TEACHING EDITORIAL

Radlonucllde Hepatoblllary Procedures: When

Can HIDA Help?

For more than two decades radionuclide hepatobiliary procedures have been performed, mainly with 1-131 rose bengal (1-131 RB) (I) or 1-131 bromsuiphathelin (2). Technetium-99m-labeled agents should, if otherwise equivalent, produce better images; and Tc99m HIDA (3), and its chemical relatives, are vigorous candidates for clinical acceptance.In 1978, more than 20 hepatobiliary research papers were presented either at the 25th

Annual Meeting of the Society of Nuclear Medicine or at the Second International Congressof the World Federation of Nuclear Medicine and Biology. More than half of these papersreported on use ofTc-99m HIDA or its relatives; interest in Tc-99m pyridoxylideneglutamate(4) and its relatives was also evident. Kinetic studies in normal animals (5) give an edge tothe HIDA family, but clinical acceptance should depend on further comparative studies ofpromising agents in a variety of diseased populations. It is not yet clear whether there areimportant clinical differences between the agents.

The developers of HIDA publish in this issue of the Journal (6) a new chapter in thestory. It provides an opportunity to consider major hepatobiliary diagnostic problems andsome radionuclide procedures developed to assess these problems, and an invitation topredict the likely roles of Tc-99m-labeled agents in performing these procedures.

Obstructive jaundice. The problem of detecting patients with extrahepatic obstructive(surgical) causes ofjaundice remains a focus of radionuclide hepatobiliary procedures (7,8).Intravenously administered radiolabeled hepatobiliary agents accumulate in hepatocytes andare excreted into the bowel through intra- and extrahepatic bile ducts. Detection of theradiopharmaceutical in the bowel indicates that the extrahepatic biliary system is not totallyobstructed. Failure to detect bowel radioactivity in initial images, however, may be due notonly to surgically correctable obstruction of the common bile duct, but also to other causes:hepatoceHular failure or hyperbilirubinemia alone are the most common. Partial extrahepaticobstruction may also be difficult to define, although blood clearance rate analyses (8) anddelayed images, up to 48 hr (9), have improved the specificity of the procedures whenperformed with 1-131 labeled agents.

Can HIDA help in the diagnosis of markedly jaundiced patients? On the basis ofclinical observations Harvey et al. suspected that HIDA, just as 1-131 RB, might be verypoorly excreted in some patients without extrahepatic obstruction. They postulated that this

could have been caused by the same mechanism whereby 1-131 RB excretion is impaired inhyperbilirubinemia. In a carefully controlled series of dog experiments, they show that I-131 RB or Tc-99m HIDA compete poorly with bilirubin for the same carrier-mediatedorganic anion hepatocellular excretory pathway. They infer that a high, yet unspecified,level of serum bilirubin or some degree of carrier-mechanism saturation would markedlyreduce HIDA excretion and thus limit the value of HIDA in markedly jaundiced patients,and they list potential alternate remedies for this limitation.

Knowledge of this limitation of HIDA allows more selective use of the agent andimproves the recognition of nonspecific results when they occur. Since delayed images may

provide evidence of late excretion of I- 131 labeled agents into the bowel (9), these agentsare the better choice in patients who may require images more than 18-24 hr after injection.Until criteria for prior selection of patients are refined, administration of 1-131 RB as asecondary agent may be necessary in some patients ifinitial HIDA images are not diagnostic.In some jaundiced patients, increased HIDA doses may overcome moderate decreases inexcretion, without unacceptable radiation risks (10). Technetium-99m images are easier to

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TEACHING EDITORIAL

interpret than those obtained with an equivalent fractional excretion of I- 131 labeled agentsbecause of the greater number of detectable photons for equivalent patient radiation doseand the superior resolution characteristics of Tc-99m emissions. Superior images improvethe incidental information obtainable about hepatic structure, show regional obstructionbetter, and make renal and bowel activity easier to distinguish. The value of these improvements has not been measured. The diagnosis of partial hepatic obstruction with radionuclidehepatobiliary agents remains a problem; ultrasound or radionuclide images may help byshowing dialated intrahepatic bile ducts in chronic partial obstructions.

