Submit a Manuscript: http://www.wjgnet.com/esps/ World J Gastrointest Pathophysiol 2016 August 15; 7(3): 276-282 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 2150-5330 (online) DOI: 10.4291/wjgp.v7.i3.276 © 2016 Baishideng Publishing Group Inc. All rights reserved. MINIREVIEWS Pancreatic disorders in inflammatory bowel disease Filippo Antonini, Raffaele Pezzilli, Lucia Angelelli, Giampiero Macarri Filippo Antonini, Giampiero Macarri, Department of Gastro- acute pancreatitis or chronic pancreatitis has been rec­ enterology, A.Murri Hospital, Polytechnic University of Marche, orded in patients with inflammatory bowel disease (IBD) 63900 Fermo, Italy compared to the general population. Although most of the pancreatitis in patients with IBD seem to be related to Raffaele Pezzilli, Department of Digestive Diseases and Internal biliary lithiasis or drug induced, in some cases pancreatitis Medicine, Sant’Orsola-Malpighi Hospital, 40138 Bologna, Italy were defined as idiopathic, suggesting a direct pancreatic Lucia Angelelli, Medical Oncology, Mazzoni Hospital, 63100 damage in IBD. Pancreatitis and IBD may have similar Ascoli Piceno, Italy presentation therefore a pancreatic disease could not be recognized in patients with Crohn’s disease and ulcerative Author contributions: Antonini F designed the research; Antonini colitis. This review will discuss the most common F and Pezzilli R did the data collection and analyzed the data; pancreatic diseases seen in patients with IBD. Antonini F, Pezzilli R and Angelelli L wrote the paper; Macarri G revised the paper and granted the final approval. Key words: Pancreas; Pancreatitis; Extraintestinal mani­ festations; Exocrine pancreatic insufficiency; Ulcerative Conflict­of­interest statement: The authors declare no conflict colitis; Crohn’s disease; Inflammatory bowel disease of interest. © The Author(s) 2016. Published by Baishideng Publishing Open­Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external Group Inc. All rights reserved. reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, Core tip: Pancreatic disorders are not uncommon in which permits others to distribute, remix, adapt, build upon this patients with inflammatory bowel disease (IBD). The work non-commercially, and license their derivative works on most frequent manifestation is acute pancreatitis (AP). different terms, provided the original work is properly cited and Causes of AP are mainly a concomitant biliary lithiasis or the use is non-commercial. See: http://creativecommons.org/ drugs used in the treatment of IBD. However for some licenses/by-nc/4.0/ IBD­related pancreatitis, idiopathic by definition, where no relationship with lithiasis or drugs can be recognized, a Manuscript source: Invited manuscript direct pancreatic damage would be hypothesized. Correspondence to: Filippo Antonini, MD, Department of Gastroenterology, A.Murri Hospital, Polytechnic University of Marche, Ospedale “A.Murri”, 63900 Fermo, Antonini F, Pezzilli R, Angelelli L, Macarri G. Pancreatic Italy. [email protected] disorders in inflammatory bowel disease. World J Gastrointest Telephone: +39-0734-6252249 Pathophysiol 2016; 7(3): 276-282 Available from: URL: http:// Fax: +39-0734-6252252 www.wjgnet.com/2150-5330/full/v7/i3/276.htm DOI: http:// dx.doi.org/10.4291/wjgp.v7.i3.276 Received: May 24, 2016 Peer­review started: May 25, 2016 First decision: June 17, 2016 Revised: July 8, 2016 Accepted: July 20, 2016 INTRODUCTION Article in press: July 22, 2016 Crohn’s disease and ulcerative colitis are the two major Published online: August 15, 2016 clinically defined forms of inflammatory bowel disease (IBD). Although they affect mainly the bowel, often present with systemic manifestations and involvement of organs other than the gastrointestinal tract. How­ Abstract ever distinguishing between proper extra­intestinal An increased incidence of pancreatic disorders either manifestations (EIMs), i.e., systemic alterations directly WJGP|www.wjgnet.com 276 August 15, 2016|Volume 7|Issue 3| Antonini F et al . Pancreatitis in inflammatory bowel disease related to the disease, and extra­intestinal complications, IBD is the number of communal either clinical features i.e., conditions secondary to metabolic disturbance, either laboratory abnormalities. Two of following three anatomic alterations or side effects of treatment, is not criteria are required to make a diagnosis of AP: (1) always straightforward. Although the most common EIMs typical abdominal pain; (2) threefold or more elevation are mucocutaneous, ophtalmologic, arthritic, hepato­ of serum pancreatic enzymes; and (3) imaging con­ biliary, pulmonary, an increased incidence of pancreatic firming inflammation of the pancreatic gland[14]. How­ disorders either acute pancreatitis (AP) or chronic ever abdominal pain is also one of the cornerstone pancreatitis (CP) has been recorded in patients with IBD in the diagnosis of IBD and also typical symptoms of compared