Data Selection and Analysis
We included studies published before May 2016 and available in English. The study population consisted of children and adolescents ages 0 to 22 years. The studies were prospective trials, retrospective reviews, and case reports, and assessed at least 1 of the following: symptoms of biliary dyskinesia, GBEF, and treatment outcomes. We excluded letters to the editor, review articles, abstracts, and proceedings from scientific meetings. We removed duplicates by reviewing citations from the retrieved articles. We screened titles and abstracts of the remaining articles to determine the appropriateness for our study. The authors independently read full text articles from promising abstracts and assessed for eligibility. Any disagreement was resolved to achieve a consensus. We extracted the following data for each eligible study onto a Microsoft Excel Spreadsheet: year and journal of publication, institution, country of origin, study design, demographic data, characteristics of symptoms, and diagnostic criteria for biliary dyskinesia. We included GBEF values, management strategy, type of cholecystectomy, gallbladder pathology, duration of follow-up, short- and long-term outcomes, factors affecting outcomes, and description of persistent symptoms when available. We conducted descriptive analysis from the included studies.
Our search yielded 916 citations. After eliminating duplicates, we screened titles, abstracts, and key words of 393 citations. We excluded 94 abstracts in languages other than English, 145 did not match our age group, and 105 did not match the research questions. Of the 49 remaining full text articles, 10 were not relevant to the evaluation or treatment of biliary dyskinesia, 9 were in adults, and 2 were not in English. Twenty-eight studies met the inclusion criteria; we added 3 articles manually from the searched references. We included 31 studies conducted between 1990 and 2015 (Table 2) (16–46).
Twenty-seven were from investigators in the United States (20–46), 2 from Turkey (16,17), 1 from Puerto Rico (18), and 1 from Australia (19). Twenty-five studies were published in pediatric surgery (16,18,19,23,25–41,43–46) and 6 in pediatric or gastroenterology journals (17,20–22,24,42). All were retrospective chart reviews. There were no prospective randomized controlled trials. The total sample size collectively included 1833 children. Twenty-six studies described symptoms of biliary dyskinesia in 1251 children (16–19,21–27,29,31–36,39–46). All studies evaluated the role of GBEF in 1792 subjects, whereas 30 studies assessed treatment outcomes in 1437 children (16–19,21–46). The largest study that evaluated GBEF included 310 children (20). The next largest assessed symptoms and cholecystectomy outcomes in 213 children (21). Sample size ranged from 3 to 82 subjects in other studies. Age range was 3 to 22 years (M = 13 years), and 74% were girls. In 5 studies noting race, 89% were white (20,27,29,42,45). In 12 studies reporting body mass index (BMI), 48% were obese (18,21,23,24,26–28,31,34,36,37,40).
Diagnostic criteria for biliary dyskinesia included abdominal pain and a normal gallbladder ultrasound in 7 studies (Table 3) (20,21,27,28,30,37,41). Of the 27 studies that included abdominal pain in the diagnosis, 4 required “biliary type abdominal pain” without further explanation (18,21,40,41), 2 specified biliary colic (34,37), and 8 required right upper quadrant and/or epigastric or upper abdominal pain (19,23,25,28–30,42,45), whereas 12 included a broad inclusion criteria of “abdominal pain or other symptoms” (16,22,26,27,31–33,35,36,38,43,44,46). One study included patients with either biliary colic or nonspecific pain accompanied by a low GBEF (39). Six studies included nausea or vomiting (22,27,28,30,32,36), 2 postprandial symptoms (28,29), 2 fatty food intolerance (18,32), and 2 had appetite disturbance (30,36) in the diagnostic criteria. Except for 5 studies, all provided characteristics of symptoms (16–19,21–27,29,31–36,39–46). Duration of symptoms from onset to treatment ranged from 3 days to 10 years (M = 11 months). Abdominal pain was the dominant symptom in most children, and was described in the right upper quadrant in 502 (40%), epigastric in 217 (17%), both in 90 (7%), diffuse in 178 (14%), or not specified for 166 (13%) children. Twelve studies described details regarding pain location, frequency, and association with meals: 57 (5%) had periumbilical pain, 27 (2%) had “lower abdominal pain,” and 25 (2%) had “upper abdominal pain” (16,21–24,27,33–35,40,42,45). Pain was described as daily in 61%, constant in 16%, and weekly in 11%. Only 2 studies described biliary colic in 63% of patients (23,24). Postprandial symptoms were reported in 60%. Night waking due to pain was reported in 43%. Twenty-five studies described nausea and/or vomiting in 215 (18%), nausea alone in 408 (34%), and vomiting in 284 (23%) children (16–19,21–27,31–36,39–46). Twenty-three studies reported fatty food intolerance in 174 (51%), anorexia in 53 (16%), weight loss >3 kg in 94 (16%), diarrhea in 102 (18%), and constipation in 57 children (12%) (16–19,21–23,25,26,29,31–33,35–37,40–46). Back pain (30%), headaches (18%), fatigue (11%), heartburn (25%), rumination (12%), flatulence (8%), bloating (7%), belching (5%), and lactose intolerance (3%) were symptoms noted in 10 studies (16,21,23,25,29,35,40,41,44,45).
