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Natural history of pancreatic involvement in paediatric inflammatory bowel disease

Digestive and Liver Disease, 5, 47, pages 384 - 389

Abstract

Background

Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease.

Aim

To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia.

Methods

We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year.

Results

From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis (p = 0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia.

Conclusions

In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve.

Keywords: Amylase, Crohn's disease, Lipase, Pancreas, Pancreatitis, Ulcerative colitis.

1. Introduction

Inflammatory bowel disease (IBD), characterized by chronic, relapsing immune-mediated inflammation of the gastrointestinal tract is often associated with extra-intestinal manifestations (EIMs) affecting multiple organs. EIM are reported to occur in 18–47% of paediatric and adult patients with IBD[1], [2], [3], [4], and [5]. Acute and chronic pancreatitis as well as pancreatic insufficiency have been reported as one of EIMs in IBD [6] .

Acute pancreatitis (AP) in children is a costly and increasingly recognized disease. Several studies have documented an increase during the past 10–15 years [7] . Estimated incidences range from 3.6 to 13.2 cases per 100,000 children per year[8] and [9]. The reasons for the increase are not entirely clear and may be multifactorial. An Australian study suggests that the increasing number is mainly due to the complications of systemic illness [9] . Patients with IBD are at increased risk of developing both acute and chronic pancreatitis. Clinical symptoms of IBD-associated pancreatitis are found in about 2% of patients but the actual frequency of the disease could be much higher. According to several studies, hyperamylasemia and exocrine pancreatic insufficiency are found in 6–16 and 21–80% of adult patients, respectively, whereas histological changes are observed in 38–53% of postmortem pathological examinations[6], [10], [11], and [12]. There are only limited published data on the incidence of acute pancreatitis in paediatric patients with IBD[13] and [14]. Although pancreatitis can be seen in association to drugs assumption, biliary lithiasis, Crohn's disease (CD) duodenal involvement or sclerosing cholangitis, the contribution of these etiological factors to histopathology-proved pancreatitis appears to be low and IBD itself seems to contribute to the pathogenesis [5] . In addition, a previous study also indicates that the rarer variant, autoimmune pancreatitis, occurs more often among IBD patients [15] . Regards to drugs, several case reports about drug-induced pancreatitis have been published [16] . Nevertheless, it is always difficult to establish a causal role for medications in the pathogenesis of pancreatitis, but a few medications are clearly associated with a high risk for drug-induced pancreatitis. This is true with regard to some medications used in IBD management. Of the medications, the possible agents inducing pancreatitis include sulfasalazine, 5-aminosalicylic acid (ASA) compounds, azathioprine (AZA), metronidazole and steroids[17] and [18]. Complicating the scenario it appears that IBD-associated pancreatic involvement may be often a silent disease in children. Various possible explanations for asymptomatic hyperamylasemia and hyperlipasemia in IBD patients have been proposed. The pancreatic enzyme elevation observed in more extensive or active disease can represent the abnormal passage of pancreatic amylase from the gut lumen to the blood due to increased permeability of the inflamed mucosa [19] . In addition, there are several potential mechanisms for the suggested enzyme leakage from the pancreas. First, the pancreas might be affected in some way directly by the extent of IBD. Another explanation could be an enzyme increase related to the pancreatic effects of inflammatory mediators and cytokines released from the inflamed gut. A third mechanism might be associated with inflammation of pancreatic ducts [6] .

Despite scattered case reports, the relationship between pancreatic involvement and IBD has not been further investigated. The primary aim of the present study was to investigate prevalence and disease course of paediatric IBD patients presenting with pancreatitis; secondary aim was to evaluate the clinical significance of exclusive hyperamylasemia and hyperlipasemia in children with IBD.

