Risk Factor For Chronic Pancreatitis Research Articles

Heterozygous Spink1 deficiency promotes trypsin-dependent chronic pancreatitis in mice

Heterozygous SPINK1 mutations are strong risk factors for chronic pancreatitis in humans yet heterozygous disruption of mouse Spink1 yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous Spink1-deleted mice (Spink1-KOhet) in the C57BL/6N strain, and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models. We investigated severity of acute pancreatitis and progression to chronic pancreatitis in Spink1-KOhet mice after transient (10 injections) and prolonged (2×8 injections) cerulein hyperstimulation. We crossed Spink1-KOhet mice with T7D23A and T7D22N,K24R mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis. . Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice relative to the C57BL/6N control strain. After the acute episode, Spink1-KOhet mice developed progressive disease with chronic pancreatitis-like features whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the Spink1-KOhet allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains. Heterozygous Spink1 deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation, and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous Spink1 deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function SPINK1 mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.

Impact of alcohol and smoking cessation on the course of chronic pancreatitis

OBJECTIVESAlcohol and nicotine are the two most important risk factors of chronic pancreatitis and they often occur together. It is still unclear how much they influence the severity of the disease and which of the two addictions should be treated with priority. METHODSWe performed a single-center, retrospective, cross-sectional study in a mixed medicosurgical cohort of 870 patients diagnosed with chronic pancreatitis (CP). We analyzed the impact of the drinking pattern and abstinence for alcohol and nicotine on the course of the disease. Patients with alcoholic CP were subdivided in I) patients with “life-time drinking history” (LTDH), II) “current drinkers” with current alcohol abuse without signs of LTDH, and III) “former drinkers” who stopped or reduced alcohol intake dramatically. RESULTSCompared to patients with LTDH, “former drinkers” had a lower rate of exocrine insufficiency (29% vs. 59%) and pseudocysts (33% vs. 49%), were more often relapse-free (37% vs. 5%) and had less abdominal pain. There was no correlation detected between the quantity of alcohol consumption and the severity or progression of the disease. Regarding nicotine, 29 pack years are the threshold for developing early stage of CP. Under nicotine abstinence, only slightly more patients were relapse-free (37% vs. 22%). In contrast, the cumulative amount of nicotine consumed correlated with overall disease severity and the development of pseudocysts. The need for surgery was increased with odds ratios of 1.8 for both, alcohol and nicotine abuse. CONCLUSIONSAlcohol cessation in chronic pancreatitis reduces exocrine insufficiency, abdominal pain and local complications. The effect of nicotine cessation is less pronounced in our cohort. However, nicotine abuse represents an important factor for the development of the disease.

Smoking as the most important risk factor for chronic pancreatitis in the general population.

We tested the hypothesis that six toxic risk factors from the TIGAR-O classification system are equally important for risk of chronic pancreatitis, at the level of the individual patient and in the general population. 108,438 women and men aged 20-100years participating in the Copenhagen General Population Study from 2003 to 2015 were included. Associations of smoking, alcohol intake, waist/hip ratio, kidney function, plasma triglycerides, plasma Ca2+, and diseases within the causal pathway with risk of chronic pancreatitis, and corresponding population attributable risks were estimated. Information on chronic pancreatitis was from national Danish health registries. During median 9years (range: 0-15) of follow-up, 313 individuals had a first diagnosis of chronic pancreatitis; the incidence of chronic pancreatitis per 10,000 person-years were 3.1 overall, 2.8 in women, and 3.5 in men. Of the six toxic risk factors and relative to individuals with low values, individuals in the top 5% had hazard ratios for chronic pancreatitis of 3.1(95% CI 2.1-4.5) for pack-years smoked, 2.5(1.5-4.0) for alcohol intake, and 1.6(1.1-2.6) for plasma triglycerides. Corresponding values versus those without the baseline disease were 12.6 (7.9-20.2) for acute pancreatitis, 1.9 (1.2-2.8) for gallstone disease, and 1.9 (1.3-2.7) for diabetes mellitus. The highest population attributable fractions were for women (1) ever smoking (31%), (2) gallstone disease (5%), and (3) diabetes mellitus (4%), and for men (1) ever smoking (38%), (2) acute pancreatitis (7%)/high alcohol intake (7%), and (3) high plasma triglycerides (5%). Smoking is the most important risk factor for chronic pancreatitis in the general population.

