Clinical Radiology 69 (2014) 1027e1033
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Feasibility of gadoxetate disodium-enhanced MR cholangiography in chronic cholestatic biliary disease € hn a, *, M. Spoerl a, A. Nassif b, M. Mester a, W. Weitschies c, J.-P. Ku W. Siegmund b, N. Hosten a, B. Mensel a a
Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-SauerbruchStraße NK, Greifswald, D-17475, Germany b Department of Clinical Pharmacology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany c Department of Biopharmacy and Pharmaceutical Technology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany
art icl e i nformat ion Article history: Received 10 January 2014 Received in revised form 5 May 2014 Accepted 8 May 2014
AIM: To investigate the feasibility of gadoxetate disodium-enhanced magnetic resonance (MR) cholangiography in chronic obstructive cholestatic biliary disease in the clinical setting. MATERIALS AND METHODS: Twenty-three patients with dilated bile duct trees and ten volunteers underwent gadoxetate disodium-enhanced liver MR cholangiography and were enrolled in the present retrospective study. Gadoxetate disodium was given in a standardized manner as a bolus injection at a dose of 0.25 mmol/kg of body weight (0.1 ml/kg). Region of interest-based measurement of mean enhancement of the dilated bile ducts was performed in series before gadoxetate disodium administration and during hepatobiliary phases. RESULTS: Direct comparison of mean bile duct enhancement during hepatobiliary phases in the clinical imaging window between healthy volunteers [4.7 2.2 arbitrary units (au)] and patients with dilated bile ducts (0.1 0.3 au) revealed significantly lower or absent enhancement in dilated bile ducts (p ¼ 0.001). CONCLUSION: Standard clinical gadoxetate disodium-enhanced MR cholangiography is not a reliable technique for the evaluation of the biliary trees, because of altered biliary gadoxetate disodium elimination in patients with chronic obstructive biliary diseases. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction
€ hn, Department of Radiology and * Guarantor and correspondent: J.-P. Ku Neuroradiology, Experimental Radiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany. Tel.: þ49 3834 866960; fax: þ49 3834 867096. € hn). E-mail address: [email protected] (J.-P. Ku
Gadoxetate disodium is an established hepatocellular contrast agent characterized by biphasic liver enhancement1: early initial extracellular distribution is followed by selective uptake of the contrast agent into hepatocytes. Hepatocellular uptake may be impaired or even absent in patients with chronic liver disease or focal liver lesions. Therefore, the contrast-to-noise ratio during the
0009-9260/$ e see front matter Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2014.05.009
€ hn et al. / Clinical Radiology 69 (2014) 1027e1033 J.-P. Ku
1028
hepatobiliary phase of gadoxetate disodium, and hence, the detection of focal lesions, is dependent on the differences in uptake by healthy and injured liver tissue.2,3 In humans, gadoxetate disodium is eliminated in roughly equal amounts in bile and urine. Biliary excretion of gadoxetate disodium might be exploited diagnostically, e.g., for detection of biliary diseases by magnetic resonance (MR) cholangiography. Hepatobiliary enhancement by gadoxetate disodium should theoretically enable MR visualization of the bile duct system to obtain more specific diagnostic information regarding bile duct diseases.4 Several authors assume gadoxetate disodium-enhanced MR cholangiography to be a reliable tool for visualization of biliary anatomy, assessment of bile duct injury including leakage and stricture, evaluation of biliaryeenteric anastomoses, and detection of bile duct obstruction.4 In addition, Lee et al.4 also hypothesized that the amount of gadoxetate disodium appearing in bile ducts is highly dependent on the level of obstruction. However, to the authors’ knowledge, no systematic investigation of MR cholangiography using gadoxetate disodium in chronic obstructive bile duct disease has been published so far. Specific hepatocellular uptake of gadoxetate disodium is mediated by the liver-specific organic anion transporting polypeptides (OATP) 1B1 and 1B3 and the sodium taurocholate co-transporting polypeptide (NTCP).5 The adenosine triphosphate (ATP)-driven, highly affine multidrugresistance-related transporter protein ABCC2 (former name MRP2) secretes gadoxetate disodium through the hepatobiliary membrane into bile ducts, whereas the basolateral, lower affine ABCC3 (former name MRP3) may pump it back into the sinusoidal blood. If biliary secretion via ABCC2 is impaired, however, gadoxetate disodium is predominantly (back) secreted into the blood following upregulation of the basolateral ABCC3 as recently confirmed by experimental studies in ABCC2-deficient rats (GY/TR-), in which ABCC3 is overexpressed.6 These results indicate that there is a compensatory elimination route for gadoxetate disodium via blood and urine (ABCC3 pathway) when the biliary route (ABCC2 pathway) is impaired. Interestingly, ABCC2 is downregulated in rats with intrahepatic and obstructive cholestasis.7 Because of these experimental observations, there is considerable doubt that MR cholangiography using gadoxetate disodium can be used reliably in patients with chronic obstructive bile duct disease.
