Ma, Michael H.*; Bai, Harrison X.*; Park, Alexander J.†; Latif, Sahibzada U.‡; Mistry, Pramod K.*; Pashankar, Dinesh*; Northrup, Veronika S.§; Bhandari, Vineet*; Husain, Sohail Z.*
Acute pancreatitis is a severe inflammatory disease of the pancreas, which accounts for >210,000 hospitalizations annually (1). Biliary pancreatitis is a leading cause of acute pancreatitis in children, comprising 12% to 30% of all cases (2). Although gallstones and other biliary diseases are common causes of acute pancreatitis in adults, little is known about the presentation, risk factors, and outcomes of pediatric biliary pancreatitis or the features that distinguish it from other causes. Several studies have shown an increase in the incidence of acute pancreatitis in children during the last 20 years (3–5). In a previously published report, we found a 53% increase in cases of acute pancreatitis between 1995 to 2000 and 2001 to 2006 (6). This finding was attributed to an increase in pediatric emergency department visits. Because cases of biliary pancreatitis have become more prevalent in children and endoscopic or surgical intervention may be urgently needed, improved knowledge of factors that will assist in its timely diagnosis has become increasingly important (7).
In children, biliary pancreatitis includes several causes such as obstruction of the common bile duct (CBD) by gallstones, biliary sludge or microlithiasis, choledochal cyst, and biliary tree anomalies (6,7). Predisposing factors for the development of gallstones include chronic hemolytic disease, obesity, cystic fibrosis, ileal resection, and chronic liver disease (8). In contrast, biliary sludge often results from gallbladder stasis, such as with parenteral nutrition or during pregnancy (9). Sludge may gradually develop into gallstones and obstruct the CBD, leading to pancreatitis (10).
In the present study, we aimed to characterize the presentation of childhood biliary pancreatitis, identify factors that distinguish children with biliary pancreatitis from those with other causes of pancreatitis, compare biliary pancreatitis in younger and older children, and examine differences between childhood gallstone- and sludge-induced pancreatitis.
Study Group and Inclusion Criteria
We evaluated 76 episodes of biliary pancreatitis occurring in 68 children from a database of 271 cases of acute pancreatitis in children ages 0 to 20 years (224 children). These children were admitted to Yale-New Haven Children's Hospital in New Haven, CT, between August 1994 and July 2007. We screened hospital admissions for cases of acute pancreatitis using International Classification of Disease (ICD-9) codes. All of the personal identifiers were removed in the database for the study. The institutional review board of the Yale School of Medicine approved the study protocol. Discussions of the overall cohort of patients, including etiologies, ethnic breakdown, referral trends for pancreatitis over time, and presentation and management trends, have been published by us (6,11).
Inclusion criteria for acute pancreatitis in this cohort are as previously described (6). Briefly, inclusion in the study group required that pediatric patients possess any 1 of the following 3 characteristics relevant to acute pancreatitis: serum amylase or lipase >3 times the upper limit of normal (ULN); radiographic evidence demonstrating acute pancreatitis (minimum of changes in pancreatic parenchyma or peripancreatic fluid) on computed tomography (CT) and ultrasound (US); and serum lipase increased >1.5 times the ULN (not a result of nonpancreatic causes of hyperlipasemia), along with the presence of 2 of 3 clinical features—abdominal pain characteristic of acute pancreatitis, nausea or vomiting, or epigastric tenderness. As previously reported, the overwhelming majority of patients (90%) met the first or second inclusion criteria (6).
Of the 594 records (282 patients) identified by ICD-9 codes for acute pancreatitis, 323 records were excluded because they failed to meet inclusion criteria, had an incomplete chart record (46), or were cases of chronic pancreatitis (18). The latter was evidenced by calcifications observed on CT or the presence of chronic pancreatic duct abnormalities by endoscopic retrograde cholangiopancreatography (ERCP).
Collected information included the causes of pancreatitis; patient characteristics such as age, sex, ethnicity, and weight-for-age percentiles; biomarkers of pancreatitis (amylase, lipase, liver function tests); radiography; and hospital management. The cause of pancreatitis assigned to each case was determined by the association reported in the chart record. Biliary pancreatitis was defined as gallstone pancreatitis, biliary sludge or microlithiasis, pancreatic divisum, sphincter of Oddi dysfunction, and other/structural. A diagnosis of sludge-induced pancreatitis required radiographic evidence of sludge in the gallbladder or CBD, CBD dilatation, and the absence of gallstones. Sphincter of Oddi dysfunction was diagnosed using sphincter of Oddi manometry (12). Other/structural biliary pancreatitis included cases in which an anatomic abnormality caused a disruption in normal pancreaticobiliary function. Nonbiliary causes of pancreatitis included medications, idiopathic, systemic illness, trauma, viral infection, a metabolic condition, ERCP, cystic fibrosis, and alcohol.
