Secondary Logo

Journal Logo

Original Articles: Pancreatology

Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors

Schwarzenberg, Sarah J.; Uc, Aliye; Zimmerman, Bridget; Wilschanski, Michael§; Wilcox, C. Mel||; Whitcomb, David C.¶,#,∗∗,††; Werlin, Steven L.‡‡; Troendle, David§§; Tang, Gong||||; Slivka, Adam; Singh, Vikesh K.¶¶; Sherman, Stuart##; Shah, Uzma∗∗∗; Sandhu, Bimaljit S.†††; Romagnuolo, Joseph††; Rhee, Sue‡‡‡; Pohl, John F.§§§; Perito, Emily R.‡‡‡; Ooi, Chee Y.||||||; Nathan, Jaimie D.¶¶¶; Muniraj, Thiruvengadam###; Morinville, Veronique D.∗∗∗∗; McFerron, Brian††††; Mascarenhas, Maria‡‡‡‡; Maqbool, Asim‡‡‡‡; Liu, Quin§§§§; Lin, Tom K.¶¶¶; Lewis, Michele||||||||; Husain, Sohail Z.¶¶¶¶; Himes, Ryan####; Heyman, Melvin B.‡‡‡; Guda, Nalini∗∗∗∗∗; Gonska, Tanja†††††; Giefer, Matthew J.‡‡‡‡‡; Gelrud, Andres§§§§§; Gariepy, Cheryl E.||||||||||; Gardner, Timothy B.¶¶¶¶¶; Freedman, Steven D.#####; Forsmark, Christopher E.∗∗∗∗∗∗,††††††; Fishman, Douglas S.####; Cote, Gregory A.∗∗∗∗∗; Conwell, Darwin‡‡‡‡‡‡; Brand, Randall E.; Bellin, Melena; Barth, Bradley§§; Banks, Peter A.§§§§§§; Anderson, Michelle A.||||||||||||; Amann, Stephen T.¶¶¶¶¶¶; Alkaade, Samer######; Abu-El-Haija, Maisam¶¶¶; Abberbock, Judah N.||||; Lowe, Mark E.∗∗∗∗∗∗∗; Yadav, Dhiraj

Author Information
Journal of Pediatric Gastroenterology and Nutrition: April 2019 - Volume 68 - Issue 4 - p 566-573
doi: 10.1097/MPG.0000000000002279

Abstract

What Is Known

  • Chronic pancreatitis is a devastating disease leading to pain and lost school/work time.
  • Understanding the similarities and differences in chronic pancreatitis between these groups is critical to providing appropriate care to children in transition from pediatric to adult providers.

What Is New

  • Children and adults with chronic pancreatitis exhibit remarkable similarity in demographics, treatment of chronic pancreatitis, and pain experience.
  • Adults and children with chronic pancreatitis have different risk factors for their disease: genetic factors in children versus alcohol and smoking in adults. This may explain the variations in disease progression in these 2 populations.

Chronic pancreatitis (CP) is a fibroinflammatory disease of the pancreatic parenchyma with variable and complex etiologies, features, and severity (1). Episodic and chronic pain, which is frequently intractable, leads to loss of work and school time (2–5), and increased utilization of healthcare resulting in high medical costs (6,7). CP is most commonly described in adults as associated with excessive use of alcohol and tobacco (8). CP is increasingly recognized as a disease of children (2,9–12), although the prevalence of disease is lower than in adults (13). This may represent a true rise in prevalence in children or improved ascertainment.

Two large, multicenter studies have described the characteristics of individuals with CP: The North American Pancreatitis Study 2 (NAPS2, adults) (14–16) and the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE, children) (2,17,18). Both groups recruited individuals from secondary and tertiary referral centers. Each examined demographic and risk factors for CP, and disease-related outcomes in a cross-sectional manner.

The separate analyses of pediatric and adult CP cohorts hamper investigation of the full clinical course of CP. Genetic risk factors are reported to be more common in children than in adults with CP (2). This difference, however, may represent true differences in the genesis of CP in children compared with adults or may represent differences in clinical practice; that is, providers treating adults are less likely to order genetic testing. Adults and children may have differences in the progression of CP, or it may be that reports in adults and children represent an ongoing disease examined at different stages. Recent guideline publications by both adult and pediatric pancreas experts highlight the need to understand the full spectrum of disease (19,20).

