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Intrahepatic Versus Extrahepatic Cholestasis
GASTROENTEROLOGY 1986;90:734-43
Intrahepatic Versus Extrahepatic Cholestasis Discrimination With Biliary Scintigraphy Combined With Ultrasound DAVID A. LIEBERMAN and GERBAIL T. KRISHNAMURTHY
Division of Gastroenterology, Medical Service and Nuclear Medicine Service, Portland Veterans Administration Medical Center and Oregon Health Sciences University, Portland, Oregon
Biliary scintigraphy and ultrasound imaging were performed in 52 patients with suspected biliary tract pathology. Results were correlated with the findings of direct cholangiography. Several new innovations in scintigraphic technique were used. The combination of ultrasound imaging and scintigraphy correctly identified biliary tract obstruction in 17 of 19 patients, 12 of whom had dilated bile ducts on ultrasonography. Intrahepatic cholestasis was correctly diagnosed in 11 of 13 patients. Accurate discrimination between intrahepatic and extrahepatic cholestasis was achieved in 28 of 32 patients (88%) with the combined studies. Scintigraphy also provided a correct diagnosis of acute cholecystitis in all 9 patients with surgically confirmed disease. Eleven additional patients with gallbladder or pancreatic disease had normal bile ducts at scintigraphy, which was confirmed with cholangiography. When combined with ultrasound imaging, modern biliary scintigraphy can (a) provide excellent discrimination between intrahepatic and extrahepatic cholestasis and (b) help determine the need for subsequent invasive diagnostic studies in selected patients. The detection of biliary tract obstruction by noninvasive means can be difficult, particularly when the obstruction is partial or intermittent, the onset of obstruction recent, and the elevation of bilirubin modest (1-5). The relative merits of ultrasound (US), computed tomography (CT), and biliary scintigraphy with first-generation hepatobiliary agents have been Received March 1, 1985. Accepted October 7, 1985. Address requests for reprints to: David A. Lieberman, M.D., Division of Gastroenterology, Portland Veterans Administration Medical Center, P.O. Box 1034, Portland, Oregon 97207. © 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
previously reviewed (6-8). This literature becomes rapidly outdated as technologic advances are made. The evolution of hepatobiliary scintigraphy has been no less dramatic than improvements in US and CT over the past 5 yr (9-11). Prior studies have suggested that modern US and scintigraphy may be complementary in the evaluation of cholestasis (12). If these noninvasive modalities can accurately distinguish intrahepatic from extrahepatic cholestasis, the decisions about whether to proceed with invasive studies (cholangiography or liver biopsy) may be improved. We have prospectively performed biliary scintigraphy and abdominal US examination in 52 patients with intrahepatic or extrahepatic cholestasis and compared the results with findings at cholangiography. The purpose of this study was to determine the accuracy of scintigraphy in various clinical situations where biliary obstruction was suspected.
Materials and Methods Fifty-two patients (49 men and 3 women), aged 26-88 yr, were the subjects of this study. These patients represent an unselected consecutive series who underwent hepatobiliary scintigraphy, US, and direct cholangiography. Six patients had prior cholecystectomy. Based on presenting symptoms, physical examination, and laboratory tests, biliary tract disease was suspected. Written informed consent was obtained from all patients. This study was approved by the Portland Veterans Hospital Subcommittee on Human Studies on June 14, 1983.
Ultrasonography Multiple US images in transverse, sagittal, and oblique views were obtained after 4-6 h of fasting with a Abbreviations used in this paper: CBD, common bile duct; CT, computed tomography; US, ultrasound.
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Figure 1. A. Normal hepatobiliary scintigraphy. There is clear delineation of the common bile duct, gallbladder, and small intestine. B. Normal quantitative biliary dynamic study after administration of cholecystokinin-octapeptide (OP-CCK, arrows). The gallbladder ejection fraction (EF), ejection period (EP), and ejection rate (ER) are normal. There is no reflux of radioactivity into the hepatic duct, and flow of activity into the duodenum is normal, suggesting no impedance to bile flow.
real-time, 3-5-MHz, multiplexed phased array transducer with a focal length of 4-13.5 cm (ATL MK3001). Transducer output and receiver gain settings were optimized for each patient. Every attempt was made to follow the length of the common bile duct (CBD) by employing various views in the supine and oblique positions. The common hepatic duct was measured with an electronic size marker distal to where it passes the common hepatic artery. The CBD was considered to be dilated if the diameter was >5 mm. The sonographic demonstration of intrahepatic ducts was taken as evidence of duct dilation. The presence or absence of gallstones within the gallbladder was noted, but it did not influence the diagnosis of either the presence or absence of CBD obstruction.
Biliary Scintigraphy After the subjects had fasted for a minimum of 46 h, biliary imaging was performed. Each subject received 2-8 mCi of 99IDTc-labeled disophenin (DISIDA, New England Nuclear, Billerica, Mass.) while lying supine under a large field-of-view 'Y-camera (G.D. Searle & Co., Skokie, Ill.) fitted with a low-energy, all-purpose parallel hole collimator. The dose of the agent was adjusted for serum bilirubin levels. Patients with normal or mildly elevated bilirubin
levels «2 mg/dl) received 2-3 mCi, patients with moderate levels (2-5 mg/dl) received 4-5 mCi, and patients with high bilirubin levels (>5 mg/dl) received doses of 6-8 mCi, the maximum dose being 8 mCL Radiation dosage was calculated to be -1.2 rads to the gallbladder and 34 mrads to the total body. The 'Y-camera spectrometer was set for 140 keY with a 20% window. The analogue images in the anterior view were obtained every 2 min for 60 min and were recorded on 8 x 10 x-ray film (Figure lA). Right lateral and posterior images were also taken. The data were simultaneously recorded on a 64X64 computer matrix at 1 frame per minute for 60 min. The images were repeated at 4 and 24 h if the entire biliary tree and the small intestine were not seen by 60 min or 4 h. The analogue images were analyzed serially, and the time of appearance of the hepatic duct, CBD, gallbladder, and small intestine was noted. The bile flow characteristics and the evidence of bile stasis within segmental ducts, right and left hepatic ducts, and the CBD were noted. The CBD was scrutinized carefully for evidence of segmental narrowing or intraluminal filling defects. One region of interest (75-100 pixel size) was drawn over the superolateral aspect of the right hepatic lobe, after excluding all the major draining ducts by reviewing all the images of the first 60 min in the rapid cine mode computer
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video display. A second region of interest of similar size was drawn over the spleen or right lower quadrant to represent the blood background. The background count was subtracted from the hepatic count. The net count was corrected for physical decay and then subjected to nonlinear least-squares analysis. From this analysis, the hepatic excretion half-time (biologic half-time) for 99ffiTc_ DISIDA was calculated (13). The hepatic excretion halftime calculation was based on all of the data obtained for the first 60 min. Normal hepatic excretion half-time ranges from 6 to 32 min (14).
Quantitative Dynamic Scintigraphy Dynamic scintigraphy using identical instrumentation was performed in 7 patients with partial CBD obstruction to quantitate impedance to bile flow after cholecystokinin administration (Figures 1B and 2). A pinhole collimator was chosen on some occasions for better separation of structures whenever there was a superimposition of the gallbladder over the CBD or the duodenum during the first 60 min of the study. (By the nature of its geometry, the pinhole collimator accomplished better separation of structures.) This phase of the study required an additional 3D-min data collection (60-90 min after injection of 99ffiTc_ DISIDA). With the patient in the supine position, analogue images were obtained at 2-min intervals and the data were simultaneously acquired on a 64 x 64 computer matrix at 1 frame per minute. An infusion of a saline placebo (2 ml) at 5 min was followed by infusion of 10 ng/kg of cholecystokinin-octapeptide via an infusion pump at 10 min. This infusion was performed over a 3-min period at a rate of 3.3 ng/kg· min. The regions of interest were drawn over the gallbladder, CBD, and liver. From this data, the gallbladder ejection period, ejection fraction, and ejection rate were calculated (Figure 1B) as described (15). An ejection fraction of <35% and an ejection rate of <3.5% per minute suggest impedance to bile flow through the CBD (10). The ejection rate may provide a quantitative estimate of the degree of obstruction (16).
Scintigraphic Criteria for Diagnosis The scintigraphic diagnosis of each disease entity was based on the criteria outlined in Table 1. Diagnosis was based primarily on image pattern rather than the appearance time of biliary tract structures and the intestine (Figure 2). Quantitat. ve data such as hepatic excretion half-time and gallbladder ejection rates were used to complement the image interpretation. In each case, a scintigraphic diagnosis was made before cholangiography to avoid bias. In most cases, a definitive interpretation was possible. In a small subgroup of patients with severe cholestasis, however, the scintigraphic interpretation was equivocal. These patients had delayed hepatic excretion of radionuclide, resulting in faint visualization of biliary tract structures and delayed intestinal appearance. In these patients, ductal delineation was insufficient to determine if bile duct obstruction was present or absent. Therefore, discrimination between high-grade obstruction and severe
GASTROENTEROLOGY Vol. 90, NO.3
intrahepatic disease was not possible based on the image pattern.
