jnm/ EDITORIAL
Hepatobiliary Clinical
Radiopharmaceuticals: Role
Will
Be a Galling
Since the original work on the iminodiacetic acid derivatives at the University ofMaryland (1-3)and on the pyridoxylidene-amino acid Schiffs bases at the South Australian Institute of Medical and Veterinary Science (4—6), it has become a matter of some interest and importance to evaluate the kinetics of these two
Defining
their
Experience
peting with the OCG in the diagnosis of cholelithiasis (6, 7). On the other hand, the OCO is a nonquantita tive examination and diethyl IDA may find a role in
quantitative physiologic studies of gallbladder function. Unlike the OCO, the intravenous (contrast) cholangiogram (IVCC) is not an innocuous proce groups of compounds in relation to those of the dure. It is associated with a significant incidence of commercially available hepatobiliary agents, partic ularly rose bengal. In an excellent study, “An severe contrast reactions; a reaction requiring active therapeutic intervention occurs once in 700 examina Evaluation of Technetium-Labeled Hepatobiliary tions, a life-threatening reaction once in 1600 Agents―reported in this issue, Wistow and co-workers examinations, and death once in 5000 examinations have shown very convincingly that N, a-(2, 6-diethyl acetanilide)-iminodiacetic acid or diethyl IDA is (8). This represents roughly 10 times the frequency of reactions to urographic contrast media. (It is superior to all other experimental and commercial interesting to speculate how the FDA would respond hepatobiliary agents tested by them in a normal to an IND for a radiopharmaceutical with such baboon model. Indeed, with 80% cumulative 3-hr toxicity.) A less hazardous alternative to the IVCC is biliary excretion and only 5% cumulative 3-hr urinary certainly needed and the intravenous (radionuclide) excretion, diethyl IDA leaves room for only marginal cholangiogram (IVRC) using diethyl IDA may improvement by future contenders. Whether or not perhaps fill this role. One of the major current uses of diethyl IDA will make a significant clinical impact on the diagnosis of disorders of the liver and bile ducts in the IVCC is the demonstration of patency ofthe cystic man—and if so, which disorders—must now be duct in patients with suspected acute cholecystitis. If the contrast medium enters the gallbladder, the cystic determined by clinical trials. Defining the clinical role of a new technique or duct is patent and acute cholecystitis is most unlikely. radiopharmaceutical is not an activity in which we in Failure to visualize the gallbladder, however, does not nuclear medicine have traditionally excelled. The necessarily mean cystic duct obstruction, since as history of nuclear medicine is replete with examples of many as 22% of gallbladders seen by OCG fail to show new procedures for which exaggerated or inappro on IVCC (9). Studies with 99mTc@dihydrothioctic priate claims were initially made, only to be later acid (99mTc-DHTA) (10) and 99mTc..pyridoxylidene. modified or withdrawn under the glare of the clinical glutamate (99mTc..pyG) (6,7) have also revealed a spotlight. It is self-evident, although often forgotten, failure of accumulation of radiotracer in a significant that the clinical role of any new diagnostic test should proportion of normal gallbladders. Three out of 8 be defined in relation to relevant existing procedures. normal subjects failed to show galbladder accumula The new test should provide either new information, tion of 99mTcDHTA over 90 mm (10), while 3 out of or at least the same information more reliably, more 10 failed to show 99mTc..pyGin the gallbladder over 1 safely, more economically, or, preferably, all of the hr (6). This phenomenon also occurred in 5 subjects in above. jected with 99mTcpyG within 2 hr after a fatty meal, It is unlikely that diethyl IDA will prove an effective but did not occur when the study was repeated after alternative to the oral cholecystogram (OCG). The the subjects had been placed on a fat-free diet (7). OCGis not only noninvasive,but extremelyeffective Protocols for clinical trials of diethyl IDA should take in diagnosing cholelithiasis and a variety of other these observations into account. disorders of the gallbladder. Sheer lack of resolution In the jaundiced patient, the first clinical objective is will prevent any radiotracer technique from corn to establish whether the jaundice is due to hemolytic, 488
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EDITORIAL
hepatocellular, or obstructive
[email protected] obstructive jaundice is present, the next objective is to determine the nature and site of the obstruction. Noninvasive contrast and radiotracer techniques are as yet unable to distinguish reliably between hepatocellular and obstruction
jaundice.
