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PubMed1979

Radioimmunoassay of trypsin. A new aid in the assessment of pancreatic function.

This review describes the development and application of a novel test to determine levels of human immunoreactive trypsin, an enzyme produced solely by the pancreas, in biological fluids. Being organ-specific, the assay of immunoreactive trypsin should be an ideal marker of pancreatic function, and this is supported by the results of a number of clinical and research investigations. Use of this assay in studies of chronic pancreatitis, juvenile-onset diabetes, and cystic fibrosis has yielded much valuable data, and it is expected that further research will lead to an improved understanding of these and other conditions associated with the pancreas in health and disease.

Cystic Fibrosis↗
PubMed1997

The cystic fibrosis transmembrane conductance regulator as a marker of human pancreatic duct development.

BACKGROUND & AIMS: The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a small conductance adenosine 3',5'-cyclic monophosphate (cAMP)-activated chloride ion channel found in the apical membranes of epithelia within the pancreas, airway, intestine, bile duct, sweat gland, and male genital ducts. Pancreatic insufficiency is a feature of about 85% of patients with cystic fibrosis and is believed to be caused by pancreatic autolysis after pancreatic duct obstruction. The aim of this study was to investigate the expression of CFTR in the pancreas from early development to postnatal life to establish whether the CFTR plays a key role in development of the pancreatic duct epithelium. METHODS: Expression of CFTR from the start of the mid-trimester of human development through term to adult life by messenger RNA (mRNA) in situ hybridization was examined. RESULTS: CFTR mRNA is detected throughout the pancreatic duct epithelium and its pattern of expression follows the differentiation of the duct system. CONCLUSIONS: CFTR is a valuable marker of human pancreatic duct cell development and differentiation.

Aging↗
PubMed2004

Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events.

Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous DeltaF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.

Absorption↗
PubMed1993

A cohort study of cystic fibrosis and malignancy.

A cohort of 412 patients first attending a cystic fibrosis (CF) clinic between 1961 and 1989 were followed up to 30 June 1989. The number of malignancies observed in the cohort was compared with the number expected based on the age, sex and calendar-year-specific cancer registration rates for England and Wales. Four CF patients were diagnosed as having malignancies before 30 June 1989. The tumours were: adenocarcinoma of the terminal ileum; adenocarcinoma of the pancreas, testicular teratoma, and B-cell lymphoma. This compares with 0.89 malignancies expected on the basis of rates in England and Wales (Standardised Registration Ratio = 452; 95% confidence interval 122-1150, P = 0.03). The single case of adenocarcinoma of the terminal ileum contrasts with less than 0.001 expected (P = 0.003) and that of the pancreas with 0.007 expected (P = 0.01). A further adenocarcinoma of the pancreas was diagnosed 2 years after the end of the study period. The two cases of pancreatic cancer compare with 0.008 expected (P = 0.0001) during the period to mid 1991. On the basis of the present findings and previous case reports in the literature adenocarcinoma of the pancreas and adenocarcinoma of the terminal ileum may be associated with cystic fibrosis.

Adenocarcinoma↗
PubMed1982

A survey of pancreatic lesions in nonhuman primates.

Approximately 3,000 microslides of hematoxylin and eosin (HE)-stained sections of pancreas from 1,000 nonhuman primates were reviewed. Sections were from 557 females and 443 males; 658 were adults of unknown age and 342 were laboratory-born animals of known age. The latter included 94 animals less than one year old, 92 from one to five years old, and 156 from five to more than 20 years old. There were 326 squirrel monkeys, 319 rhesus monkeys, 100 great apes, 123 other macaques, 61 other Old World monkeys, 39 other New World monkeys, and 32 prosimians. Pancreatic lesions of varied severity found in 187 (18.7%) of these nonhuman primates included focal parenchymal or periductal accumulations of mononuclear inflammatory cells with varied degrees of periductal fibrosis in 77; hyalinized islets (amyloidosis) in 29; acute or chronic diffuse pancreatitis in 18; chronic focal pancreatitis with or without ductal hyperplasia in ten; neoplasms in 11; hemorrhage of the parenchyma or islets in eight; parasites in seven; lymphoid or ectopic splenic nodules of the parenchyma in six; acinar ectasia in six; focal parenchymal fat in six; ectopic pancreas in four; parenchymal cysts without fibrosis in three; acinar cell atrophy in one; and cystic fibrosis-like changes in one.