Cholangiography Direct visualization of the bile duct was achieved in each patient by either endoscopic retrograde, percutaneous, or operative cholangiography. Scintigraphy and cholangiograms were interpreted independently by different individuals unaware of the results of the other study. The diagnosis of intrahepatic pathology was based on the presence of a normal cholangiogram and either abnormal liver histology or a consistent clinical course.
Results The patients were divided into the following four groups based on their final diagnosis (Table 2). Common Bile Duct Obstruction This group consisted of 19 patients. Twelve patients had partial and 7 patients had high-grade or complete bile duct obstruction based on cholangiographic results. Among the 12 patients with partial obstruction, 7 patients had bilirubin levels >1.7 mg/dl and 2 patients had a markedly elevated alkaline phosphatase (>500 IU). Biliary tract disease was suspected in 3 other patients with partial obstruction who had pancreatitis (serum amylase range 3581100 IU) with gallstones, accompanied by transient elevation of alkaline phosphatase. All 7 patients with high-grade obstruction had hyperbilirubinemia (range 5.2-23 mg/dl) and profound elevation of alkaline phosphatase (range 350-952 IU). Ultrasound revealed dilated intrahepatic or extrahepatic ducts or CBD stones in 12 patients, 11 of whom had a serum bilirubin level >2.0 mg/dl. Extrahepatic duct diameter was 2:1.0 cm in 9 patients, 0.6 cm in 1 patient, and normal in 2 patients with dilated intrahepatic ducts. In 7 other patients with normalcaliber bile ducts (duct diameter :54 mm), US revealed gallbladder stones in 4 patients and a pancreatic pseudocyst in 1 patient. Biliary scintigraphy correctly identified partial obstruction in 10 of 12 patients and high-grade or complete biliary obstruction in 4 of 7 patients. The scintigraphic interpretation was equivocal in 3 patients, all of whom had severe high-grade obstruction. In these patients, there was no visualization of the biliary tract or intestine for 24 h. This finding is consistent with either total biliary obstruction or very severe intrahepatic cholestasis. In all 3 patients, US revealed a CBD enlargement >1.0 cm. Therefore, the combined results of US and scintigraphy were consistent with CBD obstruction in 17 of 19 (89%) patients. The location of obstruction was accurately identified by scintigraphy in patients with partial
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+4
+6
+8
+10
+12
+14
+16
Figure 2. Benign stricture of the common bile duct (CBD), characterized by a smooth tapering of the distal CBD (arrow) and bile stasis proximal to the stricture 60 min after administration of radionuclide. Cholecystokinin-octapeptide (OP-CCK) administration results in poor emptying of the gallbladder (ejection rate 1.3%lmin, normal >3.5%), consistent with marked impedance to bile flow.
duct obstruction (Figure 2) but not in patients with complete CBD obstruction. The hepatic excretion half-time correlated well with the degree of obstruction (Figure 3). A normal excretion half-time of 5-32 min was seen in 6 patients, moderate prolongation of excretion «100 min) was seen in 4 patients, severe
prolongation (200-BOO min) was seen in 5 patients, and no excretion was seen in 4 patients with complete obstruction. Dynamic scintigraphy with cholecystokinin was available in 7 patients, 4 of whom had reduction of the gallbladder ejection rate consistent with impedance to bile flow (Figure 2). In
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GASTROENTEROLOGY Vol. 90, No.3
Table 1. Scintigraphic Criteria for DiagnosisO
Table 2. Final Diagnoses
Partial CBD obstruction Bile stasis in ducts proximal to the level of obstruction Abrupt cutoff of the CBD Segmental narrowing of the CBD Filling defects in the CBb Reduced GB ejection fraction, ejection period, and ejection rate Normal hepatic uptake with normal or mildly prolonged hepatic excretion of radionuclide
Partial or complete bile duct obstruction (n Choledocholithiasis Pancreatic carcinoma Inflammatory stricture Sclerosing cholangitis Choledochal cyst Ampullary polyp
Total CBb obstruction Nonvisualization of biliary structures including intrahepatic ducts, CBD, and GB Nonvisuallzation of intestine for 24 h Marked prolongation of hepatic excretion half-time Persistent visualization of the heart and kidneys in late images
Intrahepatic cholestasis (n = 13) Extensive liver metastaBes Cirrhosis Sepsis Congestion with hepatic necrosis Postoperative Hodgkin's disease Unexplained
Intrahepatic cholestasis Fair to poor visualization of biliary tract structures due to markedly prolonged excretion half-time; visualization of bile duct adequate to rule out CBD obstruction Normal or deiayed visualization of intestine by 4 and 24 h after radio nuclide infusion Variable hepatic uptake and excretion of radionuclide with persistent visualization of heart and kidneys Indeterminant category Combined features of total CBD obstruction and severe intrahepatic cholestasis Poor visualization of RHD, LHD, CBD, and intestine; ductal delineation insufficient to determine the presence or absence of ductal obstruction Acute cholecystitis Nonvisualization of the GB Normal visualization of the RHD, LHD, CBD, and intestine Normal hepatic excretion half-time Nonvisualization of the heart or kidneys in late images Chronic cholecystitis or cholelithiasis Normal hepatic uptake and excretion of radionuclide Normal visualization of hepatiC dUcts, CBD, and intestine Normal or delayed visualization of the GB Reduction of the GB ejection fraction and ejection period with a normal ejection rate CBD. common bile duct; GB, gallbladder; LHD: left hepatic duct; RHD, right hepatic duct. a Listed in order of relative importance.
=
19) 9 4 3
1 1 1 3 4 2
1 1 1 1
Acute cholecystitis (n = 9) Miscellaneous patients with suspected biliary tract disease (n = 11) Chronic cholecystitis Pancreatitis Possible passage of gallstone possible biliary dyskinesia Gastritis No pathology found
3 3 2 1 1 1
sent in 11 patients, and alkaline phosphatase levels were elevated in 12 of i3 patients. In each patient, the diagnosis of extrahepatic obstruction was considered in the differential diagnosis. Ultrasound imaging revealed gallbladder stones in 4 patients and 00
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2 patients, neither US nor scintigraphy was diagnos-
tic of biliary obstruction. In both of these patients, surgery was performed for symptomatic gallbladder disease and small stones were identified in the ampullary portion of the duct. Intrahepatic Cholestasis This group consisted of 13 patients whose final diagnosis of intrahepatic cholestasis was based on normal cholangiography, with positive liver histology (10 patients) or a consistent clinical course (3 patients). Jaundice (bilirubin >2.0 mg/dl) was pre-
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Diagnosis Figure 3. Hepatic excretion half-time (minutes) for each clinical group. The degree of extrahepatic obstruction by cholangiography is noted in brackets.
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EVALUATION OF CHOLESTASIS
4
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probable liver metastases in 1 patient. No ductal dilation was noted on any US examination. Hepatobiliary scintigraphy (Figure 4) revealed intrahepatic cholestasis ih 8 patients, all of whom had no evidence of obstruction to bile flow in the major biliary ducts. In 3 patients with profound jaundice (bilirubin 15.8-17.0 mg/dl), scintigraphy results were equivocal. In each patient, there was nonvisualization of the biliary tree and intestine, precluding clear discrimination between severe intrahepatic disease and high-grade extrahepatic obstruction. The failure of US to demonstrate ductal dilatation in these 3 patients with profound jaundice was interpreted as being consistent with the diagnosis of intrahepatic disease. When the combination of scintigraphic and US results were analyzed, biliary obstruction was considered to be an unlikely cause of cholestasis in these 3 patients. In 2 patients with extensive liver metastases, the hepatic excretion half-times were 32 min and 41 min (upper limit of normal 32 min) and the exams were interpreted as normal. In 11 of 13 patients, the combination of US and hepatobiliary imaging correctly suggested a diagnosis of intrahepatic cholestasis. Hepatic excre-
739
Figure 4. Intrahepatic cholestasis in a man presenting with profound jaundice (bilirubin 17 mg/dl). Ultrasound examination showed normal bile ducts. Poor hepatic uptake is observed with prolonged cardiac activity (arrowhead) up to 60 min (normal < 6 min). Biliary tract structures are never well visualized but intestinal activity is faint at 3 h and apparent by 20 h (arrow), ruling out total bile duct obstruction. Excretion half-time was delayed (442 min, normal 5-32 min) .
