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MR imaging of the biliary tract with Gd-EOB-DTPA: Effect of liver function on signal intensity
European Journal of Radiology 77 (2011) 325–329
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
MR imaging of the biliary tract with Gd-EOB-DTPA: Effect of liver function on signal intensity Hidemasa Takao a,∗ , Hiroyuki Akai a , Taku Tajima a , Shigeru Kiryu b , Yasushi Watanabe c , Hiroshi Imamura d , Masaaki Akahane a , Naoki Yoshioka a , Norihiro Kokudo e , Kuni Ohtomo a a
Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Radiology, Institute of Medical Science, University of Tokyo, 74-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Department of Radiological Technology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan d Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan e Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan b c
a r t i c l e
i n f o
Article history: Received 13 July 2009 Received in revised form 30 July 2009 Accepted 6 August 2009 Keywords: Gadoxetic acid Gd-EOB-DTPA Cholangiography Cholangiopancreatography Chronic liver disease Liver function
a b s t r a c t Objective: To quantitatively evaluate the signal intensity of the biliary tract in gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging and to investigate the effect of liver function on the signal intensity of the biliary tract. Materials and methods: A total of 32 patients with and without chronic liver disease (normal liver group, n = 15; chronic liver disease group, n = 17) were included in this study. All patients were prospectively enrolled for evaluation of known or suspected focal liver lesions. In the chronic liver disease group, the etiologies were chronic hepatitis C virus infection (n = 12) and chronic hepatitis B virus infection (n = 5). The median Child-Pugh score was 5 (range, 5–7). Each patient received the standard dose of Gd-EOBDTPA (0.025 mmol/kg of body weight). Post-contrast T1-weighted MR images were obtained at 5, 10, 15, 20, 25, and 30 min after administration of Gd-EOB-DTPA. Maximum signal intensities (SIs) of the right and left hepatic ducts, common hepatic duct, and common bile duct were measured. Relative signal intensity was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . Serum albumin level, serum total bilirubin level, prothrombin time, indocyanine green retention rate at 15 min (ICG-R15), and estimated glomerular filtration rate were entered into regression analysis. Results: The signal intensity of the bile duct reached a peak 30 min after administration of Gd-EOB-DTPA. The mean relative signal intensity of the right and left hepatic ducts at the peak time point was not significantly different between the two groups, while increase in signal intensity was delayed in the chronic liver disease group. The mean relative signal intensity of the common hepatic duct and that of the common bile duct at the peak time point were significantly different between the two groups (Wilcoxon rank-sum test, P = 0.03, respectively). Stepwise regression analysis revealed that ICG-R15 was a significant predictor of the signal intensity of the bile duct (right and left hepatic ducts, P = 0.04; common hepatic duct, P = 0.008; common bile duct, P = 0.003). Conclusions: The results of our study demonstrate that the presence of chronic liver disease significantly affects the signal intensity of the bile duct in Gd-EOB-DTPA-enhanced MR imaging. ICG-R15 was only a significant predictor of the signal intensity of the bile duct. The signal intensity of the bile duct may reflect underlying liver function. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is one hepatocyte-specific contrast agent that has the prolonged T1-shortening effect on liver parenchyma [1–3]. After injection, rapid and specific hepatocyte uptake with biliary excretion occurs in approximately 50% of the injected dose. As a
∗ Corresponding author. Tel.: +81 3 5800 8666; fax: +81 3 5800 8935. E-mail address: [email protected] (H. Takao). 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.08.008
result of hepatocyte uptake, normal areas of liver exhibit T1 shortening, whereas most focal liver lesions do not exhibit T1 shortening (except hepatocellular lesions such as focal nodular hyperplasia). Therefore, Gd-EOB-DTPA can be useful for the detection and characterization of liver lesions. Biliary excretion of Gd-EOB-DTPA provides positive intrabiliary contrast during T1-weighted imaging [4–10]. Magnetic resonance (MR) cholangiography can be potentially enhanced by using GdEOB-DTPA [5]. Only a few studies have been evaluated MR cholangiography with Gd-EOB-DTPA. Most of them qualitatively evaluated the biliary tract in subjects with normal liver function.
