To determine if cholecystokinin (CCK) cholescintigraphy could successfully identify patients with depressedgallbladder motor function secondary to a chronicallyinflamed, partially obstructed, or functionally impairedgallbladder, we retrospectively analyzed the maximal gallbladder ejection fraction response to CCK in 374 symptomatic (recurrent postprandial right upper quadrant painand/or biliary colic) patients with normal oral cholecystograms and/or biliary sonograms and correlated themwith their final medical/surgical diagnosis. In addition,CCK cholescintigrams were performed in 27 patients (recruited as “control―volunteers) without subjective/clinicalevidence of biliary disease to determine if the degree ofgallbladder contraction post-CCK differed in patients withand without recurrent postprandial right upper quadrantpain and biliary colic.

MATERIALS AND METHODS

CCKcholescintigramswere performedin 374 patientswithrecurrent postprandial right upper quadrant pain, biliary colic,and a normalgallbladdersonogramand/orcholecystogram.The results of these examinations were correlated with thepatients'finalmedical/surgicaldiagnoses.Twenty-sevenpatients recruited as control volunteers without objective clinicalevidence of biliary disease also underwent CCK cholescintigraphyto determineif the degreeof gallbladdercontractionpost-CCK differs in symptomatic versus asymptomatic subjects. Decreased gallbladder motor function was identified(maximal gallbladder ejection fraction response to CCK lessthan 35%) in 94% of patients with histopathologically confirmed chronic acalculouscholecystitisor the cystic ductsyndrome and in 88% of patients clinically believed to havechronic acalculous biliary disease. Decreased gallbladder motor function does not distinguish symptomatic from asymptomatic gallbladder disease.

J NucIMed 1991;32:1695—1699

Between November 1981 and December 1984, CCK cholescintigrams were performed in 374 patients (286 female, 88 male)with recurrent postprandial right upper quadrant pain, biliary

colic, and a normal gallbladder sonogram and/or oral cholecystogram. In addition, the maximal gallbladder ejection fractionresponseto CCK wasdeterminedin 27 (19 female,8 male;ages15—53yr) asymptomatic subjects recruited as control volunteers,

each of whom had a biliary sonogram within 1-2 wk of theirCCKcholescintigrams.

After an overnight fast, each patient and/or asymptomaticrecruited control volunteer received 5 mCi of 99mTc@Jisofeflin(HepatoliteTM) intravenously. Utilizing a large field of viewgamma camera and a low-energy medium-resolution all-purposecollimator, and a 20% window centered at 140 keY, anterior500,000 count hepatobiliary images were obtained every 10 mmx 6, or until the gallbladder maximally filled (little to no activitywithin the major hepatic radicals, most within the gallbladder

itself).Imageacquisitiontime was approximately2—3mm andnever exceeded 5 mm. An infusion of 0.02 ag/kg of CCK (Sincalide) was then administered over 3 mm. Following the CCKinfusion, anterior post-CCK analog hepatobiliary images wereobtained q.5 mm x 4 for set times. The post-CCK analogueimages were obtained for set times, not counts, and the time per

he chronic acalculous disorders of the biliary treeinclude chronic acalculous cholecystitis, the cystic ductsyndrome, and sphincter of Oddi and gallbladder dyskinesia. Clinically, all are manifested by recurrent postprandial right upper quadrant pain and biliary colic. Diagnosisis difficult because routine blood chemistries, oral cholecystograms and biliary sonograms are normal. Endoscopicretrograde cholangiopancreatography is also normal, except in some patients with sphincter of Oddi dyskinesia,who have either elevated basal and/or cholecystokinininduced sphincter of Oddi pressures (1,2). Diagnosis isimportant, for without it, patients with chronic acalculousbiliary disease may be improperly treated (if at all) andforced to endure continuous postprandial pain.

ReceivedSept.10,1990;revisionacceptedApr.23,1991.Forreprintscontact:DarleneFink-Bennett,MD,NuclearMedicineDepart

mont, William Beaumont Hospital, 3601 West 13 Mile Rd., Royal Oak, Ml48073-6769.

