DIAGNOSTIC AND THERAPEUTIC ADVANCES IN HEPATOLOGY
Hepatocyte-Specific Magnetic Resonance
Imaging Contrast Agents
Jeff Fidler and David Hough
The Case
A 59-year-old female with a past history of oral
contraceptive use presents with right upper quadrant
pain. Her physical examination and liver biochemical
tests are normal. The alpha-fetoprotein level is also
within normal limits. The abdominal computed tomography (CT) scan shows a small mass in the kidney
that raises the suspicion of renal cell carcinoma.
Images through the liver show a vague mass with some
peripheral hyperenhancement in the right lobe of the
liver (Fig. 1A). What is the role of magnetic resonance
imaging (MRI) in the characterization of indeterminate liver masses? Is there any benefit in using newer
MRI contrast agents such as Eovist?
The Problem
Improvements in imaging technology and more
widespread utilization of imaging techniques have led
to increased detection of liver masses. In many cases, a
lesion can be diagnosed with certainty because of its
characteristic appearance. However, the appearances
may not always be typical.
Hepatic masses may be enhanced more than, less than,
or equally to normal hepatic parenchyma; this depends on
the nature of the lesion, the timing of the scan with respect
to the contrast bolus, and the attenuation of the liver during CT (e.g., normal attenuation versus low attenuation
from fatty infiltration). Lesions that typically show arterial
phase hyperenhancement include cavernous hemangioma
(CH), focal nodular hyperplasia (FNH), hepatic adenoma
(HA), hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma (FL-HCC), and certain metastases
Abbreviations: CH, cavernous hemangioma; CT, computed tomography; FLHCC, fibrolamellar hepatocellular carcinoma; FNH, focal nodular hyperplasia;
HA, hepatic adenoma; HCC, hepatocellular carcinoma; MRI, magnetic
resonance imaging; NSF, nephrogenic systemic fibrosis.
From the Department of Radiology, Mayo Clinic, Rochester, MN.
Address correspondence to: Jeff Fidler, M.D., Department of Radiology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: fidler.jeff@mayo.
edu; fax: 507-266-4609.
C 2011 by the American Association for the Study of Liver Diseases.
Copyright V
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.24158
Potential conflict of interest: Nothing to report.
678
(e.g., neuroendocrine tumors and breast cancer). The
degree, pattern, and temporal appearance of the enhancement are all helpful in the characterization of these masses.
CHs typically show nodular or globular, discontinuous
peripheral enhancement with progressive centripetal filling over time. Small CHs may show more homogeneous
flash filling during the early arterial phase. On MRI, the
lesions are usually well defined with high signal intensity
on T2-weighted images. On ultrasound, they are typically echogenic with through transmission, but they may
be hypoechoic in a fatty liver.
The typical appearance of FNH is a diffusely homogeneous, hyperenhancing, slightly lobulated mass during the arterial phase of imaging (Fig. 1B).1-6 The
contrast enhancement quickly equilibrates with the
normal liver parenchyma during the portal venous
phase, and the lesion may be difficult to visualize
(Fig. 1C). On MRI, FNH may have subtle, low signal
intensity on T1-weighted images and minimal, high signal intensity on T2-weighted images. A central scar is
usually present; however, central scars can also be seen
in other tumors.1 The scar in FNH usually has high
signal intensity on T2-weighted images secondary to the
presence of vessels and bile ducts within the scar.
Delayed scans may show enhancement of the scar. This
appearance may help to differentiate the more fibrotic
scar of FL-HCC, which typically is hypointense and has
less enhancement.1 The visualization of a central feeding
artery or draining vein can improve diagnostic specificity. On ultrasound, FNH can have variable echogenicity.
FNH lesions are usually isoechoic to the normal liver
and have been termed stealth lesions. Color and power
Doppler may show increased central stellate vascularity.
The appearance of HAs varies according to the size and
complexity of the lesions. On CT and MRI, smaller lesions
typically show nearly homogeneous hyperenhancement.