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H. Takao et al. / European Journal of Radiology 77 (2011) 325–329
The purpose of this study was to quantitatively evaluate the signal intensity of the biliary tract in Gd-EOB-DTPA-enhanced MR imaging and to investigate the effect of liver function on the signal intensity of the biliary tract. To our knowledge, this is the first study that quantitatively evaluated the effect of liver function on biliary excretion of Gd-EOB-DTPA. 2. Materials and methods 2.1. Patients A total of 32 patients (10 females and 22 males; mean age, 63.7 ± 11.2 years; age range, 37–88 years) with and without chronic liver disease (normal liver group, n = 15; chronic liver disease group, n = 17) were included in this study. All patients were prospectively enrolled for evaluation of known or suspected focal liver lesions. The patients’ characteristics are shown in Table 1. In the chronic liver disease group, the etiologies were chronic hepatitis C virus infection (n = 12) and chronic hepatitis B virus infection (n = 5). The Child-Pugh score was 5 (n = 11), 6 (n = 5), or 7 (n = 1). Patients were excluded if they had a history of segmental resection of the liver or hemi-hepatectomy, cholecystectomy, or transarterial hepatic chemoembolization/infusion or portal vein embolization within 2 months, if they had biliary duct dilatation, if they had non-B non-C hepatocellular carcinoma, or if they had renal dysfunction. The local ethical committee approved this study. After a complete explanation of the study to each subject, written informed consent was obtained. 2.2. MR imaging MR data were obtained on a 1.5-T scanner (Signa HDx; GE Medical Systems, Milwaukee, WI) with a 12-channel body phased array coil. Axial T1-weighted images were acquired using a fat-suppressed three-dimensional fast spoiled-gradient recalled echo sequence (LAVA, liver acceleration volume acquisition) (repetition time = 3.9 ms; echo time = 1.9 ms; inversion time = 8 ms; flip angle = 15◦ ; field of view = 350–450 mm; slice thickness = 5 mm; acquisition matrix = 320 × 160; number of excitations = 0.75; phase field of view = 0.80; acquisition time = 19 s; image matrix = 512 × 512; slice spacing = 2.5 mm). Parallel imaging (ASSET, array spatial sensitivity encoding technique) was not used. Each patient received the standard dose of Gd-EOB-DTPA (0.025 mmol/kg of body weight) as an intravenous bolus injection, which was administered at a rate of 2 mL/s. The bolus injection was followed by a 20-mL saline flush. Post-contrast T1-weighted images were obtained at 5, 10, 15, 20, 25, and 30 min after administration of Gd-EOB-DTPA. Fast spoiled gradient echo images, single-shot fast
spin echo images with short and long TE, T2-weighted fast spin echo images, diffusion-weighted images, and pre-contrast LAVA images were also obtained. 2.3. Image analysis Image analysis was performed by one board-certified radiologist, who was blinded to patients’ liver function. Maximum signal intensities (SIs) of the right and left hepatic ducts, common hepatic duct, and common bile duct were measured. Mean signal intensity of the right erector spinae muscle was measured using a circular region-of-interest (approximately 100 mm2 ) at the level of the porta hepatis. Relative signal intensity was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . If Gd-EOB-DTPA did not reach the bile duct, we assumed that the relative signal intensity was 0.5. 2.4. Statistical analysis In each group, we determined the time point when the mean relative signal intensity reached a peak. The mean relative signal intensity at each time point and that at the peak time point were compared using a Wilcoxon signed-rank test. Next, we compared the mean relative signal intensity at the peak time point between the two groups using a Wilcoxon rank-sum test. Finally, we evaluated which parameters influence the relative signal intensity at the peak time point, using stepwise regression analysis (P value to enter <0.25, P value to remove >0.25), including all patients of both groups. Serum albumin level, serum total bilirubin level, prothrombin time (international normalized ratio), indocyanine green retention rate at 15 min (ICG-R15), and estimated glomerular filtration rate (eGFR) [11] were entered into the analysis. Indocyanine green is a dye that is exclusively cleared by the liver and has been used to evaluate liver function. Child-Pugh classification alone is usually inadequate to select patients with sufficient hepatic reserve for resection. ICG-R15 is utilized as a defining criterion for selection of resection type by many groups (especially in Asia) [12]. All statistical analyses were performed using JMP 8.0 (SAS Institute, Cary, NC). A P value of <0.05 was considered to indicate a statistically significant difference. 3. Results Fig. 1 and Table 2 show the time courses of the mean relative signal intensities of the right and left hepatic ducts, common hepatic duct, and common bile duct in both groups. Each of them reached a peak 30 min after administration of Gd-EOB-DTPA. The
Table 1 Patient characteristics.
Age (yrs) Sexa Female Male Body weight (kg) Serum albumin (g/dL) Serum total bilirubin (mg/dL) Prothrombin time, international normalized ratio Indocyanine green retention rate at 15 min (%) Estimated glomerular filtration rate (mL/(min 1.73 m2 ))
Normal liver group
Chronic liver disease group
Mann–Whitney test
N = 15
N = 17
P value
60.5 ± 12.6 (37–88)
66.5 ± 9.3 (48–78)
0.09
6 9 58.6 ± 13.1 (39–85) 4.0 ± 0.4 0.7 ± 0.2 0.94 ± 0.03 7.4 ± 4.9 73.2 ± 15.2 (44.8–99.6)
Note: Unless otherwise specified, data are mean value ± standard deviation, with the range in parentheses. a Data are numbers of patients with the given characteristic.
