Recurrent acute pancreatitis: an algorithmic approach to identification and elimination of inciting factors.

Recurrent acute pancreatitis represents a challenging clinical problem associated with significant morbidity, impairment in quality of life, and expense. If unchecked, recurrent episodes of acute pancreatitis may lead to chronic pancreatitis. In this work we have combined the opinion of experts in pancreatology and an extensive review of the literature to develop a logical algorithm that facilitates the stepwise identification and elimination of inciting factors using current technology. The approach taken in recurrent acute pancreatitis is clearly dependent on adequate and appropriate evaluation and treatment of the patient with an initial episode of acute pancreatitis. Future advances in the treatment of these patients will almost certainly depend on improved imaging modalities, prospective clinical trials assessing the efficacy of endoscopic and surgical intervention, a better understanding of mutations and pathophysiologic mechanisms responsible for recurrent acute pancreatitis, and the development of novel, effective preventive and therapeutic strategies.

Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study.

BACKGROUND: Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available. AIM: To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene. METHODS: Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree. RESULTS: A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred. CONCLUSIONS: The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.

How cystic fibrosis affects pancreatic ductal bicarbonate secretion.

Pancreatic bicarbonate secretion is impaired in patients with cystic fibrosis. This article reviews recent advances in bicarbonate dependent transporters in pancreatic duct cells and discusses their regulation in cystic fibrosis.

Growth factors, receptors, and molecular alterations in pancreatic cancer. Putting it all together.

Because of the dismal prognosis of advanced ductal pancreatic adenocarcinoma, recent investigational strategies have focused on improved detection and therapeutic intervention in early-stage pancreatic cancer. The obvious cost constraints of screening populations at risk but with a low tumor yield will restrict screening protocols to only the highest risk groups (hereditary pancreatitis = age 50, certain hereditary pancreatic cancer kindreds). The vast majority of patients, either lacking or exhibiting an inherited predisposition to pancreatic cancer, will continue to present with disease not resectable for cure. The authors believe that the best hope for these patients lies in the further delineation of the integrative pathophysiology driving tumor growth; this would facilitate the future development of a computer program or other modality that would predict the dominant pathways driving the growth and spread of each tumor based on its "molecular profile." This article reviews the authors' current knowledge regarding the growth factors, receptors, and molecular alterations driving uncontrolled proliferation, local invasion, and metastatic spread of these tumors. The current and potential contributions of studies in cohorts with an inherited predisposition to pancreatic cancer to this pathophysiologic model are also discussed. The future strategy for incorporating this information into a working pathophysiologic road map with clinical relevance is subsequently outlined.

Pancreatic cancer surveillance in a high-risk cohort. Is it worth the cost?

Pancreatic adenocarcinoma is the 10th most common malignancy and 4th largest cancer killer in adults. Earlier tumor detection through screening of high risk groups, presumably to increase the percentage of cases resectable for cure in these cohorts, has emerged as a prominent strategy to combat this disease. This article examines the feasibility of this strategy in patients with hereditary pancreatic cancer (HPC) and hereditary pancreatitis (HP). Because of a variety of factors, specific cost projections for screening with HPC kindreds are problematic at best. Patients with HP exhibit a 53-fold increased risk of pancreatic cancer, with a cumulative risk of 40% by age 70. The authors discuss the modalities available to screen this cohort and subsequently perform a theoretical cost analysis. The authors' findings suggest that screening has the potential to be cost-effective only in hereditary pancreatitis patients = 50 years-of-age. The most cost-effective option will likely combine an initial serologic test with high sensitivity and a subsequent serologic or pancreatic juice test with sufficient specificity to act as a "gatekeeper" to imaging with endoscopic ultrasound (EUS). Banking of blood and pancreatic juice samples should be mandatory in any screening protocol. The lower tumor yield in other high-risk groups (e.g., non-hereditary chronic pancreatitis) will effectively preclude the use of such screening protocols. The vast majority of patients will continue to present with unresectable disease.

Hereditary pancreatitis. Gene defects and their implications.