Natural history, clinical characteristics, outcomes, and long-term follow-up of pain-free chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by chronic abdominal pain and functional insufficiency. However, a small subset of patients with prior acute pancreatitis (AP) and/or underlying risk factors for developing CP may be pain-free at diagnosis and may have a different clinical course. We aimed to compare the clinical characteristics, outcomes, and healthcare utilization between CP patients with and without pain. Reviewed patients with established CP were followed in our Pancreas Center between January 2016 and April 2021. Patients without risk factors for developing CP and/or without AP prior to their diagnosis and only with incidental radiologic features of CP were excluded, so as to minimize confounding factors of pancreatopathy unrelated to CP. Patients were divided into painful and pain-free groups to analyze differences in demographics, outcomes, and healthcare utilization. Of 368 CP patients, 49 (13.3%) were pain-free at diagnosis and had remained so for >9 years. There were no significant differences in body mass index, race, sex, or co-morbidities between the two groups. Pain-free patients were older at diagnosis (53.9 vs 45.7, P = 0.004) and had less recurrent AP (RAP) (43.8% vs 72.5%, P < 0.001) and less exocrine pancreatic insufficiency (EPI) (34.7% vs 65.7%, P < 0.001). Pain-free patients had less disability (2.2% vs 22.0%, P = 0.003), mental illness (20.4% vs 61.0%, P < 0.001), surgery (0.0% vs 15.0%, P = 0.059), and therapeutic interventions (0.0% vs 16.4%, P = 0.005) for pain. We described a unique subset of patients with underlying risk factors for CP and/or prior AP who were pain-free at diagnosis. They were older at diagnosis, had less EPI and RAP, and overall favorable outcomes with minimal resource utilization.

Chronic pancreatitis: analysis of disease progression factors

Alcohol and tobacco are important risk factors for chronic pancreatitis (CP). To analyze the effect of etiological factors such as tobacco and alcohol and pancreatic enzyme replacement therapy (PERT) in the progression of CP. Patients with a diagnosis of CP were recruited and grouped according to variables such as tobacco, alcohol and PERT. They were followed for 18 months. Subsequently, different variables and analytical parameters involved in the progression of the disease were analyzed. A total of 50 patients diagnosed with CP were included. Of these, 28 patients underwent PERT, 39 were smokers and 33 were alcohol users. Compared with patients without PERT, those with PERT had a higher proportion of diabetes (64 and 32%, respectively), had a higher need for endoscopic treatment (25 and 0%, respectively) and a normal body mass index (71 and 27.3%, respectively. The smokers had higher calcium levels and increased lymphocytosis and leukocytosis. The alcohol consumption group had a higher mean age (p = 0.04) Conclusions: PERT may improve the nutritional status but does not reduce the need for endoscopic or surgical treatment. Smoking and alcohol consumption favored the progression of CP. Also, smoking induced a pro-inflammatory state.

Epidemiologic risk factors for patients admitted with chronic pancreatitis and pancreatic ductal adenocarcinoma in the United States

Epidemiological studies of chronic pancreatitis (CP) and its association with pancreatic ductal adenocarcinoma (PDAC) are limited. Understanding demographic and ethno-racial factors may help identify patients at the highest risk for CP and PDAC. To evaluate the ethno-racial risk factors for CP and its association with PDAC. The secondary aim was to evaluate hospitalization outcomes in patients admitted with CP and PDAC. This retrospective cohort study used the 2016 and 2017 National Inpatient Sample databases. Patients included in the study had ICD-10 codes for CP and PDAC. The ethnic, socioeconomic, and racial backgrounds of patients with CP and PDAC were analyzed. Hospital admissions for CP was 29 per 100000, and 2890 (0.78%) had PDAC. Blacks [adjusted odds ratio (aOR) 1.13], men (aOR 1.35), age 40 to 59 (aOR 2.60), and being overweight (aOR 1.34) were significantly associated with CP (all with P < 0.01). In patients with CP, Whites (aOR 1.23), higher income, older age (aOR 1.05), and being overweight (aOR 2.40) were all significantly associated with PDAC (all with P < 0.01). Men (aOR 1.81) and Asians (aOR 15.19) had significantly increased mortality (P < 0.05). Hispanics had significantly increased hospital length of stay (aOR 5.24) (P < 0.05). Based on this large, nationwide analysis, black men between 40-59 years old and overweight are at significantly increased risk for admission with CP. White men older than 40 years old and overweight with higher income were found to have significant associations with CP and PDAC. This discrepancy may reflect underlying differences in healthcare access and utilization among different socioeconomic and ethno-racial groups.

