Acute Pancreatitis in Children: It's Not Just a Simple Attack.

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Published in final edited form as: Gastroenterology. 2025 Apr 12;169(4):572–584. doi: 10.1053/j.gastro.2025.04.001 Search in PMC Search in PubMed View in NLM Catalog Add to search Acute Pancreatitis in Children: It’s Not Just a Simple Attack Faizan Ahmed Faizan Ahmed 1 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; Find articles by Faizan Ahmed 1 , Maisam Abu-El-Haija Maisam Abu-El-Haija 1 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 2 Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. Find articles by Maisam Abu-El-Haija 1, 2 Author information Article notes Copyright and License information 1 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 2 Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. ✉ Correspondence: Maisam Abu-El-Haija, MD, MS, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, [email protected] Issue date 2025 Sep. PMC Copyright notice PMCID: PMC12353169  NIHMSID: NIHMS2074178  PMID: 40228704 The publisher's version of this article is available at Gastroenterology Abstract Acute pancreatitis (AP) in children presents unique challenges distinct from adult manifestations, requiring specialized diagnostic and therapeutic approaches. Compared to adults, pediatric AP has lower mortality rates but still carries significant morbidity and potential long-term complications. This review examines current evidence on pediatric AP, highlighting recent advances in diagnosis, risk stratification, and management strategies. Current diagnostic approaches utilize serum lipase and amylase testing, along with various imaging modalities that have different diagnostic values. Recent research has identified promising biomarkers for predicting severe acute pancreatitis (SAP), including blood urea nitrogen, C-reactive protein, and specific cytokine signals. Emerging evidence suggests a role of gut microbiome dysbiosis in disease pathogenesis, opening new therapeutic possibilities targeting the gut-pancreas axis. Genetic factors, specifically pancreatitis risk genes, influence disease progression to recurrent and chronic pancreatitis. In this review, we summarize the consequences of an isolated AP episode in children. Our review highlights for the first time how AP can lead to significant long-term sequelae, including exocrine/nutritional deficiencies, endocrine pancreatic dysfunction, diabetes, recurrent pain, and decreased quality of life compared to healthy population controls. The goal of this review is to summarize advances in understanding of pediatric AP and to emphasize the importance of early recognition, appropriate risk stratification, and comprehensive follow-up after the first pediatric AP episode, while highlighting areas requiring future research to optimize patient outcomes. Keywords: acute pancreatitis, pediatric, first episode, long term complications, severity Introduction Acute pancreatitis (AP) in children is an entity with distinct characteristics in etiology, clinical presentation, and disease progression compared to adult AP, necessitating specific considerations. While adults have a limited list of risk factors including alcohol consumption or gallstones 1 , the underlying causes and risk factors in children are more variable than in adults, which predominantly encompass genetic factors, drug-related and pharmacological agents, infections, trauma, congenital anatomical variations, gallstones, and other systemic diseases. 2 There have been lower fatality rates in pediatric AP at around 4% compared to adult AP which can be as high as 25%; however, the severity of AP progression itself can carry significant morbidities. 3 – 6 AP in pediatric patients often necessitates hospitalization and inpatient management, with approximately 25% of children experiencing a severe course of the disease. These severe cases lead to extended hospitalization periods, potential intensive care unit (ICU) admissions, and increased healthcare expenditures. 7 Furthermore, a significant proportion of pediatric AP patients- up to ~30% are prone to recurrent episodes, resulting in repeated hospitalizations, heightened morbidity, and increased utilization of healthcare resources beyond the initial AP episode. 8 AP is notably an inflammatory and painful condition primarily affecting the exocrine region of pancreas, but it can also significantly influence its endocrine compartment within the pancreas and organs beyond the pancreas. Various pancreatic enzymes may become activated within the acinar cells, possibly contributing to pancreatic injury, though the exact mechanisms need further investigation. Regardless of the cause of pancreatitis, once it occurs, the pathophysiological mechanisms leading to systemic effects are consistent. Beyond localized damage, the activated enzymes can trigger inflammatory pathways, resulting in cytokine production, followed by extensive systemic inflammation, injuring the surrounding tissues both locally and systemically. 9 The similarities and differences between AP in pediatric and adult populations are still not very well understood and warrant further study. The possible complications of AP can be split into immediate and long-term categories. Immediate complications include multi-organ failure and pancreatic/peri-pancreatic necrosis, while long-term sequalae include exocrine pancreatic dysfunction (EPD), recurrent abdominal pain, reduced quality of life (QOL), endocrine dysfunction (new-onset diabetes or prediabetes), relapse of AP, and/or progression to chronic pancreatitis (CP). 10 AP is an entity that requires identification of the etiological factors, timely intervention with appropriate management during the initial presentation, efficacious use of healthcare resources, accurate diagnostic testing, supportive care, and efforts to limit the potential recurrence of AP or its progression toward a more severe or chronic state. Most cases of AP in children are single episodes, with recurrence in only about 30% of cases. Even in cases of AP limited to one occurrence without recurrence or progression to CP, emerging evidence suggests that morbidity can arise from a single episode in pediatric patients. This review aims to summarize the updates in our understanding of AP in children, and highlighting updated findings that can advance our understanding of the long-term risks post-AP in this population. 1. Incidence and epidemiological aspects of AP in children AP ranks amongst the most prevalent gastrointestinal disorders leading to hospital admissions in the US. According to a study on the nationwide AP cases from 2007–2014, the condition’s numbers have been stable in children between 3.6 and 13.2 reported cases per 100,000 individuals while the annual incidences in adults have been estimated at 40 cases per 100,000 individuals. 