Misra retrospectively reviewed charts of 61 children and found that 59 (approximately half of whom underwent cholecystectomy) met diagnostic criteria for a functional gastrointestinal disorder: 39 subjects met criteria for functional abdominal pain and 20 met criteria for functional dyspepsia. None of the children met adult Rome criteria for a functional gallbladder disorder (22). One study reported 40% with atypical pain (23). In a large study, 44% underwent cholecystectomy, even though their presentation was not consistent with the diagnostic criteria for biliary dyskinesia in adults (21).
Gallbladder Ejection Fraction
The diagnosis of biliary dyskinesia required an abnormal GBEF in 24 studies (16–19,22–26,29,31–36,38–40,42–46). Eighteen studies defined abnormal GBEF as <35% (16–18,22–25,29,31,35,36,38–40,42,43,45,46), 2 <40% (32,44), and 2 <50% (19,26). Two studies included only patients with hyperkinesia, GBEF >70% (33) and >80% (34), respectively. All studies assessed GBEF. GBEF was measured by cholescintigraphy following a commercial fat preparation in 1 (24), CCK-CS in 25 studies (16,18–23,29–46), and CCK-CS and/or an ultrasound following a fatty meal in 5 studies (17,25–28). Different protocols for CCK-CS were used, but most followed technique described by Fink-Bennett et al or Ziessman (3,47). Six studies included CCK infusion during 30 to 60 minutes in their protocol (19,21,25,31,43,46), 10 included a bolus over 30 seconds to 15 minutes (16–18,22,23,26,29,32,44,45), whereas 14 did not specify (20,27,28,30,33–42). Sixteen studies measured gallbladder emptying at 30 minutes (16,17,19,22–26,29,31,32,35,39,43–45), 3 at 60 minutes (18,42,46), and 12 did not specify (20,21,27,28,30,33,34,36–38,40,41). Two studies included pain during CCK administration in their biliary dyskinesia criteria (36,38). Eleven studies documented pain during CCK injection in 48% (19,21,23,28,32–34,36–38,40). GBEF ranged from 0% to 98% (M = 22%). Five studies described better cholecystectomy outcomes in patients with delayed gallbladder emptying, GBEF <11% (29), <15% (30,31), and < 35% (23,32). Two studies reported patients with GBEF >70% (33) and >80% (34) to benefit from cholecystectomy. Twelve studies showed no correlation between GBEF and outcomes (21,22–24,27,28,35–40). In the largest study, GBEF had no influence on the decision for cholecystectomy (20). Symptoms did not correlate with GBEF (26). In 3 studies assessing GBEF on 2 occasions, a majority of subjects with abnormal GBEF had a normal value when the test was repeated (35,41), whereas 1 study found consistently low GBEF on repeat testing (24). GBEF values measured by CCK-CS and ultrasound following a fatty meal did not correlate (27).