20houl
tion half-time (Figure 3) was elevated in these 11 patients (mean 179 min, range 43-673 min). Acute Cholecystitis This group consisted of 9 patients with acute cholecystitis confirmed at surgery. Ultrasound revealed gallbladder stones in 8 patients and a thickened gallbladder wall in 1 patient. Scintigraphy demonstrated nonvisualization of the gallbladder, consistent with acute cholecystitis, in all 9 patients. In each patient, the CBD appeared normal on scintigraphy, a finding confirmed in each case by operative cholangiography. The mean hepatic excretion half-time in this group was 25 min (range 14-46 min). Miscellaneous Gallbladder or Pancreatic Disease This group consisted of 11 patients with probable gallbladder or pancreatic disease who underwent cholangiography because of possible extrahepatic obstruction. In each patient, the bile ducts were normal. Bilirubin levels >1.0 mg/dl were noted in 3
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Table 3. Summary of Results Scintigraphy alone Patient groups Bile duct obstruction (n = 19) Detection of intrahepatic cholestasis (n = 13) Miscellaneous biliary tract disease (n = 11)
Accurate result
Ultrasound imaging plus scintigraphy Accurate result
Falsenegative
14 (74%)
17 (89%)
2 (11%)
8 (62%)
11 (85%)
2 (15%)
11 (100%)
11 (100%)
0
patients. Alkaline phosphatase was modestly elevated in 6 patients, and in 1 patient, a greater than threefold elevation was noted at the time of scintigraphy. Amylase was increased in 4 patients with gallbladder stones, raising the possibility of gallstone pancreatitis. Ultrasound and scintigraphy were evaluated in these patients to assess their specificity. The final diagnoses are shown in Table 2. In 1 patient, US appeared to demonstrate a common duct stone with CBD dilatation (1.1 cm diameter) after cholecystectomy. Endoscopic retrograde cholangiopancreatography revealed this finding to be a postsurgical artifact. In each of the 11 patients, scintigraphy accurately demonstrated normal bile ducts. Five patients had slight prolongation of hepatic excretion half-life consistent with mild intrahepatic cholestasis, which was of no clinical significance. The mean hepatic excretion half-time in this group was 34 min (range 15-86 min). The noninvasive evaluation of our patients with suspected extrahepatic obstruction is summarized in Table 3. Accurate distinction between extrahepatic and intrahepatic cholestasis was achieved with US alone in 12 patients in whom biliary ducts were observed to be dilated and in 1 patient with intrahepatic metastases. The combination of US and biliary scintigraphy successfully distinguished between intrahepatic and extrahepatic cholestasis in 28 of 32 patients. No false-positive scintigraphic studies were observed.
Discussion The challenge of distinguishing intrahepatic and extrahepatic cholestasis noninvasively remains formidable despite recent advances in US, CT, and scintigraphy. This differentiation is crucial because the clinical approach to each entity differs dramatically, and includes invasive, expensive studies. The clinical evaluation (history, physical exam, and laboratory studies) has been shown to be quite sensitive
but poorly specific in the detection of extrahepatic obstruction (7,17,18). Ultrasound may detect dilated ducts in patients with high-grade obstruction (1,2,6,19,20) and is exquisitely sensitive in some centers (21). Several recent studies have demonstrated that common duct stones are frequently found in normal-caliber bile ducts (3-5,22-24). The sensitivity of US depends upon the degree and persistence of obstruction, and correlates well with the level of hyperbilirubinemia (2). Recent reports suggest that the sensitivity of US is further increased by studying the response of the common hepatic duct to a fatty meal (25). Failure to localize and determine the cause of obstruction in most cases are additional significant limitations of US, although localization of distal obstructing calculi may be enhanced by performing erect transverse imaging (24). Ductal dilation may be present in postcholecystectomy patients, resulting in false-positive results (26,27). Computed tomography scanning has the advantage of improved localization of obstruction (19,28-30), but successful differentiation of extrahepatic and intrahepatic cholestasis is similar to US. Because of the threefold to fourfold difference in cost compared with US, CT is most appropriately reserved for patients with suspected pancreatic disease as a cause of obstruction (31). Scintigraphic visualization of bile duct structures was achieved with the introduction of 99IDTc-labeled iminodiacetic acid (IDA) compounds in 1976 (32). These compounds are protein-bound in serum and are transported through the hepatocyte via a carriermediated organic anion pathway similar to bilirubin (33). Modification of the chemical structure has improved the hepatic uptake and excretion of these compounds, even in the setting of significant liver disease (34). 99mTc-DISIDA is a "new" generation compound with excellent hepatic uptake (90%) and rapid excretion into bile (mean half-time 18 min), properties that are well maintained in the setting of partial CBD obstruction. When the bile duct is totally obstructed, hepatic uptake is maintained, but excretion is impaired, although visualization of the biliary tree (but not the intestine) may be possible for several hours (35,36). After 24 h of total obstruction, radionuclide will not appear in the bile, possibly because of high ductal pressures (35). The delayed excretion observed in patients with intrahepatic cholestasis in the presence of normal bile ducts is poorly understood, but may indicate a major defect in intrahepatocyte transport mechanisms. Accuracy of hepatobiliary scintigraphy using firstgeneration 99IDTc_IDA agents in the evaluation of cholestasis has been poor when compared with other noninvasive modalities (6-8). We have found that the following new innovations enhance the accuracy
March 1986
of the study. (a) Use of a radionuclide agent (99mTc_ DISIDA) with improved hepatic extraction and excretion (9) enhances the resolution of biliary imaging. (b) Short imaging intervals (every 2 min) during the first hour of imaging improves the detection and localization of obstruction. (c) Repeated imaging for up to 24 h if no intestinal radionuclide is seen after the first hour helps to distinguish severe intrahepatic from extrahepatic cholestasis. It is important to emphasize that interpretation of scintigraphy should be based primarily on the image pattern. The hepatic excretion half-time and gallbladder emptying rate after cholecystokinin may quantitate the degree of impedance to bile flow when partial obstruction is identified by image pattern. The objective data alone cannot be used to discriminate among various disease entities. It is clear that US and scintigraphy provide different and potentially complementary data in the evaluation of cholestasis. Ultrasound can detect ductal dilation, which if present, may suggest bile duct obstruction. Scintigraphy provides a bile flow image pattern independent of duct dilatation. With additional quantitation of hepatic radionuclide excretion and gallbladder emptying rate, the degree of bile duct obstruction can be estimated (16). Finally, scintigraphic images can reveal impairment of hepatic uptake of radionuclide, indicative of intrahepatic disease, in the presence of normal bile ducts. In the present study, 52 patients with suspected biliary tract pathology were studied with US, biliary scintigraphy, and cholangiography. Ultrasound provided evidence of ductal dilation in 13 patients, consistent with biliary tract obstruction (including one false-positive study) and revealed hepatic metastases in 1 patient. In 39 patients, US failed to provide a definite diagnosis of CBD pathology, despite clinical suspicion of bile duct disease. In these patients, the clinical dilemma of whether to proceed with invasive cholangiography or liver biopsy was not resolved by US. Biliary scintigraphy, when combined with US findings, provided accurate diagnostic information about the biliary tree in 48 of 52 patients, with no false-positive results. The differentiation of intrahepatic and extrahepatic cholestasis was accurate in 28 of 32 patients when the findings of US and scintigraphy were combined. Among the 27 patients with elevated serum bilirubin levels, US revealed ductal dilatation in 11 patients. In the remaining 16 patients, cholangiography demonstrated bile duct obstruction in only 3 patients. Since biliary imaging was accurate in 14 of these 16 patients, unnecessary invasive cholangiography might be avoided in some jaundiced patients. The hepatic excretion half-time was not discriminating in distinguishing between extrahepatic and
EVALUATION OF CHOLESTASIS
741
intrahepatic cholestasis. When obstruction was identified by imaging pattern, however, the degree of obstruction correlated well with hepatic excretion half-time (Figure 3). Six patients with partial duct obstruction had normal excretion half-times, suggesting that the degree of obstruction was mild and that intrabiliary pressures were not increased enough to interfere with hepatocyte clearance mechanisms. The diagnosis of obstruction in 4 of these patients was based on the imaging pattern. We observed false-negative scintigraphic studies in 2 patients with small stones in the ampulla of Vater. The periampullary region is a potential scintigraphic blind spot because of persistent overlapping duodenal activity. In most patients, the duodenal radioactivity is transient, so that the periampullary region can be intermittently visualized. Scintigraphic diagnosis may also be problematic in patients with underlying intrahepatic disease who develop extrahepatic obstruction. 99mTc-DISIDA resists displacement by bilirubin for hepatic uptake and excretion, resulting in good delineation of the biliary tree, even in the setting of moderate hyperbilirubinemia. Scintigraphic interpretation is not impaired if bile duct visualization is adequate. Based on the data presented, we propose the following clinical approach to cholestasis, which represents some modification of previously published algorithms (37,38). Clinical suspicion of intrahepatic or extrahepatic causes for cholestasis can be derived from a thorough history, physical examination, and laboratory tests. When extrahepatic obstruction is suspected, we recommend proceeding to abdominal US. In the setting of probable pancreatic disease, CT scan would be the preferred noninvasive imaging modality (31). If obstruction is still suspected despite a negative or equivocal US or CT finding, hepatobiliary scintigraphy should be considered as the next procedure of choice. Patients with early partial or intermittent bile duct obstruction, with normal or modestly elevated serum bilirubin levels, represent a subgroup in which US may be nondiagnostic despite recent advances in sonography. This is precisely the setting where modern dynamic biliary imaging is optimal and most reliable. Therefore, we propose that scintigraphy is most useful when early partial biliary obstruction is suspected despite a non diagnostic US examination. With excellent sensitivity and specificity in this setting, biliary imaging may help determine whether to proceed with direct ductal visualization, surgery, liver biopsy, or observation. Scintigraphy may also help to determine the timing of interventions by quantitating the degree of obstruction. At the other end of the clinical spectrum are patients with severe cholestasis and marked hyper-
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bilirubinemia, who are likely to have sonographically dilated ducts if obstruction is present (2,6,20). Intrahepatic disease is most likely present if the US demonstrates normal bile ducts in the setting of severe cholestasis. If extrahepatic obstruction is still clinically suspected in patients with profound jaundice despite a negative US finding, scintigraphy could be used to reinforce the US finding and avoid unnecessary cholangiography. In conclusion, we have demonstrated that hepatobiliary scintigraphy can provide accurate information in the evaluation of cholestasis. When combined with US, scintigraphic imaging can provide excellent discrimination between intrahepatic and extrahepatic cholestasis. The optimal clinical setting for scintigraphy is when early biliary obstruction is suspected and sonography is nondiagnostic. When CBD obstruction is present, dynamic scintigraphy can be used to quantify the degree of obstruction with measurement of hepatic, 5,llbladder, and bile excretion rates (16). The scintigral-lhic results can be used to determine the urgency of subsequent diagnostic tests and treatment. This scintigraphic methodology can be applied in virtually any nuclear medicine department. Hepatobiliary scintigraphy may also provide a valuable research tool in the evaluation and prognosis of a variety of intrahepatic and extrahepatic diseases. The study may be helpful in evaluating the effect of therapy, including biliary tract balloon dilation or stenting, and endoscopic sphincterotomy for sphincter of Oddi dysfunction.
