplasia and may serve as diagnostic or therapeutic targets.

Adenocarcinoma↗
PubMed2005

[Chronic pancreatitis--pancreas cancer: influence of genetic factors].

Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.

Carrier Proteins↗
PubMed1977

Distribution of serum amylase isoenzymes in cystic fibrosis homozygotes and heterozygotes.

A simple method has been elaborated for the routine separation and quantitative determination of amylase isoenzymes. The ratio P/S, the quotient of the activity values obtained by densitometric evaluation of the pancreatic and salivary isoenzymes, is used to characterize their distribution. In healthy adults and children the value for P/S is above 1 in 80% of the cases, with a mean of 1.87 +/- 0.23. In 90% of heterozygote CF gene-carriers, the P/S is below 1 with a mean of 0.68 +/- 0.13. In addition to the higher total amylase activity, in MV homozygote patients P/S is less than 0.1, and even 0.001. The phenomenon is explained by a compensatory enhancement of salivary activity. The method is a suitable diagnostic test of the exocrine function of the pancreas and for evaluation of the serum amylase isoenzymes. The P/S value allows to differentiate heterozygote CF gene-carriers from homozygotes and healthy individuals.

Adult↗
PubMed1988

A new faecal chymotrypsin method for evaluating the exocrine pancreatic function in patients with different pancreatic diseases.

Using a new colorimetric method we measured the faecal chymotrypsin in 407 subjects, divided as follows: 252 adult subjects with a normal exocrine pancreatic function as shown by duodenal intubation, 24 adult patients with a mild to moderate pancreatic insufficiency, and 26 adult patients with severe pancreatic insufficiency. In addition, 40 healthy children, 50 children with chronic diarrhoea, and 15 with cystic fibrosis were studied before and after substituting enzyme therapy. Faecal chymotrypsin was found to be useful in evaluating the degree of exocrine functional insufficiency in subjects with diseases of the pancreas that had already been clinically ascertained. The same cannot be said for its ability to provide an early diagnosis of subjects with a slight-moderate insufficiency in exocrine pancreatic function.

Adult↗
PubMed2002

Cystic fibrosis and Chiari type I malformation: autopsy study of two infants with a rare association.

Cystic fibrosis (CF), an epithelial cell transport disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is not generally associated with malformations of the central nervous system (CNS). This report describes two African-American children who died at less than 2 years of age with known Chiari I malformations and were found, unexpectedly at autopsy, to have the classic pancreatic and respiratory changes of CF. Both patients had suffered from failure to thrive that had been attributed to their CNS malformations. One child also had recurrent pneumonia and died with Pseudomonas sepsis. Mutational analysis for > 70 common CFTR mutations identified a single delta F508 mutation in one patient and a single 3120+1G to A mutation in the other. Their second CFTR mutations were not identified. The association of CF with Chiari I malformation is not likely to be purely coincidental, as the probability of such an occurrence in African-Americans is greater than one in 7,500,000 patients. It is possible that the CFTR gene may play a previously unrecognized role in CNS development. Alternatively, this CNS abnormality may be acquired due to the metabolic and electrolyte imbalances that characteristically occur in CF.

Arnold-Chiari Malformation↗
PubMed1991

Probing the basic defect in cystic fibrosis.

The concurrent developments in electrophysiology studies and the identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has provided a unique opportunity to probe the basic cellular defect underlying cystic fibrosis. Various properties of the CFTR protein have been deduced from its primary sequence, the variety of mutations in patients and genotype-phenotype correlations, as well as the results of more recent DNA transfection studies. The most exciting observation is the fact that CFTR acts like a cAMP-regulated Cl- channel.

Chloride Channels↗
PubMed2004

Maldigestion and malabsorption of 13C labelled tripalmitin in gastrostomy-fed patients with cystic fibrosis.