Outcomes of Cholecystectomy
Of the 1437 cholecystectomies, 78% were performed laparoscopically, 3% were open, and 19% did not specify.
Thirty articles provided pathology of resected gallbladders (16–21,23–46). Inflammation rates ranged from 15% to 100%. One study reported increased number of activated mast cells in the gallbladder wall compared with healthy controls and found low mast cell density to correlate with complete resolution of symptoms (42). One study observed a correlation between preoperative symptom duration and severity of cholecystitis (18). Another study showed that chronic cholecystitis correlated with persistent postoperative symptoms (31). In a majority of studies, pathologic changes did not correlate with GBEF (18,20,42) or response to cholecystectomy (23,27,28,30,32,35–40).
Thirty studies reported outcomes using clinic records (12), telephone surveys (14), or both (4) (Table 4) (16–19,21–46). Duration following surgery ranged from 6 days to 11 years (M = 24 months). Most studies defined resolution as complete cessation of symptoms without recurrence. Thirteen studies reported short-term resolution of symptoms (2 weeks to 6 months) in 54% to 100% of patients (M = 73%) (21–27,33,35,37,39,42,43). Only 66% of patients remained symptom-free at long-term follow-up (6 months to 11 years). Resolution rates in individual studies ranged from 34% to 100%. Postoperative symptoms included abdominal pain (49%), nausea (24%), food intolerance (15%), emesis (10%), diarrhea (9%), gastroesophageal reflux (5%), constipation (4%), and anorexia (2%). After cholecystectomy 18% were not attending school due to abdominal pain, and 52% were diagnosed with another condition in 7 studies (14% irritable bowel syndrome, 10% cyclic vomiting, Crohn disease, hiatal hernia; 12% another functional gastrointestinal disorder, 10% gastroesophageal reflux disease, 3% with Sphincter of Oddi dysfunction, 2% with pancreas divisum, and 1% with wheat allergy) (25,26,30,36,38,39,41).
Five nonrandomized chart reviews assessed benefit from cholecystectomy versus medical management or observation (22,26,35,41,43). Two studies included a trial with acid blockers before laparoscopic cholecystectomy (LC) and had contradictory results (26,41). Dumont and Caniano (26) reported long-term resolution after cholecystectomy in 88% of children who failed a 4-week trial with a proton pump inhibitor or a histamine-H2 receptor antagonist. In contrast, in a small study by Karnaskul, success rates were comparable with LC (44%), use of proton pump inhibitors (40%), and observation (67%) (41). Similarly, Scott-Nelson showed comparable success rates after 2 years but a quicker resolution of symptoms in 35 children who underwent LC (74%) than 20 children (75%) who were managed nonoperatively (35). Misra reported pain resolution in 88% children at 3 to 6 months after cholecystectomy compared with 55% managed medically. After 5 years, only 52% remained symptom free in the cholecystectomy group, but 86% reported complete resolution in those treated without surgery (22). One study could not assess outcomes in the group managed without surgery due to a poor follow-up (43).
Twenty-one studies assessed factors influencing outcomes (18,21–25,27–40,42). Four studies reported poor outcomes in those with a longer duration of symptoms (23,27,29,36). Nausea (30), vomiting (27), epigastric pain (27), male sex (23), weight loss (35), absence of comorbid conditions (36), “lower gastrointestinal disease” (27), and GBEF <11% (29) and <15% (30,31) were reported as independent predictors of successful outcomes in different studies. Lyons et al (29) showed a trend for favorable outcomes with right upper quadrant pain. Brownie et al (28) found a negative correlation between overweight and obesity and symptom resolution. Reproduction of pain with administration of CCK, age, race, BMI, psychologic disorders, gallbladder pathology, and several other factors failed to predict outcomes (22,24,32,37–40). Three studies compared factors influencing outcomes in cholecystectomy for biliary dyskinesia and cholelithiasis (18,21,25). Operating time and length of hospital stay were lower in biliary dyskinesia (25). Children with biliary dyskinesia were more likely to have dyspepsia (18), lower BMI, right upper quadrant pain, bloating, diarrhea, chronic headaches (21), persistent symptoms at short-term follow-up, food intolerance (25), weight loss, constipation, and a longer duration of symptoms (21,25).