We stratified our cohort into 3 subsets. The first was a comparison between 2 groups within the entire cohort: nonbiliary and biliary cases of pancreatitis. The second analysis evaluated differences between 2 age groups within the biliary subset: young children (0–10 years) and adolescents (11–20 years). The third was a comparison of 2 subsets of the biliary group: gallstone- and sludge-induced pancreatitis.
Continuous variables were analyzed using the Student t test and the Wilcoxon rank sum test for normally and non-normally distributed data, respectively. Comparisons of discrete variables were performed by χ2 and Fisher exact test. P < 0.05 in bivariate analyses was considered statistically significant. Associations with P < 0.10 from the bivariate analyses were included in multiple logistic regression models. Non-normally distributed data were log-transformed before we conducted the adjusted analyses. Selection of important clinical predictors was performed using the backward stepwise approach. In the logistic regression models, variables with P < 0.05 were considered significant independent predictors. Data were analyzed with SPSS 16 software (SPSS Inc, Chicago, IL). Age-adjusted percentiles for weight-for-age data were calculated using a program provided by the Centers for Disease Control (Atlanta, GA) and SAS (SAS Institute, Cary, NC).
Causes of Biliary Pancreatitis
Biliary causes accounted for 28% of the 271 acute pancreatitis cases and represented the most common cause in our study cohort. In 3% (2) of biliary cases, >1 other cause was present. Gallstone- and sludge-induced pancreatitis accounted for most causes of biliary pancreatitis (55% and 21% of causes, respectively).
Other biliary causes included sphincter of Oddi dysfunction (5%), pancreas divisum (5%), and other/structural causes (14%). The latter included pancreatic cyst or mass compressing the pancreatic duct, pancreatic duct stenosis, annular pancreas, and choledochal cyst. A direct comparison of these biliary causes was not conducted because the sample size was small.
Comparison of Biliary and Nonbiliary Pancreatitis
There were 76 cases (68 children) of biliary and 195 cases (156 children) of nonbiliary pancreatitis. In the biliary pancreatitis group, there were 17% fewer white children and a 3-fold increase in Hispanic children than in the nonbiliary group (30.7% vs 10.9%, respectively; P = 0.001) (online-only supplemental Table 1 [http://links.lww.com/MPG/A71]). We found that twice as many overweight children were in the biliary group (P = 0.04).
In the biliary group, the median amylase and lipase levels were 3.6 and 14.7 times greater than the ULN (online-only supplemental Table 1 [http://links.lww.com/MPG/A71]). Children with biliary pancreatitis had serum levels of amylase, lipase, and aspartate aminotransferase (AST) that were 64% (P = 0.05), 49% (P = 0.04), and 225% (P < 0.001) greater, respectively, than in children with nonbiliary pancreatitis. Although an 80% higher median total bilirubin was seen in children with biliary pancreatitis (P < 0.001), the total bilirubin levels were within normal limits in both groups. Therefore, this difference did not appear to be clinically relevant.
The majority of children with pancreatitis (83%) had radiographic imaging performed (online-only supplemental Table 1 [http://links.lww.com/MPG/A71]). In the biliary group, 13% more children had radiographic tests performed (P = 0.01). In patients who underwent radiography, a US was the most commonly performed test with >80% frequency in both biliary and nonbiliary cases. CT scans were performed in 51% more children with nonbiliary pancreatitis than with biliary pancreatitis (P = 0.03). Examination of hospital management trends included length of hospital stay, rate of gastroenterology consultation, and method of nutrition after a nil per os (NPO) status (oral or parenteral). There were no significant differences between the 2 groups in any of these parameters.
In the adjusted analysis, Hispanic ethnicity (P = 0.01) and AST (P < 0.001) were significant independent predictors of biliary pancreatitis (Table 1). Hispanic children had a 2.85 (P = 0.01) and 5.59 (P = 0.003) higher probability for biliary pancreatitis than white and black children, respectively. Although the unadjusted association of weight-for-age percentiles with the outcome was significant, it was not found to be an independent predictor in the final model. This was explained by the finding that Hispanic children were more likely to be overweight than other children (P = 0.03).
