Background Acute recurrent pancreatitis (ARP) in childhood can rapidly progress to chronic pancreatitis (CP). Prospectively-collected data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) provides novel insight into disease progression. Methods INSPPIRE subjects were categorized as persistent ARP (pARP = remained ARP through last follow-up), incident CP (iCP = ARP at enrollment, developed CP), or prevalent CP (pCP = CP at enrollment). Time-to-sequelae and risk factors were analyzed. Results Of 626 total children, 384 (61%) were ARP at baseline; of these, 81 (21.1%) were iCP at follow-up.iCP were more likely to have PRSS1 mutations, obstructive risk factors, and more acute pancreatitis episodes (AP) vs. pARP, but didn't differ in age at first AP.Exocrine pancreatic insufficiency (EPI) developed in 24% during follow-up, 10% of pARP, 32% of iCP. In all CP, 50% had EPI by 17.7yrs, median 10yrs after first AP.Diabetes mellitus (DM) developed in 8% during follow-up, 6% of pARP, 5% of iCP. In all CP, median event-free survival from birth and after first AP was not reached. Conclusions Prospective follow-up of children with ARP revealed nearly 1 in 5 progressed to CP, with a subset developing irreversible sequelae, and highlighted risk factors associated with progression including genetics, obstructive disease, and episode frequency.

This is the summary of an April 2025 Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) workshop highlighting the accomplishments of INSPPIRE ( IN ternational S tudy Group of P ediatric P ancreatitis: I n search for a cu RE )-2. INSPPIRE-2 goals and objectives have been to study the risk factors, natural history and outcomes of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Structured patient and physician questionnaires have been used to collect information on demographics, clinical history, family and social history, and disease outcomes. Biosamples have been collected primarily for DNA isolation and analysis of key genes associated with pancreatitis, alongside ancillary studies aimed at elucidating disease pathophysiology and advancing the development of improved diagnostic and therapeutic strategies. Twenty-six sites have enrolled >1000 subjects into the INSPPIRE-2 database with available prospective data to evaluate disease progression, phenotypes, complications and outcomes. The available resources are outlined along with key discoveries offering readers topic specific information about INSPPIRE’s progress.

OBJECTIVES:Transabdominal ultrasound (TAUS) is frequently utilized in pediatric acute pancreatitis, but less is known about its use in acute recurrent (ARP) or chronic pancreatitis (CP). Our aim was to describe TAUS utilization and findings from the largest multicenter cohort of pediatric ARP and CP, the International Study Group of Pediatric Pancreatitis: In Search for a CuRE-2 (INSPPIRE-2). METHODS:Demographic and imaging data from physician questionnaires were obtained for patients with available TAUS data. Utilization and findings were compared between ARP and CP groups. Kappa statistics were used to compare agreement of TAUS to computed tomography (CT), magnetic resonance imaging/cholangiopancreatography (MRI/MRCP), endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography (ERCP) for CP findings. RESULTS:There were 895 patients (460 ARP, 435 CP) included with 2531 TAUS examinations. Mean number of TAUS per year was similar between CP and ARP patients (0.90 vs. 0.90, p = 0.97). The pancreas was well visualized in 65% of examinations (60% ARP vs. 68% CP, p ≤ 0.001). TAUS and CT demonstrated the most consistent agreement among other modalities with kappa values ranging from 0 to 0.66 with substantial agreement for pancreatic duct irregularities (ĸ = 0.62) and moderate agreement for calcifications (ĸ = 0.57). Agreement between other modalities and TAUS was generally lower and diminished closer to CP diagnosis date. CONCLUSION:This is the largest report of TAUS findings in children with ARP or CP. TAUS has several benefits in the initial or emergent evaluation of ARP including availability and tolerance. The ability of TAUS to screen for progression of disease requires further study.

Congenital pancreatic lipase deficiency (CPLD, OMIM #614338) is a rare exocrine pancreatic disorder presenting in late infancy with steatorrhea, fat-soluble vitamin deficiency, and low pancreatic lipase activity. Variants of the pancreatic triglyceride lipase (PNLIP) gene have been linked to CPLD. Six children from four Amish families exhibited CPLD symptoms, and two had decreased fecal elastase levels when tested. A novel homozygous PNLIP variant, c.869G>A (p.S290N), was identified in these children. This study aimed to characterize the PNLIP variant to understand its mechanism underlying CPLD. The variant impact was first evaluated using computational modeling. Functional analyses included activity assays, cellular PNLIP partition assessments, and endoplasmic reticulum (ER) stress evaluation in transfected cells. Computational modeling showed that p.Ser290 is highly conserved across species and the variant causes steric hindrance, resulting in protein misfolding. Functional assays revealed that the PNLIP variant had a complete loss of activity compared to the wild type (WT), with defects in catalytic function and secretion. Immunoblotting showed reduced PNLIP variant in the medium and increased accumulation in the detergent-insoluble fraction, consistent with protein misfolding. Variant-expressing cells had elevated levels of BiP, an ER stress marker, and increased Xbp1 mRNA splicing, suggesting an elevated ER stress and unfolded protein response (UPR). In conclusion, the PNLIP p.S290N variant causes CPLD through a loss-of-function mechanism, characterized by loss of enzymatic activity and defective secretion due to protein misfolding. Further studies are needed to determine whether the misfolding variant protein induces proteotoxicity, potentially increasing the risk of pancreatic injury, including chronic pancreatitis.

