Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis.

BACKGROUND & AIMS: Alcohol has been implicated in the development of chronic pancreatitis (CP) in 60%-90% of patients, although percentages in the United States are unknown. We investigated the epidemiology of alcohol-related CP at tertiary US referral centers. METHODS: We studied data from CP patients (n = 539) and controls (n = 695) enrolled in the North American Pancreatitis Study-2 from 2000 to 2006 at 20 US referral centers. CP was defined by definitive evidence from imaging or histologic analyses. Subjects and physicians each completed a study questionnaire. Using physician-assigned diagnoses, patients were assigned to an etiology group: alcohol (with/without other diagnoses), nonalcohol (any etiology of CP from other than alcohol), or idiopathic (no etiology identified). RESULTS: The distribution of patients among etiology groups was: alcohol (44.5%), nonalcohol (26.9%), and idiopathic (28.6%). Physicians identified alcohol as the etiology more frequently in men (59.4% men vs 28.1% women), but nonalcohol (18% men vs 36.7% women) and idiopathic etiologies (22.6% men vs 35.2% women) more often in women (P < .01 for all comparisons). Nonalcohol etiologies were equally divided among obstructive, genetic, and other causes. Compared with controls, patients with idiopathic CP were more likely to have ever smoked (58.6% vs 49.7%, P < .05) or have a history of chronic renal disease or failure (5.2% vs 1.2%, P < .01). In multivariate analyses, smoking (ever, current, and amount) was independently associated with idiopathic CP. CONCLUSIONS: The frequency of alcohol-related CP at tertiary US referral centers is lower than expected. Idiopathic CP and nonalcohol etiologies represent a large subgroup, particularly among women. Smoking is an independent risk factor for idiopathic CP.

Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study.

OBJECTIVE: To compare patients with chronic pancreatitis (CP) with constant pain patterns to patients with CP with intermittent pain patterns. METHODS: This was a prospective cohort study conducted at 20 tertiary medical centers in the USA comprising 540 subjects with CP. Patients with CP were asked to identify their pain from five pain patterns (A-E) defined by the temporal nature (intermittent or constant) and the severity of the pain (mild, moderate or severe). Pain pattern types were compared with respect to a variety of demographic, quality of life (QOL) and clinical parameters. Rates of disability were the primary outcome. Secondary outcomes included: use of pain medications, days lost from school or work, hospitalisations (preceding year and lifetime) and QOL as measured using the Short Form-12 (SF-12) questionnaire. RESULTS: Of the 540 CP patients, 414 patients (77%) self-identified with a particular pain pattern and were analysed. Patients with constant pain, regardless of severity, had higher rates of disability, hospitalisation and pain medication use than patients with intermittent pain. Patients with constant pain had lower QOL (by SF-12) compared with patients who had intermittent pain. Additionally, patients with constant pain were more likely to have alcohol as the aetiology for their pancreatitis. There was no association between the duration of the disease and the quality or severity of the pain. CONCLUSIONS: This is the largest study ever conducted of pain in CP. These findings suggest that the temporal nature of pain is a more important determinant of health-related QOL and healthcare utilisation than pain severity. In contrast to previous studies, the pain associated with CP was not found to change in quality over time. These results have important implications for improving our understanding of the mechanisms underlying pain in CP and for the goals of future treatments and interventions.

Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis.

BACKGROUND & AIMS: Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor SPINK1 further increase the risk of pancreatitis in these patients. METHODS: We screened patients and controls for variants in SPINK1 associated with risk of chronic pancreatitis and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, 150 unrelated controls, 375 additional controls for limited genotyping. CFTR wild-type and p.R75Q were cloned and expressed in HEK293 cells, and relative conductances of HCO(3)(-) and Cl(-) were measured. RESULTS: SPINK1 variants were identified in 36% of subjects and 3% of controls (odds ratio [OR], 18.1). One variant of CFTR not associated with CF, p.R75Q, was found in 16% of subjects and 5.3% of controls (OR, 3.4). Coinheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.38% of controls (OR, 25.1). Patch-clamp recordings of cells that expressed CFTR p.R75Q showed normal chloride currents but significantly reduced bicarbonate currents (P = .0001). CONCLUSIONS: The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk of pancreatitis. Coinheritance of p.R75Q or CF causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.