Cystic duct patency. The problem of assessing the patency of the cystic duct in patientswith suspected acute cholecystitis is a second major challenge for hepatobiliary diagnosticprocedures. Cystic duct obstruction initiates acute cholecystitis (11), so detection of obstruction is diagnostic during the acute phase of the disease. An accurate radionuclideprocedure for assessment of cystic duct patency is performed by administration of cholecystokinin (CCK) i.v. , followed by a hepatobiliary radiopharmaceutical (12, 13). Subsequentaccumulation of radioactivity in the gallbladder indicates that the cystic duct is patent.Failure to visualize the gallbladder is highly specific and sensitive for cystic duct obstruction—lOO% accurate in the initial series of 39 patients—if hepatic excretory function isadequate to produce detectable tracer in the bowel. Inadequate excretion is seldom aproblem in acutely ill patients, for bowel radioactivity can usually be detected in thepresence of hyperbilirubinemia up to levels of 10 mg/dl and can often be imaged well abovethis level. Jaundiced patients may require images at 24 hr or later, in which case 1-131labeled agents should be used.

Cholecystokinin was incorporated in this procedure initially on the basis of pilot animaland human studies. Subsequent reports of the use of hepatobiliary agents without CCK incholescintigraphy show low false-negative rates and tend to confirm the advisability of theuse of CCK for maximum reliability in assessment of cystic duct patency. Occasional falsepositives have been reported, not only in nonfasting normals (14), but also in patients (15)when CCK was omitted from the procedure. Another group using this technique withoutCCK (16) found it highly accurate in diagnosing cholecystitis, but in their initial analyses itis not clear how they distinguished between acute cholecystitis and chronic cholecystitiswith patent cystic duct. In another series, CCK was given to some patients who initiallyfailed to show gallbladder visualization (17). Those patients who then showed gallbladdervisualization when a second dose of radiopharmaceutical was administered were independently diagnosed as having chronic cholecystitis with patent cystic duct. One patient withchronic cholecystitis had gallbladder visualization by contrast study 2 wk earlier but failedto show gallbladder accumulation of radiopharmaceutical after CCK. This finding couldhave been a false-positive result or could have been due to cystic duct occlusion occurringbetween the two procedures. Administration of CCK only after a positive initial resultwould increase the duration of the test by at least 1-3 hr in most patients with acutecholecystitis.

Cholecystokinin is inexpensive and causes no appreciable adverse effects from a totalof 40 Ivy dog units or one Crick-Harper-Raper unit/kg (16) administered i.v. in adults overa 5-mm period. Users in the USA, however, must utilize a foreign supplier with attendant

paperwork. Data are not yet available to justify the routine substitution of sincalide (18), amore readily available octapeptide with CCK-like activity.

Any false-positive diagnosis of cystic duct obstruction could be dangerous. Surgerycould be unnecessarily precipitated or delayed, depending on the patient's clinical course.An occasional false-positive result is possible, even if CCK is used. Since cystic ductobstruction often resolves spontaneously a late negative test does not exclude earlier obstruction. The test is an adjunct to, not a substitute for, thoughtful, clinical evaluation ofthe patient.

In nonjaundiced patients reports suggest that the major Tc-99m-labeled agents appearat least as quickly in the gallbladder as 1-131 RB. When early images suffice, the improvedanatomic information obtained with the Tc-99m-labeled agents is valuable. Iodine- 131 RBwill retain a role in patients who require very late images. The questiOn of whether to useCCK is not necessarily linked to the question of choice of agent.