Comparison of Younger and Older Children With Biliary Pancreatitis
There were 15 cases (15 children) in the younger (0- to 10-year-olds) group and 61 cases (54 children) in the older (11- to 20-year-olds) group with biliary pancreatitis. The younger group constituted 20% of cases (online-only supplemental Table 2 [http://links.lww.com/MPG/A71]). The most common etiologic category among younger cases was other/structural, occurring with a 6-fold greater frequency than in older cases (43.7% vs 7.8%, respectively; P = 0.001).
Comparison of Gallstone- and Sludge-induced Pancreatitis
There were 42 cases (40 children) of gallstone-induced and 16 cases (15 children) of sludge-induced pancreatitis. Cases of gallstone pancreatitis represented 72% of patients in this comparison group (Table 2). More than one-third of children with gallstone pancreatitis were obese, whereas there were no such cases among those with sludge-induced pancreatitis (P = 0.01). No significant differences in age, ethnicity, abdominal pain, and nausea or vomiting were observed.
Analysis of serum biomarkers also showed significant differences between both groups (Table 2). Median lipase in the gallstone group was 30.2 times the ULN and 2.3-fold higher than the sludge group (P = 0.02). Similarly, median AST levels were nearly double the ULN and 84% higher than the sludge group (P = 0.03). The median amylase level in the gallstone group was 4.80-fold higher than the ULN; and, although not statistically significant, there was a trend toward amylase levels being 90% greater than the sludge group (P = 0.07).
Most children with gallstone- and sludge-induced pancreatitis underwent radiographic imaging, with US as the most commonly performed test (Table 2). ERCP was only conducted in patients with gallstone pancreatitis (29% of gallstone cases, P = 0.02). Hospital management trends differed significantly between the 2 groups. The median length of hospital stay in children with sludge-induced pancreatitis was 3 days longer than for children with gallstone pancreatitis (P = 0.003). Conversely, the median time to starting oral or parenteral nutrition after acute NPO status in the sludge group was 2 days shorter than in the gallstone group (P = 0.002). In addition, compared with children with gallstone pancreatitis, 53% more children with sludge-induced pancreatitis had preexisting comorbidities (eg, leukemia, insulin-dependent diabetes mellitus, seizure disorders, asthma, inflammatory bowel disease).
In multiple logistic regression analysis, weight-for-age percentile was a significant independent predictor of gallstone pancreatitis in children (P = 0.02) (Table 1). Neither amylase, AST, nor ethnicity was found to be a significant predictor of gallstone pancreatitis.
The present study uniquely characterizes the presentation of 76 cases of biliary pancreatitis in children from a total cohort of 271 cases of acute pancreatitis. The main findings were that among children with acute pancreatitis, Hispanic ethnicity is a risk factor and an elevated serum AST level is a biomarker for a biliary cause. Additionally, in children with gallstone- or sludge-induced pancreatitis, obesity is a risk factor for gallstone pancreatitis.
Biliary tract disease represented the plurality (28%) of our pancreatitis cases, consistent with previous reports, which have shown that biliary tract disease accounts for 1 of the top 3 causes of acute pancreatitis in children (7,13–17). Because endoscopic or surgical intervention may be needed urgently in the management of acute biliary pancreatitis, it is critically important to examine risk factors that distinguish biliary from nonbiliary pancreatitis (7). The finding that Hispanic ethnicity is a risk factor for a biliary cause may be explained by higher rates of biliary tract disease in this population group, perhaps because of a genetic predisposition or obesity (18–20). We also observed that Hispanic children were disproportionately overweight compared with white and black children. In logistic regression analysis, however, we found that Hispanic ethnicity was independently associated with biliary pancreatitis, whereas obesity was not. Thus, a biliary cause should be suspected in Hispanic children with acute pancreatitis.
Serum amylase and lipase measurements are commonly used in the diagnosis of acute pancreatitis (2,11,15,21). We found that the height of amylase, lipase, and AST levels was significantly higher in children with biliary pancreatitis than with nonbiliary pancreatitis. A similar result was observed in adults (22). In adjusted analysis, AST was found to be a significant biomarker for biliary pancreatitis. Although AST is a hepatic enzyme, obstruction of the CBD, which may occur in biliary pancreatitis, can lead to hepatic injury and thus an increase in AST and ALT levels (23). Our results confirm that a biliary cause should be suspected in children with acute pancreatitis who present with high levels of amylase, lipase, or AST; however, further studies validating an appropriate cutoff level are necessary.
