hepatobiliary contrast agents - uni-heidelberg.de · Gd-DTPA Magnevist® Gd-BOPTA MultiHance®...

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


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


~ 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


~ 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



• Grading



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



• Grading



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



• Grading



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



• Grading




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



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


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