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IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

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.

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 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

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 CFTR(sev), 9 CFTR(BD), 1 compound heterozygote with CFTR(sev) and CFTR(BD)), 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.

Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. Methods: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. Results: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. Discussion: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

The development of cystic fibrosis transmembrane conductance regulator (CFTR) targeted therapy for cystic fibrosis has generated interest in maximizing membrane residence of mutant forms of CFTR by manipulating interactions with scaffold proteins, such as sodium/hydrogen exchange regulatory factor-1 (NHERF1). In this study, we explored whether COOH-terminal sequences in CFTR beyond the PDZ-binding motif influence its interaction with NHERF1. NHERF1 displayed minimal self-association in blot overlays (NHERF1, Kd= 1,382 ± 61.1 nM) at concentrations well above physiological levels, estimated at 240 nM from RNA-sequencing and 260 nM by liquid chromatography tandem mass spectrometry in sweat gland, a key site of CFTR function in vivo. However, NHERF1 oligomerized at considerably lower concentrations (10 nM) in the presence of the last 111 amino acids of CFTR (20 nM) in blot overlays and cross-linking assays and in coimmunoprecipitations using differently tagged versions of NHERF1. Deletion and alanine mutagenesis revealed that a six-amino acid sequence1417EENKVR1422and the terminal1478TRL1480(PDZ-binding motif) in the COOH-terminus were essential for the enhanced oligomerization of NHERF1. Full-length CFTR stably expressed in Madin-Darby canine kidney epithelial cells fostered NHERF1 oligomerization that was substantially reduced (∼5-fold) on alanine substitution of EEN, KVR, or EENKVR residues or deletion of the TRL motif. Confocal fluorescent microscopy revealed that the EENKVR and TRL sequences contribute to preferential localization of CFTR to the apical membrane. Together, these results indicate that COOH-terminal sequences mediate enhanced NHERF1 interaction and facilitate the localization of CFTR, a property that could be manipulated to stabilize mutant forms of CFTR at the apical surface to maximize the effect of CFTR-targeted therapeutics.

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

Chronic pancreatitis is a syndrome characterized by chronic inflammation of the pancreas, with variable pain, calcifications, necrosis, fatty replacement, fibrosis and scarring and other complications. Disease susceptibility, severity, progression and pain patterns vary widely and do not necessarily parallel one another. Much of the variability in susceptibility to recurrent acute and chronic pancreatitis is now clearly shown to be related to genetic differences between patients. This review highlights recent advances and future directions in genetic research.The strongest risk factors are associated with genetic variations in PRSS1, SPINK1, CFTR, and to a lesser extent, CTRC and CASR. The latest research suggest that a single factor rarely causes pancreatitis, and the majority of patients with recurrent acute and chronic pancreatitis have multiple variants in a gene, or epistatic interactions between multiple genes, coupled with environmental stressors.Pancreatic diseases have a strong genetic component. Rather than a classic Mendelian disorder, recurrent acute and chronic pancreatitis represents truly complex diseases with the interaction and synergism of multiple genetic and environmental factors. The future will require new predictive models to guide prevention and therapy.

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

Background/Objectives Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF−α) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS. Methods We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 h) and MODS. MODS was defined as failure of ≥2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 h. Subjects were genotyped by DNA sequencing and analyzed for SNPs at −1031 C/T (rs1799964), −863 A/C (rs1800630), −857 C/T (rs1799724), −308 A/G (rs1800629), and −238 A/G (rs361525). Results Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at −1031C (56.5% vs. 32.4% P = 0.022, OR: 2.7; 95%CI: 1.12–6.51) and −863A (43.5% vs. 21.8% P = 0.022, OR: 2.76; 95%CI: 1.12–6.74). Conclusion TNFA promoter variants do not alter susceptibility to AP, but rather the TNF−α expression-enhancing −1031C and −863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF−α in the overall AP syndrome.