11 A recent systematic and meta-analytic study on global incidences of AP, incorporating research from last 56 years (1961 to 2016), showed that the overall global incidences of AP increased per year by 3.07%, while the pooled data for the pediatric global incidences showed an increase at 5.44% per year. Though this study demonstrated a steady increase in incidences with time in major countries of the Western world, they did specify that further studies are required to capture the change in incidences of AP in Latin America, Africa, and Asia. 12 Another study examined a decade of data from Pediatric Health Information System (PHIS) on pediatric AP admissions and costs in the US. The percentage of pediatric AP admissions was on the rise significantly in comparison to all other pediatric admission diagnoses, having increased from 0.12% to 0.15% of all admissions between 2004 to 2014. 8 AP-associated admission costs accounted for 0.16% to 0.21% of the overall hospitalization costs. 8 While the costs per day for AP-related hospitalizations increased over time, and that was after adjusting for inflation, the overall costs decreased due to shorter lengths of stay, potentially due to improved diagnostic testing and treatment strategies. The study also found that 5–9% of AP admissions required intensive care annually. 8 2. Diagnosis of AP in children The diagnosis of AP in pediatrics similar to the adult definition requires meeting a minimum of at least two of the following three criteria: (1) Clinical presentation: presence of pancreatic-origin of abdominal discomfort determined by sudden onset of deep, severe, constant pressure -like pain in the upper abdomen (usually epigastric), which may radiate posteriorly to the back; (2) Biochemical markers: elevation in pancreatic lipase and/or amylase blood levels to a minimum of three times the upper limit of normal, as defined by the reference range of the testing laboratory; and, (3) Radiological evidence: imaging studies indicative of characteristic findings consistent with AP such as edema, interstitial or peripancreatic fluid accumulations, among other imaging findings. 13 , 14 The biochemical and imaging indicators of AP are comparable in both children and adults; however, the manifestations of AP symptoms can vary from person to person and across different ages, particularly in younger children. Other than abdominal pain, patients may experience nausea or emesis, and symptomatic relief by assuming an upright posture or through anterior flexion of the torso. In a report presenting research concerning AP in children, it was reported that abdominal pain is present in 80% to 95% of cases. The epigastric region has been identified as the most frequent site of pain, occurring in 62% to 89% of cases. However, epigastric pain was accompanied by back pain in less than 10% of instances, with pain radiating to the back in only 1.6% to 5.6% of cases, while only 12% to 20% of patients reported diffuse abdominal pain. Nausea or vomiting was associated with these symptoms, affecting 40% to 80% of patients. 15 Another comparison between infants and toddlers and children aged 3 to 20 years revealed that the younger group exhibited lower incidences of nausea (29% vs 76%), abdominal pain (43% vs 93%), and tender epigastric region (57% vs 90%). 16 AP in patients is classically identified using biochemical markers from blood, notably elevated serum concentrations of pancreatic enzymes such as amylase and/or lipase. The diagnosis of AP is supported by an elevated serum amylase and lipase activities, specifically when they exceed thrice the upper limit of normal, although the lack of imaging confirming AP in some studies may lead to uncertainty in the diagnosis The kinetics of amylase activity are characterized by a rapid increase within the initial 6–12-hour period following symptom onset, followed by a return to baseline levels over a three to five-day interval. 17 The diagnostic efficacy of amylase for AP, in terms of sensitivity and specificity, is contingent upon the selected threshold value. Elevating the cut-off point to 1000 International Units per Liter (IU/L), results in a high specificity of approximately 95%. However, this comes at the cost of reduced sensitivity, which some studies report to be as low as 61%. 18 In contrast to serum amylase, the activity of serum lipase remains elevated for a longer duration, typically between 8 to 14 days, which enhances its sensitivity in patients who present symptoms later. Lipase demonstrates superior accuracy with most studies reporting specificities exceeding 95% and sensitivities ranging from 55% to 100% at a threshold activity level of 600 IU/L. 19 Although these tests have excellent sensitivities, they may have a few limitations such as being poor predictors of severity and lower specificity, due to their alterations during non-pancreatic pathologies in addition to pancreatitis. Their activities may be inconsistent during inflammatory, kidney or other gastrointestinal diseases, with another disadvantage of their sensitivity and specificity varying between different testing timelines from the exact onset of AP. Keeping this in mind, other markers were discovered to overcome these limitations in blood and urine. Studies have reported various biochemical markers for AP such as plasma elastase (sensitivity: 92%, specificity: 91%, cut-off: 110 μg/L), serum trypsin 2-(alpha)1 antitrypsin complex (sensitivity: 95%, specificity: 65%, cut-off: 12 μg/L), urinary amylase (sensitivity: 83%, specificity: 88%, cut-off: 2000 U/L, and, urinary trypsinogen-2 dipstick test (sensitivity: 94%, specificity: 95%, cut-off: 50 ng/mL). 20 – 22 The urinary tests differ in sensitivity and specificity, have limited number of available biomarkers, higher detection limits, and median peak levels decreasing rapidly over time after disease onset, in comparison to the blood biomarker tests. A recent study from our group investigated the use of urine proteomics profiling to discover novel biomarkers for AP in children. The study involved a prospective discovery cohort of 130 subjects (28 AP) aged < 21 years and healthy controls, utilizing global quantitative proteomics on urine samples to identify proteins differentially expressed between the groups. The analysis identified 2137 urine proteins, with CELA2A/B, CRP, AMY2A, emerging as potential biomarkers, with CELA2A showing a sixty-one-fold increase, in comparison to AMY2A showing only a two fold increase, highlighting its promise for a diagnostic potential. This study addressed the limitations of current diagnostic methods through utilization of urine proteomics as a tool for discovering new biomarkers. 