4 13 60.0 ± 12.0 (38–83) 3.8 ± 0.4 1.1 ± 0.8 0.98 ± 0.06 21.6 ± 11.9 76.4 ± 16.6 (55.5–105.7)
0.79 0.18 0.09 0.06 0.0006 0.69
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Fig. 1. Relative signal intensities of the right and left hepatic ducts (A), common hepatic duct (B), and common bile duct (C) in both groups (solid lines, normal liver group; dotted lines, chronic liver disease group). Relative signal intensity (SI) was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . Error bars indicate standard deviation.
mean relative signal intensity of the right and left hepatic ducts at the peak time point (30 min after administration of Gd-EOB-DTPA) was not significantly different between the two groups (normal liver group, 3.45 ± 0.81; chronic liver disease group, 3.44 ± 1.36; Wilcoxon rank-sum test, P = 0.62), while increase in signal intensity was delayed in the chronic liver disease group. The mean relative signal intensity of the common hepatic duct and that of the common bile duct at the peak time point (30 min after administration of Gd-EOB-DTPA) were significantly different between the two groups ([common hepatic duct] normal liver group, 4.91 ± 1.04; chronic liver disease group, 4.21 ± 1.70; Wilcoxon rank-sum test, P = 0.03) ([common bile duct] normal liver group, 4.28 ± 1.16; chronic liver disease group, 3.35 ± 1.62; Wilcoxon rank-sum test, P = 0.03). Stepwise regression analysis revealed that ICG-R15 was a significant predictor of the signal intensity of the bile duct (right and left hepatic ducts, P = 0.04; common hepatic duct, P = 0.008; common bile duct, P = 0.003). No other parameters were significantly associated with the signal intensity of the bile duct. 4. Discussion In this study, we quantitatively evaluated the effect of liver function on the signal intensities of the right and left hepatic ducts, common hepatic duct, and common bile ducts. The presence of chronic liver disease significantly affected the signal intensity of
the bile duct. In our study patients, ICG-R15 was only a significant predictor of the signal intensity of the bile duct. After intravenous administration, Gd-EOB-DTPA is taken up by hepatocytes, and then excreted into the biliary tract. Gd-EOB-DTPA is eliminated nonmetabolized in approximately equal proportions by hepatobiliary excretion and glomerular filtration [1]. Alterations in hepatocyte function will affect hepatocyte uptake and biliary excretion of Gd-EOB-DTPA, which weaken contrast enhancement of the biliary tract. MR cholangiography can be potentially enhanced by using GdEOB-DTPA [5]. Biliary excretion of Gd-EOB-DTPA provides positive intrabiliary contrast during T1-wighted imaging [4–10]. There have been a few studies that evaluated MR cholangiography with GdEOB-DTPA. Bollow et al. [4] qualitatively evaluated the time course of contrast enhancement in bile ducts after administration of Gd-EOBDTPA. In a clinical phase I study, 16 healthy volunteers underwent MR imaging with four different doses of Gd-EOB-DTPA (0.10, 0.25, 0.50, and 1.0 mmol/kg; 4 subjects per dosage). In all 16 subjects, the common bile duct showed intense signal enhancement beginning 5–16 min after administration of Gd-EOB-DTPA (mean, 10 min). Carlos et al. [5] visually assessed the efficacy of Gd-EOB-DTPA in depicting biliary structures compared with T2-weighted MR cholangiography in 10 patients with known hepatic masses. Gd-
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Table 2 Relative signal intensities of the biliary tract. Time after administration of Gd-EOB-DTPA 5 min
10 min
15 min
20 min
25 min
30 min
0.50 0.00 <0.001
1.77 0.97 <0.001
2.84 0.81 <0.001
3.18 0.90 0.046
3.37 0.84 0.22
3.45 0.81 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
1.09 1.06 <0.001
2.30 1.46 <0.001
2.86 1.57 <0.001
3.26 1.40 0.005
3.44 1.36 –
0.50 0.00 <0.001
2.63 1.11 <0.001
3.97 1.02 <0.001
4.33 1.09 <0.001
4.79 1.00 0.19
4.91 1.04 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
1.58 1.25 <0.001
2.87 1.77 <0.001
3.58 1.85 <0.001
4.06 1.80 0.059
4.21 1.70 –
0.50 0.00 <0.001
1.79 1.30 <0.001
3.32 1.19 <0.001
3.90 1.18 0.010
4.22 1.19 0.59
4.28 1.16 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
0.84 0.68 <0.001
2.02 1.43 <0.001
2.84 1.52 <0.001
3.29 1.66 0.55
3.35 1.62 –
Right and left hepatic ducts Normal liver group Mean SD P value
Common hepatic duct Normal liver group Mean SD P value
Common bile duct Normal liver group Mean SD P value
Note: Relative signal intensity (SI) was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . In each group, the mean relative signal intensity at each time point and that at the peak time point were compared using a Wilcoxon signed-rank test. SD indicates standard deviation.