Larger lesions may appear more heterogeneous and may
contain areas of fat, hemorrhaging, necrosis, and rarely calcification. A fibrous capsule may be present in one-third of
an HA. On ultrasound, the echogenicity depends on the
presence of fat, hemorrhaging, or calcification.7
The detection of HCC in a cirrhotic liver is often challenging, and differentiation from regenerative nodules
and perfusion abnormalities can be difficult. Multiphase
imaging with CT and MRI is important for optimizing
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679
Fig. 1. FNH: a 59-year-old woman with newly diagnosed renal cell carcinoma and a past history of oral contraceptive use. (A) CT demonstrates a vague mass with some peripheral enhancement in the right lobe of the liver (arrows). MRI with gadoxetate disodium during (B) the arterial phase, (C) the portal venous phase, and (D) the delayed hepatocyte phase shows a lobulated, hyperenhancing mass (arrows). This mass
retains contrast during the delayed hepatocyte phase. The enhancement during the hepatocyte phase suggests a tumor of hepatocyte origin with
normally functioning hepatocytes. According to the morphology and enhancement characteristics, this mass is consistent with FNH.
the detection and characterization of lesions. The presence of an arterial hyperenhancing mass that shows
washout (low attenuation on CT or low signal intensity
on MRI with respect to the normal parenchyma) on
portal venous phase or delayed images is considered
diagnostic. HCC may also demonstrate some peripheral
delayed enhancement secondary to a pseudocapsule.
FL-HCCs are hyperenhancing masses that may have a
central fibrotic scar with a low density on CT and a low
signal intensity on MRI. The scar usually is not enhanced
on delayed images and may have areas of calcification
Although the classic appearance of the aforementioned
hepatic masses is well known, atypical appearances are
not uncommon and can lead to uncertainty in diagnosis.
Atypical findings may occur in 10% to 50% of FNH
cases.2 Several atypical findings have been reported; they
include a high T1 signal (fat, hemorrhaging, or copper),
a low T2 signal (iron), less intense arterial enhancement,
tumor heterogeneity, an unusual appearance of the central
scar such as no enhancement or an absence (up to 50%),
and the presence of a pseudocapsule (10%-37%).1,2 In
such situations, it may be difficult to differentiate FNH
from adenoma, HCC, or metastases. Therefore, in these
inconclusive cases, further imaging or biopsy is usually
performed. Currently, MRI offers several advantages over
other techniques, including improved soft tissue contrast
and the ability to use different contrast agents to improve
lesion detection and characterization.
MRI Contrast Agents
There are two main categories of gadolinium contrast
agents used for hepatic imaging: extracellular agents and
hepatocyte-specific agents (Table 1).8,9 The most widely
used are the extracellular gadolinium agents, which are
used for routine imaging throughout the body. These
agents circulate in the vascular system, are distributed
into the extracellular space, and are excreted by the
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Table 1. Comparison of Contrast Agents for Liver MRI
Type of Agent
Hepatocyte-Specific
Extracellular
Generic name
Trade name
Gadobenate dimeglumine
MultiHance
Gadoxetate disodium
Eovist and Primovist
Biliary excretion (%)
Dose (mmol/kg)
Hepatocyte phase
(minutes)
Advantages
3-5
0.1
60-90
50
0.025
10-20
Arterial and portal venous phase
characteristics similar to those
of extracellular agents
Long delay to the hepatocyte phase
Intense hepatocyte phase
enhancement Short delay
to the hepatocyte phase
Unique lesion imaging characteristics due to rapid
extraction from the blood pool Technical
challenges due to the smaller contrast volume
Limitations
kidneys. The enhancement characteristics of hepatic
lesions are similar to those seen on CT. However, in
some cases, the enhancement may be more conspicuous
on MRI because of the increased soft tissue contrast.
There are two liver-specific contrast agents: gadobenate
dimeglumine (MultiHance, Bracco) and gadoxetate disodium (Eovist from Bayer HealthCare, which is also
known as Primovist in Europe).8,9 These agents are taken
up by normally functioning hepatocytes and are excreted
into the biliary system. Therefore, these agents may be
able to differentiate tumors that have normally functioning
hepatocytes and biliary excretion from those that do not.
Both gadobenate dimeglumine and gadoxetate disodium are injected dynamically and are circulated and
distributed in the extracellular space similarly to extracellular gadolinium agents. Therefore, similarly to the
extracellular agents, imaging can be performed during
the arterial and portal venous phases. However, the
ability to allow delayed hepatocyte-specific imaging
provides additional information.
