Pediatric Normokinetic Biliary Dyskinesia: Pain with Cholecystokinin on Hepatobiliary Iminodiacetic Acid Scan Predictive of Symptom Resolution After Cholecystectomy

Abstract

Introduction:

Biliary dyskinesia is typically defined as a gallbladder ejection fraction (EF) <35% on hepatobiliary iminodiacetic acid scan with cholecystokinin stimulation (CCK-HIDA) testing. Cholecystectomy often leads to resolution of associated biliary colic symptoms. Alternatively, there is a subset of symptomatic patients with normal gallbladder EF on CCK-HIDA. It has been proposed that pain with CCK injection is more predictive of symptom resolution after cholecystectomy than low gallbladder EF. We reviewed our experience with pediatric patients with positive CCK provocation testing and a normal gallbladder EF in the absence of gallstones.

Materials and Methods:

We retrospectively reviewed the records of all pediatric patients with normal hepatobiliary iminodiacetic acid EFs (35%–80%) and pain with CCK injection at a tertiary care center between 2016 and 2020. Age, gender, body mass index (BMI), CCK-HIDA results, and pathology analysis were noted. Short- and long-term resolution of symptoms was determined by patient self-reporting at a mean of 3 weeks and 46 months, respectively.

Results:

Seventeen patients met inclusion criteria. Average age was 15.1 years (range, 12–17 years) with median BMI 24.9 (± 4.9 kg/m²). Mean CCK-HIDA EF was 56.3% (± 11.4%). In total, 62.5% of patients had evidence of chronic cholecystitis and/or cholesterolosis on pathology analysis. Of patients available for short-term and long-term postoperative follow-up, 80% and 83% reported complete or near complete resolution of symptoms, respectively.

Conclusions:

Normokinetic biliary dyskinesia is poorly understood but appears to be associated with chronic inflammation and cured by surgical intervention. Laparoscopic cholecystectomy results in resolution of symptoms for a majority of patients and should be considered in those with pain with CCK injection despite normal imaging studies. Clinical Trial Registration Number: 1657640-2.

Introduction

As the incidence of symptomatic biliary dyskinesia has significantly increased over the past several decades, so too have the rates of pediatric cholecystectomy.^1–4 The distribution of pediatric gallbladder and biliary disease is shifting as the pediatric population is changing. Although the rates of congenital biliary disease have remained relatively stable, the rates of acquired pathologies such as cholelithiasis and biliary dyskinesia have increased.^1,3 Therefore, the indications for pediatric cholecystectomy may need revision as the landscape of pediatric gallbladder disease changes.

The adult and pediatric literature both support cholecystectomy as an effective treatment for hypokinetic biliary dyskinesia. Hypokinetic biliary dyskinesia is most commonly defined as symptomatic biliary colic in the absence of cholelithiasis with evidence of a depressed ejection fraction (EF) (typically defined as EF <35%) on a hepatobiliary iminodiacetic acid (HIDA) scan with cholecystokinin (CCK) stimulation. The current evidence demonstrates symptomatic relief after cholecystectomy in this subset of pediatric patients.^4–16

More recently, biliary hyperkinesia, with an EF on HIDA >65%–80%, has emerged as an underdiagnosed etiology of abdominal pain in both children and adults. Like hypokinetic biliary dyskinesia, this disease process can be cured with cholecystectomy.^17–23 Pediatric patients with biliary hyperkinesia at our centers have demonstrated significant symptom resolution after cholecystectomy.²²

However, there is another subset of patients who exhibit a normal EF but have pain that is reproducible on CCK-HIDA testing despite the absence of cholelithiasis. Current evidence in the adult literature, although limited, suggests that reproduction of pain after administration of CCK may be a better predictor of symptom resolution after cholecystectomy than the calculated EF.^24,25 Our aim was to determine whether the same is true for pediatric patients. The objective of this study was to determine whether pediatric patients with normokinetic biliary dyskinesia (i.e., patients with normal gallbladder EF [35%–80%] and reproducible pain after CCK injection in the absence of cholelithiasis) would symptomatically benefit from cholecystectomy.

Materials and Methods

With IRB approval, we performed a retrospective chart review of pediatric patients (age ≤18 years) who underwent laparoscopic cholecystectomy between January 2016 and March 2020, and preoperatively were found to have both a normal HIDA EF (35%–80%) and right upper quadrant or epigastric abdominal pain during CCK injection. This combination of normal gallbladder EF and reproducible pain with CCK injection was defined as “normokinetic biliary dyskinesia.” Preoperative clinical characteristics such as age, gender, body mass index (BMI), and CCK-HIDA results were obtained. In addition, the operation performed and postoperative outcomes such as pathology results and patient self-reported symptom resolution were reviewed.

