North American Pancreatitis Study Research Articles

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

Pancreatitis-Associated PRSS1-PRSS2 Haplotype Alters T-Cell Receptor Beta (TRB) Repertoire More Strongly Than PRSS1 Expression

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

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. 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. 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). 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.

Lifetime smoking history and cohort-based smoking prevalence in chronic pancreatitis

Background/objectiveSmoking prevalence in patients with chronic pancreatitis [CP] is high. We aimed to understand lifetime history of smoking and cohort trends in CP patients to inform effective strategies for smoking cessation. MethodData on 317 CP patients from the North American Pancreatitis Study 2 [NAPS2] Continuation and Validation Study and the NAPS2 Ancillary Study were analyzed. Smoking history was assessed for each phase of life from the onset of smoking to study enrollment. Data on second-hand smoke and drinking history were also collected. We compared demographic factors, drinking history, pain level and pancreas morphology by smoking status at age 25 (non-smoking, <1 pack per day [PPD], ≥1 PPD). We compared smoking prevalence by birth cohorts: 1930–1949, 1950–1969, 1970–1989. ResultFifty-one percent of CP patients reported smoking at the time of enrollment. Those who smoked ≥1 PPD at age 25 smoked a cumulative total of 30.3 pack-years of cigarettes over a lifetime. Smoking at age 25 was associated with greater lifetime drinking and greater exposure to second-hand smoke at home and at workplace. Pancreatic atrophy and pseudocysts were more common among smokers. Pancreatic pain was more severe among smokers, and 12–13% of smokers reported smoking to alleviate pain. Male CP patients born in 1950–1969 reported the highest peak prevalence of smoking, and female CP patients born in 1970–1989 reported highest peak prevalence of smoking. ConclusionCP patients exhibit intense and sustained smoking behavior once established in the 20s. Regardless, cohort analyses demonstrate that the behaviors could potentially be altered by policy changes.

Divergent trends in lifetime drinking and smoking between Black and White Americans diagnosed with chronic pancreatitis

Background/objectivesBlack Americans are at increased risk of chronic pancreatitis (CP) compared to their White counterparts. We aimed to describe the race-specific smoking history and lifetime drinking in patients diagnosed with CP. MethodsWe analyzed data on 334 Black and White CP participants of the North American Pancreatitis Study 2 Continuation and Validation Study and Ancillary Study. Lifetime drinking history and lifetime smoking history were collected through in-person interviews. Intensity, frequency, duration and current status of drinking and smoking were compared between Black and White CP participants, stratified by physician-defined alcohol etiology. In addition, drinking levels at each successive decades in life (20s, 30s, 40s) were compared by race and graphically portrayed as heat diagrams. ResultsAmong patients with alcoholic CP, current smoking levels were not different by race (67–70%), but a smaller proportion of Black patients reported having smoked 1 or more packs per day in the past (32%) as compared to White patients (58%, p < 0.0001). Black patients were more likely to report current consumption of alcohol (31%), as opposed to White patients (17%, p = 0.016). Black patients also reported more intense drinking at age 35 and 45 years as compared to White patients, while age at CP onset were similar between the two groups. ConclusionWe found more intense drinking but less intense smoking history in Black CP patients as compared to White CP patients. Effective alcohol abstinence and smoking cessation program with sustained impact are needed in CP patients.

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis

BackgroundChronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function. AimTo define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP. MethodsSerum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features. ResultsA final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures). ConclusionsVery low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.

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.&#x0D; 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).&#x0D; Results: Enrolling physician identified smoking as a risk factor in significantly (all p&lt; 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.&#x0D; 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.

Bone health assessment in clinical practice is infrequenty performed in patients with chronic pancreatitis

BackgroundChronic pancreatitis (CP) patients have a high prevalence of osteoporotic fractures. In addition to prevalence of osteoporotic fractures, we evaluated how often bone health is assessed by dual-energy x-ray absorptiometry (DXA) in clinical practice, and the performance of Fracture Risk Assessment Tool (FRAX®) in predicting fracture risk in CP patients. MethodsMedical records of CP patients age ≥40 years prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2) from the University of Pittsburgh Medical Center from 2000 to 2014 were retrospectively reviewed to gather additional relevant data before, at, and after enrollment until December 2016. We determined if patients underwent DXA, compared their observed prevalence of fractures with published data from two large US studies based on administrative data, and their predicted fracture risk with US population based on FRAX®. ResultsOnly 21% (49/239) patients were evaluated by DXA during their care. The observed cumulative prevalence of fragility fractures in NAPS2 CP patients (9.2%, 95% confidence interval 5.9–13.6) was significantly greater than in controls (1.46% and 2.16%, p ≤ 0.001 for each comparison) and CP patients (4.66%, and 5.13%, p < 0.005 for each comparison) in the two US administrative data studies. The FRAX® 10-year probability of major osteoporotic fracture of ≥20% (5.1% vs. 8.3%, p > 0.05) and for hip fracture of ≥3% (19.6% vs. 18.9%, p > 0.05) in NAPS2 CP patients did not differ from the US population. ConclusionsDespite their high risk of fragility fractures, bone health is infrequently assessed in CP patients. FRAX® may not adequately predict fracture risk in CP patients.

Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort.

Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10-16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes includingROBO2, CTNND2, SGCZ, CNTN5andBAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2,andCTNND2). Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted. Clinicaltriasl.gov.# NCT01545167.

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

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. 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. 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. 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.

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

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. 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. 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). 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.

(123) Visceral Pain Mechanisms: Features of Constant Pain and Genetic Linkage in Chronic Pancreatitis Patients

Abdominal pain is the most distressing feature of chronic pancreatitis (CP) and drives health care utilization. Compared to intermittent pain, constant CP pain is associated with significantly lower physical and mental quality of life scores. However, the characteristics of constant pancreatic pain appears to be different from constant somatic pain, and pain classification correlates poorly with environmental and metabolic factors. Our Aim was to determine whether genetic factors contribute to severe and/or constant pain in patients with CP. We utilized data from the North American Pancreatitis Study II (NAPS2), including 1,195 CP and 1,109 control subjects from 2000 to 2014.1 Information on demographics, disease characteristics, comorbidities, environmental exposures, quality of life measures (SF12), and details of pain experience (presence, temporal nature, severity) was collected from detailed case report forms. DNA was collected for genetic analysis.2 Additional genotyping, genotype imputation, whole exome sequencing, and targeted sequencing was completed. A nested GWAS based on the presence or absence of pain characteristics was completed (nested GWAS in CP patients). Six loci were identified with LOD scores of >6. Each includes biologically plausible candidate genes that interfere with neuronal function, adaptation or psychological tolerance, but not pancreatic pathology. These data are the first of their kind to explore a genetic basis for the severe and constant pain in patients with CP. Deeper phenotyping, genotyping, experimental models and targeted clinical trials that repurpose existing agents should be completed. (1. Machicado, Am J Gastroenterol, 2017; 2. Whitcomb, Nat Genet, 2012) Supported by a grants R21DK098560 (DCW) and the National Pancreas Foundation (DCW).

Gene, environment and Surgical risk of diabetes mellitus in patients with chronic pancreatitis from the North American pancreatitis study 2 (NAPS2)

Gene, environment and Surgical risk of diabetes mellitus in patients with chronic pancreatitis from the North American pancreatitis study 2 (NAPS2)

Acute Pancreatitis Has a Long-term Deleterious Effect on Physical Health Related Quality of Life.

It is not clear how acute pancreatitis (AP) affects health related quality of life (HRQOL). We aimed to determine the long-term independent effect of AP on physical and mental HRQOL. We analyzed data from 91 patients (mean 52 years of age, 54% women) admitted with AP to the University of Pittsburgh Medical Center from 2011 to 2015 who responded to telephone surveys at a median of 14 months after hospital discharge (interquartile range, 12-16 months). Individuals who did not answer the telephone survey were sent a questionnaire by regular mail. Patients answered questions from the 12-Item Short-Form Survey, and answers were used to calculate mental component summary (MCS) and physical component summary (PCS) scores with norm-based scoring (normal ≥50). HRQOL for these subjects was compared with that of age- and sex-matched individuals without pancreatitis (1:2) identified from the North American Pancreatitis Study. We controlled for other covariates using multivariable regression analysis. At follow-up, individuals with AP had a significantly lower PCS score (46.2 ± 11.8) than did control subjects (51.1 ± 9.5; P < .01), but a similar MCS score. A 4-point reduction of the PCS was attributed to AP after controlling for sociodemographic factors and medical comorbidities. The only pancreatitis-related factor associated with low PCS score was multisystem organ failure. Presence of abdominal pain, analgesic use, disability, and current smoking at the time of follow-up were also associated with lower PCS scores. Etiology of AP, disease severity (byRevised Atlanta classification), use of nutritional support, and performance of pancreatic interventions did not affect HRQOL at follow-up. In a 14-month follow-up of patients hospitalized with AP, we found a meaningful, independent, and deleterious effect of AP in the physical HRQOL of these patients, compared to individuals without AP. Further research is needed to determine the duration of this impairment and to evaluate the effects of modifying risk factors.

The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population.

