Edward D. Purich

A Randomized Crossover Study of Secretin-Stimulated Endoscopic and Dreiling Tube Pancreatic Function Test Methods in Healthy Subjects

OBJECTIVES:We have developed an endoscopic method of secretin endoscopic pancreatic function testing (ePFT) to simplify duodenal fluid collection. Validation of the ePFT requires a direct comparison to the traditional PFT using a Dreiling tube (DT). Our aim was to compare bicarbonate concentrations [HCO3−] obtained by the ePFT and DT methods in healthy subjects (HS).METHODS:HS were randomized to either DT or ePFT, then crossed over to the other test after a minimum 1-wk washout. An age/weight-based sedation bolus was used for each test. DT protocol: Endoscopic placement of a DT was confirmed by fluoroscopy. After a baseline 15-min collection and administration of IV synthetic secretin, fluid was continuously collected in 15-min aliquots for an hour. ePFT protocol: Endoscopy was performed using a 6-mm endoscope. After gastric aspiration and discard and IV secretin, duodenal aspirates were obtained every 15-min for an hour. Fluid specimens were auto-analyzed for [HCO3−].RESULTS:Twelve HS were enrolled (6F, mean age 37 yr). The difference in [HCO3−] between the two methods was not significant at the 0-, 30-, 45-, or 60-min collections. An excellent correlation in peak [HCO3−] was observed (R2= 0.84, p < 0.001). Using a peak [HCO3−] cutpoint 80 mEq/L, there was 100% agreement between the methods; using cutpoint 90 mEq/L, there was 83% agreement.CONCLUSIONS:The accuracy of the ePFT is similar to DT: There were minimal differences in [HCO3−] at each of the timed collections and at peak. There is an excellent correlation in peak [HCO3−] and high level of diagnostic agreement between the tests.

Evaluation of Duct-Cell and Acinar-Cell Function and Endosonographic Abnormalities in Patients With Suspected Chronic Pancreatitis

BACKGROUND & AIMS Endoscopic ultrasound (EUS) detects mild and severe structural abnormalities of the pancreas that correlate with fibrosis. Direct pancreatic function tests (PFTs) detect mild exocrine insufficiency associated with early fibrosis. The primary aim of this study was to compare EUS structural criteria with duct-cell and acinar-cell function. METHODS Fifty patients evaluated for chronic pancreatitis underwent combined EUS and secretin endoscopic PFTs (ePFT) on day 1 and CCK ePFT on day 2. EUS images were videotaped and interpreted by consensus of 3 blinded expert reviewers. RESULTS There were inverse correlations of EUS consensus score with both duct-cell bicarbonate secretion (R = -0.71, P < .001) and acinar-cell lipase secretion (R = -0.52, P < .001). With secretin ePFT as reference standard, EUS (>or=4 criteria) showed a sensitivity of 71% (95% confidence interval [CI], 53%-89%) and specificity of 92% (95% CI, 75%-99%). With CCK ePFT as reference standard, EUS had a sensitivity of 63% (95% CI, 43%-82%) and specificity of 85% (95% CI, 71%-98%). Main duct dilation, irregularity, calcifications, and visible side-branches were most predictive of exocrine insufficiency (positive predictive value >80% for both acinar- and duct-cell insufficiency). CONCLUSIONS Acinar- and duct-cell function decreases as EUS structural abnormalities increase. EUS has fair sensitivity and very good specificity compared with secretin and CCK functional reference standards.

Intravenous synthetic secretin reduces the incidence of pancreatitis induced by endoscopic retrograde cholangiopancreatography.

Objectives: This study aimed to evaluate whether synthetic secretin is effective in reducing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Methods: This is a single academic medical center, prospective, randomized, double-blind, placebo-controlled trial using secretin (dose of 16 &mgr;g) administered intravenously immediately before ERCP. Patients were evaluated for the primary outcome of post-ERCP pancreatitis as diagnosed by a single investigator. Results: A total of 1100 patients were screened, of whom 869 were randomly assigned to receive secretin (n = 426) or placebo (n = 443) before ERCP and were evaluated after the procedure for efficacy of secretin. The incidence of pancreatitis in the secretin group compared with the placebo group was 36 (8.7%) of 413 patients versus 65 (15.1%) of 431 patients, respectively, P = 0.004. In the subgroup analysis, secretin was highly protective against post-ERCP pancreatitis for patients undergoing biliary sphincterotomy (6/129 vs 32/142, P < 0.001), patients undergoing cannulation of the common bile duct (26/339 vs 56/342, P < 0.001), and patients not undergoing pancreatic sphincterotomy (26/388 vs 57/403, P = 0.001). Analysis of the interaction between these groups reveals that the primary effect of secretin prophylaxis was prevention of post-ERCP pancreatitis in patients undergoing biliary sphincterotomy. Conclusions: Synthetic secretin reduces the risk of post-ERCP pancreatitis, particularly in patients in undergoing biliary sphincterotomy.

