Dear Editor,
Chronic pancreatitis (CP) is an inflammatory disease resulting in irreversible changes in the pancreas including acinar cell loss, fibrosis, ductal changes and calcifications [1]. Patients with CP suffer from abdominal pain and complications of exocrine pancreatic insufficiency (EPI) and diabetes mellitus [2]. Due to significant implications on child health and well-being, it is essential that childhood CP is recognized early, and sequalae are treated promptly [3].
Our INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) study includes children with CP but did not report previous episodes of acute pancreatitis (AP) prior their enrollment. Here, we report the risk factors and clinical phenotypes of children enrolled in INSPPIRE who present “silent CP” [1,4].
Our study design included data collection utilizing patient/parent and physician questionnaires from children who fulfilled the criteria for CP at nineteen INSPPIRE centers and were ≤19 years of age at the time of enrollment [4,5]. INSPPIRE criteria were used for the diagnosis of AP, ARP and CP as previously reported [1,4]. Patients were grouped in the “traditional CP” cohort “ if they reported any history of AP prior to their CP diagnosis, and in “silent CP” cohort, if they did not.
Summary statistics were presented as mean with standard deviation (SD), median with interquartile range (IQR), or frequency count with percentage. Subject characteristics, risks and clinical variables were compared between children with CP and no prior AP or ARP (silent CP, n = 20) and children with CP and AP or ARP episodes prior (traditional CP, n = 185). A p-value <0.05 was considered statistically significant.
Among 205 children with CP, 185 had traditional CP (90%), 20 silent CP (10%). These two groups were not different in age, sex, race, ethnicity or age at diagnosis of CP (Table 1).
Table 1.
Demographics and clinical characteristics of patients’ groups.
| Variables | Silent CP (n = 20) | Traditional CP (n = 185) | p-value |
|---|---|---|---|
| Sex (Female) | 13 (65%) | 105/184 (57%) | 0.495 |
| Ethnicity (Hispanic) | 3/18 (17%) | 31/168 (18%) | 1.0 |
| Race | (n = 17) | (n = 162) | 0.316 |
| White | 15(88%) | 131 (81%) | |
| Multi-racial | 0 (0%) | 11 (7%) | |
| African American | 0 (0%) | 7(4%) | |
| Asian | 2 (12%) | 7 (4%) | |
| Other | 0 (0%) | 6 (4%) | |
| Age at first diagnosis | (n = 175) | 0.162 | |
| Mean (SD) | 10.0 (3.2) | 8.6 (4.6) | |
| Range | 5.3–16.3 | 1.0–17.4 |
Subjects in both groups had genetic risk factors (PRSS1, SPINK 1, CFTR, and CTRC), but the differences between the groups were not statistically significant (Table 2). Likewise, the family history of AP or CP, and obstructive and environmental risk factors were also not different. Children with silent CP were more likely to have autoimmune pancreatitis (AIP) compared to traditional CP (20% vs 3%, p = 0.008) (Table 2). Other autoimmune diseases and inflammatory bowel disease (IBD) were not different between the groups.
Table 2.
Risk factors of CP.