This is the first systematic review evaluating biliary dyskinesia in children, to our knowledge. We incorporated a search strategy that included 7 databases and bibliographies of all included studies, and we obtained data from nearly 1900 children. We established inclusion criteria and the authors individually reviewed studies to decrease reviewer error and bias. We examined diagnostic criteria, validity of GBEF measured by CCK-CS or an ultrasound following a fatty meal, and outcomes after cholecystectomy. We appraised study methods, summarized results, and presented key findings.
Overall, the observational, retrospective study designs that dominated in our review limited interpretation of safety, utility, and efficacy of the investigations and treatment (48). There was no standard, generally agreed upon definition for the biliary dyskinesia diagnosis. Daily and constant pain and its inconsistent location in >50% of patients was incongruent with the definition of biliary colic, a requirement for the diagnosis of biliary dyskinesia in adults. Approximately half of the studies included a broad definition of abdominal pain or associated gastrointestinal symptoms that did not include typical biliary colic.
CCK-CS is used in adults to diagnose sphincter of Oddi dysfunction, to differentiate common duct obstruction from normal variation, and to exclude acute acalculous cholecystitis (4). This procedure uses technetium 99m–labeled iminodiacetic acid to assess GBEF after administration of CCK (49). There is variability in technique in terms of dose, duration, abnormal cut-offs, and use of a commercial CCK analogue or a fatty meal. Different techniques have employed 3-minute injections or 30- to 60-minute infusions and established normal GBEF values at 35% (3,47,49) and 40% (2). Short duration infusions and boluses are deemed nonphysiologic and result in inefficient contractions (50).
Delayed gallbladder emptying occurs in 15% to 25% of healthy adults (4,51) and can be associated with achalasia, diabetes, sprue, sickle cell disease, and pregnancy (4). Narcotics, proton-pump inhibitors, calcium channel agonists, progesterone, and parenteral nutrition also slow gallbladder emptying (52). One study in children showed delayed emptying in food allergies, obesity, parasitic infections, gastroesophageal reflux disease, and constipation (7). Studies in adults (4,5) and 3 studies in children (6–8) demonstrated delayed gallbladder emptying in irritable bowel syndrome, functional abdominal pain, and functional dyspepsia. We found variability in techniques measuring GBEF and in CCK-CS protocols. GBEF values had a wide range; they were inconsistent, even in individual patients and did not correlate with symptoms. GBEF differed or normalized on repeat testing in a few. A third of the studies did not include GBEF in their diagnostic criteria for biliary dyskinesia. Of those that did, abnormal values varied. Different authors came to different conclusions regarding its prognostic value. GBEF did not correlate with outcomes in some studies. Hypokinesia and hyperkinesia contradicted in independently predicting successful outcomes after cholecystectomy. GBEF measured by CCK-CS failed to consistently prove diagnostic or prognostic in biliary dyskinesia. Our conclusion is similar to the published literature regarding GBEF in biliary dyskinesia (4,52). Studies are needed to standardize the method and to assess the validity and reliability of CCK-CS in children.
There was variability in gallbladder histopathology, with mucosal inflammation in many specimens. Is there a spectrum of mucosal inflammation in biliary dyskinesia or does mucosal inflammation mean that patients with cholecystitis were mistakenly diagnosed with biliary dyskinesia? There were increased inflammatory cells in other functional disorders: lamina propria lymphocytes in postinfectious irritable bowel syndrome (53), and duodenal eosinophilia and mastocytosis in functional dyspepsia (54,55). It is possible that there is mucosal inflammation in some cases of biliary dyskinesia because there is in some cases of irritable bowel syndrome and functional dyspepsia. Without asymptomatic age-matched children for comparison, it is not possible to come to conclusions.