When the serum bilirubin con
centration rises above 2 mg/ 100 ml, or the Bromsul phalein retention rises above 30%, the incidence of successful visualization
of the biliary tree by the IVCC
drops precipitously (11). Conflicting results have been obtained using 99mTc..pyo to differentiate between hepatocellular and obstructive jaundice (6,7,12). Results
of studies
with
diethyl
IDA
are eagerly
awaited. The unbiased observer might point out, however, that ultrasonography and CT scanning are much more promising techniques for demonstrating a distended biliary tree—and hence for distinguishing between
hepatocellular
and obstructive
jaundice
than either IVCC or IVRC. Already, in most large hospitals, the possibility of obstructive jaundice is initially evaluated by ultrasonography. The demon stratiônof a distended biliary tree by ultrasonography or CT scanning should generally be followed by percutaneous transhepatic cholangiography (PTC) to determine the nature and site of the obstruction. The success rate of this procedure in the presence of obstructive jaundice is virtually 100%. The incidence of complications is significant (at least 2%) but acceptable,
considering
the quantity and quality of the
diagnostic information obtained (13). When there is a contraindication
to the PTC (e.g., bleeding diathesis,
severe anemia, infection, or ascites), endoscopic retrograde cholangiopancreatography (ERCP) may be performed. The success rate of ERCP is lower than that ofPTC(around 75%), but the complication rate is also lower (13). The advantage of this combination of ultrasound (or CT scanning) and PTC (or ERCP) lies in (A) reliable detection of biliary obstruction, and (B) specific determination of the nature and level of the obstruction. It seems unlikely to me that diethyl IDA, or indeed any radiotracer, will be able to provide equivalent information. These remarks require some qualification. Although PTC is a simple, rapid, and inexpensive procedure, and should be available in virtually all radiology departments, ERCP is technically
difficult,
time consuming,
certainly prove useful. PETER M. RONAI,
Unfortunately, not all patients with extrahepatic biliary obstruction have proximal bile duct distension.
In biliary atresia the intrahepatic biliary radicles are often rudimentary and PTC is then usually unsuc cessful. Further, patients with this disorder are too small for ERCP. Accordingly, a real diagnostic hiatus exists in biliary atresia and this would be an obvious application for which diethyl IDA should be
M.D.,
University of Colorado Denver, Colorado
Ph.D.
Medical
Center
REFERENCES
most uncom
fortable for the patient, and as yet available in relatively few institutions.
Volume 18, Number 5
evaluated. Biliary atresia is an arena in which 131!.. rose bengal has long been a protagonist, with results that leave much to be desired. Technetium-99m-PyG has proved to be of no value in diagnosing this disease (unpublished observations). Our previous experience with radiotracers therefore gives us little grounds for optimism. At the University of Colorado Medical Center, the IVRC has been most useful in evaluating the patency of surgically devised drainage pathways of the biliary system—particularly after liver transplantation and after the Kasai procedure for biliary atresia. In patients with liver transplants who develop liver dysfunction, it has been possible to differentiate with confidence between rejection and obstruction in virtually all cases. In babies who have had Kasai procedures, we have on several occasions been able to show a dramatic re-establishment of bile drainage. Neither of these clinical situations, however, represents a pressing problem in the average hospital. In summary, diethyl IDA promises to be the best hepatobiliary radiopharmaceutical to date. Its effectiveness in man and its ultimate role in clinical diagnosis are as yet unknown. In