| Variables | Silent CP | Traditional CP | p-value |
|---|---|---|---|
| (n = 20) | (n = 185) | ||
| Family history | |||
| Acute pancreatitis | 4/16 (25%) | 45/145 (31%) | 0.778 |
| Chronic pancreatitis | 5/18 (28%) | 49/151 (32%) | 1.0 |
| Genetic Risk Factors: | |||
| PRSS1 | 9/15 (60%) | 66/153 (43%) | 0.210 |
| SPINK1 | 2/14 (14%) | 34/136 (25%) | 0.520 |
| CFTR | 3/14 (21%) | 48/147 (33%) | 0.551 |
| CTRC | 0/7 (0%) | 6/95 (6%) | 1.0 |
| Obstructive factors | 6 (30%) | 54/184 (29%) | 0.952 |
| Pancreas divisum | 2/19 (11%) | 23/181 (13%) | 1.0 |
| Risk factors | |||
| Alcoholic | 1 (5%) | 4/184 (2%) | 0.406 |
| Active smoker | 1 (5%) | 2/184 (1%) | 0.267 |
| Passive smoking exposure | 3 (15%) | 12/179 (7%) | 0.180 |
| Hyperlipidemia | 0/18 (0%) | 5/159 (3%) | 1.0 |
| Medications | 1/18 (6%) | 10/173 (6%) | 1.0 |
| Autoimmune pancreatitis | 4 (20%) | 4/144 (3%) | 0.008 |
| Other autoimmune diseases | 1/19 (5%) | 12/177 (7%) | 1.0 |
| Ulcerative colitis | 0/19 (0%) | 2/177 (1%) | 1.0 |
| Indeterminate colitis/IBD-U | 0/19 (0%) | 1/176 (1%) | 1.0 |
Cationic trypsinogen (PRSS1), Serine Protease Inhibitor Kazal-Type1 (SPINK1), Cystic fibrosis transmembrane regulator (CFTR) and Chymotrypsin receptor C (CTRC).
Table 3 summarizes all imaging findings for ERCP, Computed tomography (CT), Magnetic resonance imaging (MRI/MRCP) and Endoscopic Ultrasound (EUS) during the course of their disease. Results were consistent with imaging findings typical of CP including duct irregularities, pancreatic atrophy, duct dilatation, and calcifications. Findings consistent with acute inflammatory changes in the pancreas were found in both silent and traditional CP if an imaging study was done at initial presentation or at a subsequent evaluation. Ductal stones were significantly more common in silent CP compared to traditional CP (10/18 [56%] vs 49/161 [30%]; p = 0.032); no other differences were observed.
Table 3.
Imaging findings.
| Variables | Silent CP | Traditional CP | p-value |
|---|---|---|---|
| (n = 20) | (n = 185) | ||
| Imaging studies performed ERCP | 14 (70%) | 129 (70%) | 1.0 |
| Number ERCP (range) | (1–7) | (1–9) | |
| 1 | 9 | 67 | |
| 2 | 2 | 31 | |
| 3 | 1 | 13 | |
| ≥4 | 2 | 18 | |
| CT scan | 11 (55%) | 102 (55%) | 0.991 |
| MRI (not performed with MRCP) | 3 (15%) | 59 (32%) | 0.118 |
| MRCP | 14 (70%) | 155 (84%) | 0.130 |
| EUS | 4 (20%) | 32 (17%) | 0.759 |
| Findings (CT/MRI) | |||
| Focal Acute Pancreatitis | 3/15 (20%) | 24/153 (16%) | 0.712 |
| Inflammatory changes in Pancreas | 6/16 (38%) | 57/153 (37%) | 0.985 |
| Pancreatic Gland Enlargement | 2/16 (12%) | 25/154 (16%) | 1.0 |
| Pancreatic Atrophy Present | 10/16 (62%) | 67/155 (43%) | 0.140 |
| Calcifications in Pancreas present | 4/16 (25%) | 24/154 (16%) | 0.306 |
| Duct Irregularities | 11/15 (73%) | 89/153 (58%) | 0.254 |
| Pancreatic duct dilatation present | 11/16 (69%) | 93/153 (61%) | 0.533 |
| Lesions present in the pancreas | 2/16 (12%) | 5/158 (3%) | 0.127 |
| Gallstones/Sludge | 1/15 (7%) | 11/156 (7%) | 1.0 |
| Intrahepatic biliary dilatation | 3/16 (19%) | 13/154 (8%) | 0.178 |
| Changes suggestive of cirrhosis and/or portal hypertension | 1/15 (7%) | 9/154 (6%) | 1.0 |
| Findings (CT/MRI/MRCP/ERCP) | |||
| Pancreatic duct obstruction (stricture) | 5/19 (26%) | 67/175 (38%) | 0.305 |
| CBD stricture (Intrapancreatic portion) | 3 (15%) | 9/177 (5%) | 0.109 |
| Dilated CBD | 3/19 (16%) | 40/178 (22%) | 0.770 |
| CBD Stone | 2 (10%) | 10/178 (6%) | 0.347 |
| Findings (CT/MRI/EUS) | |||
