Biliary Imaging with Gd-EOB-DTPA:Is a 20-minute Delay Sufficient?1

Ruth C. Carlos, MD, MS, Jill D. Branam, Qian Dong, MD, Hero K. Hussain, MD, Isaac R. Francis, MD

Rationale and Objectives. The authors performed this study to quantitate the change in intrabiliary signal intensity 20minutes after gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) injection and to correlate thedegree of biliary visualization with changes in biliary signal intensity.

Materials and Methods. Sixteen patients with known hepatic masses (without known biliary disease) who were candi-dates for resection were enrolled in an open-label protocol of Gd-EOB-DTPA. Three-dimensional spoiled gradient-echomagnetic resonance (MR) images obtained in the coronal plane with breath holding before and 20 minutes after Gd-EOB-DTPA made up the biliary MR cholangiogram study. Manually defined regions of interest were used to measure signalintensity in the bile ducts before and after contrast material administration. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated. Biliary visualization was qualitatively assessed by using a five-point scale.

Results. The SNR and CNR significantly increased (P � .0002) after the administration of contrast material. Average bili-ary visualization ratings were excellent, with moderate to excellent interobserver agreement. There was no correlation be-tween measured SNR or CNR and visualization ratings.

Conclusion. A 20-minute delay after Gd-EOB-DTPA administration appears to be sufficient for adequate biliary enhance-ment. Residual hepatic enhancement does not appear to interfere with biliary visualization.

Key Words. Bile ducts, MR; gallbladder, MR; gadolinium.

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Magnetic resonance (MR) cholangiography can poten-tially be enhanced by using biliary contrast agents. Unliketraditional non–organ-specific gadolinium chelates, whichrapidly enter the extracellular space from the intravascularspace, newer contrast agents such as mangafodipir andgadolinium ethoxybenzyl diethylenetriaminepentaaceticacid (Gd-EOB-DTPA) demonstrate hepatocellular uptakeand excretion into the biliary tree (1,2). The T1-shorten-ing effects of these agents provide positive intrabiliary

contrast during T1-weighted spoiled gradient-echo imag-ing (3).

Gd-EOB-DTPA is actively transported by the hepato-cytes, and biliary excretion of Gd-EOB-DTPA has beenidentified in previous biologic efficacy studies in animals(1,2,4). Furthermore, in previous animal studies, it hasbeen shown that a 20–40-minute delay after administra-tion of Gd-EOB-DTPA is optimal for hepatic imaging,although biliary enhancement is present as early as 10minutes after Gd-EOB-DTPA administration (1). The re-sults of a recent clinical study (5) demonstrated that Gd-EOB-DTPA helped improve the visualization of the bili-ary tree compared with standard single-shot fast spin-echoimaging; however, the degree of visualization was notcorrelated with quantitative measures of changes in intra-biliary signal intensity after Gd-EOB-DTPA administra-tion.

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1 From the Department of Radiology, MRI Section, University of MichiganHealth System, 1500 E Medical Center Dr, UH B2B311D/0030, Ann Arbor,MI 48109-0030. Received July 16, 2002; accepted July 17. Supported by agrant from Berlex. R.C.C. supported in part by the GE-AUR Radiology Re-search Academic Fellowship. Address correspondence to R.C.C.

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Technical Report

The purpose of this study was twofold: (a) to quantita-tively determine the change in biliary signal intensity 20minutes after Gd-EOB-DTPA administration and (b) tocorrelate the degree of biliary visualization with changesin biliary signal intensity.

MATERIALS AND METHODS

Sixteen patients (six men, 10 women; mean age, 63.5years; range, 42–84 years) with known hepatic masseswho were candidates for surgical resection were prospec-tively enrolled in an open-label study of Gd-EOB-DTPA(Eovist; Berlex, Montville, NJ) between November 1998and January 2001. None of the patients had or were sus-pected of having biliary abnormalities. Informed consentwas obtained from all participants by using a protocolapproved by the Institutional Review Board.

MR Imaging TechniqueA 1.5-T magnet (Signa; GE Medical Systems, Milwau-

kee, Wis) was used with a torso phased-array coil. Biliaryimaging was performed by obtaining three-dimensionalspoiled gradient-echo images in the coronal plane withbreath holding before and 20 minutes after intravenousadministration of Gd-EOB-DTPA at more than 2 mL/sec.Imaging parameters were as follows: repetition time of5–8 msec, minimum echo time, 50° flip angle, 20 2.6–5.0-mm-thick partitions with interpolation to 40 1.3–2.5-mm-thick sections, and a 256 � 128–160 matrix. Thestandard dose of Gd-EOB-DTPA (25 �mol per kilogramof body weight) was followed by a 20-mL saline flush.