S1860 Diffuse Large B Cell Lymphoma Presenting as Acute Recurrent Pancreatitis

Introduction: Extra-nodal Non-Hodgkin’s lymphomas are mostly made of gastrointestinal sites1. Primary pancreatic lymphomas account for < 1% of all extra-nodal lymphomas and are extremely rare. Diagnosis is often missed or delayed due to the prevalence of chronic pancreatitis or pancreatic adenocarcinoma as thought to be the main causes of any pancreatic stricture or mass seen when diagnosing a patient. We present a case of pancreatic lymphoma presenting as acute recurrent pancreatitis. Case Description/Methods: A 51-year-old male with past medical history of rheumatoid arthritis and nicotine use presented with jaundice, abdominal pain, and fatigue and 30-pound weight loss. MRCP showed intra- and extra-hepatic biliary dilation, showing double duct sign. CT suggested acute pancreatitis. ERCP was done showing a single localized biliary malignant appearing stricture in the lower third of the main bile duct with upstream dilation. EUS showed a 19 mm by 19 mm mass in the head of pancreas and 8 mm dilation of the common bile duct. EUS fine needle biopsy showed chronic pancreatitis with dense fibrosis and benign peri-pancreatic lymph nodes. PET CT showed activity in the pancreas and retroperitoneal lymph nodes. Tumor markers (AFP, CEA, CA 19-9) were within normal limits. (Figure) Patient had no known risk factors for chronic pancreatitis therefore, the acute presentation and biopsy results in congruent with the clinical history led us to repeat EUS one month later. This showed a 20 mm by 15 mm irregular mass in the head of the pancreas with upstream pancreatic duct dilation. This time, pathology was sent for flow cytometry and came back positive for lymphoid infiltrate with a preponderance of B-cells surrounded by dense fibrosis and was positive for CD 19, 20, 22 and 10. By this point, malignancy other than adenocarcinoma was suspected and IR guided biopsy of retroperitoneal lymph nodes confirmed a diagnosis of diffuse large B cell lymphoma. Patient started chemotherapy with a 70% chance of being cured. ERCP one month later showed the stricture had resolved and the stent was removed. Discussion: Keeping a broad differential in mind for pancreatic masses is essential to prevent delayed diagnoses. With that in mind, although rare, pancreatic lymphoma should always be in the differential and physicians should consider sending for flow cytometry to avoid missing this diagnosis. When patients present with recurrent pancreatitis and no risk factors, lymphoma should be kept in the differential.Figure 1.: a) CT showing inflammatory reaction of the pancreas with bile duct dilation; b) Bile duct stricture on ERCP; c) EUS image showing common bile duct stent.

Urolithin A attenuates severity of chronic pancreatitis associated with continued alcohol intake by inhibiting PI3K/AKT/mTOR signaling.

Heavy alcohol consumption is the dominant risk factor for chronic pancreatitis (CP); however, treatment and prevention strategies for alcoholic chronic pancreatitis (ACP) remains limited. The present study demonstrates that ACP induction in C57BL/6 mice causes significant acinar cell injury, pancreatic stellate cell (PSC) activation, exocrine function insufficiency, and an increased fibroinflammatory response when compared with alcohol or CP alone. Although the withdrawal of alcohol during ACP recovery led to reversion of pancreatic damage, continued alcohol consumption with established ACP perpetuated pancreatic injury. In addition, phosphokinase array and Western blot analysis of ACP-induced mice pancreata revealed activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and cyclic AMP response element binding protein (CREB) signaling pathways possibly orchestrating the fibroinflammatory program of ACP pathogenesis. Mice treated with urolithin A (Uro A, a gut-derived microbial metabolite) in the setting of ACP with continued alcohol intake (during the recovery period) showed suppression of AKT and P70S6K activation, and acinar damage was significantly reduced with a parallel reduction in pancreas-infiltrating macrophages and proinflammatory cytokine accumulation. These results collectively provide mechanistic insight into the impact of Uro A on attenuation of ACP severity through suppression of PI3K/AKT/mTOR signaling pathways and can be a useful therapeutic approach in patients with ACP with continuous alcohol intake.NEW & NOTEWORTHY Our novel findings presented here demonstrate the utility of Uro A as an effective therapeutic agent in attenuating alcoholic chronic pancreatitis (ACP) severity with alcohol continuation after established disease, through suppression of the PI3K/AKT/mTOR signaling pathway.