OBJECTIVES:Recurrent acute pancreatitis (RAP) is a complex inflammatory disorder that may progress to fibrosis and other irreversible features recognized as chronic pancreatitis (CP). Chymotrypsinogen C (CTRC) protects the pancreas by degrading prematurely activated trypsinogen. Rare mutations are associated with CP in Europe and Asia. We evaluated the occurrence of CTRC variants in subjects with RAP, CP, and controls from the North American Pancreatitis Study II cohort.METHODS:CP (n=694), RAP (n=448), and controls (n=1017) of European ancestry were evaluated. Subgroup analysis included CFTR and SPINK1 variants, alcohol, and smoking.RESULTS:We identified previously reported rare pathogenic CTRC A73T, R254W, and K247_R254del variants, intronic variants, and G60G (c.180 C>T; rs497078). Compared with controls (minor allele frequency (MAF)=10.8%), c.180T was associated with CP (MAF=16.8%, P<0.00001) but not RAP (MAF=11.9% P=NS). Trend test indicated co-dominant risk for CP (CT odds ratio (OR)=1.36, 95% confidence interval (CI)=1.13–1.64, P=0.0014; TT OR=3.98, 95% CI=2.10–7.56, P<0.0001). The T allele was significantly more frequent with concurrent pathogenic CFTR variants and/or SPINK1 N34S (combined 22.9% vs. 16.1%, OR 1.92, 95% C.I. 1.26–2.94, P=0.0023) and with alcoholic vs. non-alcoholic CP etiologies (20.8% vs. 12.4%, OR=1.9, 95% CI=1.30–2.79, P=0.0009). Alcohol and smoking generally occurred together, but the frequency of CTRC c.180 T in CP, but not RAP, was higher among never drinkers–ever smokers (22.2%) than ever drinker–never smokers (10.8%), suggesting that smoking rather than alcohol may be the driving factor in this association.CONCLUSIONS:The common CTRC variant c.180T acts as disease modifier that promotes progression from RAP to CP, especially in patients with CFTR or SPINK1 variants, alcohol, or smoking.

Chronic Pancreatitis Pain Pattern and Severity Are Independent of Abdominal Imaging Findings

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. 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, weclassified patients' pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms. 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. 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.

Early-Onset and Late-Onset Idiopathic Chronic Pancreatitis in the North American Pancreatitis Study (NAPS2-CV) Cohort

Introduction: Idiopathic chronic pancreatitis (ICP) defines a group of patients in whom no etiology is evident after standard clinical work-up. ICP is heterogeneous and can be divided into early-onset ICP (EO-ICP) and late-onset ICP (LO-ICP). Layer et al reported clinical differences between EO-ICP and LO-ICP, inlcluding pain, pancreatic insufficiency, and clinical course at Mayo Clinic.[1] These findings have not been replicated or validated in an independent North American cohort. Aims: To compare features of ICP between the NAPS2-CV and Mayo Clinic cohorts and potentially validate classification of ICP into EO-ICP and LO-ICP groups. Methods: NAPS2-CV prospectively ascertained patients with chronic pancreatitis using detailed demographic, phenotypic, and etiological case report forms. The diagnosis of ICP was made by expert physicians and then divided by age (EO-ICP: <35 years, and LO-ICP >35 years). We compared the clinical features of the NAPS2-CV and Mayo Clinic cohorts. Results: ICP was identified in 126/521 (24%). The fractions of ICP as EO-ICP versus LO-ICP were similar between NAPS2-CV and Mayo cohorts. Patients with EO-ICP were more likely to have pain than LO-ICP. EO-ICP and LO-ICP had similar rates of exocrine insufficiency, endocrine insufficiency, and calcifications. Prevalence of distinct clinical features were similar between NAPS2-CV and Mayo cohorts (Table). Conclusion: EO-ICP and LO-ICP differ primarily with respect to pain. The clinical profiles of NAPS2-CV replicate Layer. Further insights will require analysis of deeper data sets.Table 1

Variation in the γ-Glutamyltransferase 1 Gene and Risk of Chronic Pancreatitis

Individuals with chronic pancreatitis are at increased risk for pancreatic cancer. We hypothesized that genetic variation in the γ-glutamyltransferase 1 (GGT1) gene, which was recently reported associated with pancreatic cancer risk in a genome-wide association study, is also associated with risk of chronic pancreatitis. Associations between common polymorphisms in GGT1 and chronic pancreatitis were evaluated using data and samples from the North American Pancreatitis Study 2. Patients (n = 496) and control subjects (n = 465) were genotyped for 4 single-nucleotide polymorphisms: rs4820599, rs2017869, rs8135987, and rs5751901. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) for chronic pancreatitis risk were calculated using multiple logistic regression models. Interactions with cigarette smoking and alcohol use were explored. Single-nucleotide polymorphisms rs8135987 and rs4820599 were both statistically significantly associated with risk of chronic pancreatitis; compared with common allele homozygotes, individuals with at least 1 minor allele were at increased risk (rs8135987: OR, 1.36; 95% CI, 1.03-1.80 [P(trend) = 0.01]; rs4820599: OR, 1.39; 95% CI, 1.04-1.84 [P(trend) = 0.0]; adjusted for age, sex, race, smoking status, and alcohol use). No significant interactions with cigarette smoking and alcohol use were observed. Our results suggest that common variation in the GGT1 gene may also affect risk of chronic pancreatitis.

