Search

The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP.Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP.Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.

Pseudocysts are localised fluid collections, usually developing as a complication of acute or chronic pancreatitis. Pancreatic ductal or parenchymal calcifications are commonly seen in routine radiological imaging, but calcification of pseudocyst is extremely rare. Calcified pseudocysts have been reported in literature as case reports, but a calcified pseudocyst in the lesser sac, without underlying pancreatic calcification, has not been reported. We report a case of a pancreatic pseudocyst with a calcified wall, requiring surgical excision and histological examination confirming the diagnosis.

The impact of fatty pancreas on pancreatic parenchymal changes is unclear. The aim of this study is to assess parenchymal alterations over time in patients with fatty pancreas (FP).This is a retrospective study (2014-2021) of patients with FP identified on endoscopic ultrasound (EUS). Subjects with follow up imaging studies including Computed Tomography (CT) scan, Magnetic Resonance Imaging (MRI), and EUS at least two years after the initial EUS were included.A total of 39 patients with a mean age of 51.21 ± 12.34 years were included. Mean initial weight was 80.17 ± 17.75 kg. Diabetes, hepatic steatosis, and EPI were present in 15%, 46% and 33% of the patients at baseline, respectively. In 25 patients with available follow up EUS over 2.4 ± 0.76 years, 16% progressed to chronic pancreatitis (CP) and 24% had progressive parenchymal changes without meeting the criteria for CP. One patient progressed from focal to diffuse FP, while one patient had resolution of FP. In multivariate analysis, progressive parenchymal changes on EUS were associated with an increase in weight over time (p-value 0.04), independent of the effects of gender, alcohol, or tobacco.Progressive parenchymal changes were noted in 44%. Our result suggests that FP is a dynamic process with the possibility of progression or regression over time.

Alterations in genes specifically expressed in the pancreas have been associated with chronic pancreatitis (CP). A significant percentage of patients with non-alcoholic CP, however, do not have mutations in known risk genes, suggesting the existence of further susceptibility genes. Four aquaporins are expressed in the exocrine pancreas: AQP1, AQP5, AQP8 and AQP12, the latter being found exclusively in this organ. Therefore, we investigated the two AQP12 genes, AQP12A and AQP12B, in CP patients.We analyzed all exons and adjacent intronic regions of AQP12A and AQP12B in 292 German patients with non-alcoholic CP and 143 control subjects by direct DNA sequencing.In total, we discovered 41 non-synonymous changes, three of which were nonsense variants. Genotype and allele frequencies of these variants did not differ significantly between patients and controls (all p-values0.05). Remarkably, we found a common nonsense variant in AQP12B, p.S152Tfs∗24, with an allele frequency of 15.7% in controls, including 2.8% homozygous subjects. This finding suggests that AQP12B is physiologically dispensable for normal pancreatic function.Our results suggest that genetic alterations in AQP12A and AQP12B do not predispose to the development of non-alcoholic CP.

/Objectives: Sequence variants in several genes have been identified as being associated with an increased inherited risk to develop chronic pancreatitis (CP). In a genetic survey of a CP patient we identified in the PRSS1gene a new c.380C G sequence variation, giving rise to a non-synonymous p.S127C mutation. Functional studies were performed to analyze the associated pathophysiology of the variant.Following generation of an expression vector for the new PRSS1 variant we compared its expression, secretion and catalytic activity with already known PRSS1 risk variants in HEK 293T cells. The intracellular protein accumulation and induction of endoplasmic reticulum (ER)-stress was analyzed.Prediction tool analysis indicated a probably deleterious effect of the p.S127C variant on protein function which was confirmed by detection of a secretion defect in HEK293T cells leading to intracellular protein accumulation. While protein misfolding was associated with reduced trypsin activity, the increased expression of BIP and presence of spliced XBP1 indicated that the p.S127C variant induces ER stress and activates the UPR signaling pathway.The disease mechanism of the PRSS1 p.S127C variant involves defective protein secretion and the induction of ER-stress due to accumulation of presumably misfolded trypsinogen within the ER. The new variant should be considered disease-causing with an incomplete penetrance. Our results confirm that in addition to dysregulated trypsin-activity or reduced fluid secretion, ER-stress induction is an important trigger for acinar cell damage and the development of recurrent or chronic pancreatic inflammation.

