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To establish the sensitivity of the gallbladder in relation to plasma concentrations of cholecystokinin, a dose-response study was performed in five normal volunteers. Cholecystokinin octapeptide was infused in ascending incremental dose sequence, interval blood samples taken for estimation of plasma hormone concentrations and gallbladder emptying rates monitored continuously using 99mTc-HIDA. In five other volunteers, gallbladder emptying rates following a liquid fat meal were measured. Infusion rates of 0.0, 0.75 +/- 0.2, 6.8 +/- 0.5, 23.8 +/- 1.6 and 66.1 +/- 2.5 pmol cholecystokinin kg-1 h-1 produced plasma concentrations of less than 3.0 (undetectable), less than 3.0, 6.6 +/- 1.8, 13.3 +/- 1.5 and 26.9 +/- 2.9 pmol l-1 respectively and gallbladder emptying rates (% min-1) of 0.0, 0.0, 0.14 +/- 0.15, 1.57 +/- 0.38 and 4.29 +/- 1.12. Following the fat meal, peak plasma cholecystokinin concentrations reach 30 pmol l-1 and gallbladder emptying rates (% min-1) are 3.86 +/- 1.01. We conclude that the threshold of the gallbladder to circulating cholecystokinin octapeptide is around 6 pmol l-1, but that infusions which result in plasma levels of around 25 pmol l-1 produce gallbladder emptying rates comparable with those seen after oral fat. This suggests that the gallbladder is equally sensitive to endogenous and exogenous cholecystokinin and that plasma concentrations observed after oral fat can entirely account for the gallbladder response.

The extraction efficiencies of the liver were studied in rabbits by injection in the portal vein of 99mTc-IDA and 131I-Rose Bengal in two experimental conditions. In the first experiment blood samples were collected for one minute from a catheter inserted into the vena cava with the tip at the sovrahepatic veins outflow level. The vena cava was ligated upperstream. In the second experiment blood was collected from the general circulation every other minute for 20' after administration. Control experiments were performed in rabbits by administration of 99mTc-Pertechnetate and 99mTc-Albumin. The results showed that the extraction of diethyl-IDA from the blood flowing through the liver is almost total.

The duodenogastric bile reflux rate in 33 patients with gastric ulcer is compared with the rates in 33 non-ulcer patients. Duodenogastric bile reflux was measured by a non-invasive isotope method using 99mTc-diethyliminodiacetic acid. Reflux occurred significantly oftener in the ulcer patients (27 of 33) than in the non-ulcer patients (14 of 33) (p less than 0.01) but did not differ significantly in quantity between these two groups. The results suggest that the magnitude of bile reflux cannot be used to distinguish between ulcer patients and non-ulcer patients.

The presence of bile in the peritoneal cavity and obstructive jaundice without liver derangement in the neonatal period is pathognomonic of spontaneous perforation of the bile-ducts. These features can be demonstrated preoperatively with ultrasound, nuclide imaging and liver function tests, without recourse to paracentesis, and the risk of contaminating the bile ascites. Furthermore, the presence of isotope in the general peritoneal cavity will exclude the diagnosis of a choledochal cyst so that jejunum should not be anastamosed to the 'false capsule' of a spontaneous perforation.

Bile reflux may occur after a variety of reconstructive procedures in the gastro-intestinal tract and biliary system. The present paper deals with reflux into the duodenum, jejunum, stomach, oesophagus and into blind loops. The demonstration of reflux by 99mTc labelled IDA acid derivatives, and a possible quantitative approach, are discussed. The advantages of an isotope method are: 1. Direct demonstration of bile reflux without any intervention in the physiological process and with little trouble to the patient, 2. The ability to use the method for various reconstructive procedures and 3. The additional information obtained which may help in the differential diagnosis of blind loops, biliary obstructions, cholecystitis or liver metastases if there has been a gastrectomy for a malignant tumour. In combination with a second administration of a radio-isotope tracer, one may be able to demonstrate abnormalities in the motility of the stomach or gut, or pyloric stenosis or gastro-oesophageal reflux.