This study compares the NAPS2 and INSPPIRE CP cohorts, examining demographics, risk factors, disease duration, management, and outcomes. Our goals are to better understand the natural history of CP and to initiate a dialog on protocols for care across age groups to improve outcomes across the age spectrum.

METHODS

Study Design and Participants

INSPPIRE is a cross-sectional, multinational study from 19 institutions, collecting demographic and clinical data by means of 2 sets of questionnaires: 1 completed by the patient or parent and the other completed by the physician on children who fulfilled the criteria for CP and were <19 years old at the time of enrollment (18). Diagnosis of CP required at least 1 of the following: abdominal pain and imaging suggestive of changes associated with chronic pancreatic; exocrine pancreatic insufficiency and imaging findings suggestive of chronic pancreatic damage; or endocrine pancreatic insufficiency and imaging findings suggestive of chronic pancreatic damage (21). Data for this analysis was entered into the Research Electronic Data Capture (REDCap, hosted at University of Iowa) database between August 22, 2012 to March 20, 2017 and represents baseline information from the cohort. All centers had institutional review board approval or the equivalent for their country. All centers obtained written informed consent and assent, when required, from parents and children. Some of the pediatric patients included in this study have been previously reported (2,17,22–24).

The NAPS2 is a series of 3 sequential cross-sectional studies (original NAPS2 study (14), NAPS2 continuation and validation and NAPS2 Ancillary Study) (14–16) involving 26 US centers that prospectively recruited CP patients from 2000 to 2014. CP was defined as definitive evidence of CP on either endoscopic retrograde cholangiopancreatography using the Cambridge classification or magnetic resonance cholangiopancreatography (MRCP), computed tomography (CT) scan, or endoscopic ultrasound (EUS) (≥5 criteria or calcifications), or histologic evidence of CP (14). Data in this study was also collected by sets of questionnaires completed by the patient and the physician. Some adult patients included in this study have been previously reported (14–16).

Questionnaires for INSPPIRE were modeled after those for NAPS2, adapted for children. Both studies collected similar information on demographics, family and personal history, environmental history including smoking and alcohol consumption, and clinical questions related to pancreatitis, medication use, and disability. The similarity in study methodology allows comparison of these 2 cohorts. Physician questionnaires included documentation of risk factors and medical or surgical therapies before enrollment (14,18). Risk factors for CP were by physician report, using the physicians’ determination for the significance of alcohol or tobacco use, hypertriglyceridemia, and hypercalcemia. Duration of disease was calculated from the time of first diagnosis of acute pancreatitis (AP), CP, or symptoms of pancreatitis (whichever came first) to entry into either NAPS2 or INSPPIRE.

In INSPPIRE, genetic risk factors were extracted from the physician report; the number of CP risk factor genes tested was variable. For the NAPS2 cohort, results reported here are based on post hoc testing for mutations in 4 genes (PRSS1 [cationic trypsinogen gene], CFTR [cystic fibrosis transmembrane conductance regulator gene], SPINK1 [serine protease inhibitor Kazal type 1 gene], CTRC [chymotrypsin C gene]) that all subjects underwent as part of a research study (25). Analysis was done in a single laboratory by a combination of sequencing and Taq-man assays (Thermo-Fischer, Waltham, MA).

Statistical Analysis

Demographic, clinical, and treatment variables were compared between pediatric and adult patients using t-test or Wilcoxon rank-sum test for continuous variables, Pearson chi-square test or Fisher exact test for categorical variables, and Wilcoxon rank-sum test for ordinal variables. Summary statistics are presented as mean (standard deviation) or median (interquartile range, IQR) for continuous variables, frequency count (percent) or median (IQR) for ordinal variables, and frequency count (percent) for categorical variables. All statistical analyses were performed using SAS (version 9.4).

RESULTS

Population

The NAPS2 cohort included 1195 subjects. Of these, 1063 had age at onset of symptoms or diagnosis of AP or CP (whichever came first) as adults (>18 years); 76 reported onset of symptoms or diagnosis of AP or CP at <18 years of age; age at onset of symptoms could not be determined in the remaining 56 patients. The INSPPIRE cohort included 224 childhood-onset CP subjects. None were in the NAPS2 cohort. All subjects included in the study met criteria for CP at enrollment in the study.

In the primary analysis, the 1063 NAPS2 subjects with adult onset of disease were compared with the 224 INSPPIRE subjects with childhood onset. As a secondary analysis, the NAPS2 subjects with childhood onset were compared with the INSPPIRE subjects. In the secondary analysis, only the subjects specifying white race were compared (158 INSPPIRE, 69 NAPS2) because of the small size of the nonwhite population (n = 7) in this NAPS2 subset.