It is believed that acute pancreatitis (AP), recurrent AP (RAP) and chronic pancreatitis (CP) represent stages of the same disease spectrum. We aimed to identify risk factors, clinical presentation and outcomes in patients with prior RAP who develop CP.We retrospectively reviewed patients with CP who were seen at our Pancreas Center during 2016-2021. We divided them into two groups: with and without RAP (≥2 episodes of AP). We compared demographics, clinical presentation and resource utilization between the two groups.We identified 440 patients with CP, of which 283 (64%) patients had preceding RAP. These patients were younger (55.6 vs 63.1 years), active smokers (36% vs 20%) and had alcohol-related CP (49% vs 25%) compared to those without RAP and CP (p 0.05). More patients with RAP had chronic abdominal pain (89% vs 67.9%), nausea (43.3% vs 27.1%) and exocrine pancreatic insufficiency (65.8% vs 46.5%) (p 0.05). More patients with RAP used opioids (58.4% vs 32.3%) and gabapentinoids (56.6% vs 34.8%) (p 0.05). They also had more ED visits resulting in an opioid prescription (9.68% vs 2%) and more CP flares requiring hospitalization (3.09 vs 0.87) (p 0.05).Young age, smoking and alcohol use are seen in patients with RAP who progress to CP. These patients are highly symptomatic and use more healthcare resources, suggestive of an overall a more course compared to those patients who develop CP without preceding RAP. Early identification and counselling of these patients may slow down progression to CP.

OBJECTIVE Diabetes that arises from chronic pancreatitis (CP) is associated with increased morbidity and mortality. Methods to predict which patients with CP are at greatest risk for diabetes are urgently needed. We aimed to examine independent risk factors for diabetes in a large cohort of patients with CP. RESEARCH DESIGN AND METHODS This cross-sectional study comprised 645 individuals with CP enrolled in the PROCEED study, of whom 276 had diabetes. We conducted univariable and multivariable regression analyses of potential risk factors for diabetes. Model performance was assessed by area under the receiver operating characteristic curve (AUROC) analysis, and accuracy was evaluated by cross validation. Exploratory analyses were stratified according to the timing of development of diabetes relative to the diagnosis of pancreatitis. RESULTS Independent correlates of diabetes in CP included risk factors for type 2 diabetes (older age, overweight/obese status, male sex, non-White race, tobacco use) as well as pancreatic disease–related factors (history of acute pancreatitis complications, nonalcoholic etiology of CP, exocrine pancreatic dysfunction, pancreatic calcification, pancreatic atrophy) (AUROC 0.745). Type 2 diabetes risk factors were predominant for diabetes occurring before pancreatitis, and pancreatic disease–related factors were predominant for diabetes occurring after pancreatitis. CONCLUSIONS Multiple factors are associated with diabetes in CP, including canonical risk factors for type 2 diabetes and features associated with pancreatitis severity. This study lays the groundwork for the future development of models integrating clinical and nonclinical data to identify patients with CP at risk for diabetes and identifies modifiable risk factors (obesity, smoking) on which to focus for diabetes prevention.

