What Is Known
- Wide variations exist in the diagnostic evaluation and treatment of children with autoimmune pancreatitis.
- The approach to children with autoimmune pancreatitis is based largely on adult data.
What Is New
- A panel of pediatric pancreatologists from International Study Group of Pediatric Pancreatitis: In search for a cuRE generated recommendations to help standardize the approach for diagnostic evaluation and management of autoimmune pancreatitis in children.
- The gaps in knowledge and research needs to advance the field are highlighted.
Autoimmune pancreatitis (AIP) is a distinct, infrequent form of pancreatitis in children with a poorly understood pathophysiology. In the International Study Group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) population, only 4% of children with chronic pancreatitis have AIP listed as the primary risk factor (1). We have recently published a report combining AIP cases from multiple pediatric sites and cases listed in the literature; and were able to describe the characteristics of pediatric AIP (P-AIP) (2).
We have shown that P-AIP can occur at any age, but most commonly around adolescence and can affect children from all racial and ethnic backgrounds (2). P-AIP mainly presents with abdominal pain and/or obstructive jaundice. On cross-sectional imaging, focal or diffuse pancreatic enlargement, abnormal (rim-like) gland enhancement, and/or pancreatic duct irregularity are commonly found. In cases were pancreas biopsies were obtained, histopathologic features included a combination of granulocytic epithelial lesions, storiform fibrosis, and lymphoplasmacytic infiltration. P-AIP generally responds well to corticosteroids although 10% to 15% will eventually develop exocrine pancreatic insufficiency (EPI) or diabetes during the course of the disease. A quarter of patients with P-AIP will develop other immune/inflammatory diseases (2).
In contrast to adult AIP (A-AIP), there are no established guidelines directing a common diagnostic and therapeutic approach for P-AIP. In fact, most previous published case series have relied on adult criteria for P-AIP management decisions. In our recent study we, however, recognized differences in the clinical presentation and the disease course in children compared to adults. Furthermore, we evidenced wide variations in diagnosis and management of P-AIP between pediatric centers.
To resolve these issues, we have now made use of the expertise of a large panel of pediatric pancreatologists to develop pediatric-focused clinical recommendations for the definition, diagnosis, and treatment approach of P-AIP based on our previously collected data on the disease. We addressed gaps in knowledge and research needs that require further investigation.
METHODS
INSPPIRE is the first and largest international multicenter effort studying children with acute recurrent and chronic pancreatitis. INSPPIRE has enrolled more than 400 patients with acute recurrent and chronic pancreatitis since 2012, from 22 different sites worldwide with the goal to study the risk factors, natural history, and outcome of the disorders in children (3).
A working group within INSPPIRE was created in July 2015 with the following members: I.S., J.J.P., S.F., M.W., U.S., A.U., and T.G. They were tasked with the critical review of the literature and development of recommendations for P-AIP.
The first part of the project was focused on summarizing the actual clinical experience about AIP in children (2).
The working group then developed a working definition as well as diagnostic and therapeutic recommendations for P-AIP as follows: the INSPPIRE P-AIP working group drafted 15 statements including definition, diagnosis, and management of P-AIP following the review and appraisal of our collected data; The statements were presented to a panel of 30 pediatric gastroenterologists, all within the INSPPIRE group and having a special interest and/or expertise in pediatric pancreatology for review and discussion; and 25 panel members participated in the voting process (agree/disagree) and offered comments as necessary. The percentage of agreement on each statement was reported to the panel members. Statements with <80% agreement were discussed, revised and then recirculated for a second vote. Statements 8 and 9 were edited and underwent a 3rd vote to respond to input and discussions from the panel.
RESULTS
Working Definition of Autoimmune Pancreatitis
There has been increasing awareness of AIP in children over the years; however, it is still difficult to unambiguously diagnose P-AIP. The panel members agreed on a specific pediatric working definition as P-AIP has distinct features compared to adults.
Clinical Presentation of Pediatric Autoimmune Pancreatitis
Although A-AIP mainly presents with painless jaundice, children with AIP often complain about abdominal pain and/or jaundice (2). Other common signs in children include weight loss, fatigue, and vomiting.