| Peripancreatic inflammation/fat stranding | 3/16 (19%) | 58/154 (38%) | 0.133 |
| Findings (CT/MRI/MRCP/ERCP/EUS) | |||
| Cysts/Pseudocysts | 4 (20%) | 41/178 (23%) | 1.0 |
| Findings (MRCP/ERCP) | |||
| Main Pancreatic Duct - Abnormal | 15/18 (83%) | 135/168 (80%) | 1.0 |
| Abnormal Side Branches | 8/18 (44%) | 77/157 (49%) | 0.712 |
| Intraductal filling defects of Calculi | 10/18 (56%) | 49/161 (30%) | 0.032 |
| Pancreas Divisum | 3/18 (17%) | 24/163 (15%) | 0.736 |
Magnetic resonance cholangiopancreatography (MRCP), Endoscopic retrograde cholangiopancreatography (ERCP), Computed tomography (CT), Endoscopic Ultrasound (EUS).
Medical therapy including pancreatic enzymes, pain medications, antioxidants, steroids, and diabetes medications was utilized in 13 of 20 (65%) of the silent CP patients and 126 of 185 (71%) traditional CP patients (Table 4). Corticosteroids were more commonly used in the silent CP group (3/18 [17%]) compared to the traditional CP (4/166 [2%], p = 0.022) probably reflecting the increased proportion of AIP in the silent CP group. Overall, no other significant differences were observed in the frequency of endoscopic or surgical therapies between the groups.
Table 4.
Treatment modalities.
| Variables | Silent CP | Traditional CP | p-value |
|---|---|---|---|
| (n = 20) | (n = 185) | ||
| Medical therapies (from provider response) | 13 (65%) | 126/178 (71%) | 0.592 |
| Medications (from patient response) | |||
| Pain medications | 5/17 (29%) | 81/166 (49%) | 0.127 |
| Pancreatic enzymes | 7/18 (39%) | 95/166 (57%) | 0.137 |
| Vitamins/anti-oxidants | 7/18 (39%) | 81/166 (49%) | 0.424 |
| Steroids | 3/18 (17%) | 4/166 (2%) | 0.022 |
| Diabetic medications | 0/18 (0%) | 18/167 (11%) | 0.224 |
| Medication helpful in controlling/treating pancreatitis (from patient response of those using medication) | |||
| Pain medications helpful | 3/5 (60%) | 47/58 (81%) | 0.273 |
| Pancreatic enzymes helpful | 2/2 (100%) | 43/54 (80%) | – |
| Vitamins/anti-oxidants helpful | 1/5 (20%) | 12/40 (30%) | 1.0 |
| Steroids helpful | – | 3/3 (100%) | – |
| Diabetic medications helpful | – | 6/12 (50%) | – |
| Procedures | |||
| Any ERCP | 14 (70%) | 125/179 (70%) | 0.988 |
| Biliary sphincterotomy | 4 (20%) | 45/172 (26%) | 0.550 |
| Pancreatic sphincterotomy | 9 (45%) | 86/170 (51%) | 0.636 |
| Pancreatic duct stent | 9 (45%) | 75/174 (43%) | 0.871 |
| Biliary stent | 1 (5%) | 14/174 (8%) | 1.0 |
| Pancreatic duct stone removal | 8 (40%) | 40/173 (23%) | 0.107 |
| Surgeries | |||
| Surgical therapies | 4 (20%) | 74/180 (41%) | 0.066 |
| Cholecystectomy | 3 (15%) | 33/180 (18%) | 1.0 |
| Celiac nerve block | 0 (0%) | 6/180 (3%) | 1.0 |
| Cyst/pseudo-cyst operation | 1 (5%) | 9/180 (5%) | 1.0 |
| Lateral pancreatojejunostomy | 0 (0%) | 17/180 (9%) | 0.228 |
| Partial pancreatectomy | 0 (0%) | 4/180 (2%) | 1.0 |
| Total pancreatectomy/islet auto transplant | 3 (15%) | 39/179 (22%) | 0.577 |
Our study demonstrates that CP may occur without prior AP or ARP in children. In the INSPPIRE cohort, one in ten children with CP reported no previous AP episodes. Children with this “silent” presentation are more likely to have AIP, advanced morphological changes, including pancreatic intraductal stones and tendency for chronic pain compared to the traditional presentation. Pediatricians need to be aware of this insidious presentation of CP and consider imaging patients with persistent pain or an episode suggestive of AP. Early recognition of “silent CP” is essential for the timely treatment of underlying causes and associated sequelae.
