Tyler Stevens

Pathogenesis of Chronic Pancreatitis: An Evidence-Based Review of Past Theories and Recent Developments

In the past several decades, four prominent theories of chronic pancreatitis pathogenesis have emerged: the toxic-metabolic theory, the oxidative stress hypothesis, the stone and duct obstruction theory, and the necrosis-fibrosis hypothesis. Although these traditional theories are formulated based on compelling scientific observations, substantial contradictory data also exist for each. Furthermore, the basic premises of some of these theories are directly contradictory. Because of the recent scientific progress in the underlying genetic, cellular, and molecular pathophysiology, there have been substantial advances in the understanding of chronic pancreatitis pathogenesis. This paper will provide an evidence-based review and critique of the traditional pathogenic theories, followed by a discussion of the new advances in pancreatic fibrogenesis. Moreover, we will discuss plausible pathogenic sequences applied to each of the known etiologies.

American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines.

Abstract The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.

Endoscopic Ultrasound, Secretin Endoscopic Pancreatic Function Test, and Histology: Correlation in Chronic Pancreatitis

OBJECTIVES:Endoscopic ultrasound (EUS) and hormone-stimulated pancreatic function tests are considered useful, and possibly complementary, in the diagnosis of early chronic pancreatitis (CP). Few past studies have compared either methods with a histological gold standard. The aims were to assess correlations of EUS score and endoscopic pancreatic function test (ePFT) results with the degree of histological fibrosis, as well as the sensitivity of each method for detecting fibrosis.METHODS:This was a retrospective study of patients who underwent EUS, ePFT, or both within 12 months of pancreatic resection or wedge biopsy. EUS scoring was performed using 9 standard criteria, with ≥4 considered abnormal. An ePFT peak bicarbonate concentration <80 mM was considered abnormal. Surgical specimens were reviewed in a blinded manner by an expert pancreatic pathologist and assigned a fibrosis score from 0 to 12. Correlations of the EUS score and ePFT peak bicarbonate with the fibrosis score are reported using the Spearman correlation coefficient. Sensitivity and specificity was calculated for each method against the histological gold standard (fibrosis score ≥2).RESULTS:Twenty-five patients were included. The fibrosis score significantly correlated with the EUS score (r=0.72; 95% confidence interval (CI)=0.43, 0.87; P<0.001) and the ePFT peak bicarbonate (r=−0.57; 95% CI=−0.81, −0.10; P=0.016). EUS had a sensitivity of 84% (95% CI=69, 100) and specificity of 100% (95% CI=40, 100) compared with histology. The ePFT had a sensitivity of 86% (95% CI=67, 100) and specificity of 67% (95% CI=13, 100). When both modalities were combined, the sensitivity increased to 100% (95% CI=63, 100).CONCLUSIONS:Both EUS and ePFT are useful tests in the diagnosis of CP. Combining EUS with ePFT may improve the sensitivity for detection of early fibrosis.

Histologic and Imaging Features of Mural Nodules in Mucinous Pancreatic Cysts

BACKGROUND & AIMS Mural nodules predict malignancy within pancreatic cysts, but it is not clear whether endoscopic ultrasound (EUS) and computed tomography (CT) accurately identify nodules. We assessed images and the histology of mural nodules in branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) and mucinous cystic neoplasms (MCNs) and identified criteria to distinguish mural nodules from mucus. METHODS We reviewed pathology specimens and EUS and CT images from consecutive patients with resected BD-IPMNs or MCNs. A blinded interobserver study of the EUS images was then conducted to identify features that distinguished nodules from mucus. After education about these features, the raters interpreted the EUS images again. RESULTS On the basis of histologic analysis, 22 of 57 cases had epithelial nodules. Cancer or high-grade dysplasia was found in 23% of cysts with nodules versus 3% without nodules (P = .02). On the basis of reports, EUS detected epithelial nodules with 75% sensitivity and 83% specificity, whereas these values were 24% and 100%, respectively, for CT. Mucus accounted for 65% of intracystic lesions detected by EUS and was often diagnosed by using change in body position and fine-needle aspiration. Interobserver analysis identified 3 features that were detected by EUS (echogenicity, edge, and rim) that distinguished mucus from epithelial nodules. The diagnostic accuracy of the raters improved from a mean of 57% to 79% after education about these features (P = .004); accuracy was 90% when all 3 features of mucus were present. CONCLUSIONS Malignancy is associated with epithelial nodules in BD-IPMNs and MCNs, but most echogenic lesions detected in cysts by EUS are mucus. Knowledge of features that discriminate mucus from mural nodules improves the diagnostic accuracy of EUS.