23 Imaging techniques are crucial for diagnosing and managing AP in children. Transabdominal ultrasonography (TUS) is commonly used due to its availability and safety, though it has moderate sensitivity. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the Society for Pediatric Radiology formed consensus guidelines where TUS was recommended as the primary imaging technique for pediatric cases with suspected AP. This recommendation was based on US’s high sensitivity for detecting gallstones and biliary obstruction, and its lack of ionizing radiation exposure. 24 Recent studies in pediatric population have indicated that US’s sensitivity for AP detection ranges from 47% to 52%. 25 Computed tomography (CT) offers higher sensitivity but involves use of radiation. A study on CT showed that CT severity index ≥ 3 had sensitivity and specificity of 89% and 72%, respectively, in prediction of patients needing admission to pediatric special care unit. The study also observed that the only tomographic parameter associated with SAP was pancreatic necrosis greater than 30%. 26 Magnetic resonance cholangiopancreatography (MRCP) is useful for anatomical assessment without radiation but may require sedation in certain instances, an example is in a toddler who won’t hold still. Endoscopic retrograde choleangiopancreatography (ERCP) and endoscopic US are less utilized for imaging, but more so to provide therapeutic options, as they require sedation, have limited applicability in AP, but are used extensively in gallstones, blocked bile duct and distrupted ducts in traumatic AP. Clinicians must balance the benefits and drawbacks of each method, often starting with US and progressing to magnetic resonance imaging (MRI) or CT for complex cases. A retrospective study on pediatric AP, involving 112 children, yielded significant insights into diagnostic criteria and their test sensitivities. 47% met all diagnostic criteria (clinical, biochemical, and imaging), with serum lipase demonstrating high sensitivity at 95%, markedly outperforming amylase sensitivity at 39%. Imaging studies showed an overall sensitivity of 61%, where US sensitivity alone was 52%, while CT/MRI alone exhibiting higher sensitivity at 78%. Interestingly, combinations of diagnostic criteria did not surpass the efficiency of laboratory testing alone. These findings underscore the varying efficacy of different diagnostic approaches in pediatric AP, highlighting serum lipase as a superior biochemical marker compared to amylase and revealing the role of different imaging modalities in this context. 27 In another recent study, the role of pancreatic enzymes and imaging, both individually, and in combination, in diagnosing initial AP episodes in 127 pediatric patients was evaluated. They assessed the diagnostic utility of concurrent serum amylase and lipase levels in children with first-attack AP. The observations highlighted serum lipase had a higher sensitivity (90.4%) compared to serum amylase (54.3%). The sensitivity values for detecting the condition were 42.2% for contrast-enhanced computed tomography (CECT), and 36.4% for US. Out of 117 children, the combination of US and serum lipase successfully identified 113 cases, achieving a detection rate of 96.6%, but when US was used in conjunction with measurements of both amylase and lipase, all 117 cases were accurately identified. 28 These studies on combinations of diagnostic and imaging techniques highlight that lipase is superior to amylase in diagnosis of AP in children, while US in combination with the serum tests can successfully show higher detection of AP. Table 1 summarizes the diagnostic evaluations in different adult and pediatric AP studies. Table 1: Diagnostic testing summary for AP in adults and pediatrics Pediatric or adult study Authors and year Study subjects (n) Test Diagnostic Performance blood/urine Imaging Diagnostic Perfomance Combined Adult Hedstrom et al 1996 21 110 Trypsin 2-(alpha)1 antitrypsin complex, sens 95%, spec 64% Adult Kemppainen et al 1997 22 53 Urinary trypsinogen dipstick (50 ng/mL), sens 94%, spec 95% Urinary trypsinogen assay (50 ng/mL), sens 92%, spec 93% Amylase dipstick (2000 U/L), sens 79%, spec 89% serum amylase (359 U/L), sens 83%, spec 95% Urinary amylase (2000 U/L), sens 83%, spec 88% Adult Keim et al 1998 73 32 Amylase (440U/L), sens 71%, spec 98% Lipase (6.4 μKat/L), sens 94%, spec 95% Amylase+Lipase, sens 71%, spec 84% Adult Kylänpää-Bäck et al 2002 74 78 Urinary trypsinogen-2 dipstick, sens 73.1%, spec 62.5% Adult Muller et al 2002 75 AP 85 HC 20 Amylase <48 h (304 U/L, sens 90%, spec 87% ProCAPB <48 h (2.5 nmol/L), sens 95%, spec 95% CAPAP <48 h (0.3 nmol/L), sens 81%, spec 83% Adult Saez et al 2005 76 50 Amylase (>330 U/L), sens 74%, spec 86.4% Lipase (>180 U/L), sens 84%, spec 85.7% CAPAP (>1.53 nmol/L), sens 85%, spec 90.9% Urinary CAPAP (>2.32 nmol/L), sens 66.7%, spec 95.5% Urinary TAP (>10.01 nmol/L), sens 68.8%, spec 40% Urinary trypsinogen2, sens 68%, spec 86.4% Adult Domínguez-Muñoz et al 2006 20 224 Polymorphonuclear elastase (110 μg/L), sens 92%, spec 91% Pediatric Chang et al 2011 77 180 Amylase, mean 1478 U/L Lipase, mean 8067 U/L US, sens 92% Pediatric Izquierdo et al 2018 26 30 CT, sens 89%, spec 72% Pediatric Orkin et al 2019 27 112 Amylase, sens 39% Lipase, sens 95% CT or MRI, sens 78% US, sens 52% Laboratory+Clinical, sens 95% Clinical+Imaging, sens 60% Laboratory+Imaging, sens 56% Pediatric AlEdreesi and AlAwamy, 2021 78 127 Amylase, sens 54.3% Lipase, sens 90.4% CT, sens 42.2% US, sens 36.4% Amylase+Lipase, sens 95.2% US+Amylase, sens 72% US+Lipase, sens 96.6% US+Amylase+Lipase, sens 100% CT+Amylase, sens 73.3% CT+Lipase, sens 91.1% CT+Amylase+Lipase, sens 97.8% Open in a new tab Abbreviations: AP, acute pancreatitis; HC, healthy controls; sens, sensitivity; spec, specificity; proCAPB, procarboxypeptidase B; CAPAP, carboxypeptidase B activation peptide; TAP, trypsinogen activation peptide; US, ultrasonography; CT, computed tomography. 3. Classification of AP in children and severity prediction markers Severity of childhood AP in the past years was based on systemic inflammatory response syndrome, death, ICU admission, surgical intervetions, and many other different criteria. Given the lack of a consistent definition of severe pancreatitis, designing comparativeeffectiveness studies in pediatrics was challenging. However, it was not until recently in the year of 2017 that pediatric AP had agreed upon classification for mild, moderate and severe state of disease. 