Risk factors for the progression from acute recurrent to chronic pancreatitis among children in China.

BackgroundRisk factors for progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children are poorly understood.AimTo summarize the clinical characteristics of children with ARP and CP, identify the risk factors of CP, and investigate the factors associated with rapid progression from initial onset of ARP to CP.MethodsThe following variables were included in the risk factor analysis: sex, age at onset, family history, pancreas or biliary tract structural abnormalities, and genetic variations. Univariate and multivariate logistic regression analyses were used to assess the risk factors of CP. The Kaplan–Meier curves of the ARP progression to CP for various risk factor groupings were constructed and compared using the log-rank test. The Cox proportional hazard regression model was fitted to estimate the hazard ratio (HR) of progression to CP for each risk variable.ResultsIn total, 276 children were studied, of whom 136 progressed to CP. Among them, 41 had pancreatic duct obstructive disease; 105 underwent genetic testing, of whom 68 were found to have genetic variations. Among the remaining 140 patients who did not progress to CP, 61 had biliary obstructions. Forty-three of these children underwent genetic testing, and 15 were found to have genetic variations. Risk factor analysis showed that children with gene mutations were at a higher risk of progressing to CP [odds ratio (OR) = 3.482; 95% confidence interval (CI): 1.444–8.398; P = 0.005]; children with pancreas divisum (PD) had a higher risk of CP than those without (OR = 8.665; 95% CI: 1.884, 9.851; P = 0.006). Further, children whose first ARP occurred at an older age might develop CP faster (HR = 1.070; 95% CI: 1.003, 1.141; P = 0.039). Children with gene mutations had a faster rate of progression to CP after onset than children without gene mutations (HR = 1.607; 95% CI: 1.024, 2.522; P = 0.039), PRSS1 gene mutations were more associated (P = 0.025). There was no difference in the rate of progression from ARP to CP in children with PD (P = 0.887); however, endoscopic retrograde cholangiopancreatography (ERCP) intervention delayed the progression to CP in ARP patients with PD (P = 0.033).ConclusionPRSS1 gene mutations and PD are key risk factors for ARP progression to CP in children. PD itself does not affect the disease progression rate, but therapeutic ERCP can be beneficial to patients with ARP with symptomatic PD and delay the progression to CP.

The Risk Factors for Progression to Chronic Pancreatitis in Patients with Past-History of Acute Pancreatitis: A Retrospective Analysis Based on Mechanistic Definition.

Background: According to the mechanistic definition, the history of acute pancreatitis (AP) is a risk factor for chronic pancreatitis (CP). However, the etiology and severity of previous AP involved in the progression to CP have not been clarified. Here, we investigated risk factors for the progression to CP in patients with past-history of AP. Methods: Sixty-four patients with AP who were followed-up for at least two years at our institution between April 2009 and March 2017 were enrolled. The multivariate analysis was performed based on the risk factors extracted by univariate analysis. Results: Among the 64 patients, 13 patients (20.3%) progressed to CP (PCP group), while 48 did not (non-PCP group). Regarding the etiology of AP, rate of alcohol AP was significantly higher in the PCP group (76.9% vs. 33.3%, p = 0.003). In univariate analysis, smoking, number of previous AP, and alcohol consumption and drinking habits (Alcohol Use Disorders Identification Test-Concise; AUDIT-C) were identified as factors associated with progression to CP. Furthermore, multivariate analysis showed that AUDIT-C ≥ 6 points (male) and 4 points (female) after AP was a significant risk factor for CP (p = 0.003). Conclusions: Our results indicated that AUDIT-C ≥ 6 points (male) and 4 points (female) after AP was a risk factor in the process of progression to CP in patients with past-history of AP.

