1977, British Journal of Radiology, 50, 735-739
OCTOBER 1977
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate: a new hepatobiliary agent A preliminary report By H. S. L. M. Tjen, M.D., W. B. van der Pompe, M.Sc, and P. H. Cox, B.Sc. Ph.D., M.P.S. AcT. Department of Nuclear Medicine, Rotterdamsch Radio-Therapeutisch Instituut, Groene Hilledijk 301, Rotterdam, Netherlands. (Received December, 1976 and in revised form April, 1977) ABSTRACT
A new hepatobiliary reagent " T c m diethyl-acetanilidoiminodiacetate has been examined in a small group of patients to evaluate its potential as a clinical reagent. The radiopharmaceutical accumulated readily in the hepatocytes and was rapidly excreted via the biliary system. It would appear possible to develop a dynamic test of hepatocyte function coupled with an evaluation of the patency of the biliary system. No adverse reactions were observed.
In the past a number of radiopharmaceuticals have been proposed to study the hepatobiliary system, but few of them have been developed into clinically useful compounds. The most widely used to date has been 131I-Rose Bengal (Burke and Halko, 1966; Eyler et al., 1968; Davies et al., 1976), but this compound has a number of inherent disadvantages. In 1975 Baker et al. described the use of 99Tcm labelled pyridoxylidene glutamate (PDG) for studies of the hepatobiliary system. In normal human subjects accumulation of PDG was observed in the liver parenchyma within five minutes of intravenous injection. Activity could be observed in the common bile duct and duodenum ten minutes post injection and in the gall-bladder within 15 minutes of injection. Loberg et al. (1976) made comparative studies of a number of alternative compounds based upon the
N-substitution of imino-diacetic acid and reported favourably on their radiochemical and biological characteristics. In the study reported here the uptake and excretion of "Tc m -Sn-labelled diethyl-acetanilidoiminodiacetate has been examined in a limited group of patients to evaluate its potential as a radiopharmaceutical for the hepatobiliary system. The reagent was obtained in kit form from commercial sources*. MATERIAL AND METHODS
The reagent was provided in the form of a sterile, pyrogen-free lyophilized tin complex. On the aseptic addition of 1-4 ml sterile pertechnetate to the contents of the labelling vial a clear solution is obtained, which is ready for use. All the patients included in this pilot study were adults. No special premedication or other precautions were taken. In all cases an intravenous dose of 5 mCi was administered. Scintigraphy was performed with the aid of a Nuclear Chicago HP gamma camera using a 140 keV diverging collimator. An on line computer (MED II, General Electric) accumulated one minute frames for 45 minutes post *HIDA ® Solco Nuclear Basle, Switzerland.
TABLE I RESULTS OF CHOLESCINTIGRAMS IN PATIENTS WITH VARIOUS DIAGNOSES ON ADMISSION
Patient
Diagnosis on admission
Cholescintigram
1. 2.
Upper abdominal pain. Liver function disturbance Obstructive jaundice
3. 4. 5. 6.
Obstructive jaundice Duodenal ulcer Hepatitis Obstructive jaundice
7. 8.
Alcohol abuse. Liver function disturbance Obstructive jaundice
9.
Obstructive jaundice
10. 11.
Obstructive jaundice Obstructive jaundice. Palpable mass upper abdomen
735
No visualization of gall-bladder Complete obstruction. No visualization of gallbladder Normal Normal Normal Incomplete obstruction. Space occupying lesion. No visualization of gall-bladder Normal Complete obstruction. No visualization of gallbladder Incomplete obstruction. No visualization of gallbladder No visualization of gall-bladder Incomplete obstruction. Space occupying process.
VOL.
50, No. 598 H. S. L. M. Tjen, W. B. van der Pompe and P. H. Cox
injection. The patient was placed in the supine position with the camera over the heart, liver and upper abdomen. The reagent was administered with the patient already positioned under the camera and the data storage system was started simultaneously. Scintigrams were recorded on Polaroid and X-ray film. The digital information was analyzed by selecting regions of interest and generating time activity curves. The regions selected were heart, liver, gall-bladder, common bile duct and duodenum. When no intestinal activity was observed on the scintigrams after 45 minutes, an additional scintigram was prepared 18-24 hours post injection.