A randomized controlled crossover study comparing synthetic porcine and human secretins with biologically derived porcine secretin to diagnose Zollinger–Ellison Syndrome

Although biologically‐derived porcine secretin is approved for the diagnosis of Zollinger–Ellison Syndrome, it is no longer available in the United States. Pure human and porcine secretins have now been synthesized and new drug applications have been filed with the Federal Drug Administration (FDA).

A double-blind, randomized, dose response study testing the pharmacological efficacy of synthetic porcine secretin

Biologically derived porcine secretin has been used as a diagnostic agent in clinical gastrointestinal practice for many years. Pure synthetic porcine secretin is now available for investigational clinical use.

Pancreatic duct compliance after secretin stimulation: a novel endoscopic ultrasound diagnostic tool for chronic pancreatitis.

Objectives Endoscopic ultrasound (EUS) evaluation of pancreatic duct compliance after secretin stimulation (sEUS) along with EUS morphologic examination (EUS) and duodenal fluid [HCO3−] measurement (endoscopic pancreatic function test, ePFT) in 1 endoscopic session has not been reported as a means of evaluating for chronic pancreatitis (CP). We evaluated the feasibility of the combined examination and compared EUS measurements of pancreatic ductal compliance with duodenal fluid [HCO3−] for diagnosing CP. Methods The study is a prospective case series of patients with suspected CP who underwent a combined EUS, sEUS, and ePFT examination in 1 endoscopic session. The main outcome measures were the feasibility of performing the combination examination and the correlation between ductal compliance and ePFT. Results All examinations were completed in 1 endoscopic session, and there were no complications in 35 patients. Although there was a trend toward less change from baseline head and body ductal diameter in patients with CP, only the percent change from baseline in the tail was significant (CP 144.3% vs healthy patients 240.9%, P < 0.01). Regression analysis demonstrated fair correlation between maximum change in ductal diameter and duodenal fluid [HCO3−] (r2 = 0.27). Conclusions Combined EUS, sEUS, and ePFTs are feasible and safe, with preliminary results demonstrating a positive correlation between pancreatic ductal compliance and duodenal fluid [HCO3−].

A phase II trial of human secretin infusion for refractory type B pain in chronic pancreatitis.

Objective We aimed to determine if intravenous synthetic human secretin (sHS) improves refractory type B pain in patients with chronic pancreatitis (CP). Methods In a phase II dose escalation trial, patients with CP received sHS of varying doses (0.05–0.8 µg/kg) for 3 days. The primary outcomes were changes in the visual analogue pain score (VAS), short form (SF) - 36, and opiate use from baseline at 30 days after infusion. Results Twelve patients (mean age, 42 years, 6 men) were included. Mean pain scores (VAS) were 5.79, 4.80, 4.72, and 4.90, at baseline, day 4, day 10, and day 30, respectively (P = 0.25, 0.19, and 0.27 when compared with baseline, respectively). Daily opiate use (oral morphine equivalents) decreased throughout the study from a baseline value of 136 to 111 mg on day 4 (P = 0.52) and to 104 mg on day 30 (P = 0.34). In subgroup analysis, women had the most improvement (VAS baseline, 5.42 vs VAS day 30, 3.67; P = 0.07; baseline morphine equivalents, 107 mg vs. 84 mg; P = 0.21). Conclusions In patients, especially women, with refractory type B pain from CP, intravenous sHS administration demonstrated a trend toward improvement in self-reported pain and opiate use at 30 days after infusion, although statistical significance was not achieved (clinicaltrials.gov registration number NCT01265875).