1695Biliary Disease Detection •Fink-Bennett et al

Cholecystokinin Cholescintigraphy: Detection ofAbnormal Gallbladder Motor Function inPatients with Chronic Acalculous GallbladderDiseaseDarlene Fink-Bennett, Peter DeRidder, William Z. Kolozsi, Richard Gordon, and Robert Jaros

WilliamBeaumontHospital,RoyalOak,Michigan;Salem CommunityHospital,Salem,Ohio;and CatholicMedicalCenter, Manchester, New Hampshire

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TABLE 1MGBEF/Outcomeof 124 Post-CCKTreated PatientsClinicallySuspectedof Chronic Acalculous Biliary Disease(CABD)Patients

Histopath.Dx MGBEF-to-CCKClinicalstatus108

CABD <35%1 05—Improvedto asymptomatic1—Nochange2—Losttofollow-up7

CABD >35%7—Improved toasymptomatic5Normalgallbladder <35%5—Improved toasymptomatic4Normalgallbladder >35%3_lmproved*

1—Losttofollow-upe

Lysis of adhesions, treatment of irritable bowel, s/p sphincterotomy.

image was determined from the number of seconds required toobtain the pre-CCKanterior 500,000count biliaryscintiscan.

Gallbladder ejection fractions were determined from data simultaneouslyacquired on the computer at I frame/mm for 20mm storedon a 64 x 64 x 16computer matrix. Acquisitionwasbegun 1 mm prior to and continued for 20 mm following theintravenousadministrationof CCK. Ejection fractionswere determined by manually assigning areas of interest around thegallbladder and an adjacent background area on the pre-CCK,5-, 10-, 15-, 20-mm post-CCK digital images The backgroundarea [regionof interest (ROI)]was selectedadjacent and to therightofthe gallbladder,with a width measuringapproximately5pixels and a length equal to the anterior maximal height of thegallbladderitself.Backgroundactivitywas subtractedfrom bothpre-and pOSt-CCKimages@Totalcountsand the numberofpixelswithin each ROI were determined and the ejection fraction wascalculatedaccordingto the followingformula:

GBEF(i)=

Net pre-CCKGB ct- Net post-CCKGB cts (at t i mm),Net pre-CCK GB cts

where i = the time post-CCK administration, and for eachobservation Net GB cts = Total GB cts - BK where BK =(backgroundeta/pixel)x (the number of pixelsin the GB ROI).

A normal gallbladderejection fraction responseto CCK wasdefined as one in which the gallbladder ejected at least 35% of itscontents.

Pathologic criteria of chronic cholecystitis and/or the cysticduct syndrome included hypertrophy of the gallbladder wall(>1.5-2 mm), diffuse hypertrophy ofthe muscularis propria withor withouta concomitantmonocellularinfiltrate,the presenceofAschoff-Rokitanskysinuses and/or foamy macrophagesfillingthe tips of mucosal folds and yellowpapillary nodules. Cysticduct syndromewas deemed present if fibrosisof the cysticductproducing at least a 60% luminal narrowing was demonstratedhistologicallyand/or kinkingor adhesionsof the cysticduct wasseenat surgery(3).

Histopathologic diagnoses were obtained in 124 patients, theother 221 patients had their final diagnosesgleaned from theirmedical records and/or were obtained from their primary carephysicians.Currentclinicalstatuswasobtainedfrom the patientsthemselves or their primary care physicians. The duration offollow-upranged from 3-48 mo in both post-cholecystectomyand medically treated patients@

‘ci

‘àyFIGURE1. AbnormalCCKcholescintigram.Pre-CCKandq.5mmpost-CCK(set time,not counts)anteriorhepatobiliaryimagesx 4. Qualitatively, there is no evidence to suggest that thegallbladder has ejected greater than or equal to 35% of itscontents.

RESULTS

Of the 374 symptomatic patients who had a CCK cholescintigram, 124 have had a cholecystectomy, 2 hadexploratory laparotomy, and 248 have been medicallyfollowed/managed. Twenty-seven of the 248 medicallymanaged patients have been lost to follow-up and thereforehave been excluded from this analysis.

