Digestive Diseases and Sciences https://doi.org/10.1007/s10620-021-06899-2 REVIEW Pancreatic Disorders in Patients with Inflammatory Bowel Disease Marilia L. Montenegro1 · Juan E. Corral1 · Frank J. Lukens1 · Baoan Ji2 · Paul T. Kröner1 · Francis A. Farraye1 · Yan Bi1 Received: 21 October 2020 / Accepted: 8 February 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021 Abstract Inflammatory bowel disease (IBD) can involve multiple organ systems, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases is more frequent in patients with Crohn’s disease and ulcerative colitis than in the general population. Pancreatic manifestations in IBD include a heterogeneous group of disorders and abnormalities ranging from mild, self-limited disorders to severe diseases. Asymptomatic elevation of amylase and/or lipase is common. The risk of acute pancreatitis in patients with IBD is increased due to the higher incidence of cholelithiasis and drug-induced pancreatitis in this population. Patients with IBD commonly have altered pancreatic histology and chronic pancreatic exocrine dysfunction. Diagnosing acute pancreatitis in patients with IBD is challenging. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD. Keywords Inflammatory bowel disease · Pancreatitis · Extraintestinal manifestations · Crohn’s disease · Ulcerative colitis Abbreviations AIPAutoimmune pancreatitis 5-ASA5-Aminosalicylic acid CIConfidence interval ERCPEndoscopic retrograde cholangiopancreatography IBDInflammatory bowel disease IgImmunoglobulin OROdds ratio TNFTumor necrosis factor * Yan Bi bi.yan@mayo.edu Marilia L. Montenegro Montenegro.Marilia@mayo.edu Juan E. Corral jcorralhu@phs.org Frank J. Lukens Lukens.Frank@mayo.edu Baoan Ji Ji.Baoan@mayo.edu Paul T. Kröner Kroner.Paul@mayo.edu Francis A. Farraye Farraye.Francis@mayo.edu 1 Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA 2 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA Introduction Inflammatory bowel disease (IBD) has two main subtypes: ulcerative colitis and Crohn’s disease. IBD may affect any part of the gastrointestinal tract, causing chronic and recurrent inflammation, and manifests with a wide variety of symptoms. In the USA, the prevalence of IBD is 1.3% and continues to increase, affecting over 3 million persons [1]. IBD is a systemic disease, and in up to 47% of patients, there is extraintestinal involvement of the musculoskeletal system, hepatobiliary tract, eyes, or skin [2]. Recently, interest has increased regarding potential pancreatic abnormalities in patients with IBD, ranging from asymptomatic elevation of pancreatic enzymes to acute pancreatitis and pancreatic cancer. In this review, we discuss the manifestations and possible causes of pancreatic abnormalities in patients with IBD. Serum Pancreatic Enzymes in Patients with IBD Asymptomatic increases in serum amylase and/or lipase are found in 8% to 21% of patients with IBD, unrelated to pancreatic disease and without any morphologic abnormalities of the pancreas on imaging[3–5]. The elevated levels may be associated with other conditions related to IBD, such as acute or chronic kidney disease, salivary gland disease, macroamylasemia, dysfunction of the sphincter of Oddi after 13 Vol.:(0123456789) Digestive Diseases and Sciences cholecystectomy, chronic narcotic use, or possible increased amylase absorption in the inflamed gut [3–6]. IBD and Risk of Acute Pancreatitis Patients with IBD have three times higher odds of developing acute pancreatitis than the general population [7, 8]. The annual incidence of acute pancreatitis in patients with ulcerative colitis is 152.9 per 100,000 persons [9]. For Crohn’s disease, acute pancreatitis has a 10-year expected incidence of 1.4% [10]. In a nationwide Danish study, Crohn’s disease had a fourfold and ulcerative colitis a twofold increased risk of acute pancreatitis compared with the general population [11]. A Taiwanese study showed an overall 3.56-fold increase (8.91 overall incidence) of acute pancreatitis in the IBD population (28.2/10,000 person-years, ulcerative colitis; 34.3/10,000 person-years, Crohn’s disease) [12]. Etiologies of Pancreatitis in Patients with IBD Similar to the general population, acute pancreatitis in patients with IBD has multiple causes, including overuse of alcohol, biliary tract disease, and postprocedure complication of endoscopic retrograde cholangiopancreatography [13]. The common causes of acute pancreatitis are summarized in Table 1. Gallstones Gallstones are the most common etiology of acute pancreatitis in the general population, being the reported cause in up to 50% of cases [14]. Among patients with Crohn’s disease, the incidence of gallstones is two times that of the general population (11–34% vs 5–15%) [15]. A retrospective cohort study showed an incidence of gallstones of 14.3 per 1,000 person-years for patients with Crohn’s disease compared with an incidence of 7.75 in matched controls diagnosed with gastrointestinal functional disorders [16]. For patients with ulcerative colitis, 11.8% of acute pancreatitis can be attributed to gallstones [9]. The reported gallstone incidence rate was 7.48/1,000 person-years in Table 1 Causes of acute pancreatitis in inflammatory bowel disease Cause Gallstones Alcohol Medications Comments IBD doubles the risk of gallstone disease Less frequent use than in the general population Thiopurines (6MP and AZA), metronidazole, corticosteroids, and cyclosporine Duodenal Crohn’s disease Only for Crohn’s disease Procedure-related ERCP: Particularly patients with UC and PSC Abdominal surgery: Risk increases with vascular procedures DBE: Frequently causes hyperamylasemia, rarely causes moderate or severe pancreatitis Hypertriglyceridemia Proportionally increasing after triglyceride levels > 500 mg/dL Hypercalcemia Unclear mechanisms. Precipitated by abrupt concentration changes of more than maximum serum calcium levels Thrombosis/ischemia/vasculitis IBD is a hypercoagulable state associated with substantial risk of thrombotic events. Multiple case reports showing different types of vasculitis (RA, SLE, HS purpura, cocaine use) associated with acute pancreatitis Autoimmune pancreatitis Typically type 2 autoimmune pancreatitis. IgG4-negative disease characterized by idiopathic duct-centric pancreatitis. Low relapse risk compared with type 1 Estimated percentage of cases References 21% 15% 12% [13, 105] [13, 105] [13, 105] 13% 3–5% of ERCPs performed population < 2% of surgical procedures in general population < 1% of DBE in general population [13, 105] [106] [77] [107] NA [108] NA [109] NA [110] 1/3 of patients with autoimmune pancreatitis type 2 have concomitant IBD [66] 6MP 6-mercaptopurine, AZA azathioprine, DBE double-balloon enteroscopy; ERCP endoscopic retrograde cholangiopancreatography, HS Henoch-Schonlein, IBD inflammatory bowel disease, IG immunoglobulin, NA not applicable, PSC primary sclerosing cholangitis, RA rheumatoid arthritis, SLE systemic lupus erythematosus, UC ulcerative colitis 13 Digestive Diseases and Sciences patients with ulcerative colitis compared with 6.06/1,000 person-years among matched controls [16]. Cholelithiasis was more prevalent in patients with ulcerative colitis (8%) than in the general population (3.9%) [17]. Cholesterol and pigment gallstones are both found in patients with Crohn’s disease [18]. Patients with IBD and ileal disease or after an ileal resection have an increased risk of pigment stone formation [19], and those without ileal surgery have an increased risk of cholesterol gallstone formation [20]. The pathophysiology of increased gallstone formation in Crohn’s disease is not completely understood, but it is likely multifactorial. Factors involved include impaired enterohepatic circulation from diseased ileum and/or previous intestinal resection, gallbladder dysmotility, and hypersaturation of bile cholesterol and bilirubin. Age greater than 50 years, longer disease duration (> 10 years), frequent disease relapses (> 3), frequent hospitalizations, long hospitalizations, and total parenteral nutrition are also risk factors for gallstone development [21]. For patients with ulcerative colitis, older age (≥ 65 years), multiple flare-ups (≥ 3 hospitalizations), and colectomy are associated with increased risk of cholelithiasis [17, 22]. Drug‑Induced Pancreatitis In the general population, drug-induced pancreatitis is an uncommon condition, with reported rates from 0.1 to 2% of acute cases [23]. However, most data regarding druginduced pancreatitis come from case reports, so the true incidence may be higher [24]. Drug-induced pancreatitis is mainly a diagnosis of exclusion. The following three conditions must be met to confirm it: temporal sequence between medication introduction and onset, rapid improvement after a suspected causative drug is discontinued, and recurrence of acute pancreatitis after reexposure [24]. A drug rechallenge is rarely considered for ethical reasons, making a firm diagnosis of drug-induced pancreatitis challenging [24]. Badalov et al. [24] developed a classification system for drug-induced pancreatitis that separates drugs into four classes. • Class I • Class 1a: At least one case report supports a positive rechallenge with other causes of acute pancreatitis properly excluded; • Class Ib: At least one case report supports a positive rechallenge with other potential causes of acute pancreatitis not excluded; • Class II: At least three of four case reports (75%) in