SUMMARY Sequential hepatobiliary scintigraphy using Tc-99m-diethyI-IDA of an omphalopagus conjoined twins indicated the anatomic size, contour and position of fusion of the livers pre-operatively. There was absence of significant cross-circulation between the twins. It demonstrated separate gall bladders and biliary ducts which emptied into separate proximal duo-denas. In addition, fusion of the proximal midgut from which separate ilea arose was shown. Separate kidneys and bladders were also demonstrated. This case illustrates a significant advantage of this non-invasive technique over other methods in the evaluation of the anatomy and function of the liver and biliary system of omphalopagus conjoined twins.

A prospective study is undertaken in order to demonstrate the ability of scintigraphy with a non compartmental analysis to quantitate the duodeno-gastric reflux. 24 patients have been examined, sitting in front of a gamma camera: 12 with an endoscopically proved reflux and 12 normal subjects or volunteers. About 15 min after an injection of 148 to 222 MBq 99Tcm-IDA they were given a meal labelled with 37 MBq 113Inm-DTPA. Images were recorded for 2 h. Equal size gastric and duodenal ROIs were selected over the duodenum and stomach, avoiding overlap with neighbouring organs. The reflux index based upon the occupancy principle is calculated from the gastric and duodenal curves. It is the ratio between the gastric and duodenal ROI IDA fluxes. The value of the reflux index is 3 +/- 1.8% in normal subjects and 45 +/- 33% in pathological cases. Our method, which does not require intubation, quantitatively evaluates biliary reflux independently of injected dose and hepatic or gallbladder function.

In order to determine the effect of biliary obstruction on hepatocyte clearance and bile flow, five dogs were imaged before, and three times a week after, surgical ligation of the common bile duct. THe first postoperative study was performed 3 hr after surgery. Bile flow and duct function were evaluated from analog images; hepatocyte clearance (HC) was estimated in digital images from the ratio of liver to cardiac blood-pool counts at 3 min. Liver function tests were measured serially. 3 hr after surgery the HC index and liver function tests were still normal. Analog images showed no intestinal radioactivity, but accumulation was seen in the distending biliary tract. on the third postoperative day, all liver function tests were abnormal and the HC index was significantly decreased (p less than 0.01). The biliary tract was never seen beyond the first postoperative day. Thus, complete obstruction of the common bile duct does not stop bile flow or cause significant hepatocyte damage in the first few hours. By the third day of obstruction, however, no bile flow is detectible and significant hepatocyte damage has occurred.

Biliary and pancreatic juice has been implicated as a cause of regional inflammation or carcinoma after gastric surgery. We studied 38 patients after gastrectomy using a modification of cholescintigraphy (185 mBq 99m-Tc-DESIDA i.v.). As soon as the tracer had reached the duodenum, a dynamic study (30 min, 120 frames) was started. Thereafter a static image of the epigastrium and thorax in the anterior view with more than 1000 cts/cm2 was recorded. This procedure was repeated after a meal. Of 29 patients without complaints only 4 had a reflux into the jejunal loop. By contrast in 7 of 9 patients with suggestive symptoms this examination demonstrated bile reflux which reached the oesophagus in 6 cases. A stenosis of the distal oesophagus prevented oesophageal reflux in one patient. 2 patients with oesophageal reflux had a history of oesophageal stenosis and oesophagitis confirmed by endoscopy. The remaining 2 patients without demonstrable reflux had neither oesophagitis nor radiologically verified reflux. Cholescintigraphy as modified by us may detect clinical relevant bile reflux into the oesophagus. This is important for surgeons selecting patients with potential benefit from a reoperation. Since most patients with complaints after gastrectomy have had demonstrable bile reflux, reflux-reducing surgical techniques should be used in all.