Funding
Dr. Aliye Uc is supported by the National Institute of Health grants (U01 DK108334, R01 DK118752, R24 DK096518); INSPPIRE registry was developed by CTSA (2UL1 TR000442) and REDCap.
Footnotes
Declaration of competing interest
Dr. Mark Lowe is on the Board of Directors of the National Pancreas Association; receives royalties from Millipore Inc and UpToDate. Dr. Tanja Gonska received a research grant from Vertex Pharmaceuticals. Dr. John Pohl is on the speaker’s bureau for Medical Education Resources, Inc.; Dr. Melena Bellin is a consultant for AbbVie Inc and ARIEL Precision Medicine. Dr. Chee Y. Ooi is a consultant for Vertex Pharmaceuticals. Dr. Sohail Husain owns equity in PrevCon. Dr Michael Wilschanski received a research grant from Vertex Pharmaceuticals, Dr. Aliye Uc is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology. The other authors declare no conflicts of interest.
Contributor Information
Maisam Abu-El-Haija, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Mark Lowe, Washington University School of Medicine, St. Louis, MO, USA.
Bradley Barth, University of Texas Southwestern Medical School, Dallas, TX, USA.
Melena D. Bellin, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA
Douglas S. Fishman, Section of Pediatric Gastroenterology, Hepatology and Nutrition Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
Steve Freedman, Harvard Medical School, Boston, MA, USA.
Cheryl Gariepy, Nationwide Children’s Hospital, Columbus, OH, USA.
Matthew J. Giefer, University of Washington, Seattle Children’s Hospital, Seattle, WA, USA
Tanja Gonska, Hospital for Sick Children, Toronto, ON, Canada.
Melvin B. Heyman, University of California San Francisco, San Francisco, CA, USA
Ryan Himes, Section of Pediatric Gastroenterology, Hepatology and Nutrition Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA.
Sohail Husain, Children’s Hospital; of Pittsburgh, Pittsburgh, PA, USA.
Tom K. Lin, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Quin Liu, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Brian McFerron, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
Veronique Morinville, Montreal Children’s Hospital, McGill University, Montreal, QC, Canada.
Jaimie Nathan, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Chee Y. Ooi, School of Women’s and Children’s Health, Medicine, University of New South Wales and Sydney Children’s Hospital Randwick Sydney, Australia
Emily Perito, University of California San Francisco, San Francisco, CA, USA.
John F. Pohl, University of Utah, Salt Lake City, UT, USA
Sarah Jane Schwarzenberg, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA.
Uzma Shah, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, USA.
David Troendle, University of Texas Southwestern Medical School, Dallas, TX, USA.
Steven Werlin, Medical College of Wisconsin, Milwaukee, WI, USA.
Michael Wilschanski, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Bridget Zimmerman, University of Iowa, Department of Biostatistics, Iowa City, IA, USA.
Aliye Uc, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA, USA.
References
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