the literature showed consistent latency between drug administration and occurrence of acute pancreatitis. Drug latency was divided into short (< 24 h), intermediate (1–30 days), and long (> 30 days) periods. • Class III: At least two case reports but without a rechallenge or a consistent latency period; • Class IV: Only one case report, no rechallenge, and drug does not fit into other categories. Common medications prescribed for patients with IBD that may cause acute pancreatitis are described in Table 2, along with their respective Badalov classification. Drug-induced pancreatitis is the cause of acute pancreatitis in about 45% of patients with ulcerative colitis, and about 12% of patients with Crohn’s disease [9, 13]. Medications used to treat IBD, such as thiopurines (azathioprine, 6-mercaptopurine), 5-aminosalicylic acid (5-ASA) agents (mesalamine, sulfasalazine, olsalazine), antibiotics (e.g., metronidazole), corticosteroids, and cyclosporine, have all been implicated as causes of acute pancreatitis, although pancreatitis associated with metronidazole or corticosteroids is exceedingly rare [25]. Drug-induced pancreatitis can occur any time during treatment, although symptoms often develop soon after a patient begins taking a medication [7]. Azathioprine (Class Ia) In a study of 510 patients with IBD treated with azathioprine, the reported incidence of pancreatitis was 7.3% (Crohn’s disease, 8.6%; ulcerative colitis, 3.2%), and the median intermediate latency was 21 days. About 43% of patients required hospitalization (median length of stay, 5 days) [26]. The development of pancreatitis was not associated with the dose of azathioprine. Smoking (vs not smoking) increased the risk of azathioprine-induced acute pancreatitis (odds ratio [OR], 3.24) [95% confidence interval (CI), 1.74–6.02]; P = 0.0002) and, among smokers, in a dose-dependent manner: 1.9 in smokers of fewer than 3 packs/week to 2.8 in smokers of more than 3 packs/week [26]. Female sex was a risk factor for azathioprine-induced pancreatitis (OR 3.4 [95% CI 1.3–9.3]; P = 0.012) [27].The class II HLA gene region (at rs2647087) was reported to be an important marker of thiopurine-induced acute pancreatitis (9%, heterozygotes; 17%, homozygotes) [28]. Interestingly and for unclear reasons, drug-induced pancreatitis associated with azathioprine was significantly higher (P < 0.05) in patients with Crohn’s disease (4.9%) than for other conditions treated with it, such as rheumatoid arthritis (0%), systemic lupus erythematosus (0%), Wegener granulomatosis (0%), ulcerative colitis (1.1%), and post-kidney transplant (0.5%) or liver transplant (0.4%) [29]. These data support the hypothesis that IBD and Crohn’s disease, in particular, increase the risk of acute pancreatitis independent of the medication used for therapy [30]. 13 Digestive Diseases and Sciences Table 2 Associations of drugs used frequently for inflammatory bowel disease and drug-induced acute pancreatitis Drug Badalov classification [24] Analgesic agents Acetaminophen Ia Acetaminophen–codeine Ia Anti-inflammatory and immunomodulatory drugs Ia 5-aminosalicylic acid agents: mesalamine, sulfasalazine, olsalazine Ib Thiopurines: Ib azathioprine 6-mercaptopurine Ib Corticosteroids: Ib Dexamethasone Ib Hydrocortisone II Prednisone Prednisolone Antibiotics Metronidazole Ia Trimethoprim/sulfamethoxazole Ia Tetracycline Nitrofurantoin Antacids H2 blockers: Cimetidine Ranitidine Proton pump inhibitors: Omeprazole Miscellaneous Cannabis Propofol *Anti-tumor necrosis factor *Vedolizumab *Cyclosporine Pancreatitis severity Comments Severe NA Generally seen in suicide attempts. One death reported. One case with late presentation (1 month after ingestion) Mild Oral and rectal formulations Severe Mild Cohort studies and randomized trials Mild Severe Severe Severe One death with hydrocortisone Moderate Severe Ia Ib Mild Mild Ia Ia Severe Mild Ib Severe Ia Ib IV IV III Moderate Severe Not applicable Mild Severe The exact pathogenesis of azathioprine-induced pancreatitis is unknown, but some mechanisms have been proposed, such as immunologic reactions, association with circulating pancreatic antibodies, and direct toxic effects [29]. Corticosteroids (Class Ib) Although corticosteroids rarely cause pancreatitis [31], a population-based study with 6,161 cases and 61,637 controls showed a twofold increased risk of patients developing acute pancreatitis if they were taking oral glucocorticoids (vs not) [32]. Additionally, a recent study of drug-induced pancreatitis showed that the severity of pancreatitis caused by corticosteroids was higher than pancreatitis caused by other anti-inflammatory drugs for IBD [33]. 