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Prof. Dr. Stefan O. Schoenberg
Professor and Chairman of Radiology
Department of Clinical Radiology and Nuclear MedicineUniversity Hospital Mannheim,
Medical Faculty Mannheim – University of Heidelberg, Germany
Annual RSNA meeting, Chicago, 2007Annual RSNA meeting, Chicago, 2007
Hepatobiliary Contrast Agents
http://www.ma.uni-heidelberg.de/inst/ikr/RSNA2007/Livercontrastmedia
1. Unenhanced (signal on T1w, T2w images; morphology)
2. With contrast agents:
• specific enhancement pattern in the early dynamic
acquisition (during bolus administration)
• tissue-specificity: reticular endothelial system,
hepatocytes
MR imaging of the liver:detection - localization - characterization
http://www.ma.uni-heidelberg.de/inst/ikr/RSNA2007/Livercontrastmedia
Characterization with unenhanced MRI
Hemangioma Metastasis FNH
complexity
Pitfalls in Hypervascular MetastasisWrong timing Wrong conclusion
portalvenous
arterial
arterial
liver-specific EOB
Missed metastases DDX: FNH
MR contrast agents for liver imaging
Pre-contrast liver MRI (T1w, T2w, morphology)
Extracelullar contrast agents• Gd-chelates
• good safety profile (> 30ml/min clearance)
• dynamic enhancement characteristics
Liver-specific contrast agents• SPIO (Iron Particles)
• Hepato-biliary agents
MR contrast agents for liver imaging
Hepatocyte-selective agents
� signal-rise in T1w
• Multihance® (Gd-BOPTA )
• Teslascan® (Mn-DPDP)
• Gd-EOB® (Gd-EOB-DTPA)
RES-specificity
� signal-loss in T2w
• Endorem® (SPIO)
• Resovist® (SHU 555 A)
• Sinerem® (USPIO)
Courtesy of Quondamatteo, Uni Göttingen
Kupffer-Cell Hepatocyte
Liver-specific Contrast Agents
Courtesy of
Quondamatteo
Uni Göttingen
O
(4S)-4-(4-EthOxyBenzyl)-3,6,9-tris(carboxylato-
methyl) -3,6,9-triaza-undecandioic acid
-OCC
-OCC
N
NN
CCO -
CCO -CCO
-
2 NaGd+3
GdGd--complexcomplex
Gd-EOB - Chemistry
• hydrophilic, ionic, highly water soluble Gd-DTPA-derivate with lipophilic ethoxybenzyl (EOB)
• high liver-specific uptake, bolus injectable
• uptake via the organic anion-transporting polypeptide 1 (OATP1), a membrane transport system
• active hepato-biliary excretion via canalicular multi-specific organic anion transporter (cMOAT)
• � Elimination by:excretion into bile and feces (50%)renal pathway via glomerular filtration into urine (50%)
Gd-EOB - Primovist®Gd-EOB
CM Entrapment � FNH
Gd-DTPA (Magnevist)
Gd-EOB (Primovist)
t~ 10 min
T1w pre
arterial, portal-venous equilibrium
liver-specific phase
~ 4-5 min ~15 min
dynamic
studies
bolus injection
T2w +MRCP
~ 5-10min
Examination Protocol Gd-EOB
recommended dose: 0.025 recommended dose: 0.025 mmolmmol /kg/kg
Hirohashi S et al., ISMRM 2003
• Gd-EOB - clinical development
– 3 phase I-studies (66 volunteers): good safety profile
– Phase II (553 patients): „
– Phase III (detection)
– Phase III (characterization)
Safety Profile of Gd-EOB
48 (3.4%)1404
Patients with at least
one AE related to the drug
Total number
of patients
0.3Injection site reaction(pain edema)
0.3Paresthesia
0.5Nausea
0.6Taste perversion
0.7Headache
0.8Vasodilatation
%Most frequent
adverse events
Gd-DTPA
Magnevist®
Gd-BOPTA
MultiHance®
Gd-BOPTA (Multihance®)
benzyloxymethyl group
t~ 10 min
T1w pre
arterial, portal-venous equilibrium