Image Processing and AnalysisThin-section (1.2-mm) axial images were reformatted

from the coronal three-dimensional source images by us-ing a commercially available workstation (AdvantageWindows; GE Medical Systems). The axial reformattedimages were used to quantitate the signal intensity in thecommon bile duct, right hepatic duct, and left hepaticduct with operator-defined regions of interest. Measure-ments were obtained before and after Gd-EOB-DTPAadministration. Noise was estimated by using the standarddeviation of the region-of-interest value obtained at a por-tion of the image in which no anatomic structure waspresent (6). Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated before and after con-trast material administration (6), as follows: SNR �SIduct/noise and CNR � (SIduct � SIliver)/noise, where SI is

the signal intensity. Subsequently, two readers (R.C.C.,Q.D.) independently rendered a qualitative assessment ofthe degree of biliary visualization by using a five-pointscale, where 1 � opacification and 5 � excellent opacifi-cation.

Statistical AnalysisChanges in CNR and SNR before and after contrast

material administration were compared by using the Stu-dent t test. Interobserver variability in the assessment ofbiliary visualization was estimated by using � analysis.

RESULTS

Contrast was identified within the biliary tree in allpatients after contrast material administration on imagesobtained after a 20-minute delay (Figs 1, 2).

The mean intrabiliary signal intensity (� standard de-viation) before contrast material administration was 8 � 7in the common bile duct, 8 � 8 in the right hepatic duct,and 7 � 5 in the left hepatic duct. Twenty minutes aftercontrast material administration, the mean signal intensity(� standard deviation) was 92 � 70 in the common bileduct, 92 � 70 in the right hepatic duct, and 83 � 61 inthe left hepatic duct. Changes in SNR and CNR after Gd-EOB-DTPA administration were tabulated (Table).

With the five-point scale, the average rating for biliaryvisualization was 4.7 for the common bile duct (� �0.43), 3.9 for the right hepatic duct (� � 0.59), and 4.1for the left hepatic duct (� � 0.84). Interobserver agree-ment was moderate to excellent across the biliary struc-tures evaluated.

We further evaluated the relationship between quantita-tive assessment of biliary enhancement and qualitativeassessment of biliary opacification. There was no correla-tion (r2 � 0.01) between measured ductal signal intensityand observer assessment of opacification, regardless ofstructure (Figs 3, 4). The results of qualitative assessmentof opacification were independent of the magnitude ofCNR and SNR, which is suggestive of the robustness ofthe technique.

DISCUSSION

Previous studies performed in humans to evaluatehepatobiliary enhancement and excretion of Gd-EOB-DTPA showed rapid early enhancement of the liver, withenhancement peaking 20 minutes after injection (1). He-

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patic signal intensity plateaus and then begins to decrease90 minutes after injection. In rhesus monkeys, hepaticenhancement peaked 4 minutes after injection and thenslowly declined (2). In both studies, the authors recom-mended a minimum delay of 20 minutes before liver im-aging (1,2). Biliary excretion was observed as early as 10minutes after contrast material administration (1,4); how-ever, peak contrast enhancement of the gallbladder wasdependent on the dose, occurring between 30 and 60 min-utes (1). In a smaller patient population without known ornot suspected to have biliary abnormalities, biliary opaci-fication was present 20 minutes after injection on the ba-sis of visual inspection (5). The degree of enhancement,however, was not quantitated. In our study, statisticallysignificant enhancement of the biliary tree occurred 20minutes after contrast material administration, with nostatistically significant difference in enhancement betweenthe right and left hepatic ducts and the common bile duct.

We evaluated biliary enhancement 20 minutes aftercontrast material administration, a delay that coincideswith previously reported time to peak hepatic enhance-ment (1,2); therefore, we performed additional qualitativeassessment of biliary opacification. Overall visual assess-ment of the biliary tree indicated good to excellent opaci-fication. Furthermore, the qualitative assessment of biliary

visualization was independent of the measured CNR andSNR, which suggests that residual hepatic enhancementdoes not interfere with biliary visualization.

The emerging literature suggests that MR imaging maybe sufficient as the sole imaging technique for compre-hensive hepatobiliary examination before hepatic trans-plantation (7,8), particularly when combined with a con-trast agent that permits both hepatic and biliary enhance-ment. Mangafodipir and Gd-EOB-DTPA similarly opacifythe liver and bile ducts and can potentially contribute tosingle-modality imaging of the hepatobiliary system. Gd-

CNR and SNR before and after Gd-EOB-DTPA Administration

Structure CNR SNR

Before Gd-EOB-DTPACommon bile duct �2 � 8 7 � 4Right hepatic duct �3 � 9 7 � 3Left hepatic duct �3 � 9 6 � 3

After Gd-EOB-DTPACommon bile duct 35 � 11 53 � 27Right hepatic duct 20 � 24 44 � 27Left hepatic duct 28 � 12 46 � 28

Note.—Changes in CNR and SNR after Gd-EOB-DTPA admin-istration were statistically significant (P � .0002).

