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PubMed1999

Pancreatitis and cystic fibrosis gene mutations.

Cystic fibrosis (CF) is a genetic disease with multisystem involvement in which defective chloride transport across membranes causes dehydrated secretions. The protein encoded by the CF gene--the cystic fibrosis transmembrane conductance regulator (CFTR)--functions as a cyclic adenosine monophosphate-regulated chloride channel. The ability to detect CFTR mutations has led to the recognition of its association with a variety of conditions, including chronic bronchitis, sinusitis with nasal polyps, pancreatitis, and, in men, infertility. This article reviews the impact of CF on the pancreas, the role of the CFTR protein in pancreatic secretion, and some of the exciting research identifying mutations in the CFTR gene as a risk factor for idiopathic acute and chronic pancreatitis.

Alleles↗
PubMed1975

Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes.

Ten adolescent and young adults with cystic fibrosis (CF) have had well-documented recurrent attacks of acute pancreatitis. The diagnosis of CF in each patient was delayed because they did not have pancreatic insufficiency. The diagnosis of CF was documented by the typical pulmonary involvement and elevated sweat sodium and chloride levels in all cases and a positive family history in six of the ten patients. Two patients were diagnosed as having acute pancreatitis before the diagnosis of CF was made, thus indicating that acute pancreatitis may be the presenting complaint in the young adult with CF. The diagnosis of acute pancreatitis was based on the presence of severe abdominal pain, usually with vomiting, tenderness in the mid-epigastrium, elevated serum and urinary amylase and serum lipase. Attacks were precipitated by fatty meals, alcohol ingestion; postcholecystectomy and tetracycline administration. In some patients no precipitating event could be elicited. Intravenous secretin-pancreozymin stimulation tests revealed a diminished bicarbonate secretion with little effect on the secretion of the zymogen enzymes. A mild attack of pancreatitis occurred after secretin-pancreozymin stimulation. The endocrine pancreatic function tested in four patients was normal as revealed by the glucose tolerance tests and determinations of serum insulin, growth hormone and free fatty acid. Transduodenal pancreatograms were performed in three patients; one showed a normal pancreatic duct, one showed duct obstruction and in the third patient a beady type of narrowing was found. The selenomethionine Se 75 uptake of the pancreas was noted only in the head of the pancreas. This suggests that loss of function occurs initially to a greater extent in the tail and body of the pancreas. Three patients died and showed characteristic lesions of CF.

Acute Disease↗
PubMed2004

Macromolecular interactions and ion transport in cystic fibrosis.

Cystic fibrosis (CF) is a genetic disease caused by autosomal recessive mutations of the CF transmembrane regulator, CFTR. CFTR functions in the plasma membrane of epithelial cells lining the lung, pancreas, liver, intestines, sweat duct, and the epididymis. The primary problem in CF is that mutations in CFTR affect its ability to be made, processed, and trafficked to the plasma membrane and/or its function as a Cl(-) channel and conductance regulator. Many proteins and processes normally interact with normal CFTR throughout its life cycle and mutant CFTR during the disease process. Understanding the function of these proteins and processes is expected to provide a clearer understanding of how normal CFTR is involved in salt movement and how mutant CFTR is handled by the cell and leads to the pathophysiology of CF. Recently, efforts to find therapies that correct defective CFTR have been intensifying. To facilitate our understanding of normal and mutant CFTR and the identification of new drug targets for developing novel therapies, a panel of experts was convened by the National Heart, Lung, and Blood Institute to explore the critical questions, challenges, and current opportunities to highlight new areas of research that would facilitate a integrated understanding of the processes and proteins that impact CFTR. The meeting highlighted the multiple pathways and interacting proteins involved in CFTR folding and biosynthesis, processing, and trafficking. A number of critical areas for future study were identified. Although these therapies are promising, a big question remains as to whether simply correcting defective CFTR will lead to significant improvement in patient health or whether the symptoms manifested in CF will require therapies in addition to those that target defective CFTR specifically.

Cell Membrane↗
PubMed2001

[The elastases].

Elastases are proteinases capable of solubilizing fibrous elastin. They may belong to the class of serine proteinases, cysteine proteinases and metalloproteinases. Mammalian elastases occur mainly in the pancreas and the phagocytes. Among non-mammalian elastases there is a great variety of bacterial metallo and serine elastases. The elastolytic activity varies from one elastase to another and is usually not correlated with the catalytic efficiency of these proteinases. One may measure this activity using native or labelled elastins. With pure elastases one may use synthetic substrates. There is a large number of natural (proteins) and synthetic elastase inhibitors. Elastases play a pathologic role in pulmonary emphysema, cystic fibrosis, infections, inflammation and atherosclerosis.