Smoking is underrecognized as a risk factor for chronic pancreatitis.

BACKGROUND/AIMS: Smoking is an established risk factor for chronic pancreatitis (CP). We sought to identify how often and in which CP patients physicians consider smoking to be a risk factor. METHODS: We analyzed data on CP patients and controls prospectively enrolled from 19 US centers in the North American Pancreatitis Study-2. We noted each subject's self-reported smoking status and quantified the amount and duration of smoking. We noted whether the enrolling physician (gastroenterologist with specific interest in pancreatology) classified alcohol as the etiology for CP and selected smoking as a risk factor. RESULTS: Among 382/535 (71.4%) CP patients who were self-reported ever smokers, physicians cited smoking as a risk factor in only 173/382 (45.3%). Physicians cited smoking as a risk factor more often among current smokers, when classifying alcohol as CP etiology, and with higher amount and duration of smoking. We observed a wide variability in physician decision to cite smoking as a risk factor. Multivariable regression analysis however confirmed that the association of CP with smoking was independent of physician decision to cite smoking as a risk factor. CONCLUSIONS: Physicians often underrecognize smoking as a CP risk factor. Efforts are needed to raise awareness of the association between smoking and CP. and IAP.

Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis.

BACKGROUND: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are associated with alcohol consumption and cigarette smoking. The etiology of RAP and CP is complex, and effects of alcohol and smoking may be limited to specific patient subsets. We examined the current prevalence of alcohol use and smoking and their association with RAP and CP in patients evaluated at US referral centers. METHODS: The North American Pancreatitis Study 2, a multicenter consortium of 20 US centers, prospectively enrolled 540 patients with CP, 460 patients with RAP, and 695 controls from 2000 to 2006. Using self-reported monthly alcohol consumption during the maximum lifetime drinking period, we classified subjects by drinking status: abstainer, light drinker (< or =0.5 drink per day), moderate drinker (women, >0.5 to 1 drink per day; men, >0.5 to 2 drinks per day), heavy drinker (women, >1 to <5 drinks per day; men, >2 to <5 drinks per day), or very heavy drinker (> or =5 drinks per day for both sexes). Smoking was classified as never, past, or current and was quantified (packs per day and pack-years). RESULTS: Overall, participants' mean (SD) age was 49.7 (15.4) years; 87.5% were white, and 56.5% were women. Approximately one-fourth of both controls and patients were lifetime abstainers. The prevalence of very heavy drinking among men and women was 38.4% and 11.0% for CP, 16.9% and 5.5% for RAP, and 10.0% and 3.6% for controls. Compared with abstaining and light drinking, very heavy drinking was significantly associated with CP (odds ratio, 3.10; 95% confidence interval, 1.87-5.14) after controlling for age, sex, smoking status, and body mass index. Cigarette smoking was an independent, dose-dependent risk factor for CP and RAP. CONCLUSIONS: Very heavy alcohol consumption and smoking are independent risks for CP. A minority of patients with pancreatitis currently seen at US referral centers report very heavy drinking.

Acute pancreatic graft fistula and peripancreatic fluid collection: demonstration by secretin-stimulated MRI.

Peripancreatic fluid collections are among the common post pancreas transplant complications, which are mainly due to leakage from the anastomosis site to bowel and graft pancreatitis. Differentiation between these two entities is important because they are treated differently. In this case, secretin stimulated magnetic resonance cholangiopancreatography revealed gradual intraperitoneal fluid collection and accumulation of fluid in small bowel excluded leakage from the anastomosis of the pancreas to bowel and changed the management from surgery to medical treatment.

Pancreatic diffusion-weighted imaging (DWI): comparison between mass-forming focal pancreatitis (FP), pancreatic cancer (PC), and normal pancreas.