Figure 1. Axial 1.5-mm reconstructions from the coronally ac-quired three-dimensional MR cholangiogram (a) before and (b) 20minutes after Gd-EOB-DTPA administration. Arrow indicates thecommon bile duct.

Figure 2. Oblique coronal maximum intensity pro-jection from a three-dimensional MR cholangiogramobtained 20 minutes after Gd-EOB-DTPA adminis-tration adequately demonstrates the biliary tree. G �gallbladder, open arrow � common bile duct, arrow-head � right hepatic duct, solid arrow � left hepaticduct.

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EOB-DTPA retains an advantage over mangafodipir be-cause it can be administered as a rapid bolus (� 2 mL/sec), enabling dynamic imaging of the liver (9) and po-tentially allowing isolation of the arterial and venousphases for full evaluation of the vascular anatomy. Theinjection rate approved by the U.S. Food and Drug Ad-ministration for mangafodipir, conversely, is limited toslow injection during 1 minute (10).

Before new imaging techniques or contrast agents areadopted, it must be proved that they contribute to diagnosticaccuracy, ease of interpretation, or clinical throughput. Thedemonstration of predictable biliary enhancement 20 minutesafter Gd-EOB-DTPA administration can assist protocol de-velopment and optimization and can potentially enhancepatient throughput in practices that are considering compre-hensive hepatobiliary imaging with MR imaging.

In conclusion, a 20-minute delay after intravenous ad-ministration of Gd-EOB-DTPA appears to be sufficientfor adequate biliary enhancement. There is no correlationbetween the qualitative assessment of biliary opacificationand standard quantitative measures of biliary signal inten-sity (eg, CNR or SNR).

REFERENCES

1. Hamm B, Staks T, Muhler A, et al. Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacoki-netics, and MR imaging. Radiology 1995; 195:785–792.

2. Runge VM. A comparison of two MR hepatobiliary gadoliniumchelates: Gd-BOPTA and Gd-EOB-DTPA. J Comput Assist Tomogr1998; 22:643–650.

3. Shuter B, Wang SC, Roche J, Briggs G, Pope JM. Relaxivity of Gd-EOB-DTPA in the normal and biliary obstructed guinea pig. J MagnReson Imaging 1998; 8:853–861. [Erratum: J Magn Reson Imaging1998; 8:1337.]

4. Clement O, Muhler A, Vexler V, Berthezene Y, Brasch RC. Gadolinium-ethoxybenzyl-DTPA, a new liver-specific magnetic resonance contrastagent: kinetic and enhancement patterns in normal and cholestaticrats. Invest Radiol 1992; 27:612–619.

5. Carlos RC, Hussain HK, Song JH, Francis IR. Gadolinium-ethoxyben-zyl-diethylenetriamine pentaacetic acid as an intrabiliary contrastagent: preliminary assessment. AJR Am J Roentgenol 2002; 179:87–92.

6. Coffin CM, Diche T, Mahfouz A, et al. Benign and malignant hepato-cellular tumors: evaluation of tumoral enhancement after mangafodipirtrisodium injection on MR imaging. Eur Radiol 1999; 9:444–449.

7. Earls JP, Bluemke DA. New MR imaging contrast agents. Magn ResonImaging Clin N Am 1999; 7:255–273.

8. Lee VS, Rofsky NM, Morgan GR, et al. Volumetric mangafodipir triso-dium–enhanced cholangiography to define intrahepatic biliary anat-omy. AJR Am J Roentgenol 2001; 176:906–908.

9. Stern W, Schick F, Kopp AF, et al. Dynamic MR imaging of liver me-tastases with Gd-EOB-DTPA. Acta Radiol 2000; 41:255–262.

10. Teslascan [package insert]. Roskilde, Denmark: Nycomed, 1999.

Figure 3. Graph shows results of qualitative assessment of bili-ary opacification as a function of SNR after Gd-EOB-DTPA ad-ministration. There was no correlation (r2 � 0.01) between SNRand degree of opacification. cbd � common bile duct, lhd � lefthepatic duct, rhd � right hepatic duct.

Figure 4. Graph shows results of qualitative assessment of bili-ary opacification as a function of CNR after Gd-EOB-DTPA ad-ministration. There was no correlation (r2 � 0.01) between CNRand degree of opacification. cbd � common bile duct, lhd � lefthepatic duct, rhd � right hepatic duct.

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