Liver Scintigraphy in Veterinary Medicine Federica Morandi, DVM, MS, DACVR, DECVDI The most common veterinary application of liver scintigraphy is for the diagnosis of portosystemic shunts (PSSs). There has been a continual evolution of nuclear medicine techniques for diagnosis of PSS, starting in the early 1980s. Currently, transplenic portal scintigraphy using pertechnetate or 99mTc-mebrofenin is the technique of choice. This technique provides both anatomical and functional information about the nature of the PSS, with high sensitivity and specificity. Hepatobiliary scintigraphy has also been used in veterinary medicine for the evaluation of liver function and biliary patency. Hepatobiliary scintigraphy provides information about biliary patency that complements finding in ultrasound, which may not be able to differentiate between biliary ductal dilation from previous obstruction vs current obstruction. Hepatocellular function can also be determined by deconvolutional analysis of hepatic uptake or by measuring the clearance of the radiopharmaceutical from the plasma. Plasma clearance of the radiopharmaceutical can be directly measured from serial plasma samples, as in the horse, or by measuring changes in cardiac blood pool activity by region of interest analysis of images. The objective of this paper is to present a summary of the reported applications of hepatobiliary scintigraphy in veterinary medicine. Semin Nucl Med 44:15-23 C 2014 Elsevier Inc. All rights reserved.
Scintigraphic Diagnosis of Portosystemic Shunts (PSS)
P
SSs are anomalous vascular communications that allow direct drainage of portal blood into the systemic circulation, bypassing the hepatic parenchyma.1 PSSs are a wellrecognized disease entity in dogs,1,2 and have also been reported in cats,3,4 potbelly pigs,5 foals,6,7 calves,7 and crias.8 They can be either congenital (single, or rarely, double vessels) or acquired (multiple vessels); congenital PSSs are further classified into intrahepatic or extrahepatic shunts. In dogs and cats, single extrahepatic PSSs comprise approximately 66%75% of all congenital shunts, whereas single intrahepatic PSSs account for approximately 25%-34% of all congenital PSSs.1 Certain breeds are known to be predisposed to congenital PSSs: small and toy breeds are usually affected by extrahepatic shunts, with highest prevalence reported in Havanese, Yorkshire Terrier, Maltese, Dandie Dinmont Terrier, Pug, Silky Terrier, Bichon Frise, Shih Tzu, Miniature Schnauzer, and Jack Russell Terrier.1,3,9,10 Large breed dogs most commonly present with intrahepatic shunts, with Irish Wolfhound, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN. Address reprint requests to Federica Morandi, DVM, MS, DACVR, DECVDI, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, C247 Veterinary Teaching Hospital, 2407 River Dr, Knoxville, TN 37996. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.002
retrievers, Australian cattle dog, and Australian shepherds being overrepresented. Cat breeds with higher incidence of PSS include the Himalayan, domestic short-hair, Persian, Siamese, and Burmese.1,3,9,10 Inheritance of PSS has been documented in Irish Wolfhounds and Maltese dogs, and is suspected in Yorkshire terriers.1 Multiple acquired PSSs are present in about 20% of dogs with PSS, and develop secondary to portal hypertension.1 Although congenital PSSs are treated by surgical ligation, multiple acquired PSSs are not amenable to surgical intervention, and are managed medically, therefore differentiating them is important for treatment planning.1,11 Various scintigraphic techniques have been used in the evaluation of animals with PSS, dating back to the 1980s, with the first such report describing an altered pattern of radiocolloid uptake. In normal dogs, 99mTc-sulfur colloid (SC) localizes in the mononuclear phagocytes of the reticuloendothelial system after intravenous (IV) injection, with activity visible in the liver, spleen, and bone marrow within 20 minutes of injection.12 Dogs with PSS exhibit a small liver with redistribution of the radiopharmaceutical to other nonhepatic reticuloendothelial sites, most prominently the pulmonary macrophages.13 Studies evaluating 99mTc-SC scintigraphy in dogs with PSS and biliary cirrhosis demonstrated decreased plasma clearance rate, decreased percent hepatic uptake, and increased percent pulmonary uptake of the radiopharmaceutical owing to decrease in hepatic reticuloendothelial activity in dogs with experimentally induced liver disease.14,15 The main limitation of this technique is its lack of specificity, as any 15
16 pathology causing a decrease in hepatic reticuloendothelial function results in the same scintigraphic findings. Further, species differences limit the use of colloidal scintigraphy: cats, horses, and other ungulates possess a normal population of pulmonary macrophages, resulting in pulmonary uptake in normal animals.12 IV injection of 99mTc-SC was also used to evaluate hepatic arterial and portal venous blood flow on firstpass studies, calculating the hepatic perfusion index (HPI).16 This technique required the acquisition of a dynamic study, with placement of regions of interest (ROIs) over the liver and kidneys to generate a time-activity curve (TAC) characterized by 2 phases: a first phase representing arterial flow (determined via the renal ROI) and a second phase representing portal flow (determined via the hepatic ROI). In normal dogs, the slope of both phases is similar, with an HPI o2:1 (normal mean ⫾ standard deviation [SD]: 0.9 ⫾ 0.4). In dogs with PSS, portal flow is reduced compared with arterial flow, resulting in an increase in HPI (42:1). Similar to previous techniques, this also lacked specificity, as any disease increasing hepatic arterial flow (such as liver tumors) or decreasing portal flow (cirrhosis) results in increased HPI. In the mid-1980s, transcolonic (perrectal) administration of 123 I-iodoamphetamine (IMP) was investigated in a dog model of surgically created PSS17,18 and in dogs with naturally occurring PSS.18 These studies demonstrated that 123I-IMP is absorbed unchanged through the colonic mucosa, and in normal dogs, it is almost completely removed from the liver on first pass; in dogs with PSS, however, extraction of 123I-IMP on first pass is incomplete, and the radiopharmaceutical is also delivered through the lungs, thus allowing for shunt fraction (SF) quantification (lung activity/[lung activity þ liver activity]). Disadvantages of this technique included the high cost (and now unavailability) of 123I-IMP and the longer half-life (12 hours).19 Transcolonic (perrectal) scintigraphy was also investigated using 201Tl in a rat model with promising results20; however its long half-life (3.04 days) was not ideal for animal studies. The use of pertechnetate (99mTcO 4 ) was proposed shortly thereafter. Pertechnetate has the following advantages: short half-life (6.02 hours), ideal photon energy (140 KeV), lower cost, ready availability, and unchanged absorbption through the colonic mucosa. Perrectal portal scintigraphy (PRPS) using pertechnetate was first described in the early 1990s19,21-23 and rapidly proved to be a sensitive and specific method to screen for the presence of PSS.5 This technique is simple and quick and is performed as follows: with the animal in right lateral recumbency, a lubricated soft rubber catheter is introduced into the rectum and descending colon, to the level of the wing of the ilium, and a dose of 5-20 mCi (185-740 MBq, depending on the animal's size) of pertechnetate is administered. The use of a lead shield under the pelvis is suggested to limit image bloom from the radioactive bolus in the colon, which can obscure the low count density uptake in the liver and heart, and result in dead time loss. The use of external radioactive markers positioned at the level of the liver and heart is also suggested to provide an external anatomical reference. A dynamic frame-mode acquisition (1 frame every 4 seconds) is started at the time of injection of the radioisotope, and the
F. Morandi
Figure 1 Perrectal scintigraphy in a normal dog (A) and a dog with portosystemic shunt (B). Each right lateral image represents approximately 4 seconds of data of a dynamic acquisition obtained after administration of pertechnetate in the colon. In the normal dog, after deposition of the radioactive dose in the colon (arrow) the portal vein is visible (open arrow) followed by activity in the liver (L), with predominant ventral distribution (left divisional streamlining); this is followed by activity in the heart (H) approximately 12 seconds later. In the dog with portosystemic shunt, activity is seen in the heart, with only faint activity in the area of the liver at approximately the same time. Notice the marked bloom from the colon in (B), despite the use of a lead shield under the caudal half of the body.