Amyloidosis↗
PubMed2002

The electrolyte/fluid secretion stimulatory peptides guanylin and uroguanylin and their common functional coupling proteins in the rat pancreas: a correlative study of expression and cell-specific localization.

INTRODUCTION: Guanylin and uroguanylin are intestinal or urine peptides that stimulate epithelial electrolyte/fluid secretion by activating the cystic fibrosis gene product (CFTR). AIMS: Because CFTR is essentially involved in the electrolyte secretion of the pancreatic duct cells, the rat pancreas was investigated for expression and cell-specific localization of guanylin and uroguanylin; expression of major components of the guanylin signaling pathway, i.e., the guanylin/uroguanylin receptor guanylate cyclase C (GC-C), cGMP-dependent protein kinase II, and CFTR; and expression of the epithelial Cl-/HCO3- exchanger AE2. METHODOLOGY AND RESULTS: Reverse transcriptase polymerase chain reaction analyses revealed high expression of guanylin, uroguanylin, and the functional coupling proteins in the rat pancreas. At the cellular level, guanylin and uroguanylin were localized by immunohistochemistry to the centroacinar cells and proximal duct cells of the exocrine pancreas. The guanylin/uroguanylin receptor GC-C, cGKII, CFTR, and AE2 were all found in the same segments of the ductal system, where they were confined to the apical membrane of centroacinar cells and proximal duct epithelial cells, a circumstance suggesting that both peptides may act through the ductal lumen. CONCLUSION: In view of the well-known functional significance of guanylin and uroguanylin, the presence and cell-specific expression not only of the both peptides but also of their common functional coupling proteins implicates a regulatory function of these peptides in the electrolyte/fluid secretion within the rat exocrine pancreas.

Animals↗
PubMed2004

Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation.

BACKGROUND & AIMS: Cystic fibrosis (CF) results from abnormal production of sticky mucus, which obstructs many organs. In most cases, the pancreas is severely compromised, but 10%-15% of patients with CF have pancreas sufficiency (PS) and are subject to develop pancreatitis. The aim of this study is to determine which specific genotypes lead to the development of pancreatitis in patients with CF. METHODS: We used prospective data collected by the Cystic Fibrosis Foundation and performed a nested case-control study with all patients who reported at least 1 episode of pancreatitis constituting the cases. We used logistic regression to assess the association between pancreatitis and genotype and the Kaplan-Meier method to estimate the cumulative incidence of pancreatitis for selected genotypes. RESULTS: Three hundred sixty-four of 17,871 genotyped patients with CF (2.0%) reported at least 1 episode of pancreatitis. Only 0.9% of 12,997 patients with genotypes generally associated with pancreas insufficiency reported pancreatitis against 11.9% of 868 patients carrying at least 1 mild CF mutation generally associated with PS. The greatest rate of pancreatitis (19.0%) was observed for patients carrying an R334W mutation: 48% of these 79 patients were Hispanic and 13 patients were living in Puerto Rico. CONCLUSIONS: Of all patients with CF, those carrying an R334W mutation have the greatest risk for developing pancreatitis. This mutation is found mostly in Hispanic patients with CF living in Puerto Rico. There are no current data to determine whether asymptomatic carriers of the R334W mutation are at greater risk for developing pancreatitis or whether this mutation is frequent in Hispanics with idiopathic pancreatitis.

Adolescent↗
PubMed1986

Age-related alterations of immunoreactive pancreatic cationic trypsinogen in sera from cystic fibrosis patients with and without pancreatic insufficiency.