Demographics

Demographic data for the primary analysis from the 2 cohorts are presented in Table 1. Age at presentation of CP was, by definition, divergent. Children presented at a mean age of 11.9 ± 3.9 years, whereas adults presented at a mean age of 52.7 ± 13.3 years. The cohorts were similar with respect to race. Female sex was more common in the pediatric cohort (56% girls in pediatric cohort vs 45% in adult cohort, P = 0.003). Adults with CP were more likely to be overweight or underweight, compared with children (adult cohort 10% underweight and 27% overweight vs pediatric cohort 5% underweight and 13% overweight, P = 0.001 and P < 0.0001, respectively). History of acute or acute recurrent pancreatitis was reported in pediatric CP 92% and 83%, respectively, versus 71% and 66% of adult CP (P < 0.0001 for each). Family history of CP was significantly more common in children with CP (23% in children vs 8% in adults, P < 0.0001). This may reflect the difference in risk factors for the 2 groups, discussed below.

TABLE 1
TABLE 1:
Demographic characteristics of pediatric and adult subjects with chronic pancreatitis in the INSPPIRE and NAPS2 cohorts

The pediatric cohort had a mean period of 3.6 ± 3.3 years from patient or physician-reported presentation of disease to enrollment in INSPPIRE whereas adults had a 6.9 ± 7.1-year period between disease onset and enrollment (P < 0.0001).

Risk Factors

Risk factors for CP in the 2 populations are presented in Table 2. Adults reported environmental risk factors significantly more than children. Alcohol exposure was a risk in 53% of adults and 1% of children (P < 0.0001), and tobacco exposure was a risk in 50% of adults and 7% of children (P < 0.0001). Hypertriglyceridemia was also more common in adults (11%) vs. children (4%) (P = 0.007). Medications were more frequently identified as risk factors in children compared with adults (7% vs 3%, P = 0.0007). Children were more likely to be diagnosed with autoimmune pancreatitis than adults (6% vs 2%, P = 0.039). Obstructive factors were found more commonly in children (29%) compared with adults (19%), P = 0.001.

TABLE 2
TABLE 2:
Distribution of risk factors in pediatric and adult subjects with chronic pancreatitis according to the TIGAR-O classification in the INSPPIRE and NAPS2 cohorts

Analysis of 4 genetic risk factors for CP, PRSS1, SPINK1, CFTR, and CTRC, was done in every adult. As children were tested as part of clinical care, and often for a more limited group of genes, all 4 genetic risk factor results are not available for all children. Despite the more complete testing in adults, all 4 genetic risk factors were significantly more common in children than adults (P < 0.0001 for each gene, Table 2).

Morphologic Features

Morphologic features of the pancreas and biliary tree are important in the diagnosis of CP. Few differences were found between imaging features of the pancreas and biliary tree in adults and children (Table 3). Pancreatic calcifications, cysts, and pseudocysts were significantly more common in adults (calcifications, 15% in children vs 57% in adults, P < 0.0001; cysts/pseudocysts 22% in children vs 31% in adults, P = 0.007). Pancreatic atrophy (fatty or fibrous replacement of the pancreas), which has been reported as more common in children with CP (2) was equal in occurrence in children and adults in this head-on comparison (P = 0.063).

TABLE 3
TABLE 3:
Select morphological features, exocrine and endocrine insufficiency, pain, resource utilization, and disability in pediatric and adult subjects with chronic pancreatitis in the INSPPIRE and NAPS2 cohorts

Disease Impact

The impact of CP was measured as frequency and intensity of pain, frequency of complications (exocrine pancreatic insufficiency or diabetes), and frequency of interference with daily life (Table 3). Pain was common in both adults and children, in both groups only 13% to 14% reported being always or usually pain-free. Adults reported more pain overall, with a higher percentage of adults reporting constant mild-to-moderate pain with episodes of severe pain. Prevalence of constant severe pain, however, was similar between the 2 groups (5% of children, 6% of adults). Adults were more likely to use pain medication of any kind (57% of children vs 70% of adults, P = 0.0006), and more commonly used opioids either alone or in combination with nonopioids (children 42% vs adults 62%, P < 0.0001).