The present study shows that gallstone pancreatitis is common, representing a little more than half (55%) of our acute biliary pancreatitis cases. Sludge-induced pancreatitis (21%) was the second most common biliary cause. To our knowledge, this is the first study to compare the presentation and management of gallstone- with sludge-induced pancreatitis. We report that obesity is a significant independent risk factor for the diagnosis of gallstone pancreatitis in children with acute biliary pancreatitis. Although an odds ratio of 1.02 for weight-for-age percentiles appears low, the effect of this variable is sizeable. Our findings signify that for each unit increase in weight-for-age percentile, the probability of being diagnosed as having gallstone-induced pancreatitis rather than sludge-induced pancreatitis increases by 2%. Therefore, compared with children of average weight-for-age (ie, 50th percentile), overweight children (ie, 85th–95th percentile) have a 70% to 90% increased probability and obese children (ie, 95th–100th percentile) have a 90% to 100% increased probability of presenting with gallstone-induced pancreatitis over sludge induced. Our findings are in some ways consistent with studies in adults, which demonstrate that obesity is a risk factor for the development of gallstones and for the severity of pancreatitis (24–26). Thus, gallstone pancreatitis should be suspected in obese children with biliary pancreatitis.
In children with gallstone pancreatitis, the height of the lipase level was nearly double and AST was 86% higher than those with sludge-induced pancreatitis. A potential reason for this finding may be that, although biliary pancreatitis is associated with elevated hepatic enzyme levels, gallstones are more likely to cause a complete, albeit transient, obstruction of the CBD than sludge and thus lead to higher serum levels of AST. These biomarkers may be clinically useful in conjunction with radiographic imaging to differentiate gallstone- from sludge-induced pancreatitis.
A potential confounder in the interpretation of elevated transaminases as a biomarker of biliary pancreatitis is nonalcoholic steatohepatitis (NASH). Yener et al (27) found that 55% of adult patients with gallstones had associated NASH. We know that obese patients are more likely to have NASH and gallstone pancreatitis; however, at least by US, none of the children in our cohort had evidence of NASH or fatty liver.
Abdominal US was the most frequently used method of diagnostic imaging in all of our study groups, and it is one of the primary diagnostic studies used to evaluate gallstones and sludge (28). Because of constraints imposed by air- and fluid-filled loops of bowel lying above the pancreas, the detection of gallstones in the CBD using abdominal US has a low sensitivity (50%) in patients with acute biliary pancreatitis (29). Given the limitations of abdominal US, algorithms that incorporate risk factors, biomarkers, and diagnostic imaging may assist in the swift and accurate diagnosis of acute biliary pancreatitis. The increased use of CT scans in cases of nonbiliary pancreatitis is likely caused by the need for further investigation to ascertain the definitive cause of pancreatitis.
Although our findings require further validation in a multicenter, prospective study, taken together, they may be used in establishing a framework for diagnosing biliary pancreatitis in children. With the earlier recognition of biliary pancreatitis and more accurate differentiation between gallstone- and sludge-induced pancreatitis, appropriate interventions including ERCP, ursodeoxycholic acid (in children with sludge), and/or cholecystectomy can be pursued more expeditiously, provide relief of symptoms, and reduce the recurrence of pancreatitis (30). In addition to constraints inherent in a retrospective study, the limitations in our study are that all of the cases of pancreatitis were mild and based at a single center. Despite these limitations, to our knowledge our study is the first to examine and distinguish the presentation and risk factors associated with gallstone- versus sludge-induced pancreatitis in childhood.
In summary, elevated AST, lipase, and amylase levels may distinguish biliary pancreatitis from other causes. Hispanic children are more likely to be diagnosed as having biliary pancreatitis. Finally, obesity as well as elevated levels of AST and lipase in children with biliary pancreatitis may be useful in distinguishing gallstone-induced pancreatitis from sludge-induced cases. We hope that our findings will assist in the development of algorithms to accurately diagnose biliary pancreatitis. Furthermore, these data may facilitate the design of prospective studies to determine the optimal evaluation and management of children with biliary pancreatitis.
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