29 This first attempt at its classification based on published literature and parameters from studies on pediatric AP, while reviewing relevant factors from the adult classication, was made by members of the Pancreas Committee within NASPGHAN. 29 Within this, classification of AP severity in pediatric patients was categorized into mild, moderately severe, and severe forms as: (1) Pediatric mild AP: This form of AP is characterized by the absence of organ failure lacking both local and systemic complications, which typically resolve within the first week following presentation, and is the most prevalent type of pediatric AP; (2) Pediatric moderately severe AP: This classification involves either transient organ failure or dysfunction lasting no more than 48 hours, or the emergence of local (development of peripancreatic or pancreatic fluid collections or necrosis) or systemic (exacerbation of pre-existing co-morbid conditions, such as kidney or lung diseases) complications; (3) Pediatric severe AP: This severe form is marked by organ dysfunction persisting beyond 48 hours, which can either be single or multiple, and may develop after the initial 48 hours of presentation. The organ failure definitions utilized pediatric specific criteria. 29 For this reason, we are summarizing recent studies that followed this new classification system for consistency purposes. Identifying prediction models that can be applied on presentation, to predict the risk of developing SAP is crucial, and calls for closer monitoring of high-risk patients including their potential transfer to facilities with specialized expertise becomes warranted. A study aimed to identify early predictors of SAP in pediatric patients experiencing the first episode of AP was conducted on a cohort of >100 patients involving a prospective analysis of clinical data. Of these patients, 18.6% progressed to SAP during their initial AP episode. Patients that progressed to SAP exhibited significantly elevated levels of admission values for: blood urea nitrogen (BUN), glucose, C-reactive protein, magnesium and sodium at p<0.05. BUN was utilized in a logistic regression model as a predictor of SAP which outperformed all combinations of variables (95% confidence interval: 0.61–0.89) with a specificity of 81%, sensitivity of 63%, and negative predictive value of 91%. The study conclusively proposed a predictive model for elevated BUN as a significant indicator of SAP risk. 30 Another study in pediatric AP patients showed a comprehensive panel of matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), investigating MMPs and TIMPs as novel biomarkers in these AP patients. The findings of this study indicated elevated levels of plasma MMP-9 and TIMP-1 on admission in patients who progressed to SAP (inclusive of moderately severe and severe AP) compared to those with mild AP. Additionally, patients with AP exhibited significantly higher levels of TIMP-1, TIMP-4, MMP-1, MMP-7, and MMP-8 compared to healthy control (HC) subjects. The study also developed a prognostic predictive model using significantly elevated MMPs and TIMPs where the multivariable regression model utilizing both MMP-9 and TIMP-1 outperformed individual models in SAP prediction (AUROC 0.8, 95% CI 0.76–0.98). This highlights that using multiple biomarkers as SAP predictors is superior to single biomarkers. 31 In a recent study to identify the multiple chemokines and cytokines as biomarkers to predict severity of AP in children on admission, 62 cytokines were assessed using Luminex platform by Human Immune Monitoring Center at Stanford University (Human 62-plex Procarta kits from eBiosciences/Affymetrix/Thermo Fisher, Santa Clara, California, USA) across 66 pediatric samples, which included 20 HC, 36 mild AP, and 10 SAP subjects. This study identified interleukin 6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) as significantly different between mild and severe cases, both with a p-value of 0.02. In the validation cohort, 76 cytokines (EMD Millipore Corporation, Burlington, Massachusetts, USA)) were evaluated among 10 HC, 19 mild AP, and 6 SAP subjects where IL-6 and MCP-1 were reidentified as significant in distinguishing between mild and severe cases with p-value of 0.02 and 0.007, respectively. The study also considered C-reactive protein (CRP) levels as a marker, showing that there is a strong association with the development of severe disease, with a p-value of less than 0.0001. This study took an important direction towards predicting SAP based on individual and combination of inflammatory cytokines which were identified and validated in two distinct cohorts, after the new guidelines on SAP by NASPGHAN. 32 There are several other studies which have focused on different predictions of severity of AP in children providing several important biomarkers and variables as SAP predictors. A 20-year study on 68 patients observed that moderate to severe form of AP was prevalent significantly in younger children at presentation with odds ratio of 3.8 in patients younger than 12 years and 5.8 in patients younger than 6 years for developing moderate to severe disease, indicating that children younger than 12 years of age had a higher prediction towards AP severity in their cohort. 4 The advantage of this study is that a simple predictor such as age can be useful for early recognition in young populations though age alone may not capture the multifactorial nature of AP severity. Another study aiming at developing a model system for severity prediction for pediatric AP patients, showed that 29% of cases were consistent with SAP, where scoring BUN ≥ 12.5 mg/dL and hemoglobin < 13 mg/dL as variables exhibited sensitivity at 81.5% and specificity at 64.1% in predicting SAP with a value of ≥ 1 point. 33 Also, a modified Balthazar grading system was established after revised Atlanta classification to define pediatric patients with Balthazar grade A-C as mild, grade D as moderate AP, and grade E as SAP, remaining in complete agreement with the revised Atlanta classification for AP severity scoring. 34 The modified Balthazar grading system provides consistency and harmonizes imaging and clinical data for prediction, but it may require standardized imaging protocols to ensure reliability. Serum CRP was also recently highlighted as a promising marker for predicting pediatric AP severity, where it was shown that serum CRP value of more than 108 mg/L within 48 hours of admission produced a sensitivity and specificity of 91% and 84%, respectively and predicting severity with a receiver operating characteristic area under the curve (ROC-AUC) of 0.92. 