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9.
10.
11. 12.
13.
14. 15.
16. 17. 18. 19. 20.
References
21.
1. Behan M, Kazam E. Sonography of the common bile duct:
value of the right anterior oblique view. AJR 1978;130:701-9. 2. Lapis JL, Orlando RC, Mittelstaedt CA, Staab EV. Ultrasonography in the diagnosis of obstructive jaundice. Ann Intern Med 1978;89:61-3. 3. Cronan n, Mueller PR, Simeone JF, et al. Prospective diagnosis of choledocholithiasis. Radiology 1983;146:467-9. 4. Gross BH, Harter LP, Gore RM, et al. Ultrasonic evaluation of common bile duct stones: prospective comparison with endoscopic retrograde cholangiopancreatography. Radiology 1983;146:471-4. 5. Laing FC, Jeffrey RB Jr. Choledocholithiasis and cystic duct obstruction: difficult ultrasonographic diagnosis. Radiology 1983;146:475-9. 6. Matzen P, Malchow-M011er A, Brun B, et al. Ultrasonography, computed tomography, and cholescintigraphy in suspected obstructive jaundice--a prospective comparative study. Gastroenterology 1983;84:1492-7. 7. O'Connor KW, Snodgrass PJ, Swonder JE, et al. A blinded prospective study comparing four current noninvasive approaches in the differential diagnosis of medical versus surgical jaundice. Gastroenterology 1983;84:1498-504. 8. Scott BB, Evan JA, Unsworth J. The initial investigation of jaundice in a district general hospital: a study of ultrasonog-
22. 23. 24. 25.
26.
27. 28.
29.
raphy and hepatobiliary scintigraphy. Br J Radiol 1980; 53:557-62. Klingensmith WC III, Fritzberg AR, Spitzer VM, Koep LJ. Clinical comparison of TC-99m-diethyl-IDA and Tc-99mPIPIDA for evaluation of the hepatobiliary system. Radiology 1980;134:195-9. Krishnamurthy GT, Bobba VR, McConnell D, Turner F, Mesgarzadeh M, Kingston E. Quantitative biliary dynamics: introduction of a new noninvasive scintigraphic technique. J Nucl Med 1983;24:217-23. Stadalnik RC, Matolo NM. Radionuclide imaging of the biliary tree. Surg Clin North Am 1981;61:827-42. Klingensmith WC III, Johnson ML, Kuni CC, Dunne MG, Fritzberg AR. Complementary role of TC-99m-diethyl-IDA and ultrasound in large and small duct biliary tract obstruction. Radiology 1981;138:177-84. Bobba VR, Krishnamurthy GT, Kingston E. Comparison of biokinetics and biliary imaging parameters of four Tc-99m iminodiacetic acid derivatives in normal subjects. Clin Nucl Med 1983;8:70-5. Williams W, Krishnamurthy GT, Brar HS, Bobba VR. Scintigraphic variations of normal biliary physiology. J Nucl Med 1984;25:160-5. Krishnamurthy GT, Bobba VR, Kingston E. Radionuclide ejection fraction: a technique for quantitative analysis of motor function of the human gallbladder. Gastroenterology 1981;80:482-90. Krishnamurthy GT, Lieberman DA, Brar HS. Detection, localization and quantitation of degree of common bile duct obstruction by scintigraphy. J Nucl Med 1985;26:726-35. Martin WB, Apostolakos PC, Roazen H. Clinical versus actuarial prediction in the differential diagnosis of jaundice. Am J Med Sci 1960;240:571-8. Schenker S, Balint J, Schiff L. Differential diagnosis of jaundice: report of a prospective study of 61 proven cases. Am J Dig Dis 1962;7:449-63. Ferrucci JT Jr. Body ultrasonography (part II). N Engl J Med 1979;300:590-602. Baron RL, Stanley RJ, Lee JK, et al. A prospective comparison of the evaluation of biliary obstruction using computed tomography and ultrasonography. Radiology 1982;145:91-8. Cooperberg PL, Li D, Wong P, Cohen MM, Burhenne HJ. Accuracy of common duct size in the evaluation of extrahepatic biliary obstruction. Radiology 1980;135:141-5. Muhletaler CA, Gerlock AJ Jr, Fleischer AC, James AE Jr. Diagnosis of obstructive jaundice with nondilated bile ducts. AJR 1980;134:1149-52. Beinart C, Efremidis S, Cohen B, Mitty HA. Obstruction without dilation: importance in evaluating jaundice. JAMA 1981;245:353-6. Laing FL, Jeffrey RB, Wing VW. Improved visualization of choledocholithiasis by sonography. AJR 1984;143:949-52. Simeone JF, Butch RJ, Mueller PR, et al. The bile ducts after a fatty meal: further sonographic observations. Radiology 1985;154:763-8. Graham MF, Cooperberg PL, Cohen MM Jr, Burhenne HJ. Ultrasonographic screening of the common hepatic duct in symptomatic patients after cholecystectomy. Radiology 1981; 138:137-9. Weinstein BJ, Weinstein DP. Biliary tract dilatation in the nonjaundiced patient. AJR 1980;134:899-906. Pedrosa CS, Casanova R, Rodriguez R. Computed tomography in obstructive jaundice. Part I. The level of obstruction. Radiology 1981;139:627-34. Pedrosa CS, Casanova R, Lezana AH, Fernandez Me. Computed tomography in obstructive jaundice. Part II. The cause of obstruction. Radiology 1981;139:635-45.
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30. Reid MH, Phillips HE. The role of computed tomography and ultrasound imaging in biliary tract disease. Surg Clin North Am 1981;61:787-825. 31. Whalen JP. Impact of new imaging methods. AJR 1979; 133:587-618. 32. Loberg MD, Cooper M, Harvey E, Callery R, Faith W. Development of new radio pharmaceuticals based on N-substitution of iminodiacetic acid. J Nucl Med 1976;17:633-8. 33. Harvey E, Loberg MD, Siroski S, Faith W, Cooper M. Hepatic clearance mechanism of Tc-99m-HIDA and its effect on quantitation of hepatobiliary function. J Nucl Med 1979;20:310-3. 34. Klingensmith WC III, Fritzberg AR, Spitzer VM, Kuni CC, Williamson MR, Gerhold JP. Work in progress: clinical evaluation of TC-99m-trimethylbromo-IDA and Tc-99m-diiso-
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35.
36. 37. 38.
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propyl-IDA for hepatobiliary imaging. Radiology 1983;146: 181-4. Klingensmith WC III, Whitney WP, Spitzer VM, Klintmalm GBG, Koep LM, Kuni CC. Effect of complete biliary tract obstruction on regional hepatobiliary imaging in an experimental model: concise communication. J Nucl Med 1981; 22:8661-8. Blue PW. Hyperacute complete common bile duct obstruction demonstrated with 99-Tc-IDA cholescintigraphy. Nucl Med Commun 1985;6:275-9. Scharschmidt BF, Goldberg HI, Schmid R. Approach to the patient with cholestatic jaundice. N Engl J Med 1983; 308:1515-9. Vennes JA, Bond JH. Approach to the jaundiced patient. Gastroenterology 1983;84:1615-8.