images are inspected to determine the route of distribution of pertechnetate after absorption through the colonic mucosa. In normal animals, activity is identified in the portal vein, liver, and several seconds later, the heart and lungs (Fig. 1). In normal dogs, the time needed for the radionuclide to travel through the liver into the heart (portal transit time) averages 12 seconds but may be quicker in small dogs.12,22 If a PSS is present, heart and lung activity is seen before or at the same time as liver activity (Fig. 1).22 In both normal animals and animals with PSS, the eventual distribution of pertechnetate in the liver is not always homogenous, and predominant ventral, dorsal, or central distributions can be seen. This appearance is owed to streamlining of the radionuclide within discrete channels of portal blood flow,24 with resulting preferential distribution of activity into one or more of the branches of the portal vein. In one study, left divisional streamlining (ventral distribution) was seen in 29.4% of cases, whereas right divisional streamlining (dorsal distribution) and central divisional streamlining (central distribution) were seen in 19.6% of cases each.25 For quantitative analysis, ROIs are drawn over the liver and heart to determine the respective total counts in the 12 seconds after the first appearance of radioactivity in either the liver or the heart; SF is determined by dividing the total counts in the heart by the summed total counts in the heart and
Liver scintigraphy in veterinary medicine liver.19,22 The mean SF in normal dogs has been reported to be 5%22; however, in cases of poor radioisotope absorption, it can be as high as 20%.12 SF values have been found to have neither predictive nor prognostic value with respect to response to therapy; they show no correlation to serum chemistry results and cannot differentiate between congenital and acquired shunts.12 Further, SF values are not reproducible among different observers: one study found that interobserver variability in SF calculation ranged from 0.4%-59.6%, with greater variability in positive studies.26 Such high variability may be due to several factors, including scan quality, ROI placement, and designation of time of first appearance of activity in the liver or heart. This finding suggests that SF calculation may also be of limited value in the postsurgical evaluation of animals that undergo shunt ligation. There are several other limitations associated with PRPS. The quality of the study (and the accuracy of interpretation) is greatly dependent on percent absorption of pertechnetate through the colonic mucosa, which is, at best, only 15%.21,27 Enema administration before PRPS is recommended to empty the colon and maximize absorption; however, in a recent study in which all the dogs had received an enema approximately 2 hours before PRPS, mean absorption of the radionuclide from the colon was only 9%.28 Because of the poor absorption, a relatively high dose must be used (up to 20 mCi [740 MBq]) with resulting high personnel exposure. A second, major limitation of PRPS is that description of the shunt morphology is usually not possible, because these studies are inherently of low count density,12,28 therefore, differentiating intrahepatic from extrahepatic shunts, and most importantly single congenital from multiple acquired shunts, is typically not possible. Errors in radionuclide placement can affect study interpretation; if the pertechnetate dose is deposited near the transverse colon, the bloom effect from the high background activity in the colon can make identification of the heart and liver difficult, especially in small and toy breed dogs, and in poor absorbers. In addition, if the radionuclide is deposited too far caudally in the rectum, absorption can occur via the caudal rectal vein, which is an indirect tributary of the caudal vena cava; if this occurs in a normal animal, it would result in a false-positive study.12 Finally, PRPS does not allow identification of microscopic venous-parenchymal communications (hepatic portal venous hypoplasia or microvascular dysplasia).1,12,28 A scintigraphic technique retaining the high specificity and sensitivity of PRPS, while overcoming its limitations, was needed. In human medicine, reports describing the transplenic injection of pertechnetate for the evaluation of the portal venous system date back to the mid-1970s.24,29-31 In dogs, one study from 1994 described the injection of 99m Tc-macroaggregated albumins in the splenic vein of dogs using sonographic guidance.32 In normal dogs, 99m Tc-macroaggregated albumin localized solely in the liver, whereas in dogs with PSS activity, it bypassed the liver through the anomalous vessel, localizing in the lungs via capillary blockade.12,32 Mean shunt index was calculated by dividing the lung counts by the sum of lung and liver counts, and was 0.01 in normal dogs and 0.94 in dogs with
17 congenital PSS.32 The first report describing a technique for transplenic portal scintigraphy (TSPS) using pertechnetate was published in 2005 and was performed as follows: with the animal in right lateral recumbency, a small area of hair is clipped in the left cranial abdomen to allow identification of the spleen using a 7.5-MHz ultrasound probe. After the skin is cleaned with alcohol, a 22-G, 1.5-in needle attached to a shielded syringe containing the radionuclide dose (1-5 mCi [37-185 MBq] in 0.1-0.5 mL volume) is placed in the splenic pulp under sonographic guidance. A dynamic frame-mode acquisition (4 frames/s) is started immediately before radionuclide injection, and the needle is withdrawn upon completion of the injection. External radioactive markers positioned at the level of the liver and heart can be used (as in PRPS) for external anatomical reference.28 In normal animals, activity flows from the splenic injection site into the splenic vein, portal vein, liver, and after a mean delay of 7 seconds, to the heart (Fig. 2). Compared with PRPS, TSPS provides a high-quality nuclear angiogram of the portal vasculature, with the ability to identify the splenic vein and portal vein as distinct, separate vessels. Absorption of pertechenetate from the spleen is consistently much higher (mean ⫾ SD: 52.5% ⫾ 19.1%) than absorption from the colon (9.2% ⫾ 5.7%), resulting in much higher total counts in the liver and spleen compared with PRPS, in turn improving count statistics.28 The use of a smaller radionuclide dose in TSPS significantly lowers patient and personnel exposure, resulting in shorter hospitalization, earlier surgical intervention, improved personnel safety, and overall improved patient care.11,28 Normal SF for pertechnetate TSPS is calculated with the same formula used for PRPS, using the 7-seconds transit time, and is 2.6% ⫾ 1.3% (mean ⫾ SD), smaller than the normal SF in PRPS. In place of pertechnetate, TSPS can also be performed with 99m Tc-mebrofenin.33 This iminodiacetic acid (IDA) derivate is a lidocaine analogue, which is extracted by the hepatocytes through the same carrier-mediated transport mechanism as bilirubin, and is excreted in the bile; in healthy dogs hepatic extraction efficiency of 99mTc-mebrofenin is consistently 490%.34,35 In normal dogs, transplenic injection of 99m Tc-mebrofenin results in a nuclear angiogram of the splenic and portal veins followed by distribution of the radiopharmaceutical in the liver, without visible activity in the heart. A static right lateral view obtained 5 minutes after injection reveals no visible blood pool and cardiac activity, with the radiopharmaceutical confined to the liver and injection site in the spleen (Fig. 2). Absorption of 99mTc-mebrofenin from the spleen is higher than absorption of pertechnetate (87.9% ⫾ 8.2% vs 52.5% ⫾ 19.1%, mean ⫾ SD). In the paper first describing this technique, transit time from the liver to heart could not be calculated owing to the high hepatic extraction of 99m Tc-mebrofenin; SF was 0.8% ⫾ 0.8% (mean ⫾ SD).33 Because TSPS with 99mTc-mebrofenin provides a better morphologic evaluation of the liver compared with pertechnetate, it makes placement of ROIs for SF quantification easier. In addition, route of excretion through the feces is advantageous, compared with excretion in the urine for pertechnetate, from a radiation safety standpoint.
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Figure 2 Transplenic scintigraphy in normal dogs using pertechnetate (top images) and 99mTc-mebrofenin (bottom images). Each right lateral image represents 1.5 (top) and 1.25 (bottom) seconds of data during the dynamic acquisition. Static right lateral views (to the right) were obtained 5 minutes after transplenic injection. After injection in the spleen (open arrow), activity is seen in the splenic vein, portal vein, and liver (L). A small amount of radioactivity reaches the heart (H) 47 seconds later (C). The linear area of activity extending caudally from the splenic injection site (open arrowhead) represents the syringe being removed after injection is completed. On the static lateral view with 99mTc-mebrofenin (D), notice that activity is limited to the liver and spleen (S); on the static lateral view with pertechnetate (B), the silhouette of the dog is clearly seen and the thyroid is visible (black arrowhead).
In dogs with PSS, the radioactivity flows from the splenic injection site into the portal venous system where it bypasses the liver and reaches the heart first (or sometimes at the same time as the liver). Three different shunting patterns can be identified: shunt termination in the caudal vena cava, azygos vein, or internal thoracic vein (Figs. 3-5).36 If 99m Tc-mebrofenin is used, a static right lateral view should be obtained 5 minutes after injection and will reveal persistent, variable blood pool and cardiac activity, indicative of incomplete clearance of the radiopharmaceutical from the blood. Single and double congenital PSS can be differentiated from multiple acquired PSS, which are often seen as a plexus of anomalous vessels in the middle to caudal abdomen (Fig. 6).36 However, not all cases of multiple acquired PSS
exhibit this typical pattern, likely owing to the small size of the anomalous vessels, which can be beyond the resolution limits of the gamma camera. The most consistent scintigraphic feature of multiple acquired PSS is hepatofugal flow extending caudal to the level of the right kidney, which in a retrospective study was seen in all but one of the confirmed multiple acquired shunts, and in none of the congenital PSS.11 Therefore, careful scrutiny of the dynamic images to determine direction of flow of the radioactive bolus is imperative, and in cases where hepatofugal flow is present, multiple acquired shunts are likely even if a single channel of activity is visible on the nuclear angiogram.11 A recent study comparing PRPS with TSPS found that TSPS was 100% sensitive and specific for the diagnosis of PSS, and more likely than PRPS to identify shunt number and
Figure 3 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital portocaval shunt; each right lateral image represents 0.75 seconds of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in the splenic vein, then curves ventrally in the portal vein, after which a focal vascular dilation (asterisk) is seen in the plane of the liver, followed by activity reaching the heart (H) from the caudal aspect of this organ. The focal vascular dilation was a large left divisional intrahepatic shunt.
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Figure 4 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital portoazygos shunt; each right lateral image represents 1 second of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in a vessel that bypasses the liver and enters the heart (H) from the dorsal aspect, consistent with the azygos vein.
termination; in addition, TSPS studies were of higher quality compared with PRPS, allowing consistent interpretation among different observers.37 TSPS, however, does not permit reliable differentiation between intrahepatic and extrahepatic location of portocaval shunts. Like PRPS, TSPS does not allow identification of microscopic venous-parenchymal communications (portal vein hypoplasia or microvascular dysplasia). At the author's institution, we have used 99mTc-mebrofenin for all TSPS studies since 2005 and have performed over 1000 studies since introducing this technique, with no complications. TSPS has reduced the proportion of nondiagnostic studies from approximately 25% with PRPS to o2%. We have found that the occasional nondiagnostic studies result from peritoneal extravasation of radiopharmaceutical at time of injection, or from lack of splenic absorption; in this situation, a second injection can be attempted immediately, or the study can be repeated the following day. Although there is a debate regarding the possibility that a congenital PSS originating caudal to the junction of the splenic vein and portal vein may be missed with TSPS37 (a fact that has been reported with splenoportography),8,38 most congenital PSSs originate from
splenic or gastric vessels and even when the shunt vessel is caudal to the splenic vein, the blood flow will follow the path of least resistance. At our institution, we have not to this day had a false-negative study.
