Author Affiliations: Department of Surgery (Goussous N, Maqsood H, Kowdley GC and Cunningham SC) and Department of Nuclear Medicine (Spiegler E), Saint Agnes Hospital, Baltimore, USA

Corresponding Author: Steven C Cunningham, MD, FACS, Director of Pancreatic and Hepatobiliary Surgery, Director of Research, Saint Agnes Hospital and Cancer Institute, 900 Caton Avenue, MB 207, Baltimore, MD 21229, USA (Clinical Phone: +443-574-8500; Academic Phone: +667-234-8815; Fax: +410-719-0094; Email: Steven.Cunningham@stagnes.org)

 

This study has been presented in the Digestive Disease Week 2015 as part of the Society of Surgery for the Alimentary Tract meeting, Washington DC, May 2015.

 

© 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60188-1

Published online March 14, 2017.

 

 

Contributors: SE, KGC and CSC proposed the study. GN, MH, SE and CSC performed the research, collected and analyzed the data, and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. CSC is the guarantor.

Funding: None.

Ethical approval: This study was approved by the Ethics Committee Saint Agnes Hospital.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Despite the increasing use of fatty meal (FM) as a substitute for cholecystokinin (CCK) in pain reproduction during hepato-imino-diacetic acid (HIDA) scan in functional gallbladder disorder, there are no studies comparing the differences between CCK and FM. The present study was to compare the efficacy of FM in comparison of CCK in FGBD application.

 

METHODS: Patients undergoing HIDA scans from August 2013 to May 2014 were divided into two groups: those undergoing CCK-stimulated HIDA scan versus FM-stimulated HIDA scan. These groups were compared according to demographics and HIDA results.

 

RESULTS: Of 153 patients, 70 received CCK and 83 FM. There was no difference regarding age, gender, gallstones, gallbladder ejection fraction and time to visualization. However, significantly more of the patients receiving CCK than FM experienced pain reproduction (61% vs 30%, P<0.01).

 

CONCLUSIONS: Stimulation of gallbladder contractility with a FM during HIDA is less than half as likely to reproduce biliary symptoms compared to CCK, despite similar ejection fractions and other parameters. It is essential that providers account for this difference when counseling patients regarding cholecystectomy for functional gallbladder disorder.

 

(Hepatobiliary Pancreat Dis Int 2017;16:197-201)

 

KEY WORDS: gallbladder dysfunction; biliary dyskinesia; cholecystokinin; hepato-imino-diacetic acid

Functional gallbladder disorder (FGBD) is a motility disorder affecting the gallbladder. It is defined, based on the Rome III criteria,^[1-4] as a recurrent, progressive, intermittent, moderate-to-severe, right upper quadrant or epigastric pain, not otherwise explained by cystic-duct obstruction, constipation, musculoskeletal pain, or acid-related peptic ulcer disease. The character of the pain is similar to biliary colic but without the associated gallstones often seen on transabdominal ultrasound. The diagnosis of FGBD is often associated with a low gallbladder ejection fraction (GBEF), typically <35%, on hepato-imino-diacetic acid (HIDA) scan following cholecystokinin (CCK) stimulation.^[5] However, due to national shortage of CCK in the United States, a fatty meal (FM), typically Ensure®, is increasingly being used instead of CCK during the stimulation phase of HIDA scan.^[6] The FM works by inducing endogenous CCK secretion and hence stimulating gallbladder contraction and emptying of bile.^[6-9]

 

The management of FGBD remains controversial and ranges from conservative medical therapy to operative treatment in the form of cholecystectomy (CCY).^[10] The majority of studies available in the literature pertaining to the management of FGBD are retrospective and the reported symptomatic improvement following operative intervention is highly variable, with partial or complete pain relief following CCY ranging from <50% to 100%.^[11] GBEF calculated at the time of CCK-HIDA scan has been studied as a predictor for symptom resolution after CCY in multiple studies with conflicting results.^[12] By contrast, the reproduction of abdominal pain during stimulated HIDA has been recently reported to be superior to GBEF in predicting symptom resolution following CCY.^[13] Despite the increasing use of FM as a replacement for CCK, there are no studies comparing the differences in pain reproduction during HIDA scan when the GBEF is stimulated with CCK versus FM. The purpose of our study is to compare HIDA results, especially abdominal pain reproduction during HIDA scan, when CCK is used as a stimulant compared to FM. We hypothesize that more patients stimulated with CCK will report abdominal pain as compared to FM, and that this information could be important in the selection of patients for cholecystectomy.