Hereditary pancreatitis is a rare condition characterized by acute and chronic pancreatitis transmitted in an autosomal dominant fashion. There also is an epidemiologic link to pancreatic cancer in some affected families. Failure of a secondary brake mechanism responsible for inactivation of prematurely activated cationic trypsin in acinar cells seems to be the fundamental defect in type I hereditary pancreatitis (R117H cationic trypsin), and also may explain the pathogenesis of type II hereditary pancreatitis (N211 cationic trypsin). The diagnosis is made based on clinical history and, in certain cases, by molecular diagnostic testing for these gene defects. Medical management of acute and chronic hereditary pancreatitis currently does not differ from that of nonhereditary AP. As in nonhereditary pancreatitis, the surgical approach must be tailored to the individual problem, with an understanding that disease restricted to the head of the gland is atypical and that residual acinar tissue continues to drive the disease state. Although diagnosis and management of pancreatic adenocarcinoma are similar in this cohort, the increased age-accumulated risk suggests that thoughtful screening protocols eventually may be clinically and cost-effective.

Pancreatic disease in the elderly.

This article reviews age-related alterations in pancreatic structure and function and provides an update of advances in clinical understanding of the epidemiology, pathogenesis, and pathophysiology of acute pancreatitis, chronic pancreatitis, and pancreatic adenocarcinoma. This article also provides guidelines for the integration of recent radiologic, endoscopic, surgical, and oncologic advances in these areas into the current clinical practice of the gerontologist and gastroenterologist.

Endoscopic pancreatic duct stenting to treat pancreatic ascites.

BACKGROUND: Management of pancreatic ascites with conservative medical therapy or surgery has met with limited success. Decompression of the pancreatic ductal system through transpapillary stent placement, an alternative strategy, has been reported in only a handful of cases of pancreatic ascites. METHODS: We reviewed all cases from 1994 to 1997 in which patients with pancreatic ascites underwent an endoscopic retrograde pancreatogram documenting pancreatic duct disruption with subsequent placement of a transpapillary pancreatic duct stent. Clinical end points were resolution of ascites and need for surgery. RESULTS: There were 8 cases of pancreatic ascites in which a 5F or 7F transpapillary pancreatic duct stent was placed as the initial drainage procedure. Pancreatic ascites resolved in 7 of 8 patients (88%) within 6 weeks. Ascites resolved in the eighth patient, a poor candidate for surgery, following placement of a 5 mm expandable metallic pancreatic stent. No infections, alterations in ductal morphology, or other complications related to stent placement were noted. There was no recurrence of pancreatic ascites or duct disruption at a mean follow-up of 14 months. CONCLUSIONS: Our experience doubles the number of reported cases in which transpapillary pancreatic stent placement safely obviated the need for surgical intervention in the setting of pancreatic ascites. This therapeutic endoscopic intervention should be seriously considered in the initial management of patients with pancreatic ascites.

Prevalence and predictors of severe acute pancreatitis in patients with acquired immune deficiency syndrome (AIDS).

OBJECTIVE: Recent case control data suggested that a severe course of acute pancreatitis in HIV+ patients was 1) common (50% of cases), 2) poorly predicted by Ranson's criteria (sensitivity 41%), and 3) accurately predicted by a diagnosis of AIDS (positive predictive value 67%). However, the definition of severity included length of stay in hospital and excluded commonly accepted markers (local complications, systemic complications, and need for surgery). The aim of this study was to determine 1) the prevalence of severity and 2) the value of these predictors with regard to severity, as defined by commonly accepted standardized criteria in patients with AIDS and acute pancreatitis. METHODS: A retrospective review identified 50 patients with AIDS exhibiting clinical, laboratory, and/or radiological features of acute pancreatitis. RESULTS: Only five patients followed a severe course as defined by accepted markers. Of these patients, 29 had values available for at least nine of 11 of Ranson's criteria (sensitivity 80%, specificity 54%). Points were awarded most commonly for decreased serum Ca2+ (n = 14) and elevated serum LDH (n = 7). CONCLUSIONS: In patients with AIDS and acute pancreatitis at our institutions, 1) the prevalence of severity and 2) the sensitivity of Ranson's criteria with regard to severity is comparable to that reported in large historical case series of immunocompetent patients. Pseudohypocalcemia and/or elevation in LDH are frequent, likely due to the catabolic infectious disease state.

CFTR drives Na+-nHCO-3 cotransport in pancreatic duct cells: a basis for defective HCO-3 secretion in CF.