EOB-DTPA-enhanced MR cholangiography was obtained 20 min after administration of Gd-EOB-DTPA. Combining T2-weighted MR cholangiography and Gd-EOB-DTPA-enhanced MR cholangiography significantly improved biliary visualization over each test alone. Carlos et al. [6] quantitated the change in intrabiliary signal intensity 20 min after administration of Gd-EOB-DTPA in 16 patients with known hepatic masses. The signal intensities of the right and left hepatic ducts and common bile duct significantly increased after administration of Gd-EOB-DTPA. Average biliary visualization ratings were excellent, with moderate to excellent interobserver agreement. They concluded that a 20-min delay after administration of Gd-EOB-DTPA is sufficient for adequate biliary enhancement. Dahlström et al. [8] evaluated the biliary enhancement dynamics of Gd-EOB-DTPA and gadolinium benzyloxy-propionic tetraacetic acid (Gd-BOPTA) in 10 normal healthy subjects. The signal intensity of the common hepatic duct was measured. The biliary signal intensity rose at 10 min after administration of Gd-EOB-DTPA and decreased after 40 min. Tschirch et al. [9] assessed the quality of biliary duct visualization in Gd-EOB-DTPA-enhanced MR cholangiography in 40 patients with liver cirrhosis and 20 individuals with normal liver parenchyma. The grade of visualization of the bile duct was significantly different between the two groups. In MR cholangiography obtained 20 min after administration of Gd-EOB-DTPA, biliary visualization was sufficient in all subjects of the control group, but in only 16/40 patients of the cirrhosis group. In our study, the signal intensity of the bile duct reached a peak 30 min after administration of Gd-EOB-DTPA. This is compatible with previous reports [4,6,8]. Our patients with chronic liver disease had milder liver dysfunction than the patients in the study of Tschirch et al. [9]. However, the presence of chronic
liver disease significantly affected the signal intensity of the bile duct. The indocyanine green retention rate at 15 min has been reported to be a significant predictor of postoperative liver failure and mortality [12]. The safety limit of the hepatic parenchymal resection rate can be estimated using the ICG-R15 [12]. In our study, ICG-R15 was only a significant predictor of the signal intensity of the bile duct. No other parameters were significantly associated with the signal intensity of the bile duct. The signal intensity of the bile duct may reflect underlying liver function. There are several limitations to our study. First, the number of patients was relatively small. Next, in this study, MR images were obtained up to 30 min after administration of Gd-EOB-DTPA, and the mean relative signal intensities of the biliary tract reached a peak 30 min after administration of Gd-EOB-DTPA. This is compatible with previous reports [4,6,8]; however, there is a possibility that the time to peak was longer than 30 min (especially in the chronic liver disease group). In each group, however, the differences between the signal intensities at 25 and 30 min were small. In the study of Tschirch et al. [9], biliary duct visualization in Gd-EOBDTPA-enhanced MR cholangiography was qualitatively evaluated in patients with liver cirrhosis. The patients with insufficient visualization of the biliary tract within 30 min were followed up to 180 min. In most patients, the visualization of the biliary tract remained insufficient. Their patients had more severe liver dysfunction than the patients in our study. An increase in signal intensity after 30 min will be small, if any. In conclusion, the results of our study demonstrate that the presence of chronic liver disease significantly affects the signal intensity of the bile duct in Gd-EOB-DTPA-enhanced MR imaging. ICG-R15 was only a significant predictor of the signal intensity of the bile duct. The signal intensity of the bile duct will reflect underlying liver function.
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References [1] Hamm B, Staks T, Mühler A, et al. Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology 1995;195(3):785–92. [2] Reimer P, Rummeny EJ, Shamsi K, et al. Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology 1996;199(1):177–83. [3] Bluemke DA, Sahani D, Amendola M, et al. Efficacy and safety of MR imaging with liver-specific contrast agent: U.S. multicenter phase III study. Radiology 2005;237(1):89–98. [4] Bollow M, Taupitz M, Hamm B, Staks T, Wolf KJ, Weinmann HJ. Gadoliniumethoxybenzyl-DTPA as a hepatobiliary contrast agent for use in MR cholangiography: results of an in vivo phase-I clinical evaluation. Eur Radiol 1997;7(1):126–32. [5] Carlos RC, Hussain HK, Song JH, Francis IR. Gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid as an intrabiliary contrast agent: preliminary assessment. Am J Roentgenol 2002;179(1):87–92. [6] Carlos RC, Branam JD, Dong Q, Hussain HK, Francis IR. Biliary imaging with GdEOB-DTPA: is a 20-minute delay sufficient? Acad Radiol 2002;9(11):1322–5.