35 Although this model demonstrated high discriminative ability it may be limited due to potential elevation of CRP in other inflammatory conditions. Table 2 summarizes past and recent AP severity prediction models in children. Table 2: Prediction of severity in pediatric AP prior to the new classification system and after the new classification in 2017. Authors and year Study subjects Biomarker and predictive factors Sensitivity Specificity AUROC Lautz et al 2012 7 64 PAPS 81 76 0.744 Modified Glasgow 53 72 0.834 Ranson 71 87 0.842 CTSI 71 87 0.882 Coffey et al 2013 79 69 Lipase, 7≥ULN 85 56 Boskovic et al 2014 80 36 D-dimer, 1189 μg/L 100 87.5 0.914 Bierma et al 2016 81 175 Lipase ≥50% decrease 73 54 Calcium trough ≤2.15 mmol/L 59 81 Lipase (≥7xULN) + calcium trough (≤2.15 mmol/L) 46 89 Hashimoto et al 2016 82 33 PAPS 81 37.5 0.592 Modified Glasgow 42.9 81.3 0.621 Ranson 52.4 81.3 0.668 CTSI 50 76.9 0.635 Izquierdo 2018 33 130 Hemoglobin (<13 g/dL) and/or BUN (≥12.5 mg/dL) 81.5 64.1 Farrell et al 2020 83 73 BUN, ≥13 mg/dL 68 73 0.73 BUN (≥13 mg/dL) + Albumin (<3.6 g/dL) 71 79 0.83 Farrell et al 2021 32 46 BUN 0.72 BUN + CRP 0.79 IL-6 0.83 BUN + IL-6 0.82 MCP-1 0.88 BUN + MCP-1 0.88 Vitale et al 2022 31 59 MMP9 0.79 TIMP1 0.81 Kwiatek-Średzińska et al 2022 84 55 CRP, ≥127.2 mg/L 60 96 WBC, ≥13500 /uL 60 86 Platelets, ≥ 372000 /uL 60 82 Open in a new tab Abbreviations: sens, sensitivity; spec, specificity; PAPS, pediatric acute pancreatitis severity; CTSI, computed tomography severity index; ULN, upper limit of normal; BUN, blood urea nitrogen; CRP, reactive protein; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; MMP9, matrix metalloproteinase-9; TIMP1, tissue inhibitor matrix metalloproteinase-1; WBC, white blood cells. 4. Management of AP in pediatric population Management of pediatric AP was recently reviewed and summarized in a society guidelines and recommendation paper from NASPGHAN. 36 The evidence for most sections was derived from the limited pediatric studies available and relevant adult literature. The cornerstones of therapy are early feeding and intravenous fluids. While there are no studies on proactive feeding through nasogastric or nasojejunal tubes for the patients who do not meet their nutritional demands, allowing patients to eat on admission was feasible and associated with lower length of stay. Rates of intravenous fluids are recommended at 1.5–2 times maintenance rates 37 , and the preferred fluid is Lactated Ringer’s due to limited studies including a recent randomized controlled study that showed that Lactated Ringer’s were associated with a faster discharge rate when administered compared to normal saline. 38 There is a limited role for antibiotics in AP unless there is evidence of an infection. Also, endoscopic management is reserved for cases where there is a ductal disruption, or management of walled off necrosis. 36 5. Acute pancreatitis observational cohort studies For the longest time, previous studies in AP have been mostly single-centered and retrospective in nature which have created difficulty in understanding AP course in the pediatric subjects who may be at a greater risk for advancement towards SAP or acute recurrent pancreatitis (ARP). There is a limited number of trials and research being conducted at centers for studying AP in children. There is an ongoing international observational clinical trial by the Pediatric Section of the Hungarian Pancreatic Study Group known as Analysis of Pediatric Pancreatitis (APPLE). This trial aims to systematically gather a substantial amount of clinical data and biomedical samples. The APPLE-R component focuses on individuals under 18 with a history of pancreatitis, aiming to uncover genetic variants that may influence the disease prognosis, while the APPLE-P component targets those under 18 diagnosed with AP, selecting participants based on two out of three Atlanta criteria and aiming to collect comprehensive data on etiology, laboratory results, physical examination findings, imaging, initial treatment, medical history, complications, and symptoms. 39 Another study aimed at addressing the gap in evidence-based guidelines for approaching abdominal pain during emergency settings and determining when serum pancreatic enzyme testing is warranted in cases of abdominal pain was conducted. Here, researchers established the Pain in Early Phase of Pediatric Pancreatitis (PINEAPPLE-P) as an investigation aimed at creating an evidence-based, cost-effective protocol for determining the necessity of pancreatic enzyme testing, US imaging and CT scans in pediatric abdominal pain cases. 40 Given the paucity of observational cohort studies in pediatric AP, there remains a missing link in assessing long term sequalae from AP. This led to the design of the AP observational cohort study at our center. This study included screening and the collection of different types of samples from admission during the first episode, followed by systematic follow-ups of pediatric AP subjects over the first 3 years after the episode. We designed an alert system such that when lipase or amylase levels meet the threshold for patient identification, the research team receives, in real time, a notification for patient enrollment. Patients are enrolled during their baseline admission with AP. After enrollment, research samples such as plasma and urine, are obtained within the first 48 hours of presentation for future biomarker-based studies and SAP prediction models. In addition, stool is collected for microbiome studies, Hemoglobin A1c (HbA1c) and insulin levels are measured for pre-diabetes and diabetes model building, and deoxyribonucleic acid (DNA) is banked for analyzing genetic factors in research studies. Subjects in the AP cohort then provide samples at their 3-month or 12-month follow-ups where HbA1c, glucose, fasting insulin, nutritional status, and vitamin levels are assessed (including fecal elastase) and recurrence of AP is evaluated. These follow-ups also include documentation of nutritional data as well as the exocrine and endocrine functions of the pancreas. There are currently several published and ongoing studies related to the AP registry focusing on clinical variables such as microbiome, metabolomics, genetics, proteomics, and other factors related to pancreatitis. 