Animals↗
PubMed1999

Nitric oxide inhibits whole-cell current in cystic fibrosis pancreatic epithelial cells.

We characterized the effects of nitric oxide (NO) on whole-cell current in pancreatic epithelial cell lines from control (PANC-1) and cystic fibrosis patients (CFPAC-1). The nitric oxide donor S-nitrosoglutathione (GSNO) significantly reduced whole-cell current in CFPAC-1 cells but had no effect in PANC-1 cells. This inhibitory effect of NO could be eliminated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or charybdotoxin, suggesting the involvement of DIDS-sensitive Cl- channels and charybdotoxin-sensitive K+ channels. Pretreatment of cells with a selective inhibitor of soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3,1]quinoxalin-1-one (ODQ, 10 microM), eliminated the inhibitory effect of NO, but not 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP; 1 mM), indicating that NO acts via a cGMP-dependent pathway. There was a striking difference in cGMP production in response to GSNO in CFPAC-1 cells as compared with PANC-1 cells. GSNO induced a 90-fold increase in cGMP level in CFPAC-1 cells, compared with a threefold increase in PANC-1. Similarly, CFPAC-1 cells showed elevated levels of sGC and constitutive nitric oxide synthase activity as compared with PANC-1 cells. Therefore excessive production of NO, as is seen in inflammatory states, may contribute to the CF phenotype by inhibiting transepithelial ion movement and preventing secretion of digestive enzymes produced by the pancreas.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Genotype-phenotype correlation in cystic fibrosis patients.

Cystic fibrosis (CF) is the most common severe recessive disease in Caucasians. The gene responsible for the disease encodes a protein named cystic fibrosis transmembrane conductance regulator, which is predicted to function as a cAMP-regulated chloride channel. Reduced chloride secretion is at the basis of insufficient hydratation of ductural mucus in the airways, reproductive system and pancreas, leading to progressive obstructive damage. The clinical expression of the disease is heterogeneous but most CF patients typically present with chronic obstructive lung disease, elevated electrolyte concentration in sweat and insufficient pancreatic exocrine function. Approximately 10-15% of CF patients have pancreatic sufficiency, 2 to 5% of patients have liver disease and infertility is present in almost all adult males, due to congenital bilateral absence of the vas deferens, and frequently in females. To date, over 500 mutations have been identified in the CFTR gene. A genotype-phenotype correlation has been observed only with pancreas status, while severity of lung involvement is not clearly related to the CFTR genotype, suggesting that this phenotype might be modulated by additional genetic or environmental factors; liver disease in general is not genetically determined. A large proportion of sterile healthy men with congenital bilateral absence of the vas deferens carry a mutation in at least one of their CFTR genes. The data collected so far suggest that the relationship between the CFTR genotype and the clinical manifestation is multiple and complex.

Adult↗
PubMed1986

Prenatal diagnosis in 200 pregnancies with a 1-in-4 risk of cystic fibrosis.

Prenatal diagnosis of cystic fibrosis was performed in 200 pregnancies with a 1-in-4 risk, and was based on significant modifications in amniotic fluid taken at 17, 18, 19 weeks of pregnancy, of six enzymatic assays: gamma-glutamyl-transpeptidase, aminopeptidase M, and alkaline phosphatase (total and isoenzymes). On the basis of normal values, normal outcome was predicted in 135 pregnancies reaching term, all the babies were normal. On the basis of significantly abnormal enzymatic values, an affected fetus was predicted in 56 pregnancies, 53 were terminated, and 3 went to term; the infants were affected. There were discrepancies in enzymatic values in nine cases, in eight cases normal outcome was predicted, six babies were normal and two were affected; in one case an affected baby was predicted, the pregnancy went to term and the baby is normal. Criteria giving evidence for cystic fibrosis in fetuses have been described: macroscopic observation of a typical meconium ileus, significant increase of albumin content in the meconium, and PAS-positive mucus-like material in some pancreatic acini. Using these criteria, diagnosis of cystic fibrosis has been confirmed in all the examined fetuses. The recurrence rate of cystic fibrosis was 22.5% in 147 diagnoses in which the index case had cystic fibrosis without a history of meconium ileus at birth, but was 47.5% when the index case had meconium ileus. The results of the study suggest that prenatal diagnosis of cystic fibrosis can be performed with an accuracy of 98%.