RESULTS
Eleven patients were investigated. The diagnoses are shown in Table I. In all cases the liver function was evaluated by measuring conjugated and nonconjugated bilirubin, alkaline phosphatase and transaminase serum levels and urobilin and bilirubin levels in the urine. All but one patient had disturbed liver function at the time of admission. The patient with normal liver function was suffering from a duodenal ulcer.
X-ray investigations were also made including a simple radiograph of the abdomen and in some cases intravenous cholangiography (IVC). In two patients IVC was performed within the first week after admission; in the others it was not possible because of jaundice. Scintigraphy was performed within a week of admission except in one case. In the normal scintigram a liver image was seen between three minutes and 15 minutes post injection. The common bile duct and gall-bladder were best visualized between 25 minutes and 60 minutes and intestinal activity was observed within 60 minutes. The scintigrams obtained are described in Table I. The clinical findings were confirmed by X-ray investigation, liver biopsy and laparotomy and in some cases colloid scintigraphy (Table II). A Polaroid image of a normal study is shown in Fig. 1. In three patients with a final diagnosis of diffuse liver function disturbance, normal scintigrams were obtained, but in two similar cases there appeared to be a delayed liver excretion. More information from similar cases must be obtained to evaluate the significance of this. Kidney and bladder activity was observed in four patients, all suffering from a malignancy. Two patients had carcinoma of the pancreas head, one patient a liver carcinoma and
TABLE II COMPARISON OF CHOLESCINTIGRAM, CONTRAST RADIOLOGICAL PROCEDURES AND FINAL DIAGNOSIS
Patient 1. 2. 3. 4. 5. 6. 7. 8. 9.
Intravenous cholangiogram
Cholescintigram No visualization of gall-bladder Complete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Normal. Normal Normal Incomplete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Space occupying process. Normal Complete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Incomplete obstruction. No visualization of gallbladder. Kidney and bladder visualization.
10.
No visualization of gall-bladder
11.
Incomplete obstruction
obstructed cystic duct —
Final diagnosis pancreatitis* carcinama of pancreas headj
obstructed cystic duct normal
cholangitis* duodenal ulcer]! cholestatic hepatitisf malignancy in liverf ^f
—
liver cirrhosisf liver cirrhosisf carcinoma of head of pancreasj Tumour common bile duct}; choledocholithiasis
— —
—• choledocholithiasis post-cholecystectomy cholangiogram obstructed cystic duct excretion contrast by kidney
liver cirrhosis §f liver metastasis §
Confirmed by *clinical/laboratory diagnosis fliver biopsy % laparotomy §colloid scan TfX-ray investigation
736
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate
FIG.1.
Gamma camera images of a normal subject at different time intervals. Clear visualization of heart, liver, common bile duct, gall-bladder and intestinal activity can_be seen in the different images.
one patient a tumour of the common bile duct. The computer image of a patient suffering from carcinoma of the head of the pancreas is shown in Fig. 2. Two patients suffering from carcinoma of the head of the pancreas showed complete biliary obstruction, while no activity was seen in the abdomen 24 hours post injection. Incomplete obstruction was observed in two patients. During the 45 minutes of the study no activity was seen in the abdomen. Twentyfour hours post injection the scintigram showed good
intestinal activity. Both patients were suffering from malignancies involving the liver. Liver areas suspected of poor uptake of the reagent were further investigated by colloid scintigraphy. There was a good agreement. In two patients with a suspected space-occupying lesion in the liver appearing on the cholescintigram this was confirmed by colloid scintigrams. One patient (no. 3), admitted with obstructive jaundice, showed a normal scintigram, but the IVC showed an obstructed cystic duct. The final diagnosis, confirmed
737
1 VOL.
50, No. 598 H. S. L. M. Tjen, W. B. van der Pompe and P. H. Cox
FIG. 2. Computer display of serial scintigrams of a patient suffering from carcinoma of the head of the pancreas.
by clinical and laboratory examinations, was inflammation of the common bile duct. The IVC was performed ten days before cholescintigraphy. At time of the latter study the patient was symptom free.
