Validation of prediction tools for GI bleeding in patients on dual anti-platelet therapy after percutaneous coronary intervention.

BACKGROUND AND AIMS: The management of dual anti-platelet therapy after percutaneous coronary intervention (PCI) and GI bleeding (GIB) remains a clinical dilemma. We sought to identify predictors of GIB and recurrent bleeding and to determine whether recurrent bleeding increases the risk of major adverse cardiovascular events (MACEs). METHODS: In this single-center retrospective study, patients undergoing PCI were identified. The primary and secondary endpoints were GIB at 180 days and recurrent bleeding or MACE at 365 days. Logistic regression was used to identify predictors of GIB and recurrent bleeding. Cox proportional hazards modeling was used to determine whether recurrent bleeding can predict a MACE. RESULTS: Five hundred thirty-six patients were included. On multivariable analysis, PCI for acute coronary syndrome was associated with a 95% increased odds of GIB (P < .001). The P2Y12 inhibitor was continued in >90% of patients, which trended toward significance for recurrent bleeding (P < .10). The HAS-BLED score (Hypertension, Abnormal renal and liver function, Stroke, Bleeding tendency or predisposition, Labile INRs, Elderly, Drugs), including a labile international normalized ratio and prior major bleeding, was strongly associated with recurrent bleeding (P ≤ .009). Recurrent bleeding was associated with a 115% increased risk of MACEs (P = .02). We derived a novel risk score, named the SIGE score ([S]TEMI at PCI, having a labile [I]NR at PCI, index [G]IB within 180 days of PCI, and previous precatheterization [E]ndoscopy within 6 months), to predict recurrent bleeding at 365 days with a high predictive accuracy (area under the curve, .773; 95% confidence interval, .702-.845). CONCLUSIONS: The SIGE score may help to predict recurrent bleeding, which was shown to be associated with an increased risk of MACEs. Further external validation is needed.

Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3-5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort.

BACKGROUND & AIMS: Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP. METHODS: We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. RESULTS: Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. CONCLUSIONS: We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain.

INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.

Serum biomarkers for chronic pancreatitis pain patterns.

OBJECTIVES: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. METHODS: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. RESULTS: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. DISCUSSION: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.

Increased awareness enhances physician recognition of the role of smoking in chronic pancreatitis.

BACKGROUND: We have previously reported that physicians under-recognize smoking as a chronic pancreatitis (CP) risk factor. We hypothesized that availability of empiric data will influence physician recognition of this relationship. METHODS: We analyzed data from 508 CP patients prospectively enrolled in the North American Pancreatitis Study-2 Continuation and Validation (NAPS2-CV) or NAPS2-Ancillary (AS) studies (2008-2014) from 26 US centers who self-reported ever-smoking. Information on smoking status, physician-defined etiology and identification of smoking as a CP risk factor was obtained from structured patient and physician questionnaires. We compared how often physician identified smoking as a CP risk factor in NAPS2-CV/NAPS2-AS studies with NAPS2-original study (2000-2006). RESULTS: Enrolling physician identified smoking as a risk factor in significantly (all p < 0.001) greater proportion of patients in NAPS2-CV/AS studies when compared with NAPS2-original study among ever (80.7 vs. 45.3%), current (91.3 vs. 53%), past (60.3 vs. 30.2%) smokers, in those who smoked ≤1 pack/day (79.3 vs. 39.5%) or ≥1 packs/day (83 vs. 49.8%). In multivariable analyses, the enrolling physician was 3.32-8.49 times more likely to cite smoking as a CP risk factor in the NAPS2-CV/NAPS2-AS studies based on smoking status and amount after controlling for age, sex, race and alcohol etiology. The effect was independent of enrolling site in a sub-analysis limited to sites participating in both phases of enrollment. CONCLUSIONS: Availability of empiric data likely enhanced physician recognition of the association between smoking and CP. Wide-spread dissemination of this information could potentially curtail smoking rates in subjects with and those at risk of CP.

Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors.

OBJECTIVES: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. METHODS: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables. RESULTS: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011). CONCLUSIONS: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

Recurrent Acute Pancreatitis Significantly Reduces Quality of Life Even in the Absence of Overt Chronic Pancreatitis.