Intrahepatic Versus Extrahepatic Cholestasis Discrimination With Biliary Scintigraphy Combined With Ultrasound DAVID A. LIEBERMAN and GERBAIL T. KRISHNAMURTHY
Division of Gastroenterology, Medical Service and Nuclear Medicine Service, Portland Veterans Administration Medical Center and Oregon Health Sciences University, Portland, Oregon
Biliary scintigraphy and ultrasound imaging were performed in 52 patients with suspected biliary tract pathology. Results were correlated with the findings of direct cholangiography. Several new innovations in scintigraphic technique were used. The combination of ultrasound imaging and scintigraphy correctly identified biliary tract obstruction in 17 of 19 patients, 12 of whom had dilated bile ducts on ultrasonography. Intrahepatic cholestasis was correctly diagnosed in 11 of 13 patients. Accurate discrimination between intrahepatic and extrahepatic cholestasis was achieved in 28 of 32 patients (88%) with the combined studies. Scintigraphy also provided a correct diagnosis of acute cholecystitis in all 9 patients with surgically confirmed disease. Eleven additional patients with gallbladder or pancreatic disease had normal bile ducts at scintigraphy, which was confirmed with cholangiography. When combined with ultrasound imaging, modern biliary scintigraphy can (a) provide excellent discrimination between intrahepatic and extrahepatic cholestasis and (b) help determine the need for subsequent invasive diagnostic studies in selected patients. The detection of biliary tract obstruction by noninvasive means can be difficult, particularly when the obstruction is partial or intermittent, the onset of obstruction recent, and the elevation of bilirubin modest (1-5). The relative merits of ultrasound (US), computed tomography (CT), and biliary scintigraphy with first-generation hepatobiliary agents have been Received March 1, 1985. Accepted October 7, 1985. Address requests for reprints to: David A. Lieberman, M.D., Division of Gastroenterology, Portland Veterans Administration Medical Center, P.O. Box 1034, Portland, Oregon 97207. © 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
previously reviewed (6-8). This literature becomes rapidly outdated as technologic advances are made. The evolution of hepatobiliary scintigraphy has been no less dramatic than improvements in US and CT over the past 5 yr (9-11). Prior studies have suggested that modern US and scintigraphy may be complementary in the evaluation of cholestasis (12). If these noninvasive modalities can accurately distinguish intrahepatic from extrahepatic cholestasis, the decisions about whether to proceed with invasive studies (cholangiography or liver biopsy) may be improved. We have prospectively performed biliary scintigraphy and abdominal US examination in 52 patients with intrahepatic or extrahepatic cholestasis and compared the results with findings at cholangiography. The purpose of this study was to determine the accuracy of scintigraphy in various clinical situations where biliary obstruction was suspected.
Materials and Methods Fifty-two patients (49 men and 3 women), aged 26-88 yr, were the subjects of this study. These patients represent an unselected consecutive series who underwent hepatobiliary scintigraphy, US, and direct cholangiography. Six patients had prior cholecystectomy. Based on presenting symptoms, physical examination, and laboratory tests, biliary tract disease was suspected. Written informed consent was obtained from all patients. This study was approved by the Portland Veterans Hospital Subcommittee on Human Studies on June 14, 1983.
Ultrasonography Multiple US images in transverse, sagittal, and oblique views were obtained after 4-6 h of fasting with a Abbreviations used in this paper: CBD, common bile duct; CT, computed tomography; US, ultrasound.
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Figure 1. A. Normal hepatobiliary scintigraphy. There is clear delineation of the common bile duct, gallbladder, and small intestine. B. Normal quantitative biliary dynamic study after administration of cholecystokinin-octapeptide (OP-CCK, arrows). The gallbladder ejection fraction (EF), ejection period (EP), and ejection rate (ER) are normal. There is no reflux of radioactivity into the hepatic duct, and flow of activity into the duodenum is normal, suggesting no impedance to bile flow.
real-time, 3-5-MHz, multiplexed phased array transducer with a focal length of 4-13.5 cm (ATL MK3001). Transducer output and receiver gain settings were optimized for each patient. Every attempt was made to follow the length of the common bile duct (CBD) by employing various views in the supine and oblique positions. The common hepatic duct was measured with an electronic size marker distal to where it passes the common hepatic artery. The CBD was considered to be dilated if the diameter was >5 mm. The sonographic demonstration of intrahepatic ducts was taken as evidence of duct dilation. The presence or absence of gallstones within the gallbladder was noted, but it did not influence the diagnosis of either the presence or absence of CBD obstruction.
Biliary Scintigraphy After the subjects had fasted for a minimum of 46 h, biliary imaging was performed. Each subject received 2-8 mCi of 99IDTc-labeled disophenin (DISIDA, New England Nuclear, Billerica, Mass.) while lying supine under a large field-of-view 'Y-camera (G.D. Searle & Co., Skokie, Ill.) fitted with a low-energy, all-purpose parallel hole collimator. The dose of the agent was adjusted for serum bilirubin levels. Patients with normal or mildly elevated bilirubin
levels «2 mg/dl) received 2-3 mCi, patients with moderate levels (2-5 mg/dl) received 4-5 mCi, and patients with high bilirubin levels (>5 mg/dl) received doses of 6-8 mCi, the maximum dose being 8 mCL Radiation dosage was calculated to be -1.2 rads to the gallbladder and 34 mrads to the total body. The 'Y-camera spectrometer was set for 140 keY with a 20% window. The analogue images in the anterior view were obtained every 2 min for 60 min and were recorded on 8 x 10 x-ray film (Figure lA). Right lateral and posterior images were also taken. The data were simultaneously recorded on a 64X64 computer matrix at 1 frame per minute for 60 min. The images were repeated at 4 and 24 h if the entire biliary tree and the small intestine were not seen by 60 min or 4 h. The analogue images were analyzed serially, and the time of appearance of the hepatic duct, CBD, gallbladder, and small intestine was noted. The bile flow characteristics and the evidence of bile stasis within segmental ducts, right and left hepatic ducts, and the CBD were noted. The CBD was scrutinized carefully for evidence of segmental narrowing or intraluminal filling defects. One region of interest (75-100 pixel size) was drawn over the superolateral aspect of the right hepatic lobe, after excluding all the major draining ducts by reviewing all the images of the first 60 min in the rapid cine mode computer
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LIEBERMAN AND KRISHNAMURTHY
video display. A second region of interest of similar size was drawn over the spleen or right lower quadrant to represent the blood background. The background count was subtracted from the hepatic count. The net count was corrected for physical decay and then subjected to nonlinear least-squares analysis. From this analysis, the hepatic excretion half-time (biologic half-time) for 99ffiTc_ DISIDA was calculated (13). The hepatic excretion halftime calculation was based on all of the data obtained for the first 60 min. Normal hepatic excretion half-time ranges from 6 to 32 min (14).
Quantitative Dynamic Scintigraphy Dynamic scintigraphy using identical instrumentation was performed in 7 patients with partial CBD obstruction to quantitate impedance to bile flow after cholecystokinin administration (Figures 1B and 2). A pinhole collimator was chosen on some occasions for better separation of structures whenever there was a superimposition of the gallbladder over the CBD or the duodenum during the first 60 min of the study. (By the nature of its geometry, the pinhole collimator accomplished better separation of structures.) This phase of the study required an additional 3D-min data collection (60-90 min after injection of 99ffiTc_ DISIDA). With the patient in the supine position, analogue images were obtained at 2-min intervals and the data were simultaneously acquired on a 64 x 64 computer matrix at 1 frame per minute. An infusion of a saline placebo (2 ml) at 5 min was followed by infusion of 10 ng/kg of cholecystokinin-octapeptide via an infusion pump at 10 min. This infusion was performed over a 3-min period at a rate of 3.3 ng/kg· min. The regions of interest were drawn over the gallbladder, CBD, and liver. From this data, the gallbladder ejection period, ejection fraction, and ejection rate were calculated (Figure 1B) as described (15). An ejection fraction of <35% and an ejection rate of <3.5% per minute suggest impedance to bile flow through the CBD (10). The ejection rate may provide a quantitative estimate of the degree of obstruction (16).
Scintigraphic Criteria for Diagnosis The scintigraphic diagnosis of each disease entity was based on the criteria outlined in Table 1. Diagnosis was based primarily on image pattern rather than the appearance time of biliary tract structures and the intestine (Figure 2). Quantitat. ve data such as hepatic excretion half-time and gallbladder ejection rates were used to complement the image interpretation. In each case, a scintigraphic diagnosis was made before cholangiography to avoid bias. In most cases, a definitive interpretation was possible. In a small subgroup of patients with severe cholestasis, however, the scintigraphic interpretation was equivocal. These patients had delayed hepatic excretion of radionuclide, resulting in faint visualization of biliary tract structures and delayed intestinal appearance. In these patients, ductal delineation was insufficient to determine if bile duct obstruction was present or absent. Therefore, discrimination between high-grade obstruction and severe
GASTROENTEROLOGY Vol. 90, NO.3
intrahepatic disease was not possible based on the image pattern.