23 , 25 , 30 – 32 , 41 – 47 These observational studies in pediatric AP are directed towards answering multiple questions regarding how AP presents at first-attack, the determination of its diagnostics and severity, the management elements, and their associations with baseline AP outcomes. The longitudinal aspects of follow-up will help in determining future implications and impacts of AP on future outcomes, including comorbidities resulting from AP and health-related quality of life in pediatric AP. 6. Microbiome discovery in pediatric AP Alteration in gut microbiota may significantly contribute to the development of AP and influence its prognosis. This includes disruptions in the microbial community structure and the translocation of the bacteria. Given that the gastrointestinal tract is anatomically connected to the pancreas via pancreatic duct, the presence of microbiota in pancreas has been observed to occur in various normal and diseased states. 48 The passage by which microbiota can enter pancreas are debated, but several routes such as oral, translocation through portal circulation from the lower gastrointestinal tract, mesenteric lymph nodes are corroborated by different studies. 49 These changes can impact the host’s metabolic processes, elevate the production of harmful metabolites, and influence the therapeutic outcomes of AP. Intestinal dysfunction is characterized by damage to the mucosal barrier and impaired intestinal motility. Maintaining a balanced intestinal microecology can mitigate bacterial overgrowth and reduce the incidence of infections originating from the gut by modulating metabolic pathways, the immune response, and establishing a biological barrier. Recent studies have increasingly highlighted the crucial role of gut microbiota in AP progression, but research in children remains limited. 50 A recent study on the relationship between AP severity and gut microbiota dysbiosis in children involved 30 pediatric patients experiencing their first-episode of AP and 34 healthy controls (HC), utilizing shotgun metagenomics sequencing on stool samples to assess the gut microbiome composition and function. The findings revealed significant differences in gut microbiome profiles between AP patients and HC, with the AP cohort showing reduced alpha diversity and notable changes in microbiome profiles, such as increased relative abundances of Enterococcus , Ruminococcus , Veillonella , and Clostridium , and decreased levels of Bacteroidetes. 47 Functional pathway analysis indicated that AP is associated with alterations in fatty acid beta-oxidation and amino acid metabolism, which are involved in pancreatic inflammation. 47 The study suggests that gut dysbiosis is an important feature of pediatric AP and proposes that interventions targeting the gut microbiome could potentially improve outcomes in children by influencing the gut-pancreatic axis. Further research involving longitudinal analysis of AP and its relationship with the microbiome will help further clarify the mechanisms of this association and explore microbiome-based therapeutic options. 7. Metabolite and lipid derangements Metabolomics research involves extensive analysis of small molecule metabolites within tissues or cells, aimed at exploring global alterations of numerous metabolites using various analytical technologies, followed by comprehensive data analysis and bioinformatics. These metabolites may play diverse roles in disease progression, including signaling molecules, and hormones. Regarding AP in children, metabolomics can offer a precise and non-invasive approach to identifying biomarkers that predict disease onset, its progression, and severity, while also providing insights into underlying mechanistic abnormalities. Previously, it has been observed that various inborn errors of metabolism can lead to the development of AP, including other disorders involving alterations of lipids in hyperlipidemia, branched chain amino acid disorders, cationic aminoacidurias, glycogen storage diseases, hypercalcemia, and homocystinuria. 51 Another cause of metabolite-based pancreatitis in children may be medication or drug-induced pancreatitis, but the literature on pediatric occurrences is sparse. 46 A metabolomic case-control study investigated vitamin A metabolism in acute lymphoblastic leukemia pediatric and adult patients receiving asparaginase, comparing 24 cases developing pancreatitis with 26 matched controls who did not develop pancreatitis. 52 Analysis revealed the presence of distinct patterns in plasma carotenoids post-induction therapy. Controls showed an increase in plasma carotene diol isomers while pancreatitis cases showed no increase. Beta-cryptoxanthin was decreased in pancreatitis cases but remained stable in controls, while both groups showed retinol increase, though less pronounced in the pancreatitis cases. Pathway enrichment analysis identified carotenoid and retinoid metabolism as the primary affected pathways. Also, correlation analysis revealed a positive relationship between carotenoids and retinol, with specific metabolites showing association in pancreatitis cases against the control groups. Another metabolite-related type of AP in children may be hypertriglyceridemia (HTG)-induced AP which may be caused due to high fasting triglyceride levels such as in chylomicronemia or overproduction of very low-density lipoproteins (VLDL) in hyperlipoproteinemia. 53 , 54 The mechanism may be that breakdown of triglycerides by pancreatic lipase enzymes occurs within the pancreatic blood vessels, resulting in elevated levels of free fatty acids (FFAs). When these FFAs accumulate, they trigger a destructive cascade - damaging both the acinar cells and the blood vessel lining. This damage creates a harmful cycle where reduced blood flow leads to tissue oxygen deprivation, increased local acidity, and enhanced FFA-mediated cellular injury. 55 A classification system for pediatric HTG was developed through the integration of adult Endocrine Society criteria and pediatric expert recommendations which established thresholds for elevated triglyceride levels, where 500–999 mg/dL were very high, 1,000 to 1,999 mg/dL were severe, and measurements at or exceeding 2,000 mg/dL were very severe. 56 , 57 The triglyceride levels thus are known to play an important role in HTG-induced AP in children. Apart from single drug- or metabolite-induced AP, detailed studies using metabolomics or lipidomics showing alterations in metabolites or lipids on a larger scale are still missing for the pediatric AP. 8. Genetics Research has revealed that genetic alterations can be categorized into distinct pathological cascades culminating in pancreatitis due to pancreatic inflammation. These cascades can be primarily divided into three primary categories: pathways affecting ductal function, those dependent on trypsin, and the ones related to protein misfolding. Researchers have successfully mapped these mechanistic pathways down to their genetic components, highlighting the crucial role of genetic research in understanding disease progression for possible therapeutic interventions. 