Cystic Fibrosis Of The Pancreas Research Articles

Cystic Fibrosis of the Pancreas: The Role of CFTR Channel in the Regulation of Intracellular Ca2+ Signaling and Mitochondrial Function in the Exocrine Pancreas.

Cystic fibrosis (CF) is the most common genetic disorder that causes a significant damage in secretory epithelial cells due to the defective ion flux across the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Pancreas is one of the organs most frequently damaged by the disease leading to pancreatic insufficiency, abdominal pain and an increased risk of acute pancreatitis in CF patients causing a significant decrease in the quality of life. CFTR plays a central role in the pancreatic ductal secretory functions by carrying Cl- and HCO3- ions across the apical membrane. Therefore pathophysiological studies in CF mostly focused on the effects of impaired ion secretion by pancreatic ductal epithelial cells leading to exocrine pancreatic damage. However, several studies indicated that CFTR has a central role in the regulation of intracellular signaling processes and is now more widely considered as a signaling hub in epithelial cells. In contrast, elevated intracellular Ca2+ level was observed in the lack of functional CFTR in different cell types including airway epithelial cells. In addition, impaired CFTR expression has been correlated with damaged mitochondrial function in epithelial cells. These alterations of intracellular signaling in CF are not well characterized in the exocrine pancreas yet. Therefore in this review we would like to summarize the complex role of CFTR in the exocrine pancreas with a special focus on the intracellular signaling and mitochondrial function.

Cystic Fibrosis

Cystic fibrosis, a genetic disease with an autosomal recessive mode of inheritance, was first described in 1936 by Fanconi et al. He described the disease in a paper entitled The Coeliac Syndrome with congenital cystic pancreatic fibromatosis and bronchietasis. Since then the disease has been known by various names such as Cystic Fibrosis of the Pancreas, Mucoviscidoses, fibrosis of the pancreas until it was shortened to Cystic Fibrosis in the 1960s.Cystic Fibrosis represents the commonest autosomal recessive disorder in Caucasian populations. The mutant gene, recently identified on the long arm of chromosome 7 has a carrier rate equal to 1 in 22 among Caucasians. The overall incidence of the disease in 1 per 2000 live births. However it has a much lower incidence amongst non- Caucasian populations. Amongst the UK population there are 5000 cystic fibrosis sufferers. Slightly more than 300 affected babies are born annually.The disease affects many tissues, especially the endocrine glands. It results in the production of abnormally viscous secretions which cause duct obstruction and are therefore responsible for pancreatic insufficiency, malabsorption syndromes, biliary cirrhosis and male infertility. The lungs of cystic fibrosis patients are found to be normal at birth but are very prone to infection. Recurrent infection is responsible for the irreversible secondary lung damage which is usually responsible for the shortened life expectancy of cystic fibrosis patients.Death usually results from a severe bacterial pneumonia or is related to the development of cor pulmonale from lung disease.

50 Years Ago in The Journal of Pediatrics: Hypoproteinemia and Edema in Infants with Cystic Fibrosis of the Pancreas

50 Years Ago in The Journal of Pediatrics: Hypoproteinemia and Edema in Infants with Cystic Fibrosis of the Pancreas

Targeting protein–protein interactions to rescue Δf508‐cftr: a novel corrector approach to treat cystic fibrosis

Cystic fibrosis (CF) is one of the most prevalent life‐threatening autosomal recessive disorders in the Western World, with an estimated incidence of 1 in 2000–3000 Caucasian newborns and a median age of survival of 40 years. The first report of CF as a distinct pathology was published in 1938 by Dorothy Andersen, a physician at the Babies & Children's Hospital of Columbia University, who differentiated its diagnosis from celiac disease in the pancreas (Andersen, 1938). This seminal description was followed by other contributions that linked CF to altered Cl− permeability in epithelial cells in the gastrointestinal and hepato‐billiary systems, respiratory tract, reproductive system and sweat glands (Kreindler, 2010); and culminated with the discovery of the gene responsible of the disease, referred to as the cystic fibrosis transmembrane regulator (CFTR) (Riordan et al, 1989). The CFTR is a cAMP‐regulated chloride and bicarbonate channel that controls anion conductance in epithelial cells located in mucosal surfaces. Functional alteration of CFTR leads to the accumulation of mucous secretions that cannot be cleared favouring inflammation and infection. Cumulative evidence shows a strong correlation between the severity of the CF phenotype and the degree of CFTR dysfunction, being stronger for those patients where the channel function is absent (Kreindler, 2010). The CF phenotype is caused by more than 1000 mutations of the CFTR gene including missense, such as R117H or G551D that significantly reduce channel activity, and nonsense like G542X, R553X or W1282X, which abrogate protein expression (Kreindler, 2010). However, the most prevalent mutation in CF patients (70%) is the in‐frame deletion of Phenylalanine at position 508 (ΔF508‐CFTR) (Kreindler, 2010; Rowe & Verkman, 2013). This deletion produces a partially unfolded CFTR protein that is retained in the endoplasmic reticulum and diverted to degradation by the proteosome, resulting in a virtually absent CFTR activity …