Successful outcomes after LC varied from 34% to 100%. Longer duration of symptoms predicted poorer outcome. In designing drug trials for functional disorders, investigators usually plan on a 40% placebo effect when determining sample size. Similarly, surgical procedures to reduce pain are subject to the placebo response (56). Several instances of placebo-controlled trials for pain did not demonstrate superiority of frequently performed operations over sham-operated controls (57,58). One possibility is that in our study the short-term success rates were improved by the placebo effect of surgery. The observational design limited definitive evidence that LC has an advantage over nonsurgical treatment for chronic upper abdominal pain. Cholecystectomy may be an attractive proposition for those experiencing chronic pain, because it offers a quick fix to the problem, and the opportunity to provide symptom relief may motivate the surgeon.
Functional Dyspepsia and Management
Functional dyspepsia is the most common upper functional gastrointestinal disorder in children (59). There are validated criteria for a functional dyspepsia diagnosis. Functional dyspepsia may be managed with pharmacologic and/or behavioral interventions. The Cochrane Center for Registered Trials includes 300 prospective randomized controlled trials assessing treatment of functional dyspepsia in adults and 10 in children. There are at least 7 high-quality double-blinded randomized controlled trials in the treatment of functional dyspepsia in children (60).
The symptoms of pediatric functional dyspepsia overlap with symptoms of pediatric biliary dyskinesia. The diagnosis of functional dyspepsia includes one or more of the following bothersome symptoms at least 4 days per month for at least 2 months: postprandial fullness, early satiety, epigastric pain or burning not associated with defecation, and after appropriate evaluation, the symptoms cannot be fully explained by another medical condition (61). Some clinicians familiar with dyspepsia and functional dyspepsia may conduct an evaluation for upper abdominal pain and/or discomfort and diagnose endoscopy negative patients with functional dyspepsia. Clinicians unfamiliar with functional dyspepsia may diagnose biliary dyskinesia on patients with the same symptoms. Studies of functional dyspepsia rarely mention biliary dyskinesia. Studies of biliary dyskinesia rarely mention functional dyspepsia. There are 2 explanations for the overlap between symptoms in biliary dyskinesia and functional dyspepsia: biliary dyskinesia does not exist in pediatrics; functional dyspepsia and biliary dyskinesia may coexist in the same patient. They are both functional disorders, manageable without surgery.
Children with upper abdominal pain are managed medically or surgically based on the provider. The gastroenterologist practicing the biopsychosocial model of medicine and familiar with functional disorders will diagnose children with endoscopy negative upper abdominal pain in the absence of warning signs of disease (weight loss, fever, or blood in stools) as having functional dyspepsia. The gastroenterologist using the biomedical model of practice, not recognizing the functional gastrointestinal disorders but believing all true symptoms are explained by measurable tissue abnormality, is likely to diagnose biliary dyskinesia and refer to the pediatric surgeon. There is no well-defined nonsurgical management of biliary dyskinesia.
Although it is unethical to randomize children into cholecystectomy and sham laparoscopy groups, it might be possible to conduct a randomized controlled trial comparing medical and surgical management. In fact, a recent prospective trial in adults compared cholecystectomy to amitriptyline 25 mg at bedtime. Most patients in the amitriptyline group crossed over to surgery and data could not be analyzed due to incongruent group sizes (62). Meanwhile, it may be prudent to advocate medical over surgical management for 2 reasons: biliary dyskinesia is not a life-threatening disorder and there are no serious complications; some children continue to experience symptoms after cholecystectomy.
Our review found heterogeneity in requirements for a diagnosis of biliary dyskinesia, the execution and interpretation of gallbladder emptying studies, and surgical outcomes. The absence of correlation between gallbladder emptying studies and symptoms cast doubt that GBEF is a marker for biliary dyskinesia. The uncontrolled studies employed diverse criteria, and were subject to the investigators’ bias. New clinical studies will require a consensus on entry criteria and outcome measures. There is a need for prospective randomized controlled trials comparing medical versus surgical management in children with upper abdominal pain.
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Keywords:© 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
cholescintigraphy; functional dyspepsia; gallbladder; laparoscopic cholecystectomy; upper abdominal pain