Lawrence K. Gates

Acute pancreatitis in children

OBJECTIVES:Currently, there is no scoring system for predicting severity in acute pancreatitis in children. Our intent was to evaluate the performance of existing scoring systems in children, to develop a system for children, and to examine the etiology of acute pancreatitis in children.METHODS:A chart review of children with acute pancreatitis was conducted at six centers, three serving as criterion centers and three as validation centers. Ranson and Glasgow scores were calculated for each admission. Additional clinical data were collected, and parameters correlating with severity were incorporated into a new scoring system. Performance characteristics were calculated for each system.RESULTS:A total of 301 admissions were reviewed, 202 in the criterion group and 99 in the validation group. Eight parameters were included in a new scoring system for children. The parameters were as follows: age (<7 yr), weight (<23 kg), admission WBC (>18,500), admission LDH (>2,000), 48-h trough Ca2+ (<8.3 mg/dl), 48-h trough albumin (<2.6 g/dl), 48-h fluid sequestration (>75 ml/kg/48 h), and 48-h rise in BUN (>5 mg/dl). When the cut-off for predicting a severe outcome was set at 3 criteria, the new system had better sensitivity versus Ranson and Glasgow scores (70% vs 30% and 35%, respectively) and a better negative predictive value (91% vs 85% and 85%). The specificity (79% vs 94% and 94%) and positive predictive value (45% vs 57% and 61%) fell slightly.CONCLUSION:The new scoring system performs better in this group than do existing systems.

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, otehr 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.

Expression and penetrance of the hereditary pancreatitis phenotype in monozygotic twins

BACKGROUND Hereditary pancreatitis (HP) is a rare autosomal dominant disorder with variable expression and an overall lifetime penetrance of 80%. We hypothesised that (1) monozygotic twins within similar environments would develop the typical signs of HP at a similar age, and (2) if penetrance were due to modifier genes or environment, all twin pairs would be concordant for expression of HP. AIM Identify monozygotic twins with HP and determine the penetrance, concordance, and age of onset of symptoms. METHODS Twins from HP kindreds were identified from the Midwest Multicenter Pancreatic Study group database, referrals, and literature searches. Each twin set was assessed for phenotypic expression, concordance, and difference in age of phenotypic onset of pancreatitis. The difference in onset of symptoms for symptomatic affected non-twin sibling pairs as well as non-twin pairs that were mutation, sex, and age matched were calculated as two comparison groups. RESULTS Seven of 11 monozygotic pairs identified were suitable for evaluation and four were concordant for pancreatitis. Forty eight affected sibling pairs and 33 pairs of mutation, sex, and age matched (cationic trypsinogen R122H (30 pairs) and N29I (three pairs)) subjects were identified for comparison groups. The median (quartiles Q1, Q3) difference in the age of phenotypic onset in the concordant twins was 1 (0, 2.4) years, 2 (1, 6) for the affected siblings, and 7 (2, 15) years in the comparison control group. Three of the seven sets of twins (43%) were discordant for phenotypic expression of pancreatitis. The overall penetrance in the seven pairs of monozygotic twins was 78.6%. CONCLUSIONS Genetic and/or environmental factors contribute to expression and age of onset of HP. Nuclear genes or general environmental factors alone cannot explain the 80% penetrance. Determining the mechanism of non-penetrance may help in developing a strategy to prevent the phenotypic expression of pancreatitis in individuals with an underlying genetic predisposition.

Mallory-Weiss tear : Predisposing factors and predictors of a complicated course

OBJECTIVES:Little has been published regarding predictors of a complicated course after Mallory-Weiss tear (MWT). The aims of this study were to identify risk factors for a Mallory-Weiss tear and factors predictive of a complicated course.METHODS:At our university hospital, we searched a computerized endoscopy database. At our Veterans Affairs hospital we manually searched printed endoscopy reports. Proposed risk factors for MWT were: history of alcohol use, recent alcohol binge, nonbloody initial emesis, anticoagulation, other coagulopathy, nonsteroidal anti-inflammatory use, and hiatal hernia. Proposed predictors of a complicated course were: age, hematemesis, melena, hematochezia, visible vessel, adherent clot, active bleeding, multiple tears, other pathology at endoscopy, admission Hct, hypotension or orthostatic changes, and coagulopathy. A complicated course was defined on the basis of >6 U of blood transfused, rebleeding, angiography, surgery, or death. Predictors of a complicated course were evaluated using the Mann-Whitney U test or Fisher exact test.RESULTS:A total of 73 cases were reviewed. The most common risk factor was alcohol use, which was found in 44% of cases. In all, 23% of patients had no risk factors. Of the patients, 17 (23%) had a complicated course. Patients with a complicated course had a lower admission Hct (p = 0.009) and active bleeding at initial endoscopy (p = 0.013).CONCLUSION:The predictive value of active bleeding supports early endoscopy for stratification and intervention.

Cytokine Production by CAPAN-1 and CAPAN-2 Cell Lines

Recently, there has been a great deal of interest in the role of cytokines in acute pancreatitis. Serum levels of IL-1, IL-6, and TNF-α have been demonstrated to be elevated in acute pancreatitis. We hypothesized that cytokines may be produced primarily by pancreatic parenchymal cells. Reasoning that ductal epithelium is the cell type most likely to be exposed to noxious stimuli in common causes of pancreatitis, such as ERCP and passage of a gallstone, we examined the response of well differentiated pancreatic ductal adenocarcinoma cell lines to stimuli known to stimulate cytokine production in other cells. CAPAN-1 and CAPAN-2 cells were incubated with endotoxin or TNF-α. The supernatant was assayed for production of IL-1, IL-6, and IL-8 by ELISA. The cells were assayed for activation of the transcription factor NF-κB by electrophoretic mobility shift assay. There was no detectable production of IL-1 by either cell line. CAPAN-1 cells had concentration-dependent production of IL-6 and IL-8 in response to both endotoxin and TNF-α. CAPAN-2 cells had concentration-dependent production of IL-6 and IL-8 in response to TNF-α. They had low level expression of IL-8 that was unaffected by any concentration of LPS, and no detectable production of IL-6 in response to LPS. These findings suggest that pancreatic duct cells may take an active part in the pathogenesis of acute pancreatitis through the production of cytokines.