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[7] Zizka J, Klzo L, Ferda J, Mrklovsky´ M, Bukac J. Dynamic and delayed contrast enhancement in upper abdominal MRI studies: comparison of gadoxetic acid and gadobutrol. Eur J Radiol 2007;62(2):186–91. [8] Dahlström N, Persson A, Albiin N, Smedby O, Brismar TB. Contrast-enhanced magnetic resonance cholangiography with Gd-BOPTA and Gd-EOB-DTPA in healthy subjects. Acta Radiol 2007;48(4):362–8. [9] Tschirch FT, Struwe A, Petrowsky H, Kakales I, Marincek B, Weishaupt D. Contrast-enhanced MR cholangiography with Gd-EOB-DTPA in patients with liver cirrhosis: visualization of the biliary ducts in comparison with patients with normal liver parenchyma. Eur Radiol 2008;18(8):1577– 86. [10] Asbach P, Warmuth C, Stemmer A, et al. High spatial resolution T1-weighted MR imaging of liver and biliary tract during uptake phase of a hepatocyte-specific contrast medium. Invest Radiol 2008;43(11):809–15. [11] Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53(6):982–92. [12] Seyama Y, Kokudo N. Assessment of liver function for safe hepatic resection. Hepatol Res 2009;39(2):107–16.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
MR imaging of the biliary tract with Gd-EOB-DTPA: Effect of liver function on signal intensity Hidemasa Takao a,∗ , Hiroyuki Akai a , Taku Tajima a , Shigeru Kiryu b , Yasushi Watanabe c , Hiroshi Imamura d , Masaaki Akahane a , Naoki Yoshioka a , Norihiro Kokudo e , Kuni Ohtomo a a
Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Radiology, Institute of Medical Science, University of Tokyo, 74-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Department of Radiological Technology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan d Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan e Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan b c
a r t i c l e
i n f o
Article history: Received 13 July 2009 Received in revised form 30 July 2009 Accepted 6 August 2009 Keywords: Gadoxetic acid Gd-EOB-DTPA Cholangiography Cholangiopancreatography Chronic liver disease Liver function
a b s t r a c t Objective: To quantitatively evaluate the signal intensity of the biliary tract in gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging and to investigate the effect of liver function on the signal intensity of the biliary tract. Materials and methods: A total of 32 patients with and without chronic liver disease (normal liver group, n = 15; chronic liver disease group, n = 17) were included in this study. All patients were prospectively enrolled for evaluation of known or suspected focal liver lesions. In the chronic liver disease group, the etiologies were chronic hepatitis C virus infection (n = 12) and chronic hepatitis B virus infection (n = 5). The median Child-Pugh score was 5 (range, 5–7). Each patient received the standard dose of Gd-EOBDTPA (0.025 mmol/kg of body weight). Post-contrast T1-weighted MR images were obtained at 5, 10, 15, 20, 25, and 30 min after administration of Gd-EOB-DTPA. Maximum signal intensities (SIs) of the right and left hepatic ducts, common hepatic duct, and common bile duct were measured. Relative signal intensity was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . Serum albumin level, serum total bilirubin level, prothrombin time, indocyanine green retention rate at 15 min (ICG-R15), and estimated glomerular filtration rate were entered into regression analysis. Results: The signal intensity of the bile duct reached a peak 30 min after administration of Gd-EOB-DTPA. The mean relative signal intensity of the right and left hepatic ducts at the peak time point was not significantly different between the two groups, while increase in signal intensity was delayed in the chronic liver disease group. The mean relative signal intensity of the common hepatic duct and that of the common bile duct at the peak time point were significantly different between the two groups (Wilcoxon rank-sum test, P = 0.03, respectively). Stepwise regression analysis revealed that ICG-R15 was a significant predictor of the signal intensity of the bile duct (right and left hepatic ducts, P = 0.04; common hepatic duct, P = 0.008; common bile duct, P = 0.003). Conclusions: The results of our study demonstrate that the presence of chronic liver disease significantly affects the signal intensity of the bile duct in Gd-EOB-DTPA-enhanced MR imaging. ICG-R15 was only a significant predictor of the signal intensity of the bile duct. The signal intensity of the bile duct may reflect underlying liver function. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is one hepatocyte-specific contrast agent that has the prolonged T1-shortening effect on liver parenchyma [1–3]. After injection, rapid and specific hepatocyte uptake with biliary excretion occurs in approximately 50% of the injected dose. As a
∗ Corresponding author. Tel.: +81 3 5800 8666; fax: +81 3 5800 8935. E-mail address: [email protected] (H. Takao). 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.08.008
result of hepatocyte uptake, normal areas of liver exhibit T1 shortening, whereas most focal liver lesions do not exhibit T1 shortening (except hepatocellular lesions such as focal nodular hyperplasia). Therefore, Gd-EOB-DTPA can be useful for the detection and characterization of liver lesions. Biliary excretion of Gd-EOB-DTPA provides positive intrabiliary contrast during T1-weighted imaging [4–10]. Magnetic resonance (MR) cholangiography can be potentially enhanced by using GdEOB-DTPA [5]. Only a few studies have been evaluated MR cholangiography with Gd-EOB-DTPA. Most of them qualitatively evaluated the biliary tract in subjects with normal liver function.