liver-specific phase
~ 4-5 min ~40-60 min
dynamic
studies
bolus injection
T2w +
MRCP
Examination Protocol Gd-BOPTA
recommended dose: 0.05recommended dose: 0.05--0.1mmol /kg0.1mmol /kg
Re-schedule patient
• Study MH 109: 151 patients intra-individual comparison
Gd-DTPA vs. Gd-BOPTA(Maravilla KR et al., Radiology 2006)
• No significant difference between two study agents
• No serious AE’s
• 14 non-serious AE’s reported for each agent (~9%)
• 1 each withdrew due to AE (contrast extravasation at injection site)
• Phase 3 liver study gadobutrol vs. Gd-BOPTA
• No significant difference between two study agents
Safety profile of Gd-BOPTA
t~ 10 min
T1w pre
liver-specific phase
~ 5 min ~20 min – 120 min
slow iv infusion(2-3 mL/min, 10-20 min)
T2w +MRCP
~ 5-10min
Examination Protocol Mn-DPDP (Teslascan®)
recommended dose: 0.005 recommended dose: 0.005 mmolmmol /kg/kg
Martí-Bonmatí L et al. Radiología 2003;45:19, Martí-Bonmatí L et al. Radiología 1999;41:431Wang C. Acta Radiol Suppl 1998;415:1
MnDPDP Contrast Administration
•• T1WT1W--spoiledspoiled--GRE sequences are preferredGRE sequences are preferred
•• TE must be as shortest as possible, outTE must be as shortest as possible, out--ofof--phase favorablephase favorable
•• Flip angle between 60Flip angle between 60--80º80º
•• Fat suppression improves small lesionFat suppression improves small lesion--toto--liver contrastliver contrast
•• T2W images are not influence by T2W images are not influence by MnDPDPMnDPDP at the usual doseat the usual dose
Martí-Bonmatí L et al. Eur Radiol 2003;13:1685
Safety profile of Mn-DPDP
•• From a large series of patients, only 7% showed From a large series of patients, only 7% showed
adverse events. adverse events.
•• Adverse events are mild in most patients, being quite Adverse events are mild in most patients, being quite
rare the severe adverse events.rare the severe adverse events.
•• They consist mainly in nausea, vomiting, They consist mainly in nausea, vomiting, urticariaurticaria, rash , rash
and generalized anaphylactic reactions. Serious life and generalized anaphylactic reactions. Serious life
threatening reactions are extremely rare.threatening reactions are extremely rare.
•• Administration as a bolus injection (1 ml/s) is feasible Administration as a bolus injection (1 ml/s) is feasible
but related to increase rate of minor adverse events but related to increase rate of minor adverse events
like warm sensation and hot flushes in the face.like warm sensation and hot flushes in the face.
• Detection, multifocality
• Lesion characterization: benign vs. malignant
• Grading
• Comprehensive protocols
• Intervention / operability
Value of liver specific contrast agents
T1w in phase T2w fs TSE
Metastasis of Renal Cell Carcinoma @ 3T
T1w Gd-EOB portal-venous T1w Gd-EOB liver-specific 20 min
2D vs 3D post Gd-EOB
T1w 2D GRE fs 40min T1w 3D GRE (VIBE) fs 30min
T1w pre
6mm + 0.6 3mm4 x 15 sec. 20 sec.
Potential for ultra-high resolution 3D-sequences under steady state conditions
with liver specific agents
Multifocality
Multiple metastases of rectal CA
3D GRE 20 min post Gd-EOB
Detection of Small Lesions @ 3T
T1w VIBE pv Gd-EOB
T2 FSE fs
Metastasis of Klatskin´s tumor
Gd-EOB
T1w FS 20 min postcontrast
Ruling Out Lesions on MSCT ?