Preoperative clinical characteristics were assessed by chart review. Resolution of biliary colic symptoms was determined by documentation of subjective resolution of symptoms at the patients' first postoperative follow-up appointment at an average of 24 days postoperatively. Patients and/or their parents were again contacted by telephone between September and October 2021 for long-term follow-up. Any patients who were not able to be reached by telephone after three attempts were determined to be lost to follow-up. Patients were each asked three questions using an IRB-approved telephone script.

The first question inquired as to whether patients had any episodes of recurrence of the abdominal pain that prompted them to see a surgeon initially. If they responded in the affirmative, they were asked three additional questions regarding their pain: Has it improved in severity or frequency? Has it caused any difficulties with eating? During the past 30 days, for about how many days did this pain make it hard for the patient to do his/her usual activities such as self-care, work, or recreation? The last question was adapted from the Centers for Disease Control and Prevention (CDC) Health-Related Quality of Life (HRQOL)—14 “Healthy Days Measure,” and specifically, the “Healthy Days Symptom Module.”²⁶

The second question was regarding whether the patient needed to see a doctor or undergo another procedure or surgery for any reason related to their cholecystectomy.

The third question asked whether the patient's quality of life had changed since their operation using a 5-point Likert scale (1 = significantly decreased, 2 = somewhat decreased, 3 = no change, 4 = somewhat improved, 5 = significantly improved).

Descriptive statistics were utilized with qualitative data reported in percentages and quantitative data reported in averages with associated standard deviations.

Results

Between January 2016 and March 2020, 17 pediatric patients (age <18 years) underwent cholecystectomy for normokinetic biliary dyskinesia, defined as a normal HIDA EF and pain with CCK injection in the absence of gallstones. During the same study period, another 62 and 14 patients underwent cholecystectomy for hypokinetic and hyperkinetic biliary dyskinesia, respectively, and were not included in the analysis. A majority of the patients with normokinetic biliary dyskinesia were female (88.2%) and adolescents with a mean age of 15.1 years (± 1.3 years). The mean BMI was 24.9 (± 4.9) kg/m² (Table 1). The average HIDA EF was 56.3% (± 11.4).

Table 1.

Demographics of Pediatric Patients with Normokinetic Biliary Dyskinesia Who Underwent Cholecystectomy

Demographic	Frequency or mean (N = 17)	Standard deviation
Gender
Female	88.2%
Male	11.8%
Age (years)	15.1	±1.3
BMI (kg/m²)	24.9	±4.9
HIDA EF	56.3%	±11.4

BMI, body mass index; EF, ejection fraction; HIDA, hepatobiliary iminodiacetic acid.

Preoperative clinical characteristics and postoperative outcomes for our 17 patients are given in Table 2. Five patients presented with undifferentiated chronic abdominal pain for which they underwent concomitant cholecystectomy and appendectomy. On surgical pathology analysis, only one of these patients was found to have a normal gallbladder but chronic inflammation of the appendix. As for the entire cohort's pathological analysis, approximately two-thirds of patients (62.5%) had evidence of cholecystitis and/or cholesterolosis.

Table 2.

Individual Characteristics of Pediatric Patients with Normokinetic Biliary Dyskinesia Who Underwent Cholecystectomy

						Short-term follow-up	Long-term follow-up
Patient number	Gender	Age (years)	HIDA EF (%)	Procedure	Surgical pathology	Resolution of abdominal pain	Recurrence of abdominal pain	Need to see a doctor or undergo procedure	Change in quality of life	Comments
1	M	12	66	LC + appy	Chronic cholecystitis	+	−	+	5	Saw physician for hereditary angioedema secondary to NSAID use postoperatively
2	F	15	66	LC	Chronic cholecystitis with cholesterolosis	RUQ pain resolved. Persistent diffuse abdominal pain.				Unable to be reached for long-term follow-up
3	F	14	39	LC	Chronic cholecystitis with cholesterolosis	+	−	−	3	Pain resolved. Persistent nausea at long-term follow-up.
4	F	14	45	LC	Normal GB	+	−	−	5
5	F	13	42	LC	Chronic cholecystitis	+	−	−	5
6	F	16	56	LC + appy	Normal GB. Chronic appendiceal inflammation.	RUQ pain resolved. Persistent diffuse abdominal pain.	+	−	3	1A. No improvement in severity or frequency1B. Pain and postprandial diarrhea with specific foods1C. No limitations to self-care, work, or recreation, but 7 days of symptoms of past 30 days
7	F	16	62	LC + appy	Chronic cholecystitis	+	+	−	4	1A. Improved in severity and frequency1B. Intolerance to fatty foods1C. 4 days of past 30 days
8	M	14	64	LC	Normal	Improved but not completely resolved.	−	−	5
9	F	15	67	LC	Chronic cholecystitis	+	−	−	5
10	F	15	61	LC + appy	Normal GB. Appendix with intraepithelial neutrophils.	−	+	−	3	1A. No improvement in severity or frequency1B. Must decrease size of meals1C. 0 days of past 30 days
11	F	15	50	LC	Chronic cholecystitis	+	−	−	5
12	F	13	53	LC	Chronic cholecystitis	+	−	−	5
13	F	13	44	LC	Chronic cholecystitis with cholesterolosis	Unable to be reached for short-term follow-up	−	−	5
14	F	17	70	LC + appy	Not available	+				Unable to be reached for long-term follow-up
15	F	16	77	LC	Normal	+				Unable to be reached for long-term follow-up
16	F	15	42	LC	Normal	+				Unable to be reached for long-term follow-up
17	F	15	53	LC	Chronic cholecystitis with cholesterolosis	Unable to be reached for short-term follow-up				Unable to be reached for long-term follow-up