Therefore, the aim of the present study was to investigate the clinical feasibility of MR cholangiography in patients with chronic obstructive bile diseases.
Materials and methods In the present retrospective study, MR imaging was performed in the clinical setting in patients with a clinical indication for liver MR imaging and in a group of healthy participants included as controls in an earlier pharmacokinetic/pharmacogenomic MR imaging study.5 All participants gave written informed consent prior to the gadoxetate disodium-enhanced MR examination. The study was approved by the local ethics committee of Greifswald University Medicine Centre.
Healthy participants In a first step, biliary excretion in gadoxetate disodiumenhanced MR imaging in healthy controls was investigated. Ten participants (three males, seven females; age 25.5 2.3 years) with the wild-type genotype for known uptake transporter’s OATP1B1, 1B3, and the efflux transporter ABCC2 underwent a dynamic gadoxetate disodiumenhanced MR imaging examination. Liver and renal diseases were excluded by thorough medical history, physical examination, and routine clinical chemical and haematological screening. MR imaging was performed using a 1.5 T MR imaging system (Magnetom Symphony; Siemens Healthcare, Erlangen, Germany) using gadoxetate disodium at a standard concentration (0.025 mmol/kg body weight; 0.1 ml/kg body weight with a flow of 1 ml/s). MR imaging was performed, and mean enhancement of the common bile duct was analysed using unenhanced images and the hepatobiliary phases until 60 min after contrast medium injection. Imaging parameters of the dynamic MR imaging sequences are shown in Table 1.
Patients A retrospective analysis of 613 gadoxetate disodiumenhanced liver MR imaging examinations acquired since 2005 using a standard clinical protocol was performed to select patients with dilatation of the intrahepatic or central bile ducts. Bile duct dilatation was identified on T2weighted images acquired using this protocol. Bile ducts
Table 1 Imaging parameters of unenhanced and hepatobiliary contrast-enhanced sequences on different magnetic resonance imaging machines.
Scanner Cases Repetition time, ms Echo time, ms Flip angle Section thickness, mm Matrix Bandwidth, Hz/pixel
Volunteers
Patients (retrospective evaluation)
1.5 T Symphony 10 3.4 1.4 12 3 256 158 490
1.5 T Symphony 15 3.4 1.4 12 3 256 158 490
1.5 T Aera 6 3.5 1.4 15 3.5 256 209 455
1.5 T Avanto 1 5.5 2.4 10 4 256 131 250
3 T Verio 1 3.8 1.7 9 3 384 230 685
€ hn et al. / Clinical Radiology 69 (2014) 1027e1033 J.-P. Ku
were defined as dilated if the minimum diameter was >7 mm for extrahepatic bile ducts and >3 mm for the intrahepatic bile duct.8 MR examinations were performed using different machines (Magnetom Symphony, Magnetom Avanto, Magnetom Aera, Verio; all Siemens Healthcare) with a clinical standard protocol consisting of a dynamic volumetric interpolated breath-hold examination (VIBE), diffusion-weighted imaging, a T2-weighted sequence with fat separation, and additional VIBE sequences in the hepatobiliary phase. The unenhanced VIBE and contrastenhanced hepatobiliary VIBE images were always acquired using the same sequence parameters. Hepatobiliary phases were used to detect focal liver lesions and were mostly acquired 10e20 min after bolus injection of gadoxetate disodium (0.025 mmol/kg body weight; 0.1 ml/kg body weight with a flow of 1.0 ml/s). The acquisition parameters of unenhanced and hepatobiliary VIBE sequences are shown in Table 1.