2. Subjects and methods

We retrospectively reviewed data collected in the IBD web-registry of the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Paediatric gastroenterologists from all the Italian paediatric IBD centers belonging to the SIGENP, established in 2008 a prospective registry to collect demographic, clinical, and epidemiologic data from paediatric patients with IBD. The registry started the 1st January 2009 and included patients less than 18 years with a new diagnosis of IBD. Data of all paediatric patients enrolled and stored in the registry from January 1, 2009 to November 30, 2012 (data retrieval date) were used for this study. Nine sites participated to this study; trained investigators at each centre obtained information from the medical records (electronic and paper charts) and standardized information was entered into the registry. Eligible subjects included all patients with any form of IBD [ulcerative colitis (UC), CD and inflammatory bowel disease unclassified (IBD-U)]. Diagnosis of IBD was based on clinical history, physical examination, endoscopic appearance, histologic findings, and radiologic studies, according to Porto criteria [20] . All patients presenting with serum amylase ≥100 IU/L (normal range: 28–100 IU/L) and serum lipase ≥60 IU/L (normal range: 13–60 IU/L) were included in the study. Participants were additionally evaluated within 6 months, and 1 year from enrolment. AP was defined as the presence of 2 of the following criteria: (a) abdominal pain compatible with AP, (b) serum amylase and/or lipase values ≥3 times upper limits of normal, (c) imaging findings of AP [21] . Acute recurrent pancreatitis (ARP) was defined as: ≥2 distinct episodes of AP with intervening return to baseline. The severity of AP episodes was assessed with the Paediatric Acute Pancreatitis Score (PAPS), developed by DeBanto and colleagues [22] . The system has eight parameters, scored at admission and at 48 h. The admission criteria include: age <7 years, weight <23 kg, white blood cell count >18,500/mm3, and LDH > 2000 U/L. The 48-h criteria are trough calcium < 8.3 mg/dl, trough albumin < 2.6 mg/dl, fluid sequestration > 75 ml/kg/48 h, and a rise in BUN > 5 mg/dl. One point is assigned for each criterion met; a score of ≥3 is predictable of a severe course of disease [22] . Chronic pancreatitis (CP) was diagnosed if one of the following criteria was present: (a) typical abdominal pain plus characteristic imaging findings; (b) exocrine insufficiency plus imaging findings; (c) endocrine insufficiency plus imaging findings. Exclusive hyperamylasemia and hyperlipasemia was used to describe those patients who did not meet diagnostic criteria for pancreatitis [20] .

The information retrieved for the purpose of this study included demographic features (age, gender), IBD type (CD, UC, IBD-U), median lag time period between the diagnosis of IBD and pancreatic involvement episodes, and disease location. The disease location at the diagnosis and at follow-up was established by endoscopic and imaging evaluations in all patients according to the availability of individual methods for each centre and reported in the registry. For the purpose of this manuscript, disease location was described according to Paris classification [23] . Disease activity at the diagnosis was scored by the Paediatric Crohn's Disease Activity Index (PCDAI) [24] or the Paediatric Ulcerative Colitis Activity Index (PUCAI) [25] for CD and UC, respectively. Laboratory tests included full blood count, C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), nutritional, renal, and liver function parameters. In addition, pancreatic laboratory studies including serum amylase and lipase, were collected. Data on imaging methods used for the diagnosis of pancreatic involvement including transabdominal ultrasound (US), magnetic resonance cholangiopancreatography (MRCP), abdominal computed tomography scan (CT) or endoscopic retrograde cholangiopancreatography (ERCP), were evaluated. In patients with CP if available, details on genetic testing (CFTR, SPINK1, PRSS1) or on exocrine pancreatic function assessed with the faecal elastase, were recorded. In addition, pancreatic involvement episode characteristics, including drug exposure, severity, complications, in-hospital stay, actions taken post-pancreatic involvement were reported.

Institutional review board approval for the registry protocol and the informed consent and assent forms were obtained at each site before subject enrolment and data collection. Signed parental and patient informed consent and signed youth assent when appropriate were required from all patients enrolled.

2.1. Statistical analysis

Statistical analysis was performed using SPSS statistical software package for Windows (13.0; SPSS, Chicago, IL). Means and medians were calculated for dimensional variables after controlling for normality of distribution. Categorical data were expressed as frequencies and percentages. The Student'st-test and the Mann–Whitney test for continuous variables and theχ2and Fisher's exact tests for categorical variables were used where appropriate. Apvalue of 0.05 or less was considered significant.

