- 1. There is an increased incidence of pediatric pancreatitis, probably because of increased awareness.
- 2. Although rare, recurrent pancreatitis in children is associated with significant disease burden and overall rapid progression to CP.
- 3. Genetic mutations are the most common risk factors for pediatric ARP and CP. Certain genetic factors are associated with an aggressive phenotype (ie, PRSS1 with early-onset disease and rapid progression to CP).
- 4. Children with ARP or CP would benefit from a thorough evaluation of risk factors and sequalae of CP including exocrine pancreatic insufficiency and diabetes.
- 5. Prospective, randomized, controlled clinical trials are needed to determine the usefulness of available interventions (ie, therapeutic endoscopy for pancreas divisum).
- 6. Longitudinal studies with careful data, biosample collection, and genotyping are important to better understand the natural history of pediatric pancreatic diseases.
The incidence of pediatric acute pancreatitis (AP) has increased over the last several years, affecting approximately 1 in 10,000 children (1,2). Acute recurrent pancreatitis (ARP), characterized as 2 or more discrete episodes of AP, is reported in ∼15% to 20% of children following an initial AP episode (3,4). Chronic pancreatitis (CP), in which children have imaging or functional evidence of irreversible pancreatic damage (5), is estimated to have an incidence of ∼2 per 100,000 children per year (2,6). We expect that an increasing number of physicians will begin caring for these patients, therefore, it is imperative to have a better understanding of these diseases, their natural history and prognosis.
ARP and CP are considered as disease continuum. They are both associated with significant disease burden (7,8). Children with ARP or CP experience frequent abdominal pain, emergency room (ER) visits, and hospitalizations. They undergo numerous endoscopic and surgical procedures (9). Overall, diagnostic and therapeutic approaches are limited. This review will summarize the most recent developments in risk factors associated with recurrent episodes, opioid use, progression to CP, and its sequelae (7,10–13), diagnostic methods to evaluate for causes of ARP or CP (14,15), autoimmune pancreatitis (AIP) (16,17) and toxic-metabolic risk factors (18) and potential therapies (19,20).
A thorough review of the medical literature through MEDLINE and PubMed was conducted up to January 2019, using the following keywords pediatric pancreatitis, ARP, chronic pancreatitis, hereditary pancreatitis, child, childhood, children. The most recent developments presented in the Body of Review section are limited to papers published on or after January 2016. When possible, priority was given to European and North American Societies of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN and NASPGHAN) focused work, consensus statements or guidelines, studies with large sample sizes or multicenter studies such as INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) (21,22). INSPPIRE is the first multicenter, multinational, multidisciplinary collaboration with expertise in pediatric gastroenterology, pediatric endocrinology, and pediatric surgery to investigate the pathogenesis, risk factors, natural history, and outcomes of children with ARP and CP through careful longitudinal studies.
The etiologies of pediatric ARP and CP were recently reviewed (23,24). We will focus on the most recent developments in genetic, obstructive, and toxic/metabolic risk factors.
Gene variants are the leading risk factor in recurrent attacks of pancreatitis in childhood involving roughly 50% of children with ARP and 75% with CP (7). The genes most commonly associated with pediatric pancreatitis are: cationic trypsinogen (PRSS1), serine protease inhibitor Kazal-type 1 (SPINK1), chymotrypsin C (CTRC), carboxypeptidase A1 (CPA1), Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (7,14,25–28). Gain-of-function mutations in PRSS1 are linked to increased susceptibility for trypsin activation or sustained trypsin activity within the pancreas, and they are associated with hereditary pancreatitis (29). SPINK1 is a trypsin inhibitor with mutations found in 1% to 3% of the general population, but SPINK1 mutations (particularly N34S variant) have been described in ∼13% to 25% of children with ARP or CP (7,30–32). CFTR is an anion channel involved in anion transport: its complete loss of function leads to inspissated secretions, duct obstruction, and destruction of the pancreas in cystic fibrosis (33). CFTR mutations may cause impaired CFTR expression in pancreatic ducts and increase susceptibility to ARP and CP via several mechanisms including diminished intraluminal pH, decreased wash-out of pancreatic enzymes, more viscous and protein-rich ductal fluid causing obstruction, stone formation, and organ atrophy (34).