DISCUSSION
In this pilot study with 99Tcm labelled diethylacetanilido-iminodiacetate no side effects were observed at the dose level used and no contraindications are known. It was easily prepared using the
738
OCTOBER 1977
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate "instant kit" provided. In normal subjects there is good visualization of heart, liver, common bile duct, gall-bladder and intestine. The study can be completed without inconvenience for the patient within 45 minutes of injection. Visualization of kidneys and bladder was always observed with hepato-cellular disease or total obstruction. Space-occupying lesions could be readily observed on liver images obtained between five and ten minutes post injection. Because the dynamic study prevents the preparation of liver images in various positions a follow-up investigation by means of a colloid scan is indicated. Ronai et al. (1975) concluded that a negative image of the gall-bladder was characteristic of incomplete obstruction. In one case we observed a positive image of the gall-bladder in a patient with incomplete obstruction. A good correlation was found between the qualitative scintigraphic findings and the final diagnosis. More information is needed to evaluate the uptake and excretion curves obtained by the computer from the different regions of interest. Although curves have been prepared for every patient no overall conclusion can yet be drawn. From the small number of analyses available, a significant difference seems to exist between the curves obtained from normal patients and the "delayed" values of the liver excretion-curves in patients with hepato-cellular disease. "Tcm-Sn-diethyl-acetanilido-iminodi-acetate would appear to be a potentially useful reagent for the diagnosis of functional and pathological
changes of the biliary tree. The relatively simple chemical structure and stability of the complex compared with other reagents, coupled with its excellent biological characteristics (Van Heertum et al., 1975), suggest that it could eventually become the reagent of choice for cholescintigraphy.
REFERENCES BAKER, R. J., BELLEN, J. C , and RONAI, P. M., 1975.
Technetium-99m-pyridoxylidene glutamate: a new hepato-biliary radiopharmaceutical. I. Experimental aspects. Journal ofNuclear Medicine, 16, 720—727. BURKE, G., and HALKO, A., 1966. Dynamic clinical studies
with radioisotopes and the scintilation camera II. Rose Bengal 131I liver function studies. Journal of the American Medical Association, 198, 608-618. DAVIES, E. R., MORRIS, J. N., READ, A. E., and POWELL, N.,
1976. 131I Rose Bengal scanning and clearance ratios in the investigation of jaundiced patients. Clinical Radiology, 27, 227-235.
EYLER, W. R., SCHUMAN, B. M., DUSALT, L. A., and
HINSEN, R. E., 1968. The radioiodinated Rose Bengal liver scan as an aid in the differential diagnosis of jaundice. American Journal of Roentgenology, 94, 469—476. LOBERG, M. D., COOPER, M., HARVEY, E., CALLERY, P., and FAITH, W., 1976. Development of new radiopharma-
ceuticals based on N-substitution of iminodiacetic acid, Journal of Nuclear Medicine, 17, 633—638. RONAI, P. H., BAKER, R. J., BELLEN, J. C , COLLINS, P. J., ANDERSON, P. J., and LANDER, H., 1975. Technetium-
99m-pyridoxylidene glutamate: a new hepatobiliary radiopharmaceutical. II. Clinical aspects. Journal of Nuclear Medicine, 16, 728-737. VAN HEERTUM, R. L., SUBRAMANIAN, G., THOMAS, F. D., MCAFEE, J. G., HALL, R. C , HEMINGER, L., and VESCIO,
739
P., 1975. Comparative evaluation of Tc-99m labelled hepato-biliary agents with 1-131 -Rose Bengal. Journal of Nuclear Medicine, 16, 577-578.