The recently proposed "new mechanistic definition of chronic pancreatitis (CP)" categorized early CP as a reversible condition. However, there is no clear explanation regarding the pathological condition of early CP, the reason for the development of the disease in only a small portion of the patients with risk factors, and the mechanism for transition from a reversible pathological condition to an irreversible one.Based on the available information, a mechanism that could provide answers to the queries associated with CP was proposed.Acinar-ductal coordination is very important for the physiological secretion of pancreatic juice. Inflammation originating from acinar cells undermines the function of proximal ducts and leads to a vicious cycle of sustained inflammation by increasing the viscosity and decreasing the alkalinity of pancreatic juice. Persistent elevation of ductal pressure due to stagnation of pancreatic juice caused by protein plugs, stones, or fibrous scar of ducts converts the reversible pathological condition of early CP to an irreversible one. Diagnostic criteria for early CP proposed by Japanese researchers have enabled to the recognition of patients showing a progression from early to established CP. However, most patients diagnosed with early CP do not experience progression of the disease, suggesting the inadequate specificity of the criteria.The "acinar-ductal hybrid mechanism" may explain the pathological condition and progression of early CP. To diagnose early CP more accurately, it is essential to discover specific biomarkers that can discriminate "early CP" from "acute pancreatitis (AP)/recurrent acute pancreatitis (RAP)" and "established CP." Therapeutic intervention in clinical practices through various new approaches is expected to improve the prognosis of patients with CP.

Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature.We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance.The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-92 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-937 U/mL, 39.7%, 94.1%, and 76.3%, respectively.The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Pancreatic intraductal pressure is related to the development of pancreatitis, including post-ERCP (endoscopic retrograde cholangiopancreatography) pancreatitis. In this study, we investigate pancreatic intraductal pressure in various mouse models of acute and chronic pancreatitis.Post-ERCP pancreatitis was induced by retrograde infusion of normal saline or radiocontrast at the constant rate of 10 or 20 μL/min. Obstructive pancreatitis was induced by ligation of the pancreatic duct followed by a single injection of caerulein and the changes of intraductal pressure were recorded in day 3 for obstructive acute pancreatitis and day 14 for obstructive chronic pancreatitis. Non-obstructive pancreatitis was induced by repetitive intraperitoneal injections of caerulein. The changes of intraductal pressure were recorded right after the last caerulein injection for non-obstructive acute pancreatitis and after the completion of 4-week caerulein injections for non-obstructive chronic pancreatitis.Elevated pancreatic intraductal pressure was observed in both normal saline and radiocontrast infusion groups and was furtherly indicated that was positively correlated with the viscosity of solution but not genders. In the models of obstructive pancreatitis, a rise in intraductal pressure was observed in both acute and chronic pancreatitis; whereas in the models of non-obstructive pancreatitis, a rise in intraductal pressure was only observed in chronic, but not acute pancreatitis.During ERCP, the elevations in pancreatic intraductal pressure are induced by increasing rate or viscous solution of infusion. During different forms of experimental acute and chronic pancreatitis, obstructive or non-obstructive etiologies of pancreatitis also induces the elevations in pancreatic intraductal pressure.

This review aims to discuss recent developments in the nutritional management in chronic pancreatitis.Nutritional assessment should be comprehensive and include dietary history, anthropometry, and biochemical nutritional parameters. Micronutrients should be evaluated at least yearly and dual-energy X-ray absorptiometry (DEXA) at every 2-yearly intervals. Studies on pancreatic enzyme replacement therapy (PERT) have primarily evaluated coefficient of fat excretion (CFA), coefficient of nitrogen excretion (CNA), and stool weight. Two RCTs, in which patients were treated with PERT for 7 days in a blinded manner and subsequently extended for 6-12 months in an open-label manner, showed improvement in nutritional parameters. However, two subsequent RCTs failed to show any benefit, and the most recent observational study demonstrated persistence of malnutrition even after PERT. The reason for the latter findings were nonadherence to PERT and poor oral intake of calories. Therefore, it is essential to educate the patients on adherence, counsel on taking high-protein, high-calorie diet, and supplement nutrients in those with inadequate oral intake. Other associated manifestations, such as diabetes and related complications, and anxiety/depression could also contribute to malnutrition directly or indirectly, and should, therefore, be adequately managed.Nutritional assessment should be performed meticulously. Nutritional therapy should not be restricted to only PERT and nutritional supplementation, but should also include dietary counselling and disease related education.

Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1GA variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1GA, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.

Background & Aims Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. Methods We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. Results The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15–1.45), female sex (OR, 3.08; 95% CI, 1.75–5.43), white race (OR, 2.68; 95% CI, 1.20–6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56–34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. Conclusion In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. ClinicalTrials.gov number, NCT03099850.

Recurrent acute pancreatitis and chronic pancreatitis represent high morbidity diseases, which are frequently associated with chronic abdominal pain, pancreatic insufficiencies, and reduced quality of life. Currently, there are no therapies to reverse or delay disease progression, and clinical trials are needed to investigate potential interventions that would address this important gap. This conference report provides details regarding information shared during a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored workshop on Clinical Trials in Pancreatitis that sought to clearly delineate the current gaps and opportunities related to the design and conduct of patient-focused trials in recurrent acute pancreatitis and chronic pancreatitis. Key stakeholders including representatives from patient advocacy organizations, physician investigators (including clinical trialists), the US Food and Drug Administration, and the National Institutes of Health convened to discuss challenges and opportunities with particular emphasis on lessons learned from trials in participants with other painful conditions, as well as the value of incorporating the patient perspective throughout all stages of trials.

Endoscopic stone removal and stenting of pancreatic strictures are the initial treatment for treating chronic pancreatitis-related pain. Surgery is considered when endoscopic interventions fail to improve symptoms. In this meta-analysis, we have compared early surgery versus endoscopic interventions.The study was performed as per the PRISMA statement. The literature search was conducted on online databases to identify studies that compared endoscopy and surgery for the management of chronic pancreatitis symptoms. Primary outcomes of interest were pain relief, complications, and exocrine/endocrine insufficiency. Secondary outcomes were mean length of stay and mean number of procedures. Pooled odds ratio (OR) was calculated using random-effects model with 95% confidence interval (CI).Of a total of 9880 articles that were screened, three randomized controlled trials and two retrospective studies with 602 patients (71.4% males) were found to be eligible. Endoscopic interventions were performed in 317 patients and 285 patients underwent early surgery. Early surgery provided significantly better pain relief compared to endoscopy (OR 0.46; 95%CI 0.27-0.80; p = 0.01; ICompared to endoscopy, early surgery appears to be better in controlling chronic pancreatitis-related pain, with no significant difference in procedure-related complications. However, larger randomized controlled trials are needed to ascertain their efficacy.

Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. Sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength and is commonly associated with chronic pancreatitis. Regular physical activity and adequate functional fitness have been found to ameliorate the risk and effects of sarcopenia in other chronic diseases. The objective of this systematic review was to collate all the published evidence which has examined any type of physical activity as an intervention in the chronic pancreatitis patient population.This systematic review was conducted in accordance with the PRISMA guidelines. The search strategy was designed by the medical librarian (DM) for Embase and then modified for the other search platforms. Two of the researchers (BM) and (AM) then performed the literature search using the databases Embase, Medline, CINAHL, and Web of Science.An electronic identified a total of 571 references imported to Covidence as 420 when the duplicates (151) were removed. 420 titles were screened and 390 were removed as not relevant from their titles. 30 full text papers were selected and from these, only one full text paper was deemed suitable for inclusion.There is currently insufficient evidence to advise physical activity in the chronic pancreatitis population. However, given the evidence to support physical activity in many other chronic diseases this review highlights the need for urgent investigation of physical activity as an intervention on this specific patient population.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest-grade malignancies in the world. More effective biomarkers and treatment plans are necessary to improve the diagnosis rate and clinical outcome. The oncogenesis of PDAC is influenced by several factors, including chronic pancreatitis (CP). Keratin 8 (KRT8) is an important member of the keratin protein family and plays a role in regulating the cellular response to stress stimuli and mediating inflammatory reactions. However, the role of KRT8 in pancreatitis and PDAC is still poorly understood. Here we assessed the differentially expressed genes (DEGs) by bioinformatic methods with expression profiles available online for a caerulein-induced mouse model and human PDAC tissue. The prognostic value was evaluated by Kaplan–Meier analysis and Cox regression analysis. The diagnostic value was evaluated by Receiver Operating Characteristic analysis (ROC). The function of the genes was predicted by protein-protein interaction analysis, correlation analysis, and GO analysis. The conclusion was further validated in rat pancreatitis model, human tissue, and PDAC cell lines, including immunohistochemical staining (IHC), CCK-8 assay, wound healing assay, and flow cytometry. KRT8 was found to be upregulated in murine pancreatitis tissue, human CP tissue, and human PDAC tissue. High expression of KRT8 had a negative impact on the prognosis of PDAC patients. KRT8 was predicted to be involved in the regulation of the migration and viability of PDAC cells, which was validated in PDAC cell lines. Knockdown of KRT8 impaired the migration and proliferation and induced apoptosis in PDAC cell lines. In conclusion, keratin 8 is an inflammation-induced molecule and could serve as a diagnostic and prognostic marker for PDAC patients. More studies are needed for further validation from the perspective of precision and individualized medicine.

