Chumpitazi, Bruno P.*; Malowitz, Stanton M.*; Moore, Warren†; Gopalakrishna, G.S.*; Shulman, Robert J.*
Functional gallbladder disease, commonly known as biliary dyskinesia (BD), is a recognized cause of dyspeptic symptoms, including epigastric or right upper quadrant abdominal pain, nausea, and vomiting in adults (1). Although not formally recognized by the Rome III committee for functional gastrointestinal disorders in children (2), an increasing consensus is forming that children, like adults, also have BD (3). In fact, BD is the most common indication for pediatric cholecystectomy at certain institutions (3). Biliary dyskinesia may result in significant morbidity given that up to 52% of children and 23% of adults with BD may have no improvement or continue to have significant symptoms despite undergoing surgical cholecystectomy, the primary treatment (4). The reason for this remains unclear, leaving those affected and the clinicians caring for them to struggle with determining whether a cholecystectomy is helpful and the aftermath if a cholecystectomy is done without resolution of symptoms.
One potential aspect of the difficulty with the diagnosis and treatment of BD may lie in its nonspecific presentation and the manner in which it is diagnosed. Evaluation is often done through cholecystokinin (CCK)-stimulated cholescintigraphy with calculation of a gallbladder ejection fraction. A calculated gallbladder ejection fraction of ≤35% is considered to be abnormal in children (5,6); however, a standardized protocol followed by all pediatric institutions has not been proposed to date. Moreover, dyspeptic symptoms are not specific to gallbladder disorders, and may occur in children with other entities, including gastroparesis (GP) (7).
To our knowledge, a potential overlap between GP and functional gallbladder disease has not been explored. We hypothesized that a subgroup of children with a diagnosis of BD may have concomitant GP, and those with both motor disorders would be more likely to have an unfavorable clinical outcome. We therefore undertook a study to determine the prevalence of concomitant GP in children with BD, and to determine whether its presence affected long-term clinical outcome in children with BD.
A retrospective chart review of all children undergoing CCK-stimulated cholescintigraphy at Texas Children's Hospital from 2002 to 2008 was completed. All of the children with a gallbladder ejection fraction of <35% who had completed a solid-phase gastric emptying study within 1 year of the cholescintigraphy were identified. Of these children, those with documented cholelithiasis, microlithiasis, gallbladder wall thickening, pericholecystic fluid, or bile duct dilatation via ultrasonography or any other radiologic modality before or within 3 months after the cholescintigraphy were excluded. Children with an identified organic (eg, peptic ulcer disease) cause on endoscopic evaluation that could account for the dyspeptic symptoms as determined by the judgment of the primary gastroenterologist were excluded. Children who had laboratory elevations in aminotransferases, bilirubin, or γ-glutamyl transferase were also excluded. The study was approved by the Baylor College of Medicine institutional review board.
CCK-stimulated cholescintigraphy was performed in the same manner in all of the children. Children took nothing per os and were not allowed to be taking any form of narcotics for at least 4 hours before tracer injection. Up to 5.0 mCi (adjusted based on Clark's formula for those <70 kg) of technecium-99m (99mTc) methyltribromoiminodiacetic acid was injected (8). Nuclear images were obtained for 1 minute per frame through 60 minutes, with extension up to 120 minutes if slow gallbladder filling occurred. After gallbladder filling, CCK (Sincalide, Bracco Diagnostics, Princeton, NJ) was injected at a dose of 0.02 μg kg−1 (maximum 2 μg) intravenously for 5 minutes. Images were obtained at 1 minute per frame for 30 minutes after the start of the injection. Gallbladder ejection fraction was calculated as maximum emptying for the 30 minutes following injection, with usage of the immediate preinjection frame activity as the baseline (9,10).
Solid-state gastric emptying scintigraphy was performed using a meal consisting of 120 mL of scrambled eggs, although 1 child with an egg allergy used oatmeal. The meal was radiolabeled with 0.5 mCi 99mTc sulfur colloid and orally fed to the patient. Images were obtained in the left anterior oblique projection while the patient was supine for 90 minutes. A half-emptying time was calculated by using a linear fit method. A half-emptying time of >90 minutes was considered delayed based on our institution's predetermined standards.
Demographic data, height, weight, clinical symptoms, and interventions were captured. Proton pump inhibitors or histamine receptor antagonists were classified as antisecretory agents. Metoclopramide, domperidone, and erythromycin were classified as prokinetics. Tricyclic antidepressants, gabapentin, or selective serotonin receptor antagonists were classified as neuromodulators. Medications were included as an intervention if they were prescribed by the primary gastroenterologist for the dyspeptic symptoms at any point during the follow-up period whether they were still being used at the time of the last follow-up visit.