Amniocentesis↗
PubMed2005

[Clinical implications of genetic risk factors of chronic pancreatitis].

The identification of a specific mutation in the human cationic trypsinogen gene in large kindreds with hereditary pancreatitis was the key to understand the genetic background of chronic pancreatitis. Rapidly, other variants within the same gene were identified-even in small families with a minority of patients. Later, mutations of the most important intrapancreatic trypsin inhibitor SPINK1 were found with high prevalence in patients with idiopathic, tropical and alcoholic chronic pancreatitis. We summarize interesting genetic and biochemical findings, point to clinical features and review recommendations for genetic analysis, follow-up and cancer prevention.

Carrier Proteins↗
PubMed1991

CFTR: development of high- affinity antibodies and localization in sweat gland.

Rabbit antisera were raised to six synthetic peptides corresponding to amino acid sequences contained in the protein product of the cystic fibrosis gene, CFTR. For two peptides, [Lys102]CFTR(102-116) and CFTR(1468-1480), antibody-peptide binding was of high affinity in that half-maximal binding occurred at peptide concentrations below 10 nM. Monospecific antibodies were prepared using these peptides, and these antibodies were used to stain human skin. Specific staining was detected in the cells lining the reabsorptive duct of the sweat gland. Within these lumenal cells, staining was most prominent at the apical domain but was also detected near the basolateral surface. This finding agrees well with predictions based on the effects of cystic fibrosis on sweat gland function, and suggests that these antibodies will be useful for studying CFTR in other human tissues.

Amino Acid Sequence↗
PubMed1994

Pathophysiology of the pancreatic defect in Johanson-Blizzard syndrome: a disorder of acinar development.

We compared pancreatic acinar and ductal secretion in two patients with Johanson-Blizzard syndrome, age-matched control subjects, and patients with other primary pancreatic diseases. Patients with Johanson-Blizzard syndrome had preservation of ductular output of fluid and electrolytes, as in patients with Shwachman syndrome but differing from those with cystic fibrosis, who have a primary ductular defect. They also had decreased acinar secretion of trypsin, colipase and total lipase, and low serum immunoreactive trypsinogen levels, consistent with a primary acinar cell defect.

Case-Control Studies↗
PubMed2001

Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis.

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF, a finding that has been extended to all CFTR-expressing cells. Subsequent cloning of the gene showed that CFTR functions as a cyclic-AMP-regulated Cl- channel; and some CF-causing mutations inhibit CFTR Cl- channel activity. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters, including Cl(-)-coupled HCO3- transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. HCO3- and pH affect mucin viscosity and bacterial binding. We have examined Cl(-)-coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO3- transport, and those associated with pancreatic sufficiency show reduced HCO3- transport. Our findings demonstrate the importance of HCO3- transport in the function of secretory epithelia and in CF.

Bicarbonates↗
PubMed1990

Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum.

Respiratory distress and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. More than 30 yr ago it was suggested that the large amounts of DNA in purulent secretions contribute to its viscosity and that bovine pancreatic DNase I could reduce the viscosity. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of cystic fibrosis, we have cloned, sequenced, and expressed rhDNase. Catalytic amounts of rhDNase greatly reduce the viscosity of purulent cystic fibrosis sputum, transforming it within minutes from a nonflowing viscous gel to a flowing liquid. The reduction in viscosity is associated with a decrease in size of DNA in the sputum. Inhalation of a rhDNase aerosol may be a simple direct approach that will help individuals with cystic fibrosis and other patients with pneumonia or bronchitis to clear their airways of purulent secretions.

Amino Acid Sequence↗
PubMed1999

Triglyceride oxidation in cystic fibrosis: a comparison between different 13C-labeled tracer substances.