OCTOBER 1977
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate: a new hepatobiliary agent A preliminary report By H. S. L. M. Tjen, M.D., W. B. van der Pompe, M.Sc, and P. H. Cox, B.Sc. Ph.D., M.P.S. AcT. Department of Nuclear Medicine, Rotterdamsch Radio-Therapeutisch Instituut, Groene Hilledijk 301, Rotterdam, Netherlands. (Received December, 1976 and in revised form April, 1977) ABSTRACT
A new hepatobiliary reagent " T c m diethyl-acetanilidoiminodiacetate has been examined in a small group of patients to evaluate its potential as a clinical reagent. The radiopharmaceutical accumulated readily in the hepatocytes and was rapidly excreted via the biliary system. It would appear possible to develop a dynamic test of hepatocyte function coupled with an evaluation of the patency of the biliary system. No adverse reactions were observed.
In the past a number of radiopharmaceuticals have been proposed to study the hepatobiliary system, but few of them have been developed into clinically useful compounds. The most widely used to date has been 131I-Rose Bengal (Burke and Halko, 1966; Eyler et al., 1968; Davies et al., 1976), but this compound has a number of inherent disadvantages. In 1975 Baker et al. described the use of 99Tcm labelled pyridoxylidene glutamate (PDG) for studies of the hepatobiliary system. In normal human subjects accumulation of PDG was observed in the liver parenchyma within five minutes of intravenous injection. Activity could be observed in the common bile duct and duodenum ten minutes post injection and in the gall-bladder within 15 minutes of injection. Loberg et al. (1976) made comparative studies of a number of alternative compounds based upon the
N-substitution of imino-diacetic acid and reported favourably on their radiochemical and biological characteristics. In the study reported here the uptake and excretion of "Tc m -Sn-labelled diethyl-acetanilidoiminodiacetate has been examined in a limited group of patients to evaluate its potential as a radiopharmaceutical for the hepatobiliary system. The reagent was obtained in kit form from commercial sources*. MATERIAL AND METHODS
The reagent was provided in the form of a sterile, pyrogen-free lyophilized tin complex. On the aseptic addition of 1-4 ml sterile pertechnetate to the contents of the labelling vial a clear solution is obtained, which is ready for use. All the patients included in this pilot study were adults. No special premedication or other precautions were taken. In all cases an intravenous dose of 5 mCi was administered. Scintigraphy was performed with the aid of a Nuclear Chicago HP gamma camera using a 140 keV diverging collimator. An on line computer (MED II, General Electric) accumulated one minute frames for 45 minutes post *HIDA ® Solco Nuclear Basle, Switzerland.
TABLE I RESULTS OF CHOLESCINTIGRAMS IN PATIENTS WITH VARIOUS DIAGNOSES ON ADMISSION
Patient
Diagnosis on admission
Cholescintigram
1. 2.
Upper abdominal pain. Liver function disturbance Obstructive jaundice
3. 4. 5. 6.
Obstructive jaundice Duodenal ulcer Hepatitis Obstructive jaundice
7. 8.
Alcohol abuse. Liver function disturbance Obstructive jaundice
9.
Obstructive jaundice
10. 11.
Obstructive jaundice Obstructive jaundice. Palpable mass upper abdomen
735
No visualization of gall-bladder Complete obstruction. No visualization of gallbladder Normal Normal Normal Incomplete obstruction. Space occupying lesion. No visualization of gall-bladder Normal Complete obstruction. No visualization of gallbladder Incomplete obstruction. No visualization of gallbladder No visualization of gall-bladder Incomplete obstruction. Space occupying process.
VOL.
50, No. 598 H. S. L. M. Tjen, W. B. van der Pompe and P. H. Cox
injection. The patient was placed in the supine position with the camera over the heart, liver and upper abdomen. The reagent was administered with the patient already positioned under the camera and the data storage system was started simultaneously. Scintigrams were recorded on Polaroid and X-ray film. The digital information was analyzed by selecting regions of interest and generating time activity curves. The regions selected were heart, liver, gall-bladder, common bile duct and duodenum. When no intestinal activity was observed on the scintigrams after 45 minutes, an additional scintigram was prepared 18-24 hours post injection.