Cholangiography Direct visualization of the bile duct was achieved in each patient by either endoscopic retrograde, percutaneous, or operative cholangiography. Scintigraphy and cholangiograms were interpreted independently by different individuals unaware of the results of the other study. The diagnosis of intrahepatic pathology was based on the presence of a normal cholangiogram and either abnormal liver histology or a consistent clinical course.
Results The patients were divided into the following four groups based on their final diagnosis (Table 2). Common Bile Duct Obstruction This group consisted of 19 patients. Twelve patients had partial and 7 patients had high-grade or complete bile duct obstruction based on cholangiographic results. Among the 12 patients with partial obstruction, 7 patients had bilirubin levels >1.7 mg/dl and 2 patients had a markedly elevated alkaline phosphatase (>500 IU). Biliary tract disease was suspected in 3 other patients with partial obstruction who had pancreatitis (serum amylase range 3581100 IU) with gallstones, accompanied by transient elevation of alkaline phosphatase. All 7 patients with high-grade obstruction had hyperbilirubinemia (range 5.2-23 mg/dl) and profound elevation of alkaline phosphatase (range 350-952 IU). Ultrasound revealed dilated intrahepatic or extrahepatic ducts or CBD stones in 12 patients, 11 of whom had a serum bilirubin level >2.0 mg/dl. Extrahepatic duct diameter was 2:1.0 cm in 9 patients, 0.6 cm in 1 patient, and normal in 2 patients with dilated intrahepatic ducts. In 7 other patients with normalcaliber bile ducts (duct diameter :54 mm), US revealed gallbladder stones in 4 patients and a pancreatic pseudocyst in 1 patient. Biliary scintigraphy correctly identified partial obstruction in 10 of 12 patients and high-grade or complete biliary obstruction in 4 of 7 patients. The scintigraphic interpretation was equivocal in 3 patients, all of whom had severe high-grade obstruction. In these patients, there was no visualization of the biliary tract or intestine for 24 h. This finding is consistent with either total biliary obstruction or very severe intrahepatic cholestasis. In all 3 patients, US revealed a CBD enlargement >1.0 cm. Therefore, the combined results of US and scintigraphy were consistent with CBD obstruction in 17 of 19 (89%) patients. The location of obstruction was accurately identified by scintigraphy in patients with partial
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+4
+6
+8
+10
+12
+14
+16
Figure 2. Benign stricture of the common bile duct (CBD), characterized by a smooth tapering of the distal CBD (arrow) and bile stasis proximal to the stricture 60 min after administration of radionuclide. Cholecystokinin-octapeptide (OP-CCK) administration results in poor emptying of the gallbladder (ejection rate 1.3%lmin, normal >3.5%), consistent with marked impedance to bile flow.
duct obstruction (Figure 2) but not in patients with complete CBD obstruction. The hepatic excretion half-time correlated well with the degree of obstruction (Figure 3). A normal excretion half-time of 5-32 min was seen in 6 patients, moderate prolongation of excretion «100 min) was seen in 4 patients, severe
prolongation (200-BOO min) was seen in 5 patients, and no excretion was seen in 4 patients with complete obstruction. Dynamic scintigraphy with cholecystokinin was available in 7 patients, 4 of whom had reduction of the gallbladder ejection rate consistent with impedance to bile flow (Figure 2). In
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Table 1. Scintigraphic Criteria for DiagnosisO
Table 2. Final Diagnoses
Partial CBD obstruction Bile stasis in ducts proximal to the level of obstruction Abrupt cutoff of the CBD Segmental narrowing of the CBD Filling defects in the CBb Reduced GB ejection fraction, ejection period, and ejection rate Normal hepatic uptake with normal or mildly prolonged hepatic excretion of radionuclide
Partial or complete bile duct obstruction (n Choledocholithiasis Pancreatic carcinoma Inflammatory stricture Sclerosing cholangitis Choledochal cyst Ampullary polyp
Total CBb obstruction Nonvisualization of biliary structures including intrahepatic ducts, CBD, and GB Nonvisuallzation of intestine for 24 h Marked prolongation of hepatic excretion half-time Persistent visualization of the heart and kidneys in late images
Intrahepatic cholestasis (n = 13) Extensive liver metastaBes Cirrhosis Sepsis Congestion with hepatic necrosis Postoperative Hodgkin's disease Unexplained
Intrahepatic cholestasis Fair to poor visualization of biliary tract structures due to markedly prolonged excretion half-time; visualization of bile duct adequate to rule out CBD obstruction Normal or deiayed visualization of intestine by 4 and 24 h after radio nuclide infusion Variable hepatic uptake and excretion of radionuclide with persistent visualization of heart and kidneys Indeterminant category Combined features of total CBD obstruction and severe intrahepatic cholestasis Poor visualization of RHD, LHD, CBD, and intestine; ductal delineation insufficient to determine the presence or absence of ductal obstruction Acute cholecystitis Nonvisualization of the GB Normal visualization of the RHD, LHD, CBD, and intestine Normal hepatic excretion half-time Nonvisualization of the heart or kidneys in late images Chronic cholecystitis or cholelithiasis Normal hepatic uptake and excretion of radionuclide Normal visualization of hepatiC dUcts, CBD, and intestine Normal or delayed visualization of the GB Reduction of the GB ejection fraction and ejection period with a normal ejection rate CBD. common bile duct; GB, gallbladder; LHD: left hepatic duct; RHD, right hepatic duct. a Listed in order of relative importance.
=
19) 9 4 3
1 1 1 3 4 2
1 1 1 1
Acute cholecystitis (n = 9) Miscellaneous patients with suspected biliary tract disease (n = 11) Chronic cholecystitis Pancreatitis Possible passage of gallstone possible biliary dyskinesia Gastritis No pathology found
3 3 2 1 1 1
sent in 11 patients, and alkaline phosphatase levels were elevated in 12 of i3 patients. In each patient, the diagnosis of extrahepatic obstruction was considered in the differential diagnosis. Ultrasound imaging revealed gallbladder stones in 4 patients and 00
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2 patients, neither US nor scintigraphy was diagnos-
tic of biliary obstruction. In both of these patients, surgery was performed for symptomatic gallbladder disease and small stones were identified in the ampullary portion of the duct. Intrahepatic Cholestasis This group consisted of 13 patients whose final diagnosis of intrahepatic cholestasis was based on normal cholangiography, with positive liver histology (10 patients) or a consistent clinical course (3 patients). Jaundice (bilirubin >2.0 mg/dl) was pre-
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Diagnosis Figure 3. Hepatic excretion half-time (minutes) for each clinical group. The degree of extrahepatic obstruction by cholangiography is noted in brackets.
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EVALUATION OF CHOLESTASIS
4
6
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probable liver metastases in 1 patient. No ductal dilation was noted on any US examination. Hepatobiliary scintigraphy (Figure 4) revealed intrahepatic cholestasis ih 8 patients, all of whom had no evidence of obstruction to bile flow in the major biliary ducts. In 3 patients with profound jaundice (bilirubin 15.8-17.0 mg/dl), scintigraphy results were equivocal. In each patient, there was nonvisualization of the biliary tree and intestine, precluding clear discrimination between severe intrahepatic disease and high-grade extrahepatic obstruction. The failure of US to demonstrate ductal dilatation in these 3 patients with profound jaundice was interpreted as being consistent with the diagnosis of intrahepatic disease. When the combination of scintigraphic and US results were analyzed, biliary obstruction was considered to be an unlikely cause of cholestasis in these 3 patients. In 2 patients with extensive liver metastases, the hepatic excretion half-times were 32 min and 41 min (upper limit of normal 32 min) and the exams were interpreted as normal. In 11 of 13 patients, the combination of US and hepatobiliary imaging correctly suggested a diagnosis of intrahepatic cholestasis. Hepatic excre-
739
Figure 4. Intrahepatic cholestasis in a man presenting with profound jaundice (bilirubin 17 mg/dl). Ultrasound examination showed normal bile ducts. Poor hepatic uptake is observed with prolonged cardiac activity (arrowhead) up to 60 min (normal < 6 min). Biliary tract structures are never well visualized but intestinal activity is faint at 3 h and apparent by 20 h (arrow), ruling out total bile duct obstruction. Excretion half-time was delayed (442 min, normal 5-32 min) .