Exocrine pancreas insufficiency in chronic pancreatitis – Risk factors and associations with complications. A multicentre study of 1869 patients

Background/objectivesThere is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort. Patients and methodsWe retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. ResultsWe included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20–1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31–0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15–1.80), p = 0.002 and 1.54 (1.02–2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92–3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09–2.00), p = 0.02) and underweight (2.05 (OR 1.40–3.02), p < 0.001) were all associated with presence of EPI. ConclusionsSmoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients.

Acute and Chronic Pancreatitis Disease Prevalence, Classification, and Comorbidities: A Cohort Study of the UK BioBank.

INTRODUCTION:Pancreatitis is a complex syndrome that results from many etiologies. Large well-characterized cohorts are needed to further understand disease risk and prognosis.METHODS:A pancreatitis cohort of more than 4,200 patients and 24,000 controls were identified in the UK BioBank (UKBB) consortium. A descriptive analysis was completed, comparing patients with acute (AP) and chronic pancreatitis (CP). The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and severe pancreatitis and Obstructive checklist Version 2 classification was applied to patients with AP and CP and compared with the control population.RESULTS:CP prevalence in the UKBB is 163 per 100,000. AP incidence increased from 21.4/100,000 per year from 2001 to 2005 to 48.2/100,000 per year between 2016 and 2020. Gallstones and smoking were confirmed as key risk factors for AP and CP, respectively. Both populations carry multiple risk factors and a high burden of comorbidities, including benign and malignant neoplastic disorders.DISCUSSION:The UKBB serves as a rich cohort to evaluate pancreatitis. Disease burden of AP and CP was high in this population. The association of common risk factors identified in other cohort studies was confirmed in this study. Further analysis is needed to link genomic risks and biomarkers with disease features in this population.

Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large.

A diverse range of loss-of-function variants in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association.

Common calcium-sensing receptor (CASR) gene variants do not modify risk for chronic pancreatitis in a Hungarian cohort

The calcium-sensing receptor (CASR) is expressed in the pancreas where it might regulate calcium concentrations in pancreatic secretions. Two independent studies reported conflicting results claiming that commonly occurring missense variants of the CASR gene are risk factors for chronic pancreatitis (CP). Here, we attempted to replicate the association between CASR variants and CP. We analyzed 337 patients and 840 controls from the Hungarian National Pancreas Registry either by direct sequencing of exon 7 and the flanking noncoding regions or by TaqMan SNP genotyping assays. We identified two common missense variants, c.2956G>T (p.A986S), and c.2968A>G (p.R990G), three low-frequency variants, c.3031C>G (p.Q1011E), c.2610G>A (p.E870=) and c.∗60T>A, and 8 rare variants including the novel variant c.1895G>A (p.G632D). When allelic or genotype distributions were considered, none of the CASR variants associated with CP. Subgroup analysis of nonalcoholic versus alcoholic patients revealed no disease association either. Our results demonstrate that common CASR variants do not modify the risk for CP and should not be considered as genetic risk factors in the clinical setting.

Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma.

Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.

Evidence for diagnosis of early chronic pancreatitis after three episodes of acute pancreatitis: a cross-sectional multicentre international study with experimental animal model

Chronic pancreatitis (CP) is an end-stage disease with no specific therapy; therefore, an early diagnosis is of crucial importance. In this study, data from 1315 and 318 patients were analysed from acute pancreatitis (AP) and CP registries, respectively. The population from the AP registry was divided into AP (n = 983), recurrent AP (RAP, n = 270) and CP (n = 62) groups. The prevalence of CP in combination with AP, RAP2, RAP3, RAP4 and RAP5 + was 0%, 1%, 16%, 50% and 47%, respectively, suggesting that three or more episodes of AP is a strong risk factor for CP. Laboratory, imaging and clinical biomarkers highlighted that patients with RAP3 + do not show a significant difference between RAPs and CP. Data from CP registries showed 98% of patients had at least one AP and the average number of episodes was four. We mimicked the human RAPs in a mouse model and found that three or more episodes of AP cause early chronic-like morphological changes in the pancreas. We concluded that three or more attacks of AP with no morphological changes to the pancreas could be considered as early CP (ECP).The new diagnostic criteria for ECP allow the majority of CP patients to be diagnosed earlier. They can be used in hospitals with no additional costs in healthcare.