Prevalence of exocrine pancreatic insufficiency was similar between the adult and pediatric cohorts (children 26% vs adult 33%, P = 0.107). Diabetes was more commonly reported in adults than in children (36% vs 4%, respectively, P < 0.0001). Median number of emergency room visits and hospitalizations, as well as missed days of work and school in the year preceding enrollment were similar across both cohorts.

Medical and Surgical Treatment

Supplemental Table 1 (Supplemental Digital Content, http://links.lww.com/MPG/B583) includes therapies used for CP in the children and adults. Adults were more likely to use pancreatic enzymes (children 55% vs adults 66%, P = 0.004). Children were more likely to have undergone pancreatic duct sphincterotomy (P < 0.0001) and pancreatic duct stone removal (P < 0.0001) compared with adults and less likely to have undergone cholecystectomy (P = 0.0002).

Secondary Population Analysis

Table 4 compares demographic and risk factors of 69 white adults from NAPS2 who reported their CP began in childhood and 158 white subjects from the INSPPIRE cohort. These 2 cohorts were much more similar than the entire INSPPIRE and NAPS2 cohorts. Percent female sex was similar in these 2 groups, with the INSPPIRE cohort 51% female and the NAPS2 childhood onset cohort at 54% female. Prevalence of family history of CP and presence of genetic risk factors were similar between the 2 groups, as was the presence of pancreas divisum. The only risk factor significantly more common in the NAPS2 childhood onset cohort compared with the INSPPIRE cohort was alcohol as a risk factor (9% in NAPS2 and 1% in INSPPIRE cohorts, P = 0.011). Disease duration for the 2 cohorts was different; however, comparison was not made as the difference may be because of the study start periods.

TABLE 4
TABLE 4:
Demographic characteristics and risk factors for chronic pancreatitis in white subjects with chronic pancreatitis among pediatric patients (INSPPIRE cohort) and those presenting as children in the NAPS2 cohort

DISCUSSION

The NAPS2 and INSPPIRE cohorts allow large studies of demographics, risk factors, clinical course, and therapies in adults and children, respectively, with CP. Our comparison of these 2 large databases shows that children have few differences and many similarities in demographics, complications, and therapies. In contrast, marked differences exist in risk factors between children and adults.

In studies of children with CP, the most common physician-reported risk factors are genetic variants associated with CP (2,10–12,17,26). Adults more commonly have environmental risk factors, particularly alcohol and smoking (3,8,27,28). Even when adults with CP were tested post hoc, the presence of known genetic risk factors was significantly lower than in children. This difference may account for the difference in age of presentation of disease. It is likely that genetic risk factors with significant penetrance lead to onset of CP in childhood, whereas the older age when alcohol and tobacco use begins and the length of use contributes to adult-onset CP. The finding that adults with CP in the NAPS2 study who presented during childhood have a similar frequency of genetic risk factors compared with the INSPPIRE cohort supports this hypothesis. It is also possible that adults with CP have less penetrant genetic risk factors, and thus manifest later in life or when an environmental risk factor is introduced. It should be noted that the degree to which second-hand smoke might contribute to childhood CP is undetermined, as unbiased analysis of the risk of second-hand smoke (for example, using urine or blood cotinine levels) has not been done.

When comparing the INSPPIRE cohort with the patients in NAPS2 who presented as children, we did not find significant differences in the prevalence of genetic variants between the groups. Although a previous report found that PRSS1 and CTRC mutations are more prevalent in early childhood CP (22), only PRSS1 approached significance (P = 0.059) in our analysis. The average age of initial presentation of CP is older in the adults in NAPS2 who presented as children compared with the INSPPIRE cohort. This may explain the difference in the prevalence of PRSS1 and CTRC mutations.

Of great clinical significance, our data shows that children and adults report similar pain patterns in terms of severity and frequency of daily pain. Pain is one of the most severe complications of CP, and the factor most likely to lead to disability. Pain intensity is a subjective measure; thus, it is striking that both groups describe their pain patterns so similarly. Despite comparable reports of pain frequency and intensity, children report less pain medication use than adults. Our study cannot determine what level of pain management is appropriate, but these data suggest that investigation of the adequacy of pain management in adults and children is crucial to limit the long-term effects of too little or too much pain control. Increased use of pain scales and protocol medication management may improve control and outcome for both adults and children.