326
H. Takao et al. / European Journal of Radiology 77 (2011) 325–329
The purpose of this study was to quantitatively evaluate the signal intensity of the biliary tract in Gd-EOB-DTPA-enhanced MR imaging and to investigate the effect of liver function on the signal intensity of the biliary tract. To our knowledge, this is the first study that quantitatively evaluated the effect of liver function on biliary excretion of Gd-EOB-DTPA. 2. Materials and methods 2.1. Patients A total of 32 patients (10 females and 22 males; mean age, 63.7 ± 11.2 years; age range, 37–88 years) with and without chronic liver disease (normal liver group, n = 15; chronic liver disease group, n = 17) were included in this study. All patients were prospectively enrolled for evaluation of known or suspected focal liver lesions. The patients’ characteristics are shown in Table 1. In the chronic liver disease group, the etiologies were chronic hepatitis C virus infection (n = 12) and chronic hepatitis B virus infection (n = 5). The Child-Pugh score was 5 (n = 11), 6 (n = 5), or 7 (n = 1). Patients were excluded if they had a history of segmental resection of the liver or hemi-hepatectomy, cholecystectomy, or transarterial hepatic chemoembolization/infusion or portal vein embolization within 2 months, if they had biliary duct dilatation, if they had non-B non-C hepatocellular carcinoma, or if they had renal dysfunction. The local ethical committee approved this study. After a complete explanation of the study to each subject, written informed consent was obtained. 2.2. MR imaging MR data were obtained on a 1.5-T scanner (Signa HDx; GE Medical Systems, Milwaukee, WI) with a 12-channel body phased array coil. Axial T1-weighted images were acquired using a fat-suppressed three-dimensional fast spoiled-gradient recalled echo sequence (LAVA, liver acceleration volume acquisition) (repetition time = 3.9 ms; echo time = 1.9 ms; inversion time = 8 ms; flip angle = 15◦ ; field of view = 350–450 mm; slice thickness = 5 mm; acquisition matrix = 320 × 160; number of excitations = 0.75; phase field of view = 0.80; acquisition time = 19 s; image matrix = 512 × 512; slice spacing = 2.5 mm). Parallel imaging (ASSET, array spatial sensitivity encoding technique) was not used. Each patient received the standard dose of Gd-EOB-DTPA (0.025 mmol/kg of body weight) as an intravenous bolus injection, which was administered at a rate of 2 mL/s. The bolus injection was followed by a 20-mL saline flush. Post-contrast T1-weighted images were obtained at 5, 10, 15, 20, 25, and 30 min after administration of Gd-EOB-DTPA. Fast spoiled gradient echo images, single-shot fast
spin echo images with short and long TE, T2-weighted fast spin echo images, diffusion-weighted images, and pre-contrast LAVA images were also obtained. 2.3. Image analysis Image analysis was performed by one board-certified radiologist, who was blinded to patients’ liver function. Maximum signal intensities (SIs) of the right and left hepatic ducts, common hepatic duct, and common bile duct were measured. Mean signal intensity of the right erector spinae muscle was measured using a circular region-of-interest (approximately 100 mm2 ) at the level of the porta hepatis. Relative signal intensity was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . If Gd-EOB-DTPA did not reach the bile duct, we assumed that the relative signal intensity was 0.5. 2.4. Statistical analysis In each group, we determined the time point when the mean relative signal intensity reached a peak. The mean relative signal intensity at each time point and that at the peak time point were compared using a Wilcoxon signed-rank test. Next, we compared the mean relative signal intensity at the peak time point between the two groups using a Wilcoxon rank-sum test. Finally, we evaluated which parameters influence the relative signal intensity at the peak time point, using stepwise regression analysis (P value to enter <0.25, P value to remove >0.25), including all patients of both groups. Serum albumin level, serum total bilirubin level, prothrombin time (international normalized ratio), indocyanine green retention rate at 15 min (ICG-R15), and estimated glomerular filtration rate (eGFR) [11] were entered into the analysis. Indocyanine green is a dye that is exclusively cleared by the liver and has been used to evaluate liver function. Child-Pugh classification alone is usually inadequate to select patients with sufficient hepatic reserve for resection. ICG-R15 is utilized as a defining criterion for selection of resection type by many groups (especially in Asia) [12]. All statistical analyses were performed using JMP 8.0 (SAS Institute, Cary, NC). A P value of <0.05 was considered to indicate a statistically significant difference. 3. Results Fig. 1 and Table 2 show the time courses of the mean relative signal intensities of the right and left hepatic ducts, common hepatic duct, and common bile duct in both groups. Each of them reached a peak 30 min after administration of Gd-EOB-DTPA. The
Table 1 Patient characteristics.