3. Results

3.1. Patients characteristics

From 2009 to 2012 we identified 649 paediatric patients with a diagnosis of IBD, of whom 27 met the inclusion criteria and were enrolled in the study (4.1%, Fig. 1 ). Demographic and clinical characteristics for the study group are reported in Table 1 . Median lag time between the diagnosis of IBD and pancreatic involvement was 7 months (range 0–65 months). In 5/27 children (18.5%), pancreatic involvement was present at time of IBD diagnosis ( Table 2 ). Median serum amylase level was 196 (range 61–413 IU/L), and median serum lipase level was 299 (range 37–2565 IU/L). Eleven patients (40.7%) fulfilled diagnostic criteria for AP (6 CD, 4 UC, 1 IBD-U). On the basis of PAPS all 11 patients presented with an episode of mild AP ( Table 3 ). The remaining 16 patients (60.3%) presented with exclusive hyperamylasemia and hyperlipasemia. Median serum amylase level and median serum lipase level were significantly higher in AP patients compared with patients with exclusive hyperamylasemia and/or hyperlipasemia (p = 0.009 andp = 0.001 respectively; Table 2 ). Comparing the total IBD registry population with patients with pancreatic involvement, female gender resulted to be significantly associated with AP (p = 0.04; OR: 4.8; 95% confidence interval 1–22), whereas no significant difference in gender was observed in patients with exclusive hyperamylasemia and/or hyperlipasemia (p = 0.7). IBD type, ongoing treatments, and extension of disease were not significant risk factors when comparing patients with hyperamylasemia/hyperlipasemia and children with AP ( Table 2 ). Twenty-three patients (85.1%) with pancreatic involvement presented with active disease, but no significant difference was found among children with exclusive hyperamylasemia and/or hyperlipasemia and subjects with AP (p = 0.6; Table 2 ). Twenty-five patients (92.5%) with pancreatic involvement had colonic disease [11 CD, 12 UC and 2 IBDU]. Eight of the 12 children with UC and pancreatic involvement (66.6%) were affected by pancolitis ( Table 2 ). Regarding symptoms associated with pancreatic involvement, 21 patients (77.8%) reported epigastric pain as the dominant clinical characteristic, followed by nausea and/or vomiting (22.2%), and fever (22.2%). No patient experienced jaundice. No statistical significant difference was observed when comparing symptoms in patients with exclusive increase of pancreatic enzymes and AP ( Table 2 ).

gr1

Fig. 1 Prevalence of pancreatic involvement in different inflammatory bowel disease type. CD: Crohn's disease; UC: ulcerative colitis; IBD-U: unclassified-IBD; NPE: normal pancreatic enzymes; PI: pancreatic involvement.

Table 1 Baseline characteristics of 27 inflammatory bowel disease children with pancreatic involvement.

Characteristics
 Patients (N) 27
 Median age (years; range) 12.3 (5.4–15.9)
 PI onset (years; range) 12.2 (0–65)
 Gender (N, %)
  Males 13/27 (48.1)
 IBD type (N, %)
  CD 13/27 (48.2)
  UC 12/27 (44.4)
  IBD-U 2/27 (7.4)
 Paris classification
  CD (N, %)
   Ileum only (L1) 2/13 (15.3)
   Colon only (L2) 0/13 (0)
   Ileum and colon (L3) 11/13 (84.6)
   Upper gastrointestinal tract (L4a) 5/13 (38.4)
  UC (N, %)
   Proctosigmoiditis (E1) 2/12 (16.6)
   Left-sided colitis (E2) 2/12 (16.6)
   Extensive colitis (E3) 2/12 (16.6)
   Pancolitis (E4) 6/12 (50)
 IBD therapy (N, %)
  5-ASA 16/27 (59.3)
  CCS 3/27 (11.1)
  AZT 12/27 (44.4)
  MTX 1/27 (3.7)
  Biologic therapy 2/27 (7.4)

PI: pancreatic involvement; CD: Crohn's disease; UC: ulcerative colitis; IBD-U: unclassified-IBD; 5-ASA: 5-aminosalicylic acid; CCS: corticosteroids; AZT: azathioprine; MTX: methotrexate.