Quality of life score: 1 = significantly decreased, 2 = somewhat decreased, 3 = no change, 4 = somewhat improved, 5 = significantly improved.

Appy, appendectomy; EF, ejection fraction; F, female; GB, gallbladder; HIDA, hepatobiliary iminodiacetic acid; LC, laparoscopic cholecystectomy; M, male; RUQ, right upper quadrant.

The average time to short-term follow-up was 24.2 days. Of the patients who were available for short-term follow-up (n = 15 patients), 12 (80%) reported complete or near complete resolution of their preoperative symptoms. One patient had continued pain postoperatively. The remaining 2 patients had resolution of preoperative right upper quadrant pain but continued to experience diffuse chronic abdominal pain.

Follow-up contact was established for 12 of 17 patients (70.6%) between September and October 2021. The mean and median duration from date of operation to date of long-term follow-up were both 46 months. Nine patients (75%) denied recurrence of abdominal pain. One patient (8.3%) reported recurrent abdominal pain that had improved in severity and frequency, for an overall symptom improvement rate of 83.3%. Two patients reported recurrence of abdominal pain without improvement in severity or frequency.

Notably, 2 of the 3 patients who reported recurrence of their preoperative symptoms at long-term follow-up had also reported persistent symptoms at short-term follow-up. When asked about improvements, not in pain, but in their quality of life, 75% of patients reported that their quality of life had somewhat or significantly improved after cholecystectomy and 25% of patients reported no change, largely due to persistent nausea. No patients reported a decrease in their quality of life.

Discussion

The incidence of pediatric gallbladder disease has significantly increased over the past several decades, including a significant rise in the incidence of biliary dyskinesia.^1–9 As gallbladder disease increases in pediatric populations and the understanding of its underlying pathophysiology evolves, so must the conventional wisdom of surgical management. Current evidence supports the effectiveness of laparoscopic cholecystectomy for the treatment of hypokinetic and hyperkinetic biliary dyskinesia in both adult and pediatric populations.^4–23 There are limited data, however, in both the adult and pediatric literature evaluating the role for cholecystectomy in normokinetic biliary dyskinesia. Our data suggest that cholecystectomy is an effective treatment in pediatric patients with normokinetic biliary dyskinesia, defined as reproducible abdominal pain during CCK injection despite normal gallbladder EF and the absence of cholelithiasis.

To our knowledge, this is the first study to date to evaluate and demonstrate the effectiveness of cholecystectomy as a treatment for normokinetic biliary dyskinesia in pediatric patients. The majority of patients in our cohort demonstrated improvement of their preoperative symptoms after cholecystectomy at both short- and long-term follow-up at 80% and 83.3%, respectively. These findings are consistent with studies of adults who underwent cholecystectomy for normokinetic biliary dyskinesia. Pihl et al. reported that in their study of 85 adult patients with normokinetic biliary dyskinesia and pain with administration of CCK, 80% had complete resolution of symptoms and 3.5% had partial resolution of symptoms, with an overall symptom improvement rate of 83.5% after cholecystectomy.²⁴ Ducoin et al. demonstrated similar findings: 89.5% of adult patients in their cohort demonstrated complete resolution of symptoms and ∼95% experienced overall improvement after cholecystectomy.²⁵ In addition, Morris-Stiff et al. stated that 41 out of 42 patients with reproducible pain after administration of CCK had complete resolution of symptoms after cholecystectomy despite 25 of the 42 patients having a normal EF on HIDA-CCK testing.²⁷ Our findings indicate that cholecystectomy can lead to improvement of pain in pediatric patients with normokinetic biliary dyskinesia and they are consistent with previous studies evaluating adult cohorts.