Thirty-one patients with a wide range of hepatobiliary function and clinical diagnoses were studied with both diisopropyl-IDA Tc 99m and diethyl-IDA Tc 99m. Images were similar except for an increased liver-to-kidney ratio with diisopropyl-IDA Tc 99m (p less than 0.01) and a tendency toward an increased liver-to-background ratio at five minutes with diisopropyl-IDA Tc 99m (p greater than 0.05). Quantification of the relative hepatocyte extraction efficiency indicated a 16% higher extraction efficiency for diisopropyl-IDA Tc 99m (p greater than 0.05). Cumulative three-hour urine collections following injection demonstrated no significant difference in renal excretion in patients with normal total serum bilirubin levels. Both radiopharmaceuticals demonstrated increasing renal excretion with increasing total serum bilirubin levels; however, renal excretion of diisopropyl-IDA Tc 99m increased more slowly than excretion of diethyl-IDA Tc 99m (p less than 0.01). We conclude that, while the overall differences between these two radiopharmaceuticals are small, diisopropyl-IDA Tc 99m is superior because of a lower renal excretion rate in patients with decreased hepatocyte function.

Quantitative hepato-biliary functional scintigraphy (HBFS) determines the post-hepatic, ie. biliary, passage of diethyl-IDA through the liver and bile ducts. Time-activity curves of representative regions of the liver parenchyma and hilum are obtained. Subtraction of the parenchymal curve from the hilum curve produces a hilum flow curve, which provides an accurate measure of flow through the main biliary ducts. It allows one to differentiate the dynamic effects of various post-hepatic forms of obstruction. Dyskinesia and retention can be defined as pathological phenomena in a new way; dyskinesia is defined as intermittent flow, retention as delayed flow of bile into the duodenum. The method is only useful after removal of the gall bladder. The information provided is independent of the shape and size of the selected regions.

The value of the three non-invasive morphological methods--cholangiography, sonography, and cholescintigraphy--in the differential diagnosis of "surgical" and "non-surgical" cholestasis was assessed prospectively in 28 patients. The main disadvantage of cholangiography was the large number of patients (11 out of 28) in whom the biliary tract could not be visualized. Correct diagnosis was achieved by sonography in 25 out of 28 and by cholescintigraphy in 23 out of 28 patients.

Two methods of diagnosing acute cholecystitis--cholescintigraphy and infusion cholecystography--were compared in a prospective study of 105 patients. Sensitivity and specificity were very high (96-99% and 91%, respectively), without difference between the two methods. Infusion cholecystography gave transient rise in liver enzyme levels in more than half of the patients. Cholescintigraphy gave no side effects. Cholescintiscan could be performed at moderately elevated bilirubin levels. It also gave information concerning liver malignancy in four patients. On these grounds, cholescintigraphy is the preferable of the two methods.

Radionuclide liver scans and gray scale ultrasonography of the liver were compared in 456 patients with various abnormalities including normal variants, jaundice, abscesses, and metastatic diseases. In general the better resolution of sonography detected smaller and deeper focal lesions than nuclide scans, but nuclide studies were more informative in hepatocellular disorders. Nuclide studies frequently demonstrated lesions that could be further delineated by sonography as either cystic or solid. This ability was of particular significance in isolated liver lesions found during metastatic surveys.

A prospective study of the effect of cholecystectomy on duodenogastric reflux (DGR) in dogs and humans has been performed and compared with patients presenting with persisting symptoms following cholecystectomy several years earlier. After an intravenous injection of 99mTc EHIDA, assessment of DGR was made by measuring Bilirubin Output and the percentage of 99mTc EHIDA recovered in gastric juice over fifteen minute periods. Cholecystectomy resulted in a significant increase in both amount and frequency of DGR in dogs and patients. Patients with persisting symptoms following cholecystectomy showed the greatest amount and frequency of DGR. We suggest that increased DGR may be an aetiological factor in some patients with persisting symptoms following cholecystectomy.