Table 2 Clinical differences between patients with exclusive hyperamylasemia/hyperlipasemia and acute pancreatitis.

Characteristics Exclusive HA/HL Pancreatitis p
  n = 16 n = 11  
Median age (years; range) 14 (6–17) 14.4 (10–16.7) 0.07
Gender     0.01
 Males 11 (68.8) 2 (18.2)  
 Females 5 (31.2) 9 (81.8)  
PI at IBD disease onset 2 (18.2) 3 (18.8) 1
Symptoms
 Epigastric pain 11 (68.8) 10 (90.9) 0.3
 Fever 2 (12.5) 4 (36.4) 0.2
 Nausea/vomiting 3 (18.3) 3 (27.3) 0.6
Amylase (median, range) 160 (61–320) 248 (150–413) 0.009
Lipase (median, range) 140.5 (37–508) 817 (512–2565) 0.001
IBD type     0.7
 CD 7 (43.7) 6 (54.5)  
 UC 8 (50) 4 (36.3)  
 IBD-U 1 (6.2) 1 (9)  
Median disease duration (months, range) 9 (0–33) 7 (0–65) 0.4
Active disease 13 (81.2) 10 (90.9) 0.6
PUCAI (median, range) 20 (0–45) 22.5 (15–35) 1
PCDAI (median, range) 30 (18–54) 28.7 (10–70) 1
Colonic involvement 16 (100%) 9 (81.8) 0.1
Disease location
 Ileum only (L1) 0 (0) 1 (9) 0.4
 Colon only (L2) 0 (0) 0 (0) 1
 Ileum and colon (L3) 7 (43.7) 4 (36.3) 1
 Upper GI tract (L4a) 1 (6.2) 3 (27.3) 0.1
 Upper GI tract (L4b) 0 (0) 1 (9) 0.4
 Proctosigmoiditis (E1) 1 (6.2) 1 (9) 1
 Left-sided colitis (E2) 1 (6.2) 1 (9) 1
 Extensive colitis (E3) (6.2) 1 (9) 1
 Pancolitis (E4) 5 (31.2) 1 (9) 0.3
IBD therapy
 5-ASA 10 (62.5) 6 (54.5) 0.7
 CCS 3 (18.3) 1 (9) 0.6
 AZT 5 (31.2) 6 (54.5) 0.3
 MTX 0 (0) 1 (9) 0.4
 BIO 2 (12.5) 0 (0) 0.5
Imaging findings     NA
 Enlargement of the head and the body 2 (18.1)  
 Tail and head enlargement 2 (18.1)  
 Diffuse oedema 3 (25)  
 Peripancreatic/pancreatic fluid collections 1 (9)  

5-ASA: 5-aminosalicylic acid; AP: acute pancreatitis; AZT: azathioprine; BIO: biologic therapy; CCS: corticosteroids; CD: Crohn's disease; HA/HL: hyperamylasemia/hyperlipasemia; IBD: inflammatory bowel disease; IBD-U: unclassified-IBD; MTX: methotrexate; PI: pancreatic involvement; PUCAI: Paediatric Ulcerative Colitis Activity Index; PCDAI: Paediatric Crohn's Disease Activity Index; UC: ulcerative colitis.

Table 3 Paediatric acute pancreatitis score criteria.

  Patients with AP
Admission criteria
 Median age (years; range) 14.5 (10–17)
 Median weight (kg, range) 43 (26–63)
 White blood cell count, ×103/mm (median, range) 6.9 (4.1–14.8)
 LDH, U/L (median, range) 377.5 (206–639)
48-h criteria
 Calcium, mg/dl (median, range) 9.4 (8.5–10)
 Albumin, mg/dl (median, range) 4.4 (2.5–4.8)
 Fluid sequestration, ml/kg/48 h (median, range) 18.4 (6–54)
 Rise in BUN, mg/dl (median, range) 3.2 (1.2–6)
Score (N, %)
 0–2 points (mild) 11 (100%)
 3–8 points (severe) 0

BUN: blood urea nitrogen; LDH: lactic dehydrogenase.