Gadobenate dimeglumine is taken up by hepatocytes
and is excreted into the biliary system by anion transport. Delayed imaging, also known as the hepatocyte
phase, is usually performed at 60 to 90 minutes.
Delayed imaging allows the differentiation of lesions
that have normally functioning hepatocytes, which show
some degree of contrast uptake, from lesions without
normally functioning hepatocytes, which have lower
intensity in comparison with normal parenchyma.
Gadoxetate disodium is transported from the extracellular space into the hepatocytes by adenosine triphosphate–dependent organic anion transporting polypeptide 1. It is subsequently excreted into the biliary
canaliculi by the canalicular multispecific organic anion
transporter.8 Fifty percent of this agent is excreted by
the biliary system, whereas only 5% of gadobenate dime-
Several
Magnevist, Omniscan, ProHance,
OptiMARK, Dotarem, and Gadovist
None
0.1
Not applicable
Robust imaging characteristics
during arterial and portal
venous phase imaging
No hepatocyte phase
glumine is. Therefore, there is more intense enhancement
of the liver with gadoxetate disodium. In addition, the hepatocyte phase scans can be performed at only 20 minutes,
and this improves efficiency. A limitation of gadoxetate
disodium is that the recommended dose of 0.025 mmol/
kg (0.1 mL/kg) is only one-quarter of the dose of gadobenate dimeglumine and various other extracellular agents (0.1
mmol/kg or 0.2 mL/kg). The volume of contrast administered to a 70-kg patient is one-half or 7 mL. This may
lead to diminished arterial phase hepatic enhancement,
and achieving the optimal scan delay to capture peak
arterial enhancement is technically challenging.
Role of Hepatic-Specific MRI
Contrast Agents
The main role of the hepatic-specific agents is to
improve both the detection and characterization of lesions.
These agents may be helpful in improving the detection of
small or subtle masses.10-12 By increasing the contrast
between the markedly enhanced normal parenchyma and
hypoenhanced or unenhanced masses, they may improve
the detection of smaller lesions. This may be helpful in the
preoperative assessment of patients who are being evaluated
for surgical resection of malignant hepatic masses such as
metastases from colorectal cancer. These agents may also
increase the conspicuity of subtle or ill-defined masses such
as treated malignancies or intrahepatic cholangiocarcinomas. However, further studies are needed to compare these
agents to the conventional extracellular agents.
Lesions of hepatocellular origin (FNH, HA, and welldifferentiated HCC) may show uptake and retention of
these contrast agents, and this can help to differentiate
them from nonhepatocellular tumors (e.g., CH and metastases).9 Understanding the histology of these tumors
helps us to explain their appearance during the delayed
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681
phase when hepatic-specific agents are used. FNH consists of normally functioning, densely packed hepatocytes and abnormal, blind-ending bile ductules, which
result in contrast retention and delayed biliary excretion.
This combination of findings produces the high signal
intensity seen in these lesions during the delayed hepatocyte phase (Fig. 1D).8 However, the degree of
enhancement of FNH during the delayed hepatocyte
phase can vary. In a study of 59 cases of FNH using
gadoxetate disodium, the pattern of enhancement during the hepatocyte phase was homogeneous in 36% to
41%, heterogeneous in 31% to 36%, mainly in the rim
in 17% to 19%, and absent in 10% to 12%.13
HAs lack biliary ductules; therefore, no biliary
excretion is seen in these tumors.7,8 Thus, many
adenomas appear hypointense during the hepatocyte
phase (Fig. 2); however, there have been some reports
of enhancement with gadoxetate disodium.8
Because these agents are excreted into the biliary system, they can also be used to image the bile ducts. This
may be helpful for better demonstrating the biliary
anatomy or function or evidence of a bile duct leak.
Areas of Uncertainty
Even though these agents are taken up by hepatocytes
and are excreted into the biliary system, the appearance of
lesions during the portal venous phase and delayed phase
differs between these two agents. Gadoxetate disodium is
rapidly extracted from the blood pool. Therefore, the
blood vessels and CHs may begin to lose contrast during
the portal venous phase and have lower signals during the
hepatocyte phase. A lack of familiarity with these properties can result in the misdiagnosis of common lesions such
as CHs. Because of the longer delay in biliary excretion
with gadobenate dimeglumine, the blood vessels and CHs
have an enhancement appearance similar to that of extracellular agents during the portal venous phase.