Hepatobiliary investigation using 99mTc-diethyl-iminodiacetic acid (IDA) has permitted a new point of view about the morphological and functional investigation of the biliary-digestive anastomosis. Our clinical study concerning 31 patients (13 choledochoduodenostomies 10 hepaticojejunostomies, 6 choledochojejunostomies and 2 cholecystojejunostomies) helped to specify scintigraphic imaging (stasis in intrahepatic bile duct, reflux in stomach, strangulation phenomenon on the level of the mesocolon, incomplete or complete obstruction). The problems associated with current diagnostic procedures are discussed and we place the scintigraphic method amongst other radiologic methods (barium meal, endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography). This non-invasive diagonostic procedure plays a leading part in the investigation of the biliary digestive anastomosis, and particularly in the hepatico-jejunostomies.

The biokinetics (blood clearance, urinary excretion, hepatic peak time, uptake, and excretion t-1/2) and the imaging parameters (the time of appearance of the common bile duct, gallbladder, and duodenum) were determined in 34 normal subjects using Tc-99m diethyl (EIDA), Tc-99m dimethyl (HIDA), Tc-99m paraisopropyl (PIPIDA), and Tc-99m parabutyl (PBIDA) iminodiacetic acid derivatives. The blood and hepatic clearance of the four agents were significantly different (P less than 0.05) from each other. The 24-hour urinary excretion of PBIDA was significantly lower (P less than 0.05) than the urinary excretion of the other three agents. There was no difference among the four agents in the time of appearance of the gallbladder and duodenum. The time of appearance of the common bile duct was significantly delayed with PBIDA. The maximum intensity of the common bile duct usually occurred between 20 to 40 minutes with all four agents. However, gallbladder intensity continued to increase up to 3 hours. It is concluded that in the presence of normal liver function, all four Tc-99m IDA agents show definite differences in biokinetics but these differences do not have a major effect on biliary imaging parameters. If imaging alone is the primary goal, the selection of any one of the four agents will meet the clinican's need satisfactorily.

Using 99mTc diethyl HIDA, we have examined patients with duodenal and gastric ulceration for the effect of naso-gastric intubation on bile reflux. Fourteen patients with duodenal ulceration were studied supine under a gamma camera. Activity from the stomach area showed no significant change before and after naso-gastric intubation (Mann-Whitney U = 0.18). Nineteen patients with gastric ulceration were investigated for bile reflux using two techniques. One method used the gamma camera but without naso-gastric intubation. The other method involved passing a naso-gastric tube and aspirating aliquots of a liquid meal which were analysed for 99mTc HIDA content. The incidence of bile reflux in patients with gastric ulceration was the same when the results of the two methods were compared. We conclude that investigation of groups of patients for duodeno-gastric reflux by naso-gastric aspiration of gastric contents is a valid technique.

Duodeno-gastric bile reflux was studied by means of a non-invasive scintigraphic technique in 15 patients with symptomatic oesophagitis. The fate of an intravenously administered, bile-excreted radiopharmaceutic, 99Tcm-Solco-HIDA, was followed with a gamma camera. In 12 patients with an intact pylorus and in one patient operated upon by truncal vagotomy and pyloroplasty no evidence of bile reflux to the stomach was found. One of two patients earlier operated upon by a Billroth I gastrectomy had scintigraphic evidence of a severe bile reflux. We conclude that duodeno-gastric bile reflux is uncommon in patients with hiatal hernia and oesophagitis, and hence that normally pyloric incompetence is of minor importance for the development of this disorder.

Pathways and kinetics of excretion were compared to four 99mTc-IDA derivatives in healthy rabbits of both sexes. Assessment of differences between the compounds was based upon: plasma clearance, characteristics of time-activity curves measured scintigraphically over the liver (time of the peak Tmax; time for decline of activity to half the peak value - T50%), and hepatocytic mean transit time (MTT) as derived after deconvolution of the hepatic time-activity curve. Hepatocyte transit time was short and similar to 99mTc-complexes of Mebrofenin, 2,4-diethyl IDA (HEPIDA) and 3-iodo-2,6- diethylphenylcarbamoylmethyliminodiacetic acid (JODIDA); it was evidently longer for 99mTc-p-butyl-IDA (BIDA). 99mTc-HEPIDA displayed significant urinary elimination; the remaining three compounds were excreted practically completely via the biliary route. It is concluded that optimal parameters were displayed by 99mTc-Mebrofenin and 99mTc-JODIDA.