3.2. Imaging

All 11 patients with AP underwent abdominal US imaging, 6 also underwent MRCP (54.5%) and 2 a CT scan (18.1%). Pancreatic pathological findings were found in all subjects with AP. Main pancreatic findings were: enlargement of the head and the body (n = 2); tail and head enlargement (n = 2); tail enlargement (n = 3); diffuse oedema (n = 3) and peripancreatic/pancreatic fluid collections (n = 1). Primary sclerosing cholangitis (PSC) was diagnosed in 1 (9%) out of 11 patients. None of the patients with exclusive hyperamylasemia and/or hyperlipasemia showed pathological findings at imaging studies.

3.3. Treatment

Nine patients (33.3%) were receiving mesalamine (5-ASA), 14 (51.8%) were receiving immunomodulatory therapy [1 steroids, 6 AZA, 5 AZA + 5-ASA, 1 methotrexate, 1 infliximab (IFX), and 1 IFX + ASA + AZA], and 4 patients (14.8%) were not treated. Nine of 11 (81.8%) patients with AP needed therapeutic measures compared to only 5/16 patients with serum hyperamylasemia and/or hyperlipasemia (31.2%;p = 0.04). Therapeutic measures in children with AP and hyperamylasemia/hyperlipasemia are reported in Table 4 . None of the patients with AP developed early complications.

Table 4 Therapeutic measures in patients with acute pancreatitis and hyperamylasemia/hyperlipasemia.

Therapeutic measures AP (11) HA/HL (16)
Fasting with rehydration (n, %) 6 (54.5) 0 (0)
Antibiotic therapy (n, %) 3 (27.2) 0 (0)
PPIs (n, %) 1 (9) 0 (0)
Octreotide (n, %) 1 (9) 0 (0)
AZT suspension 5 (45.5) 4 (25)
5-ASA suspension 2 (18.1) 1 (6.3)
None 2 (18.1) 11 (68.7)

AP: acute pancreatitis; HA/HL: exclusive hyperamylasemia/hyperlipasemia; TPN: total parenteral nutrition; PPIs: proton pump inhibitors; AZT: azathioprine; 5-ASA: 5-aminosalicylic acid.

3.4. Natural history

At 6 and 12 months follow-up evaluations, median serum amylase level was 56 (range 8–240 IU/L) and 66.5 (range, 23–480 IU/L), respectively; median serum lipase level was 28 (range 8–633 IU/L) and 51.1 (range, 12–206 IU/L), respectively. Natural history of pancreatic involvement is reported in Fig. 2 .

gr2

Fig. 2 Natural history of 27 children with inflammatory bowel disease and pancreatic involvement at one-year follow-up. AP: acute pancreatitis; ARP: acute recurrent pancreatitis; CP: chronic pancreatitis; HA/HL: hyperamylasemia/hyperlipasemia; IBD: inflammatory bowel disease; NPE: normal pancreatic enzymes; PI: pancreatic involvement; T0: baseline; T6: 6 months; T12: 12 months.

3.4.1. Acute pancreatitis

At 6 months of follow-up 1/11 children with AP (9%) was diagnosed with ARP, while 1 patient presented with hyperamylasemia/hyperlipasemia. At 6 months, patients presenting with recurrent pancreatic involvement showed higher values of PUCAI/PCDAI scores compared with the remaining patients with a trend towards statistical significance (median: 17.5 vs. 5; range: 0–47.5;p = 0.07). At 12 months follow-up 10 patients (90.9%) had a remission from AP, while 1 patient (9.1%) showed laboratory and radiological signs of CP with reduced faecal elastase. The same patient resulted to carry a F1052V CFTR mutation in heterozygosis.