Of the 124 symptomatic patients who had a cholecystectomy, 115 had histopathologically confirmed chronicacalculous biliary disease (8 cystic duct syndrome, 11 cysticduct syndrome in conjunction with chronic acalculouscholecystitis, and 96 chronic acalculous cholecystitis) and9 hadnormalgallbladders.The maximalgallbladderejection fraction response to CCK in these patients and theirclinical outcome are depicted in Table 1 (Figs. 1 and 2).Two patients who underwent an exploratory laparotomy,but did not have their gallbladders removed have beendeleted from analysis. One had inoperable pancreatic carcinoma, the other had a lymphoma.

Of the 221 patients with adequate medical follow-up,78 are believed to have chronic acalculous biliary diseasebecause they have persistent biliary colic. Their symptomshave not been alleviated and/or stones have been demonstrated on a follow-up biliary sonogram. The remaining143 medically followed patients are believed not to have

1696 The Journal of Nuclear Medicine •Vol. 32 •No. 9 •September1991

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TABLE2MGBEF/Outcomeof 221Medically Treated Patients Clinically Suspected ofChronic Acalculous Biliary Disease(CABD)PatientsMedical

diagnosisMGBEF-to-CCKClinicalstatus130Normal

gallbladder>35%Improved statuspost-treatmentfor nongallbladderdisease1

3Normal gallbladder<35%Improved statuspost-treatmentfor nongallbladderdisease69CABD<35%Continued

symptoms9CABD>35%Continuedsymptoms

•1@ I

9 •1FIGURE2. QuantitativeCCK cholescintigramdemonstrating an abnormal ejectionfractional responseto a 3-mminfusionof CCKsincethegallbladder has failed to ejectgreater than or equal to 35%of its contents. (5, 10, 15, 20mm. GBEFs = 0%, 0%, 13%,13%).

gallbladder disease because their abdominal pain and biliary colic have been relieved following treatment for gastritis, irritable bowel disease, hiatal hernia, esophagitis,peptic ulcer disease, Chrohn's disease and esophageal reflux. Their maximal gallbladder ejection fraction responsesto CCK and their outcomes are depicted in Table 2 (Figs.3 and4).

Of the 27 individuals without a history of recurrentpostprandial right upper quadrant pain and/or biliary colicwho were recruited as control volunteers, 9 had an ejectionfraction response greater than 35%, 16 less than 35%, and2 were incalculable (bowel overlap). Of the 16 subjectswhose ejection fraction was less than 35%, 2 had cholelithiasis demonstrated sonographically, 4 had a delay(greater than 60 mm) in biliary-to-bowel transit (none ofwhom were pretreated with CCK), and 1 had a delay(greater than 60 mm) in gallbladder filling. In addition,one of these subjects subsequently had a cholecystectomythat revealed microscopic changes of chronic cholecystitis.A delay in biliary-to-bowel transit and cholelithiasiswerepresent in each of those subjects whose ejection fractionscould not be calculated due to overlying bowel activityneither of which were pretreated with CCK (Table 3).

DISCUSSION

Determining the maximum gallbladder ejection fractionresponse to CCK can be employed to confirm the presenceof reduced gallbladder motor function resulting fromchronic acalculous cholecystitis and/or the cystic duct

FIGURE3. NormalCCKcholescintiscan.Pre-CCKandq.5mmpost-CCK (set time, not counts) anterior hepatobiliary images x4. Note obvious decrease in amount of disofenin within thegallbladderpost-CCK.

syndrome. Ninety-four percent (108/1 15) of the patientswith histopathologic confirmation of one or both of thesedisorders demonstrated an abnormal (less than 35% maximal gallbladder ejection fraction) response to CCK. Fivepatients whose maximal gallbladder ejection fraction response to CCK was less than 35% did not demonstratemicroscopic changes of chronic acalculous biliary disease,but all improved postoperatively; findings that suggest thattheir decreased gallbladder motor function was a manifestation of gallbladder dyskinesia. Only seven (6%) of thepatients with confirmed chronic acalculous cholecystitisand/or cystic duct syndrome demonstrated normal gallbladder motor function and were false-negative. In addition, 69/78 (88%) ofour medically managed patients withreduced gallbladder motor function are clinically deemedto have chronic acalculous biliary disease. All have persistent recurrent right upper quadrant pain and biliarycolic and though their diagnoses are not based on anunequivocal gold standard (surgery), their symptoms arebelieved to be a manifestation of abnormal gallbladdercontraction and/or evacuation.