Endoscopic ultrasound (EUS) is an invaluable tool for assessing various GI diseases. However, using just the conventional B-mode EUS imaging may not be sufficient to accurately delineate the lesion's character. Using the principle of stress-induced tissue strain, EUS elastography (EUS-E) can help in the real-time sonographic assessment of the level of tissue stiffness or hardness of any organ of interest during a routine EUS procedure. Thus, EUS-E can better characterize the lesion's nature and highlight the more suspicious areas within an individual lesion. The most commonly studied lesions with EUS-E are the pancreatic lesions, namely, chronic pancreatitis, pancreatic cancer, and lymph nodes. However, EUS-E is gradually expanding its use for lesion characterization of the liver, bile duct, adrenals, gastrointestinal tract, and even therapy response. Moreover, the use of EUS-E along with other image enhancement techniques such as harmonic EUS and contrast-enhanced EUS can improve the accuracy of the diagnosis. However, several technical aspects need to be standardized before EUS-E can be truly used as a tool for "virtual biopsy". This review focuses on the various technical aspects of the use of EUS-E, it is established and expanding indications and an extensive outline of the various studies on EUS-E. We also discuss the current pitfalls and future trends in EUS-E.

Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure.This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals.Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation.Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Chronic pancreatitis (CP) is characterized by abdominal pain, recurrent hospitalizations, frequent exposure to antibiotics, nutritional deficiencies, and chronic opioid use. Data describing the gut microbial community structure of patients with CP is limited. We aimed to compare gut microbiota of a group of patients with severe CP being considered for total pancreatectomy with islet autotransplantation (TPIAT) with those of healthy controls and to associate these differences with severity of clinical symptoms.We collected stool from healthy donors (n = 14) and patients with CP (n = 20) undergoing workup for TPIAT, in addition to clinical metadata and a validated abdominal symptoms severity survey.Patients with CP had significantly lower alpha diversity than healthy controls ( Plt; 0.001). There was a significantly increased mean relative abundance of Faecalibacterium in healthy controls compared with patients with CP ( P = 0.02). Among participants with CP, those with lower alpha diversity reported worse functional abdominal symptoms ( P = 0.006).These findings indicate that changes in gut microbial community structure may contribute to gastrointestinal symptoms and provide basis for future studies on whether enrichment of healthy commensal bacteria such as Faecalibacterium could provide clinically meaningful improvements in outcomes for CP patients undergoing TPIAT.

To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT).TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear.TP-IAT patients at our center1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation.Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for5 years after TP-IAT for 42.7% and for10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure.QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.