Overall, children and adults have a similar incidence of complications with a few exceptions. Adults have more pancreatic calcifications on imaging and are more likely to develop diabetes. American adults in general have a high background risk of diabetes [12.2% in people in America >18 years of age (29)], but adults with CP have >2 times the baseline risk. The differences in pancreatic calcifications and diabetes between adults and children may, in part, result from the differing risk factors associated with CP, or possibly disease duration, rather than the age of the patient at disease onset (30). In the group of adult subjects with disease onset in childhood, there was also a higher frequency of pancreatic calcification and diabetes in adulthood compared with the pediatric population (data not shown). This suggests that endocrine (but not exocrine) insufficiency is dependent on longer disease duration, as both groups have similar risk factors for CP. The NAPS2 childhood onset cohort was close to the same age as the INSPPIRE cohort at their first episode of pancreatitis, but older at the age of diagnosis of pancreatitis. It is possible that environmental factors, such as alcohol or tobacco become risks as children with a previous episode of pancreatitis age into their teens.

In our cohorts, the most common risk factors in adults were alcohol and tobacco use; in children, genetic and obstructive risk factors were more common. Alcoholic pancreatitis has a more rapid progression than genetic or idiopathic pancreatitis (31–33), and cigarette smoking has a high prevalence of pancreatic calcifications and increases risk for exocrine pancreatic insufficiency (34,35). Additionally, cigarette smoking often correlates with alcohol use (36). Both alcohol use and tobacco use are independently associated with development of insulin resistance (37,38). Thus, in children and adults with similar length of CP, adults with CP would be more likely to exhibit advanced radiographic disease and be more likely to have diabetes. In this respect, children are more similar to adult women with CP, whose pancreatic morphology is different from men, likely reflecting different risk factors associated with their CP (27).

Our study has limitations. Both the NAPS2 and the INSPPIRE recruited subjects from secondary and tertiary treatment centers; individuals with milder forms of CP may not present at these centers and be underrepresented. The NAPS2 study is limited to USA whereas the INSPPIRE cohort includes subjects from sites outside USA. Environmental risk factors or clinical management may differ between countries. The discrepancy in size of cohorts may also affect statistical analysis.

CONCLUSIONS

In conclusion, despite the disparity in age of onset of disease, children and adults with CP exhibit remarkable similarity in demographics, treatment of CP, and experience of pain. Differences between the groups with respect to radiographic findings and prevalence of diabetes may be related to the differences found in the risk factors associated with disease and the length of time they have had CP. Typically, children and adults with CP are diagnosed and managed by separate medical teams. Our study suggests that to understand the natural history of CP we need to include both children and adults in future studies.

Acknowledgments

The authors acknowledge the Epidemiology Data Center, Michael O’Connell, PhD, Division of Gastroenterology & Hepatology at the University of Pittsburgh for data management of NAPS2studies, Kim Stello and Danielle Dwyer for genotyping and laboratory management, and other members of the NAPS2 consortium. Affiliation of authors during patient recruitment were: John Baillie (Duke University, Durham, NC), Darwin Conwell (Brigham & Women's Hospital, Boston, MA), Gregory A Cote (Indiana University, Indianapolis, IN), Andres Gelrud (University of Pittsburgh Medical Center, Pittsburgh, PA, University of Cincinnati, Cincinnati, OH, and University of Chicago, Chicago, IL), Thiruvengadam Muniraj (Griffin Hospital, Yale University affiliate, New Haven, CT), Joseph Romagnuolo (Medical University of South Carolina, Charleston, SC), Gregory A Cote (Indiana University, Indianapolis, IN and Medical University of South Carolina, Charleston, SC), Bimaljit S Sandhu (Virginia Commonwealth University, Richmond VA). The authors express their appreciation to Dr. John Baillie.