Choledochal cyst, first described by Vater (1728), is a localized cystic dilation of the common bile duct and may extend upwards to involve the hepatic ducts. The disease is relatively rare and affects orientals more frequently than any other race (Han et al., 1969). Early diagnosis and treatment can prevent the complications of ascending cholangitis, calculus formation, spontaneous or traumatic rupture, biliary cirrhosis, portal hypertension, varices, carcinoma of the cyst wall and death (Barlow et al., 1976). The clinical triad of abdominal pain, jaundice and abdominal mass is present in only about 20% of the cases and unless the index of suspicion is high the diagnosis will be missed (Alonso-Lej et al., 1959).

Hepatobiliary scintigraphy using Tc-99m diethyl IDA was performed on 14 jaundiced neonates. It aided greatly the differential diagnosis between neonatal hepatitis and biliary atresia. Limitations in the interpretation of the results are described, as neonatal hepatitis may be accompanied by biliary excretion ranging from zero to normal. Also both biliary atresia (intra- and extrahepatic) and neonatal hepatitis may show no biliary excretion within 24 hours.

The relationship between gallbladder function and duodenogastric reflux of bile has been investigated in the fasting phase by 99Tcm-EHIDA biliary scintigraphy in 370 patients with abdominal pain. This isotope is cleared from the blood-pool by hepatocellular function and is excreted into the biliary tract. Obstruction of the common bile duct was found in 79 patients, leaving 291 who were evaluable for duodenogastric bile reflux. Gallblader function was present in 169 and absent in 122 patients. Duodenogastric reflux of bile was observed in 82 patients, 10 of whom had had previous gastric surgery. Only 298 of 169 (17%) patients with a functioning gallbladder showed evidence of enterogastric bile reflux compared to 43 of 122 (35%) with absent gallbladder function (p less than 0.005 by Chi Square). These results suggest that continuous bile flow into the duodenum in the absence of a functioning gallbladder facilitates duodenogastric reflux.

Patients with space-occupying lesions (SOL) were studied using cholescintigraphy and varying results found. In 24 cases of SOL of 40 patients studied, we observed: (1) the presence of focal defects; (2) displacement of the intrahepatic biliary tree; (3) blocking of the passage (stop) of radioactivity to the intrahepatic biliary tree. The first indication, the presence of focal defects, had a sensitivity of 0.81 and a specificity of 0.78. The displacement and radioactivity stop was less frequent, but more specific. This is due to the fact that cholescintigraphy permits the specific study of the biliary tree and its pathological alterations. In our patients, the diagnostic errors were due to extreme hepatic damage, which produced an unclear image of the liver parenchyma and the biliary tree. This is observed in complete obstruction and in some cases of cirrhosis. When signs of displacement and stop were closely associated with focal defects, the diagnosis of SOL was highly specific.

Bilirubin kinetics and hepatobiliary excretion of some exogenous anions (BSP, 131I-rose bengal, diethyl and parabutly-IDA labeled with 99mTc) were studied in three patients presenting with Rotor's syndrome. Two were brothers; a nonjaundiced fraternal twin of one of them was also evaluated. The hepatic clearance of the radiopharmaceuticals was impaired in the affected patients but the degree of impairment was different among the tested anions, i.e., maximal for 99mTc-diethyl-IDA and minimal for 131I-rose bengal. Parabutyl-IDA was cleared better than the diethyl derivative. The metabolic derangement seems to be at the level of transfer from plasma to liver and of the hepatic storage, rather than at the level of hepatocyte excretory pathways, as in the case of Dubin-Johnson syndrome.