13 Sulfamethoxazole more frequent than trimethoprim. Two reported deaths Concomitant use of other medications One death due to sepsis with cimetidine Positive association in a systematic review Mediated by hypertriglyceridemia Combination of infliximab and adalimumab Aminosalicylates (Class Ia) Drug-induced pancreatitis associated with aminosalicylates and related medications has been reported since the 1970s regardless of route of administration (oral formulations, enemas, and suppositories), although a large case–control study from Hungary failed to show an association of 5-ASAs with the development of acute pancreatitis [34–36]. The reported incidence of acute pancreatitis for patients with ulcerative colitis treated with mesalamine was 1/million days of treatment [25]. In a study that analyzed adverse events involving 4.7 million prescriptions of sulfasalazine and 2.8 million prescriptions of mesalamine, the incidence of acute pancreatitis was 7.5/million prescriptions of mesalamine and 1.1/million prescriptions of sulfasalazine, representing about seven times higher risk of acute pancreatitis for Digestive Diseases and Sciences mesalamine-induced acute pancreatitis[37]. The most common characteristics of aminosalicylate-induced pancreatitis were long latency period (6 weeks), not dose-related, mild course, and occurrence regardless of the method of administration [25]. The pathophysiology of 5-ASA-induced acute pancreatitis is unknown [25]. Tumor Necrosis Factor‑α Inhibitors and Other Biologics (Class IV) Tumor necrosis factor (TNF)-α inhibitors reduced the severity of acute pancreatitis in animal models [38, 39] and in a pilot human clinical trial [40]. Although cases of TNF-α inhibitor-induced acute pancreatitis have been reported [41], a retrospective study involving patients with IBD showed that the odds of acute pancreatitis were lower in those taking thiopurine/TNF-α inhibitor combination therapy than in those taking thiopurine monotherapy (OR 0.04 [95% CI 0.01–0.12]) [42]. Similarly, the risk of acute pancreatitis was lower for combination therapy of mesalamine and a TNF-α inhibitor than for mesalamine monotherapy (OR 0.08 [95% CI 0.04–0.14]) [42]. Likewise, patients given triple therapy (TNF-α inhibitor, thiopurine, and mesalamine) had a lower risk of acute pancreatitis than those taking both thiopurine and mesalamine (OR 0.04 [95% CI 0.01–0.16]) [42]. Antibiotics (Class Ia) For patients with IBD, antibiotics such as metronidazole have been used to treat perianal disease and concurrent infection, including Clostridium difficile [43]. Multiple cases of metronidazole-induced acute pancreatitis have been described since 1991 when it was reported a case of a patient with Crohn’s disease and acute pancreatitis [44]. Populationbased studies showed that metronidazole was associated with a threefold increased risk of acute pancreatitis and that this risk increased to eightfold if patients received combination therapy with proton pump inhibitors and amoxicillin, macrolides, or tetracycline to treat Helicobacter pylori [45, 46]. The risk was increased within the first 30 days of treatment [45, 46]. Cannabis (Class Ia) Acute pancreatitis and recurrent acute pancreatitis have been associated with cannabis use [47], accounting for 13% of cases in patients 35 years or younger [48]. The overall prevalence of acute pancreatitis in patients using cannabis has been reported from 1.96 to 13.0% [49]. Among adolescents and young adults with IBD, cannabis use is common [50]. More than 50% of patients say they use cannabis for medical reasons, with pain being the most common explanation [50]. Cannabis has been associated with acute pancreatitis and hyperemesis syndrome, and both conditions have a similar presentation [51]. Toxicology screening should be considered in patients with idiopathic acute pancreatitis. Alcohol In the general population, 19% to 41% of acute pancreatitis cases [52] are caused by alcohol use, whereas only 15% of cases in patients with IBD are attributed to alcohol [13], although the overall pattern and quantity of alcohol consumption were reported as similar for patients with inactive IBD and the general population [53]. One study showed higher alcohol intake was associated with an increased frequency of reported IBD relapses (OR 2.71 [95% CI 1.10–6.67]) [54]. Sulfite is an additive that is usually found in alcoholic beverages, and its intake, in high doses, has also been associated with relapses (OR 2.61 [95% CI 1.08–6.30]) [54]. Primary Sclerosing Cholangitis Primary sclerosing cholangitis is an extraintestinal manifestation of IBD, with a prevalence ranging from 0.76 to 5.4% for patients with ulcerative colitis and from 1.2 to 3.4% for patients with Crohn’s disease [15]. About 50% to 80% of patients with primary