 

 

Reports of all HIDA scans performed between August 2013 and May 2014 were collected. Cases of bile leak, and cases with delayed visualization or nonvisualization of the gallbladder were excluded. Our resultant cohort was divided into two groups based on the stimulant used during the HIDA scan: CCK or FM. The results of the HIDA scan between the two groups were compared. Twenty-six patients (6 in the CCK group and 20 in the FM) were excluded from the analysis of abdominal pain reproduction at HIDA scan, for whom symptom reproduction was not recorded; this HIDA parameter is otherwise routinely recorded by the nuclear medicine technician, at the time of the study.

 

HIDA scans were performed according to the Society of Nuclear Medicine Guidelines in all patients.^[14] Briefly, patients were instructed to fast for 6 hours and to avoid taking any narcotics on the day of the procedure. A dose of 5-10 millicuries of technetium tc 99m mebrofenin (Tc-99m, aka Choletec®, dose depending per protocol on the serum bilirubin level) was administered intravenously and dynamic images of the right upper quadrant were obtained using a gamma camera for at least 60 minutes. After gallbladder visualization, the gallbladder was stimulated either with CCK or FM. In the CCK group, 0.02 mcg/kg of Sinclade®, a synthetic C-terminal octapeptide of cholecystokinin, was administered intravenously over 60 minutes. In the FM group, 1 can of EnsurePlus® was administered orally. Following the administration of the stimulant, continuous imaging was obtained for 60 minutes. Pain and discomfort experienced by the patients during stimulation was recorded.

 

GBEF was calculated as a percentage from the gallbladder time-curve using the following equation: GBEF (%)= [(net GB counts_max–net GB counts_min)/net GB counts_max]×100%, where GB is gallbladder.

 

Patient demographics and comorbidities were recorded, as were the results of the HIDA scan including GBEF, time to gallbladder visualization, time to duodenum visualization, and patient symptoms upon stimulation. Also collected were data on the utilization of other imaging modalities used to evaluation of patient symptoms, including ultrasound, computed tomography and magnetic resonance cholangiopancreatography.

 

Continuous variables were presented as mean and range, and compared using the Wilcoxon two-sample test. Categorical variables were presented as percentages and analyzed with the Fisher’s exact test. Statistical significance was defined as P<0.05.

 

 

One hundred and fifty-three patients were identified (69% females) with a mean age of 56 years (range 17-93). Seventy patients (46%) underwent HIDA scan stimulated with CCK and 83 (54%) stimulated with a FM (EnsurePlus®). Both groups had similar age and gender, and there was no statistically significant difference in the comorbidities between the two groups except for a higher percentage of hypertensive patients in the FM group (44% vs 64%, P=0.03) (Table 1). Also, there was no difference between the groups regarding the utilization of other imaging modalities in symptom evaluation (Table 2).

 

The HIDA-scan results of the CCK group and the FM group were then compared. There was no difference in the presence of gallstones (27% vs 25%, P=0.85), the GBEF (52% vs 51%, P=0.77), or the time to visualization of the gallbladder (18.4 vs 20.5 minutes, P=0.34) or duodenum (47 vs 46 minutes, P=0.73). In addition, there were equivalent proportions of patients with abnormally low GBEF (<35%) in both groups. However, given data that pain reproduction may be useful in predicting success of CCY,^[13] the CCK and FM groups were compared for differences in the reproduction of abdominal pain at HIDA scan and twice as many CCK patients than FM patients were found to experience reproduction of abdominal pain during the stimulation phase of the HIDA scan (61% vs 30%, P<0.01) (Table 3).

 

 

The true prevalence of FGBD is unknown. It seems to be, to a large degree, a uniquely American disease, given that a recent epidemiological study found that CCY is employed for FGBD 4× to 80× more commonly in the United States than in 4 comparator countries (Norway, Sweden, Poland and Australia).^[15] Whether FGBD is overdiagnosed and overtreated in the United States or underdiagnosed and undertreated elsewhere, or both, is unclear. The etiology of FGBD is unclear. Although cholesterolosis has been implicated in some small studies,^[16] a much larger, recent study found no association with GBEF.^[17] Nevertheless, the entity exists, and providers have to make decisions whether to refer patients to a surgeon for CCY.