BACKGROUND & AIMS:Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, CPA1 N256K and PNLIP T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms. METHODS:We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes. RESULTS:Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in Cpa1 N256K mice compared with Pnlip T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum stress and activating the unfolded protein response. RNA-seq analysis revealed slight differences in altered pathways at 1 month, but these differences disappeared by 3 months. Notably, apoptosis pathways were among the top upregulated pathways, confirmed by qPCR and immunohistochemistry. Differential expression and pathway analyses indicated early activation of both intrinsic and extrinsic apoptosis pathways elicited through multiple mechanisms. CONCLUSIONS:Our study demonstrates that Cpa1 N256K and Pnlip T221M mice develop CP through similar mechanisms with slight differences in progression and severity. Both models could serve as invaluable tools for developing and testing CP therapies. Targeting cell death pathways for therapy may be unfeasible given their redundancy. Instead, effective therapeutic strategies should focus on reducing the burden of misfolded digestive enzymes in the pancreas.

INTRODUCTION:Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS:Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS:Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION:In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

OBJECTIVE:To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP. STUDY DESIGN:Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed. RESULTS:In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days. CONCLUSIONS:Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP.

Background/objectives: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. Methods: This retrospective study was performed at three sites and included data from INSPPIRE-2.Results: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 +/- 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score <-2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score <-2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p 1/4 0.03, respectively).Conclusion: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.(c) 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.

The CEL-HYB1 hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene (CELP) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign. However, functional analysis revealed that Thr488 is the primary determinant of CEL-HYB1 misfolding and associated endoplasmic reticulum (ER) stress. To address this contradiction, we analyzed a cohort from Hungary and found significantly increased CEL-HYB1 carrier frequency in CP cases (9/319, 2.8%) versus controls (5/618, 0.8%), yielding an odds ratio of 3.6 (95% confidence interval 1.2-10.7, P = 0.024). All CEL-HYB1 positive carriers from Hungary had the Thr488-Thr548 haplotype. We analyzed the haplotype distribution of reported CEL-HYB1 carriers from three European cohorts and found that 14/29 CP cases from Germany and 2/6 CP cases from Poland carried the Thr488-Ile548 haplotype, which was absent in CEL-HYB1 positive controls from Germany (n = 13) and Poland (n = 8). All patients (n = 17) and controls (n = 9) from France carrying CEL-HYB1 contained the Thr488-Thr548 haplotype. Functional studies using transfected cells indicated that both CEL-HYB1 haplotypes induced significant ER stress and the Thr488-Ile548 haplotype had a stronger effect. We conclude that the Thr488-Thr548 haplotype of CEL-HYB1 is widespread in Europe and increases CP risk by almost fourfold. In contrast, the Thr488-Ile548 haplotype is regionally restricted, but confers markedly stronger CP risk.

Background & AimsProtease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP.MethodsAll coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control.ResultsWe identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress.ConclusionsOur genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

Objective The aim of this study was to determine patient-reported burdensome experiences and research interests in children with acute recurrent pancreatitis or chronic pancreatitis and their families. Materials and Methods Children with pancreatitis and their families completed a web-based survey. Subject prioritized rankings of symptoms or quality of life issues and topics for future research were assessed. Data are presented as family and children scores. Results Among 80 participants, 18 were children with pancreatitis and 62 were family members. Top 5 ranked symptoms or quality of life issues were as follows: 1) pain, 2) fatigue, 3) missing school, 4) upset stomach, and 5) not knowing when an attack will occur. Top 5 ranked future research topics were as follows: 1) how to prevent a pancreatitis attack, 2) how pancreatitis affects other parts of the body, 3) ways to treat or handle pain, 4) what is the cause of pancreatitis, and 5) teach doctors about pancreatitis. Conclusions This study highlights the importance of patient and family input in caring for children with pancreatitis. The most bothersome symptoms were pain, fatigue, and upset stomach. Children with pancreatitis and families would like future research to primarily focus on prevention of pancreatitis attacks, pain therapy, and complications of pancreatitis.