Age (yrs) Sexa Female Male Body weight (kg) Serum albumin (g/dL) Serum total bilirubin (mg/dL) Prothrombin time, international normalized ratio Indocyanine green retention rate at 15 min (%) Estimated glomerular filtration rate (mL/(min 1.73 m2 ))
Normal liver group
Chronic liver disease group
Mann–Whitney test
N = 15
N = 17
P value
60.5 ± 12.6 (37–88)
66.5 ± 9.3 (48–78)
0.09
6 9 58.6 ± 13.1 (39–85) 4.0 ± 0.4 0.7 ± 0.2 0.94 ± 0.03 7.4 ± 4.9 73.2 ± 15.2 (44.8–99.6)
Note: Unless otherwise specified, data are mean value ± standard deviation, with the range in parentheses. a Data are numbers of patients with the given characteristic.
4 13 60.0 ± 12.0 (38–83) 3.8 ± 0.4 1.1 ± 0.8 0.98 ± 0.06 21.6 ± 11.9 76.4 ± 16.6 (55.5–105.7)
0.79 0.18 0.09 0.06 0.0006 0.69
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Fig. 1. Relative signal intensities of the right and left hepatic ducts (A), common hepatic duct (B), and common bile duct (C) in both groups (solid lines, normal liver group; dotted lines, chronic liver disease group). Relative signal intensity (SI) was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . Error bars indicate standard deviation.
mean relative signal intensity of the right and left hepatic ducts at the peak time point (30 min after administration of Gd-EOB-DTPA) was not significantly different between the two groups (normal liver group, 3.45 ± 0.81; chronic liver disease group, 3.44 ± 1.36; Wilcoxon rank-sum test, P = 0.62), while increase in signal intensity was delayed in the chronic liver disease group. The mean relative signal intensity of the common hepatic duct and that of the common bile duct at the peak time point (30 min after administration of Gd-EOB-DTPA) were significantly different between the two groups ([common hepatic duct] normal liver group, 4.91 ± 1.04; chronic liver disease group, 4.21 ± 1.70; Wilcoxon rank-sum test, P = 0.03) ([common bile duct] normal liver group, 4.28 ± 1.16; chronic liver disease group, 3.35 ± 1.62; Wilcoxon rank-sum test, P = 0.03). Stepwise regression analysis revealed that ICG-R15 was a significant predictor of the signal intensity of the bile duct (right and left hepatic ducts, P = 0.04; common hepatic duct, P = 0.008; common bile duct, P = 0.003). No other parameters were significantly associated with the signal intensity of the bile duct. 4. Discussion In this study, we quantitatively evaluated the effect of liver function on the signal intensities of the right and left hepatic ducts, common hepatic duct, and common bile ducts. The presence of chronic liver disease significantly affected the signal intensity of
the bile duct. In our study patients, ICG-R15 was only a significant predictor of the signal intensity of the bile duct. After intravenous administration, Gd-EOB-DTPA is taken up by hepatocytes, and then excreted into the biliary tract. Gd-EOB-DTPA is eliminated nonmetabolized in approximately equal proportions by hepatobiliary excretion and glomerular filtration [1]. Alterations in hepatocyte function will affect hepatocyte uptake and biliary excretion of Gd-EOB-DTPA, which weaken contrast enhancement of the biliary tract. MR cholangiography can be potentially enhanced by using GdEOB-DTPA [5]. Biliary excretion of Gd-EOB-DTPA provides positive intrabiliary contrast during T1-wighted imaging [4–10]. There have been a few studies that evaluated MR cholangiography with GdEOB-DTPA. Bollow et al. [4] qualitatively evaluated the time course of contrast enhancement in bile ducts after administration of Gd-EOBDTPA. In a clinical phase I study, 16 healthy volunteers underwent MR imaging with four different doses of Gd-EOB-DTPA (0.10, 0.25, 0.50, and 1.0 mmol/kg; 4 subjects per dosage). In all 16 subjects, the common bile duct showed intense signal enhancement beginning 5–16 min after administration of Gd-EOB-DTPA (mean, 10 min). Carlos et al. [5] visually assessed the efficacy of Gd-EOB-DTPA in depicting biliary structures compared with T2-weighted MR cholangiography in 10 patients with known hepatic masses. Gd-
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Table 2 Relative signal intensities of the biliary tract. Time after administration of Gd-EOB-DTPA 5 min
10 min
15 min
20 min
25 min
30 min
0.50 0.00 <0.001
1.77 0.97 <0.001
2.84 0.81 <0.001
3.18 0.90 0.046
3.37 0.84 0.22
3.45 0.81 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
1.09 1.06 <0.001
2.30 1.46 <0.001
2.86 1.57 <0.001
3.26 1.40 0.005
3.44 1.36 –
0.50 0.00 <0.001
2.63 1.11 <0.001
3.97 1.02 <0.001
4.33 1.09 <0.001
4.79 1.00 0.19
4.91 1.04 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
1.58 1.25 <0.001
2.87 1.77 <0.001
3.58 1.85 <0.001
4.06 1.80 0.059
4.21 1.70 –
0.50 0.00 <0.001
1.79 1.30 <0.001
3.32 1.19 <0.001
3.90 1.18 0.010
4.22 1.19 0.59
4.28 1.16 –
Chronic liver disease group Mean 0.50 SD 0.00 P value <0.001
0.84 0.68 <0.001
2.02 1.43 <0.001
2.84 1.52 <0.001
3.29 1.66 0.55
3.35 1.62 –
Right and left hepatic ducts Normal liver group Mean SD P value
Common hepatic duct Normal liver group Mean SD P value
Common bile duct Normal liver group Mean SD P value
Note: Relative signal intensity (SI) was calculated as follows: relative SI = maximum SIbile duct /mean SImuscle . In each group, the mean relative signal intensity at each time point and that at the peak time point were compared using a Wilcoxon signed-rank test. SD indicates standard deviation.
