Chronic pancreatitis (CP) affects ∼3 million people worldwide, yet altering the course of the disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 37 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with a high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wild-type CFTR. Clinically available CFTR modulators stabilized mutant or wild-type CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides a comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

BACKGROUND & AIMS:Clinical data show that genetic variants are significant risk factors for acute recurrent pancreatitis and chronic pancreatitis. To expand the understanding of the role of genetics in acute recurrent pancreatitis and chronic pancreatitis, high-throughput next-generation sequencing of 14 genes was completed in a multicenter pediatric cohort. METHODS:A cross-sectional study involving 944 pediatric patients with acute recurrent pancreatitis or chronic pancreatitis was conducted. CASR, CEL, CFTR, CLDN2, CPA1, CTRC, GGT1, PRSS1, PRSS2, PRSS3, SBDS, SLC26A9, SPINK1, and UBR1 were sequenced. The frequencies of identified variants were compared with frequencies in the genome aggregation database. Group differences were calculated by odd ratios, relative risks, and 1-tailed Fisher exact test with false discovery rate adjusted P values. RESULTS:A total of 120 variants, including 79 never previously reported to be associated with pancreatitis, had an increased odds, with odds ratio >1, (false discovery rate ≤0.01) compared with the genome aggregation database. Of these, 38 focused variants found in CFTR (10 variants), PRSS1 (6), CTRC (6), SPINK1 (5), PRSS3 (3), GGT1 (3), CASR (2), CPA1 (2), and PRSS2 (1) were included for further analysis. Seventy-four percent of children with acute recurrent pancreatitis or chronic pancreatitis carried at least 1 genetic risk variant. In the acute recurrent pancreatitis group, CASR (P = .005) and CPA1 (P < .001) contained the most prevalent variants. In chronic pancreatitis, CTRC (P = .012) and PRSS1 (P < .001) variants were most common. The presence of any genetic risk variant was associated with faster disease progression from acute pancreatitis to chronic pancreatitis compared with none (P = .014). Variants in PRSS1, CTRC, and SPINK1 significantly increased progression to chronic pancreatitis. CONCLUSIONS:Our findings highlight the importance of assessing genetic risk variants in children with pancreatitis.

Endocrine and exocrine insufficiencies are well-recognized pancreatic-specific sequelae of chronic pancreatitis (CP), yet the impact of CP extends beyond the pancreas. The pathophysiology driving these complications is complex and poorly understood, resulting in inadequate recognition and an inability to stratify risk of disease progression. To address this topic, the Collaborative Alliance for Pancreatic Education and Research convened a workshop to summarize our current understanding and identify knowledge gaps related to the complications of CP. The clinical uncertainty related to who will develop systemic complications of CP, and when, negatively affects the patient's clinical experience and is an area of research that requires additional commitment. Adapting modeling strategies proven effective in other conditions (eg, type 2 diabetes) may be effective in identifying and predicting the onset of endocrine and exocrine insufficiencies. Improved understanding related to genetic risk factors, biomarkers, clinical testing, and advanced imaging techniques all represent pathways to better identify these complications and develop pancreatitis-specific interventions. Additional complications of CP, including pain, osteopathies, sarcopenia, malnutrition, and visceral neuropathies, can occur independently or as complications from endocrine and/or exocrine insufficiency. Better screening strategies to identify these conditions are required, many of which may be accomplished using opportunistic screening strategies. Future research will need to utilize existing treatment modalities and medications, in addition to developing new interventions, to treat these complications of CP that have a tremendous impact on patients' quality of life. Genetic testing in pancreatitis is likely to inform any research related to the complications of CP, but low penetrance of disease, poor genotype-phenotype associations, and health disparities that impact the use of testing across centers currently limit its clinical utility for all patients. Genetic testing remains critical in certain populations with CP and should be incorporated into research whenever possible to inform much-needed disease progression prediction models.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. Perspective Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.

Both the clinical management and study of recurrent acute pancreatitis and chronic pancreatitis are complicated by significant heterogeneity in the etiology, mechanisms, symptoms, and complications of pancreatitis. The National Institutes of Diabetes and Digestive and Kidney Disease recently convened a workshop to address current knowledge and knowledge gaps in the field. Preclinical models that better replicate human disease are important for development of new therapies. Pain is often the most common and most difficult symptom to treat, as the causes are multifactorial and effective treatment may vary depending on whether pain is neuropathic or nociceptive in origin, and the placebo effect can complicate evaluation of the efficacy of medical and procedural interventions. Novel technologies like functional magnetic resonance imaging and virtual reality may offer novel means for assessing and treating pain, respectively. Clinical trial designs will need to consider best approaches to addressing the heterogeneity of chronic pancreatitis, including careful attention to designing eligibility criteria, and establishing accepted and validated core outcomes criteria for the field. The latter may be informed by consensus in pain research. Recruitment of participants into clinical trials has been challenging, often requiring multiple centers. Establishment of a clinical trials network would facilitate greater opportunities for therapeutic trials in pancreatitis.