3.4.2. Hyperamylasemia/hyperlipasemia

At 6 months follow-up 4/16 children with exclusive increase of pancreatic enzymes developed AP (25%), while 1 (6.2%) still presented hyperamylasemia/hyperlipasemia. At 12 months follow-up, 11/16 patients (68.7%) reached a complete remission of pancreatic involvement, whereas in the 5 remaining patients (32.3%) exclusive hyperamylasemia/hyperlipasemia persisted. At 12 months, patients with recurrent pancreatic involvement had higher PUCAI/PCDAI scores compared to children who did not, without reaching statistical significance (median: 13 vs. 5; range: 0–30;p = 0.08).

4. Discussion

IBD patients are affected by an increased incidence of pancreatic involvement, including AP and exclusive hyperamylasemia/hyperlipasemia, when compared with the general population [26] . The incidence of pancreatic involvement varies widely in IBD adult patients, ranging from 5% to 21%[6] and [11]. A possible explanation for this wide range is that diagnosis of mild disease may be easily missed. There are only limited and not recent published data on the incidence of pancreatic involvement in paediatric patients with IBD. To the best of our knowledge our paper represents the first paediatric multicentre IBD registry-based study, characterizing the natural history of pancreatic involvement. Consistent with the published literature in the present cohort, the prevalence of pancreatic involvement was 4.1% and AP was diagnosed in 1.6% of cases.

The question of whether pancreatitis is an EIM of IBD remains unclear [26] . The aetiology and pathogenesis of AP are elusive and seem to be multifactorial in the majority of IBD patients. It is possible that epithelial cells of the gastrointestinal tract and pancreatic tissue may share similar target molecular or cellular structures vulnerable to injury. To support this hypothesis in our cohort of patients AP was present at IBD onset in 18%, suggesting that in some cases pancreatic dysfunction is part of a common immune disorder. The mouse model of trinitrobenzene sulfonic acid-induced colitis was shown to have concurrent pancreatic lesions [27] . Nausea and vomiting as associated features often suggest a diagnosis of acute or chronic pancreatitis. More often in CD than in UC, recurrent abdominal pain is the presenting feature [18] . Unfortunately, an elevation of serum amylase and lipase without symptoms or signs of pancreatitis is more frequent in IBD patients than in controls[6] and [11]. Various hypotheses for exclusive hyperamylasemia and hyperlipasemia in IBD patients have been proposed and are still matter of discussion [19] . Complicating the picture, symptoms of pancreatitis often overlap with IBD flares. Indeed abdominal pain in an episode of pancreatitis may be falsely attributed to active IBD and serum levels of amylase or lipase never tested resulting in an underestimation of AP incidence [18] . According to this finding, in our cohort of patients symptoms were not able to discriminate patients with exclusive increase of pancreatic enzymes from patients with AP, suggesting that pancreatic imaging should be routinely evaluated in IBD patients.

AP in adults has been reported much more commonly in CD than in UC [18] . As previously described in paediatric literature, in our study AP incidence was not different according to the IBD type, either CD or UC [13] . The relationships between pancreatitis and the extent and severity of the disease led to controversial conclusions in the recent literature [10] . According to Heikius et al. who demonstrated a correlation between the lipase increase and the histological activity of the disease, 91% of our patients with pancreatic involvement presented active disease [6] . Furthermore, patients with recurrent episodes of AP and hyperamylasemia/hyperlipasemia showed higher PCDAI/PUCAI scores at 6 and 12 months. These data may suggest that pancreatic involvement could be strictly related to the activity of disease at least in a subset of patients.

Interestingly, the majority of our patients with CD and AP showed a colonic involvement, as previously described [13] . Nevertheless, It is well known that paediatric patients with CD present with more colonic involvement [28] . The association between colonic disease and AP remains obscure. One possible explanation may be that the colon is considered a major source of the bacteria causing pancreatic necrosis in AP. Supporting this hypothesis subtotal colectomy before AP in rats was found to reduce mortality [29] .