Protein alterations associated with pancreatic cancer and chronic pancreatitis found in human plasma using global quantitative proteomics profiling

Pancreatic cancer is a lethal disease that is difficult to diagnose at early stages when curable treatments are effective. Biomarkers that can improve current pancreatic cancer detection would have great value in improving patient management and survival rate. A large scale quantitative proteomics study was performed to search for the plasma protein alterations associated with pancreatic cancer. The enormous complexity of the plasma proteome and the vast dynamic range of protein concentration therein present major challenges for quantitative global profiling of plasma. To address these challenges, multidimensional fractionation at both protein and peptide levels was applied to enhance the depth of proteomics analysis. Employing stringent criteria, more than 1300 proteins total were identified in plasma across 8-orders of magnitude in protein concentration. Differential proteins associated with pancreatic cancer were identified, and their relationship with the proteome of pancreatic tissue and pancreatic juice from our previous studies was discussed. A subgroup of differentially expressed proteins was selected for biomarker testing using an independent cohort of plasma and serum samples from well-diagnosed patients with pancreatic cancer, chronic pancreatitis, and nonpancreatic disease controls. Using ELISA methodology, the performance of each of these protein candidates was benchmarked against CA19-9, the current gold standard for a pancreatic cancer blood test. A composite marker of TIMP1 and ICAM1 demonstrate significantly better performance than CA19-9 in distinguishing pancreatic cancer from the nonpancreatic disease controls and chronic pancreatitis controls. In addition, protein AZGP1 was identified as a biomarker candidate for chronic pancreatitis. The discovery and technical challenges associated with plasma-based quantitative proteomics are discussed and may benefit the development of plasma proteomics technology in general. The protein candidates identified in this study provide a biomarker candidate pool for future investigations.

Secretin-Enhanced MRCP: Review of Technique and Application With Proposal for Quantification of Exocrine Function

OBJECTIVE The purpose of this article is to present a proposal for quantification of exocrine function using secretin-enhanced MRCP for the diagnosis of chronic pancreatitis. The article also reviews the technique and application of secretin-enhanced MRCP in evaluating various pancreatic abnormalities. SUBJECTS AND METHODS One hundred thirty-four consecutive patients with chronic abdominal pain undergoing secretin-enhanced MRCP for suspected chronic pancreatitis were included. Patients were divided into four clinical groups (normal, equivocal, early chronic pancreatitis, established pancreatitis) on the basis of clinical symptoms and additional investigations, including CT (n=98), endoscopic pancreatic function test (n=65), endoscopic ultrasound (n=84), and ERCP (n=36). The volume of secretion was obtained by drawing a region of interest around T2 bright fluid secreted on postsecretin HASTE images. The maximal rate of secretion in response to secretin was obtained by plotting change in signal intensity on sequential postsecretin images. The analysis of variance test was used to compare the clinical groups with the volume and rate of secretion. RESULTS Significant volume differences were found between the normal and established pancreatitis groups (p<0.0001) as well as the equivocal and established pancreatitis groups (p<0.0005). Marginally significant differences were found between the normal and early pancreatitis groups (p=0.0150) as well as early and established pancreatitis groups (p=0.0351). Differences in the maximal rate of secretion were not statistically significant. CONCLUSION Secretory volume measurement of secretin-enhanced MRCP data is a simple method that brings out significant differences between normal, early, and established pancreatitis patients.