Three patients in our cohort (patients 6, 7, and 10) reported having at least one episode of recurrent abdominal pain since cholecystectomy at long-term follow-up; of these, 2 patients (patients 6 and 10) had reported persistent pain at short-term follow-up. This suggests that patients with symptomatic improvement at short-term follow-up will continue to report good outcomes at long-term follow-up. However, patients without symptomatic relief at short-term follow-up will likely continue to experience symptoms long term and should, therefore, be further evaluated for other etiologies of their symptoms. Furthermore, all 3 patients with recurrent abdominal pain at long-term follow-up had originally presented with generalized symptoms and diffuse abdominal pain for which they underwent both laparoscopic cholecystectomy and appendectomy. This initial lack of clarity about the cause of pain for these patients was evidenced by the dual nature of their operation and further suggests that the root cause of their pain was likely not biliary. In addition, 2 patients (patients 3 and 7) reported resolution or improvement of their right upper quadrant abdominal pain symptoms after cholecystectomy without significant improvement in their quality of life at long-term follow-up due to nausea or persistent intolerance to fatty foods.

Together, these findings suggest that reproducible right upper quadrant or mid-epigastric abdominal pain after CCK administration is the most sensitive predictor of outcome and symptom resolution after cholecystectomy for biliary dyskinesia. Pihl et al. similarly concluded that pain is the principal symptom of true biliary dyskinesia.²⁴ Five patients in their study underwent cholecystectomy for symptoms other than pain, including postprandial nausea and bloating. Of these, 3 patients demonstrated no improvement and 2 patients reported marginal improvement after cholecystectomy.²⁴

This may have implications for preoperative counseling and evaluation of patients whose predominant symptom is not pain, including patients who present with nausea or more diffuse symptomatology, as these symptoms may be more likely to persist after surgical intervention. The complex presentation of these patients may be explained, in part, by the numerous and varying roles of CCK. CCK is a peptide hormone of the gastrointestinal system secreted by the duodenum that participates in multiple biological processes related to digestion and satiety. Although CCK is known to increase hepatic production of bile and stimulate gallbladder contraction, its actions are not specific or limited to the biliary system.^28,29 Therefore, it is possible that patients with pain on CCK-HIDA provocation testing who report persistent postprandial diffuse abdominal pain or nausea after cholecystectomy may also be suffering from intestinal dysmotility or dysfunction related to CCK. Further research is needed to better elucidate this mechanism. Our data suggest, however, that cholecystectomy is an effective treatment for pediatric patients with normokinetic biliary dyskinesia whose predominant symptom is localized right upper quadrant or mid-epigastric pain reproduced by injection of CCK.

In Morris-Stiff et al.'s study, 24 of their 25 patients with a normal gallbladder EF but positive CCK provocation test demonstrated chronic gallbladder inflammation on pathology analysis after cholecystectomy (96%).²⁷ This supported their conclusion that pain upon injection of CCK was superior to EF for diagnosis of chronic cholecystitis. Of the 16 patients with reviewable pathology in our cohort, 10 (62.5%) patients demonstrated chronic cholecystitis with or without cholesterolosis. The pathophysiology explaining the right upper quadrant abdominal pain experienced with CCK provocation has yet to be fully elucidated. Our hypotheses include uncoordinated or dysregulated contraction of the gallbladder against the cystic duct in response to CCK, resulting in bile stasis that increases intraluminal pressure, contributing to inflammation and hypertrophy seen on pathology analysis.³⁰

Although this is currently the largest cohort of pediatric patients with normokinetic biliary dyskinesia available in the current literature, the conclusions of this study are limited by its small sample size and retrospective nature. Several patients were lost to follow-up. In addition, the overrepresentation of female patients in the cohort may limit broader perspectives for any gender-specific influences on overall incidence of normokinetic biliary dyskinesia and outcomes after cholecystectomy. Future directions include a multi-institutional prospective study to further elucidate and confirm the findings of this study. Prospective evaluation would also allow for standardization of CCK administration techniques across patients at various institutions.

This study suggests that pediatric patients with normokinetic biliary dyskinesia, defined as a gallbladder EF of 35%–80% with abdominal pain after CCK provocation testing would benefit from cholecystectomy for symptomatic relief. This symptomatic improvement can be seen within weeks of cholecystectomy and is sustained long term. Our data also support current studies involving adult participants demonstrating that patients with positive CCK provocation testing frequently demonstrate chronic cholecystitis on gallbladder pathology analysis despite a normal EF. Therefore, pain with CCK injection may be a more sensitive indicator of true biliary dyskinesia and chronic cholecystitis. In conclusion, pediatric patients with reproducible right upper quadrant or mid-epigastric abdominal pain on CCK-HIDA testing would likely benefit from surgical consultation and cholecystectomy despite a normal EF.

Footnotes

Authors' Contributions

All authors are responsible for the article and have taken part in writing, reviewing, and revising the contents of the article.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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