Extraintestinal manifestations are relatively common in chronic inflammatory bowel disease (IBD). Patients with IBD are at increased risk for developing both acute pancreatitis (AP) (1) and chronic pancreatitis (2), and a recent study also indicates that the rarer variant, autoimmune pancreatitis, occurs more often among these patients (3). The clinical symptoms of AP are found in about 2% of adult patients with IBD (4,5).
Most of the studies suggest that pancreatitis can be related to the course of IBD (2,6) and could be mainly a silent disease because hyperamylasemia is found in 6% to 16% and pancreatic insufficiency in 21% to 80% of patients with IBD. Moreover, pancreatic histological changes have been documented in 38% to 53% of postmortem pathological examinations (7–12). Pancreatitis associated with IBD has mostly been thought to be caused by drugs used to treat IBD (4,13,14), biliary lithiasis (15), duodenal involvement of Crohn disease (CD) (16,17), or sclerosing cholangitis (18). There are only a few case reports, mainly in adults (6,19), describing AP as the first presenting clinical feature of IBD. Because of the rarity of such cases we undertook the task of retrospectively screening patients with IBD and characterizing the demographic, clinical, and laboratory data and the natural history of patients in whom AP preceded the appearance of IBD.
PATIENTS AND METHODS
We retrospectively identified all of the patients in whom AP preceded the clinical onset of IBD in a multicentric clinical cohort of patients diagnosed as having IBD (20). All such patients were studied at 7 university hospitals in Israel. AP was diagnosed by the concurrence of at least 2 of the following findings: acute onset epigastric abdominal pain, elevated serum amylase and/or lipase ≥3 times the upper level of normal, and characteristic radiological changes (21). Patients who developed AP during the course of IBD or patients with other known risk factors for developing pancreatitis were excluded from the study.
The clinical records from 1998 to 2008 were reviewed and the following data extracted: demographic data, type of IBD, and extension of disease (ulcerative colitis [UC]: left-sided, subtotal involvement or pancolitis; CD: small intestine, large intestine, or both). We also recorded the symptoms associated with AP and, in patients with CD, the phenotype of the disease: inflammatory, stricturing, or fistulizing.
Laboratory data including serum amylase and/or lipase, transaminases, alkaline phosphatase and total bilirubin were collected from the charts. Imaging methods used for the diagnosis of AP and the number of episodes of AP before the diagnosis of IBD were reported as well. We calculated the lag time between the onset of the first episode of AP and the diagnosis of IBD.
Statistical analysis (SPSS 12.0, SPSS Inc, Chicago, IL) included descriptive statistics. The numeric data are presented as mean ± SD. The lag time between the onset of the first episode of pancreatitis and the onset of IBD is expressed as median time. The incidence of AP was compared between adults and children with the χ2 test.
We retrospectively identified 12 patients (7 males; 10 children and 2 adults), (mean age 14.12 ± 10.08 years, range 3–37 years) with AP preceding the clinical onset and diagnosis of IBD in a cohort of 3960 patients with IBD at 7 university hospitals in Israel. The time period covered by the study was 10 years. Thirteen episodes of pancreatitis occurred in 12 patients before the diagnosis of IBD. Among the 3960 patients with IBD, 3500 were adults and 460 were children. Clinical characteristics and demographic data of patients with AP are shown in Table 1.
Epigastric pain was the dominant clinical characteristic in 11 of 12 patients (91.7%), followed by vomiting in 6 of 12 (50%), and fever and steatorrhea in 1 of 12 (8.3%). AP preceding the clinical onset of IBD was reported in 10 of the 460 pediatric patients (2.17%), with a mean age of 13 ± 4.8 (range 3–19) years, compared with only 2 in 3500 (0.06%) of the adult patients. The median lag time period between the episode of AP and the diagnosis of IBD was 24 (range 1–156) weeks. Six of the 12 patients subsequently developed UC (4 pancolitis) and 6 developed CD (2 large intestine, 2 small intestine, and 2 both small and large intestine).
Laboratory tests are shown in Table 2. The mean serum amylase level was 1002.11 ± 1147.847 (median 745; range 40–3684). The lipase blood level could be retrieved from the charts of only 3 of the 12 patients. In these patients, mean lipase blood level was found to be 833 and range was 40–2340 IU/L. Nine of the 12 patients had normal transaminases and the mean serum level of alkaline phosphatase was found to be 405.4 ± 488.09 (median 141.5, range 89–1405 IU/L). The hematological parameters revealed elevation of the erythrocyte sedimentation rate with a mean value of 48 ± 21.79 (median 40, range 25–76), and hemoglobin of 10.73 ± 1.41 (median 10.7, range 9.1–12.8) g/dL. Leukocyte count was within the normal limit.
All of the patients underwent imaging with ultrasound scan (US); 9 of the 12 (75%) had a computed tomography (CT) scan, 25% had endoscopic retrograde cholangiopancreatography (ERCP), and 25% had magnetic resonance cholangiopancreatography (MRCP).
From the imaging studies that could be retrieved, findings in the pancreas were documented per US/CT/ERCP and/or MRCP in 8 of the 12 patients. Ultrasonography revealed an enlarged pancreatic head in 4 patients and in 1 patient, a pseudocyst in the pancreatic tail and sludge in the gallbladder without bile duct dilatation. In this patient, however, ERCP demonstrated normal bile ducts without stones. CT revealed a pseudocyst in the body of the pancreas in 2 patients, a pseudocyst in the tail of the pancreas in 1 patient, and enlargement of the head of the pancreas in 3 other patients. ERCP demonstrated pathological findings in 2 of the 3 patients who underwent the procedure. One patient had a long, curved common bile duct and the other had an irregular, mildly dilated pancreatic duct. Only 3 patients underwent MRCP that was found to be normal in all of the cases.