Diagnosis of Autoimmune Pancreatitis in Children
Interestingly, serum pancreatic enzyme levels do not always support the diagnosis of P-AIP as amylase and lipase may be normal at the time of diagnosis in 46% to 57% of children (2). Although increased serum levels of IgG4 have a high diagnostic value for A-AIP (positive in 68%–92% in AIP type 1 (4) and 25% (5,6) in AIP type 2, elevated IgG4 levels are uncommon in children (22%) (2). Other autoantibodies have been identified in A-AIP, such as antibodies to carbonic anhydrase II or lactoferrin (7). These have not been systematically studied in the pediatric population.
Transabdominal ultrasound (TUS) is an important first-line tool for pancreatic imaging in children. This technique is sufficiently sensitive in evaluating pancreatic enlargement or mass formation and rule out other causes of obstructive jaundice. TUS has several limitations including difficulty to visualize the pancreas due to intestinal gas, obesity, and operator dependency for interpretation (8). Specific P-AIP findings on imaging (eg, capsule-like rim, main pancreatic duct irregularity, common bile duct tapering within an enlarged pancreatic head—Fig. 1) are best appreciated by magnetic resonance cholangiopancreatography (MRCP). Therefore, if AIP is suspected or when TUS resolution is limited, MRCP should be obtained even in young children who will require sedation for the study (9).
Two types of AIP are distinguished in adults: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct–centric pancreatitis (AIP type 2). We found that in P-AIP histopathological features of both types (granulocytic epithelial lesions and lymphoplasmacytes) are often present.
The need for pancreatic histopathology to establish the diagnosis of P-AIP and the use of papilla biopsies to evaluate for IgG4-positive plasma cells generated most of the discussion among the panel members. A histopathological diagnosis is the criterion standard for all inflammatory gastrointestinal diseases. Similarly, the diagnosis of P-AIP should ideally be confirmed by the well-described and pathognomonic histopathological features of P-AIP in a pancreas tissue specimen.
Endoscopic ultrasound (EUS)-guided pancreatic biopsies may be used to obtain specimens from children. Procedure-related complications have not been systematically evaluated in children but are low in adults (0%–2%) (10).
There may be several barriers that limit systematic realization of pancreatic biopsies in children: there are only a handful pediatric endoscopists trained to perform EUS (11), there is limited expertise in interpretation of pediatric pancreatic histopathology, and it is challenging to obtain adequate pancreatic tissue with the currently available biopsy needles (12,13).
In adults, pancreatic biopsies are necessary not only to diagnose AIP, but most importantly to rule out cancer. Because of the difficulty to diagnose AIP on a biopsy sample, increased recognition of AIP clinically and with imaging, adult gastroenterologists often skip the biopsy and start a trial with corticosteroids, which itself is used as a diagnostic criterion to confirm AIP (5,6).
Papilla biopsies are found to be less sensitive than EUS-guided pancreatic biopsies in adult studies (65% vs 79%) (14). This has never been evaluated in children.
Therapeutic Options for Autoimmune Pancreatitis and Response to Therapy
The current literature on P-AIP favors the use of corticosteroids (methylprednisolone or prednisolone) as the first-line therapy. Nevertheless, the effectiveness of any therapy has to be put in perspective with other studies reporting spontaneous resolution without any treatment (2). Further studies analyzing the short- and long-term outcomes of patients receiving medical treatments compared to a wait-and-see approach will be important to understand the true role of steroids in AIP. This is particularly important for children in whom corticosteroid therapy always bears the risk of growth restriction.
Response to corticosteroid therapy should be evaluated based on improvement or resolution of clinical symptom such as reduction in abdominal pain, jaundice, and improvement of pancreatic function tests. Furthermore, therapeutic response also needs to be assessed by repeated imaging with MRCP demonstrating normalization of the pancreas parenchyma such as regression of the pancreatic mass lesion.
There is clinical experience, similar to what has been reported for adults, that some children with AIP will relapse. There is currently no data to favor an immunosuppressant drug over the other for a steroid-sparing maintenance regimen.
Other Organ Involvement
AIP predisposes to the development of other immune/inflammatory disorders (eg, Crohn, ulcerative colitis, celiac disease, etc). It is therefore reasonable to rule out other immune-mediated diseases in the presence of suggestive symptoms.