BACKGROUND: For indirect evaluation of pancreatic lipase activity in cystic fibrosis, different 13C-labeled triglycerides may be used. METHODS: Triglyceride oxidation in patients with cystic fibrosis was investigated after administration of different 13C-labeled triglycerides by comparing 13CO2 breath exhalation. In the comparative study, five patients with cystic fibrosis (age, 8-15 years; body weight, 22.5-39.8 kg) were treated with Pangrol (individual dosages: 1-3 capsules per morning meal; Berlin-Chemie, Berlin, Germany). [1,1,1-13C3]Glyceryl tripalmitate and [1,1,1-13C3]glyceryl trioleate were administered as a single oral pulse at 8:00 A.M. (dosage, 4 mg/kg each) with the standard diet Fresubin (dosage, 10 ml/kg; Fresenius, Bad Homburg, Germany). Alternately, the same subjects were given the synthetic mixed triglyceride 1,3-distearyl, 2[13C]octanoyl glycerol (dosage, 12.5 mg/kg) contained in the standard diet Nutri-Mix (dosage, 10 ml/kg; Nutricia, Zoetemeer, The Netherlands). Breath samples were taken in 15- and 30-minute intervals over 8 hours. The 13CO2 enrichment was measured by continuous-flow isotope ratio mass spectrometry. RESULTS: After administration of the 13C-labeled tripalmitin-triolein mixture and the mixed triglyceride, mean maximum 13CO2 enrichments were 4.70 and 7.37 delta over baseline, occurring at 7.0 and 3.5 hours, respectively. The corresponding percentage cumulative 13CO2 exhalations were 12.25% and 29.19%, respectively, and differed significantly in the five paired subjects (p = 0.003). CONCLUSIONS: After using different 13C-labeled triglycerides the resultant 13CO2 exhalation reflected the triglyceride hydrolysis and subsequent oxidation. It is concluded that the different cumulative 13CO2 exhalations were mainly caused by the rate-limiting step of triglyceride hydrolysis to free fatty acids and 2-monoglycerides and by fat deposition. Noninvasive 13C breath tests using different 13C-labeled triglycerides can be used for evaluation of pancreatic lipase activity before and during enzyme supplementation.

Adolescent↗
PubMed1991

Congenital hypothyroidism and cystic fibrosis.

We report a case of dysgenetic congenital hypothyroidism associated with cystic fibrosis. Impaired exocrine pancreatic secretion and/or transit abnormalities secondary to the treatment of meconium ileus resulted in decreased absorption of L-thyroxine and difficulties in management of hypothyroidism.

Congenital Hypothyroidism↗
PubMed1993

A double blind lipase for lipase comparison of a high lipase and standard pancreatic enzyme preparation in cystic fibrosis.

A standard acid resistant microsphere pancreatic enzyme preparation was compared with identical capsules half filled with mini-tablets of a new high lipase preparation in a randomised double blind crossover study in children with cystic fibrosis. Each patient received his/her usual number of capsules and the same dose of lipase during each period of the study. Eighteen patients completed the study. There were fewer gastrointestinal symptoms when pancreatic enzyme was supplied as the high lipase preparation. There was also a significant improvement in fat absorption (17%, 95% confidence interval (CI) 6 to 27), reduction in faecal fat output (15.8 g/day, 95% CI 6.4 to 22.5), and faecal energy loss (789 kJ/day, 95% CI 211 to 1384). It is concluded that half filled capsules of the new high lipase preparation are more effective than the standard preparation and it is likely that filled capsules would allow patients to use fewer than half the number of pancreatic enzyme capsules.

Adolescent↗
PubMed1990

Pancreatic function and gene deletion F508 in cystic fibrosis.

In view of the possible relation between pancreatic function and cystic fibrosis (CF) gene mutations, a detailed study on Italian patients was performed. Seventy pancreatic insufficient and 48 pancreatic sufficient patients were included after very accurate characterisation of their pancreatic and digestive function, all performed in the same CF centre. The CF gene deletion F508 was tested to define the patients' genotypes. The results confirm that the mutation correlates with pancreatic insufficiency, and is recessive to other, as yet unreported, mutant alleles that determine pancreatic sufficiency. An indication that duodenal bicarbonate output is more severely reduced in the presence of deletion F508 is also presented. The data are discussed in relation to a hypothesis on the primary effects of CF gene deletion F508.

Adolescent↗
PubMed1992

Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease.

The clinical course of nine cystic fibrosis patients homozygous for the CF gene nonsense mutation R1162X was investigated. Since this mutation should lead to an interruption in the synthesis of the cystic fibrosis transmembrane regulator (CFTR) protein, a severe clinical course was expected. All patients showed pancreatic insufficiency, while the course of the lung disease was mild to moderate. These results suggest that this form of truncated CFTR protein, still containing the regulatory region, the first ATP binding domain, and both transmembrane domains, could be partially working in the lung tissues.

Adenosine Triphosphate↗