Children with PRSS1 variants are more likely to present with CP compared with ARP, develop early-onset CP and progress to CP faster than children without PRSS1 variants (7,10,27). There are other genetic factors that may convey an increased risk for an aggressive disease phenotype. SPINK1 or CTRC c.180TT variants are associated with CP diagnosis; CTRC with early-onset disease (7,8,27); CPA1 with early-onset CP (1,35). Carboxylesterlipase (CEL) and CEL-Hybrid(36,37) variants increase CP risk in adults. A recent pediatric study, however, found no significant difference in the carrier frequency of CEL-HYB1 allele between CP (4.8%) and controls (2.4%) (38). Future studies will entail a thorough evaluation of genetic risk factors in children that can enable genotype-phenotype correlations, diagnostic, and management decisions.
These include biliary or obstructive factors (ie, gallstones, choledochal cyst) and anatomical abnormalities (ie, pancreas divisum, pancreaticobiliary malunion), (7,14,28). Pancreas divisum (PD) is found in 14.5% of the INSPPIRE population, which is higher than expected in the normal population (∼7%), but without association to known pancreatitis gene mutations, suggesting that PD itself may be a risk factor (39). Although children frequently undergo endoscopic interventions, pancreatic sphincterotomy or minor papillotomy for PD, it is not clear whether they help prevent recurrent attacks. Therapeutic endoscopy was found most helpful if pancreatic duct was impacted with stones in children with PD. A prospective and randomized study similar to the (SpHincterotomy for Acute Recurrent Pancreatitis) SHARP trial in adults with PD (40) would be beneficial as to whether therapeutic endoscopy would be helpful for this subset.
Others are toxic/metabolic and autoimmune factors (ie, autoimmune pancreatitis, celiac disease) (7,14,28). Autoimmune and toxic/metabolic factors are rare in childhood (7,16,41). The INSPPIRE group has developed consensus recommendations for the diagnosis and management of AIP and toxic/metabolic risk factors to bring standardization to these uncommon problems (17,18).
There may be several risk factors that predispose children to recurrent attacks after the first episode of AP. In a longitudinal cohort of AP patients, most progressed to ARP within 5 months (4). Male sex, a higher weight percentile, and presence of pancreatic necrosis at the initial AP attack were associated with rapid progression to ARP (4). Exocrine pancreas function may not fully recover for several months after AP and beta cell function may be affected even in ARP (42). Obesity and severe AP during the first AP episode may be risk factors for glycemic abnormalities (43).
Chronic pancreatitis is characterized by irreversible, structural pancreatic damage with or without abdominal pain and/or evidence of exocrine pancreatic insufficiency or diabetes (5,21). In INSPPIRE cohort, children with PRSS1 mutations were diagnosed with their first episode of AP at a younger age and followed a more severe course (7,10,27). Fast progression to CP was also noted in an Indian pediatric cohort: over a median 25.5 months, 42% developed CP (44). In the INSPPIRE cohort, progression to CP was faster in children 6 years of age or older at the time of their first attack of AP or with pathogenic PRSS1 variants (10). Median time of progression from the initial attack of AP to CP was 3.79 years, and much faster (∼2.5 years) if a pathogenic PRSS1 variant was present. Within 6 years after the initial AP attack, 18% developed exocrine pancreatic insufficiency; 7.7% diabetes mellitus. Diabetes in pediatric ARP or CP was commonly associated with pancreatic atrophy (13). Seventeen percentage of children in INSPPIRE cohort reported frequent (daily/weekly) opioid use, which was associated with constant pain, more health care use, and higher levels of pain interference with daily functioning (12).