sclerosing cholangitis have IBD [55], especially pancolitis form of ulcerative colitis [56]. Acute or chronic pancreatitis may develop in up to 22% of patients with primary sclerosing cholangitis [25]. Risk factors that contribute to the higher incidence of acute pancreatitis are common bile duct and pancreatic duct strictures, as well as increased occurrence of gallstones [25]. Autoimmune Pancreatitis Autoimmune pancreatitis (AIP) is a newly described disease that commonly presents as recurrent cases of acute pancreatitis [57]. The first case of AIP was reported in 1995 as chronic pancreatitis, but it was subsequently recognized as a different entity, and the first diagnostic criteria were established in 2002 [58]. It has two subtypes (type 1 and type 2), which are based on histologic and clinical features and immunoglobulin (Ig)G4 status [59]. Type 1 AIP predominantly affects older men, and up to 90% have elevated serum IgG4 levels [60]. AIP is part of systemic IgG4 disease, which can also manifest as sclerosing cholangitis, sialadenitis, and retroperitoneal fibrosis [58, 59]. Biopsy results show lymphoplasmacytic sclerosing pancreatitis with IgG4-positive cells [58, 59]. Small and large intestine involvement is uncommon but has been described; however, IBD has not been described as a manifestation of the disease [61]. Despite this, patients with IBD have higher serum IgG4 levels and intestinal IgG4 + cells than the 13 Digestive Diseases and Sciences general population [62, 63]. These findings are more common in patients with ulcerative colitis [64] and may help in predicting disease severity and in differentiating ulcerative colitis from Crohn’s disease. Type 2 AIP is rarer than type 1. It is not a systemic disease and does not present with elevated IgG4 levels [7], but it is associated with IBD. Histologic findings are specific of Type 2 AIP and consist of idiopathic duct-centric pancreatitis with granulocytic epithelial lesions [58]. Predominant characteristics of patients with both AIP and IBD reported in a case series were male sex, ulcerative colitis, and younger age [65, 66]. The prevalence of AIP in patients with IBD has been estimated at 0.4% [67], and the association of the disease with IBD was hypothesized due to shared antigenic molecules triggering an immune response in both organs [66]. Despite this association, AIP did not affect the course of IBD [66]. Features of type 1 and type 2 AIP are described in Table 3. Diagnosing AIP is challenging. The most commonly used diagnostic tools are the HISORt criteria [68] and the International Consensus Diagnostic Criteria [69]. The HISORt criteria take into account histologic and imaging findings, IgG4 levels, multiorgan involvement, and response to corticosteroid therapy; a diagnosis of AIP can be assumed if one or more conditions are present [68, 70]. According to the International Consensus, a definitive type 1 AIP diagnosis is made if one or more of the following conditions are present: lymphoplasmacytic sclerosing pancreatitis on histology, typical imaging findings on computed tomography or magnetic resonance imaging, other organ involvement, and corticosteroid responsiveness; a definitive type 2 diagnosis requires histologic confirmation and/or clinical IBD [70]. The typical imaging findings of AIP are diffuse pancreatic enlargement with diffuse rim enhancement and a diffusely irregular attenuated pancreatic duct, which occurs in both AIP types [70]. The differentiation is usually made by the extrapancreatic findings, which are more common in AIP type 1 [71]. A study comparing computed tomographic imaging of AIP type 2 and acute gallstone pancreatitis showed multifocality, peripancreatic halo, and delayed enhancement to be specific features of AIP type 2, and findings of peripancreatic fat infiltration and fluid collection were much more frequent in gallstone pancreatitis [72]. On imaging, differences can be seen between classic gallstone pancreatitis and AIP, as illustrated in Fig. 1, which shows diffuse enlargement of the pancreatic body in AIP and the debris-filled pancreatic collections and necrosis around the pancreatic neck and proximal body for biliary pancreatitis. Metabolic Disorders Metabolic causes of acute pancreatitis such as hypertriglyceridemia, hypercalcemia, and hyperparathyroidism are rare in the IBD population. One study attributed the cause of acute pancreatitis to hypertriglyceridemia in only 1.5% of cases [30]. In a study of 11,909 patients with IBD and 47,636 controls, the prevalence of hypertriglyceridemia was 1.39% for patients with IBD vs 0.38% for controls; the prevalence of hypercalcemia was 0.23% for patients with IBD vs 0.07% for controls [12]. Hyperparathyroidism was Table 3 