20houl
tion half-time (Figure 3) was elevated in these 11 patients (mean 179 min, range 43-673 min). Acute Cholecystitis This group consisted of 9 patients with acute cholecystitis confirmed at surgery. Ultrasound revealed gallbladder stones in 8 patients and a thickened gallbladder wall in 1 patient. Scintigraphy demonstrated nonvisualization of the gallbladder, consistent with acute cholecystitis, in all 9 patients. In each patient, the CBD appeared normal on scintigraphy, a finding confirmed in each case by operative cholangiography. The mean hepatic excretion half-time in this group was 25 min (range 14-46 min). Miscellaneous Gallbladder or Pancreatic Disease This group consisted of 11 patients with probable gallbladder or pancreatic disease who underwent cholangiography because of possible extrahepatic obstruction. In each patient, the bile ducts were normal. Bilirubin levels >1.0 mg/dl were noted in 3
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Table 3. Summary of Results Scintigraphy alone Patient groups Bile duct obstruction (n = 19) Detection of intrahepatic cholestasis (n = 13) Miscellaneous biliary tract disease (n = 11)
Accurate result
Ultrasound imaging plus scintigraphy Accurate result
Falsenegative
14 (74%)
17 (89%)
2 (11%)
8 (62%)
11 (85%)
2 (15%)
11 (100%)
11 (100%)
0
patients. Alkaline phosphatase was modestly elevated in 6 patients, and in 1 patient, a greater than threefold elevation was noted at the time of scintigraphy. Amylase was increased in 4 patients with gallbladder stones, raising the possibility of gallstone pancreatitis. Ultrasound and scintigraphy were evaluated in these patients to assess their specificity. The final diagnoses are shown in Table 2. In 1 patient, US appeared to demonstrate a common duct stone with CBD dilatation (1.1 cm diameter) after cholecystectomy. Endoscopic retrograde cholangiopancreatography revealed this finding to be a postsurgical artifact. In each of the 11 patients, scintigraphy accurately demonstrated normal bile ducts. Five patients had slight prolongation of hepatic excretion half-life consistent with mild intrahepatic cholestasis, which was of no clinical significance. The mean hepatic excretion half-time in this group was 34 min (range 15-86 min). The noninvasive evaluation of our patients with suspected extrahepatic obstruction is summarized in Table 3. Accurate distinction between extrahepatic and intrahepatic cholestasis was achieved with US alone in 12 patients in whom biliary ducts were observed to be dilated and in 1 patient with intrahepatic metastases. The combination of US and biliary scintigraphy successfully distinguished between intrahepatic and extrahepatic cholestasis in 28 of 32 patients. No false-positive scintigraphic studies were observed.
Discussion The challenge of distinguishing intrahepatic and extrahepatic cholestasis noninvasively remains formidable despite recent advances in US, CT, and scintigraphy. This differentiation is crucial because the clinical approach to each entity differs dramatically, and includes invasive, expensive studies. The clinical evaluation (history, physical exam, and laboratory studies) has been shown to be quite sensitive
but poorly specific in the detection of extrahepatic obstruction (7,17,18). Ultrasound may detect dilated ducts in patients with high-grade obstruction (1,2,6,19,20) and is exquisitely sensitive in some centers (21). Several recent studies have demonstrated that common duct stones are frequently found in normal-caliber bile ducts (3-5,22-24). The sensitivity of US depends upon the degree and persistence of obstruction, and correlates well with the level of hyperbilirubinemia (2). Recent reports suggest that the sensitivity of US is further increased by studying the response of the common hepatic duct to a fatty meal (25). Failure to localize and determine the cause of obstruction in most cases are additional significant limitations of US, although localization of distal obstructing calculi may be enhanced by performing erect transverse imaging (24). Ductal dilation may be present in postcholecystectomy patients, resulting in false-positive results (26,27). Computed tomography scanning has the advantage of improved localization of obstruction (19,28-30), but successful differentiation of extrahepatic and intrahepatic cholestasis is similar to US. Because of the threefold to fourfold difference in cost compared with US, CT is most appropriately reserved for patients with suspected pancreatic disease as a cause of obstruction (31). Scintigraphic visualization of bile duct structures was achieved with the introduction of 99IDTc-labeled iminodiacetic acid (IDA) compounds in 1976 (32). These compounds are protein-bound in serum and are transported through the hepatocyte via a carriermediated organic anion pathway similar to bilirubin (33). Modification of the chemical structure has improved the hepatic uptake and excretion of these compounds, even in the setting of significant liver disease (34). 99mTc-DISIDA is a "new" generation compound with excellent hepatic uptake (90%) and rapid excretion into bile (mean half-time 18 min), properties that are well maintained in the setting of partial CBD obstruction. When the bile duct is totally obstructed, hepatic uptake is maintained, but excretion is impaired, although visualization of the biliary tree (but not the intestine) may be possible for several hours (35,36). After 24 h of total obstruction, radionuclide will not appear in the bile, possibly because of high ductal pressures (35). The delayed excretion observed in patients with intrahepatic cholestasis in the presence of normal bile ducts is poorly understood, but may indicate a major defect in intrahepatocyte transport mechanisms. Accuracy of hepatobiliary scintigraphy using firstgeneration 99IDTc_IDA agents in the evaluation of cholestasis has been poor when compared with other noninvasive modalities (6-8). We have found that the following new innovations enhance the accuracy
March 1986
of the study. (a) Use of a radionuclide agent (99mTc_ DISIDA) with improved hepatic extraction and excretion (9) enhances the resolution of biliary imaging. (b) Short imaging intervals (every 2 min) during the first hour of imaging improves the detection and localization of obstruction. (c) Repeated imaging for up to 24 h if no intestinal radionuclide is seen after the first hour helps to distinguish severe intrahepatic from extrahepatic cholestasis. It is important to emphasize that interpretation of scintigraphy should be based primarily on the image pattern. The hepatic excretion half-time and gallbladder emptying rate after cholecystokinin may quantitate the degree of impedance to bile flow when partial obstruction is identified by image pattern. The objective data alone cannot be used to discriminate among various disease entities. It is clear that US and scintigraphy provide different and potentially complementary data in the evaluation of cholestasis. Ultrasound can detect ductal dilation, which if present, may suggest bile duct obstruction. Scintigraphy provides a bile flow image pattern independent of duct dilatation. With additional quantitation of hepatic radionuclide excretion and gallbladder emptying rate, the degree of bile duct obstruction can be estimated (16). Finally, scintigraphic images can reveal impairment of hepatic uptake of radionuclide, indicative of intrahepatic disease, in the presence of normal bile ducts. In the present study, 52 patients with suspected biliary tract pathology were studied with US, biliary scintigraphy, and cholangiography. Ultrasound provided evidence of ductal dilation in 13 patients, consistent with biliary tract obstruction (including one false-positive study) and revealed hepatic metastases in 1 patient. In 39 patients, US failed to provide a definite diagnosis of CBD pathology, despite clinical suspicion of bile duct disease. In these patients, the clinical dilemma of whether to proceed with invasive cholangiography or liver biopsy was not resolved by US. Biliary scintigraphy, when combined with US findings, provided accurate diagnostic information about the biliary tree in 48 of 52 patients, with no false-positive results. The differentiation of intrahepatic and extrahepatic cholestasis was accurate in 28 of 32 patients when the findings of US and scintigraphy were combined. Among the 27 patients with elevated serum bilirubin levels, US revealed ductal dilatation in 11 patients. In the remaining 16 patients, cholangiography demonstrated bile duct obstruction in only 3 patients. Since biliary imaging was accurate in 14 of these 16 patients, unnecessary invasive cholangiography might be avoided in some jaundiced patients. The hepatic excretion half-time was not discriminating in distinguishing between extrahepatic and
EVALUATION OF CHOLESTASIS
741
intrahepatic cholestasis. When obstruction was identified by imaging pattern, however, the degree of obstruction correlated well with hepatic excretion half-time (Figure 3). Six patients with partial duct obstruction had normal excretion half-times, suggesting that the degree of obstruction was mild and that intrabiliary pressures were not increased enough to interfere with hepatocyte clearance mechanisms. The diagnosis of obstruction in 4 of these patients was based on the imaging pattern. We observed false-negative scintigraphic studies in 2 patients with small stones in the ampulla of Vater. The periampullary region is a potential scintigraphic blind spot because of persistent overlapping duodenal activity. In most patients, the duodenal radioactivity is transient, so that the periampullary region can be intermittently visualized. Scintigraphic diagnosis may also be problematic in patients with underlying intrahepatic disease who develop extrahepatic obstruction. 99mTc-DISIDA resists displacement by bilirubin for hepatic uptake and excretion, resulting in good delineation of the biliary tree, even in the setting of moderate hyperbilirubinemia. Scintigraphic interpretation is not impaired if bile duct visualization is adequate. Based on the data presented, we propose the following clinical approach to cholestasis, which represents some modification of previously published algorithms (37,38). Clinical suspicion of intrahepatic or extrahepatic causes for cholestasis can be derived from a thorough history, physical examination, and laboratory tests. When extrahepatic obstruction is suspected, we recommend proceeding to abdominal US. In the setting of probable pancreatic disease, CT scan would be the preferred noninvasive imaging modality (31). If obstruction is still suspected despite a negative or equivocal US or CT finding, hepatobiliary scintigraphy should be considered as the next procedure of choice. Patients with early partial or intermittent bile duct obstruction, with normal or modestly elevated serum bilirubin levels, represent a subgroup in which US may be nondiagnostic despite recent advances in sonography. This is precisely the setting where modern dynamic biliary imaging is optimal and most reliable. Therefore, we propose that scintigraphy is most useful when early partial biliary obstruction is suspected despite a non diagnostic US examination. With excellent sensitivity and specificity in this setting, biliary imaging may help determine whether to proceed with direct ductal visualization, surgery, liver biopsy, or observation. Scintigraphy may also help to determine the timing of interventions by quantitating the degree of obstruction. At the other end of the clinical spectrum are patients with severe cholestasis and marked hyper-
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bilirubinemia, who are likely to have sonographically dilated ducts if obstruction is present (2,6,20). Intrahepatic disease is most likely present if the US demonstrates normal bile ducts in the setting of severe cholestasis. If extrahepatic obstruction is still clinically suspected in patients with profound jaundice despite a negative US finding, scintigraphy could be used to reinforce the US finding and avoid unnecessary cholangiography. In conclusion, we have demonstrated that hepatobiliary scintigraphy can provide accurate information in the evaluation of cholestasis. When combined with US, scintigraphic imaging can provide excellent discrimination between intrahepatic and extrahepatic cholestasis. The optimal clinical setting for scintigraphy is when early biliary obstruction is suspected and sonography is nondiagnostic. When CBD obstruction is present, dynamic scintigraphy can be used to quantify the degree of obstruction with measurement of hepatic, 5,llbladder, and bile excretion rates (16). The scintigral-lhic results can be used to determine the urgency of subsequent diagnostic tests and treatment. This scintigraphic methodology can be applied in virtually any nuclear medicine department. Hepatobiliary scintigraphy may also provide a valuable research tool in the evaluation and prognosis of a variety of intrahepatic and extrahepatic diseases. The study may be helpful in evaluating the effect of therapy, including biliary tract balloon dilation or stenting, and endoscopic sphincterotomy for sphincter of Oddi dysfunction.