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EIKMAN

Unusual bile communications. A third problem for hepatobiliary diagnostic proceduresis the delineation of pathways of bile drainage and intestinal bile flow. Reflux of bile in thestomach, common with Bilroth II anastomoses, is readily diagnosed (19). Surgeons appreciate information on the patency of other bowel anastomoses with bile flow (20). Thesuperior imaging characteristics of Tc-99m-labeled agents strongly favor their use in preference to I- I31-labeled agents in quickly completed procedures of this type; the rewards ofimproved anatomic definition are substantial. In other studies of abnormal bile communications, the need for late images may preclude the use of Tc-99m-labeled agents. Childrenwith biliary atresia may occasionally be helped by surgical construction of a permanentdrain for a communicating intrahepatic bile cyst. Iodine-l31 RB images have been fruitfulin demonstrating operable cysts as late as 17 hr after injection (21). In one case, we firstdetected a cyst only after several days of serial studies. Administration of a Tc-99m-labeledhepatobiliary agent in addition to an iodinated agent may be warranted in such children (20)to more accurately define and detect any cysts that may communicate more rapidly withthe biliary system.

So far, little information is available regarding the use of Tc-99m-labeled agents inconstitutional hyperbilirubinemias. Several Japanese workers have a long-standing interestin this area (22) and are doubtless studying the use of Tc-99m-labeled agents.

The researcher choosing problems to investigate or the nuclear medicine physicianrecommending procedures for a particular patient with suspected hepatobiliary disease mustremain informed of current developments in other methods for diagnosing hepatobiliarydisease (20). The researcher or clinician is most likely to succeed when he uses any of theradionuclide hepatobiliary agents to exploit the functional information they provide, relieson Tc-99m-labeled agents for superior anatomic resolution in early images, and continuesto use 1-131-labeled agents when late images are required.

EDWARD A. EIKMANUniversity of South FloridaJamesA. HaleyVA MedicalCenterTampa,Florida

REFERENCES

I. TAPLIN GV, MEREDITH OM JR, KADE H: Radioactive (1-131 tagged) rose bengal uptake-excretion test forliver function using external gamma-ray scintillation counting techniques. J Lab Clin Med 45: 665-678, 1955

2. TuBis M, NORDYKE RA, POSNICK E, et al: The preparation and use of 1-131 labeled sulfobromphthalein inliver function testing. J Niwl Med 2: 282—288,1961

3. HARVEY E, LOBERG M, COOPER M: Tc-99m HIDA: A new radiopharmaceutical for hepato-biliary imaging. JNi,ul Med 16: 533, 1975 (abst)

4. RONAIPM, BAKERRi, BELLENJC: Technetium-99m-pyridoxylideneglutamate:Miew hepatobiliary radiopharmaceutical. I Experimental Aspects. J Nucl Med 16: 720-727, 1975

5. WisTow BW, SUBRAMANIAN G, VAN HEERTUM RL, et al: An evaluation of @°“Tc-labeledhepatobiliary agents.J Niwl Med 18: 455-461 , 1977

6. HARVEY E, LOBERG M, RYAN J, et al: Hepatic Clearance Mechanisms of @°‘9'c-HIDAand its effect onquantitation of hepatobiliary function. J Noel Med 20: 310-313, 1979

7. EYLER WR, SCHUMAN BM, DUSAULT LA, et al: The radioiodinated rose bengal liver scan as an aid in thedifferential diagnosis ofjaundice. Am J Roentgenol 94: 469-476, 1965

8. ROSENTHALL L: The Application ofRadioiodinated Rose Bengal and Colloidal Radiogold in the Detection ofHepaiobiliarv Disease. St. Louis, Green, 1969.

9. WINSTON MA, BLAHD WH: 1-131 rose bengal imaging techniques in differential diagnosis ofjaundiced patients.St'niin Nod Med 2: 167—175, 1972

/0. RYAN J, COOPER M, LOBERG M, et al: Technetium-99m-labeled [N-(2,6-dimethylphenylcarbamoylmethyl)] iminodiacetic acid (Tc-99m HIDA): a new radiopharmaceutical for hepatobiliary imaging studies. J Niw! Med 18:997-1004.1977