Baseline dyspeptic symptoms were obtained from the time of initial presentation. Dyspeptic symptoms that were evaluated included abdominal pain severity and frequency, nausea severity and frequency, and degree of food intolerance. Clinical outcome was determined by documented dyspeptic symptom characterization at the time of the last documented follow-up visit as compared to the baseline (first) visit in the electronic medical record. Food intolerance was defined as any exacerbation in a dyspeptic symptom associated with food intake. Activity limitation was defined as missing school days due to the symptoms or inability to complete desired extracurricular activities (eg, sports) due to the symptoms. Weight loss was defined as a ≥10% decrease in baseline weight attributed to the dyspepsia.
Children were categorized into 4 clinical outcome groups based on physician documentation at the time of last-follow-up:
1. Poor: Any symptom worsening or no improvement in any symptom compared to baseline or activity limitation at the time of last follow-up as compared to baseline
2. Fair: Partial improvement in some but not all of the dyspeptic symptoms at the time of last follow-up as compared to baseline
3. Good: Improvement of all of the dyspeptic symptoms but not complete resolution of the symptoms at the time of last follow-up as compared to baseline
4. Excellent: Complete resolution of all of the symptoms
For analysis purposes, excellent and good outcomes were considered to be favorable, and fair and poor outcomes were considered to be unfavorable.
Data are reported as mean ± standard deviation. Comparisons between children with GP and BD and those with BD alone were done with χ2 analysis when comparing proportions or independent Student t tests. Comparisons between baseline and outcome were done with χ2 analysis when comparing proportions or paired t test analysis. Binary multivariate forward stepwise logistic regression was completed with favorable and unfavorable outcomes being the binary dependent variable. Body mass index percentage (BMI%) was categorized into 2 groups (BMI% <85% and BMI% ≥85%) for the logistic regression analysis. χ2 analysis was used to compare proportions in all other testing done. A P value of <0.05 was considered as statistically significant. All of the statistical analyses were performed using SPSS (SPSS Inc, Chicago, IL).
One hundred seventeen children were found to have an abnormal cholescintigraphy during the study interval, 48 (41) of whom completed a gastric emptying scintigraphy study. Of these 48, 35 children met inclusion and exclusion criteria and were studied further. The mean follow-up time was 23.1 ± 17.3 (range 1.7–55.0) months with a median follow-up time of 19 months. The mean length of time between gastric emptying scintigraphy and cholescintigraphy was 2.1 ± 2.8 (range 0.1–11.0) months with a median time interval of 0.7 months. Twenty-three (67%) children completed the gastric emptying scintigraphy before the cholescintigraphy study. Fifteen children (43%) were identified as having normal gastric emptying with BD, and 20 children (57%) were identified as having concomitant GP and BD. Children with BD and concomitant GP did not differ from those with normal gastric emptying with respect to age, sex, race/ethnicity, private insurance, BMI%, ejection fraction on CCK-stimulated cholescintigraphy evaluation, number of formally diagnosed psychiatric comorbidities, or activity limitation at baseline (online-only supplemental table, http://links.lww.com/MPG/A86).
Children with concomitant GP and BD did not differ from those without GP with respect to presence of abdominal pain, exacerbation of pain with food intake, nausea, vomiting, or weight loss (supplemental table, http://links.lww.com/MPG/A86); however, children with concomitant GP were more likely to have constipation, and there was a nonstatistically significant trend for children without concomitant GP to have diarrhea (supplemental table, http://links.lww.com/MPG/A86).
Other than the usage of prokinetics, children with BD and concomitant GP did not differ from those with BD alone with respect to frequency of cholecystectomy, use of neuromodulators, or use of antisecretory therapy (supplemental table, http://links.lww.com/MPG/A86).
Among the entire follow-up population (Fig. 1), children with concomitant GP (9/20) were more likely than those with BD alone (0/15) to have a poor clinical outcome (P < 0.005). Those with concomitant GP (10/20) were less likely than those with BD alone (13/15) to have a favorable outcome (P < 0.05). With the use of multivariate regression including demographic factors, symptoms, and gastric emptying scintigraphy results, only activity limitation (odds ratio 42.8) at baseline (P < 0.005) and having an abnormal gastric scintigraphy (odds ratio 19.3) evaluation (P < 0.05) predicted an unfavorable outcome (r2 0.61).
When comparing children included in the study with a time interval of <1 month between cholescintigraphy and gastric emptying scintigraphy with those with an interval >1 month between studies, no difference was found with respect to demographics, symptoms, intervention, or outcomes. Similarly, when comparing children with a follow-up of >19 months with those <19 months, there was no difference in clinical outcome found between the groups. Therefore, the time interval between scintigraphic studies and the follow-up interval did not appear to have a measurable effect within the study.