Cigarette Smoking Is Independently Associated with Chronic Pancreatitis

Background and Aims: It is not completely understood whether smoking contributes to chronic pancreatitis (CP). Past studies have included mostly patients with alcohol-related and severe CP. Our aim was to assess the relationship of smoking and CP adjusting for alcohol and other clinical risk factors. Methods: A cross-sectional study was performed of patients referred to the pancreatic disease clinic in the past 2 years with abdominal pain and suspected CP. Patients were questioned on their smoking and alcohol habits. Patients underwent an etiological workup and diagnostic evaluation for early and late CP comprised of computed tomography scan and combined endoscopic ultrasound and secretin endoscopic pancreatic function test if indicated. Logistic regression was used to determine the association of current smoking with CP adjusting for other risk factors. Results: The adjusted odds ratio (OR) for current smoking was 1.99 (95% CI 1.01, 3.91). Other significant predictors included consumption of ≧10 alcohol drinks/week, advancing age, history of acute pancreatitis, and the presence of another etiological factor. Smoking was also independently associated with exocrine insufficiency (OR 2.00, 95% CI 1.07, 3.75) and calcifications (OR 2.68, 95% CI 1.03, 6.94). Conclusion: Active cigarette smoking is associated with CP adjusting for alcohol and other risk factors.

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.

Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease.

Objectives:There is some uncertainty regarding how to best dose and therapeutically monitor 6-mercaptopurine or azathioprine in patients with inflammatory bowel disease. The purpose of this study was to assess the relation between clinical response, 6-mercaptopurine metabolite levels, relative leukopenia, and drug dose. Methods:60 patients with inflammatory bowel disease who were on stable doses of 6-mercaptopurine or azathioprine for ≥ 3 months and who had measurements of 6-mercaptopurine metabolite levels were evaluated. Patients were classified as complete responders (N = 24), partial responders (N = 7), or non-responders (N = 29). Results:Drug dose was associated with clinical response when we analyzed adjusted doses based on molecular drug weight (P = 0.002). 6-Thioguanine levels also were associated with clinical response (P = 0.003) and the maximal difference between responders and non-responders was seen at 6-thioguanine levels greater than 260 pmol/8 × 108 RBC. Relative leukopenia, defined as white blood cell count less than either 5.0 or 4.0 K/ u L, was not associated with clinical response (P = 0.13 and 0.77 respectively). Conclusions:1. Drug dose and 6-thioguanine levels are related to clinical response in patients with inflammatory bowel disease on 6-mercaptopurine or azathioprine. 2. For 6-thioguanine levels, there is a fair amount of overlap, but maximal differentiation between responders and non-responders is seen at levels > 260 pmol/8 × 108 RBC. 3. Relative leukopenia does not correlate well with clinical response.

Colonoscopy screening in the elderly: When to stop?

OBJECTIVES:The age to begin colorectal cancer (CRC) screening is based on the risk of neoplasia and is published in screening guidelines. The age to stop screening is unknown but should be based, in part, on the same principle. The purpose of this study was to establish whether the prevalence of neoplasia detected by colonoscopy diminished with advancing age, to warrant ceasing colonoscopic screening.METHODS:The endoscopic and pathology reports of all asymptomatic subjects undergoing colonoscopy for the purpose of CRC screening or an evaluation of abdominal pain or change in bowel habits between 1997 and 2000 were reviewed. A multivariate logistic regression analysis was used to assess the effect of age, gender, and indication for examination on the prevalence of neoplasia, as well as on having more than two adenomas, advanced adenomas (tubulovillous, villous, severe dysplasia, or size ≥ 1 cm), and invasive cancers.RESULTS:A total of 915 patients were included. Of these, 50% were male, with a mean age of 65 yr (range 50–100). Neoplasia peaked in the seventh decade, with a fall thereafter (p = 0.009). Numerous adenomas, advanced adenomas, and invasive cancers increased with age. The yield for overall neoplasia, advanced adenomas, and more than two adenomas was higher in the screening group than in the symptomatic group. More invasive cancers were found in the symptomatic group compared with the asymptomatic group, but this did not achieve statistical significance (4 vs 1, p = 0.44).CONCLUSIONS:The prevalence of advanced neoplasia continues to increase with age. Subjects undergoing colonoscopy for screening had a greater risk for neoplasia than did subjects with symptoms. There is no decline in yield of advanced neoplasia to justify stopping screening colonoscopy in the elderly.