Hepatobiliary Scintigraphy Although hepatic scintigraphy with 99mTc-SC evaluates the mononuclear phagocyte population of the liver (Kupffer cells),14,15,35,39 hepatobiliary scintigraphy evaluates the hepatic parenchymal cells,35,40-42 thereby allowing quantification of liver function (even before alteration in serum chemistry become apparent), assessment of patency of the biliary tract, and evaluation of biliary tract disease. The radiopharmaceuticals of choice for hepatobiliary scintigraphy are IDA compounds, in which the IDA molecule is used as a bifunctional chelate to carry 99mTc on one side and lidocaine on the other.35,42 This configuration allows exploitation of the properties of lidocaine, which is primarily metabolized in the liver. The 2 most commonly used IDA agents are
Figure 5 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital internal thoracic shunt; each right lateral image represents 1 second of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in the splenic vein, then curves ventrally in a vessel that runs in the area of the liver, then along the ventral aspect of the body wall, curving dorsally near the thoracic inlet and entering the heart (H) from its craniodorsal aspect, consistent with the internal thoracic vein.
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Figure 6 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with multiple acquired shunts; each right lateral image represents 1.5 seconds of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical remains in the spleen for a few seconds, after which an anomalous vessel directed caudally (arrow) is seen; there is marked hepatofugal flow and the bolus fragments in at least 3 vessels, which then enter the caudal vena cava (open arrowhead), bypassing the liver and entering the heart (H). 99m
Tc-mebrofenin and 99mTc-disofenin, which are transported to the liver loosely bound to serum protein (mainly albumin). Once they have entered the space of Disse, 99m Tc-IDAs dissociate, bind with receptors on the hepatocyte's membrane, and are taken up by the hepatocytes via carrier-mediated, nonsodium-dependent mechanism that is also used by bilirubin; they are secreted in the bile in their native form, without being metabolized.35,42,43 Alternate excretion through the kidneys is seen with liver dysfunction, but also with hypoalbuminemia (which decreases the hepatic delivery of 99mTc-IDAs)35,42 and with hyperbilirubinemia (which results in competition for the same carrier molecules).42,43 In humans, 99mTc-mebrofenin is the preferred radiopharmaceutical in patients with serum bilirubin 410 mg/dL, owing to its greater resistance to displacement by bilirubin.43 Although the serum bilirubin concentration needed for competitive inhibition to occur remains undetermined in dogs and cats, a study in horses found that fasting hyperbilirubinemia up to 8.5 mg/dL did not affect the extraction efficiency of the radiopharmaceutical.43 Hepatobiliary scintigraphy with 99mTc-IDAs has been described in dogs,34,41,44-51 cats,52-54 horses,43,55 pigeons,56 and a lamb.57 In small animals, after IV injection of 1-5 mCi (37-185 MBq) of 99mTc-mebrofenin or disofenin, a dynamic frame-mode acquisition at 5 seconds per frame is obtained for 5 minutes, followed by static 60-seconds right lateral and ventral images at 5,10, 15, 20, 25, 30, 45, 60, and 90 minutes. Additional images at 120 and 240 minutes and 24 hours may be necessary depending on hepatic uptake, identification of the gall bladder, and, most importantly, identification of activity in the intestinal tract, which is necessary to confirm biliary patency.35,45,50 The study is scrutinized for assessment of hepatic size and morphology (best evaluated on the 5-minute images), hepatic function (extraction and excretion), and biliary transit and patency. In normal animals, hepatic extraction is rapid, and peak liver activity is seen at 6-9 minutes,41 with rapid clearance from the blood pool (cardiac washout) by 5 minutes. Hepatic excretion is determined by fitting a single exponential model to the downslope of the liver
TAC obtained by drawing an ROI over a peripheral region of the liver. Normal T1/2 in dogs has been reported as 16.3 ⫾ 1.2 minutes41 or 19.1 ⫾ 4.9 minutes.34 T1/2 increases with hepatocellular disease, cholangiohepatitis, and chronic extrahepatic obstruction. In normal dogs, activity can seen in the gall bladder at 15-20 minutes,41 and in the intestines within 1 hour (Fig. 7).58 In the author's experience, the gall bladder is not always visible in dogs, despite an otherwise normal scan and normal transit time in the small intestines; instead, centralization of activity in extrahepatic biliary track followed by activity in the duodenum can be seen. This may be due to the presence of inspissated bile (sludge) in the gall bladder (a common finding in dogs), which may hamper mixing of the radiopharmaceutical with gall bladder content. Similar values are reported in cats, with peak uptake in the liver r2 minutes, T1/2 of 16 minutes, and first gall bladder visualization 31 minutes after IV radiopharmaceutical injection.52,54 Quantitative analysis via calculation of the hepatic extraction fraction (HEF) has been described in dogs and cats. The HEF represents the percentage of radiopharmaceutical removed by the liver at each circulatory pass, and in normal dogs, it is 490% (often almost 100%), similar to human data,34,35,47,48,58 although in normal cats, the HEF has been reported as 85%; this may be the result of usage of different analysis methodology.54 Calculation of HEF is best done by direct radiopharmaceutical injection in the portal vein or in an afferent mesenteric vein; however, this method is invasive and requires laparotomy, and is therefore unsuitable for clinical applications. Deconvolution analysis takes into account the changing plasma concentration after a peripheral IV injection, to simulate a direct afferent injection in the portal vein, and has been validated against direct radiopharmaceutical injection into an afferent mesenteric vein.47,48 However, this method is cumbersome, time consuming, and subject to error, due to the need for consistent placement of liver ROIs over time, which is difficult after the liver starts excreting the radiopharmaceutical. An alternative, quicker, and simpler method of HEF calculation measures the clearance of the radiopharmaceutical from the blood, by drawing an ROI over the heart
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Figure 7 Static right lateral (left) and ventral (right) views during hepatobiliary scintigraphy with 99mTc-mebrofenin in a normal dog. Notice that activity is already limited to the liver on the 5-minute view; the greatest intensity in the liver is seen at 5 minutes, and activity has dropped by greater than 50% at 20 minutes; this indicates normal uptake and clearance by the hepatocytes. Centralization in the hepatic ducts occurs rapidly, the gall bladder is clearly seen by 10 minutes, and intestinal activity seen at 30 minutes.
to generate a TAC that is used in place of a plasma disappearance curve.51,59 After normalization of the TAC (to correct for dose variability, plasma volume difference, and camera efficiency), the area under the curve (AUC) is calculated, and linear regression analysis is used to describe the relationship between the AUC and hepatic extraction. A study found good correlation between the AUC and hepatic extraction, with the best correlation obtained using the 0-30 minute data (r2 ¼ 0.92).51 Hepatobiliary scintigraphy has also been described in normal fasted and fed horses using both image-based55 and plasma-based methods.43 Because of the horse's large size, changing geometry and attenuation pose unique challenges
that make measurement of plasma clearance of 99mTc-IDA preferable. This method involves the collection of multiple blood samples from 1-240 minutes after IV radiopharmaceutical administration; 1 mL aliquots of plasma are then separated and counted to generate a normalized TAC representing 99mTc-mebrofenin disappearance from blood. A 2-compartment model is used to calculate the T1/2 of the fast (distribution and extraction) and slow (elimination) portions of the curve, after which the AUC can be calculated.43 A unique feature of horses is the development of anorexia-associated hyperbilirubinemia, with unconjugated serum bilirubin concentrations rising in proportion to the number of days spent without feed.60 This phenomenon has
Figure 8 Static right lateral (left) and ventral (right) views during hepatobiliary scintigraphy with 99mTc-mebrofenin in a dog with chronic, complete extrahepatic obstruction due to a pancreatic mass (gastrinoma) and secondary hepatocellular disease. There is incomplete clearance of the radiopharmaceutical from the soft tissues, indicating decreased hepatocellular uptake. The gall bladder remains devoid of activity (asterisk). Activity is never seen in the intestines, even on the images obtained the following day (19 hours); by 90 minutes activity is seen in the urinary bladder, representing alternate route of excretion (arrow). Quantitative analysis revealed HEF of 76%, time to maximum liver uptake of 20 minutes, and liver T1/2 clearance of 194 minutes.
22 been attributed to a rise in nonesterified fatty acid concentrations that occur in response to negative energy balance: unconjugated bilirubin and nonesterified fatty acid blood concentrations are positively correlated in feed-deprived horses, suggesting that these metabolites compete for a common pathway into the liver.60 The effect that anorexiaassociated hyperbilirubinemia has on plasma clearance of 99m Tc-mebrofenin was investigated in fasted normal horses, in which clearance studies were performed at baseline, and after 48 and 96 hours of feed deprivation. Although total plasma bilirubin concentration increased from 1.3 ⫾ 0.3 mg/dL at baseline, to 6.3 ⫾ 1.3 mg/dL after 96 hours of fasting, AUC, fast-phase T1/2, and slow-phase T1/2 did not differ at the 3 time points. Serum bilirubin concentration did not correlate with AUC or fast-phase T1/2, but there was a weak correlation with slow-phase T1/2 (r ¼ 0.50), suggesting some degree of competitive inhibition between the radiopharmaceutical and serum bilirubin.43 Hepatobiliary scintigraphy can be used to differentiate between partial and complete biliary obstruction, by determining whether activity reaches the intestinal tract (Fig. 8). In an initial study in dogs and cats, lack of intestinal activity 180 minutes after IV radiopharmaceutical injection was suggested as the criterion for complete biliary obstruction, with sensitivity of 83% and specificity of 94%.45 However, a later study found that lack of intestinal activity 19-24 hours after injection was a better cutoff, resulting in both sensitivity and specificity of 83%, compared with 100% and 33%, respectively, if the 180minutes criterion was used.50 In animals with partial biliary obstruction, intestinal activity is usually of much lower intensity compared with that seen in animals with patent biliary tree, and appropriate manipulation of the image window and gray scale is required to ensure that intestinal activity is not missed.50
References 1. Berent AC, Tobias KM: Portosystemic vascular anomalies. Vet Clin North Am Small Anim Pract 2009;39:513-541 2. Lamb CR, Daniel GB: Diagnostic imaging of dogs with suspected portosystemic shunting. Compendium 2002;24:626-635 3. Hunt GB: Effect of breed on anatomy of portosystemic shunts resulting from congenital diseases in dogs and cats: A review of 242 cases. Aust Vet J 2004;82:746-749 4. Tillson DM, Winkler JT: Diagnosis and treatment of portosystemic shunts in the cat. Vet Clin North Am Small Anim Pract 2002;32:881-899 5. Koblik PD, Hornof WJ: Transcolonic sodium pertechnetate Tc99m scintigraphy for diagnosis of macrovascular portosystemic shunts in dogs, cats, and potbellied pigs: 176 cases (1988-1992). J Am Vet Med Assoc 1995;207:729-733 6. Hug SA, Guerrero TG, Makara M, et al: Diagnosis and surgical cellophane banding of an intrahepatic congenital portosystemic shunt in a foal. J Vet Intern Med 2012;26:171-177 7. Fortier LA, Fubini SL, Flanders JA, et al: The diagnosis and surgical correction of congenital portosystemic vascular anomalies in two calves and two foals. Vet Surg 1996;25:154-160 8. Ivany JM, Anderson DE, Birchard SJ, et al: Portosystemic shunt in an alpaca cria. J Am Vet Med Assoc 2002;220:1696-1699 9. Tobias KM, Rohrbach BW: Association of breed with the diagnosis of congenital portosystemic shunts in dogs: 2,400 cases (1980-2002). J Am Vet Med Assoc 2003;223:1636-1639
F. Morandi 10. Ubbink GJ, van de Broek J, Meyer HP, et al: Prediction of inherited portosystemic shunts in Irish Wolfhounds on the basis of pedigree analysis. Am J Vet Res 1998;59:1553-1556 11. Morandi F, Sura PA, Sharp D, et al: Characterization of multiple acquired portosystemic shunts using transplenic portal scintigraphy. Vet Radiol Ultrasound 2010;51:466-471 12. Daniel GB, Berry CR: Scintigraphic detection of portosystemic shunts. In: Daniel GB, Berry CR, (eds): Textbook of Veterinary Nuclear Medicine. (ed 2). ACVR; 2006 13. Hornof WJ, Koblik PD, Breznock EM: Radiocolloid scintigraphy as an aid to the diagnosis of congenital portacaval anomalies in the dog. J Am Vet Med Assoc 1983;182:44-46 14. Koblik PD, Hornof WJ, Yen CK, et al: Use of technetium-99m sulfur colloid to evaluate changes in reticuloendothelial function in dogs with experimentally induced chronic biliary cirrhosis and portosystemic shunting. Am J Vet Res 1995;56:688-693 15. Koblik PD, Hornof WJ: Technetium 99m sulfur colloid scintigraphy to evaluate reticuloendothelial system function in dogs with portasystemic shunts. J Vet Intern Med 1995;9:374-380 16. Koblik PD, Hornof WJ, Breznock EM: Quantitative hepatic scintigraphy in the dog. Vet Radiol 1983;24:226-231 17. Yen CK, Pollycove M, Crass R, et al: Portasystemic shunt fraction quantification with colonic iodine-123 iodoamphetamine. J Nucl Med 1986;27:1321-1326 18. Koblik PD, Yen CK, Hornof WJ, et al: Use of transcolonic 123IIodoamphetamine to diagnose spontaneous portosystemic shunts in 18 dogs. Vet Radiol 1989;30:67-73 19. Daniel GB, Bright R, Monnet E, et al: Comparison of per-rectal portal scintigraphy using 99m-technetium pertechnetate to mesenteric injection of radioactive microsheperes for quantification of portosystemic shunts in an experimental dog model. Vet Radiol 1990;31:175-181 20. Van Maldergem L, Jeghers O, Cadiere G, et al: Per rectal thallium scintigraphy for the assessment of portosystemic shunt: An experimental study in the bile duct ligated rats. Eur J Nucl Med 1989;15:587-590 21. Koblik PD, Komtebedde J, Yen CK, et al: Use of transcolonic 99mtechnetium-pertechnetate as a screening test for portosystemic shunts in dogs. J Am Vet Med Assoc 1990;196:925-930 22. Daniel GB, Bright R, Ollis P, et al: Per rectal portal scintigraphy using 99mtechnetium pertechnetate to diagnose portosystemic shunts in dogs and cats. J Vet Intern Med 1991;5:23-27 23. Koblik PD, Hornof WJ, Yen CK, et al: Comparison of shunt fraction estimation using transcolonic iodine-123-iodoamphetamine and technetium-99m-pertechnetate in a group of dogs with experimentallyinduced chronic biliary cirrhosis. J Nucl Med 1991;32:124-129 24. Kashiwagi T, Kamada T, Abe H: Dynamic studies on the portal hemodynamics of scintiphotosplenoportography. Streamline flow in the human portal vein. Gastroenterology 1975;69:1292-1296 25. Daniel GB, DeNovo RC, Sharp DS, et al: Portal streamlining as a cause of nonuniform hepatic distribution of sodium pertechnetate during perrectal portal scintigraphy in the dog. Vet Radiol Ultrasound 2004;45: 78-84 26. Samii VF, Kyles AE, Long CD, et al: Evaluation of interoperator variance in shunt fraction calculation after transcolonic scintigraphy for diagnosis of portosystemic shunts in dogs and cats. J Am Vet Med Assoc 2001;218: 1116-1119 27. Caride VJ: Rectal absorption of 99m Tc-pertechnetate in the dog. J Nucl Med 1973;14:600-603 28. Cole RC, Morandi F, Avenell J, et al: Trans-splenic portal Scintigraphy in normal dogs. Vet Radiol Ultrasound 2005;46:146-152 29. Kashiwagi T, Kamada T, Abe H: Dynamic studies on the portal hemodynamics by scintiphotosplenoportography: The visualization of portal venous system using 99mTc. Gastroenterology 1974;67: 668-673 30. Kashiwagi T, Kimura K, Kamada T, et al: Measurement of regional hepatic blood flow by scintiphotosplenoportography. Acta Hepatogastroenterol (Stuttg) 1978;25:260-266 31. Kashiwagi T, Kimura K, Suematsu T, et al: Dynamic studies on portal haemodynamics by scintiphotosplenoportography: Flow patterns of portal circulation. Gut 1980;21:57-62
Liver scintigraphy in veterinary medicine 32. Meyer HP, Rothuizen J, van den Brom WE, et al: Quantitation of portosystemic shunting in dogs by ultrasound-guided injection of 99MTcmacroaggregates into a splenic vein. Res Vet Sci 1994;57:58-62 33. Morandi F, Cole RC, Echandi RL, et al: Transsplenic portal scintigraphy using 99mTc-mebrofenin in normal dogs. Vet Radiol Ultrasound 2007;48: 286-291 34. Daniel GB, Bahr A, Dykes JA, et al: Hepatic extraction efficiency and excretion rate of technetium-99m-mebrofenin in dogs. J Nucl Med 1996;37:1846-1849 35. Daniel GB: Hepatic scintigraphy. In: Daniel GB, Berry CR, (eds): Textbook of Veterinary Nuclear Medicine. (ed 2). ACVR; 2006 36. Morandi F, Cole RC, Tobias KM, et al: Use of 99mTcO-4 trans-splenic portal scintigraphy for diagnosis of portosystemic shunts in 28 dogs. Vet Radiol Ultrasound 2005;46:153-161 37. Sura PA, Tobias KM, Morandi F, et al: Comparison of 99mTcO-4 transsplenic portal scintigraphy with per-rectal portal scintigraphy for diagnosis of portosystemic shunts in dogs. Vet Surg 2007;36:654-660 38. Suter PF: Portal vein abnormalities in the dog: Their angiographic diagnosis. J Am Radiol Soc 1975;16:84-97 39. Krishnamurthy GT, Krishnamurthy S: Liver and spleen function. In: Krishnamurthy GT, Krishnamurthy S, (eds): Nuclear Hepatology: A Textbook of Hepatobiliary Disease. Berlin: Springer; 2000 40. Krishnamurthy GT, Krishnamurthy S, (eds): Nuclear Hepatology: A Textbook of Hepatobiliary Disease. Berlin: Springer; 2000 41. Kerr LY, Hornof WJ: Quantitative hepatobiliary scintigraphy using 99m TC-DISIDA in the dog. Vet Radiol 1986;27:173-177 42. Krishnamurthy S, Krishnamurthy GT: Technetium-99m-iminodiacetic acid organic anions: Review of biokinetics and clinical application in hepatology. Hepatology 1989;9:139-153 43. Morandi F, Frank N, Avenell J, et al: Quantitative assessment of hepatic function by means of 99mTc-mebrofenin in healthy horses. J Vet Intern Med 2005;19:751-755 44. Rothuizen J, van den Brom WE: Quantitative hepatobiliary scintigraphy as a measure of bile flow in dogs with cholestatic disease. Am J Vet Res 1990;51:253-256 45. Boothe HW, Boothe DM, Komkov A, et al: Use of hepatobiliary scintigraphy in the diagnosis of extrahepatic biliary obstruction in dogs and cats: 25 cases (1982-1989). J Am Vet Med Assoc 1992;201: 134-141 46. Newell SM, Selcer BA, Mahaffey MB, et al: Gallbladder mucocele causing biliary obstruction in two dogs: Ultrasonographic, scintigraphic, and pathological findings. J Am Anim Hosp Assoc 1995;31:467-472
23 47. Bahr A, Daniel GB, DeNovo R, et al: Quantitative hepatobiliary scintigraphy with deconvolutional analysis for the measurement of hepatic function in dogs. Vet Radiol Ultrasound 1996;37:214-220 48. Daniel GB, Denovo R, Schultze AE, et al: Validation of deconvolutional analysis for the measurement of hepatic function in dogs with toxicinduced liver disease. Vet Radiol Ultrasound 1998;39:375-383 49. Daniel GB, DeNovo RC, Schultze AE, et al: Hepatic extraction efficiency of technetium-99m-mebrofenin in the dog with toxic-induced acute liver disease. J Nucl Med 1998;39:1286-1292 50. Head LL, Daniel GB: Correlation between hepatobiliary scintigraphy and surgery or postmortem examination findings in dogs and cats with extrahepatic biliary obstruction, partial obstruction, or patency of the biliary system: 18 cases (1995-2004). J Am Vet Med Assoc 2005;227: 1618-1624 51. Daniel GB, DeNovo R, Bahr A, et al: Evaluation of heart time-activity curves as a predictor of hepatic extraction of 99mTc-mebrofenin in dogs. Vet Radiol Ultrasound 2001;42:162-168 52. Newell SM, Selcer BA, Roberts RE, et al: Use of hepatobiliary scintigraphy in clinically normal cats. Am J Vet Res 1994;55:762-768 53. Newell SM, Selcer BA, Roberts RE, et al: Hepatobiliary scintigraphy in the evaluation of feline liver disease. J Vet Intern Med 1996;10:308-315 54. Newell SM, Graham JP, Roberts GD, et al: Quantitative hepatobiliary scintigraphy in normal cats and in cats with experimental cholangiohepatitis. Vet Radiol Ultrasound 2001;42:70-76 55. Hornof WJ, Baker DG: Biliary kinetics of horses as determined by quantitative nuclear scintigraphy. Vet Radiol 1986;27:85-88 56. Hadley TL, Daniel GB, Rotstein DS, et al: Evaluation of hepatobiliary scintigraphy as an indicator of hepatic function in domestic pigeons (Columba livia) before and after exposure to ethylene glycol. Vet Radiol Ultrasound 2007;48:155-162 57. Lofstedt J, Koblik PD, Jakowski RM, et al: Use of hepatobiliary scintigraphy to diagnose bile duct atresia in a lamb. J Am Vet Med Assoc 1988;193:95-98 58. Daniel GB, Tucker RL: Liver scintigraphy: Applications. Semin Vet Med Surg Small Anim 1991;6:154-163 59. Matwichuk CL, Daniel GB, DeNovo RC, et al: Evaluation of plasma timeactivity curves of technetium-99m-mebrofenin for measurement of hepatic function in dogs. Vet Radiol Ultrasound 2000;41:78-84 60. Engelking LR: Equine fasting hyperbilirubinemia. Adv Vet Sci Comp Med 1993;37:115-125
Scintigraphic Diagnosis of Portosystemic Shunts (PSS)
P
SSs are anomalous vascular communications that allow direct drainage of portal blood into the systemic circulation, bypassing the hepatic parenchyma.1 PSSs are a wellrecognized disease entity in dogs,1,2 and have also been reported in cats,3,4 potbelly pigs,5 foals,6,7 calves,7 and crias.8 They can be either congenital (single, or rarely, double vessels) or acquired (multiple vessels); congenital PSSs are further classified into intrahepatic or extrahepatic shunts. In dogs and cats, single extrahepatic PSSs comprise approximately 66%75% of all congenital shunts, whereas single intrahepatic PSSs account for approximately 25%-34% of all congenital PSSs.1 Certain breeds are known to be predisposed to congenital PSSs: small and toy breeds are usually affected by extrahepatic shunts, with highest prevalence reported in Havanese, Yorkshire Terrier, Maltese, Dandie Dinmont Terrier, Pug, Silky Terrier, Bichon Frise, Shih Tzu, Miniature Schnauzer, and Jack Russell Terrier.1,3,9,10 Large breed dogs most commonly present with intrahepatic shunts, with Irish Wolfhound, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN. Address reprint requests to Federica Morandi, DVM, MS, DACVR, DECVDI, Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, C247 Veterinary Teaching Hospital, 2407 River Dr, Knoxville, TN 37996. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.002
retrievers, Australian cattle dog, and Australian shepherds being overrepresented. Cat breeds with higher incidence of PSS include the Himalayan, domestic short-hair, Persian, Siamese, and Burmese.1,3,9,10 Inheritance of PSS has been documented in Irish Wolfhounds and Maltese dogs, and is suspected in Yorkshire terriers.1 Multiple acquired PSSs are present in about 20% of dogs with PSS, and develop secondary to portal hypertension.1 Although congenital PSSs are treated by surgical ligation, multiple acquired PSSs are not amenable to surgical intervention, and are managed medically, therefore differentiating them is important for treatment planning.1,11 Various scintigraphic techniques have been used in the evaluation of animals with PSS, dating back to the 1980s, with the first such report describing an altered pattern of radiocolloid uptake. In normal dogs, 99mTc-sulfur colloid (SC) localizes in the mononuclear phagocytes of the reticuloendothelial system after intravenous (IV) injection, with activity visible in the liver, spleen, and bone marrow within 20 minutes of injection.12 Dogs with PSS exhibit a small liver with redistribution of the radiopharmaceutical to other nonhepatic reticuloendothelial sites, most prominently the pulmonary macrophages.13 Studies evaluating 99mTc-SC scintigraphy in dogs with PSS and biliary cirrhosis demonstrated decreased plasma clearance rate, decreased percent hepatic uptake, and increased percent pulmonary uptake of the radiopharmaceutical owing to decrease in hepatic reticuloendothelial activity in dogs with experimentally induced liver disease.14,15 The main limitation of this technique is its lack of specificity, as any 15
16 pathology causing a decrease in hepatic reticuloendothelial function results in the same scintigraphic findings. Further, species differences limit the use of colloidal scintigraphy: cats, horses, and other ungulates possess a normal population of pulmonary macrophages, resulting in pulmonary uptake in normal animals.12 IV injection of 99mTc-SC was also used to evaluate hepatic arterial and portal venous blood flow on firstpass studies, calculating the hepatic perfusion index (HPI).16 This technique required the acquisition of a dynamic study, with placement of regions of interest (ROIs) over the liver and kidneys to generate a time-activity curve (TAC) characterized by 2 phases: a first phase representing arterial flow (determined via the renal ROI) and a second phase representing portal flow (determined via the hepatic ROI). In normal dogs, the slope of both phases is similar, with an HPI o2:1 (normal mean ⫾ standard deviation [SD]: 0.9 ⫾ 0.4). In dogs with PSS, portal flow is reduced compared with arterial flow, resulting in an increase in HPI (42:1). Similar to previous techniques, this also lacked specificity, as any disease increasing hepatic arterial flow (such as liver tumors) or decreasing portal flow (cirrhosis) results in increased HPI. In the mid-1980s, transcolonic (perrectal) administration of 123 I-iodoamphetamine (IMP) was investigated in a dog model of surgically created PSS17,18 and in dogs with naturally occurring PSS.18 These studies demonstrated that 123I-IMP is absorbed unchanged through the colonic mucosa, and in normal dogs, it is almost completely removed from the liver on first pass; in dogs with PSS, however, extraction of 123I-IMP on first pass is incomplete, and the radiopharmaceutical is also delivered through the lungs, thus allowing for shunt fraction (SF) quantification (lung activity/[lung activity þ liver activity]). Disadvantages of this technique included the high cost (and now unavailability) of 123I-IMP and the longer half-life (12 hours).19 Transcolonic (perrectal) scintigraphy was also investigated using 201Tl in a rat model with promising results20; however its long half-life (3.04 days) was not ideal for animal studies. The use of pertechnetate (99mTcO 4 ) was proposed shortly thereafter. Pertechnetate has the following advantages: short half-life (6.02 hours), ideal photon energy (140 KeV), lower cost, ready availability, and unchanged absorbption through the colonic mucosa. Perrectal portal scintigraphy (PRPS) using pertechnetate was first described in the early 1990s19,21-23 and rapidly proved to be a sensitive and specific method to screen for the presence of PSS.5 This technique is simple and quick and is performed as follows: with the animal in right lateral recumbency, a lubricated soft rubber catheter is introduced into the rectum and descending colon, to the level of the wing of the ilium, and a dose of 5-20 mCi (185-740 MBq, depending on the animal's size) of pertechnetate is administered. The use of a lead shield under the pelvis is suggested to limit image bloom from the radioactive bolus in the colon, which can obscure the low count density uptake in the liver and heart, and result in dead time loss. The use of external radioactive markers positioned at the level of the liver and heart is also suggested to provide an external anatomical reference. A dynamic frame-mode acquisition (1 frame every 4 seconds) is started at the time of injection of the radioisotope, and the
F. Morandi
Figure 1 Perrectal scintigraphy in a normal dog (A) and a dog with portosystemic shunt (B). Each right lateral image represents approximately 4 seconds of data of a dynamic acquisition obtained after administration of pertechnetate in the colon. In the normal dog, after deposition of the radioactive dose in the colon (arrow) the portal vein is visible (open arrow) followed by activity in the liver (L), with predominant ventral distribution (left divisional streamlining); this is followed by activity in the heart (H) approximately 12 seconds later. In the dog with portosystemic shunt, activity is seen in the heart, with only faint activity in the area of the liver at approximately the same time. Notice the marked bloom from the colon in (B), despite the use of a lead shield under the caudal half of the body.
images are inspected to determine the route of distribution of pertechnetate after absorption through the colonic mucosa. In normal animals, activity is identified in the portal vein, liver, and several seconds later, the heart and lungs (Fig. 1). In normal dogs, the time needed for the radionuclide to travel through the liver into the heart (portal transit time) averages 12 seconds but may be quicker in small dogs.12,22 If a PSS is present, heart and lung activity is seen before or at the same time as liver activity (Fig. 1).22 In both normal animals and animals with PSS, the eventual distribution of pertechnetate in the liver is not always homogenous, and predominant ventral, dorsal, or central distributions can be seen. This appearance is owed to streamlining of the radionuclide within discrete channels of portal blood flow,24 with resulting preferential distribution of activity into one or more of the branches of the portal vein. In one study, left divisional streamlining (ventral distribution) was seen in 29.4% of cases, whereas right divisional streamlining (dorsal distribution) and central divisional streamlining (central distribution) were seen in 19.6% of cases each.25 For quantitative analysis, ROIs are drawn over the liver and heart to determine the respective total counts in the 12 seconds after the first appearance of radioactivity in either the liver or the heart; SF is determined by dividing the total counts in the heart by the summed total counts in the heart and
Liver scintigraphy in veterinary medicine liver.19,22 The mean SF in normal dogs has been reported to be 5%22; however, in cases of poor radioisotope absorption, it can be as high as 20%.12 SF values have been found to have neither predictive nor prognostic value with respect to response to therapy; they show no correlation to serum chemistry results and cannot differentiate between congenital and acquired shunts.12 Further, SF values are not reproducible among different observers: one study found that interobserver variability in SF calculation ranged from 0.4%-59.6%, with greater variability in positive studies.26 Such high variability may be due to several factors, including scan quality, ROI placement, and designation of time of first appearance of activity in the liver or heart. This finding suggests that SF calculation may also be of limited value in the postsurgical evaluation of animals that undergo shunt ligation. There are several other limitations associated with PRPS. The quality of the study (and the accuracy of interpretation) is greatly dependent on percent absorption of pertechnetate through the colonic mucosa, which is, at best, only 15%.21,27 Enema administration before PRPS is recommended to empty the colon and maximize absorption; however, in a recent study in which all the dogs had received an enema approximately 2 hours before PRPS, mean absorption of the radionuclide from the colon was only 9%.28 Because of the poor absorption, a relatively high dose must be used (up to 20 mCi [740 MBq]) with resulting high personnel exposure. A second, major limitation of PRPS is that description of the shunt morphology is usually not possible, because these studies are inherently of low count density,12,28 therefore, differentiating intrahepatic from extrahepatic shunts, and most importantly single congenital from multiple acquired shunts, is typically not possible. Errors in radionuclide placement can affect study interpretation; if the pertechnetate dose is deposited near the transverse colon, the bloom effect from the high background activity in the colon can make identification of the heart and liver difficult, especially in small and toy breed dogs, and in poor absorbers. In addition, if the radionuclide is deposited too far caudally in the rectum, absorption can occur via the caudal rectal vein, which is an indirect tributary of the caudal vena cava; if this occurs in a normal animal, it would result in a false-positive study.12 Finally, PRPS does not allow identification of microscopic venous-parenchymal communications (hepatic portal venous hypoplasia or microvascular dysplasia).1,12,28 A scintigraphic technique retaining the high specificity and sensitivity of PRPS, while overcoming its limitations, was needed. In human medicine, reports describing the transplenic injection of pertechnetate for the evaluation of the portal venous system date back to the mid-1970s.24,29-31 In dogs, one study from 1994 described the injection of 99m Tc-macroaggregated albumins in the splenic vein of dogs using sonographic guidance.32 In normal dogs, 99m Tc-macroaggregated albumin localized solely in the liver, whereas in dogs with PSS activity, it bypassed the liver through the anomalous vessel, localizing in the lungs via capillary blockade.12,32 Mean shunt index was calculated by dividing the lung counts by the sum of lung and liver counts, and was 0.01 in normal dogs and 0.94 in dogs with
17 congenital PSS.32 The first report describing a technique for transplenic portal scintigraphy (TSPS) using pertechnetate was published in 2005 and was performed as follows: with the animal in right lateral recumbency, a small area of hair is clipped in the left cranial abdomen to allow identification of the spleen using a 7.5-MHz ultrasound probe. After the skin is cleaned with alcohol, a 22-G, 1.5-in needle attached to a shielded syringe containing the radionuclide dose (1-5 mCi [37-185 MBq] in 0.1-0.5 mL volume) is placed in the splenic pulp under sonographic guidance. A dynamic frame-mode acquisition (4 frames/s) is started immediately before radionuclide injection, and the needle is withdrawn upon completion of the injection. External radioactive markers positioned at the level of the liver and heart can be used (as in PRPS) for external anatomical reference.28 In normal animals, activity flows from the splenic injection site into the splenic vein, portal vein, liver, and after a mean delay of 7 seconds, to the heart (Fig. 2). Compared with PRPS, TSPS provides a high-quality nuclear angiogram of the portal vasculature, with the ability to identify the splenic vein and portal vein as distinct, separate vessels. Absorption of pertechenetate from the spleen is consistently much higher (mean ⫾ SD: 52.5% ⫾ 19.1%) than absorption from the colon (9.2% ⫾ 5.7%), resulting in much higher total counts in the liver and spleen compared with PRPS, in turn improving count statistics.28 The use of a smaller radionuclide dose in TSPS significantly lowers patient and personnel exposure, resulting in shorter hospitalization, earlier surgical intervention, improved personnel safety, and overall improved patient care.11,28 Normal SF for pertechnetate TSPS is calculated with the same formula used for PRPS, using the 7-seconds transit time, and is 2.6% ⫾ 1.3% (mean ⫾ SD), smaller than the normal SF in PRPS. In place of pertechnetate, TSPS can also be performed with 99m Tc-mebrofenin.33 This iminodiacetic acid (IDA) derivate is a lidocaine analogue, which is extracted by the hepatocytes through the same carrier-mediated transport mechanism as bilirubin, and is excreted in the bile; in healthy dogs hepatic extraction efficiency of 99mTc-mebrofenin is consistently 490%.34,35 In normal dogs, transplenic injection of 99m Tc-mebrofenin results in a nuclear angiogram of the splenic and portal veins followed by distribution of the radiopharmaceutical in the liver, without visible activity in the heart. A static right lateral view obtained 5 minutes after injection reveals no visible blood pool and cardiac activity, with the radiopharmaceutical confined to the liver and injection site in the spleen (Fig. 2). Absorption of 99mTc-mebrofenin from the spleen is higher than absorption of pertechnetate (87.9% ⫾ 8.2% vs 52.5% ⫾ 19.1%, mean ⫾ SD). In the paper first describing this technique, transit time from the liver to heart could not be calculated owing to the high hepatic extraction of 99m Tc-mebrofenin; SF was 0.8% ⫾ 0.8% (mean ⫾ SD).33 Because TSPS with 99mTc-mebrofenin provides a better morphologic evaluation of the liver compared with pertechnetate, it makes placement of ROIs for SF quantification easier. In addition, route of excretion through the feces is advantageous, compared with excretion in the urine for pertechnetate, from a radiation safety standpoint.
F. Morandi
18
Figure 2 Transplenic scintigraphy in normal dogs using pertechnetate (top images) and 99mTc-mebrofenin (bottom images). Each right lateral image represents 1.5 (top) and 1.25 (bottom) seconds of data during the dynamic acquisition. Static right lateral views (to the right) were obtained 5 minutes after transplenic injection. After injection in the spleen (open arrow), activity is seen in the splenic vein, portal vein, and liver (L). A small amount of radioactivity reaches the heart (H) 47 seconds later (C). The linear area of activity extending caudally from the splenic injection site (open arrowhead) represents the syringe being removed after injection is completed. On the static lateral view with 99mTc-mebrofenin (D), notice that activity is limited to the liver and spleen (S); on the static lateral view with pertechnetate (B), the silhouette of the dog is clearly seen and the thyroid is visible (black arrowhead).
In dogs with PSS, the radioactivity flows from the splenic injection site into the portal venous system where it bypasses the liver and reaches the heart first (or sometimes at the same time as the liver). Three different shunting patterns can be identified: shunt termination in the caudal vena cava, azygos vein, or internal thoracic vein (Figs. 3-5).36 If 99m Tc-mebrofenin is used, a static right lateral view should be obtained 5 minutes after injection and will reveal persistent, variable blood pool and cardiac activity, indicative of incomplete clearance of the radiopharmaceutical from the blood. Single and double congenital PSS can be differentiated from multiple acquired PSS, which are often seen as a plexus of anomalous vessels in the middle to caudal abdomen (Fig. 6).36 However, not all cases of multiple acquired PSS
exhibit this typical pattern, likely owing to the small size of the anomalous vessels, which can be beyond the resolution limits of the gamma camera. The most consistent scintigraphic feature of multiple acquired PSS is hepatofugal flow extending caudal to the level of the right kidney, which in a retrospective study was seen in all but one of the confirmed multiple acquired shunts, and in none of the congenital PSS.11 Therefore, careful scrutiny of the dynamic images to determine direction of flow of the radioactive bolus is imperative, and in cases where hepatofugal flow is present, multiple acquired shunts are likely even if a single channel of activity is visible on the nuclear angiogram.11 A recent study comparing PRPS with TSPS found that TSPS was 100% sensitive and specific for the diagnosis of PSS, and more likely than PRPS to identify shunt number and
Figure 3 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital portocaval shunt; each right lateral image represents 0.75 seconds of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in the splenic vein, then curves ventrally in the portal vein, after which a focal vascular dilation (asterisk) is seen in the plane of the liver, followed by activity reaching the heart (H) from the caudal aspect of this organ. The focal vascular dilation was a large left divisional intrahepatic shunt.
Liver scintigraphy in veterinary medicine
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Figure 4 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital portoazygos shunt; each right lateral image represents 1 second of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in a vessel that bypasses the liver and enters the heart (H) from the dorsal aspect, consistent with the azygos vein.
termination; in addition, TSPS studies were of higher quality compared with PRPS, allowing consistent interpretation among different observers.37 TSPS, however, does not permit reliable differentiation between intrahepatic and extrahepatic location of portocaval shunts. Like PRPS, TSPS does not allow identification of microscopic venous-parenchymal communications (portal vein hypoplasia or microvascular dysplasia). At the author's institution, we have used 99mTc-mebrofenin for all TSPS studies since 2005 and have performed over 1000 studies since introducing this technique, with no complications. TSPS has reduced the proportion of nondiagnostic studies from approximately 25% with PRPS to o2%. We have found that the occasional nondiagnostic studies result from peritoneal extravasation of radiopharmaceutical at time of injection, or from lack of splenic absorption; in this situation, a second injection can be attempted immediately, or the study can be repeated the following day. Although there is a debate regarding the possibility that a congenital PSS originating caudal to the junction of the splenic vein and portal vein may be missed with TSPS37 (a fact that has been reported with splenoportography),8,38 most congenital PSSs originate from
splenic or gastric vessels and even when the shunt vessel is caudal to the splenic vein, the blood flow will follow the path of least resistance. At our institution, we have not to this day had a false-negative study.
Hepatobiliary Scintigraphy Although hepatic scintigraphy with 99mTc-SC evaluates the mononuclear phagocyte population of the liver (Kupffer cells),14,15,35,39 hepatobiliary scintigraphy evaluates the hepatic parenchymal cells,35,40-42 thereby allowing quantification of liver function (even before alteration in serum chemistry become apparent), assessment of patency of the biliary tract, and evaluation of biliary tract disease. The radiopharmaceuticals of choice for hepatobiliary scintigraphy are IDA compounds, in which the IDA molecule is used as a bifunctional chelate to carry 99mTc on one side and lidocaine on the other.35,42 This configuration allows exploitation of the properties of lidocaine, which is primarily metabolized in the liver. The 2 most commonly used IDA agents are
Figure 5 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with a congenital internal thoracic shunt; each right lateral image represents 1 second of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical travels in the splenic vein, then curves ventrally in a vessel that runs in the area of the liver, then along the ventral aspect of the body wall, curving dorsally near the thoracic inlet and entering the heart (H) from its craniodorsal aspect, consistent with the internal thoracic vein.
F. Morandi
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Figure 6 Transplenic scintigraphy with 99mTc-mebrofenin in a dog with multiple acquired shunts; each right lateral image represents 1.5 seconds of data during the dynamic acquisition. After injection in the spleen (open arrow), the radiopharmaceutical remains in the spleen for a few seconds, after which an anomalous vessel directed caudally (arrow) is seen; there is marked hepatofugal flow and the bolus fragments in at least 3 vessels, which then enter the caudal vena cava (open arrowhead), bypassing the liver and entering the heart (H). 99m
Tc-mebrofenin and 99mTc-disofenin, which are transported to the liver loosely bound to serum protein (mainly albumin). Once they have entered the space of Disse, 99m Tc-IDAs dissociate, bind with receptors on the hepatocyte's membrane, and are taken up by the hepatocytes via carrier-mediated, nonsodium-dependent mechanism that is also used by bilirubin; they are secreted in the bile in their native form, without being metabolized.35,42,43 Alternate excretion through the kidneys is seen with liver dysfunction, but also with hypoalbuminemia (which decreases the hepatic delivery of 99mTc-IDAs)35,42 and with hyperbilirubinemia (which results in competition for the same carrier molecules).42,43 In humans, 99mTc-mebrofenin is the preferred radiopharmaceutical in patients with serum bilirubin 410 mg/dL, owing to its greater resistance to displacement by bilirubin.43 Although the serum bilirubin concentration needed for competitive inhibition to occur remains undetermined in dogs and cats, a study in horses found that fasting hyperbilirubinemia up to 8.5 mg/dL did not affect the extraction efficiency of the radiopharmaceutical.43 Hepatobiliary scintigraphy with 99mTc-IDAs has been described in dogs,34,41,44-51 cats,52-54 horses,43,55 pigeons,56 and a lamb.57 In small animals, after IV injection of 1-5 mCi (37-185 MBq) of 99mTc-mebrofenin or disofenin, a dynamic frame-mode acquisition at 5 seconds per frame is obtained for 5 minutes, followed by static 60-seconds right lateral and ventral images at 5,10, 15, 20, 25, 30, 45, 60, and 90 minutes. Additional images at 120 and 240 minutes and 24 hours may be necessary depending on hepatic uptake, identification of the gall bladder, and, most importantly, identification of activity in the intestinal tract, which is necessary to confirm biliary patency.35,45,50 The study is scrutinized for assessment of hepatic size and morphology (best evaluated on the 5-minute images), hepatic function (extraction and excretion), and biliary transit and patency. In normal animals, hepatic extraction is rapid, and peak liver activity is seen at 6-9 minutes,41 with rapid clearance from the blood pool (cardiac washout) by 5 minutes. Hepatic excretion is determined by fitting a single exponential model to the downslope of the liver
TAC obtained by drawing an ROI over a peripheral region of the liver. Normal T1/2 in dogs has been reported as 16.3 ⫾ 1.2 minutes41 or 19.1 ⫾ 4.9 minutes.34 T1/2 increases with hepatocellular disease, cholangiohepatitis, and chronic extrahepatic obstruction. In normal dogs, activity can seen in the gall bladder at 15-20 minutes,41 and in the intestines within 1 hour (Fig. 7).58 In the author's experience, the gall bladder is not always visible in dogs, despite an otherwise normal scan and normal transit time in the small intestines; instead, centralization of activity in extrahepatic biliary track followed by activity in the duodenum can be seen. This may be due to the presence of inspissated bile (sludge) in the gall bladder (a common finding in dogs), which may hamper mixing of the radiopharmaceutical with gall bladder content. Similar values are reported in cats, with peak uptake in the liver r2 minutes, T1/2 of 16 minutes, and first gall bladder visualization 31 minutes after IV radiopharmaceutical injection.52,54 Quantitative analysis via calculation of the hepatic extraction fraction (HEF) has been described in dogs and cats. The HEF represents the percentage of radiopharmaceutical removed by the liver at each circulatory pass, and in normal dogs, it is 490% (often almost 100%), similar to human data,34,35,47,48,58 although in normal cats, the HEF has been reported as 85%; this may be the result of usage of different analysis methodology.54 Calculation of HEF is best done by direct radiopharmaceutical injection in the portal vein or in an afferent mesenteric vein; however, this method is invasive and requires laparotomy, and is therefore unsuitable for clinical applications. Deconvolution analysis takes into account the changing plasma concentration after a peripheral IV injection, to simulate a direct afferent injection in the portal vein, and has been validated against direct radiopharmaceutical injection into an afferent mesenteric vein.47,48 However, this method is cumbersome, time consuming, and subject to error, due to the need for consistent placement of liver ROIs over time, which is difficult after the liver starts excreting the radiopharmaceutical. An alternative, quicker, and simpler method of HEF calculation measures the clearance of the radiopharmaceutical from the blood, by drawing an ROI over the heart
Liver scintigraphy in veterinary medicine
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Figure 7 Static right lateral (left) and ventral (right) views during hepatobiliary scintigraphy with 99mTc-mebrofenin in a normal dog. Notice that activity is already limited to the liver on the 5-minute view; the greatest intensity in the liver is seen at 5 minutes, and activity has dropped by greater than 50% at 20 minutes; this indicates normal uptake and clearance by the hepatocytes. Centralization in the hepatic ducts occurs rapidly, the gall bladder is clearly seen by 10 minutes, and intestinal activity seen at 30 minutes.