EOB-DTPA-enhanced MR cholangiography was obtained 20 min after administration of Gd-EOB-DTPA. Combining T2-weighted MR cholangiography and Gd-EOB-DTPA-enhanced MR cholangiography significantly improved biliary visualization over each test alone. Carlos et al. [6] quantitated the change in intrabiliary signal intensity 20 min after administration of Gd-EOB-DTPA in 16 patients with known hepatic masses. The signal intensities of the right and left hepatic ducts and common bile duct significantly increased after administration of Gd-EOB-DTPA. Average biliary visualization ratings were excellent, with moderate to excellent interobserver agreement. They concluded that a 20-min delay after administration of Gd-EOB-DTPA is sufficient for adequate biliary enhancement. Dahlström et al. [8] evaluated the biliary enhancement dynamics of Gd-EOB-DTPA and gadolinium benzyloxy-propionic tetraacetic acid (Gd-BOPTA) in 10 normal healthy subjects. The signal intensity of the common hepatic duct was measured. The biliary signal intensity rose at 10 min after administration of Gd-EOB-DTPA and decreased after 40 min. Tschirch et al. [9] assessed the quality of biliary duct visualization in Gd-EOB-DTPA-enhanced MR cholangiography in 40 patients with liver cirrhosis and 20 individuals with normal liver parenchyma. The grade of visualization of the bile duct was significantly different between the two groups. In MR cholangiography obtained 20 min after administration of Gd-EOB-DTPA, biliary visualization was sufficient in all subjects of the control group, but in only 16/40 patients of the cirrhosis group. In our study, the signal intensity of the bile duct reached a peak 30 min after administration of Gd-EOB-DTPA. This is compatible with previous reports [4,6,8]. Our patients with chronic liver disease had milder liver dysfunction than the patients in the study of Tschirch et al. [9]. However, the presence of chronic
liver disease significantly affected the signal intensity of the bile duct. The indocyanine green retention rate at 15 min has been reported to be a significant predictor of postoperative liver failure and mortality [12]. The safety limit of the hepatic parenchymal resection rate can be estimated using the ICG-R15 [12]. In our study, ICG-R15 was only a significant predictor of the signal intensity of the bile duct. No other parameters were significantly associated with the signal intensity of the bile duct. The signal intensity of the bile duct may reflect underlying liver function. There are several limitations to our study. First, the number of patients was relatively small. Next, in this study, MR images were obtained up to 30 min after administration of Gd-EOB-DTPA, and the mean relative signal intensities of the biliary tract reached a peak 30 min after administration of Gd-EOB-DTPA. This is compatible with previous reports [4,6,8]; however, there is a possibility that the time to peak was longer than 30 min (especially in the chronic liver disease group). In each group, however, the differences between the signal intensities at 25 and 30 min were small. In the study of Tschirch et al. [9], biliary duct visualization in Gd-EOBDTPA-enhanced MR cholangiography was qualitatively evaluated in patients with liver cirrhosis. The patients with insufficient visualization of the biliary tract within 30 min were followed up to 180 min. In most patients, the visualization of the biliary tract remained insufficient. Their patients had more severe liver dysfunction than the patients in our study. An increase in signal intensity after 30 min will be small, if any. In conclusion, the results of our study demonstrate that the presence of chronic liver disease significantly affects the signal intensity of the bile duct in Gd-EOB-DTPA-enhanced MR imaging. ICG-R15 was only a significant predictor of the signal intensity of the bile duct. The signal intensity of the bile duct will reflect underlying liver function.
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