 

Indeed, CCY appears to be curative in many patients, in a recent review of 30 series in the literature, comprising 1842 patients, the (weighted) average pain relief was 88%, but the quality of all these data is poor, as all but one study was retrospective.^[11] The question, therefore, is how can surgeons improve the selection of patients such that closer to 100% of those undergoing CCY for FGBD have pain relief? One way is to strictly abide by “abnormal” GBEF. When compared to healthy volunteers, those patients in whom a GBEF is <35% are deemed to have an “abnormal” test result. Although their ejection fraction (EF) may be too far from the mean to qualify for “normality,” it is not at all clear from the literature, nor intuitive, that a GBEF <35% should accurately identify all the curable patients and exclude all those who are not. Indeed, to the contrary, there are studies suggesting that even patients with “normal”^[18] or “high”^[19] GBEF have similar rates of pain relief after CCY compared to those patients with “abnormally” low GBEF.

 

Another possible way to select patients for CCY is by pain reproduction during CCK-HIDA. This, however, is also controversial. There are, however, provocative data suggesting that they will. Morris-Stiff et al^[13] studied 42 patients with a preoperative diagnosis of FGBD who underwent CCY, all of whom had reproduction of their abdominal pain during CCK-HIDA scan. After a mean follow-up period of 18 months, all but one patient reported symptom resolution, irrespective of their EF. This certainly supports the use of HIDA as a “CCK provocation HIDA test”.

 

Mention of a “CCK provocation HIDA test” conjures up memories for some, no doubt, of the old CCK provocation test, which was used without a HIDA scan, to evaluate patients with right upper quadrant pain in the absence of gallstones, as a predictor for symptom resolution after CCY. Some studies found it useful, such as Rhodes et al^[20] while others not, such as Smythe et al^[21] who published its often-cited requiem. However, it is so rarely done anymore that discussion of the requiem may well deserve its own requiem. The differences between the historic CCK provocation test of Smthye’s requiem, and the “CCK provocation HIDA test” of Morris-Stiff 13 years later may be so great as to preclude useful comparison anyway. For instance, in Smythe’s CCK provocation test, the dose of CCK was 2.5-fold higher and was administered 6-fold faster than CCK in the modern HIDA test, which Morris-Stiff et al have termed the “CCK provocation HIDA test.”

 

Given the strong possibility that pain reproduction during the CCK administration of the HIDA scan (ie, during the “CCK provocation HIDA test” of Morris-Stiff) may predict success after CCY for these patients, we were very interested to learn whether changing the stimulus for CCK contraction of the gallbladder from exogenous CCK administration to endogenous release of native CCK following a FM would impact the results. Indeed, twice as many patients had a positive result with exogenous CCK than with a FM. This of course may impact surgical decision-making for those surgeons who, like us, do consider pain reproduction when weighing the likelihood of benefit versus the risks of offering CCY to these challenging patients.

 

This simple study raises several important question. For example, will patients in the CCK group or the FM group perhaps have more long-term resolution of the pain that led to HIDA scan, depending on the various treatments they received? This question we cannot at this time answer due to lack of adequate follow-up. Additional future studies could follow patients through their operative or nonoperative course to follow the trajectory of their pain over 1-2 years. Another question, given differences in pain reproduction during HIDA scan, is why there were no other differences, for example, in GBEF between the groups? One obvious possibility is simply that EnsurePlus® is more physiologic, inducing endogenous CCK as opposed to the supraphysiologic effect of exogenous CCK administration on GB contraction. As such, the higher percentage of pain reproduction in the CCK group might be related to hyperstimulation of the GB, which reaches early its maximum ability to empty, and additional exogenous stimulation simply causes painful spasms of the GB, not further emptying.

 

Our study has several limitations. First, the current study design precludes patient interviews, we do not know how many patients in each group had worsening pain with eating. Such data might reveal a bias in the current study if, for example, all the FM patients happen not to have had worse pain with food. Second, 17% of the patients in our cohort (26 patients) were excluded from the analysis because the reproduction of abdominal pain was not recorded by their nuclear medicine technician. Third, this is a retrospective study, making it impossible to draw causal conclusion. Further prospective studies with long-term, formal, graded patient evaluations, comparing the use of CCK and FM during HIDA scanning may better address this question.

 

In conclusion, insofar as pain reproduction may predict success after CCY in cases of FGBD, the type of the stimulant used during the HIDA scan - exogenous CCK versus a FM - must be taken into consideration during the interpretation of HIDA scan results and the weighing of risks and benefits of operative management.

 

 

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