Serum immunoreactive cationic trypsinogen levels were determined in 99 control subjects and 381 cystic fibrosis (CF) patients. To evaluate the status of the exocrine pancreas all CF patients had previously undergone fecal fat balance studies and/or pancreatic stimulation tests. Three hundred fourteen CF patients had fat malabsorption and/or had inadequate pancreatic enzyme secretion (pancreatic insufficiency) requiring oral pancreatic enzyme supplements with meals. Sixty-seven CF patients did not have fat malabsorption and/or had adequate enzyme secretion (pancreatic sufficiency) and were not receiving pancreatic enzyme supplements with meals. Mean serum trypsinogen in 99 control subjects was 31.4 +/- 14.8 micrograms/liter (+/- 2 SD) and levels did not vary with age or sex. In CF infants (less than 2 yr) with pancreatic insufficiency, mean serum trypsinogen was significantly above the non-CF values (p less than 0.001). Ninety-one percent of the CF infants had elevated levels. Serum trypsinogen values in the pancreatic insufficient group declined steeply up to 5 years, reaching subnormal values by age 6. An equation was developed which described these age-related changes very accurately. Only six CF patients with pancreatic insufficiency had serum trypsinogen levels above the 95% confidence limits of this equation. In contrast, there was no age related decline in serum trypsinogen among the CF group with pancreatic sufficiency. Under 7 yr, serum trypsinogen failed to distinguish the two groups. In those over 7 yr of age, however, serum trypsinogen was significantly higher than the CF group with pancreatic insufficiency (p less than 0.001), and 93% had values within or above the control range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis.

Although dehydrated obstructing mucus is thought to account for the obstructive pathology involving the lungs, the pancreas, the reproductive system, and the intestinal tract, its relationship with CF-associated liver disease remains largely hypothetical and little is known about possible risk factors. Complete clinical and autopsy records were available in 38 of 73 deaths occurring over a 10-year period. The liver was normal in only five cases, and they were all infants. Steatosis was the only lesion present in 9, hypoxic liver disease was documented in 8, and biliary cirrhosis in 16 (focal in 10 and multilobular in 6). There was no relationship between the presence of cirrhosis, gallbladder abnormalities, age at death, and clinical status recorded during the year precoding their demise. Mucus plugs characterized by amorphous eosinophilic material within proliferated bile ductules were present in 75% of children with focal or multilobular biliary cirrhosis as opposed to 14% in those without (p = 0.015). A history of meconium ileus or its equivalent was recorded more frequently (p = 0.038) in those with cirrhosis. Finally, biliary cirrhosis was invariably present when there was a history of meconium ileus or its equivalent and when mucus plugs were noted. These findings suggest that patients with intestinal obstruction are at greater risk for the development of cirrhosis and that strategies should be developed to increase the detergent capacity of bile and its flow in order to decrease the viscosity of mucus in the biliary tree.

Bile↗
PubMed2006

CFTR chloride channel drug discovery--inhibitors as antidiarrheals and activators for therapy of cystic fibrosis.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cAMP-activated chloride channel expressed in epithelia in the lung, intestine, pancreas, testis and other tissues, where it facilitates transepithelial fluid transport. In the intestine CFTR provides the major route for chloride secretion in certain diarrheas. Mutations in CFTR cause the hereditary disease cystic fibrosis, where chronic lung infection and deterioration in lung function cause early death. CFTR is a well-validated targeted for development of inhibitors for therapy of secretory diarrheas and activators for therapy in cystic fibrosis. Our lab has identified and optimized small molecule inhibitors of CFTR, as well as activators of DeltaF508-CFTR, the most common mutant CFTR causing cystic fibrosis. High-throughput screening of small molecule collections utilizing a cell-based fluorescence assay of halide transport yielded thiazolidinone and glycine hydrazide CFTR inhibitors that block enterotoxin-mediated secretory diarrhea in rodent models, including a class of non-absorbable inhibitors that target the CFTR pore at its external entrance. Benzothiophene, phenylglycine and sulfonamide potentiators were identified that correct the defective gating of DeltaF508-CFTR chloride channels, and other small molecules that correct its defective cellular processing. Small molecule modulators of CFTR function may be useful in the treatment of cystic fibrosis, secretory diarrhea and polycystic kidney disease.