defining this role we need to take into account the contributions of OCG, IVCC, PTC, ERCP, ultrasonography, and CT scanning. These considerations suggest that diethyl IDA may prove useful in excluding cystic duct obstruction, but will otherwise have little to offer in the diagnosis of gallbladder pathology. In the jaundiced patient it seems unlikely that diethyl IDA will be able to compete effectively with a combination of ultrasonography (or CT scanning) to detect distension of the biliary tree, followed by PTC (or ERCP) if obstruction is present, to determine the nature and site of the obstruction. Biliary atresia will probably remain a frustrating diagnostic problem. Finally, in those institutions where liver transplants and Kasai procedures are performed, diethyl IDA will
1. HARVEYE, LOBEROM, COOPERM: Tc-99m-HIDA: A new radiopharmaceutical for hepato-biliary imaging. J Nuci Med 16: 533, 1975 2. LOBERGM, FIELDSA, HARVEY E, Ct al.: Radiochemistry
Tc-N.{N'-(2,6-dimethylphenyl
carbamoylmethyl)]
of
iminociiacetic
acid (Tc-HIDA). I Nuci Med 17:537, 1976 3. LOBEROM, COOPERM, HARVEYE, et al.: Development of new
radiopharmaceuticals based on N-substitution of iminodiacetic acid. J Nuci Med 17: 633—638,1976 4. BAKERRi, BELLENJC, RONAI PM:99mTc@pyridoxyljdeneg1ut@
amate—anew rapid cholescintingraphic agent. J Nuci Med 15:476, 1974
489
EDITORIAL
5. BAKER RJ, BELLEN JC, RONAI PM: Technetium-99m-
pyridoxylideneglutamate: A new hepatobiliary radiopharmaceut ical. I. Experimental aspects. J Nuci Med 16: 720-727, 1975 6. RONAI PM, BAKERRJ, BELLENJC, et al.: Technetium-99m-
pyridoxylideneglutamate: A new hepatobiliary radiopharmaceuti cal. II. Clinical aspects. J Nuci Med 16: 728-737, 1975 7. STADALNIK
RC,
MATOLO
NM,
JANSHOLD
Technetium-99m-pyridoxylideneglutamate
(PG)
A-L,
et al.:
cholescinti
graphy. Radiology 121:657-661, 1976
cholangiography with intact gallbladder. Am JRoentgenol Radium Ther Nuc! Med I 10:235—239, 1970 10. EIKMAN EA, CAMERON JL, COLMAN M, et al.: Radioactive tracer techniques in the diagnosis ofacute cholecystitis. J Nuci Med 14:393,1973 I!. FISCHER HW: Physiologic and pharmacologic aspects of
cholangiography. Radio! Clin N Am 4: 625-632, 1966 12. POtJLOSEKP, ECKELMANWC, REnA RC, et al: Evaluation of 99mTc..pyridoxylideneglutamate for the differential diagnosis of
8. ANSELL G:Adverse reaction tocontrast agents. investRadio! jaundice. Clin Nuc! Med 1: 70-72, 1976 5: 374—384,1970
9. ECKELBERG ME, CARLSONHC, MCILRATHDC: Intravenous
13. OKUDA K, ho M: Radiological Aspects of the Liver and Biliary Tract. Chicago, Year Book Medical PubL, 1976. pp 89-106
BOOKS RECEIVED The receipt of the following books is acknowledged: Chemical Carcinogens. Charles E. Searle. 788 pp. Washington, A C S Monography, 1976. $67.50. Dynamic Blood Flow Measurement with the slRb/elmKr Ratio. Gerard van Herk, 107 pp, illustrated. Groningen,
Druk: VRB Offsetdrukkerij, 1976. Medical Thermography, Theory and Clinical Applications. Edited by Sumio Uematsu. 196 pp, Los Angeles. Brent
woodPublishingCorp.,1976.$37.50. Structural Shielding Design and Evaluation for Medical Use of X-Rays and Gamma Rays of Energies up to 10 MeV. Edited by Lauriston S. Taylor and John P. Kelley, 126 pp. Washington, DC, National Council on Radiation Protec
tion and Measurements,1976. Roentgenology of the Gallbladder and Biliary Tract. Benjamin Felson. 150 pp, illustrated. New York, Grune &
Stratton, 1976.$14.50or £10.30. Financial Operation and Management Concepts in Nuclear Medicine. James L. Bennington, Hirsch Handmaker, and
Gerald S. Freedman.232 pp, illustrated. Baltimore, University Park Press,1977.$16.50. Radiation Protection for Medical and Allied Health Personnel. Edited by Lauriston S. Taylor and Edith H. Quimby. 72 pp, illustrated. Washington, ments,
490
DC, National Council on Radiation Protection and Measurements,
1976.
1976.
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