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10.
11. 12.
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14. 15.
16. 17. 18. 19. 20.
References
21.
1. Behan M, Kazam E. Sonography of the common bile duct:
value of the right anterior oblique view. AJR 1978;130:701-9. 2. Lapis JL, Orlando RC, Mittelstaedt CA, Staab EV. Ultrasonography in the diagnosis of obstructive jaundice. Ann Intern Med 1978;89:61-3. 3. Cronan n, Mueller PR, Simeone JF, et al. Prospective diagnosis of choledocholithiasis. Radiology 1983;146:467-9. 4. Gross BH, Harter LP, Gore RM, et al. Ultrasonic evaluation of common bile duct stones: prospective comparison with endoscopic retrograde cholangiopancreatography. Radiology 1983;146:471-4. 5. Laing FC, Jeffrey RB Jr. Choledocholithiasis and cystic duct obstruction: difficult ultrasonographic diagnosis. Radiology 1983;146:475-9. 6. Matzen P, Malchow-M011er A, Brun B, et al. Ultrasonography, computed tomography, and cholescintigraphy in suspected obstructive jaundice--a prospective comparative study. Gastroenterology 1983;84:1492-7. 7. O'Connor KW, Snodgrass PJ, Swonder JE, et al. A blinded prospective study comparing four current noninvasive approaches in the differential diagnosis of medical versus surgical jaundice. Gastroenterology 1983;84:1498-504. 8. Scott BB, Evan JA, Unsworth J. The initial investigation of jaundice in a district general hospital: a study of ultrasonog-
22. 23. 24. 25.
26.
27. 28.
29.
raphy and hepatobiliary scintigraphy. Br J Radiol 1980; 53:557-62. Klingensmith WC III, Fritzberg AR, Spitzer VM, Koep LJ. Clinical comparison of TC-99m-diethyl-IDA and Tc-99mPIPIDA for evaluation of the hepatobiliary system. Radiology 1980;134:195-9. Krishnamurthy GT, Bobba VR, McConnell D, Turner F, Mesgarzadeh M, Kingston E. Quantitative biliary dynamics: introduction of a new noninvasive scintigraphic technique. J Nucl Med 1983;24:217-23. Stadalnik RC, Matolo NM. Radionuclide imaging of the biliary tree. Surg Clin North Am 1981;61:827-42. Klingensmith WC III, Johnson ML, Kuni CC, Dunne MG, Fritzberg AR. Complementary role of TC-99m-diethyl-IDA and ultrasound in large and small duct biliary tract obstruction. Radiology 1981;138:177-84. Bobba VR, Krishnamurthy GT, Kingston E. Comparison of biokinetics and biliary imaging parameters of four Tc-99m iminodiacetic acid derivatives in normal subjects. Clin Nucl Med 1983;8:70-5. Williams W, Krishnamurthy GT, Brar HS, Bobba VR. Scintigraphic variations of normal biliary physiology. J Nucl Med 1984;25:160-5. Krishnamurthy GT, Bobba VR, Kingston E. Radionuclide ejection fraction: a technique for quantitative analysis of motor function of the human gallbladder. Gastroenterology 1981;80:482-90. Krishnamurthy GT, Lieberman DA, Brar HS. Detection, localization and quantitation of degree of common bile duct obstruction by scintigraphy. J Nucl Med 1985;26:726-35. Martin WB, Apostolakos PC, Roazen H. Clinical versus actuarial prediction in the differential diagnosis of jaundice. Am J Med Sci 1960;240:571-8. Schenker S, Balint J, Schiff L. Differential diagnosis of jaundice: report of a prospective study of 61 proven cases. Am J Dig Dis 1962;7:449-63. Ferrucci JT Jr. Body ultrasonography (part II). N Engl J Med 1979;300:590-602. Baron RL, Stanley RJ, Lee JK, et al. A prospective comparison of the evaluation of biliary obstruction using computed tomography and ultrasonography. Radiology 1982;145:91-8. Cooperberg PL, Li D, Wong P, Cohen MM, Burhenne HJ. Accuracy of common duct size in the evaluation of extrahepatic biliary obstruction. Radiology 1980;135:141-5. Muhletaler CA, Gerlock AJ Jr, Fleischer AC, James AE Jr. Diagnosis of obstructive jaundice with nondilated bile ducts. AJR 1980;134:1149-52. Beinart C, Efremidis S, Cohen B, Mitty HA. Obstruction without dilation: importance in evaluating jaundice. JAMA 1981;245:353-6. Laing FL, Jeffrey RB, Wing VW. Improved visualization of choledocholithiasis by sonography. AJR 1984;143:949-52. Simeone JF, Butch RJ, Mueller PR, et al. The bile ducts after a fatty meal: further sonographic observations. Radiology 1985;154:763-8. Graham MF, Cooperberg PL, Cohen MM Jr, Burhenne HJ. Ultrasonographic screening of the common hepatic duct in symptomatic patients after cholecystectomy. Radiology 1981; 138:137-9. Weinstein BJ, Weinstein DP. Biliary tract dilatation in the nonjaundiced patient. AJR 1980;134:899-906. Pedrosa CS, Casanova R, Rodriguez R. Computed tomography in obstructive jaundice. Part I. The level of obstruction. Radiology 1981;139:627-34. Pedrosa CS, Casanova R, Lezana AH, Fernandez Me. Computed tomography in obstructive jaundice. Part II. The cause of obstruction. Radiology 1981;139:635-45.
March 1986
30. Reid MH, Phillips HE. The role of computed tomography and ultrasound imaging in biliary tract disease. Surg Clin North Am 1981;61:787-825. 31. Whalen JP. Impact of new imaging methods. AJR 1979; 133:587-618. 32. Loberg MD, Cooper M, Harvey E, Callery R, Faith W. Development of new radio pharmaceuticals based on N-substitution of iminodiacetic acid. J Nucl Med 1976;17:633-8. 33. Harvey E, Loberg MD, Siroski S, Faith W, Cooper M. Hepatic clearance mechanism of Tc-99m-HIDA and its effect on quantitation of hepatobiliary function. J Nucl Med 1979;20:310-3. 34. Klingensmith WC III, Fritzberg AR, Spitzer VM, Kuni CC, Williamson MR, Gerhold JP. Work in progress: clinical evaluation of TC-99m-trimethylbromo-IDA and Tc-99m-diiso-
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35.
36. 37. 38.
743
propyl-IDA for hepatobiliary imaging. Radiology 1983;146: 181-4. Klingensmith WC III, Whitney WP, Spitzer VM, Klintmalm GBG, Koep LM, Kuni CC. Effect of complete biliary tract obstruction on regional hepatobiliary imaging in an experimental model: concise communication. J Nucl Med 1981; 22:8661-8. Blue PW. Hyperacute complete common bile duct obstruction demonstrated with 99-Tc-IDA cholescintigraphy. Nucl Med Commun 1985;6:275-9. Scharschmidt BF, Goldberg HI, Schmid R. Approach to the patient with cholestatic jaundice. N Engl J Med 1983; 308:1515-9. Vennes JA, Bond JH. Approach to the jaundiced patient. Gastroenterology 1983;84:1615-8.