Autoimmune pancreatitis characteristics based on each subtype Category Type 1 Type 2 Demographics 60–70 y, 3:1 male predominance More common in Asia than in Europe/United States Rarely 40–50 y. Similar sex distribution More common in Europe followed by USA and Asia Present in up to 30% of patients Ulcerative colitis (2%-30%) more than Crohn’s disease (1%-4%) Occasionally associated with primary sclerosing cholangitis Rare Inflammatory bowel disease Systemic involvement Pancreatic imaging Serologic findings Histologic findings Corticosteroid response Relapse Bile ducts, kidneys, salivary glands, lachrymal glands. Retroperitoneal fibrosis Diffuse enlargement Delayed enhancement rim (Fig. 1) Elevated total IgG IgG4: > 2 times upper normal limit Lymphoplasmacytic sclerosing pancreatitis. Plasma cell infiltrate Excellent, usually < 2 weeks Common (75%-100% with IBD; 20%-60% in the general population) [66] IBD inflammatory bowel disease, IgG immunoglobulin G 13 Segmental/focal enlargement Delayed diffuse enhancement Normal total IgG IgG4: 1–2 times upper normal limit Idiopathic duct-centric pancreatitis. Granulocyte infiltrate Excellent, usually < 2 weeks Rare (15%-20% with IBD; < 10% in the general population) [66] Digestive Diseases and Sciences Fig. 1 MRI and EUS of gallstone pancreatitis, autoimmune pancreatitis Type 1 and Type 2. The arrows show debris-filled, thick-walled, septated enhancing pancreatic/peripancreatic collections/walled of necrosis around the pancreatic neck and proximal body. There is only minimal fluid within these collections. AIP indicates autoimmune pancreatitis; EUS endoscopic ultrasound; MRI magnetic resonance imaging reported as a common finding among patients with Crohn’s disease who underwent bowel resection [73]. inflammation are inflammation of the ampulla, reflux of duodenal contents, duodenopancreatic fistula, and/or duodenal stenosis [7]. Duodenal Inflammation Because IBD and celiac disease are immune-mediated disorders with a partially common genetic background, it is not surprising to see a high coexistence of both [74]. For patients with IBD, the prevalence of celiac disease was reported to be 1,110/100,000 compared with 620/100,000 persons in the general populations (OR 2.23 [95% CI 1.99–2.50]) [74]. Furthermore, for patients with celiac disease, the prevalence of IBD was 2,130/100,000 compared with 260/100,000 persons in the general population (OR 11.10 [95% CI 8.55–14.40]) [74]. In a Swedish study, patients with celiac disease had an almost threefold increased risk of developing acute pancreatitis, and several factors were discussed as possible causes, including papillary inflammation and stenosis, persistent inflammation, and malnutrition [75]. In Crohn’s disease, duodenal involvement is a rare cause of acute pancreatitis (0.5%-4% of cases) [7]. The main mechanisms that have been suggested to trigger pancreatic Procedure‑Related Pancreatitis Pancreatitis occurring after endoscopic retrograde cholangiopancreatography (ERCP) accounts for 1.5% of acute pancreatitis cases in patients with IBD [30]. In a recent study of 492,175 discharged patients who underwent ERCP, the risk of patients with IBD developing post-ERCP pancreatitis was similar to that of healthy controls (4.4% of IBD cases vs 4.49% of controls) [76]. Double-balloon enteroscopy performed to diagnose or evaluate disease activity in patients with Crohn’s disease frequently causes hyperamylasemia, but the risk of clinically significant acute pancreatitis after double-balloon enteroscopy was reported as only marginally increased [59]. In the general population, 15% of acute pancreatitis cases have a postoperative cause [77]. However, procedure-associated pancreatitis is generally considered to result from the mechanical insult of the surgery itself because the frequency 13 Digestive Diseases and Sciences of acute pancreatitis is higher for biliary, pancreatic, and gastric operations [78]. Intraabdominal sepsis and increased intraabdominal pressure are associated with more severe cases of acute pancreatitis [79, 80]. Infectious Causes Various infectious microorganisms have been linked to acute pancreatitis, such as viruses (hepatitis B virus, herpes simplex virus, cytomegalovirus, varicella zoster virus, human immunodeficiency virus, mumps, and coxsackievirus), bacteria (Mycoplasma, Legionella, Salmonella, and Leptospira), fungi (Aspergillus), and parasites (Toxoplasma, Cryptosporidium, and Ascaris) [81]. Viral infections develop in about 8% of IBD patients with moderate disease [82]. Hepatitis B virus is the most common hepatitis virus associated with acute pancreatitis. Exposure (as defined by positive anti-hepatitis B core antibody) in patients with IBD varies from 5.9 to 30.1%, and