A high prevalence of intestinal complications and extraintestinal manifestations of IBD is observed in the pediatric population. In children with IBD, extraintestinal manifestations often occur before the onset of gastrointestinal symptoms (22). Our study is the first to investigate the incidence of AP in both pediatric and adult patients with IBD. We found that AP as the first clinical manifestation preceding the diagnosis of IBD is significantly more frequent among pediatric patients as compared with adults (3.6% vs 0.06%, respectively).
There are only limited published data on the incidence of AP in pediatric patients with IBD. In 2002, the frequency of AP in 124 pediatric patients with a diagnosis of IBD was retrospectively reviewed (23). Symptomatic or asymptomatic pancreatitis was found in 27% (14.5% and 12.5%, respectively). The localization of IBD was not discriminant. An association between active and severe disease was documented. Drugs (25%), duodenal localization of CD (18%), or hepatobiliary complications (15%) were found to be associated with pancreatitis. A Polish study that analyzed 101 children with IBD (79 UC, 22 CD) reported that AP was diagnosed in 4.5% of children with CD and in 5.1% of children with UC. In the present study, AP was found to occur more often in moderate or severe UC (24).
In contrast to children, AP in adults has been reported to be seen much more commonly in CD than in UC. Although the incidence of AP in patients with IBD varies in the literature, there is a consensus that it occurs more often than in the general population. The incidence of AP in England, Denmark, and the United States varies from 4.8 to 38 in 100,000 patients with IBD. Estimates vary because the diagnosis of mild disease may be missed (25). The incidence of AP in CD can be calculated as 1% to 1.4% during a period of 10 years (1). Weber and associates reviewed the episodes of AP in patients with CD. Of 852 patients, 12 developed pancreatitis in a follow-up period of 10 years, representing a frequency of 1.4% (1). Bermejo et al (4) reported a cumulative incidence of 1.6% of AP episodes in adult Spanish patients with IBD, and most of them (63.4%) were attributed to drug exposure (azathioprine/mercaptopurine or mesalazine); 12.2% were of biliary origin and 20.7% were documented to be idiopathic (4).
Moolsintong et al reported that of 48 patients with CD with a confirmed diagnosis of AP, only 8% were diagnosed as idiopathic pancreatitis (26). Moreover, in most patients with AP, a presumptive etiology could be identified.
The etiology of AP in CD seems to be multifactorial. The various etiologic factors include gallstones, anatomic abnormalities, duodenal involvement, immunological disturbances, medication, alcoholism, hypertriglyceridemia, and other rare causes (24). Gallstones and alcohol intake are uncommon in the pediatric age group, whereas upper intestinal and duodenal involvement appears to be more common (27–29). Similarities of acute and chronic pancreatitis in CD with the entity of autoimmune pancreatitis enhance a possible role for pancreatic autoantibodies in initiating or potentiating pancreatic injury in patients with CD; however, many studies found no association between pancreatic autoantibodies and pancreatitis in CD (26,30–32). In our study, all of the patients were diagnosed as having idiopathic pancreatitis before the onset of IBD. Interestingly, of the 12 patients, colonic involvement was associated more frequently with AP than isolated small-intestine disease because although 6 patients in our series had UC and 6 had CD, 4 of the patients with CD had colonic disease and only 2 had isolated small-intestine disease. Among the 6 patients with UC, 4 had pancolitis. Despite the mild course of pancreatitis in most patients, 9 patients in the present study had moderate to severe IBD. The association between colonic disease and AP is still obscure. One explanation may be the fact that the colon is considered a major source of the bacteria causing pancreatic necrosis in AP, and subtotal colectomy before AP in rats was found to reduce mortality. The speculation for this phenomenon may be caused by the published data that the bacteriodes fragilis group positively correlated with bacteremia, and that the manipulation of the bacterial flora by the administration of either prebiotics or bifidobacterial colonization optimized the regulatory bacterial translocation (33–35).
AP is a severe disease with an overall mortality of 5% (even up to 30% in patients with necrotizing pancreatitis and infected necroses) (25). It seems that AP as the first presenting clinical sign of IBD has a benign course because in our study the median length of hospital stay was found to be only 3.5 (range 0–18) days. Because most of the patients in the present study were pediatric patients and the majority of children and adolescents with AP have a mild course and symptoms that resolve without incident, we believe that the benign course of AP in our study was associated with the young age of the patients (36). We should keep in mind that the lag time period between the appearance of AP and the intestinal manifestation of IBD could sometimes be several weeks to months; in our study the median lag time was found to be 24 (range 1–156) weeks. Although the long period of time between pancreatitis and IBD diagnosis may make the association less strong, it may still point to susceptibility to a certain pathogenic process. It has already been shown that some events and findings, such as serological markers, or other extraintestinal manifestations (arthritis or primary sclerosing cholangitis), may precede IBD in years. We believe that in the patients with a long lag time, there was a connection between AP and IBD.
Our study has some limitations. First, it is a retrospective study with a small number of patients; therefore, it is impossible to analyze different subgroups of patients with IBD. Second, we did not have a control group of patients with AP without IBD; however, our study is the first to our knowledge to investigate the incidence of AP as the first presenting symptom of IBD in both children and adults. It should be noted that patients with idiopathic AP may subsequently develop IBD, specifically if they are in the pediatric age group. We would suggest that specific attention be paid to other IBD susceptibility factors (family history, serologic markers, and inflammatory indices after the AP has subsided). A low threshold for investigation by colonoscopy and gastroscopy should be maintained.
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