58 It has been shown previously that in pediatric cases of ARP and CP, genetic factors such as PRSS1 have emerged as significant contributors to AP while SPINK1 has been found to have association due to which the patients with a family history develop the disease earlier. 59 However there is a large knowledge gap in studies on genetics on pediatric AP. A retrospective study on 184 pediatric AP patients showed that genetic risk factors such as PRSS1, CTRC, SPINK1, CFTR, and CPA1 were observed in 26.8% of AP patients. 60 However, the genetic implications in all cases of AP, particularly after disease onset, remained inadequately investigated. Recent technological advances in next-generation sequencing (NGS) have enabled comprehensive analysis of multiple genetic markers associated with ARP and CP. This high-throughput approach provides extensive coverage of both exonic sequences and deep intronic regions, particularly focusing on the primary genes implicated in risk for pancreatitis. 45 A recently conducted study investigated the importance of genetics in pediatric AP patients and followed them after the first attack without progressing to ARP or CP, against a group that progressed to ARP/CP over time. A novelty of this study was the use of an extensive panel of 8 genes in AP, ARP, and CP patients using NGS platform. The panel included genes such as PRSS1, CFTR, SPINK1, CPA1, CTRC, CLDN2, CASR, and SBDS . The findings revealed that genetics is a major component in all types of pancreatitis in children, with genetic variants being most prevalent in CP cases at 31%, followed by AP at 19%, and ARP at 6%. A key discovery was that variants in SPINK1, CFTR , or PRSS1 genes were associated with faster progression from first episode of AP towards CP. 41 Another recently published study genotyped 120 pediatric patients with first episode of AP showed that the frequency of variants tested in a 10 gene panel was 53% for CFTR , 13% for SPINK1 , 10% for PRSS1, 9% for UBR1 , 5% for CTRC , 3% for CPA1 , and 2% each for CASR, CEL, and SBDS ( CLDN2 was negative for the cohort). The study also showed that the frequency of one or more variants for the tested subjects was 52.5%. 45 These studies represent a significant advancement in understanding pediatric pancreatitis progression and the crucial role of genetic factors involved. The findings have important implications, including potentially enabling early identification of high-risk patients and paving the way for the development of targeted therapeutic strategies to prevent disease progression in genetically susceptible children. There is still less known about combinations of defective genes involved in children developing AP, and this needs to be further substantiated through multi-center studies due to its extreme importance in early risk factor assessments. 9. What are the complications after a single episode of AP? In pediatric AP cases, the first episode of AP necessitates careful observation over time during follow-ups, due to the possibility of emerging complications. 61 The initial damage to the pancreas during the first AP episode can initiate inflammatory processes potentially resulting in permanent pancreatic tissue modifications, or remodeling, such as the formation of calcium deposits and an increase in fibrous tissue. 62 If these alterations continue without timely interventions, they may further evolve, affecting both the digestive enzymatic and hormone-producing functions of the pancreas. 63 The onset of AP in children triggers substantial disruptions across both the exocrine and endocrine compartments of the pancreas ( Figure 1 ). Figure 1. Acute pancreatitis in children. Open in a new tab The risk factors associated with AP in children lead to baseline episodes of AP. After the first episode of AP, the quality of life is decreased, and it may lead to other disorders such as exocrine dysfunction, endocrine dysfunction and diabetes, nutritional deficiencies, and acute recurrent and chronic pancreatitis. 9.1. Exocrine dysfunction. This dysfunction may result since the exocrine component undergoes significant cellular damage occurring through both apoptotic and necrotic pathways, while the ability of ductal cells to maintain proper fluid and bicarbonate balance may become compromised. 64 Endocrine dysfunction may result from AP given that the endocrine compartment simultaneously experiences functional decline, particularly affecting glucose regulation mechanisms. The insulin-producing beta cells show altered responsiveness to glucose stimulation, and glucagon-secreting alpha cells exhibit irregular hormone release patterns. During AP episodes, or following AP, these pathological events in both exocrine and endocrine components can extend beyond the inflammatory state, potentially resulting in chronic pancreatic dysfunction and long-term metabolic complications. 65 The exocrine pancreatic insufficiency (EPI) is not very well studied in pediatric population with AP. A recent study compared pancreatic fat digestibility in children with AP using 13 C-mixed triglyceride breath test, which revealed that AP patients showed lower cumulative dose percentage recovery compared to controls. 66.7% of AP patients exhibited EPI, which was found to persist at one-month follow-up. This shortened 4-hour breath test demonstrated a high sensitivity of 87.5% and a specificity of 93.8% for EPI detection. 66 9.2. Nutritional deficiencies: A study investigating nutritional deficiencies in 181 pediatric patients following their first AP episode showed that 77% had mild AP, while 23% had moderate to severe AP. At 3 and 12 months post-AP, deficiencies in Vitamin A, D, and E, ferritin, and low albumin levels were observed. SAP patients showed a significant body mass index (BMI) Z-score decrease and Vitamin E deficiency. These findings highlighted the need for nutritional and metabolic monitoring, and further research into post-AP nutritional and metabolic status in pediatric patients. 44 9.3. Endocrine Dysfunction and Diabetes. Another complication of post-AP course in children may be incidental diabetes. A recent study following children after their initial episode of AP for one year, concluded that 17% of the subjects developed endocrine insufficiency, with 3.5% developing diabetes mellitus (DM) and 13.5% developing pre-DM. Risk factors included SAP, or having a gene variant involved in one of the high-risk pancreatitis genes ( CASR , CLDN2 , SPINK1 , CEL , UBR1 , PRSS1 , CTRC , CPA1 , CFTR , and SBDS ). 