HCC may behave differently according to the
degree of differentiation of the tumor. Well-differentiated tumors may show some uptake and retention of
these contrast agents (Fig. 3), whereas poorly differentiated tumors usually will not. Therefore, before using
these agents, one should have a thorough understanding of the pharmacokinetics in the setting of cirrhosis.
A common problem that arises in clinical practice is
the differentiation of FNH and HA. There are limited
data on the use of these agents in differentiating these
two masses. Using gadobenate dimeglumine, Grazioli
et al.7 showed that 96.9% of 128 FNHs were hyperintense or isointense during the delayed hepatocyte phase,
whereas 100% of 107 adenomas were hypointense.
Fig. 2. Hepatic adenomatosis: a 34-year-old woman with a history
of oral contraceptive use. CT shows multiple liver masses. MRI with
gadoxetate disodium shows (A) during the arterial phase hyperenhancing masses (arrows) that rapidly wash out with peripheral rim
enhancement (B) during the portal venous phase. (C) During the
delayed hepatocyte phase, the masses are hypointense to the normal
liver. The lack of contrast retention during the hepatocyte phase suggests a tumor lacking normally functioning hepatocytes. According to
the age, history, and multiplicity, this is consistent with adenomatosis.
In a smaller study assessing several types of tumors
with gadoxetate disodium, Hupperts et al.14 found in
three cases that FNH showed heterogeneous enhancement during the delayed hepatic phase. Both adenomas
in the study showed hyperenhancement; one was
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HEPATOLOGY, February 2011
excreted through the biliary system. However, there are
currently no scientific data to confirm that these agents
reduce the risk of development of NSF.
Recommendations
In this case, MRI with either gadobenate dimeglumine or gadoxetate disodium would be recommended
to help in differentiating between FNH and adenoma
(Fig. 1B-D). In the rare situation in which these lesions
cannot be differentiated because of atypical findings,
percutaneous biopsy may be considered. If the lesion
appears to be an HA, serial follow-up would be indicated.
Fig. 3. HCC: an 83-year-old man with biopsy-proven, well-differentiated HCC. MR with gadoxetic disodium during the delayed hepatocyte
phase shows a large mass (arrows); portions of the mass are
enhanced to the same degree as the normal liver parenchyma. Welldifferentiated HCC may have some normally functioning hepatocytes
retaining contrast during the delayed hepatocyte phase.
heterogeneous, and the other was homogeneous. Therefore, further studies are needed to understand why
gadoxetate disodium uptake occurs in some adenomas.
Poorly functioning hepatocytes, which appear during
cirrhosis and biliary obstruction (bilirubin level > 3 mg/
dL), may lead to limitations in the usefulness of these
agents due to poor hepatic uptake and excretion. Thus,
these contrast agents may not be helpful in detecting
tumors in deeply jaundiced patients and in many patients
with cirrhosis. The role of these agents in the diagnosis of
cholangiocarcinoma is also unclear. Frequently, intrahepatic cholangiocarcinoma may be ill defined and difficult
to detect or quantitate because of poorly marginated borders. The ability of gadoxetate disodium to provide intense
hepatic enhancement provides a theoretical advantage over
conventional contrast agents for improving the conspicuity
of cholangiocarcinoma. However, because hilar cholangiocarcinoma frequently causes biliary obstruction, there may
be many cases in which the obstruction and the elevated
bilirubin level limit the use of gadoxetate disodium.
Safety Issues
All of the gadolinium agents have similar side effects
that rarely occur, including nausea, headache, and allergic reactions. The administration of gadolinium should
be avoided in individuals with impaired renal function
and a low estimated glomerular filtration rate to reduce
the risk of nephrogenic systemic fibrosis (NSF). Theoretically, gadolinium agents that have more stability or
have biliary excretion may be less likely to induce NSF.
Both gadoxetate disodium and gadobenate dimeglumine
are more stable than the extracellular agents and are
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