Data evaluation In healthy participants, the signal intensity (SI) of the common bile duct was measured in regions of interest (ROIs) at the requisite time points using Osirix software (Osirix version 5; Bernex, Switzerland). The contrastenhanced common bile duct was first localized in the hepatobiliary contrast-enhanced series after 60 min and the first ROI was placed. ROI size was adjusted to the diameter of the measured bile duct and always
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Feasibility of gadoxetate disodium-enhanced MR cholangiography in chronic cholestatic biliary disease € hn a, *, M. Spoerl a, A. Nassif b, M. Mester a, W. Weitschies c, J.-P. Ku W. Siegmund b, N. Hosten a, B. Mensel a a
Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-SauerbruchStraße NK, Greifswald, D-17475, Germany b Department of Clinical Pharmacology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany c Department of Biopharmacy and Pharmaceutical Technology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany
art icl e i nformat ion Article history: Received 10 January 2014 Received in revised form 5 May 2014 Accepted 8 May 2014
AIM: To investigate the feasibility of gadoxetate disodium-enhanced magnetic resonance (MR) cholangiography in chronic obstructive cholestatic biliary disease in the clinical setting. MATERIALS AND METHODS: Twenty-three patients with dilated bile duct trees and ten volunteers underwent gadoxetate disodium-enhanced liver MR cholangiography and were enrolled in the present retrospective study. Gadoxetate disodium was given in a standardized manner as a bolus injection at a dose of 0.25 mmol/kg of body weight (0.1 ml/kg). Region of interest-based measurement of mean enhancement of the dilated bile ducts was performed in series before gadoxetate disodium administration and during hepatobiliary phases. RESULTS: Direct comparison of mean bile duct enhancement during hepatobiliary phases in the clinical imaging window between healthy volunteers [4.7 2.2 arbitrary units (au)] and patients with dilated bile ducts (0.1 0.3 au) revealed significantly lower or absent enhancement in dilated bile ducts (p ¼ 0.001). CONCLUSION: Standard clinical gadoxetate disodium-enhanced MR cholangiography is not a reliable technique for the evaluation of the biliary trees, because of altered biliary gadoxetate disodium elimination in patients with chronic obstructive biliary diseases. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction
€ hn, Department of Radiology and * Guarantor and correspondent: J.-P. Ku Neuroradiology, Experimental Radiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany. Tel.: þ49 3834 866960; fax: þ49 3834 867096. € hn). E-mail address: [email protected] (J.-P. Ku
Gadoxetate disodium is an established hepatocellular contrast agent characterized by biphasic liver enhancement1: early initial extracellular distribution is followed by selective uptake of the contrast agent into hepatocytes. Hepatocellular uptake may be impaired or even absent in patients with chronic liver disease or focal liver lesions. Therefore, the contrast-to-noise ratio during the
0009-9260/$ e see front matter Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.crad.2014.05.009
€ hn et al. / Clinical Radiology 69 (2014) 1027e1033 J.-P. Ku
1028
hepatobiliary phase of gadoxetate disodium, and hence, the detection of focal lesions, is dependent on the differences in uptake by healthy and injured liver tissue.2,3 In humans, gadoxetate disodium is eliminated in roughly equal amounts in bile and urine. Biliary excretion of gadoxetate disodium might be exploited diagnostically, e.g., for detection of biliary diseases by magnetic resonance (MR) cholangiography. Hepatobiliary enhancement by gadoxetate disodium should theoretically enable MR visualization of the bile duct system to obtain more specific diagnostic information regarding bile duct diseases.4 Several authors assume gadoxetate disodium-enhanced MR cholangiography to be a reliable tool for visualization of biliary anatomy, assessment of bile duct injury including leakage and stricture, evaluation of biliaryeenteric anastomoses, and detection of bile duct obstruction.4 In addition, Lee et al.4 also hypothesized that the amount of gadoxetate disodium appearing in bile ducts is highly dependent on the level of obstruction. However, to the authors’ knowledge, no systematic investigation of MR cholangiography using gadoxetate disodium in chronic obstructive bile duct disease has been published so far. Specific hepatocellular uptake of gadoxetate disodium is mediated by the liver-specific organic anion transporting polypeptides (OATP) 1B1 and 1B3 and the sodium taurocholate co-transporting polypeptide (NTCP).5 The adenosine triphosphate (ATP)-driven, highly affine multidrugresistance-related transporter protein ABCC2 (former name MRP2) secretes gadoxetate disodium through the hepatobiliary membrane into bile ducts, whereas the basolateral, lower affine ABCC3 (former name MRP3) may pump it back into the sinusoidal blood. If biliary secretion via ABCC2 is impaired, however, gadoxetate disodium is predominantly (back) secreted into the blood following upregulation of the basolateral ABCC3 as recently confirmed by experimental studies in ABCC2-deficient rats (GY/TR-), in which ABCC3 is overexpressed.6 These results indicate that there is a compensatory elimination route for gadoxetate disodium via blood and urine (ABCC3 pathway) when the biliary route (ABCC2 pathway) is impaired. Interestingly, ABCC2 is downregulated in rats with intrahepatic and obstructive cholestasis.7 Because of these experimental observations, there is considerable doubt that MR cholangiography using gadoxetate disodium can be used reliably in patients with chronic obstructive bile duct disease.