patients with IBD have a less satisfactory response to vaccination with lower anti-hepatitis B antibody levels than controls [83]. A study conducted in India found a prevalence of 0.1% of HIV infection in patients with IBD [84]. In general, 40% of patients with HIV develop acute pancreatitis compared with 2% in the general population [85]. No studies have reported acute pancreatitis risk for patients with HIV and IBD. Patients with IBD have an increased risk of infections. The use of TNF-α inhibitors increases the risk of developing active tuberculosis during treatment for IBD, especially within the first year of treatment [86]. Opportunistic fungal infections, such as aspergillosis and pneumocystis, can occur in 5.8% of patients with IBD taking cyclosporine [82]. Cytomegalovirus is commonly found in the mucosa of patients with active IBD and is detected in up to 36% of patients with IBD and more severe disease [82, 87]. Even though the risk of infection is higher for IBD patients, acute pancreatitis from infection is rare, and reports are limited to case reports and retrospective studies [85]. Before considering infection as a cause for pancreatitis, more common causes should be excluded. Idiopathic Pancreatitis Idiopathic pancreatitis accounts for 0.06% to 8% of pancreatitis cases among patients with IBD [59]. The definition of idiopathic pancreatitis is inherently assigned by the limitations of current diagnostic tools and has been reported as an extraintestinal manifestation of IBD [13]. In a Japanese study of 1,097 patients with severe acute pancreatitis, the cause was idiopathic in 20.7% [88], and in a southern England study of 283 patients hospitalized with acute pancreatitis, the cause was idiopathic in 23% [89]. 13 Diagnosis of Acute Pancreatitis and IBD Diagnosing acute pancreatitis can be challenging in patients with IBD. First, as previously mentioned, it is not uncommon for patients with IBD to be asymptomatic with elevated pancreatic enzyme levels [5]. Second, typical symptoms of acute pancreatitis, such as abdominal pain and vomiting, can be difficult to differentiate from an IBD exacerbation [59, 67]. Although a scoring system to predict the risk of acute pancreatitis for patients with lipase elevation of three times the upper limit prior to imaging has been developed [90], it is still critical to follow diagnostic criteria. The revised Atlanta classification requires at least 2 of 3 of the following criteria to be present for the diagnosis of acute pancreatitis: abdominal pain, elevation of amylase or lipase three times the upper limit, and imaging alterations [91]. However, imaging studies are usually required for accurate diagnosis and for characterizing disease severity [92]. Figure 2 summarizes the common diagnostic tests for diagnosing acute pancreatitis in patients with IBD. Treatment Considerations for Acute Pancreatitis with IBD Acute pancreatitis is managed similarly for patients with IBD as for other patients, including supportive care with fluids, pain control, and nutritional support [7, 92]. Asymptomatic increases in lipase and amylase levels do not require therapy [7, 92]. Determining the cause of acute pancreatitis in patients with IBD is critical for early treatment. Cholecystectomy is recommended for biliary pancreatitis during the same hospitalization [59]. Medications should be reviewed carefully to ensure early diagnosis of drug-induced pancreatitis. Azathioprine, mesalamine, and thiopurine should be withdrawn until a cause is established [59]. If imaging studies suggest AIP, a systemic corticosteroid is an effective treatment to which both types of AIP respond well [70]. Most cases of acute pancreatitis in patients with IBD are mild, and the mortality rate is comparable to the rate for patients without IBD [7, 67]. A large study with 383,918 patients hospitalized with acute pancreatitis showed no significant difference between the survival rate of patients with IBD and that of controls without IBD [93]. Digestive Diseases and Sciences Fig. 2 Common diagnostic tests for acute pancreatitis in patients with inflammatory bowel disease. ALT indicates alanine aminotransferase; APBJ, abnormal pancreaticobiliary junction; EUS, endovascular ultrasound; HISORt, histology, imaging, serology, other organ involvement, and response to therapy; Ig immunoglobulin; MRI magnetic resonance imaging; MRCP magnetic resonance cholangiopancreatography Chronic Pancreatitis in Patients with IBD with 39 patients who had clinical histories and histologic findings compatible with regional enteritis showed that 38% had pancreatic fibrosis (27 men and 12 women; mean age at death, 54 years; average duration of symptoms before death, 5 years) [96]. Chronic