PURPOSE: To compare diffusion-weighted imaging (DWI) findings and the apparent diffusion coefficient (ADC) values of pancreatic cancer (PC), mass-forming focal pancreatitis (FP), and the normal pancreas. MATERIALS AND METHODS: DWI (b = 0 and 600 seconds/mm(2)) findings of 14 patients with mass-forming FP proven by histopathology and or clinical follow-up, 10 patients with histopathologically-proven PC, and 14 subjects with normal pancreatic exocrine function and normal imaging findings were retrospectively evaluated. ADC values of the masses, the remaining pancreas, and the normal pancreas were measured. RESULTS: On b = 600 seconds/mm(2) DWI, mass-forming FP was visually indistinguishable from the remaining pancreas whereas PC was hyperintense relative to the remaining pancreas. The mean ADC value of PC (1.46 +/- 0.18 mm(2)/second) was significantly lower than the remaining pancreas (2.11 +/- 0.32 x 10(-3) mm(2)/second; P < 0.0001), mass-forming FP (2.09 +/- 0.18 x 10(-3) mm(2)/second; P < 0.0001), and pancreatic gland in the control group (1.78 +/- 0.07 x 10(-3) mm(2)/second; P < 0.0005). There was no significant difference of ADC values between the mass-forming focal pancreatitis and the remaining pancreas (2.03 +/- 0.2 x 10(-3) mm(2)/second; P > 0.05). CONCLUSION: Differences on DWI may help to differentiate PC, mass-forming FP, and normal pancreas from each other.

Pancreatic function testing is best determined by the extended endoscopic collection technique.

OBJECTIVE: To evaluate whether the extended secretin-stimulated direct endoscopic pancreatic function test (ePFT) technique is superior to the rapid 15 minute secretin-stimulated ePFT in determining pancreatic exocrine function. METHODS: We conducted a retrospective study of 53 patients with chronic abdominal pain and normal pancreatic imaging. These patients had ePFT testing with the following modified endoscopic collection system. Porcine synthetic or human secretin was intravenously administered 15 minutes before endoscopic duodenal aspiration. The first 10-minute collection was performed in the third portion of the duodenum. A Liguory drainage tube was placed in the third portion of the duodenum. Two additional 10-minute-period collections were obtained via the drainage tube at 30 and 45 minutes after intravenous administration of secretin. All fluid collections were analyzed for bicarbonate (HCO3) concentration. RESULTS: Peak HCO3 concentrations at 15 minutes occurred in 62%, at 30 to 40 minutes in 23%, and at 45 to 55 minutes in 15%. Normal concentrations of HCO3 (> or =80 mEq/L) were seen in 70%, abnormal concentration in 7%, and equivocal concentrations (60-79 mEq/L) in 23% even after 55 minutes of duodenal collections. CONCLUSION: Collections beyond 15 minutes are necessary to improve accuracy of the ePFT in determining pancreatic exocrine function.

Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2).

BACKGROUND: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are complex syndromes associated with numerous etiologies, clinical variables and complications. We developed the North American Pancreatitis Study 2 (NAPS2) to be sufficiently powered to understand the complex environmental, metabolic and genetic mechanisms underlying RAP and CP. METHODS: Between August 2000 and September 2006, a consortium of 20 expert academic and private sites prospectively ascertained 1,000 human subjects with RAP or CP, plus 695 controls (spouse, family, friend or unrelated). Standardized questionnaires were completed by both the physicians and study subjects and blood was drawn for genomic DNA and biomarker studies. All data were double-entered into a database and systematically reviewed to minimize errors and include missing data. RESULTS: A total of 1,000 subjects (460 RAP, 540 CP) and 695 controls who completed consent forms and questionnaires and donated blood samples comprised the final dataset. Data were organized according to diagnosis, supporting documentation, etiological classification, clinical signs and symptoms (including pain patterns and duration, and quality of life), past medical history, family history, environmental exposures (including alcohol and tobacco use), medication use and therapeutic interventions. Upon achieving the target enrollment, data were organized and classified to facilitate future analysis. The approaches, rationale and datasets are described, along with final demographic results. CONCLUSION: The NAPS2 consortium has successfully completed a prospective ascertainment of 1,000 subjects with RAP and CP from the USA. These data will be useful in elucidating the environmental, metabolic and genetic conditions, and to investigate the complex interactions that underlie RAP and CP.