RESULTS
Eleven patients were investigated. The diagnoses are shown in Table I. In all cases the liver function was evaluated by measuring conjugated and nonconjugated bilirubin, alkaline phosphatase and transaminase serum levels and urobilin and bilirubin levels in the urine. All but one patient had disturbed liver function at the time of admission. The patient with normal liver function was suffering from a duodenal ulcer.
X-ray investigations were also made including a simple radiograph of the abdomen and in some cases intravenous cholangiography (IVC). In two patients IVC was performed within the first week after admission; in the others it was not possible because of jaundice. Scintigraphy was performed within a week of admission except in one case. In the normal scintigram a liver image was seen between three minutes and 15 minutes post injection. The common bile duct and gall-bladder were best visualized between 25 minutes and 60 minutes and intestinal activity was observed within 60 minutes. The scintigrams obtained are described in Table I. The clinical findings were confirmed by X-ray investigation, liver biopsy and laparotomy and in some cases colloid scintigraphy (Table II). A Polaroid image of a normal study is shown in Fig. 1. In three patients with a final diagnosis of diffuse liver function disturbance, normal scintigrams were obtained, but in two similar cases there appeared to be a delayed liver excretion. More information from similar cases must be obtained to evaluate the significance of this. Kidney and bladder activity was observed in four patients, all suffering from a malignancy. Two patients had carcinoma of the pancreas head, one patient a liver carcinoma and
TABLE II COMPARISON OF CHOLESCINTIGRAM, CONTRAST RADIOLOGICAL PROCEDURES AND FINAL DIAGNOSIS
Patient 1. 2. 3. 4. 5. 6. 7. 8. 9.
Intravenous cholangiogram
Cholescintigram No visualization of gall-bladder Complete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Normal. Normal Normal Incomplete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Space occupying process. Normal Complete obstruction. No visualization of gallbladder. Kidney and bladder visualization. Incomplete obstruction. No visualization of gallbladder. Kidney and bladder visualization.
10.
No visualization of gall-bladder
11.
Incomplete obstruction
obstructed cystic duct —
Final diagnosis pancreatitis* carcinama of pancreas headj
obstructed cystic duct normal
cholangitis* duodenal ulcer]! cholestatic hepatitisf malignancy in liverf ^f
—
liver cirrhosisf liver cirrhosisf carcinoma of head of pancreasj Tumour common bile duct}; choledocholithiasis
— —
—• choledocholithiasis post-cholecystectomy cholangiogram obstructed cystic duct excretion contrast by kidney
liver cirrhosis §f liver metastasis §
Confirmed by *clinical/laboratory diagnosis fliver biopsy % laparotomy §colloid scan TfX-ray investigation
736
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate
FIG.1.
Gamma camera images of a normal subject at different time intervals. Clear visualization of heart, liver, common bile duct, gall-bladder and intestinal activity can_be seen in the different images.
one patient a tumour of the common bile duct. The computer image of a patient suffering from carcinoma of the head of the pancreas is shown in Fig. 2. Two patients suffering from carcinoma of the head of the pancreas showed complete biliary obstruction, while no activity was seen in the abdomen 24 hours post injection. Incomplete obstruction was observed in two patients. During the 45 minutes of the study no activity was seen in the abdomen. Twentyfour hours post injection the scintigram showed good
intestinal activity. Both patients were suffering from malignancies involving the liver. Liver areas suspected of poor uptake of the reagent were further investigated by colloid scintigraphy. There was a good agreement. In two patients with a suspected space-occupying lesion in the liver appearing on the cholescintigram this was confirmed by colloid scintigrams. One patient (no. 3), admitted with obstructive jaundice, showed a normal scintigram, but the IVC showed an obstructed cystic duct. The final diagnosis, confirmed
737
1 VOL.
50, No. 598 H. S. L. M. Tjen, W. B. van der Pompe and P. H. Cox
FIG. 2. Computer display of serial scintigrams of a patient suffering from carcinoma of the head of the pancreas.
by clinical and laboratory examinations, was inflammation of the common bile duct. The IVC was performed ten days before cholescintigraphy. At time of the latter study the patient was symptom free.