50 Years Ago in The Journal of Pediatrics: The Effect of N-Acetylcysteine on the Viscosity of Tracheobronchial Secretions in Cystic Fibrosis of the Pancreas

50 Years Ago in The Journal of Pediatrics: The Effect of N-Acetylcysteine on the Viscosity of Tracheobronchial Secretions in Cystic Fibrosis of the Pancreas

Cystic fibrosis and anaesthesia

Cystic fibrosis (CF) was first identified in 1938 by Dorothy Hansine Anderson, who initially called it ‘cystic fibrosis of the pancreas’. It is a multisystem autosomal recessive disease and the most common lethal genetic disease in Caucasians. CF is particularly common in Western Europe. The Republic of Ireland has the highest incidence in the world, at one in 1461 live births with a carrier rate for the genetic mutation of one in 19. In the UK, the carrier rate is one in 25 with an incidence of one in 2500 live births. In 2008, there were 8513 patients with CF on the UK Register. In Ireland in 2007, there were 1170 CF patients. CF is best considered as a disease spectrum rather than a distinct single clinical entity due to the heterogeneity of genotypic and phenotypic manifestations.

50 Years Ago in T he J ournal of P ediatrics: The Flora of the Respiratory Tract of Patients with Cystic Fibrosis of the Pancreas

50 Years Ago in T he J ournal of P ediatrics: The Flora of the Respiratory Tract of Patients with Cystic Fibrosis of the Pancreas

Fifty-year perspective of “cystic fibrosis of the pancreas”

Fifty-year perspective of “cystic fibrosis of the pancreas”

Ascites after orthotopic liver transplantation in children

Ascites is a poorly understood postoperative complication of orthotopic liver transplantation (OLT). It is associated with additional morbidity and can prolong hospitalization considerably. The incidence, the factors predictive of occurrence and the etiology of this complication are not known. The charts of 118 patients with 138 OLT were analyzed according to the following criteria: ascites lasting longer than the first 10 postoperative days, assessed by loss of ascitic fluid through drainage tubes, surgical wounds or paracentesis, with a peak volume of > or =10 mL/kg/day. Patients were divided into three groups: Group 1, no ascites; Group 2, ascites associated with postoperative complications, including chylus ascites; and Group 3, ascites not associated with postoperative complications. Postoperative ascites occurred in 43 of 138 OLT (31.2%). Patients with biliary atresia, preoperative portal hypertension, postoperative pleural effusion or at retransplantation had ascites significantly more often. In 32 of 138 (23.2%) OLT, ascites was associated with postoperative complications, including thrombosis, abdominal infections, intestinal perforation, biliary leak, pancreatitis, and chylus ascites. In 11 of 138 (7.9%) OLT, ascites was the only postoperative complication (group 3). Group three patients were significantly older, and had lower preoperative platelet counts and preoperative ascites more often than group 1 patients. The primary liver diseases were mainly cystic fibrosis of the pancreas, congenital hepatic fibrosis, and North American Indian childhood cirrhosis. The serum-ascites albumin gradient suggested a hepatic origin of ascites. Postoperative ascites is associated with the duration and degree of preoperative portal hypertension. We speculate that the mechanism involved includes a disproportion between venous blood volume and liver uptake capacity of the donor organ.

Imaging changes in the pancreas in cystic fibrosis: a retrospective evaluation of 55 cases seen over a period of 9 years.