OBJECTIVES: The impact of recurrent acute pancreatitis (RAP) on quality of life (QOL) is unknown. We hypothesized that RAP would reduce QOL even in the absence of chronic pancreatitis (CP). METHODS: Data were pooled from three prospective, cross-sectional studies conducted across 27 U.S. centers (the North American Pancreatitis Studies); these included subjects with chronic pancreatitis (n = 1086), RAP alone (n = 508), and non-disease controls (n = 1025). QOL was measured using the Short Form 12 (SF-12), generating a Physical Component Summary (PCS) and the Mental Component Summary score (MCS). Multivariable regression models were developed to measure the effect of RAP on QOL, the predictors of lower QOL in those with RAP, and the differential effect QOL predictors between CP and RAP. RESULTS: Compared to controls (51.0 ± 9.4), subjects with RAP (41.1 ± 11.4) and CP (37.2 ± 11.8) had lower PCS (p < 0.01). Subjects with CP had lower PCS compared to those with RAP (p < 0.01). Similarly, MCS was lower among RAP (44.6 ± 11.5) and CP (42.8 ± 12.2) subjects compared to controls (51.7 ± 9.1, p < 0.01). Subjects with CP had lower MCS compared to those with RAP (p < 0.01). After controlling for independent predictors of PCS, RAP was associated with lower PCS (estimate -8.46, p < 0.01) and MCS (estimate -6.45, p < 0.0001) compared to controls. The effect of endocrine insufficiency on PCS was differentially greater among RAP subjects (-1.28 for CP vs. -4.9 for RAP, p = 0.0184). CONCLUSIONS: Even in the absence of CP, subjects with RAP have lower physical and mental QOL. This underscores the importance of identifying interventions to attenuate RAP before the development of overt CP.

Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry.

BACKGROUND: Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US. METHODS: We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA. Demographic and phenotypic information was obtained from structured questionnaires. Ancestry and admixture were evaluated by principal component analysis (PCA). Genotyping was performed for pathogenic genetic variants in PRSS1, SPINK1, CFTR and CTRC. Prevalence of disease-associated variants in NAPS2 subjects of AA and EA was compared. RESULTS: When compared with CP subjects of EA (n = 862), prevalence of established pathogenic genetic variants was infrequent in AA patients with CP, overall (29 vs. 8.19%, OR 4.60, 95% CI 2.74-7.74, p < 0.001), and after stratification by alcohol etiology (p < 0.001). On PCA, AA cases were more heterogeneous but distinct from EA subjects; no difference was observed between AA subjects with and without CP-associated variants. Of 19 A A patients with CP who had pathogenic genetic variants, 2 had variants in PRSS1 (R122H, R122C), 4 in SPINK1 (all N34S heterozygotes), 12 in CFTR (2 CFTRsev, 9 CFTRBD, 1 compound heterozygote with CFTRsev and CFTRBD), and 1 in CTRC (R254W). CONCLUSION: Pathogenic genetic variants reported in EA patients are significantly less common in AA patients. Further studies are needed to determine the complex risk factors for AA subjects with pancreatitis.

Patient and Disease Characteristics Associated With the Presence of Diabetes Mellitus in Adults With Chronic Pancreatitis in the United States.

OBJECTIVES: Diabetes mellitus (DM) is a common complication of chronic pancreatitis (CP). Past studies for DM risk factors in CP have been limited to single centers or highly focused on a single etiology such as alcoholic or hereditary disease. We studied risk factors for DM in a large population of patients with CP of all etiologies enrolled in the North American Pancreatitis 2 studies. METHODS: Participants (1,171) with CP (n=383 with DM, n=788 without DM) were enrolled prospectively from 26 participating centers. Questionnaires were completed by patients and physicians in a cross-sectional assessment. Patient demographics and disease characteristics were compared for CP with DM vs. without DM. Logistic regression was performed to assess the variables associated with DM diagnosis in a multivariable model. RESULTS: Diabetics were more likely to be black (P=0.02), overweight, or obese (P<0.001), and with a family history of DM (P=0.0005). CP patients with DM were more likely to have pancreatic calcifications (63% vs. 54%, P=0.002), atrophy (44% vs. 32%, P<0.0001), and prior pancreas surgery (26.9% vs. 16.9%, P<0.0001). In multivariate logistic regression modeling, the strongest risk factors for DM were obesity (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.9, 4.2) and exocrine insufficiency (OR 2.4, 95% CI 1.8, 3.2). CONCLUSIONS: In this large multicenter cohort of patients with CP, exocrine insufficiency, calcifications, and pancreas surgery conveyed higher odds of having DM. However, the traditional 'type 2 DM' risk factors of obesity and family history were similarly important in conveying risk for DM.