CT pv 3mm Sl
VIBE pv Gd-EOB VIBE 20min Gd-EOB
T2w HASTE pre
T1-w GRE 120 sec after CM T1-w FS 15 min after CMMD-CT arterial
HE, x200
• Arterial enhancement, rapid wash-out
• Hepatocyte-selective uptake,
isointense with homogeneous
enhancement in the liver-specific
phase
Multifocal HCC in liver cirrhosis (Child B)
Huppertz A, et al. Radiology 2005
Multifocal hepatocellular carcinoma with SPIO
T2*-imaging 10 min after
RES-specific SPIO CM
• Detection, multifocality
• Lesion characterization: benign vs. malignant
• Grading
• Comprehensive protocols
• Intervention / operability
Value of liver specific contrast agentsGd-BOPTA for MRI of liver metastases
Native Arterial phase Portal-venous phase (50s)
3. Phase (100s) late phase (14 min) very late phase (120 min)
peripheral wash-out in late phase
Triphasic 3D liver imaging with Gd-BOPTA
HCC
Metastases
Kane PA et al. Acta Radiol 1997; 38:650
MnDPDP: detection of metastasis
Rim enhancement in metastases: composed of compressed liver
parenchyma due to an expansive lesion� characteristic but non-specific
Courtesy of L. Marti-Bonmati, Valencia
T1w FS T1w GRE arterial T1w FS 20 min
HE, x100
• Early arterial enhancement
• Heterogeneously hyperintense in the hepatocyte-selective phase
• Non-enhancing central regions and septaecorresponding to a fibrous scar
• Delayed wash-out
Focal nodular hyperplasia (FNH) Focal nodular hyperplasia (FNH)
Signal characteristics of FNH (n=59) in different sequences
28%2%32%38%Hepatocyte phase 20 min
37%2%33%29%Hepatocyte phase 10
min
10%2%17%71%T2-w pre-contrast
6%76%14%4%T1-w pre-contrast
MixedHypointens
e
Isointens
e
Hyperinten
se
Zech CJ, et al. submitted
T1w FS T1w FS 15 min post CMT1w FS 20 min post CM
HE, x100
Adenoma
Heterogeneous hyperintensity with central hypointense spots
in the hepatocyte-selective phase
pre - VIBE
art - VIBE
40 min
Adenoma
Metastasis of Renal Cell Carcinoma ?
HE, x100
T1w GRE unenhanced
T1w GRE arterialT1w FS 10 min post CM
HE, x100
Lesion 1 Lesion 2
Typical / atypical adenoma with Gd-EOB Gd-BOPTA: adenoma versus FNH
After 1–3 hours 96.9% of FNHs hyper- or isointense, 100% of HA
and LA hypointense � sensitivity / specificity: 96.9% / 100%
Grazioli L, et al. Radiology 2005; 236:166–177
After 2 hours
S/P ovarian carcinoma, suspicion of multiple metastasis on CT
High-resolution @ 3 Tesla
T1w 2D GRE @ 1.5T320 matrix, 6mm slice thickness
T1w 2D GRE @ 3T384 matrix, 4mm slice thickness
Homogenous, increased uptake of Gd-EOB
�Benign lesions (adenomatosis)
Biph. CT : 84.7%MRI plain: 67.8%MRI EOB: 88.1%
No detection data59 FNHsZech et al. 2006, ISMRM Proc.
Biph. CT : 77.5%MRI plain: 75.6%MRI EOB: 85.4%
No detection data41 HCCsJung et al. 2006,
Acta Radiologica
Biph. CT : 58% 64% 55%
MRI EOB: 68% 77 % 58%No detection data
250 lesions(3 blinded readers)
Halavaara et al.
2006, JCAT
Biph. CT : 68.4%
MRI plain : 63.8%
MRI EOB : 70.7%
Biphasic CT: 65.9%
MRI plain : 62.7%
MRI EOB : 70.9%
316 lesionsBluemke et al. 2005,
Radiology
MRI plain: 51.2%MRI EOB: 62.8%
MRI plain: 80.8%MRI EOB: 87.4%
302 lesionsHuppertz et al. 2004, Radiology
Correct CharacterizationDetection RateNumber of
LesionsLiterature Gd-EOB
Liver MR imaging with Gd-EOB
MRI plain : 48.6 %MRI Gd-BOPTA: 74.5 %
MRI plain : 76.5 %MRI Gd-BOPTA: 91.9 %
107 / 149 lesions
Pirovano et al. 2000, AJR
No characterization dataMRI Gd-BOPTA: 81 %MRI SPIO : 97 %
37 Metastases
Del Frate et al.2002, Radiology
No characterization dataMRI Gd-BOPTA: 91.4%MRI SPIO : 81.0%
35 HCCsKim et al. 2004, AJR
Correct CharacterizationDetection RateNumber of Lesions
Literature Gd-BOPTA
Liver MR imaging with Gd-BOPTA
No characterization dataMRI Mn-DPDP: 81.4%PET-CT: 67.0%
79 metastases
Sahani et al. 2005, AJR
No characterization dataMRI Mn-DPDP: 82%MRI SPIO : 90%
53 metastases
Kim et al. 2006, AJR
No characterization dataBiph. CT : 71%MRI plain: 72%MRI Mn-DPDP: 90%
128 lesionsBartolozzi et al. 2004, Eur Radiol
Correct CharacterizationDetection RateNumber of Lesions
Literature Mn-DPDP
Liver MR imaging with Mn-DPDP
Added Value of Delayed Imaging
• For Gd-BOPTA the number of detected metastases increased from
18/37 (non-enhanced), 20/37 (dynamic phase) to 30/37 (BOPTA-
delayed) Del Frate et al. 2002, Radiology
• Up to now there is no data in the literature with regard to the added
value of the hepato-biliary phase of Gd-EOB-DTPA compared to
early dynamic imaging - based on personal experience an increase
of 5-10% can be expected
• For Mn-DPDP only delayed imaging is possible, compared to
standard Gd-chelates equal to increased detection rates are
published (- missing dynamic imaging phase!) Kettritz et al. 1996, MRI; Youk et al. 2004, AJR
-30
-20
-10
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30 35 40 45 50Case No.