pancreatitis has a higher incidence for patients with IBD than for the general population (5.75 vs 0.56/10,000 person-years, respectively), and patients with chronic pancreatitis also have a higher risk of developing Chronic pancreatitis is characterized by inflammation and subsequent fibrosis of pancreatic parenchyma, resulting in irreversible damage to the pancreas and symptoms related to loss of endocrine and exocrine function [94]. Ball et al. [95] analyzed 86 cases of chronic ulcerative colitis in an autopsy case–control study and showed that 53% of cases had chronic interstitial pancreatitis. Another study 13 Digestive Diseases and Sciences IBD [97]. Chronic pancreatitis is estimated to develop in 56% of patients with Crohn’s disease [67]. However, chronic pancreatitis and ulcerative colitis have been shown to have an inverse relation, i.e., a previous diagnosis of chronic pancreatitis was found in up to 58% of patients newly diagnosed with ulcerative colitis [98]. Patients with ulcerative colitis and chronic pancreatitis tend to have pancolitis type or a history of total colectomy [59]. In these patients, it is commonly found bile duct involvement, main pancreatic duct stenosis, and weight loss [92]. Pancreatic functional alterations and pancreatic duct abnormalities are common in patients with IBD [13]. Patients with IBD often have low fecal elastase levels, reflecting impaired exocrine function [7, 99]. Exocrine pancreatic dysfunction is more common in patients with ulcerative colitis than in patients with Crohn’s disease (22% vs 14%, respectively) [67]. When patients with chronic pancreatitis were compared with patients without chronic pancreatitis, there was a 12-fold higher risk of Crohn’s disease. For ulcerative colitis, there was a twofold increase [97]. Treatment of chronic pancreatitis varies according to disease severity, is multifactorial, and includes tobacco cessation, lifestyle guidance, glucose monitoring, enzyme replacement, pain control, and occasionally endoscopic and/ or surgical treatment of pancreatic calculi [59]. Pancreatic Cancer Risk in IBD Patients with IBD have an increased risk of multiple different cancers, such as colon cancer, lymphoma, melanoma, and pancreatic cancer [59]. In a study of 15,291 patients with IBD, Jung et al. [100] identified increased pancreatic cancer risk in patients with IBD compared to the general population. The higher risk was found especially among women with Crohn’s disease (standardized incidence ratio, 8.58 [95% CI 1.04–31.0]) [100]. A study from Denmark and Sweden showed a similar 20-year cumulative incidence of pancreatic cancer for patients with IBD and general population, 0.34% (95% CI 0.30%-0.38%) and 0.29% (95% CI 0.28%-0.30%), respectively [101]. The incidence rate per 100,000 person-years, though, was higher for patients with IBD at 22.1 (95% CI 20.1–24.2) compared with 16.6 (95% CI 16.0–17.2) for the general population [101]. In this same study, the hazard ratio for pancreatic cancer was 1.43 (95% CI 1.30–1.58) for all patients with IBD and 7.55 (95% CI 4.94–11.5) for patients with IBD and primary sclerosing cholangitis [101]. The risk of malignancy for patients with IBD may be attributed to chronic inflammation, especially with the coexistence of primary sclerosing cholangitis, or to immunosuppressive therapy [59]. In a recent study, Trivedi et al. showed that patients with both IBD and primary sclerosing 13 cholangitis were associated with increased risk of hepatopancreatobiliary cancers and colorectal cancer compared with IBD alone [102]. The incidence of pancreatic cancer was 3% for patients with IBD and primary sclerosing cholangitis and less than 1% for patients with IBD alone [102]. Primary sclerosing cholangitis has recently been associated with recurrence of pancreatitis and AIP, and these two conditions also increase the risk of pancreatic malignancies [103, 104]. Summary Pancreatic disorders are unusual extraintestinal manifestations of IBD, while they are more prevalent in the IBD population compared to the general population. A wide range of pancreatic disorders has been associated with IBD, from asymptomatic pancreatic enzyme elevation to increased risk of acute pancreatitis, chronic pancreatitis, and pancreatic cancer. Gallstone pancreatitis is the most common cause of acute pancreatitis in patients with IBD, followed by druginduced pancreatitis. Because of the higher incidence and prevalence of pancreatic disorders in patients with IBD, providers need an understanding of the disease manifestations to arrange optimal patient care. Author’s contribution MLM and JEC wrote the study. FJL, BJ, and PTK reviewed the intellectual content. 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