Biliary Dyskinesia: Role of the Sphincter of Oddi, Gallbladder and Cholecystokinin Shakuntala Krishnamurthy and Gerbail T. Krisbnamurthy Nuclear Medicine Department, Tuality Community Hospital, Hillsboro, Oregon; and Nuclear Medicine Section/Imaging Service, Veterans Affairs Medical Center, and University ofArizona, Tucson, Arizona years until Boyden's detailed work put an end to uncertainty The availability of objective and quantitative diagnostic tests in (8). The functional role of the sphincter of Oddi is now widely recent years has allowed more precise documentalion of biliary accepted. The sphincter consists of three parts: one surrounding dyskinesia. Biliary dyskinesiaconsists of two disease entities situ atedattwodifferentanatomicallocations:sphincterofOddispasm, the intraduodenal part ofthe distal CBD, called the choledochal at the distal end of the common duct, and cystic duct syndrome,in sphincter; one at the distal end of the pancreatic duct (duct of thegallbladder.Bothconditionsarecharacterizedby a paradoxical Wirsung), called pancreatic sphincter; and one surrounding the responsein which the sphincterof Oddi and the cystic duct contract common channel, called the ampullary sphincter. The distal end (andimpedebileflow)insteadof undergoingthe normaldilatation, of the common duct, surrounded by the ampullary sphincter, when the physiologicaldose of cholecystokinin is infused. Quanti opens into second part of the duodenum at the postero-medial tative cholescintigraphycan clearly differentiateone disease entity wall at an elevation called the ampulla of Vater. The name from the other.The therapiesof choice are sphincterotomy,sphinc sphincter of Oddi generally refers to all three sphincters (Fig. 1). teroplasty or antispasmodics for sphincter of Oddi spasm and cholecystectomy for cystic duct syndrome. After quantitative Bile Flow cholescintigraphy,the finalimpressionshouldidentifythe disease Of600 ml ofbile produced by the liver per day (0.4 ml/min), entity by name to assist the referring physiCian in making an about 70% enters the gallbladder during fasting, and the appropriate therapeutic decision; a mere statement that a test is consistent with biliary dyskinesiais no longer sufficient. remaining 30% enters the duodenum directly (9). The volume of hepatic bile that partitions between the two organs is Key Words biliary dyskinesia; cholecystokinin; sphincter of Oddi dependent on the sphincter of Oddi tone, which is maintained spasm; gallbladder cystic duct syndrome by periodic contractions. During fasting, the sphincter of Oddi J Nuci Med 1997;3&1824-.1830 exhibits a median of 4 contractions/mm, of which approxi mately 80% proceed antegrade, 13% proceed retrograde and the Clinicalacceptanceoftheroleofquantitativebiliarydynamicremaining 9% occur simultaneously at three levels within the studies has progressed slowly, and only recently have quanti sphincter (Table 1). The basal mean pressure of 15 mmHg tative biliary dynamic studies gotten the attention of practicing between contractions rises to 135 mmHg at the peak of the clinicians. Historically, this has been typical for the acceptance phasic wave (10). Cholecystokinin administration normally of any new knowledge in biliary anatomy, physiology or abolishes the phasic wave activity and promotes dilation of the pathology. First, doubts were expressed about the existence of sphincter of Oddi, facilitating smooth passage of the bile it a sphincter at the distal end of the common bile duct (CBD). receives from the gallbladder. Later, questions were raised as to the cause of contraction and emptying of the gallbladder. When the existence of the sphinc Cholecystokinin ter of Oddi (1) and the hormone mechanism [cholecystokinin In 1928, Ivy and Oldberg (2) first proposed a hormonal (CCK)] for gallbladderemptying (2) were proposed and con mechanism for contraction and emptying of the gallbladder firmed, new doubts were expressed about the entity of biliary induced by acidification ofupper small intestine, and named the dyskinesia (3). Measurement of sphincter of Oddi dynamics by hormone CCK. For a while, it was also called pancreozymin biliary manometry (4) and gallbladder and bile duct emptying because it increased the production ofpancreatic enzymes (11). by cholescintigraphy (5) have allowed for objective documen Later, it was shown that a single hormone produced both effects tation of biliary dyskinesia. The entity of biliary dyskinesia is (12). Because the gallbladder effect was described first, the title now well-defined (6), and appropriate therapeutic options are ofCCK hasbeen restored.Meal ingestion stimulatesthe release available (7). Diagnosis of biliary dyskinesia requires a clear ofCCK fromcells scatteredin the mucosa ofthe duodenumand understanding