PSIL (%)
Benign Malignant
In comparison: signal loss after SPIOPercentage signal loss (13 benign, 46 malignant lesions)
Threshold 25 % �12/13 benign (92.3 %) & 45/46 malignant (97.8 %)
Threshold 30 % �10/13 benign (76.9 %) & all malignant (100 %) (2 Hämangiome < 30%)
Namkung S, Zech CJ, …, Schoenberg SO. J Magn Reson Imaging 2007; 25: 755-765
FNH
Adenoma
• Detection, multifocality
• Lesion characterization: benign vs. malignant
• Grading
• Comprehensive protocols
• Intervention / operability
Value of liver specific contrast agentsCharacterization of HCC with hepatocyte-specific
agents
HCC Perfusion
Dynamic imaging with Gd-EOB
Tumor perfusion Hepatobiliary excretion
Characterization of HCC with hepatocyte-specific agents
Gd-E
OB
Gd-D
TP
A
Gra
din
gG
radin
g
Grading of HCC with hepatocyte-specific agents
Tsuda N, et al. Invest Radiol 2004; 39: 80-88
• increased delineation of the hypointense lesion
• no liver-specific CM-uptake
• Histology: moderately-poorly differentiated HCC
• hypointense lesion �hyperintense after CM
• marked CM-uptake in the center of the HCC
• Histology: highly-differentiated HCC
HCC (WHO G1 versus G2/3) – Gd-EOB
Huppertz A, Harayda S, Kraus A, Zech CJ et al., Radiology 2005
unenhanced 10min after EOBT1-w fs
Undifferentiated HCCUndifferentiated HCC
WellWell--differentiated HCCdifferentiated HCC
Grading of HCC with Mn-DPDP
Courtesy of L. Marti-Bonmati, Valencia, Spain
• Detection, multifocality
• Lesion characterization: benign vs. malignant
• Grading
• Comprehensive protocols
• Intervention / operability
Value of liver specific contrast agents Gd-EOB-enhanced MRC 3Tesla
T1w 3D GRE 2mm; 384 Matrix; Gd-EOB liver-specific phase
EOB-enhanced MRC using 3D-GRE (VIBE)
Central cholangiocarcinoma
• Detection, multifocality
• Lesion characterization: benign vs. malignant
• Grading
• Comprehensive protocols
• Intervention / operability
Value of liver specific contrast agents
Indication for stent replacement
Absent excretion of Gd-EOB, ↑ renal excretionsignificant obstruction vs. chronic dilatation of biliary tree
1.5T: 4 x 1.9 x 1.4mm 3T: 2 x 2.6 x 1.1mm
Metastases of sigmoid-CA; additional benign lesion
VIBE – Liver specific phase post Gd-EOB
Coronal MPR from a transversal acquired dataset
1.5 T 3 T
High quality reformats feasible at 3T
• Detection better than CT, probably equal for all 3
hepatobiliary agents
• Gd-EOB and Gd-BOPTA advantage of dynamic
information � superior results
• Only Gd-EOB EMEA-approved for lesion characterization,
superior results compared to CT
• CE MRC reserved for special indications � dynamic
information: e.g. obstruction
• 3D GRE sequences + higher field strength � isotropic
resolution > CT
Value of liver specific contrast agents
http://www.ma.uni-heidelberg.de/inst/ikr/RSNA2007/Livercontrastmedia
Acknowledgment
• Department of Radiology, Ludwig-Maximilians-University of
Munich, Germany:Christoph Zech MD
• Department of Radiology, University Hospital, Valencia, Spain:
Luis Marti-Bonmati MD
• Imaging Science Institute Charité-Siemens:
Alexander Huppertz MD
http://www.ma.uni-heidelberg.de/inst/ikr/RSNA2007/Livercontrastmedia
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