Su1239 A Prospective Trial of Secretin Infusion for Refractory Type B Pain in Chronic Pancreatitis

Background & Aims: Chronic pancreatitis (CP) is characterized by chronic inflammation and progressive pancreatic fibrosis leading eventually to the loss of exocrine and endocrine pancreas functions. The loss-of-function mutations of serine protease inhibitor Kazal type 1 (SPINK1) gene are associated with various forms of human CP. We previously showed that deletion of Spink3, the mouse homologue of SPINK1, causes pancreatitis-like changes in the mouse. Spink3-/mice die within 2 weeks after birth, making it impossible to monitor long-term effects of Spink3 deficiency. The aim of this study was to rescue the Spink3-/phenotype by generating Spink3-/mice with knocked-in SPINK1, and to characterize timedependent changes in the pancreas in this geneticmodel. Methods:We placedCAG promoterSPINK1 minigene (CAG-SP1) into diaphanous homolog 2 (Diap2) locus, which is located on X chromosome, using the Cre-Lox technology. X-inactivation is a process whereby one of the two copies of the X chromosome present in female mammals is inactivated. By utilizing X-inactivation, we were able to create mice in which SPINK level was partially, but not completely, reduced compared with the wild type. The CAG-SP1 knock-in mice were crossed to Spink3+/mice, thus generating Spink3-/-; CAG-SP1 knock-in mice. Mice were followed up for up to 6 months. Time-dependent changes in pancreatic histology, autophagy, inflammatory infiltration, acinar cell death, stellate cell activation, fibrosis, as well as trypsinogen activation and serum amylase were measured. Results: Spink3-/-;YXCAG-SP1, as well as Spink3-/-;XCAG-SP1/CAG-SP1 mice in which CAG-SP1 was present on both X chromosomes, showed no abnormalities in pancreas or any other organ during the 6 months of observation, indicating that human Spink1 rescues Spink3 deficiency in mice. Spink3-/-; XCAG-SP1/wild mice in which CAG-SP1 is present on only one of the two X chromosomes, showed slight growth retardation but were healthy and fertile. Pancreas of Spink3-/-; XCAGSP1/wildmice at birth contained both normal and degenerated acinar cells, with accumulation of autophagic vacuoles. The Spink3-/-;XCAG-SP1/wild mice time-dependently developed pathologic features of CP, including loss of acinar cells, intralobular fibrosis with activated stellate cells, and neutrophilic infiltration. In the interlobular areas, fibrosis was not evident, but instead prominent lipomatosis was observed. Interlobular ducts were dilated and contained protein plugs, which resembled CP in human. Older mice displayed acinar-ductal metaplasia and prominent expression of proto-oncogenes Egfr, Her2, and Ras, but did not develop pancreatic intraepithelial neoplasia. Conclusions: The results re-inforce the role of SPINK1/Spink3 deficiency in the development of CP and indicate that CP conditions trigger factors promoting pancreatic cancer development.

71 Functional Significance of Endoscopic Ultrasound (EUS) Chronic Pancreatitis (CP) Criteria: Comparison with Secretin and Cholecystokinin (CCK) Pancreatic Function Testing (Pft)

(PB), Volume (V), Volume/kg (flow), and Total Bicarbonate Output (TBO) on each patient. Questions: During SST, do V, flow, and TBO of pancreatic juice adequately predict CP as well as the PB? What level of V, flow, or TBO reliably discriminates CP from non-CP? Results: 43.2 % of patients had CP by peak bicarbonate criteria (PB<80mEq/L). Of those, the sensitivity for CP using flow was only 14%. The percent of non-CP patients, ie false positives, with low flow was still 2.7%. The sensitivity for CP using TBO was only 47.4%. TBO was low in 5.3% of non-CP (specificity of 94.7%). Using the Wilcoxon signed rank sum test, the following were observed: (1) Mean V: non-CP (281ml ± 107) vs CP patients (207ml ± 115) p<0.0001. (2) Mean flow: non-CP (4.0ml/kg ± 1.3) vs CP patients (2.8ml/ kg ± 1.3) p<0.0001. (3)Mean TBO: non-CP (23 mEq/hr ± 8.7) vs CP patients (11 mEq/hr ± 7.1) p<0.0001. Using the Spearman linear correlation test, considering all patients, the following observations were made (coefficients in parentheses and all p-values <0.0001): (1) V correlates with PB (0.3537) (2) Flow and especially TBO were more strongly correlated with PB (0.4070 and 0.6571, respectively). Receiver operating curves were made for V, flow, and TBO to see if each could predict the presence of CP. The AUCs were 0.721, 0.769, and 0.867, respectively. Conclusions: Volume and flow correlate linearly with peak bicarbonate concentration during SST but not as well as total bicarbonate output, and a large drop in volume, flow, or total bicarbonate output is required to bring a patient into the PB<80 mEq/L category. Volume and flow do predict the presence of advanced CP but are very insensitive and bicarbonate output is only a somewhat better predictor. Based on data from the secretin stimulation test, S-MRCPs use of volume will miss a significant portion of patients with early CP, particularly those with small duct disease.