Interestingly, the INSPPIRE group has found that obese or overweight children had AP at a later age and were less likely to progress to CP during the study period (11). More data is needed to fully understand the impact of obesity on ARP and progression to CP.
There are consensus recommendations from INSPPIRE and European Pancreatic Club (EPC)/Hungarian Pancreatic Study Group (HPSG) on the diagnosis and management of pediatric pancreatitis (14,15). Overall, it is recommended to obtain serum triglyceride levels, celiac serologies, immunoglobulin G subtype 4 testing, sweat chloride, genetic mutation analysis, magnetic resonance cholangiopancreatography imaging for causal evaluation of ARP and CP.
In general, acute episodes of pancreatitis associated with ARP or CP are treated similar to a single AP event with focus on supportive care including aggressive early fluid administration, pain control, and early nutrition (45). Nutritional management of AP, ARP, and CP are discussed in a position paper from NASPGHAN/ESPGHAN (46). In summary, children should be started on a regular diet and advanced as tolerated preferably by mouth compared with the nasogastric or nasojejunal route. Enteral nutrition is preferred over parenteral nutrition and a combination of enteral and parenteral nutrition is preferred over parenteral alone. The use of specialized formula is not necessary (46).
Two observational studies on people with cystic fibrosis and recurrent AP have demonstrated a reduction in AP attacks while taking ivacaftor (19,20). Ivacaftor is a CFTR potentiator that improves the function of the CFTR by increasing the open probability of the channel in people with gating mutations, such as G551D (47). These studies bring hope to the pancreas field that patients with ARP and certain CFTR mutations may benefit from gene targeting.
Long-term management consists of evaluating for progression of disease, particularly to CP, exocrine pancreatic insufficiency and diabetes, as well as avoidance of possible risk factors that could lead to progression. Environmental risk factors (ie, alcohol and tobacco) are commonly described in adults with pancreatitis, not in children (48). It is reasonable to recommend alcohol and smoking avoidance as children progress into adulthood and preventing second-hand smoke regardless of age. It would also be cautious to avoid medications with known association to pancreatitis, such as valproic acid, mesalamine, trimethoprim-sulfamethoxazole, 6-mercaptopurine, asparaginase, and azathioprine (49).
Total pancreatectomy with islet autotransplantation (TPIAT) is increasingly being performed in children with ARP or CP; specifically, those with recurrent attacks and chronic pain. It is a complex surgical procedure in which the pancreas is removed and islet cells are harvested. The patient's own islet cells are then infused into the liver. As it is an autologous procedure, the patient does not require immunomodulatory drugs (50). The goal is to eliminate pain and minimize postsurgical diabetes. TPIAT is an effective therapy for children with painful pancreatitis, and can provide sustained pain relief, reduce the need for opioids, and improve the quality of life in those with ARP and CP that failed medical and/or endoscopic therapies (50,51).
Although there has been increasing incidence and literature on pediatric pancreatic disease, there are still many unknowns. We no longer rely on adult criteria for diagnosis and management of childhood pancreatitis, but most pediatric guidelines are based on consensus recommendations, and the overall quality of evidence is low for most studies. The natural history studies, randomized placebo-controlled clinical trials are desperately needed to further understand pediatric pancreatitis, its risk factors, epidemiology, natural history, and disease burden. With ongoing research, we hope to provide optimal care for children with these diseases.
1. Morinville VD, Barmada MM, Lowe ME. Increasing incidence of acute pancreatitis at an American pediatric
tertiary care center: is greater awareness among physicians responsible? Pancreas
2. Sellers ZM, MacIsaac D, Yu H, et al. Nationwide trends in acute and chronic pancreatitis among privately insured children and non-elderly adults in the United States, 2007-2014. Gastroenterology
3. Poddar U, Yachha SK, Borkar V, et al. A Report of 320 cases of childhood pancreatitis: increasing incidence, etiologic categorization, dynamics, severity assessment, and outcome. Pancreas
4. Sweeny KF, Lin TK, Nathan JD, et al. Rapid progression of acute pancreatitis to acute recurrent pancreatitis in children. J Pediatr Gastroenterol Nutr
5. Morinville VD, Husain SZ, Bai H, et al. INSPPIRE Group. Definitions of pediatric
pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr
6. Pant C, Sferra TJ. Emergency department visits and hospitalizations in children with chronic pancreatitis in the United States. J Pediatr Gastroenterol Nutr
7. Kumar S, Ooi CY, Werlin S, et al. Risk factors associated with pediatric
acute recurrent and chronic pancreatitis: lessons from INSPPIRE. JAMA Pediatr
8. Ting J, Wilson L, Schwarzenberg SJ, et al. Direct costs of acute recurrent and chronic pancreatitis in children in the INSPPIRE Registry. J Pediatr Gastroenterol Nutr
9. Troendle DM, Fishman DS, Barth BA, et al. Therapeutic endoscopic retrograde cholangiopancreatography in pediatric
patients with acute recurrent and chronic pancreatitis: data from the INSPPIRE (INternational Study group of Pediatric
Pancreatitis: In search for a cuRE) Study. Pancreas
10. Liu QY, Abu-El-Haija M, Husain SZ, et al. Risk factors for rapid progression from acute recurrent to chronic pancreatitis in children: report from INSPPIRE. J Pediatr Gastroenterol Nutr
11. Uc A, Zimmerman MB, Wilschanski M, et al. Impact of obesity on pediatric
acute recurrent and chronic pancreatitis. Pancreas
12. Perito ER, Palermo TM, Pohl JF, et al. Factors associated with frequent opioid use in children with acute recurrent and chronic pancreatitis. J Pediatr Gastroenterol Nutr
13. Bellin MD, Lowe M, Zimmerman MB, et al. Diabetes mellitus in children with acute recurrent and chronic pancreatitis: data from the INternational Study Group of Pediatric
Pancreatitis: In Search for a CuRE Cohort. J Pediatr Gastroenterol Nutr
14. Gariepy CE, Heyman MB, Lowe ME, et al. Causal evaluation of acute recurrent and chronic pancreatitis in children: consensus from the INSPPIRE Group. J Pediatr Gastroenterol Nutr
15. Parniczky A, Abu-El-Haija M, Husain S, et al. EPC/HPSG evidence-based guidelines for the management of pediatric
16. Scheers I, Palermo JJ, Freedman S, et al. Autoimmune pancreatitis in children: characteristic features, diagnosis, and management. Am J Gastroenterol
17. Scheers I, Palermo JJ, Freedman S, et al. Recommendations for diagnosis and management of autoimmune pancreatitis in childhood: consensus from INSPPIRE. J Pediatr Gastroenterol Nutr
18. Husain SZ, Morinville V, Pohl J, et al. Toxic-metabolic risk factors in pediatric
pancreatitis: recommendations for diagnosis, management, and future research. J Pediatr Gastroenterol Nutr
19. Carrion A, Borowitz DS, Freedman SD, et al. Reduction of recurrence risk of pancreatitis in cystic fibrosis with ivacaftor: case series. J Pediatr Gastroenterol Nutr
20. Akshintala VS, Kamal A, Faghih M, et al. Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis. Pancreatology
21. Uc A, Perito ER, Pohl JF, et al. Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). INternational Study Group of Pediatric
Pancreatitis: In Search for a CuRE Cohort Study: design and rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas
22. Morinville VD, Lowe ME, Ahuja M, et al. Design and implementation of INSPPIRE. J Pediatr Gastroenterol Nutr
23. Uc A, Fishman DS. Pancreatic disorders. Pediatr Clin North Am
24. Abu-El-Haija M, Lowe ME. Pediatric
pancreatitis-molecular mechanisms and management. Gastroenterol Clin North Am
25. Xiao Y, Yuan W, Yu B, et al. Targeted gene next-generation sequencing in Chinese children with chronic pancreatitis and acute recurrent pancreatitis. J Pediatr
26. Gonska T. Genetic predisposition in pancreatitis. Curr Opin Pediatr
27. Giefer MJ, Lowe ME, Werlin SL, et al. Early-onset acute recurrent and chronic pancreatitis is associated with PRSS1 or CTRC gene mutations. J Pediatr
28. Della Corte C, Faraci S, Majo F, et al. Pancreatic disorders in children: new clues on the horizon. Dig Liver Dis
29. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet
30. Sobczynska-Tomaszewska A, Bak D, Oralewska B, et al. Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis. J Pediatr Gastroenterol Nutr
31. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet
32. Sultan M, Werlin S, Venkatasubramani N. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr
33. Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist's perspective. Nat Rev Gastroenterol Hepatol
34. Hegyi P, Wilschanski M, Muallem S, et al. CFTR: a new horizon in the pathomechanism and treatment of pancreatitis. Rev Physiol Biochem Pharmacol
35. Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet
36. Fjeld K, Weiss FU, Lasher D, et al. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet
37. Ragvin A, Fjeld K, Weiss FU, et al. The number of tandem repeats in the carboxyl-ester lipase (CEL) gene as a risk factor in alcoholic and idiopathic chronic pancreatitis. Pancreatology
38. Oracz G, Kujko AA, Fjeld K, et al. The hybrid allele 1 of carboxyl-ester lipase (CEL-HYB1) in Polish pediatric
patients with chronic pancreatitis. Pancreatology
39. Lin TK, Abu-El-Haija M, Nathan JD, et al. Pancreas divisum in pediatric
acute recurrent and chronic pancreatitis: report From INSPPIRE. J Clin Gastroenterol
40. Cote GA, Durkalski-Mauldin VL, Serrano J, et al. SHARP Consortium. SpHincterotomy for acute recurrent pancreatitis randomized trial: rationale, methodology, and potential implications. Pancreas
41. Pohl J, Morinville V, Husain SZ, et al. Toxic-metabolic risk factors are uncommon in pediatric
chronic pancreatitis. J Pediatr Gastroenterol Nutr
42. Puttaiah Kadyada S, Thapa BR, Kaushal K, et al. Incomplete functional and morphological recovery after acute and acute recurrent pancreatitis in children. J Gastroenterol Hepatol
43. Abu-El-Haija M, Hornung L, Denson LA, et al. Prevalence of abnormal glucose metabolism in pediatric
acute, acute recurrent and chronic pancreatitis. PLoS One
44. Poddar U, Yachha SK, Borkar V, et al. Is acute recurrent pancreatitis in children a precursor of chronic pancreatitis? A long-term follow-up study of 93 cases. Dig Liver Dis
45. Abu-El-Haija M, Kumar S, Quiros JA, et al. Management of acute pancreatitis in the pediatric
population: a clinical report from the North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition Pancreas Committee. J Pediatr Gastroenterol Nutr
46. Abu-El-Haija M, Uc A, Werlin SL, et al. Nutritional considerations in pediatric
pancreatitis: a position paper from the NASPHAN Pancreas Committee and ESPHAN Cystic Fibrosis/Pancreas Working Group. J Pediatr Gastroenterol Nutr
47. Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A
48. Schwarzenberg SJ, Uc A, Zimmerman B, et al. Chronic pancreatitis: pediatric
and adult cohorts show similarities in disease progress despite different risk factors. J Pediatr Gastroenterol Nutr
49. Bai HX, Ma MH, Orabi AI, et al. Novel characterization of drug-associated pancreatitis in children. J Pediatr Gastroenterol Nutr
50. McEachron KR, Bellin MD. Total pancreatectomy and islet autotransplantion for chronic and recurrent acute pancreatitis. Curr Opin Gastroenterol
51. Chinnakotla S, Bellin MD, Schwarzenberg SJ, et al. Total pancreatectomy and islet autotransplantation in children for chronic pancreatitis: indication, surgical techniques, postoperative management, and long-term outcomes. Ann Surg