Female gender resulted to be significantly associated with the onset of pancreatitis in our patients, also when comparing with the total IBD registry population. Bermejo et al. reported that female gender was a risk factor for AZA/Mercaptopurine-associated acute pancreatitis [30] . Female predominance in the majority of autoimmune disorders may be one of the possible explanations.

Among IBD children with pancreatic involvement needing therapeutic measures, 85% of subjects withdrew AZA and/or suspended ASA. Indeed, AP is a well-recognized adverse effect occurring in 2–4% of IBD patients receiving thiopurines and it is usually considered as an absolute contraindication to reintroduction of a thiopurine[30], [31], and [32]. However, the actual impact of thiopurines in AP episodes of IBD children is still questioned. In fact, pancreatic involvement is much rarer or not associated with AZA therapy in many other conditions, including rheumatoid arthritis, systemic lupus erythematosus, or in post-transplant patients [33] . This finding may suggest that AP could be more likely IBD-related rather than drug induced. Concerning mesalazine, its association with AP remains controversial. Munk et al. found no increased risk for mesalazine using data from a Danish hospital discharge registry [34] . In contrast, the UK study on AP mentioned above showed a nine-fold increased risk in patients receiving mesalazine up to 3 months before the onset of the disease [35] .

No paediatric data are reported about the clinical course of IBD patients with AP. Although in all our cases the severity of AP episodes was mild and self-limiting, some of them tend to recur during the follow up. Furthermore, in our cohort, at one-year follow-up, one showed a rapid evolution towards CP and consequent pancreatic insufficiency, suggesting that, in a subgroup of IBD patients, pancreatic dysfunction has an unfavourable course. However, the severe evolution of the patient developing CP may be partially explained by the concomitant CFTR mutation in heterozygosis, not causing cystic fibrosis, but associated with pancreatic disorders in a subgroup of patients [36] . This finding highlights the need for checking other causes of pancreatic involvement in IBD children. Although the clinical significance of exclusive hyperamylasemia/hyperlipasemia has been questioned, the natural history of our patients seems not to be always benign. In our cohort, at 6 months follow-up, 25% of children with exclusive increase of pancreatic enzymes at the enrolment developed AP and at 12 months follow-up, 32.3% had persistent hyperamylasemia/hyperlipasemia.

Our study has some limitations besides the retrospective nature. Firstly, we did not have a control group of patients with AP without IBD; second, we did not evaluate serological markers of autoimmune pancreatitis. One could argue that the number of IBD patients with pancreatic involvement is too small to draw definitive conclusions; furthermore, in this subset of patients it is difficult to clearly define the aetiology of AP, as IBD itself is a predisposing factor, and development of pancreatitis is certainly multifactorial. Nevertheless our data, based on a large paediatric IBD population, highlight once again that pancreatic involvement has a relatively low prevalence.

In conclusion, this multicentre, retrospective registry-based study suggests that prevalence of AP in children is similar to that reported in adults. AP is more common in colonic disease and female gender seems to be significantly associated with the development of AP in IBD children. This study underlines that specific attention has to be paid to the monitoring of pancreatic function in IBD children, considering that in a proportion of patients the pancreatic involvement tends to persist and in some cases pancreatic damage may evolve. Future studies on the pathogenesis of pancreatitis and its relationship to the long-term outcome in IBD are required.

Conflict of interest

None declared.

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Footnotes

a Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy

b Pediatric Gastroenterology Unit, Spirito Santo Hospital, Pescara, Italy

c Endoscopy and Gastroenterology Unit, Department of Pediatrics, University of Messina, Italy

d Department of Pediatrics, Unit of Gastroenterology, University Hospital of Padova, Italy

e Gastroenterology and Endoscopy Unit, G. Gaslini Institute for Children, Genoa, Italy

f Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Italy

g Division of Pediatrics, General Hospital I.R.C.C.S., S. G. Rotondo (Fg), Italy

h Pediatric Unit, Maggiore Hospital, Bologna, Italy

i Department of Pediatrics, University of Insubria, Varese, Italy

lowast Corresponding author at: Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Via S. Pansini, 5, 80131 Naples, Italy. Tel.: +39 081 7464565; fax: +39 081 7464565.