Quality of Life in Chronic Pancreatitis is Determined by Constant Pain, Disability/Unemployment, Current Smoking, and Associated Co-Morbidities.

OBJECTIVES: Chronic pancreatitis (CP) has a profound independent effect on quality of life (QOL). Our aim was to identify factors that impact the QOL in CP patients. METHODS: We used data on 1,024 CP patients enrolled in the three NAPS2 studies. Information on demographics, risk factors, co-morbidities, disease phenotype, and treatments was obtained from responses to structured questionnaires. Physical and mental component summary (PCS and MCS, respectively) scores generated using responses to the Short Form-12 (SF-12) survey were used to assess QOL at enrollment. Multivariable linear regression models determined independent predictors of QOL. RESULTS: Mean PCS and MCS scores were 36.7±11.7 and 42.4±12.2, respectively. Significant (P<0.05) negative impact on PCS scores in multivariable analyses was noted owing to constant mild-moderate pain with episodes of severe pain or constant severe pain (10 points), constant mild-moderate pain (5.2), pain-related disability/unemployment (5.1), current smoking (2.9 points), and medical co-morbidities. Significant (P<0.05) negative impact on MCS scores was related to constant pain irrespective of severity (6.8-6.9 points), current smoking (3.9 points), and pain-related disability/unemployment (2.4 points). In women, disability/unemployment resulted in an additional 3.7 point reduction in MCS score. Final multivariable models explained 27% and 18% of the variance in PCS and MCS scores, respectively. Etiology, disease duration, pancreatic morphology, diabetes, exocrine insufficiency, and prior endotherapy/pancreatic surgery had no significant independent effect on QOL. CONCLUSIONS: Constant pain, pain-related disability/unemployment, current smoking, and concurrent co-morbidities significantly affect the QOL in CP. Further research is needed to identify factors impacting QOL not explained by our analyses.

Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.

GOALS/BACKGROUND: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. STUDY: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. RESULTS: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. CONCLUSIONS: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Validation of Demographics, Etiology, and Risk Factors for Chronic Pancreatitis in the USA: A Report of the North American Pancreas Study (NAPS) Group.

BACKGROUND/OBJECTIVES: Our aim was to validate recent epidemiologic trends and describe the distribution of TIGAR-O risk factors in chronic pancreatitis (CP) patients. METHODS: The NAPS-2 Continuation and Validation (NAPS2-CV) study prospectively enrolled 521 CP patients from 13 US centers from 2008 to 2012. CP was defined by definitive changes in imaging, endoscopy, or histology. Data were analyzed after stratification by demographic factors, physician-defined etiology, participating center, and TIGAR-O risk factors. RESULTS: Demographics and physician-defined etiology in the NAPS2-CV study were similar to the original NAPS2 study. Mean age was 53 years (IQR 43, 62) with 55% males and 87% white. Overall, alcohol was the single most common etiology (46%) followed by idiopathic etiology (24%). Alcohol etiology was significantly more common in males, middle-aged (35-65 years), and non-whites. Females and elderly (≥65 years) were more likely to have idiopathic etiology, while younger patients (<35 years) to have genetic etiology. Variability in etiology was noted by participating centers (e.g., alcohol etiology ranged from 27 to 67% among centers enrolling ≥25 patients). Smoking was the most commonly identified (59%) risk factor followed by alcohol (53%), idiopathic (30%), obstructive (19%), and hyperlipidemia (13%). The presence of multiple TIGAR-O risk factors was common, with 1, 2, ≥3 risk factors observed in 27.6, 47.6, and 23.6% of the cohort, respectively. CONCLUSION: Our data validate the current epidemiologic trends in CP. Alcohol remains the most common physician-defined etiology, while smoking was the most commonly identified TIGAR-O risk factor. Identification of multiple risk factors suggests CP to be a complex disease.

Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.

Racial Differences in the Clinical Profile, Causes, and Outcome of Chronic Pancreatitis.

OBJECTIVES: Racial differences in susceptibility and progression of pancreatitis have been reported in epidemiologic studies using administrative or retrospective data. There has been little study, however, on the clinical profile, causes, and outcome of chronic pancreatitis (CP) in black patients. METHODS: We analyzed data on black patients with CP prospectively enrolled in the multicenter North American Pancreatitis Studies from 26 US centers during the years 2000-2014. CP was defined by definitive evidence on imaging studies or histology. Information on demographics, etiology, risk factors, disease phenotype, treatment, and perceived effectiveness was obtained from responses to detailed questionnaires completed by both patients and physicians. RESULTS: Of the 1,159 patients enrolled, 248 (21%) were black. When compared with whites, blacks were significantly more likely to be male (60.9 vs. 53%), ever (88.2 vs. 71.8%), or current smokers (64.2 vs. 45.9%), or have a physician-defined alcohol etiology (77 vs. 41.9%). There was no overall difference in the duration of CP although for alcoholic CP, blacks had a longer duration of disease (8.6 vs. 6.97 years; P=0.02). Blacks were also significantly more likely to have advanced changes on pancreatic morphology (calcifications (63.3 vs. 55.2%), atrophy (43.2 vs. 34.6%), pancreatic ductal stricture or dilatation (72.6 vs. 65.5%) or common bile duct stricture (18.6 vs. 8.2%)) and function (endocrine insufficiency 39.9 vs. 30.2%). Moreover, the prevalence of any (94.7 vs. 83%), constant (62.6 vs. 51%), and severe (78.4 vs. 65.8%) pain and disability (35.1 vs. 21.4%) were significantly higher in blacks. Observed differences were in part related to variances in etiology and duration of disease. No differences in medical or endoscopic treatments were seen between races although prior cholecystectomy (31.1 vs. 19%) was more common in white patients. CONCLUSIONS: Differences were observed between blacks and whites in the underlying cause, morphologic expression, and pain characteristics of CP, which in part are explained by the underlying risk factor(s) with alcohol and tobacco being much more frequent in black patients as well as disease duration.

Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings.

BACKGROUND & AIMS: Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain. We investigated whether abdominal imaging features accurately predict patterns of pain. METHODS: We collected data from participants in the North American Pancreatitis Study 2 Continuation and Validation, a prospective multicenter study of patients with chronic pancreatitis performed at 13 expert centers in the United States from July 2008 through March 2012. Chronic pancreatitis was defined based on the detection of characteristic changes by cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, or histology analyses. Patients were asked by a physician or trained clinical research coordinator if they had any abdominal pain during the year before enrollment, those who responded "yes" were asked to select from a list of 5 pain patterns. By using these patterns, we classified patients' pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms. RESULTS: Data were collected from 518 patients (mean age, 52 ± 14.6 y; 55% male; and 87.6% white). The most common physician-identified etiologies were alcohol (45.8%) and idiopathic (24.3%); 15.6% of patients reported no abdominal pain in the year before enrollment. The most common individual pain pattern was described as constant mild pain with episodes of severe pain and was reported in 45% of patients. The most common imaging findings included pancreatic ductal dilatation (68%), atrophy (57%), and calcifications (55%). Imaging findings were categorized as obstructive for 20% and as inflammatory for 25% of cases. The distribution of individual imaging findings was similar among patients with different patterns of pain. The distribution of pain patterns did not differ among clinically relevant groups of imaging findings. CONCLUSIONS: Mechanisms that determine patterns and severity of pain in patients with chronic pancreatitis are largely independent of structural variants observed by abdominal imaging techniques. Pancreas-relevant quantitative and qualitative pain measures should be included in the evaluation of patients with chronic pancreatitis to assess pain severity independently of imaging findings.