Mid- and Long-term Outcome of Autoimmune Pancreatitis
The natural history of P-AIP is unknown. Approximately 25% of children relapse over time (2), but there are no prospective and longitudinal studies of P-AIP patients to predict outcome.
AIP predisposes children to EPI and diabetes, with a short-term frequency of 17% and 11%, respectively (2). Diabetes mellitus can be transient in some patients (15). Ongoing chronic inflammation may favor the development of pancreatic cancer in the future. The voting panel members felt strongly that follow-up of P-AIP patients beyond childhood are essential to identify possible long-term complications.
CONCLUSION AND FUTURE GOALS
AIP is a very rare and distinct type of pancreatitis. In recent years, the disease of P-AIP has been increasingly recognized but many questions remain regarding its physiopathology, diagnosis, and treatment. In this article, we have provided a working definition of the disease and recommendations for the diagnosis and therapy of P-AIP. Our goal was to provide a standardized approach to diagnose, treat, and follow patients with P-AIP, bring uniformity to patient care and facilitate future research.
In this work, we have made use of the collective clinical experience of P-AIP that we have published earlier, and have brought together pediatric pancreatologists from our international pancreatitis consortium to establish level III evidence statements for P-AIP.
Further questions that need to be addressed in the future include understanding the natural history of P-AIP, identifying specific biomarkers of the disease, identifying new diagnostic tools, defining the best therapeutic approaches, and develop tools to predict functional outcome.
We hope that these recommendations will be useful to the clinicians and researchers worldwide, enable collaborations and prospective clinical studies to gain further insights into this rare disease entity. As clinical experience broadens and gaps in research are filled, we expect that our recommendations will evolve over time to further improve the care of our pediatric patients.
REFERENCES
1. 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: 890–896.e1.
2. Scheers I, Palermo JJ, Freedman S, et al. Autoimmune pancreatitis in children: characteristic features, diagnosis, and management.
Am J Gastroenterol 2017; 112:1612.
3. Morinville VD, Lowe ME, Ahuja M, et al. Design and implementation of INSPPIRE.
J Pediatr Gastroenterol Nutr 2014; 59:360–364.
4. Okazaki K, Kawa S, Kamisawa T, et al. Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis.
J Gastroenterol 2014; 49:567–588.
5. Hart PA, Zen Y, Chari ST. Recent advances in autoimmune pancreatitis.
Gastroenterology 2015; 149:39–51.
6. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology.
Pancreas 2011; 40:352–358.
7. Okazaki K, Uchida K, Ohana M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response.
Gastroenterology 2000; 118:573–581.
8. Lin TK, Troendle DM, Wallihan DB, et al. Specialized imaging and procedures in pediatric pancreatology: a North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Clinical Report.
J Pediatr Gastroenterol Nutr 2017; 64:472–484.
9. Refaat R, Harth M, Proschek P, et al. Autoimmune pancreatitis in an 11-year-old boy.
Pediatr Radiol 2009; 39:389–392.
10. Adler DG, Jacobson BC, Davila RE, et al. ASGE guideline: complications of EUS.
Gastrointest Endosc 2005; 61:8–12.
11. Scheers I, Ergun M, Aouattah T, et al. Diagnostic and therapeutic roles of endoscopic ultrasound in pediatric pancreaticobiliary disorders.
J Pediatr Gastroenterol Nutr 2015; 61:238–247.
12. Detlefsen S, Mohr Drewes A, Vyberg M, et al. Diagnosis of autoimmune pancreatitis by core needle biopsy: application of six microscopic criteria.
Virchows Arch 2009; 454:531–539.
13. Zhang L, Chari S, Smyrk TC, et al. Autoimmune pancreatitis (AIP) type 1 and type 2: an international consensus study on histopathologic diagnostic criteria.
Pancreas 2011; 40:1172–1179.
14. Jung JG, Lee JK, Lee KH, et al. Comparison of endoscopic retrograde cholangiopancreatography with papillary biopsy and endoscopic ultrasound-guided pancreatic biopsy in the diagnosis of autoimmune pancreatitis.
Pancreatology 2015; 15:259–264.
15. Lurz E, Gonska T. Pancreatic head mass leading to transient obstructive jaundice and diabetes mellitus in an adolescent.
Gastroenterology 2015; 149:e9–e10.