REFERENCES

1. Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology 2016; 16:218–224.
2. Schwarzenberg SJ, Bellin M, Husain SZ, et al. Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden. J Pediatr 2015; 166:890.e1–896.e1.
3. Yadav D, Timmons L, Benson JT, et al. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011; 106:2192–2199.
4. Machicado JD, Amann ST, Anderson MA, et al. Quality of Life in chronic pancreatitis is determined by constant pain, disability/unemployment, current smoking, and associated co-morbidities. Am J Gastroenterol 2017; 112:633–642.
5. Mullady DK, Yadav D, Amann ST, et al. Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut 2011; 60:77–84.
6. Hall TC, Garcea G, Webb MBA, et al. The socio-economic impact of chronic pancreatitis: a systematic review. J Eval Clin Pract 2014; 20:203–207.
7. 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 2016; 62:443–449.
8. Conwell DL, Banks PA, Sandhu BS, et al. Validation of demographics, etiology, and risk factors for chronic pancreatitis in the USA: a report of the North American Pancreas Study (NAPS) Group. Dig Dis Sci 2017; 62:2133–2140.
9. Chowdhury SD, Chacko A, Ramakrishna BS, et al. Clinical profile and outcome of chronic pancreatitis in children. Indian Pediatr 2013; 50:1016–1019.
10. Joergensen M, Brusgaard K, Crüger DG, et al. Incidence, prevalence, etiology, and prognosis of first-time chronic pancreatitis in young patients: a nationwide cohort study. Dig Dis Sci 2010; 55:2988–2998.
11. Saito N, Suzuki M, Sakurai Y, et al. Genetic analysis of Japanese children with acute recurrent and chronic pancreatitis. J Pediatr Gastroenterol Nutr 2016; 63:431–436.
12. Wang W, Liao Z, Li Z-S, et al. Chronic pancreatitis in Chinese children: etiology, clinical presentation and imaging diagnosis. J Gastroenterol Hepatol 2009; 24:1862–1868.
13. 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 2017; 46:110–115.
14. Whitcomb DC, Yadav D, Adam S, et al. North American Pancreatic Study GroupMulticenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology 2008; 8:520–531.
15. Wilcox CM, Sandhu BS, Singh V, et al. Racial differences in the clinical profile, causes, and outcome of chronic pancreatitis. Am J Gastroenterol 2016; 111:1488–1496.
16. Wilcox CM, Yadav D, Ye T, et al. Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol 2015; 13:552–560.
17. Kumar S, Ooi CY, Werlin S, et al. Risk factors associated with pediatric acute recurrent and chronic pancreatitis: lessons from INSPPIRE. JAMA Pediatr 2016; 170:562–569.
18. Morinville VD, Lowe ME, Ahuja M, et al. Design and implementation of INSPPIRE. J Pediatr Gastroenterol Nutr 2014; 59:360–364.
19. Lohr JM, Dominguez-Munoz E, Rosendahl J, et al. United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J 2017; 5:153–199.
20. Parniczky A, Abu-El-Haija M, Husain S, et al. EPC/HPSG evidence-based guidelines for the management of pediatric pancreatitis. Pancreatology 2018; 18:146–160.
21. Morinville VD, Husain SZ, Bai H, et al. Definitions of pediatric pancreatitis and survey of present clinical practices. J Pediatr Gastroenterol Nutr 2012; 55:261–265.
22. 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 2017; 186:95–100.
23. 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 2018; [Epub ahead of print].
24. 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 2017; 46:764–769.
25. Phillips AE, LaRusch J, Greer P, et al. Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry. Pancreatology 2018; [Epub ahead of print].
26. Wejnarska K, Kolodziejczyk E, Wertheim-Tysarowska K, et al. The etiology and clinical course of chronic pancreatitis in children with early onset of the disease. J Pediatr Gastroenterol Nutr 2016; 63:665–670.
27. Romagnuolo J, Talluri J, Kennard E, et al. Clinical profile, etiology, and treatment of chronic pancreatitis in North American women: analysis of a large multicenter cohort. Pancreas 2016; 45:934–940.
28. Cote GA, Yadav D, Slivka A, et al. North American Pancreatitis Study GroupAlcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011; 9:266–273.
29. Association AD. National Diabetes Statistics Report. 2017.
30. Bellin MD, Whitcomb DC, Abberbock J, et al. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States. Am J Gastroenterol 2017; 112:1457–1465.
31. Ammann RW, Buehler H, Muench R, et al. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas 1987; 2:368–377.
32. Lankisch PG, Löhr-Happe A, Otto J, et al. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993; 54:148–155.
33. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107:1481–1487.
34. Luaces-Regueira M, Iglesias-Garcia J, Lindkvist B, et al. Smoking as a risk factor for complications in chronic pancreatitis. Pancreas 2014; 43:275–280.
35. Talamini G, Bassi C, Falconi M, et al. Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas 2007; 35:320–326.
36. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med 2009; 169:1035–1045.
37. Carr RM, Correnti J. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci 2015; 1353:1–20.
38. Facchini FS, Hollenbeck CB, Jeppesen J, et al. Insulin resistance and cigarette smoking. Lancet 1992; 339:1128–1130.
Keywords:

children; diabetes; endoscopy; environmental; genetic; pain

Supplemental Digital Content

Copyright © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition