Hepatic computed tomography and cholangiography by

use of gadoxetic acid in healthy cats

Joanna L. Pilton bvsc OBJECTIVE

To evaluate 3 doses of gadoxetic acid (Gd-EOB-DPTA) for hepatic CT and
Jennifer Chau bvsc cholangiography in cats and to determine optimal timing for hepatobiliary
Timothy S. Foo bvms image acquisition and evaluation of the contrast-enhanced hepatobiliary
Evelyn J. Hall bscagr, phd anatomy.
Fernando Martinez-Taboada lv ANIMALS
6 healthy cats.
Juan M. Podadera dr med vet
Mariano A. Makara dr med vet PROCEDURES
Cats were anesthetized; sequential CT scans were performed 0, 5, 25, 45,
Received June 4, 2018. 65, and 85 minutes after IV administration of Gd-EOB-DTPA at low (0.0125
Accepted September 4, 2018. mmol/kg), medium (0.1 mmol/kg), and high (0.3 mmol/kg) doses. Hepato-
biliary enhancement for each dose was objectively assessed over time and
From the Units of Diagnostic Imaging (Pilton, Chau, by use of a subjective semiquantitative visual assessment score.
Foo, Podadera, Makara) and Anaesthesia (Martinez-
Taboada), School of Veterinary Science, Faculty of Sci- RESULTS
ence, and School of Life and Environmental Sciences No contrast-related adverse effects were detected. Each increase in dose
(Hall), Faculty of Science, University of Sydney, Sydney, of contrast medium resulted in a significant increase in HU across the hepa-
NSW 2006, Australia.
tobiliary system. The liver had a significantly higher number of HU at 45
minutes, with homogenous enhancement at all doses of contrast medium.
Address correspondence to Dr. Pilton (joanna.
[email protected]). Contrast-enhanced cystic and bile duct HU were significantly higher and
maximal at 65 minutes. Contrast-enhanced gallbladder HU did not plateau
by 85 minutes. At a high dose of contrast medium, 12 of 60 (20%) biliary
tract scores indicated no enhancement, 34 (57%) indicated poor enhance-
ment, and 14 (23%) indicated moderate enhancement. No cat had excellent
enhancement of the biliary tract at any dose.
CONCLUSIONS AND CLINICAL RELEVANCE
Gd-EOB-DTPA–enhanced hepatic CT and cholangiography in cats were
safely performed and provided good hepatic enhancement but poor to
moderate enhancement of the biliary tract. This technique may be useful
for assessing the liver parenchyma in cats, but its value for assessing the bili-
ary tract is questionable. (Am J Vet Res 2019;80:385–395)

H epatobiliary disease is common in cats because

of their unique anatomy in which the bile duct
and pancreatic duct frequently open concomitantly
mary or metastatic neoplasia, and hepatic cirrhosis.2,9
Additionally, extrahepatic hepatobiliary pathological
conditions including gallbladder mucocele; congeni-
onto the major duodenal papilla.1–4 Inflammatory tal malformations such as choledochal cysts; disor-
hepatobiliary disease (cholangitis or cholangiohepa- ders of the sphincter of Oddi; and extrahepatic bili-
titis) is commonly centered on the biliary tract with ary obstruction caused by stricture, malformations,
possible secondary involvement of the hepatic paren- parasites, choledocholiths or sludge, foreign bodies,
chyma.5,6 It can be evident as neutrophilic, lympho- pancreatitis, abscesses, or nonhepatobiliary neopla-
cytic, or chronic cholangitis (associated with liver sia have also been described.2,10–16 Regardless of the
flukes), with neutrophilic cholangitis often occur- underlying cause of hepatobiliary disease, cats of-
ring with concurrent pathological conditions such ten have nonspecific clinical signs and biochemical
as pancreatitis and inflammatory bowel disease.7,8 changes that do not reflect the prognosis or function-
Other pathological conditions of the intrahepatic al reserve of the hepatobiliary system.16–18
hepatobiliary system include hepatic lipidosis, pri- A number of imaging modalities including ultra-
sonography, radiography, cholecystography, chol-
angiography, CT, ERCP, MRI, MRCP, and nuclear
ABBREVIATIONS scintigraphy have been used to evaluate the hepato-
ERCP Endoscopic retrograde biliary system in cats.2,16–30 These techniques provide
cholangiopancreatography information on gross morphological or functional
Gd-EOB-DTPA Gadoxetic acid
MRCP Magnetic resonance abnormalities of the liver and biliary tract, although
cholangiopancreatography findings are generally not disease specific. Other limi-
ROI Region of interest tations of these techniques include poor sensitivity,

AJVR • Vol 80 • No. 4 • April 2019 385

reliance on good patient compliance or operator skill enhanced MRI can potentially provide quantita-
(or both), poor visibility of anatomic structures ow- tive assessment of liver perfusion and hepatocyte
ing to interference from bowel gas, high costs, lim- function in diffuse liver disease.37,41 The excretion
ited availability, invasiveness, the need for patients to properties of Gd-EOB-DTPA have also been used in
be anesthetized, and a lack of inherent contrast reso- the functional assessment of biliary anatomy with
lution.1,19,24,26,29 In addition, there are various adverse MRI, including bile duct injury, obstruction or
effects after IV administration of iodinated cholangio- stricture; sphincter of Oddi dysfunction; differen-
graphic contrast agents in cats.21 tiation of biliary from extrabiliary lesions (includ-
The criterion-referenced standard for evalu- ing bilomas); identification of biliary-enteric anas-
ation of the biliary tract in human medicine is tomoses; and diagnosis of cholecystitis in people.35
endoscopic retrograde cholangiography, which al- Because of their paramagnetic properties, gad-
lows for delineation of the biliary tract with high olinium-based contrast agents typically have been
spatial resolution.31 The advantage of endoscopic used in combination with MRI. The MRI procedures
retrograde cholangiography and ERCP is the op- require only a 5% to 20% molar dose of a metal,
tion for concurrent treatment and collection of bi- compared with the dose needed for CT, to provide
opsy specimens, if required.26,31–33 Disadvantages diagnostically useful tissue contrast.42 However, bili-
include the risk of acute pancreatitis, cholangitis, ary MRI requires a high-field magnet (1.5 T) that is
perforation, and hemorrhage attributable to its in- not routinely used at veterinary clinics because of
vasiveness.1,26 Although these complications were the high cost and limited availability. An alternative
not reported in a study26 that involved the use of imaging modality is CT, which is now widespread at
ERCP in cats, the risks of ERCP appear to outweigh veterinary clinics and has a faster image acquisition
the advantages in cats owing to the fact that their time, fewer artifacts, and improved image resolu-
small size makes this technique diagnostically chal- tion and reconstruction techniques and may be per-
lenging, particularly because choledocholiths and formed in sedated animals (rather than anesthetized
neoplasia seem to be less common in cats than in animals).27,33,41,44,45 Computed tomography frequently
humans. In other studies,1,33 it was reported that is used in human medicine to diagnose pathological
MRCP was as accurate as ERCP for visual evalua- biliary conditions.45 The high atomic number of gado-
tion of the biliary anatomy of humans without linium also makes it a good contrast medium for CT.42
being invasive or relying on ionizing radiation or Previous CT evaluations of the abdomen of dogs41 and
operator skill. Additionally, MRCP enables concur- humans38 after administration of gadolinium-based
contrast agents revealed adequate visual examination
rent assessment of the liver and pancreas as well as
of the liver and biliary tract.
the biliary and pancreatic ducts proximal to an ob-
To the author’s knowledge, there has been no
struction, particularly when combined with stan-
reported use of Gd-EOB-DTPA in cats. Therefore,
dard T1- and T2-weighted sequences.1,34 When con-
the objectives of the study reported here were to
current diagnostic and interventional procedures
determine a dose of Gd-EOB-DTPA that could be
are not expected, MRCP is the preferred method.
safely administered to healthy cats, identify any ad-
In addition, MRCP can be used with hepatocyte- verse effects, determine the optimal CT scan time
specific contrast agents (eg, Gd-EOB-DTPA). This for Gd-EOB-DTPA in the liver and biliary tract, and
hepatocyte-specific contrast agent has improved determine whether Gd-EOB-DTPA could improve vi-
the ability of investigators to visually examine and sual assessment of the hepatobiliary anatomy via CT
characterize focal liver lesions and provide both in healthy cats. We hypothesized that Gd-EOB-DTPA
morphological and functional information on the would be a contrast agent that could be safely used
biliary tract of humans,33–38 dogs,39–43 rats,36 and with CT to improve conspicuity of the hepatobiliary
rabbits.42 Gadoxetic acid enters hepatocytes via an system in healthy cats.
organic ion transport system and is excreted into
the biliary system via ATP-dependent glutathione Materials and Methods
S-transferase.35 Given the hepatocyte specificity
of Gd-EOB-DTPA, use of this contrast agent has re- Animals
sulted in improvements in tumor detection and the Five healthy cats were recruited from a privately
ability to distinguish between benign and malig- owned research facility.a All procedures were per-
nant lesions of hepatocellular or nonhepatocellu- formed at the veterinary teaching hospital at the
lar origin in the delayed phase, independent of the University of Sydney. Cats were included in the study
vascularity of a lesion during early dynamic phase when no abnormalities were detected during physi-
imaging.36,37 For example, lesions with altered hepa- cal examination, there were no hepatic or renal ab-
tocyte function (eg, hepatic adenoma, nodular hy- normalities on biochemical analysis and urinalysis,
perplasia, and hepatocellular carcinoma) have vari- and there were no major changes for a CBC. Ultra-
able contrast enhancement, compared with results sonographic examinationb of the hepatobiliary
for normal hepatic parenchyma.37,39–41 Similarly, system was performed on each cat prior to initial non-
metastatic lesions that lack hepatocytes have no con- contrast CT to rule out preexisting diseases. Cats were
trast enhancement.37 Additionally, Gd-EOB-DTPA– excluded from the study when hepatobiliary ultra-
386 AJVR • Vol 80 • No. 4 • April 2019
sonography or the initial noncontrast CT revealed contrast agent. Vital parameters were monitored ev-
abnormalities. The study was approved by the Ani- ery 8 hours for 3 to 5 days after injection of the con-
mal Ethics Committee of the University of Sydney. trast agent. Two weeks after each phase of the study,
the cats were examined at the research facility to as-
Experimental procedures sess general health.
Three phases of contrast-enhanced CT exami-
nations were conducted for each cat; there was a Image analysis
washout period of at least 1 week between phases. Objective analysis—One investigator (JLP) objec-
Each phase involved IV administration of a dose of tively measured the number of HU of the hepatobili-
Gd-EOB-DTPA.c The first phase involved a low dose ary system for various anatomic structures, including
of contrast agent (0.0125 mmol/kg); that dose was the liver, gallbladder, cystic duct, and bile duct. The
based on half the recommended clinical dose for cystic duct is dorsally directed and was defined as the
humans.46 The second phase involved a medium region from the neck of the gallbladder to the inser-
dose of contrast agent (0.1 mmol/kg), and the third tion of the hepatic ducts in the region of the porta
phase involved a high dose of contrast agent (0.3 hepatis.3 The hepatic ducts were defined as the ducts
mmol/kg). that drained each lobe of the liver.3 The hepatic ducts
Before each CT scan was performed, the cats may join to form a common hepatic duct before en-
were anesthetized and positioned in sternal recum- tering the cystic duct.3 The bile duct was defined
bency. Alfaxaloned (0.2 mg/kg, IM) and butorphanol as the portion of the duct distal to the union of the
tartratee (0.2 mg/kg, IM) were administered as pre- cystic duct and hepatic ducts to its opening onto the
anesthetic medications. Alfaxalone (1 to 2 mg/kg) was major duodenal papilla.3 The HU of the hepatic ducts
administered IV for anesthetic induction to enable were not measured because of the inconsistent abil-
tracheal intubation, and anesthesia was maintained ity to visually evaluate the structures.
with isofluoranef in oxygen. During the procedure, a Standardized ROIs or points of interest were
crystalloid solutiong was administered (5 mL/h, IV), drawn on transverse CT images of each structure
and physiologic variables (heart rate, respiratory rate, on a DICOM workstation and reviewed by use of
noninvasively measured blood pressure, end-tidal car- software.j Data for ROIs or points of interest were ex-
bon dioxide concentration, and oxygen saturation) of ported to a spreadsheet,k and time-attenuation curves
cats were monitored continuously. were generated for each part of the biliary tract and
Apnea was induced by hyperventilation prior to liver. When the liver was evaluated, a similar ana-
each scan to avoid motion artifact. Each CT scan was tomic location was obtained for each ROI (0.5 cm2),
conducted in accordance with the same CT protocol. and care was used to not include vessels in the ROIs.
A 16-slice multidetector CT scannerh was used. An For the gallbladder, each ROI (0.5 cm2) was measured
air calibration was performed every other day, and a at the dorsal aspect of the gallbladder (neck of the
quality control scan was performed monthly with an gallbladder) where contrast was visible. In the cystic
ROI phantom. A helical precontrast scan (0 minutes) duct and bile duct, a single point of interest was used
and 5 postcontrast scans (5, 25, 45, 65, and 85 min- to measure enhancement at a location where struc-
utes after administration of contrast agent) were ac- tures were clearly visible.
quired. Contrast agent was delivered via rapid manual Visual analysis—Two board-certified veterinary
injection, which was followed immediately by rapid radiologists (MAM and JMP) and a veterinarian in the
administration of a bolus of saline (0.9% NaCl) solu- third year of a radiology residency program (TSF) sep-
tioni (3 mL, IV). At 90 minutes after injection of the arately assessed the CT images of each cat obtained
contrast agent, cats were repositioned in dorsal re- at 65 minutes after injection of each of the 3 doses
cumbency to assess the distribution of contrast agent of contrast agent. Investigators were not aware of
within the gallbladder and to subjectively visually as- the dose administered to each cat, and images were
sess the bile duct after the change in body position. anonymous and randomized. Investigators used a vi-
No objective measurements were obtained while cats sual assessment scoring system to determine a score
were positioned in dorsal recumbency, and these for the gallbladder, cystic duct, bile duct, and hepatic
data were not included in the statistical analysis. ducts (where they were visible from the porta hepa-
The abdomen CT protocol for both sternal and tis to the insertion onto the bile duct) and comment
dorsal recumbency involved use of a detector row ar- on the ability to visually detect contrast agent in the
rangement of 16 data channels with a detector width duodenum (yes or no) and whether there was motion
of 0.75 mm (16 X 0.75 mm), tube current of 90 mA, artifact (yes or no). Visual detection of contrast agent
and tube potential of 120 kV (peak). The display field within these structures was graded on a scale of 0 to
of view was determined for each cat; it included the 3 (0 = absent, 1 = poor contrast enhancement with
diaphragm cranially and pubis caudally. Images were ill-defined borders, 2 = moderate contrast enhance-
reconstructed with a slice thickness of 1.5 mm with a ment with incomplete delineation of borders, and 3
soft tissue kernel. = excellent contrast enhancement along the length
A CBC, biochemical analysis, and urinalysis were of the duct with well-defined borders throughout
performed for each cat 48 hours after each dose of the entire length of the duct). This visual assessment
AJVR • Vol 80 • No. 4 • April 2019 387
scoring system has been used for evaluation of the ments of the biliary tract. There was a significant (P
biliary system.41 < 0.001) effect of dose of contrast agent on enhance-
ment of all hepatobiliary structures because each in-
Statistical analysis crease in dose of contrast agent resulted in a signifi-
Statistical analysis was performed with a com- cant increase in the mean number of HU (Figure 1).
mercially available software program.l For all analy- For each anatomic structure (liver, gallbladder, cys-
ses, significance was set at values of P ≤ 0.05. Data for tic duct, and bile duct) and each time point of contrast
the liver, gallbladder, cystic duct, and bile duct were enhancement, the liver had homogenous contrast en-
analyzed by use of a restricted maximum likelihood hancement at all doses and had a significantly higher
model to assess the timing and effect of the dose of number of HU at 45 minutes, compared with the num-
contrast agent on enhancement. The objectively de- ber of HU at 0, 5, and 25 minutes; however, there was
termined enhancement values (number of HU) were no significant change in the number of HU in the liver
square root transformed to ensure normality of the after 45 minutes (Table 1). Furthermore, the liver had
data. Fixed effects included age, body weight, timing, a significantly higher number of HU than all other ana-
anatomic structure, and dose of contrast agent. tomic structures (gallbladder, cystic duct, and bile duct)
Visual assessment scores of the investigators for at each time point (0, 5, 25, 45, 65, and 85 minutes; Fig-
each biliary structure (gallbladder, cystic duct, bile ure 1). Mean ± SD maximum liver enhancement was
duct, and hepatic ducts) were analyzed by use of or- 70 ± 6 HU at 0.0125 mmol/kg, 72 ± 15 HU at 0.1 mmol/
dinal logistic regression. Fixed effects included the kg, and 82 ± 17 HU at 0.3 mmol/kg. Mean difference
dose of contrast agent and investigator. Both of the between liver attenuation at time 0 and maximum liver
fixed effects and the interaction between the fixed attenuation was 2 ± 3 HU at 0.0125 mmol/kg, 15 ± 2 HU
effects were evaluated. at 0.1 mmol/kg, and 19 ± 5 HU at 0.3 mmol/kg. Number
of HU for the gallbladder differed significantly at each
Results time point and did not reach maximum enhancement
by 85 minutes after injection of contrast agent. In com-
Animals parison, the number of HU in the cystic duct and bile
None of the cats was excluded on the basis of duct was significantly higher at 65 minutes than at 0, 5,
results of the ultrasonographic examination or initial 25, and 45 minutes (Figure 2). Maximum number of
noncontrast CT examination. One cat was excluded HU in both the cystic duct and bile duct was detected at
during the first phase of the study because it devel- 65 minutes, and there was no significant difference be-
oped pneumomediastinum immediately after intuba- tween the number of HU at 65 minutes and the number
tion and prior to administration of the contrast agent. of HU at 85 minutes.
The pneumomediastinum resolved without any com- In all cats, the contrast agent distributed nonho-
plications. Another cat was recruited to replace this mogenously in the gallbladder and was concentrated
cat for the second and third phases of the study. in the nondependent portion of the gallbladder when
One cat developed diarrhea during hospitaliza- the position was changed from sternal to dorsal re-
tion after the first phase; however, this was suspected cumbency, similar to results for dogs41 and people42
to be transient or related to the diet because the di- (Figure 3). The ability to visually assess the bile duct
arrhea resolved immediately after the cat’s diet was while cats were positioned in dorsal recumbency, as
changed to a commercially available prescription determined subjectively by an investigator, was not
gastrointestinal diet. This cat was fed the same com- affected by the change in body position.
mercially available prescription gastrointestinal diet
during the subsequent phases of the study and had no Visual assessment scoring of the biliary
further episodes of diarrhea. tract
Visual assessment scoring was conducted 65
Evaluation of safety minutes after injection of the contrast agent because
Gadoxetic acid was safely used in the 4 healthy there was not a significant difference in enhance-
cats during the first phase (0.0125 mmol/kg, IV) and ment of the liver and biliary tract after that time. A
the 5 healthy cats during the second (0.1 mmol/kg, total of 48 scores was obtained for the low dose of
IV) and third (0.3 mmol/kg, IV) phases. There were contrast agent (4 anatomic structures for each of 3
no immediate contrast-related reactions and no hema- investigators for each of 4 cats), and 60 scores were
tologic, biochemical, or urinary abnormalities at 48 obtained for the medium and high doses of contrast
hours after administration of the contrast agent for dose agent (4 anatomic structures for each of 3 inves-
all of the cats at each dose of contrast agent. There tigators for each of 5 cats). There was no significant
were no physical examination abnormalities at any difference among scores of the 3 investigators for any
time after the administration of contrast agent to all anatomic structure (gallbladder, P = 0.27; cystic duct,
cats at each dose. P = 0.47; bile duct, P = 0.20; and hepatic ducts, P =
0.59). Motion artifact was not recorded by any inves-
Objective measurements tigator during any phase of the study. Contrast agent
Age (P = 0.21) and body weight (P = 0.92) of cats was not observed in the duodenum in any cat at any
did not significantly influence objective measure- dose of the contrast medium.

388 AJVR • Vol 80 • No. 4 • April 2019

 Total visual assessment scores for all anatomic 13 (22%) indicated moderate contrast enhancement
structures in the biliary tract at 65 minutes were with incomplete delineation of the borders. For the
evaluated (Figure 4). For the low dose of contrast high dose of contrast agent, 12 of 60 (20%) biliary
agent, 36 of 48 (75%) biliary tract scores indicated tract scores indicated absent contrast enhancement,
absent contrast enhancement, 12 (25%) scores indi- 34 (57%) indicated poor contrast enhancement, and
cated poor contrast enhancement with ill-defined 14 (23%) indicated moderate contrast enhancement.
borders, and 0 (0%) scores indicated moderate or None of the cats had excellent enhancement in
excellent contrast enhancement. For the medium any of the biliary structures at any dose of contrast
dose of contrast agent, 15 of 60 (25%) biliary tract agent.
scores indicated absent contrast enhancement, 32 Accordingly, there was a consistently signifi-
(53%) indicated poor contrast enhancement, and cant effect of the dose of contrast agent for each

Figure 1—Mean ± SD (A, C, and E) and maximum (B, D, and F) values for CT attenuation of the liver (A and B), gallbladder
(C and D), and bile duct (E and F) at the time of IV injection of contrast medium (time 0) and 5, 25, 45, 65, and 85 minutes after
injection. For panels A, C, and E, results represent data after injection of the high dose of Gd-EOB-DTPA (0.3 mmol/kg; n =
14), whereas for panels B, D, and F, results represent data after injection of the low (0.0125 mmol/kg; dashed line [4]), medium
(0.1 mmol/kg; dotted line [5]), or high (0.3 mmol/kg; solid line [5]) dose of Gd-EOB-DTPA. The mean CT attenuation of the
hepatobiliary system has a similar pattern of increasing contrast enhancement over time, although the liver (A) has a significantly
(P ≤ 0.05) higher number of HU at each time point, compared with values for the gallbladder (C) and bile duct (E). Contrast
enhancement reached a value (asterisk) that differed significantly (P ≤ 0.05) from the value at time 0 (in the liver at 45 minutes
after injection and in the bile duct at 65 minutes after injection); however, contrast enhancement did not reach a maximum value
in the gallbladder by 85 minutes after injection of contrast agent. For panels B, D, and F, the mean maximum CT attenuation
similarly was increased over time with increases in enhancement and increasing doses of contrast agent. Notice that the scale
on the y-axis differs among panels.

AJVR • Vol 80 • No. 4 • April 2019 389

 Table 1—Mean CT enhancement (number of HU) of anatomic structures of the hepatobiliary
system before (time 0) and at various times after IV injection of Gd-EOB-DTPA at a low (0.0125
mmol/kg; n = 4), medium (0.1 mmol/kg; 5), and high (0.3 mmol/kg; 5) dose.
Time after injection (min)

Hepatobiliary structure Dose 0 5 25 45 65 85
Liver Low 68.5 68.0 65.0 67.8 66.5 66.0
  Medium 56.6 63.0 66.0 69.2 70.8 70.2
  High 62.8 67.2 73.0 75.8 79.6 81.8

Gallbladder Low 19.8 16.2 22.8 31.5 32.5 38.0

  Medium 16.8 14.2 29.4 42.0 49.0 55.2
  High 16.8 18.0 36.4 52.4 59.6 66.6

Cystic duct Low 18.8 20.0 31.8 30.5 34.3 36.8
  Medium 19.0 17.4 33.2 48.8 49.6 49.4
  High 17.0 20.0 34.0 49.4 56.0 53.4

Bile duct Low 16.5 21.3 23.8 28.3 28.8 31.8
  Medium 13.8 18.0 18.4 34.2 39.8 38.2
  High 11.8 12.2 26.4 35.2 41.0 36.4
A 0.5-cm2 ROI was measured in the liver; care was used so that vessels were not included in the ROI. A
0.5-cm2 ROI was measured at the neck of the gallbladder. A single point of interest was obtained for the cystic
duct and bile duct where the structures were clearly visible. The cystic duct is dorsally directed and was defined
as the region from the neck of the gallbladder to the insertion of the hepatic ducts in the region of the porta
hepatis. The bile duct was defined as the portion of the duct distal to the union of the cystic duct and hepatic
ducts and extending to its opening onto the major duodenal papilla.

for the cystic duct were 10.1 and 20.0

times as likely to be higher for the me-
dium (P = 0.014) and high (P = 0.002)
dose, respectively, compared with the
visual assessment score for the low
dose. Visual assessment scores for the
bile duct were 10.4 and 5.8 times as
likely to be higher for the medium (P
= 0.005) and high (P = 0.029) dose,
respectively, compared with the visu-
al assessment score for the low dose.
Visual assessment scores for the he-
patic duct were 14.3 and 21.3 times
as likely to be higher for the medium
(P = 0.005) and high (P = 0.002) dose,
respectively, compared with the visu-
al assessment score for the low dose.
However, there was not a significant
difference in visual assessment scores
between the medium and high dose
Figure 2—Transverse plane CT images obtained by use of a soft tissue ker- for any of the anatomic structures
nel of the cystic duct (A and B) and bile duct (C and D) in a cat before (A (gallbladder, OR = 1.5; cystic duct, OR
and C) and 65 minutes after (B and D) IV administration of a high dose of = 2.0; bile duct, OR = 0.6; and hepatic
Gd-EOB-DTPA (0.3 mmol/kg). In panels A and B, the neck of the gallbladder (as- ducts, OR = 1.5).
terisk) and the cystic duct (arrowhead) are indicated. In panels C and D, notice
the bile duct (arrow with solid line) immediately proximal to the point at which The best visual assessment scores
it enters the duodenum (arrow with dashed line). were for 1 cat at the high dose of con-
trast agent. That cat had 8 of 12 scores
anatomic structure (gallbladder, cystic duct, bile that indicated moderate enhancement and 4 of 12
duct, and hepatic ducts; Figure 5). In the gallblad- scores that indicated poor enhancement of all bili-
der, visual assessment scores were 9.5 times as like- ary structures (gallbladder, cystic duct, bile duct, and
ly to be higher for the medium dose (P = 0.007) and hepatic ducts). For the same dose of contrast agent,
14.2 times as likely to be higher for the high dose another cat had 4 of 12 scores that indicated poor
(P = 0.002), compared with the visual assessment enhancement and 8 of 12 scores that indicated absent
score for the low dose. Visual assessment scores enhancement.

390 AJVR • Vol 80 • No. 4 • April 2019

 trast agent in healthy cats and that use
of Gd-EOB-DTPA resulted in some de-
gree of enhancement of the hepatobili-
ary system. No acute major adverse ef-
fects were identified after IV injection
of Gd-EOB-DTPA in cats of the present
study. Adverse effects are rare in hu-
mans (0.1% to 1%) and include nausea,
vasodilation, headache, taste perver-
sion, rash, vomiting, increases in blood
pressure, respiratory disorders, feeling
Figure 3—Transverse plane CT images obtained by use of a soft tissue ker- hot, and injection site pain.46 In dogs,
nel of the liver and gallbladder after CT cholangiography performed with a a transient prolonged corrected QT
high dose of Gd-EOB-DTPA (0.3 mmol/kg, IV) for a cat positioned in sternal interval has been reported at doses of
(A) and dorsal (B) recumbency. Notice that the contrast agent redistributes 46
nonhomogenously to the nondependent portion of the gallbladder (asterisk), Gd-EOB-DTPA of 0.1 mmol/kg. Al-
delineating the contrast agent from bile in the dependent portion of the gall- though nephrogenic systemic fi-
bladder (arrow). brosis has not been reported for
Gd-EOB-DTPA, cautious use is rec-
ommended in human patients with a
reduced glomerular filtration rate be-
cause nephrogenic systemic fibrosis
reportedly can develop within days
to weeks following administration of
other gadolinium agents.37,46,47 The cats
in the present study did not have any
adverse effects. This may have been at-
tributable to the fact that there was a
small study population, cats were anes-
thetized at the time of injection, or the
study ended too soon to enable us to
evaluate cats for nephrogenic systemic
fibrosis. There were no abnormalities
for the physical examinations per-
formed after each phase of the study
or for a medical history obtained via
verbal communication with research
facility personnel 2 weeks after phases
1 and 3 of the study.
All doses of Gd-EOB-DTPA resulted
in overall poor visual assessment of
the biliary tract in healthy cats by use
of CT, which raised questions about
the clinical value of this technique for
use in cats. In agreement with results
Figure 4—Combined subjective visual assessment scores of 3 investigators for of other studies, there were large indi-
the gallbladder (A), cystic duct (B), bile duct (C), and hepatic ducts (D) at 65 vidual differences in visual assessment
minutes after IV injection of a low (0.0125 mmol/kg; n = 4), medium (0.1 mmol/
kg; 5), and high (0.3 mmol/kg; 5) dose of Gd-EOB-DTPA to cats. Visual as- scores and objective enhancement
sessment scores were graded on a scale of 0 to 3 (0 = absent [white bars], 1 = characteristics of the biliary struc-
poor contrast enhancement with ill-defined borders [diagonal-striped bars], 2 = tures among cats within the same dose
moderate contrast enhancement with incomplete delineation of borders [black group, which was suspected to have
bars], and 3 = excellent contrast enhancement along the length of the duct with
well-defined borders throughout the entire length of the duct [gray bars]). The been attributable to individual differ-
low dose had a higher percentage of scores that indicated absent contrast for ences in the number and type of hepa-
all anatomic structures than did the medium and high doses. The medium and tocytes and biliary transport proteins
high doses provided improved visual assessment scores, with a high percentage among cats.41 The difference in results
of scores indicative of poor to moderate contrast enhancement in the biliary between the study reported here and
tract and a low percentage of scores indicative of absent contrast enhancement. 38 41,42 may
Notice that none of the biliary structures had excellent contrast enhancement. studies of humans and dogs
be related to the manner in which dif-
ferent species accumulate and excrete
Discussion compounds via the hepatobiliary system. In humans,
The study reported here provided evidence that approximately 50% of Gd-EOB-DTPA is reportedly
Gd-EOB-DTPA can be safely administered IV as a con- excreted via the hepatobiliary system,37,48 whereas
AJVR • Vol 80 • No. 4 • April 2019 391
 evaluations of Gd-EOB-DTPA in cats, it
is likely that the biliary excretion rates
of cats differ from those reported for
other species. A study50 of biliary ex-
cretion of nongadolinium compounds
with a molecular weight similar to
that of Gd-EOB-DTPA (726 Da) sug-
gested that cats had intermediate bili-
ary excretion of compounds with a
high molecular weight (355 to 495 Da),
whereas rats and dogs had good biliary
excretion and rabbits and monkeys had
poor biliary excretion. Thus, it would
be expected that cats would excrete
Gd-EOB-DTPA at least as well as hu-
mans and possibly less well than dogs.
Although pharmacokinetic evaluation
and a comparison between hepatic
and renal enhancement were beyond
the scope of the study reported here,
they would be beneficial to provide a
better understanding of the hepatobi-
liary and renal excretion properties of
Gd-EOB-DTPA in cats.
Dose of Gd-EOB-DTPA had a signifi-
cant effect on hepatobiliary enhance-
ment. Higher doses were used for the
second and third phases of the present
study, compared with the dose used for
enhanced MRI in humans46 or dogs.39,40,51
This was based on the fact that the dose
required for CT is higher than the dose
required for MRI.38,42 A low dose was
chosen for the first phase of the present
study to minimize the risk of adverse ef-
fects because use of Gd-EOB-DTPA in cats
had not been reported. A significant ef-
fect of the dose of contrast agent for each
biliary structure was detected between
the medium and high doses, compared
Figure 5—Transverse plane CT images obtained by use of a soft tissue kernel of
the gallbladder (arrow) of 2 cats (cat 1 = A, C, E, and G; cat 2 = B, D, F, and H) with results for the low dose; however,
at 65 minutes after IV injection of a high (0.3 mmol/kg; A and B), medium (0.1 there were no significant differences de-
mmol/kg; C and D), and low (0.0125 mmol/kg; E and F) dose of Gd-EOB-DTPA tected between the medium and high
and before administration of contrast agent (G and H). Although there was a doses. This was most likely attributable
similar pattern of an increase in subjective enhancement of the gallbladder with to the smaller increase in dose (factor of
an increase in dose of contrast agent for both cats, there were differences in the
number of HU and visual assessment scores between cats for the same dose of 3) between the medium and high doses,
contrast agent. There was similar contrast enhancement within the gallbladder compared with a larger increase (factor
of cats 1 and 2 for the high dose (A and B); however, for the medium and low of ≥ 10) between the low dose and medi-
doses, cat 1 (C and E, respectively) had greater contrast enhancement within the um or high dose. Despite this, increases
gallbladder than did cat 2 (D and F, respectively).
in the dose of contrast agent resulted in
higher mean enhancement values (inde-
excretion via the same system in rats48 is 63% to 80% pendent of age and body weight) for all anatomic struc-
and in monkeys48 is 32% to 34%. Variability in the tures in the hepatobiliary system. This is similar to the
excretion rates of contrast agents among species has dose-dependent enhancement seen for dogs in other
also been confirmed in other evaluations of nonhe- studies.41,42 Although the relationship between dose
patocyte-specific contrast agents (eg, gadobenate and enhancement in the present study is similar to that
dimeglumine), which are agents that have the high- detected in studies of dogs41,42 and humans,38,43,47 the
est biliary excretion rate when administered to rats, overall biliary enhancement in the study reported here
followed by dogs, rabbits, and monkeys.49 Although was lower in cats when considering a similar dose of
the authors are not aware of any pharmacokinetic contrast agent.

392 AJVR • Vol 80 • No. 4 • April 2019

 Despite the fact there were suboptimal biliary study were below the saturation value that results in
tract visual assessment scores, optimal objective CT delayed biliary excretion in dogs.42 Future studies are
contrast enhancement of the cystic and bile ducts needed to investigate higher doses of contrast agents
was detected at 65 minutes at all doses. This timing and longer periods of image acquisition.
is similar to results in a study41 of dogs in which the For all anatomic structures (gallbladder, cystic
time of contrast agent enhancement was also not duct, and hepatic ducts), except for the bile duct, the
dose dependent. Therefore, future clinical investiga- odds of having a higher visual assessment score were
tions of biliary pathological conditions of cats by use increased when considering the high dose to the low
of Gd-EOB-DTPA could be conducted between 65 and dose and comparing that with the medium dose to
85 minutes after injection of contrast agent because the low dose. Interestingly, the OR for the bile duct
there was not a significant difference in the number was higher when comparing the medium dose to the
of HU between these times. In the present study, con- low dose (OR, 10.4) than when comparing the high
trast enhancement of the gallbladder differed signifi- dose to the low dose (OR = 5.8). The reason for this
cantly at each time point and did not reach a plateau relationship is unclear, but it may have been attribut-
by the time of the last scan (85 minutes after injection able to the small size and sinuous shape of the bile
of contrast agent). Therefore, maximal enhancement duct. In the case of the cystic duct, a possible expla-
of the gallbladder was not determined in the study nation for the low visual assessment scores may have
reported here. In human medicine, Gd-EOB-DTPA– been related to border effacement with the adjacent
enhanced MRI evaluations revealed intense enhance- hepatic parenchyma. Another reason may have been
ment of the bile duct from 10 minutes after injection their tortuosity. In most of the cats, the hepatic ducts
of contrast agent, with scanning and assessment of were visible only along part of their length (typically
the biliary tract recommended at 20 to 30 minutes just proximal to their entry into the bile duct). This
after injection.35,37,52 However, improved image qual- finding is similar to that for a study41 of dogs in which
ity of the bile ducts was detected after a scan delay of the hepatic ducts were also found to be the least reli-
50 to 60 minutes for patients without hepatobiliary ably visible structure with Gd-EOB-DTPA–enhanced
dysfunction.52 It is unclear whether further increas- CT.
ing a delay for image acquisition of cats would result Limitations of the present study included the
in increased enhancement of the gallbladder. small number of cats in each phase, particularly
Clear homogenous contrast enhancement of the because 1 cat was excluded from the first phase of
liver was detected in the present study. This finding the study. However, because significant differences
has potential use for the characterization of diffuse or were detected with the small study population, the
focal hepatic disease in cats by use of CT in clinical use of an additional cat in the first phase was con-
studies. The time of contrast enhancement of the liv- sidered unnecessary. A single investigator performed
er was similar in all cats, with no significant change the objective contrast measurements of the hepato-
in liver enhancement after 45 minutes for all doses biliary system, which may have introduced bias. Fur-
of contrast agent. Similar to results of CT and MRI thermore, because the feline biliary tract is small and
evaluations of dogs with hepatic lesions,39,40,43 cats tortuous, in particular the bile duct, measurements
with diffuse or focal hepatic pathological conditions were difficult to obtain for some cats and may have
may have a reduction in, delay of, or lack of contrast included additional sampling error or volume averag-
enhancement in affected regions of the liver, com- ing. Thinner slices may have reduced this limitation.
pared with values for normal hepatic parenchyma. The study ended at 85 minutes, and the plateau and
On the basis of results for the study reported here, any decline in enhancement for the gallbladder were
these changes may be best visually assessed between not identified. Therefore, we cannot be certain that
45 and 85 minutes after injection of contrast agent. maximum enhancement was identified. However,
Despite a continued increase in the number of HU additional time for image acquisition and anesthesia
after 45 minutes, it is unclear whether a longer in- did not appear to be warranted, given the data from
terval after injection of the contrast agent would studies of humans and dogs. Higher doses were not
have improved conspicuity of hepatic lesions given tested in the study reported here because of ethical
that there was not a significant difference in liver en- considerations and cost limitations for implementing
hancement after 45 minutes. The enhancement curve additional phases.
for the liver of the cats in the present study differed In the study reported here, Gd-EOB-DTPA–
from that described for dogs.42 In that study,42 time enhanced hepatic CT and cholangiography provided
of maximum enhancement in dogs was dose depen- clear homogenous hepatic enhancement but poor to
dent. It was argued that saturation may have delayed moderate enhancement of the biliary tract. These
peak enhancement.42 The reason that the highest results suggested that this technique may be useful
dose in the present study did not result in delayed for image analysis of the liver parenchyma; however,
hepatic enhancement is unclear. A possible explana- its value for evaluation of the biliary tract of cats is
tion would be that we may have terminated the study questionable. No major adverse effects were detected
before maximum enhancement was reached. Alter- in the healthy cats of the present study. A positive
natively, it is possible that the doses in the present relationship in contrast enhancement was reported

AJVR • Vol 80 • No. 4 • April 2019 393

with increases in the dose of contrast agent. Optimal plex gallbladder and biliary mucocele associated with par-
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