Animals↗
PubMed2001

Pancreatitis: etiology, diagnosis, and management.

Inflammation of the pancreas (pancreatitis) has many presentations in children and adolescents, ranging from intrauterine congenital onset with sequelae of early exocrine pancreatic insufficiency as in the diseases of cystic fibrosis and Shwachman-Diamond syndrome to postnatal onset as a consequence of embryologic anomalies affecting pancreatic drainage postulated to exist in pancreas divisum, or of traumatic, obstructive, hemodynamic, metabolic or biochemical insults. The etiology is often elusive with up to 30% of cases being idiopathic. Modern imaging modalities of endoscopic ultrasonography and magnetic resonance cholangiopancreatography extend the diagnostic power of conventional abdominal ultrasonography and computed tomography. In addition, there is increasing pediatric experience with endoscopic retrograde cholangiopancreatography. Medical management remains supportive, with optimal timing and indications for surgery in cases of pancreatic necrosis and pseudocyst assessed. Three temporal patterns of pancreatitis appear in children: acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. Acute pancreatitis is of abrupt onset, often attributable to a specific cause, and of variable severity and duration but self-limited with eventual resolution. Acute attacks of pancreatitis recurring after periods of remission characterize acute recurrent pancreatitis and indicate an intrinsic problem or susceptibility. Chronic pancreatitis is present in most of these cases in which pancreatic inflammation and destruction never completely remits.

Acute Disease↗
PubMed1992

Altered sulfate transport via anion exchange in CFPAC is corrected by retrovirus-mediated CFTR gene transfer.

PANC-1 (a permanent epithelioid cell line initiated from a pancreatic carcinoma of ductal origin) and CFPAC (a ductal epithelioid cell line established from a cystic fibrosis patient with pancreatic adenocarcinoma) display sulfate transport via carrier-mediated anion exchange as supported by the following lines of evidence: 1) saturation kinetics, 2) inhibition by the anion exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 3) substrate specificity. The DIDS-sensitive component of sulfate uptake is markedly inhibited by S2O3(2-) and MoO4(2-) but not by HAsO4(2-), H2PO4-, or gluconate-. Competitive inhibition of SO4(2-) uptake by extracellular Cl- (Cl-o) and stimulation of SO4(2-) efflux by Cl-o support the possibility that SO4(2-) transport occurs via a SO4(2-)-Cl- exchange mechanism. Inhibition of sulfate uptake and stimulation of sulfate efflux by extracellular HCO3- indicate that SO4(2-)-HCO3- exchange is an alternative mechanism for sulfate transport in these cells. Further support for SO4(2-) being transported via a typical anion exchanger is the stimulation of its uptake at low extracellular pH and high intracellular pH. Amphotropic viruses have been used by others (M. L. Drumm, H. A. Pope, W. H. Cliff, J. M. Rommens, S. A. Marvin, L.-C. Tsui, F. S. Collins, R. A. Frizzell, and J. M. Wilson. Cell 62: 1227-1233, 1990) to transduce a functional cystic fibrosis transmembrane regulator (CFTR) cDNA into CFPAC, resulting in the PLJ-CFTR clones. Control clones (PLJ) were obtained by exposing CFPAC cells to control virus. In the present study, we report a striking 10-fold increase in the capacity of the DIDS-sensitive component of the sulfate transporter in two PLJ-CFTR clones (which had been shown by others to express corrected Cl- channel activity) compared with CFPAC and two PLJ clones. Our findings indicate that expression of the CFTR gene from a retroviral vector, which confers normal Cl- channel activity in the PLJ-CFTR pancreas epithelial clones, is capable of correcting a second aspect of the cystic fibrosis phenotype, altered sulfate transport via an anion exchange mechanism.

Anions↗