of the physiological relationship between the upperjejunum (Fig. 1). There are no CCK-secreting cells in the sphincter of Oddi and the gallbladder and of the effect of CCK esophagus, stomach or intestine, beyond the terminal jejunum on them in both good health and disease. In this article, we first (13). Two forms of CCK have been identified: one with 33 and will review the basic pathophysiology and later summarize the another with 39 amino acids. The form with 33 amino acids is scintigraphic approach to the diagnosis of biliary dyskinesia. the most abundant. The biological action ofthe hormone resides mainly at the C-terminal tetrapeptide (14). Cholecystokinin-33 can be cleaved at different locations (Fig. 2), and the fragment SPHINCTER OF ODDI that retains the C-terminal tetrapeptide continues to have most In 1887, Rugero Oddi first proposed a sphincter mechanism of the biological function of the parent molecule (15). Other at the distal end of the CBD, which today bears his name (1). peptides such as gastrin and cerulein, which have the identical The presence of the sphincter remained controversial for many C-terminal tetrapeptide, also possess a cholecystokinetic effect. A peptideconsisting ofthe terminaleight amino acids (CCK-8) ReceivedNov.12,1996;revisionacceptedJan.20,1997. Forcorrespondenceor reprintscontactS. Kiishnamurthy,MD.NudearMedicine, ofthe hormone has been synthesized and marketed as Sincalide TUaIity community Hospital, 335 8th Ave. S.E, Hilisboro, OR 97123. or Kinevac. The seventh amino acid, tyrosine, is sulfated, which 1824 THEJou@u'@i.OFNUCLEARMEDICINE•Vol. 38 •No. 11 November 1997 Sphincter CCK-Receptor Duct CCKSecreting Cell FIGURE 1. Sphincter of Oddi. Choledochal sphincter covers the intraduoderiai part of the CBD before it joins the pancrea@c duct. The pancreatic sphincter coversthedistalendof thepancreaticduct.Theampullarysphinctercoversthecommonthannelformedbytheunionof theCBDandthepancreaticduct (ductof Wirsung).Thenamesphincterof Oddirefersto allthreesphincters. is an essential requirement for retaining the biologic potency of contraction of the muscle in the body and fundus of the the hormone (16). gallbladder (19). The cystic duct, therefore, does not contract when a physiological dose of CCK is infused. When large, Actions of Cholecystokinin nonphysiological CCK doses are given, however, the gallblad In addition to inducing gallbladder contraction, pancreatic der ejection fraction decreases, probably related to cystic duct enzyme secretion and sphincter of Oddi dilatation, CCK has contraction when the dose exceeds the threshold value for many other biological actions: contraction (18). The degree of gallbladder emptying also is Contraction and emptying of the gallbladder. related directly to the total number of receptors in the gallblad Relaxation of the sphincter of Oddi. der wall smooth muscle (20). In addition to inducing contrac Increase in pancreatic enzyme secretion. tion of the gallbladder, CCK simultaneously relaxes the sphinc Increase in secretion of insulin, glucagon and somtatostatin ter of Oddi, mainly by abolishing phasic wave activity (Fig. 3). by Islet cells. The sphincter of Oddi relaxation is attributed to the binding of Inhibition of gastric emptying by contraction of the pyloric CCK to inhibitory receptors. The dose recommended in the sphincter. Sincalide package insert was developed for oral cholecystogram Increase in hepatic bile secretion. and for inducing pancreatic enzyme production and was found Increase in intestinal peristalsis. Increase in intestinal blood flow. TABLE I Suppression of appetite. Pressure and Wave Frequency, Sequence and Amplitude Decrease in systolic blood pressure. Changes in a Normal Sphincter of Oddi Cholecystokinin acts by attaching to CCK receptors (Fig. 1) NormalParameters distributed in the smooth muscle of the gallbladder and sphinc ter of Oddi (1 7). The degree of gallbladder emptying is CCK Median Range Abnormal dose-dependent. Gallbladder ejection fraction increases as the Basalpressure(mmHg) 15 5-15 >40 dose is enhanced from 0.5 ng/kg/min to 3.3 ng/kg/min (10 Waveamplitude(mmHg) 135 95—195 >300 ng/kg/3 mm) and then begins to decrease when larger doses are Wavefrequency(noimin) 4 2-6 >7 infused, especially when CCK is given as a rapid intravenous Sequence bolus (18). This seemingly paradoxical response in normal Antegrade(%) 80 12—100 subjects is attributed to the different threshold level ofthe CCK Simultaneous(%) 13 0-50 receptors in the body, fundus and cystic duct. In animals, it was Retrograde(%) 9 — >50 shown that the cystic duct smooth muscle threshold for CCK induced contraction is much higher than the threshold for ReproducedfromRef 10withpermissionfromtheauthorandpublisher. BILIARY DYSKINESIA •Krishnamurthy