to the general population[1]. The first report of pancreatitis, like nausea, vomiting and diarrhea, may be association between IBD and pancreatitis dates back to present in Crohn’s disease and ulcerative colitis. Moreover 1950, when Ball et al[2] published a post­mortem study of elevation of pancreatic enzymes may be found in pati­ 86 patients with ulcerative colitis where pancreatic lesions ents with IBD with no clinical evidence of pancreatic either macroscopic or microscopic were detected in 14% disease[15]. Therefore an exacerbation of IBD might be and 53% respectively. A similar autopsy study of 39 mistaken for AP and vice versa. patients with Crohn’s disease revealed pancreatic fibrosis [3] in 38% of them . No one of the cases in both studies Etiology had presented with symptoms or signs of pancreatitis, Biliary lithiasis: Incidence of biliary lithiasis increases what suggests pancreatic disease had been subclinical or in IBD compared to the general population, in particular silent. Increasing number of cases of either acute or CP in Crohn’s disease with figures between 13% and 34%, have been reported since[4­7]. where this variability depends either on study design In the pediatric population pancreatic disease is rare either on selection criteria[16­19]. Nonetheless it seems also (0.7%­1.6%) but higher than in the general population. related to site and extension of intestinal disease (distal Incidence of AP is higher in females than in males with vs proximal ileum). Risk of biliary lithiasis is as high as a greater occurrence in those with active and severe three times in patients with extensive ilieal involvement, IBD. Children with IBD also have an increased risk of and this may be explained by a reduced enterohepatic developing CP and asymptomatic hyperamylasemia[8]. circulation as a result of inflammation[18]. In fact, after However most of the pancreatitis in patients with IBD, surgery involving small bowel where the absorbing both adults and children, seem to be related to biliary surface for biliary acids results reduced, incidence of lithiasis or drug induced[9]. biliary lithiasis is about 24%[20]. Drugs: Most of the drugs used to treat IBD may be AP associated with an increased risk of pancreatitis[21­23]. Epidemiology Azathioprine (AZA) and its active metabolite 6­mer­ AP is the most common pancreatic disease associated captopurine have AP as well­known side effect[24­27]. with IBD; it is also the one associated with the highest However other drugs as mesalamine, salazopyrin, morbidity. No definitive data are available regarding metronidazole and steroids are reported to induce pan­ incidence of idiopathic AP in IBD. Figures obtained creatitis[28­35]. Toxic pancreatitis typically arises within the from small series estimate an incidence between 1.2% first weeks of treatment, presents with a mild clinical and 3.1%, higher in Crohn’s disease than in ulcerative course and resolves quickly as soon as the drug is colitis[10,11]. The odd for AP seems to be as high as discontinued[21­23]. A prospective multicentric registration 4.3 and 2.1 times in Crohn’s disease and in ulcerative study has been recently carried out in 510 patients respectively compared to the general population[12]. One with IBD of which 338 with Crohn’s disease, 117 with study including patients with Crohn’s disease after a 10 ulcerative colitis and 15 with unspecified colitis[36]. All years follow up showed a significantly higher incidence of patients were enrolled as soon as they started AZA; AP than in the general population (1.4% vs 0.007%)[13]. AP were diagnosed in accordance with international A large series of patients with Crohn’s disease looked guidelines. AZA was stopped by 186 patients (36.5%). at etiology of AP: 21% and 15% of cases were due to The most common cause of discontinuation was nausea biliary lithiasis and alcohol respectively; 12% and 13% of (12.2%). Pancreatitis occurred in 37 patients (7.3%): cases were associated with drugs or Crohn’s disease to 43% were admitted with a median inpatient length of [7] the duodenum; 8% of AP were defined as “idiopathic” . stay of 5 d (10% had peripancreatic fluid collection, 24% In Seyrig’s study idiopathic AP was only 1.5% (5 in 331 had vomiting and 14% had fever). No patient underwent patients with IBD), but not all patients were investigated non­surgical or surgical interventions. At univariate [10] with ERCP . In Heikius’s study incidence of idiopathic and multivariate analysis smoking was found to be the AP was 3% in patients with IBD but 4% in the subgroup strongest risk factor for AZA­induced AP[36]. However a [13] with Crohn’s disease . meta­analysis showed that the risk of AZA­induced AP is very low[37]. Diagnosis However drug­induced pancreatitis could develop The main issue in analyzing association between AP and any time during the course of the treatment and it is not WJGP|www.wjgnet.com 277 August 15, 2016|Volume 7|Issue 3| Antonini F et al .