Protein misfolding in combination with other risk factors in CEL-HYB1-mediated chronic pancreatitis.

The hybrid allele of the carboxyl ester lipase gene (CEL-HYB1) is a genetic risk factor for chronic pancreatitis (CP) although the mechanism promoting disease development is largely unknown. Here, we aimed to clinically describe subjects carrying the CEL-HYB1 allele and to elucidate why the protein product is pathogenic by analyzing pancreatic secretions and cellular models. Norwegian cases (n = 154) diagnosed with recurrent acute pancreatitis or CP were subjected to genetic screening by a CEL-HYB1-specific PCR assay followed by Sanger sequencing. For investigation of CEL-HYB1 protein secretion, duodenal juice samples from cases and controls were analyzed by western blotting. HEK293cells were transfected with constructs expressing CEL-HYB1 or the normal CEL protein (CEL-WT) and analyzed by qPCR, cell fractionation and western blotting. Two CEL-HYB1-positive families were identified. In both pedigrees, CEL-HYB1 did not fully co-segregate with disease. One proband had recurrent acute pancreatitis and was an active smoker. Her mother was a CEL-HYB1 carrier who had suffered from several attacks of acute pancreatitis until she stopped smoking. The other proband was diagnosed with CP and pancreas divisum. Her CEL-HYB1-positive parent was symptom-free but exhibited pancreatic imaging changes. When analyzing the CEL protein in duodenal juice, CEL-WT was readily detectable but no band corresponding to the risk variant was seen. In CEL-HYB1-transfected cells, we observed impaired protein secretion, protein aggregation and endoplasmic reticulum stress. Our data suggest that CEL-HYB1, in combination with well-known pancreatitis risk factors, causes disease through the misfolding-dependent pathway of genetic CP risk.

The histopathology of SPINK1-associated chronic pancreatitis

BackgroundThe identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. MethodsHistologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. ResultsPatients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. ConclusionsWithin this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.

S0077 Probable Association of Idiopathic Pancreatitis With Smoking of Tobacco

INTRODUCTION: Acute pancreatitis is a serious disease with high morbidity and mortality rates. Research shows that among the primary admissions for acute pancreatitis, 26.9% had gallstone pancreatitis, 25.1% had alcoholic pancreatitis and 36.5% had idiopathic pancreatitis. Idiopathic pancreatitis accounted for a higher mortality rate than both gallstone pancreatitis and alcoholic pancreatitis patients (Chen et al., 2013).1 Recent studies have shown that cigarette smoking can also be a risk factor of acute pancreatitis. The two main metabolites from cigarette smoke are nicotine and NNK, which cause histologic changes to the pancreas. There is also indirect evidence that nicotine and acrolein cause ductal secretion due to CFTR dysfunction. As mentioned above, this can be a direct cause of inducing an attack of acute pancreatitis (Barreto, 2016).2 METHODS: This study is a retrospective chart review of adult patients that would include all adults (age >18 years), both genders, of all ethnic backgrounds, adults presenting with symptoms consistent with acute pancreatitis. The rate of pancreatitis will be compared among tobacco smokers and non-tobacco smokers. The association between pancreatitis and tobacco use will be tested for significance at P < 0.05 with Chi-square analysis. The magnitude of the risk of use will be calculated using Odds Ratio. RESULTS: There was 301 total number of patients in the study. Mean age was 58.76 (SD: 14.13) years and predominantly male (n = 164, 54.5%). There is a 2.32 (odds ratio) higher risk of acute pancreatitis and a smoker. This study showed a significance of P-value <0.0001 between idiopathic pancreatitis and tobacco use. CONCLUSION: Tobacco use is a risk factor for chronic pancreatitis but has not been associated directly with acute pancreatitis previously. There were multiple case reports in the literature that reported tobacco use associated with acute pancreatitis. This study has shown a significant association between tobacco use and acute idiopathic pancreatitis.Table 1.: smoking_use * idiopathic_acute_pancreatitis CrosstabulationTable 2.: Chi-Square Tests

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.