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.

Vertebral osteomyelitis mimicking chronic pancreatitis

SummaryVertebral osteomyelitis rarely mimics pancreatitis. However, the potential consequences of longstanding unrecognized disease, including neurological impairment and bony deformity, should make it an item in the differential diagnosis of chronic pancreatitis. In the evaluation of our patient, four items were of particular importance: awareness of his previously documentedS. aureus bacteremia, a markedly elevated ESR, an abnormal chest radiograph, and the positive bone scan.

4695 The frequency of altered duct morphology and natural history of patients following appropriate pancreatic duct stent management.

Background: Studies describing alterations in duct morphology following pancreatic duct stent (PDS) placement have raised concerns about stentrelated morbidity. Limitations included small numbers and inconsistencies in PDS management (e.g. indications for and duration of stenting). The frequency of alterations in duct morphology attributable to appropriately managed PDS remains in doubt, and natural history following PDS removal has yet to be ascertained. Aims: (1) assess the frequency of alterations in duct morphology attributable to appropriately managed PDS, and (2) ascertain the natural history of patients following PDS removal. Methods: Review of endoscopic databases at U. Cincinnati and U. Kentucky. Patients who underwent PDS placement were identified. A data collection form and questionnaire were composed prior to chart review and patient telephone interviews. Exclusion criteria included malignancy, prior pancreatic surgery, alcohol use, and AIDS. In 69% of cases, PDS were either changed or removed within 8 weeks. Data included indication for PDS, ERP findings preceding PDS, stent diameter/length, ERP findings after PDS removal, and complications. Natural history data included physician visits for symptoms attributable to acute/chronic pancreatitis, pain, analgesic use, symptoms of malabsorption, and diabetes. Results: 41 patients were identified who met inclusion and exclusion criteria, 3 SOD and no pancreatitis, 13 acute pancreatitis (AP) (6 duct disruption, 5 SOD, 2 pancreas divisum), and 25 chronic pancreatitis (CP) (13 duct stricture, 7 duct disruption, 5 pancreas divisum). PDS ranged from 5 Fr - 11.5 Fr and 2.5 cm - 15 cm. ERP following stent removal was available in 1/3 SOD, 8/13 AP, and 17/25 CP patients (26/41 total). Alterations in ductal morphology attributable to PDS were noted in 0/1 SOD, 2/8 AP, and 2/17 CP patients (4/26 total). Natural history data was available on 2/3 SOD, 7/13 AP, and 12/25 CP patients (21/41 total). Mean follow-up from PDS placement was 15.6 months. Development/progression of symptoms attributable to pancreatic disease subsequent to PDS removal occurred in 0/2 SOD, 0/7 AP, and 5/12 CP patients. Conclusions: Alterations in duct morphology attributable to PDS were less frequent than previously reported. Acknowledging the limited follow-up time in these cohorts, few alterations in natural history attributable to PDS were identified. Prospective validation of the safety of appropriately managed PDS is warranted.

⁎3338 A prospective study of prokinetics in peg-based bowel lavage for colonoscopy.

Background The ideal regimen for colonoscopy preparation would be inexpensive, safe, easily administered and tolerated, and would reliably cleanse the colon of solid material. Towards this end, many institutions have modified the conventional PEG regimen by addition of prokinetic agents such as metoclopramide and cisapride. These agents promote gastric emptying and, in the case of cisapride, colonic motility which should enhance patient tolerance and compliance. One study compared PEG lavage with and without metoclopramide and found no difference in effectiveness or tolerability. A study of PEG with and without cisapride found a decrease in the volume of PEG required to achieve adequate preparation. There have not been any trials comparing metoclopramide and cisapride. Aims To compare patient tolerance and adequacy of preparation with three PEG based colonoscopy regimens, PEG alone, or PEG with metoclopramide or cisapride. Methods We enrolled 120 patients scheduled for outpatient colonoscopy. Patients were randomized to one of three regimens (Group A: PEG and cisapride, Group B: PEG alone, and Group C: PEG and metoclopramide). Prior to colonoscopy, patients completed a questionnaire using a visual analog scale (0-10) to assess interference with daily routine, abdominal pain, nausea, vomiting, and dizziness. The quality of the preparation and depth of insertion of the colonoscope were graded by the endoscopist. Results Ninety-one patients completed the study, with an even distribution of patients between groups. The groups were well matched for age and sex. Using the ANOVA with Bonferronis correction of the post test, there was no statistically significant difference in interference with daily routine (4.5, 5.9, 4.2 for groups A, B, and C, respectively), abdominal pain (2.9, 3.8, 3.1), nausea (2.3, 3.6, 1.8) vomiting (1.2, 0.9, 0.8) and dizziness (1.2, 1.8. 1.0). In regards to adequacy of preparation and depth of insertion there was no difference between the three groups. When statistical analysis was performed using a Students t test to compare PEG alone (Group B) with PEG and any prokinetic agent (Groups A and C combined), a statistically significant difference was noted in favor of the addition of a prokinetic agent in the severity of nausea and the depth of insertion. Conclusion Addition of any prokinetic agent slightly but significantly improves the patients toleration of precolonoscopy preparation with PEG, and adequacy of the examination. There was a nonsignificant trend favoring metoclopramide over cisapride.