Other investigators have had an equally sanguine experiences in detecting patients with reduced gallbladder motor function resulting from chronic acalculous biliary disease. Jaros et al. (1 7), Swayne et al. (18), Bruger et al. (19)and Pickleman et al. (20) have performed CCK cholescintigrams on over 150 patients suspected of having impairedgallbladder contraction and/or evacuation, 52 of whomhave had a cholecystectomy. The sensitivity and positivepredictive value of an abnormal gallbladder ejection fraction response to CCK being a manifestation of decreased

1697Biliary Disease Detection •Fink-Bennett et al

iii'

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>35%Non-calculable<35%92

Gallstonesdelayedbiliaryto-boweltransit16

Gallstones(2)Delayed

biliary-to-.boweltransit(4)

Delayedgallbladderfilling(1)

Symptoms+ (Surgery.—@chronic acalculous

cholecystitis)(1)

All have responded to treatment for those conditions andare free oftheir “biliarysymptomatology.―

The results of CCK cholescintigrams performed on our27 asymptomatic control voluntary recruits indicate thatreduced gallbladder motor function occurs in symptomaticand asymptomatic gallbladder disease. Four patients whostated that they did not experience postprandial right upperquadrant pain and/or biliary colic with reduced gallbladder motor function had cholelithiasis, while one had cholelithiasis and histologically confirmed chronic cholecystitis. An additional five patients had scintigraphic findingsindicative of underlying gallbladder disease; four had delayed biliary-to-bowel transit and one had delayed gallbladder filling (15). None were pre-treated with CCK norhad they ingested opiates, thereby excluding delay in biliary-to-bowel transit as a manifestation of preferential gallbladder filling following pretreatment with CCK or fromincreased resistance to bile flow secondary to opiate-induced increased Sphincter of Oddi pressure (22,23).

We did not monitor total gallbladder dynamics or onsetof pain post-CCK administration. We only evaluated themaximal gallbladder ejection fraction to CCK to determine ifthis parameter could identify depressed gallbladdermotor function in symptomatic subjects with chronic acalculous cholecystitis or cystic duct syndrome. In retrospect,we could and probably should have done this, but we didnot. Our data, however, indicate that determining themaximal gallbladder ejection fraction response to CCKcan identify decreased gallbladder motor function resultingfrom a chronically inflamed gallbladder and/or a partiallyobstructed cystic duct. Thus, when interpreted in an appropriate clinical setting, CCK cholescintigraphy can beemployed to confirm the gastroenterologist's and/or surgeon's clinical impression of symptomatic acalculous billary disease. Its high negative predictive value should alertthe physician that in the absence of abnormal gallbladdermotor function, recurrent postprandial right upper quadrant pain and biliary colic is probably not the result ofchronic acalculous biliary disease and another etiology fortheir patient's symptomatology should be sought.

ACKNOWLEDGMENTS

The authors are indebted to Cassandra Fasano, ChristineGoryl, and Maureen Rotarius for their work in preparing themanuscript.

REFERENCES

1. Hogan W, Greenen J, Dodds J, et al. Paradoxical response to cholecystokinin (CCK-OP) in patients with suspected Sphincter ofOddi dysfunction[Abstract].Gastroenterology1982;82:1085.

2. Tooulc J, Roberts-Thompson IC, Dent J, Lee J. Manometric disorders inpatients with suspected Sphincter of Oddi dysfunction. Gastroenterologyl985;88:1243—1245.

3. Anderson WHD. Pathology. St. Louis: C.V. Mosby Co., 1971:1261-1265.4. Fleiss LI. Statistical methods for rates and proportions, second edition.