BACKGROUND & AIMS: Some patients with cystic fibrosis continue to have excessive losses of stool lipid, despite the use of pancreatic enzyme replacement therapy to improve digestion. The aim of this study was to explore the residual capacity of the gastrointestinal tract to digest and absorb dietary lipid using stable isotopic methodology in ten patients with cystic fibrosis who were gastrostomy fed in comparison to eight healthy children. We sought to test the hypothesis that a reduction in the availability of dietary lipid may arise from malabsorption of the products of digestion, rather than maldigestion alone. METHODS: All subjects consumed [1,1,1-(13)C] tripalmitin (10mg/kg body weight) with a standardised meal but the patients with cystic fibrosis did not take their habitual pancreatic enzymes. Total enrichment of (13)C was measured by isotope ratio mass spectrometry in stools collected over 3 days. Maldigestion and malabsorption was differentiated by measuring (13)C-label excretion in stool triglyceride and fatty acid fractions, respectively. RESULTS: The patients with cystic fibrosis had elevated (13)C-label losses in total stools (56.7%, 6.8-77.9%)(median and range; % administered dose), triglyceride (6.6%, 0-31.2%) and fatty acid (16.7%, 3.4-50.3%) fractions compared to healthy children (1.9%, 0-10.9%, P<0.001; triglyceride: 0.2%, 0-0.6%, p<0.01; fatty acid 0.9%, 0-6.5%, P<0.001). CONCLUSIONS: These results highlight differences between gastrostomy fed patients with cystic fibrosis to both digest and absorb dietary lipid. There is a need to extend these observations and apply this approach to patients both with and without pancreatic enzyme replacement therapy.

Adolescent↗
PubMed2000

What do children with cystic fibrosis and their parents know about nutrition and pancreatic enzymes?

OBJECTIVE: To describe the development and validation of questionnaires designed to assess nutrition and pancreatic enzyme replacement therapy knowledge and cystic fibrosis self-management skills, and the results obtained when the questionnaires were used. DESIGN: A cross-sectional study using validated questionnaires to interview the respondents. The outcome measures were scores for knowledge, appropriate and inappropriate self-management, and Socioeconomic Index. SUBJECTS: Forty-two children with cystic fibrosis aged 6 to 11 years and 55 caregivers of 2 to 11-year-old patients of the Princess Margaret Hospital Cystic Fibrosis Clinic, Perth, Australia. STATISTICAL ANALYSES: Descriptive statistics and correlations between scores were used for statistical analyses. Associations between knowledge scores were examined using Pearson's correlation coefficient. Spearman's rank correlation was used to examine the associations between knowledge and self-management scores and socioeconomic index. RESULTS: Children's and caregivers' mean knowledge scores were 63% and 85%, respectively. Mean appropriate and inappropriate self-management scores for children were 55% and 21%, respectively, and for the caregivers were 74% and 32%, respectively. There was a statistically significant (P < .05) positive association between caregivers' and children's knowledge (r = 0.32), and children's knowledge and appropriate self-management scores (r = 0.41); and a statistically significant negative association between caregivers' knowledge and inappropriate self-management scores (r = -0.35); and no statistically significant associations between Socioeconomic Index and children's and caregivers' knowledge and self-management scores. APPLICATIONS: This study identified areas in which the nutrition knowledge of children with cystic fibrosis and their caregivers needs to be enhanced to increase the likelihood that optimum dietary and pancreatic enzyme therapy is achieved. The questionnaires that were developed for the study could be refined and used in the clinical setting to identify knowledge and self-management deficits. Alternatively, the questionnaires could become valuable research tools for assessing the type of intervention required and in planning and evaluating programs.

Adult↗
PubMed2001

Three autopsied cases of cystic fibrosis in Japan.

The incidence of cystic fibrosis (CF) is very rare in Japanese, while it is frequent in Caucasians. Here we report on three Japanese cases of CF. One of the patients had consanguineous parents. All three patients initially developed meconium ileus, and hepatobiliary and pancreatic changes became more severe as age increased. The DeltaF508 mutation, the most frequent mutation associated with CF in Caucasians, was not found in these patients. To evaluate the relationship between the severity of hepatic lesions and a history of meconium ileus, we examined hepatic lesions in the present three cases, and we reviewed 22 Japanese autopsied cases of CF in the literature. No correlation was found between the incidence of biliary cirrhosis and a history of meconium ileus, because the cases with meconium ileus showed a high mortality during the neonatal period, before biliary cirrhosis developed. The high incidence of meconium ileus in Japanese CF patients may relate to a clinically severe phenotype and reflect a different genetic background between Caucasians and Japanese.

Adolescent↗