Diffusion-weighted MRI of the pancreas: correlation with secretin endoscopic pancreatic function test (ePFT).

RATIONALE AND OBJECTIVES: To evaluate the correlation between apparent diffusion coefficient (ADC) values of the pancreas on diffusion-weighted imaging (DWI) and pancreatic exocrine function determined by HCO(3) concentration in the secretin endoscopic pancreatic function test (ePFT). MATERIALS AND METHODS: Mean ADC values derived from 10 different points of the pancreatic gland on DWI were reviewed in 14 patients with normal (peak HCO(3) > or = 80 mEq/L) and 14 patients with abnormal (peak HCO(3) < 80 mEq/L) ePFT results. Magnetic resonance cholangiopancreatography (MRCP) images of the same patients were evaluated for the diagnosis of chronic pancreatitis. Correlation between ADC values and HCO(3) concentration as well as Cambridge scores in MRCP was performed using Spearman's correlation test. RESULTS: Mean ADC value of the pancreas was 1.52 +/- 0.13 x 10(-3) mm(2)/s in patients with abnormal ePFT results and 1.78 +/- 0.07 x 10(-3) mm(2)/s in the normal group. There was a significant statistical difference between the ADC values of the pancreas in the two groups (P < .0001). There was also a statistically significant correlation between HCO(3) level and ADC value of the pancreas in the study patients (r = 0.771, P < .0001). Morphologic changes of the pancreas according to the Cambridge classification were also well correlated with the mean ADC values (r = -0.763, P < .0001). CONCLUSIONS: Strong correlation between ADC value and pancreatic exocrine function as well as Cambridge score for chronic pancreatitis exists. Further studies are needed to determine the cut off ADC value for chronic pancreatitis.

Markedly elevated serum CA 19-9 levels in association with a benign biliary stricture due to primary sclerosing cholangitis.

We report on the case of a 55-year-old man with long-standing ulcerative colitis who developed jaundice. This led to a diagnosis of primary sclerosing cholangitis being made, with a dominant stricture in the common bile duct. Serum CA 19-9 was initially markedly raised at 26,321 U/mL but fell promptly into the normal range after stenting of the stricture. Long-term follow up of this patient has failed to show evidence of cholangiocarcinoma. We conclude that serum CA 19-9 levels need to be assessed in the clinical context of biliary obstruction and should ideally be measured after relief of that obstruction, as it may be falsely elevated due to benign biliary strictures.

Serial contrast-enhanced MRI of the pancreas: correlation with secretin-stimulated endoscopic pancreatic function test.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine the relationship between the pancreatic enhancement on serial contrast-enhanced MRI (CEMRI) and pancreatic exocrine function using the secretin-stimulated endoscopic pancreatic function test (ePFT). MATERIALS AND METHODS: A total of 30 patients with clinical symptoms consistent with chronic pancreatitis underwent CEMRI of the abdomen and ePFT within a 1- to 4-week interval. CEMRI was performed in arterial, early venous, and late venous phases. Secretin ePFT was performed with the measurement of HCO(3) concentration from the duodenal aspirates after secretin stimulation. Contrast enhancement ratio of the arterial phase to early venous phase was measured on CEMRI (SIRa/SIRv). A three-point evaluation system was used for grading the HCO(3) concentration and the enhancement ratio on MRI. For the significance of correlation, kappa statistics was used. Sensitivity and specificity of CEMRI was determined for the diagnosis of early chronic pancreatitis accepting ePFT as a reference. RESULTS: Twenty patients had identical scores on both secretin ePFT and CEMRI. Ten patients revealed discrepancy in scores. Kappa statistics revealed moderate agreement between MRI and ePFT (kappa = 0.44). Sensitivity and specificity values for the diagnosis of pancreatitis were 82% and 57%, respectively. Positive predictive value was 56%, and negative predictive value was 86%. CONCLUSION: The results of our data indicate that serial CEMRI is an appropriate imaging technique to rule out early chronic pancreatitis. However, secretin-stimulated imaging or ePFT may still be needed for the definite diagnosis of pancreatic exocrine dysfunction.