When comparing the long-term outcome among only those children who underwent a cholecystectomy, children with concomitant GP were still more likely to have an unfavorable outcome, P < 0.01). Among all of the children studied, no differences in outcome were found in those with constipation, usage of prokinetics, status postcholecystectomy, or having cholecystitis status postcholecystectomy,
We found that concomitant GP may occur in children with BD, and that those with concomitant GP were more likely to have an unfavorable clinical outcome. In addition to concomitant GP, having activity limitation at baseline increased the likelihood of an unfavorable outcome.
More standardized methods are needed to help identify the primary cause of dyspeptic symptoms in children, particularly if a motor abnormality such as GP or BD is suspected. Consensus recommendations to standardize solid-phase gastric emptying scintigraphy and cholescintigraphy in adults have been proposed (11,12). Similar standardization of nuclear medicine techniques and normal values are lacking in children. The normal gastric emptying scintigraphy values in our study are used clinically on an everyday basis within our institution based on internal standards. A cholescintigraphy ejection fraction of ≤35% to identify children with BD is the most common cutoff used in the literature (5,6), and we followed this growing consensus.
The reason for a less favorable outcome in children with concomitant GP and BD is unclear. One possibility may include misdirected therapies. Given that the symptoms of GP may overlap with those of BD, identifying if one or the other is causing the majority of the symptoms is likely to be difficult. Therapies directed at only BD (eg, cholecystectomy) may not address the symptoms if there is GP present and vice versa. Having concomitant gastric and biliary motor abnormalities may suggest that a more diffuse neuroenteric abnormality is occurring, and directed therapies may not be able to address this well. Diffuse motor abnormalities of numerous gastrointestinal organs, including the gallbladder and stomach, have been described in adults with chronic intestinal dysmotility (13).
Children with concomitant GP and BD were more likely to have constipation in our study. In contrast, there was a trend toward diarrhea in children with BD alone. These bowel habit findings may aide clinicians in identifying children in whom to consider further diagnostic testing for the etiology of dyspeptic symptoms, and may also support the possibility of a more diffuse process. Others have suggested a connection between bowel habits and dysmotility of other gastrointestinal organs. Altered gallbladder motility as measured via cross-sectional ultrasound in children with chronic constipation has been described (14). The authors found that children with constipation, whether affected or unaffected, were significantly more likely to have impaired gallbladder contractility as compared with controls (14). In a similar vein, another group recently identified dyspeptic symptoms and slowed gastric emptying in children with functional constipation (15). Both the dyspeptic symptoms and gastric emptying improved following osmotic laxative usage (15). Although having constipation did not predict an unfavorable outcome in a univariate or a multivariate analysis in our study, given the potential relation of constipation to both gastric emptying and gallbladder function, we suggest identifying the possible presence of constipation and if present, addressing constipation in every child with dyspeptic symptoms.
Multivariate analysis identified baseline activity limitation as a predictor of an unfavorable clinical outcome in our population. This may have been in part due to the usage of activity limitation within the clinical outcome measure in our study. Activity limitation (eg, school absences) as an outcome has been used to measure success following cholecystectomy for childhood BD (16) and is included in general pediatric quality of life measures (17) and those specific to childhood chronic abdominal pain (18). Given this, we believed it was important to include this information in assessment of clinical outcome. Activity limitation due to symptoms may be a marker of severity, and this may account for more unfavorable outcomes at time of follow-up, although further evaluation of this is needed prospectively.
Other groups have identified factors such as sex (male), shorter duration of symptoms, type of symptoms (eg, nausea), and ejection fraction on cholescintigraphy <15% as being predictive of successful resolution of symptoms following cholecystectomy in children with BD (5,19); however, different studies have not identified the same predictive factors. In a similar vein, baseline activity limitation and/or presence of GP as predictive factors have not been evaluated for by others. Part of the challenge may lie in the relatively small number of children described in the literature to date. Larger studies that take into account candidate predictive factors with more uniform outcome measures are needed for children with functional gallbladder disorders.
There are several limitations to the present study. First, the study is retrospective and therefore concomitant medications (eg, antacids), probiotics, diet, follow-up intervals, and characterization of dyspeptic symptoms were not standardized; however, this may have been ameliorated in part by the fact that 1 gastroenterologist (G.S.G.) was involved in the care of the majority of the patients, helping to make management and outcome assessment more uniform. Second, generalizability may be limited because scintigraphic testing and protocols were institution standardized and may not reflect the protocols used in other institutions. Third, selection bias may have occurred because not all of the children have routinely undergone both a gastric emptying scintigraphy and cholescintigraphy for dyspeptic symptoms at our institution. The included children may have had clinical factors that made clinicians suspect concomitant GP as being more likely.
To our knowledge, the present study is the first to determine that children with BD may have concomitant GP and the potential clinical effect of this association. Pending further studies investigating the relation with BD and GP, we suggest consideration for assessment for both motor disorders, particularly in a child with dyspepsia who has activity limitation at the time of presentation.
We thank Cynthia Tsai for assistance with obtaining portions of the data.
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