DISCUSSION
In this pilot study with 99Tcm labelled diethylacetanilido-iminodiacetate no side effects were observed at the dose level used and no contraindications are known. It was easily prepared using the
738
OCTOBER 1977
Technetium-99m-labelled diethyl-acetanilido-iminodiacetate "instant kit" provided. In normal subjects there is good visualization of heart, liver, common bile duct, gall-bladder and intestine. The study can be completed without inconvenience for the patient within 45 minutes of injection. Visualization of kidneys and bladder was always observed with hepato-cellular disease or total obstruction. Space-occupying lesions could be readily observed on liver images obtained between five and ten minutes post injection. Because the dynamic study prevents the preparation of liver images in various positions a follow-up investigation by means of a colloid scan is indicated. Ronai et al. (1975) concluded that a negative image of the gall-bladder was characteristic of incomplete obstruction. In one case we observed a positive image of the gall-bladder in a patient with incomplete obstruction. A good correlation was found between the qualitative scintigraphic findings and the final diagnosis. More information is needed to evaluate the uptake and excretion curves obtained by the computer from the different regions of interest. Although curves have been prepared for every patient no overall conclusion can yet be drawn. From the small number of analyses available, a significant difference seems to exist between the curves obtained from normal patients and the "delayed" values of the liver excretion-curves in patients with hepato-cellular disease. "Tcm-Sn-diethyl-acetanilido-iminodi-acetate would appear to be a potentially useful reagent for the diagnosis of functional and pathological
changes of the biliary tree. The relatively simple chemical structure and stability of the complex compared with other reagents, coupled with its excellent biological characteristics (Van Heertum et al., 1975), suggest that it could eventually become the reagent of choice for cholescintigraphy.
REFERENCES BAKER, R. J., BELLEN, J. C , and RONAI, P. M., 1975.
Technetium-99m-pyridoxylidene glutamate: a new hepato-biliary radiopharmaceutical. I. Experimental aspects. Journal ofNuclear Medicine, 16, 720—727. BURKE, G., and HALKO, A., 1966. Dynamic clinical studies
with radioisotopes and the scintilation camera II. Rose Bengal 131I liver function studies. Journal of the American Medical Association, 198, 608-618. DAVIES, E. R., MORRIS, J. N., READ, A. E., and POWELL, N.,
1976. 131I Rose Bengal scanning and clearance ratios in the investigation of jaundiced patients. Clinical Radiology, 27, 227-235.
EYLER, W. R., SCHUMAN, B. M., DUSALT, L. A., and
HINSEN, R. E., 1968. The radioiodinated Rose Bengal liver scan as an aid in the differential diagnosis of jaundice. American Journal of Roentgenology, 94, 469—476. LOBERG, M. D., COOPER, M., HARVEY, E., CALLERY, P., and FAITH, W., 1976. Development of new radiopharma-
ceuticals based on N-substitution of iminodiacetic acid, Journal of Nuclear Medicine, 17, 633—638. RONAI, P. H., BAKER, R. J., BELLEN, J. C , COLLINS, P. J., ANDERSON, P. J., and LANDER, H., 1975. Technetium-
99m-pyridoxylidene glutamate: a new hepatobiliary radiopharmaceutical. II. Clinical aspects. Journal of Nuclear Medicine, 16, 728-737. VAN HEERTUM, R. L., SUBRAMANIAN, G., THOMAS, F. D., MCAFEE, J. G., HALL, R. C , HEMINGER, L., and VESCIO,
739
P., 1975. Comparative evaluation of Tc-99m labelled hepato-biliary agents with 1-131 -Rose Bengal. Journal of Nuclear Medicine, 16, 577-578.