OBJECTIVES A risk association has been observed between non-O blood groups and pancreatic adenocarcinoma. Chronic pancreatitis also increases risk for pancreatic cancer, raising questions as to whether non-O blood groups are a risk for chronic pancreatitis and whether the pathophysiologic pathways are linked. Our goal was to determine whether ABO blood group may affect the risk of chronic pancreatitis. METHODS The study cohort included chronic pancreatitis patients (n = 499) and healthy controls (n = 631) from the North American Pancreatitis Study 2 study. Genotyping was performed using Sequenom assay of rs8176746 A/C and rs505922 C/T to classify participants into ABO blood groups. RESULTS O blood group was nonsignificantly more common among cases (44.7% vs 42.0%; P = 0.36), particularly among cases with alcohol-related chronic pancreatitis (49.3% vs 42%; P = 0.060). Alcoholic patients without coexisting high-risk PRSS1, CFTR, or SPINK1 variants had a significant overrepresentation of O blood type when compared with controls (odds ratio, 1.54; 95% confidence interval, 1.09-2.17; P = 0.01). CONCLUSIONS A, B, and AB blood groups were not associated with a greater likelihood of having chronic pancreatitis and may decrease the risk of chronic pancreatitis in individuals who are very heavy drinkers. These results suggest that the mechanism linking non-O blood type with pancreatic pathology is specific to carcinogenesis.

The C-terminal PDZ-binding motifs are required for polarized apical/basolateral localization of many membrane proteins. To determine the specificity of the PDZ-binding motifs in establishing cellular distribution, we utilized a 111-amino acid region from the C-terminus of cystic fibrosis transmembrane conductance regulator (CFTR) that is able to direct apical localization of fused reporter proteins. Substitution of the C-terminal PDZ-binding motif of CFTR with corresponding motifs necessary for basolateral localization of other membrane proteins did not lead to the redistribution of the fusion protein to the basolateral membrane. Instead, some fusion proteins remained localized to the apical membrane, whereas others showed no specific distribution. The specificity of the PDZ-based interactions was substantially increased when specific amino acids located upstream of the classical PDZ-binding motifs were included. However, even the presence of a longer C-terminal motif from a basolateral protein could not ensure basolateral distribution of the fusion protein. Our results indicate that the C-terminal PDZ-binding motifs are not the primary signals for polarized protein distribution, although they are required for targeting and/or stabilization of protein at the given location.

Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1 alpha. We show that HIF-1 regulates the expression of genes encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth factor alpha; and autocrine motility factor, which are proteins that play established roles in the pathophysiology of invasion. Neutralizing antibodies against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.

Introduction: The genetic events and molecular mechanisms underlying pancreatic regeneration after acute pancreatitis are poorly understood. Cerulein, a cholecystokinin analog, induces acute pancreatitis in mice with pronounced acinar cell injury and acinar-ductal metaplasia within three days. Thereafter, regeneration with normal pancreatic cellular morphology and function occurs. Methods: To address what molecular factors promote injury and regeneration, we isolated RNA and performed gene expression analysis of the challenged cell population at different time points (day 0, 1, 3, and 5) by using the cerulein-induced acute pancreatitis in C57BL/6 mice and saline in age-matched wild-type littermates. Results: Unsupervised gene clustering analysis underscored that changes in gene expression are mostly limited to the early time points, specifically days 1-3, consistent with the observed morphologically changes. The experimental design of this study allowed us to identify temporally regulated genes during defined phases of injury and regeneration. On day 1 of pancreatitis 224 genes were highly significant upor down-regulated, respectively (more than 2.5-fold, false discovery rate 0.1), compared to day 0 and matched controls. Analysis of the gene expression data by computational pathway analysis tools revealed several specific regulatory networks that are deregulated. Interestingly, besides pathways that regulate DNA replication, and repair, cell cycle, cellular assembly and organization, as well as embryonic development, the top networks are related to growth, proliferation, tumor morphology, and cancer. Conclusion: This study not only provides new insights into gene expression during regeneration but might provide evidence for overlapping and distinct gene expression signatures of development, regeneration, and cancer in the pancreas.