Pathologic changes of the pancreas have been observed as early as the recognition of the disease termed initially "cystic fibrosis of the pancreas". Atrophy of the gland and its fatty infiltration were considered as usual features. The aim of this study was to follow-up the evolution of cystic fibrosis pancreas and to define its successive stages in correlation with the clinical, biochemical, and imaging findings. Fifty-five patients were followed up during 9 years. The patients' genetic backgrounds were systematically performed. Blood lipase levels were analyzed systematically at each consultation of the patients and in the event of bouts of abdominal pains. Imaging using mainly echograms and tomodensitometric scans were regularly performed: echograms every 6 months, and tomodensitometric scans every 1 to 2 years. Magnetic resonance imaging was performed in four patients. Five groups of patients were identified on the basis of tomodensitometric scan findings: normal pancreas (n = 4), incomplete lipomatosis of the pancreas (n = 9), complete lipomatosis of the pancreas (n = 23), cystic pancreas (n = 5), macrocystic pancreas (n = 1), atrophic pancreas (n = 13). Pancreas exocrine function was not correlated with findings. Forty episodes of pancreatitis were observed in seven patients. They had bouts of abdominal pain and elevation of lipase levels. Five of these patients were composite heterozygotes (D508/other). Incomplete lipomatosis represents an intermediate stage leading toward complete lipomatosis or toward atrophy after pancreatitis. Studies of pancreatic function should be performed routinely in cystic fibrosis, especially in pancreatic sufficiency or in patients with normal pancreas images. Acute pancreatitis should be diagnosed and properly identified to be differentiated from other acute abdominal syndromes occurring in cystic fibrosis.

Cystic Fibrosis of the Pancreas: Involvement of MUC6 Mucin in Obstruction of Pancreatic Ducts

Cystic fibrosis (CF) is characterized by pancreatic destruction following the gradual obstruction of small pancreatic ducts, from the mid-trimester of gestation onwards. To date, the material causing the obstruction has not been identified. The MUC6 mucin cDNA was isolated from human stomach and has been shown to be expressed in a number of other tissues in the gastrointestinal tract, including the gall bladder and parts of the ileum and colon. We have examined the expression of MUC6 mucin in the human pancreas, both during development and postnatally, by mRNA in situ hybridization and immunocytochemistry. In this report we establish that MUC6 transcripts are abundant in pancreatic epithelial cells and show a very similar pattern of expression in the epithelium lining small ducts and centroacinar cells to that shown by the cystic fibrosis transmembrane conductance regulator gene (CFTR). In addition, material obstructing the pancreatic ducts of CF pancreas was shown to contain MUC6 mucin. We have identified MUC6 mucin as a significant constituent of the material obstructing the small pancreatic ducts in CF.

Chloride channels and cystic fibrosis of the pancreas

Cystic fibrosis (CF) affects approximately 1 in 2000 people making it one of the commonest fatal, inherited diseases in the Caucasian population. CF is caused by mutations in a cyclic AMP-regulated chloride channel known as CFTR, which is found on the apical plasma membrane of many exocrine epithelial cells. In the CF pancreas, dysfunction of the CFTR reduces the secretory activity of the tubular duct cells, which leads to blockage of the ductal system and eventual fibrosis of the whole gland. One possible approach to treating the disease would be to activate an alternative chloride channel capable of bypassing defective CFTR. A strong candidate for this is a chloride channel regulated by intracellular calcium, which has recently been shown to protect the pancreas in transgenic CF mice. Pharmacological intervention directed at activating this calcium-activated Cl- conductance might provide a possible therapy to treat the problems of pancreatic dysfunction in CF.

EPIDEMIOLOGICAL STUDY OF CYSTIC FIBROSIS OF THE PANCREAS

414 patients seen at Hospital de Niños Ricardo Gutiérrez between 1968 and 1988 with the diagnosis of Cystic Fibrosis of the Pancreas (CFP) were studied. The purpose was to find risk factors during follow up. The items investigated were age at diagnosis and at admission, sex, year and severity at admission, total number of siblings and of affected siblings and follow up. The mean age at diagnosis, admission and death were 3.28 ± 4.2; 3.76 ± 4.55 years; and 8.55 ± 7.06, respectively. The mortality rate was 8.1 deaths per 100 year/patients. This rate was 10.2 for 1968-74, 9.5 for 1975-81 and 6.0 for 1982-88 (p < 0.05). Severity on admission, monitored by the Shwachman score, was decreasing. In the 1968-74 period half of the patients had severe forms of the disease while in 1982-88 only 26.3% were severe (p < 0.05). This was inversely correlated with patient survival. Sex wasn't significant for prognosis. Patients who were older on admission had higher mortality rates. Because of the high rate (74.8%) of patients with a severe forms without follow up, we couldn's demonstrate significant differences in patient survival according to age at admission. Patients who had one or more siblings with CFP had lower mortality rates. After 3 years of follow up survival of patients reached 68.5%, after 6 years this was 50% and after 10 years; 34.8%. During 1982-88 3 year survival was (82.4%) more frequent than in 1968-74 (67.5%) and 1974-81 (71.8%). These significant differences disappeared at 6 and 10 years of follow up.