45 The study observed that in the group with endocrine insufficiency, there was a higher prevalence of SAP (58% compared to 20%; p=0.001) and at least one genetic mutation (79% compared to 47%; p=0.01). Also, a predictive model for analyzing the development of pre-diabetes/diabetes incorporated the severity of AP (odds ratio-5.27; p=0.005) and a genetic risk score (odds ratio-4.89; p=0.002). The study observed that AP disease severity and risk genes were linked with pre-DM or DM development post-AP. 45 A different study found that 4.5% of a group of 176 children and adolescents diagnosed with AP developed diabetes (at least one glucose measurement exceeding 200 mg/dL, along with an insulin prescription upon discharge) while hospitalized. Though it is important to note that many of these patients had notable comorbidities, and the study did not evaluate long-term risk of developing diabetes. 67 A study on potential long-term risk of diabetes in individuals who experienced AP during childhood and its association on incident diabetes in adulthood, showed that 4.6% of subjects who had resolved pancreatitis developed incident diabetes. The study observed that amongst the study participants with diabetes who were diagnosed with pancreatitis in childhood, 92% developed diabetes before reaching the age of 40 as compared to only 47% in the unexposed cohort. 68 9.4. Recurrent and chonic pancreatitis. AP in children can further lead to ARP which has significant long-term consequences, including the development of CP and its associated complications. Physiologically recurrent episodes may result in impaired growth, malabsorption, and pancreatic exocrine and endocrine insufficiency, necessitating long-term lifestyle, dietary modifications, supplementation of enzymes or needing diabetes treatment. 69 9.5. Pain and Quality of Life Measures: Frequent episodes of pain, or chronic pain patterns, may compromise the patients’ QoL by increasing hospitalizations, and burden them psychologically due to the chronic nature of the condition. A prospective study investigating the history of AP and its progression to ARP in pediatric patients experiencing their first episode of AP, with follow-ups, revealed that 17% of the subjects progressed to ARP, with a significant majority of 70% doing so within five months of the initial AP episode. The study highlighted that increased weight or obesity was among the risk factors for a rapid progression to ARP in comparison with those who progressed later. The importance of studies towards early interventions after the first episode of AP to reduce the progression towards ARP cannot be overstated. 70 Patient-reported outcomes are essential for evaluating how pediatric AP affects QoL. Children suffering from AP frequently endure considerable physical and physiological challenges, including persistent pain, dietary limitations, and emotional difficulties. These issues lead to a reduced QoL, impacting their daily routines, school attendance, academic performance, and their participation in the various aspects of their childhood social lives. Additionally, the diverse range of severity in symptoms and recovery courses makes assessing patient-reported outcomes more complex. 71 Utilizing validated QoL assessments in clinical settings can deepen insights into the long-term effects of AP, thereby facilitating personalized interventions that enhance patients’ well-being and health outcomes. A pediatric study following children after their first AP episode, utilizing the validated Pediatric Quality of Life Inventory ™ (PedsQL ™ ) 4.0 Generic Core Scales and the PedsQL ™ Gastrointestinal Symptoms and Worry Scales, showed that about half of the children experienced a decreased QoL across 81 items on both scales compared to their healthy peers. 72 10. Conclusions and future directions of research In pediatric patients, AP manifests as a complex disorder with widespread systemic effects that need to be addressed. The condition initiates with pancreatic inflammation and can escalate to affect multiple organs outside the pancreas, while local complications cause the formation of pseudocysts, a necrotizing course, and the compromise of the pancreatic structure. It involves multiple other systems or signaling pathways, and the cascade of events leading to AP in children needs a deep understanding and research in different aspects to identify root causes and substantially help improve clinical outcomes. Given the heterogeneous nature of etiologies in children, the field is in need of etiology-directed management pathways and outcome studies. Post AP, even after a single episode there are risks for long-term complications, exocrine and nutritional deficiencies, endocrine insufficiencies like prediabetes or diabetes, chronic abdominal pain, and lower QoL measures. To reduce the physiological impacts during and following an initial episode of AP in children, it is critical to employ a strategy utilizing precision medicine to elucidate risk profiles for at-risk patients who need long-term follow up, this includes severe AP as well as other clinical characteristics that need to be further defined in future studies. Clinicians and researchers should be aware of the AP course, progression, and long-term complications of a single episode in children. Abbreviations: μg/L microgram per liter AP acute pancreatitis APPLE analysis of pediatric pancreatitis ARP acute recurrent pancreatitis BMI body mass index BUN blood urea nitrogen CAPAP carboxypeptidase B activation peptide CECT contrast-enhanced computed tomography CP chronic pancreatitis CRP C-reactive protein CT computed tomography CTSI computed tomography severity index DM diabetes mellitus DNA deoxyribonucleic acid EPD exocrine pancreatic dysfunction EPI exocrine pancreatic insufficiency ERCP endoscopic retrograde choleangiopancreatography FFAs free fatty acids HBA1c Hemoglobin A1c HC healthy controls HTG hypertriglyceridemia ICU intensive care unit IL-6 interleukin-6 IU/L International units per liter MCP-1 monocyte chemotactic protein-1 MMPs matric metalloproteinases MRCP magnetic resonance choleangiopancreatography MRI magnetic resonance imaging NASPGHAN North American Society for Pediatric Gastroenterology, Hepatology and Nutrition ng/L nanogram per liter PAPS pediatric acute pancreatitis severity PedsQL ™ Pediatric Quality of Life inventory ™ PINEAPPLE pain in early phase of pediatric pancreatitis proCAPB procarboxypeptidase B QoL quality of life ROC-AUC receiver operating characteristic area under the curve SAP severe acute pancreatitis sens sensitivity spec specificity TAP trypsinogen activation peptide TMPs tissue inhibitors of metalloproteinases US transabdominal ultrasonography ULN upper limit of normal VLDL very low-density lipoproteins WBC white blood cells Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. 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