Physical and Mental Quality of Life in Chronic Pancreatitis

The objective of this study was to define the quality of life (QOL) in patients with chronic pancreatitis (CP).We studied 443 well-phenotyped CP subjects and 611 control subjects prospectively enrolled from 20 US centers between 2000 and 2006 in the North American Pancreatitis Study 2. Responses to the SF-12 questionnaire were used to calculate the mental (MCS) and physical component summary scores (PCS) with norm-based scoring (normal ≥50). Quality of life in CP subjects was compared with control subjects after controlling for demographic factors, drinking history, smoking, and medical conditions. Quality of life in CP was also compared with known scores for several chronic conditions.Both PCS (38 [SD, 11.5] vs 52 [SD, 9.4]) and MCS (44 [SD, 11.5] vs 51 [SD, 9.2]) were significantly lower in CP compared with control subjects (P < 0.001). On multivariable analyses, compared with control subjects, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. Quality of life in CP was similar to (heart, kidney, liver, lung disease) or worse than (nonskin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions.The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions.

Endoscopic Therapy Is Effective for Patients With Chronic Pancreatitis

Endoscopic therapy (ET) frequently is used to treat patients with painful chronic pancreatitis (CP), but little is known about outcomes of patients for whom ET was not successful who then underwent surgery, or outcomes after ET compared with only medical treatment. We evaluated use and long-term effectiveness of ET in a well-defined cohort of patients with CP. We analyzed data from 146 patients with CP who participated in the North American Pancreatitis Study 2 at the University of Pittsburgh Medical Center from 2000 to 2006; 71 (49%) patients received ET at the University of Pittsburgh Medical Center. Success of ET and surgery were defined by cessation of narcotic therapy and resolution of episodes of acute pancreatitis. Disease progression was followed up from its onset until January 1, 2011 (mean, 8.2 ± 4.7 y). Patients who underwent ET had more symptoms (pain, recurrent pancreatitis) and had more complex pancreatic morphology (based on imaging) than patients who received medical therapy. ET had a high rate of technical success (60 of 71 cases; 85%); its rates of clinical success were 51% for 28 of 55 patients for whom follow-up data were available (mean time, 4.8 ± 3.0 y) and 50% for 12 of 24 patients who underwent surgery after receiving ET. Patients who responded to ET were significantly older, had a shorter duration of disease before ET, had less constant pain, and required fewer daily narcotics than patients who did not respond to ET. Among the 36 symptomatic patients who received medical therapy and were followed up for a mean period of 5.7 ± 4.1 years, 31% improved and 53% had no change in symptoms; of these, 21% underwent surgery. ET is clinically successful for 50% of patients with symptomatic CP. When ET is not successful, surgery has successful outcomes in 50% of patients. Symptoms resolve in 31% of symptomatic patients who receive only medical therapy.

Framework for interpretation of genetic variations in pancreatitis patients

Chronic pancreatitis (CP) is defined by irreversible damage to the pancreas as a result of inflammation-driven pancreatic tissue destruction and fibrosis occurring over many years. The disorder is complex, with multiple etiologies leading to the same tissue pathology, and unpredictable clinical courses with variable pain, exocrine and endocrine organ dysfunction, and cancer. Underlying genetic variants are central CP susceptibility and progression. Three genes, with Mendelian genetic biology (PRSS1, CFTR, and SPINK1) have been recognized for over a decade, and little progress has been made since then. Furthermore, application of high-throughput genetic techniques, including genome-wide association studies (GWAS) and next generation sequencing (NGS) will provide a large volume of new genetic variants that are associated with CP, but with small independent effect that are impossible to apply in the clinic. The problem of interpretation is using the old framework of the germ theory of disease to understand complex genetic disorders. To understand these variants and translate them into clinically useful information requires a new framework based on modeling and simulation of physiological processes with or without genetic, metabolic and environmental variables considered at the cellular and organ levels, with integration of the immune system, nervous system, tissue injury and repair system, and DNA repair system. The North American Pancreatitis Study 2 (NAPS2) study was designed to capture this type of date and construct a time line to understand and later predict rates of disease progression from the initial symptom to end-stage disease. This effort is needed to target the etiology of pancreatic dysfunction beginning at the first signs of disease and thereby prevent the development of irreversible damage and the complications of CP. The need for a new framework and the rational for implementing it into clinical practice are described.