Fecal chymotrypsin levels in children with pancreatic insufficiency

The fecal chymotrypsin (FC) levels in samples collected over 24 h were determined by a new commercial colorimetric method from Boehringer Mannheim in 82 children suffering from various pancreatic disorders. The patients were divided into 4 groups, in accordance with the following etiologies: cystic fibrosis of the pancreas (CFP), chronic severe hepatic disorders (CSH), primary malabsorption syndrome (PMS) and malnutrition due to nondigestive causes (M). The control group comprised 48 children of similar ages. The 24th FC levels as U/g (mean +/- SD) were: 34 +/- 6 in the control group, 2 +/- 2 in the CFP group, 15 +/- 6 in the M group, 19 +/- 9 in the CSH group and 43 +/- 13 in the PMS group. The differences between the CFP patients and all the other groups were statistically significant. These results indicate that the FC levels may be suitable as a diagnostic indication of CFP and capable of differentiating between this disorder and other causes of pancreatic insufficiency.

Soy Formula

To the Editor.— The excellent commentary by the Committee on Nutrition of the American Academy of Pediatrics on soy-protein formulas1 needs an addition to the instances when soy-protein should not be used. Soy-protein may be harmful in cystic fibrosis of the pancreas as the protein is contaminated with trypsin inhibitors which can aggravate the pancreatic insufficiency and interfere with absorption of protein resulting in hypoalbuminemia and its manifestations.2-4 I think this addition will remind pediatricians that soy-based formulas are not recommended for patients with cystic fibrosis.

The meconium ileus equivalent in mucoviscidosis

Meconium ileus equivalent (MIE) complicating cystic fibrosis of the pancreas (CF) increases in frequently with increasing age of patients. In the present paper the course of 11 children and adolescents with MIE diagnosed and treated at the University Dept. of Paediatrics in Zürich during the last 15 years, i.e. 9% of 120 CF patients, is analyzed. 9 were successfully managed by medical treatment alone, 1 three months old infant was treated surgically with no later relapse and a 26 years old patient with a chronic deleterious course leading to opiate dependency could be relieved only by ileostomy. 5 patients experienced only 1 episode of MIE, 2- two to three and in 4 a chronic refractory course with multiple episodes was probably due to an inadequate medical management. The evaluation of the events in our patients and of the available data from the literature allows the following conclusions: MIE is a preventable condition in CF patients; a rigorous medical treatment of exocrine pancreatic insufficiency supplemented with mucolytic agents orally can usually prevent MIE and relieve an established MIE; surgical treatments is indicated only in desperate situations.

Renin substrate depletion in salt-losing congenital virilizing adrenal hyperplasia: Low plasma renin activity despite increased renin concentration

fibrosis (CF): Composition and enzyme content. Pediatr Res 16:164A, 1982. 4. Shiffman ML, Swender PT, Clark DA: Breast milk composition in a women with cystic fibrosis. Cystic Fibrosis Club Abstracts, vol 22, Twenty-Second Annual Meeting, May I, 1981, San Francisco. Rockville, Md., 1981, Cystic Fibrosis Foundation, p 51. 5. Seale TW, Flux M, Rennert OM, Shiffman ML, Swender PT: Breast feeding by two mothers with cystic fibrosis. Pediatr Res 16:176A, 1982. 6. Berlin CM: Pharmacologic considerations of drug use in the lactating mother. Obstet Gynecol 58:17S, 1981. 7. Ladenson JH, Apple FS, Koch DD: Misleading hyponatremia due to hyperlipidemia: A method-dependent error. Ann Intern Med 95:707, 1981. 8. Gross S J, Geller MS, Tomarelli RM: Composition of breast milk from mothers of preterm infants. Pediatrics 68:490, 1981. 9. Peaker M: Lactation: Some cardiovascular and metabolic consequences, and the mechanism of lactose and ion secretion into milk. In Breast feeding and the mother (Ciba Foundation Symposium No. 45, NS). Amsterdam, 1976, Elservier/ Excerpta Medica, pp 87-97. 10. Mangos JA, McSherry NR: Sodium transport: Inhibitory factor in sweat of patients with cystic fibrosis. Science 158:135, 1967. 11. Mangos JA, McSherry NR, Benke P J: A sodium transport inhibitory factor in the saliva of patients with cystic fibrosis of the pancreas. Pediatr Res 1:436, 1967. 12. Anand SK, Sanborg C, Robinson RG, Lieberman E: Neonatal hypernatremia associated with elevated sodium concentration of breast milk. J PEDIATR 96:66, 1980. 13. Oski FA, Stockman JA, editors: The year book of pediatrics 1981. Chicago, 1981, Year Book Medical Publishers, p 326.