Therefore, the aim of the present study was to investigate the clinical feasibility of MR cholangiography in patients with chronic obstructive bile diseases.
Materials and methods In the present retrospective study, MR imaging was performed in the clinical setting in patients with a clinical indication for liver MR imaging and in a group of healthy participants included as controls in an earlier pharmacokinetic/pharmacogenomic MR imaging study.5 All participants gave written informed consent prior to the gadoxetate disodium-enhanced MR examination. The study was approved by the local ethics committee of Greifswald University Medicine Centre.
Healthy participants In a first step, biliary excretion in gadoxetate disodiumenhanced MR imaging in healthy controls was investigated. Ten participants (three males, seven females; age 25.5 2.3 years) with the wild-type genotype for known uptake transporter’s OATP1B1, 1B3, and the efflux transporter ABCC2 underwent a dynamic gadoxetate disodiumenhanced MR imaging examination. Liver and renal diseases were excluded by thorough medical history, physical examination, and routine clinical chemical and haematological screening. MR imaging was performed using a 1.5 T MR imaging system (Magnetom Symphony; Siemens Healthcare, Erlangen, Germany) using gadoxetate disodium at a standard concentration (0.025 mmol/kg body weight; 0.1 ml/kg body weight with a flow of 1 ml/s). MR imaging was performed, and mean enhancement of the common bile duct was analysed using unenhanced images and the hepatobiliary phases until 60 min after contrast medium injection. Imaging parameters of the dynamic MR imaging sequences are shown in Table 1.
Patients A retrospective analysis of 613 gadoxetate disodiumenhanced liver MR imaging examinations acquired since 2005 using a standard clinical protocol was performed to select patients with dilatation of the intrahepatic or central bile ducts. Bile duct dilatation was identified on T2weighted images acquired using this protocol. Bile ducts
Table 1 Imaging parameters of unenhanced and hepatobiliary contrast-enhanced sequences on different magnetic resonance imaging machines.
Scanner Cases Repetition time, ms Echo time, ms Flip angle Section thickness, mm Matrix Bandwidth, Hz/pixel
Volunteers
Patients (retrospective evaluation)
1.5 T Symphony 10 3.4 1.4 12 3 256 158 490
1.5 T Symphony 15 3.4 1.4 12 3 256 158 490
1.5 T Aera 6 3.5 1.4 15 3.5 256 209 455
1.5 T Avanto 1 5.5 2.4 10 4 256 131 250
3 T Verio 1 3.8 1.7 9 3 384 230 685
€ hn et al. / Clinical Radiology 69 (2014) 1027e1033 J.-P. Ku
were defined as dilated if the minimum diameter was >7 mm for extrahepatic bile ducts and >3 mm for the intrahepatic bile duct.8 MR examinations were performed using different machines (Magnetom Symphony, Magnetom Avanto, Magnetom Aera, Verio; all Siemens Healthcare) with a clinical standard protocol consisting of a dynamic volumetric interpolated breath-hold examination (VIBE), diffusion-weighted imaging, a T2-weighted sequence with fat separation, and additional VIBE sequences in the hepatobiliary phase. The unenhanced VIBE and contrastenhanced hepatobiliary VIBE images were always acquired using the same sequence parameters. Hepatobiliary phases were used to detect focal liver lesions and were mostly acquired 10e20 min after bolus injection of gadoxetate disodium (0.025 mmol/kg body weight; 0.1 ml/kg body weight with a flow of 1.0 ml/s). The acquisition parameters of unenhanced and hepatobiliary VIBE sequences are shown in Table 1.
Data evaluation In healthy participants, the signal intensity (SI) of the common bile duct was measured in regions of interest (ROIs) at the requisite time points using Osirix software (Osirix version 5; Bernex, Switzerland). The contrastenhanced common bile duct was first localized in the hepatobiliary contrast-enhanced series after 60 min and the first ROI was placed. ROI size was adjusted to the diameter of the measured bile duct and always