/1. SHERLOCK S: Diseases ofthe Liver and Biliarv System, Philadelphia, FA Davis Company. 1975, p 738/2. EIKMAN EA, CAMERON JL, COLMAN M, et al: Radioactive tracer techniques in the diagnosis of acute

cholecystitis. J Nut! Med 14: 393, 1973 (abst)13. EIKMAN EA, CAMERON JL, COLMAN M, et al: A test for patency of the cystic duct in acute cholecystitis. Ann

Intern Med 82: 318—322,1975/4. STADALNIKRC, MATOLONM, JANSHOLTAL, et al: Technetium-99m pyridoxylideneglutamate (PG) choles

cintigraphy.Radiology 121:657-661,1976/5. HALL AW, WI5BEY ML, HUTCHINSON F, et al: A prospective, comparative trial ofhepatobiliary scanning and

contrast radiology in the diagnosis of acute cholecystitis. Br J Surg 65: 361, 1978 (abst)

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16. WEISSMANN H, FRANK M, ROSENBLATT R, et al: Correlation of Tc-99m HIDA with anatomic imaging in

patients with hepatobiliary disease. J Nuc! Med 19: 738, 1978 (abet)17. PARE P. SHAFFER EA, ROSENTHALL L: Nonvisualization of the gallbladder by @“Tc-HIDAcholescintigraphy

as evidence of cholecystitis. Can Med Assoc J 118: 384-386, 197818. RIJBIN B, ENGEL SL, DRUNGIS AM, et al: Cholecystokinii@1ike activities in guinea pigs and in dogs of the C-

terminal octapeptide (SQ 19,844) of cholecystokinin. J Pharm Sci 58: 955—959,1969/9. MALMUD LS, TOLIN R, MENIN R, et al: Detection and quantitation ofbile reflux following Billroth II surgery.

World Federation of Nuclear Medicineand Biology, 2nd International Congress, Washington, DC, 1978,p 123(abst)

20. RONAI PM: Hepatobiliary radiopharmaceuticals: Defining their clinical role will be a galling experience. J NuciMed 18: 488—490, 1977

21. WILLIAMS LE, FISHER JH, COURTNEY RA, et al: Preoperative Diagnosis of choledochal cyst by hepatoscintography. N Eng! J Med 283: 85—86,1970

22. 110 M, YAMADA H, KITANI K, et al: Constitutional JaundIces, Differentiation by 131-I BSP SequentialScanning. Nuclear Hepatology: clinical and physiological aspects of liver disease by radioisotopes. Tokyo,igaku Shoin Ltd, 1973, pp 65—78

(#@@ SOUThEASTERN CHAPTERThE SOCIETY OF NUCLEAR@MEDICINE

20th ANNUAL MEETING

Oct. 31-Nov. 3, 1979 Orlando Hyatt House Orlando, Florida

ANNOUNCEMENT AND CALL FOR ABSTRACTSThe Southeastern Chapter of the Society of Nuclear Medicine announces its TwentiethAnnual Meeting, to be held October 31-November 3, 1979, at the Orlando Hyatt House inOrlando, Florida.

The Scientific Program Committee, chaired by F. David Rollo, M.D., Ph.D., welcomes thesubmission of original contributions in nuclear medicine from members and nonmembersof the Society of Nuclear Medicine for consideration for the Scientific Sessions.

Accepted abstracts will be published in the Proceedings of the meeting along with themanuscripts of the Continuing Education lectures.

The program will be approved for credit toward the AMA Physicians' Recognition Awardunder Continuing Medical Education Category I through the Society of Nuclear Medicine,and VOICEcredits will be available to technologists.

Awards will be given for the best papers submitted by technologists.

Abstracts must be prepared in final form for direct photoreproduction on the official abstractform.

For abstract forms and further information, contact:

Robert H. Rohrer, Ph.D.Administrative Director, SEC/SNMDepartment of PhysicsEmory UniversityAtlanta, GA 30322(404) 321 1241

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1979;20:358-361.J Nucl Med.   Edward A. Eikman  Radionuclide Hepatobiliary Procedures: When Can HIDA Help?

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