Pancreatic dysfunction in patients with cystic fibrosis (CF) is felt to result primarily from impairment of ductal HCO-3 secretion. We provide molecular evidence for the expression of NBC-1, an electrogenic Na+-HCO-3 cotransporter (NBC) in cultured human pancreatic duct cells exhibiting physiological features prototypical of CF duct fragments (CFPAC-1 cells) or normal duct fragments [CAPAN-1 cells and CFPAC-1 cells transfected with wild-type CF transmembrane conductance regulator (CFTR)]. We further demonstrate that 1) HCO-3 uptake across the basolateral membranes of pancreatic duct cells is mediated via NBC and 2) cAMP potentiates NBC activity through activation of CFTR-mediated Cl- secretion. We propose that the defect in agonist-stimulated ductal HCO-3 secretion in patients with CF is predominantly due to decreased NBC-driven HCO-3 entry at the basolateral membrane, secondary to the lack of sufficient electrogenic driving force in the absence of functional CFTR.

Hereditary pancreatitis: new insights, new directions.

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis with a familial predisposition. Recently, the gene mutations causing most cases of hereditary pancreatitis have been identified in the cationic trypsinogen gene. The known mutations are trypsinogen R117H and N211. These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. Accumulation of active trypsin mutants are hypothesized to initiate a digestive enzyme activation cascade in the pancreatic acinar cells leading to autodigestion, an intense inflammatory response, and acute pancreatitis. The observation that these patients also develop typical chronic pancreatitis and may later develop pancreatic cancer provides strong evidence that these conditions are linked. Knowledge of the pathophysiological conditions leading to acute and chronic pancreatitis and the development of a transgenic mouse expressing the mutant human trypsinogen genes will provide directions and tools necessary for the effective treatment or prevention of this human disease.

Cellular distribution of secretin receptor expression in rat pancreas.

Secretin is an important regulator of pancreatic function, but the molecular basis of its actions is not well understood. We have, therefore, used in situ autoradiography, photoaffinity labeling, and RNase protection assays with healthy rat pancreas, dispersed acinar cells, and pancreas depleted of acinar cells to explore the cellular distribution and molecular identity of high-affinity secretin receptors in this complex organ. The autoradiographic examination of 125I-labeled [Tyr10]rat secretin-27 binding to normal pancreas demonstrated saturable and specific high-affinity binding sites on both acinar and duct cells, with a uniform lobular distribution, but with no binding above background over islets or vascular structures. Photoaffinity labeling demonstrated that the ductular binding site in acinar cell-depleted copper-deficient rat pancreas represented the same glycoprotein with a molecular weight of 50,000-62,000 that was present on acinar cells. RNase protection assays confirmed the molecular identity of the secretin receptors expressed on these distinct cells. The apparent absence or extreme low density of similar secretin receptors on islets and pancreatic vascular structures suggests that the pharmacological effects of secretin on those cells may either be indirect or mediated by another secretin family receptor that recognizes this hormone with lower affinity.

Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG)

OBJECTIVES: Because there are no markers for hereditary pancreatitis (HP), diagnosis has relied on clinical features and inferences. Identification of the HP disease gene locus on chromosome 7q35 provides the first genetic marker for HP, allowing an accurate comparison of the clinical diagnosis of HP with the presence of a high-risk HP haplotype. Our objectives were to compare the clinical diagnosis of HP with inheritance of the HP gene and to characterize the common clinical features. METHODS: A detailed questionnaire was administered to 102 study participants of a large HP kindred. Blood samples were taken for DNA extraction and high-risk haplotype determination. Clinical findings were compared with the presence of a high-risk haplotype. RESULTS: A family tree of more than 500 members and eight generations was constructed, and clinical features of the 102 participants were determined. HP occurred before the age of 5 yr in 58% of subjects, who presented with common symptoms of abdominal pain, nausea/vomiting, and frequent attacks. Thirty-five probands, of whom 80% had clinical symptoms, carried the high-risk haplotype, confirming previous estimates of 80% penetrance. Thirty-two of the study participants had been clinically diagnosed with HP, whereas 70 were clinically unaffected. With regard to the presence of the high-risk haplotype, 87.5% of the clinically diagnosed patients were affected by HP (true positive), whereas 12.5% did not carry the high-risk haplotype (false positive). Seven obligate carriers were identified through DNA analysis; three had previously been unrecognized because of lack of affected offspring. CONCLUSIONS: The diagnosis of hereditary pancreatitis on clinical grounds alone may be inaccurate in less severe cases, as is the exclusion of carrier status through family tree analysis. Therefore, a definitive diagnosis of hereditary pancreatitis in equivocal cases or exclusion of a carrier state should include analysis of genetic markers.