New York: John Wiley & Sons; 1981:113—123.5. McFarland J, Cumn J. Cholecystokinin and the cystic duct syndrome:

clinical experience in a community hospital. Am J Gastroenterol

1698 The Journal of Nuclear Medicine•Vol.32 •No. 9 •September1991

FIGURE4. NormalquantitativeCCKcholescintigramdemonstrafing a normal maximal gallbladder ejection frac@onalresponseto a 3-mminfusionof CCK.(5, 10, 15, 20 mm.GBEFs= 53%,72%, 69%, 68%).

gallbladder motor function secondary to chronic acalcubus cholecystitis and/or the cystic duct syndrome rangedfrom 82% to 100% and 90% to 100%, respectively. Recently, however, Westlake et al. (21) reported that a lowgallbladder ejection fraction did not correlate with abnormal gallbladder pathology, did not predict a good clinicaloutcome, nor did histologic findings predict clinical outcome. Why their experience differs from ours and theother advocates of CCK cholescintigraphy is not totallyclear, but probably is related to technical differences (i.e.,their use of a 30-mm infusion of Sincalide and a gallbladder ejection fraction response to CCK of less than 65%,indicating reduced gallbladder motor function). In addition, they did not section the cystic duct. Possibly, hadthey employed our technique and microscopically evaluated the cystic duct, their results would have been different.

The negative predictive value ofCCK cholescintigraphyis 91% since 130/140 patients with normal gallbladdermotor function who were originally thought to havechronic acalculous biliary disease have ultimately beenfound to have another etiology for their recurrent postprandial right upper quadrant pain and/or biliary colic.

TABLE3Maximal Gallbladder Ejection Fraction of 27 Asymptomatic

“ControlVolunteer―Recruits

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13. KrishnamurthyG, Bubba V, McConell D, et al. Quantitative biliarydynamics: introduction of a new noninvasive scintigraphic technique. JNucIMed 1983;24:217—222.

14. Fink-BennettD, DeRidderP, Kolozsi,et al. Cholecystokinincholescintigraphic findings in the cystic duct syndrome. J NucI Med l985;26:1 123—1128.

15. Weissmann HS, Sugarman LA, Freeman LM. The clinical role of techne

tium-99m-iminodiacetic acid cholescintigraphy. In: Freeman LM, Weissman HS, eds. Nuclear medicine annuaL New York: Raven Press; 1981:35—91.

16. Freitas JE. Cholescintigraphy in acute and chronic cholecystitis. SeminNucl Med l982;l2:l8—26.

17. Jaros R. Cholecystokinin (CCK) cholescintigraphy in patients suspected ofacalculous biliary disease. Presented at the RSNA, November 1985.

18. Swayne L, Palace F, Rothenberg J, ci al. Sensitivity (SENS), specificity(SPEC), and accuracy (ACC) of CCK cholescintigraphy (CCK-C) in acalculous biliary disease (ABD) [Abstract]. J Nuc/Med 1986:27:882.

19. Brugge W, Brand D, Atkins H, et al. Gallbladder dyskinesia in chronicacalculous cholecystitis. Dig Dis Sci l986;3 1:461—467.

20. Pickleman J, Peiss RL, Henkin R, et al. The role ofSincalide cholescintigraphy in the evaluation of patients with acalculous gallbladder disease.Arch Surg l985;120:693—697.

21. Westlake PJ, et al. Chronic right upper quadrant pain without gallstones:does HIDA scan predict outcome after cholescintigraphy? Am J Gastroenterol 1990;85;8:986—990.

22. Kim CK, ci al. Delayed biliary-to-bowel transit in cholescintigraphy aftercholecystokinin treatment. Radiology 1990:176:2:553—556.

23. Kim EE, Pjura G, Lowry P. et al. Morphine-augmented cholescintigraphyin the diagnosis ofacute cholecystitis. AJR l986;l47: 1177—1179.

1699Biliary Disease Detection •Fink-Bennett et al

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1991;32:1695-1699.J Nucl Med.   Darlene Fink-Bennett, Peter DeRidder, William Z. Kolozsi, Richard Gordon and Robert Jaros  in Patients with Chronic Acalculous Gallbladder DiseaseCholecystokinin Cholescintigraphy: Detection of Abnormal Gallbladder Motor Function

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