to generate a TAC that is used in place of a plasma disappearance curve.51,59 After normalization of the TAC (to correct for dose variability, plasma volume difference, and camera efficiency), the area under the curve (AUC) is calculated, and linear regression analysis is used to describe the relationship between the AUC and hepatic extraction. A study found good correlation between the AUC and hepatic extraction, with the best correlation obtained using the 0-30 minute data (r2 ¼ 0.92).51 Hepatobiliary scintigraphy has also been described in normal fasted and fed horses using both image-based55 and plasma-based methods.43 Because of the horse's large size, changing geometry and attenuation pose unique challenges
that make measurement of plasma clearance of 99mTc-IDA preferable. This method involves the collection of multiple blood samples from 1-240 minutes after IV radiopharmaceutical administration; 1 mL aliquots of plasma are then separated and counted to generate a normalized TAC representing 99mTc-mebrofenin disappearance from blood. A 2-compartment model is used to calculate the T1/2 of the fast (distribution and extraction) and slow (elimination) portions of the curve, after which the AUC can be calculated.43 A unique feature of horses is the development of anorexia-associated hyperbilirubinemia, with unconjugated serum bilirubin concentrations rising in proportion to the number of days spent without feed.60 This phenomenon has
Figure 8 Static right lateral (left) and ventral (right) views during hepatobiliary scintigraphy with 99mTc-mebrofenin in a dog with chronic, complete extrahepatic obstruction due to a pancreatic mass (gastrinoma) and secondary hepatocellular disease. There is incomplete clearance of the radiopharmaceutical from the soft tissues, indicating decreased hepatocellular uptake. The gall bladder remains devoid of activity (asterisk). Activity is never seen in the intestines, even on the images obtained the following day (19 hours); by 90 minutes activity is seen in the urinary bladder, representing alternate route of excretion (arrow). Quantitative analysis revealed HEF of 76%, time to maximum liver uptake of 20 minutes, and liver T1/2 clearance of 194 minutes.
22 been attributed to a rise in nonesterified fatty acid concentrations that occur in response to negative energy balance: unconjugated bilirubin and nonesterified fatty acid blood concentrations are positively correlated in feed-deprived horses, suggesting that these metabolites compete for a common pathway into the liver.60 The effect that anorexiaassociated hyperbilirubinemia has on plasma clearance of 99m Tc-mebrofenin was investigated in fasted normal horses, in which clearance studies were performed at baseline, and after 48 and 96 hours of feed deprivation. Although total plasma bilirubin concentration increased from 1.3 ⫾ 0.3 mg/dL at baseline, to 6.3 ⫾ 1.3 mg/dL after 96 hours of fasting, AUC, fast-phase T1/2, and slow-phase T1/2 did not differ at the 3 time points. Serum bilirubin concentration did not correlate with AUC or fast-phase T1/2, but there was a weak correlation with slow-phase T1/2 (r ¼ 0.50), suggesting some degree of competitive inhibition between the radiopharmaceutical and serum bilirubin.43 Hepatobiliary scintigraphy can be used to differentiate between partial and complete biliary obstruction, by determining whether activity reaches the intestinal tract (Fig. 8). In an initial study in dogs and cats, lack of intestinal activity 180 minutes after IV radiopharmaceutical injection was suggested as the criterion for complete biliary obstruction, with sensitivity of 83% and specificity of 94%.45 However, a later study found that lack of intestinal activity 19-24 hours after injection was a better cutoff, resulting in both sensitivity and specificity of 83%, compared with 100% and 33%, respectively, if the 180minutes criterion was used.50 In animals with partial biliary obstruction, intestinal activity is usually of much lower intensity compared with that seen in animals with patent biliary tree, and appropriate manipulation of the image window and gray scale is required to ensure that intestinal activity is not missed.50
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Liver scintigraphy in veterinary medicine 32. Meyer HP, Rothuizen J, van den Brom WE, et al: Quantitation of portosystemic shunting in dogs by ultrasound-guided injection of 99MTcmacroaggregates into a splenic vein. Res Vet Sci 1994;57:58-62 33. Morandi F, Cole RC, Echandi RL, et al: Transsplenic portal scintigraphy using 99mTc-mebrofenin in normal dogs. Vet Radiol Ultrasound 2007;48: 286-291 34. Daniel GB, Bahr A, Dykes JA, et al: Hepatic extraction efficiency and excretion rate of technetium-99m-mebrofenin in dogs. J Nucl Med 1996;37:1846-1849 35. Daniel GB: Hepatic scintigraphy. In: Daniel GB, Berry CR, (eds): Textbook of Veterinary Nuclear Medicine. (ed 2). ACVR; 2006 36. Morandi F, Cole RC, Tobias KM, et al: Use of 99mTcO-4 trans-splenic portal scintigraphy for diagnosis of portosystemic shunts in 28 dogs. Vet Radiol Ultrasound 2005;46:153-161 37. Sura PA, Tobias KM, Morandi F, et al: Comparison of 99mTcO-4 transsplenic portal scintigraphy with per-rectal portal scintigraphy for diagnosis of portosystemic shunts in dogs. Vet Surg 2007;36:654-660 38. Suter PF: Portal vein abnormalities in the dog: Their angiographic diagnosis. J Am Radiol Soc 1975;16:84-97 39. Krishnamurthy GT, Krishnamurthy S: Liver and spleen function. In: Krishnamurthy GT, Krishnamurthy S, (eds): Nuclear Hepatology: A Textbook of Hepatobiliary Disease. Berlin: Springer; 2000 40. Krishnamurthy GT, Krishnamurthy S, (eds): Nuclear Hepatology: A Textbook of Hepatobiliary Disease. Berlin: Springer; 2000 41. Kerr LY, Hornof WJ: Quantitative hepatobiliary scintigraphy using 99m TC-DISIDA in the dog. Vet Radiol 1986;27:173-177 42. Krishnamurthy S, Krishnamurthy GT: Technetium-99m-iminodiacetic acid organic anions: Review of biokinetics and clinical application in hepatology. Hepatology 1989;9:139-153 43. Morandi F, Frank N, Avenell J, et al: Quantitative assessment of hepatic function by means of 99mTc-mebrofenin in healthy horses. J Vet Intern Med 2005;19:751-755 44. Rothuizen J, van den Brom WE: Quantitative hepatobiliary scintigraphy as a measure of bile flow in dogs with cholestatic disease. Am J Vet Res 1990;51:253-256 45. Boothe HW, Boothe DM, Komkov A, et al: Use of hepatobiliary scintigraphy in the diagnosis of extrahepatic biliary obstruction in dogs and cats: 25 cases (1982-1989). J Am Vet Med Assoc 1992;201: 134-141 46. Newell SM, Selcer BA, Mahaffey MB, et al: Gallbladder mucocele causing biliary obstruction in two dogs: Ultrasonographic, scintigraphic, and pathological findings. J Am Anim Hosp Assoc 1995;31:467-472
23 47. Bahr A, Daniel GB, DeNovo R, et al: Quantitative hepatobiliary scintigraphy with deconvolutional analysis for the measurement of hepatic function in dogs. Vet Radiol Ultrasound 1996;37:214-220 48. Daniel GB, Denovo R, Schultze AE, et al: Validation of deconvolutional analysis for the measurement of hepatic function in dogs with toxicinduced liver disease. Vet Radiol Ultrasound 1998;39:375-383 49. Daniel GB, DeNovo RC, Schultze AE, et al: Hepatic extraction efficiency of technetium-99m-mebrofenin in the dog with toxic-induced acute liver disease. J Nucl Med 1998;39:1286-1292 50. Head LL, Daniel GB: Correlation between hepatobiliary scintigraphy and surgery or postmortem examination findings in dogs and cats with extrahepatic biliary obstruction, partial obstruction, or patency of the biliary system: 18 cases (1995-2004). J Am Vet Med Assoc 2005;227: 1618-1624 51. Daniel GB, DeNovo R, Bahr A, et al: Evaluation of heart time-activity curves as a predictor of hepatic extraction of 99mTc-mebrofenin in dogs. Vet Radiol Ultrasound 2001;42:162-168 52. Newell SM, Selcer BA, Roberts RE, et al: Use of hepatobiliary scintigraphy in clinically normal cats. Am J Vet Res 1994;55:762-768 53. Newell SM, Selcer BA, Roberts RE, et al: Hepatobiliary scintigraphy in the evaluation of feline liver disease. J Vet Intern Med 1996;10:308-315 54. Newell SM, Graham JP, Roberts GD, et al: Quantitative hepatobiliary scintigraphy in normal cats and in cats with experimental cholangiohepatitis. Vet Radiol Ultrasound 2001;42:70-76 55. Hornof WJ, Baker DG: Biliary kinetics of horses as determined by quantitative nuclear scintigraphy. Vet Radiol 1986;27:85-88 56. Hadley TL, Daniel GB, Rotstein DS, et al: Evaluation of hepatobiliary scintigraphy as an indicator of hepatic function in domestic pigeons (Columba livia) before and after exposure to ethylene glycol. Vet Radiol Ultrasound 2007;48:155-162 57. Lofstedt J, Koblik PD, Jakowski RM, et al: Use of hepatobiliary scintigraphy to diagnose bile duct atresia in a lamb. J Am Vet Med Assoc 1988;193:95-98 58. Daniel GB, Tucker RL: Liver scintigraphy: Applications. Semin Vet Med Surg Small Anim 1991;6:154-163 59. Matwichuk CL, Daniel GB, DeNovo RC, et al: Evaluation of plasma timeactivity curves of technetium-99m-mebrofenin for measurement of hepatic function in dogs. Vet Radiol Ultrasound 2000;41:78-84 60. Engelking LR: Equine fasting hyperbilirubinemia. Adv Vet Sci Comp Med 1993;37:115-125