Comparisons of eccrine sweat gland anatomy in genetic, chromosomal, and other diseases, and a suggested procedure for use of sweat gland measurements in differential diagnosis.

Statistical analysis of the dimensions of microdissected eccrine sweat glands (duct length, coil volume, ratio of coil volume to duct length, and axis ratio of coil) was performed for several diseases (cystic fibrosis of the pancreas, Werdnig-Hoffmann disease, tetralogy of Fallot, chronic renal disease, and trisomies 13, 18, and 21) using both individual and grouped age-matched control patients. Duct length, coil volume, and the ratio of the two all rise with age. Eccrine gland duct length was found to be significantly large in tetralogy of Fallot and Werdnig-Hoffmann disease and small in chronic renal disease (less so in males than in females, trisomy 13 and trisomy 18). Secretory coil volume was significantly smaller than normal in trisomy 21 (Down syndrome) and in chronic renal disease, and the ratio of coil volume to duct length was low in trisomy 21 and chronic renal disease. The shape of the secretory coil (axis ratio) was possibly abnormal in trisomy 13. Gland dimensions were normal for cystic fibrosis. Using the multivariate procedure of discriminant analysis, it was found that sweat gland measures significantly contributed to the differentiation of diseases, after adjustments were made for variations in age-at-death. This suggested the possibility that criteria for distinction of clinically similar genetic, metabolic, or chromosomal diseases by study of the anatomic properties of eccrine glands obtained by skin biopsy could be developed. A procedure of analysis comparing the "percentage of normal" of gland dimensions for each disease to control values, and thereby differentiating disease categories on the basis of the "percentage of normal" values, is presented.

Determination of protease-cleaved p-aminobenzoic acid (PABA) in serum after oral administration of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (PABA-peptide) in children.

A modification of the urine PABA tet published by Imondi et al. is described. Ninety minutes after oral administration of PABA peptide, PABA was determined in serum. The average concentration in healthy children was 0.42 +/- 0.055 mg per 100 ml. Up to that time we recovered in the urine 66.1 +/- 6.1% of the substance previously administered. In the children with cystic fibrosis of the pancreas (CF) serum PABA concentrations were less than 0.1 mg per 100 ml. The infants under 2 months old also had clearly low serum concentrations, on average 0.29 +/- 0.06 mg per 100 ml, whereas the PABA concentrations in the older babies lay within the range for the older children (0.40 +/- 0.07 mg%).

The Radioimmunoassay of Human Urinary Kallikrein and Comparisons with Kallikrein Activity Measurements*

Human urinary kallikrein was purified to homogeneity, and an antiserum to it was raised in rabbits. A RIA was devised which uses this rabbit antiserum (Keq = 2.75 x 10(11) M-1) in a final dilution of 1:2,500,000 and the purified kallikrein labeled with 125I using a lactoperoxidase method. Assay sensitivity is 8 pg kallikrein. Thus far, the assay is specific for human and perhaps monkey urinary kallikrein. Correlations between this assay of immunoreactive kallikrein and the alpha-N-Tosyl-L-arginine-[3H]methylester (Tos-Arg-OMe) activity method or a kininogenase assay were highly significant (r = 0.94 and 0.96, respectively) and show that each assay measures human urinary kallikrein comparably. Low or high dietary sodium intakes, maneuvers known to change human urinary Tos-Arg-OMe esterase excretion, change immunoreactive kallikrein to an equivalent degree. Normal black children, already known to excrete significantly less Tos-Arg-OMe esterase than white children, excrete similarly reduced amounts of immunoreactive kallikrein. Kallikrein excretion in children with cystic fibrosis of the pancreas was not different from that in normal children. The data show that a specific and sensitive direct RIA for human urinary kallikrein has been developed and that both the Tos-Arg-OMe esterase and kininogenase assays measure human urinary kallikrein activity specifically, at least in the described circumstances.