Genetic variants disrupting the expression or function of the Serine Protease Inhibitor, Kazal Type 1 (SPINK1) gene—encoding the pancreatic secretory trypsin inhibitor (PSTI, also called SPINK1)—elevate the risk ofpancreatitis and pancreatic cancer. This review elucidates SPINK1’s role as a key inhibitor of active trypsin, detailing its protective mechanism alongside other regulatory factors. We emphasize human SPINK1 variants, spotlighting the high-risk haplotype tagged by p.N34S (Table 1) and other risk, predisposing or pathogenic variants (Table 2). Additionally, we explore the conditions and co-factors—genetic and environmental—that trigger acute pancreatitis (AP) and progression to chronic pancreatitis (CP), providing a comprehensive framework for understanding SPINK1’s clinical significance

PURPOSE OF REVIEW:Pancreatic ductal adenocarcinoma (PDAC) has a dismal 13% 5-year survival rate, necessitating early detection and personalized treatment. This review evaluates whether germline genetic testing, integrated with clinical decision support (CDS) tools, is ready for widespread use in PDAC screening. We focus on its potential to identify high-risk individuals (HRIs) beyond those with strong family histories to complex risk and biomarkers, stratifying patients into low-risk and high-risk virtual populations for targeted surveillance. RECENT FINDINGS:Germline genetic testing identifies pathogenic variants linked to hereditary cancer syndromes (HCS), enabling multiorgan surveillance and precision oncology (e.g., PARP inhibitors for BRCA2 mutations). Polygenic risk scores (PRS) combined with clinical markers like new-onset diabetes (NOD) increase the positive predictive value (PPV) for PDAC (e.g., 86.7% in high-PRS quintiles). Genetic testing also adjusts for biomarker variability (e.g., CA19-9 levels via FUT2/FUT3 genotyping) and optimizes chemotherapy through pharmacogenetics, reducing toxicity. Comprehensive platforms integrating genetic, clinical, and biomarker data enhance early detection and risk stratification. SUMMARY:Genetic testing is ready for prime time in PDAC screening. It stratifies patients into low-risk (no surveillance) and high-risk (surveillance warranted) groups, improving early detection, outcomes, and cost-effectiveness, thus transforming PDAC prognosis through targeted intervention.

Imaging is critical to determining the etiology and progression of pancreatic diseases. The most commonly utilized modality is computed tomography (CT), typically, contrast enhanced CT (CECT). Here we present a primer for health care providers on the evaluation of a normal triphasic pancreas imaging (pancreas protocol CT), and examples of end-stage disease. Compared to normal, we provide images of an atrophic pancreas, advanced chronic pancreatitis (CP), residual pancreas post Whipple procedure and fatty pancreas. Each image is described in a systematic way with a brief differential diagnosis.

INTRODUCTION:Ariel Dynamic Acute Pancreatitis Tracker (ADAPT) is an artificial intelligence tool using mathematical algorithms to predict severity and manage fluid resuscitation needs based on the physiologic parameters of individual patients. Our aim was to assess whether adherence to ADAPT fluid recommendations vs standard management impacted clinical outcomes in a large prospective cohort. METHODS:We analyzed patients consecutively admitted to the Los Angeles General Medical Center between June 2015 and November 2022 whose course was richly characterized by capturing more than 100 clinical variables. We inputted these data into the ADAPT system to generate resuscitation fluid recommendations and compared with the actual fluid resuscitation within the first 24 hours from presentation. The primary outcome was the difference in organ failure in those who were over-resuscitated (>500 mL) vs adequately resuscitated (within 500 mL) with respect to the ADAPT fluid recommendation. Additional outcomes included intensive care unit admission, systemic inflammatory response syndrome (SIRS) at 48 hours, local complications, and pancreatitis severity. RESULTS:Among the 1,083 patients evaluated using ADAPT, 700 were over-resuscitated, 196 were adequately resuscitated, and 187 were under-resuscitated. Adjusting for pancreatitis etiology, gender, and SIRS at admission, over-resuscitation was associated with increased respiratory failure (odd ratio [OR] 2.73, 95% confidence interval [CI] 1.06-7.03) as well as intensive care unit admission (OR 2.40, 1.41-4.11), more than 48 hours of hospital length of stay (OR 1.87, 95% CI 1.19-2.94), SIRS at 48 hours (OR 1.73, 95% CI 1.08-2.77), and local pancreatitis complications (OR 2.93, 95% CI 1.23-6.96). DISCUSSION:Adherence to ADAPT fluid recommendations reduces respiratory failure and other adverse outcomes compared with conventional fluid resuscitation strategies for acute pancreatitis. This validation study demonstrates the potential role of dynamic machine learning tools in acute pancreatitis management.

INTRODUCTION:Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). METHODS:In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation. RESULTS:Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors. DISCUSSION:These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.

Precision medicine is often at odds with medical genetics in classifying gene mutations that have high impact on protein expression or function but do not “cause” disease. A new proposal aims to expand the terminology for genetic variants along a spectrum: (1) pathogenic (retaining Medical Genetics meaning) (2) predisposing (new term) (3) risk (as used in PRS) (4) benign (used in contrast to “pathogenic” but may be “predisposing” in some circumstances and context) This framework bridges the gap between binary classifications and the nuanced reality of variant effects, paving the way for more accurate risk assessment in clinical practice. It is time for adoption by geneticists and major professional societies.

Chronic pancreatitis (CP) affects ~3 million people worldwide, yet altering the course of disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 36 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wildtype CFTR. Clinically available CFTR modulators stabilized mutant or wildtype CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides the first comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.