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Primovist, Eovist: What to expect?

  • Bernard E. Van Beers
    Correspondence
    Corresponding author. Address: Service de Radiologie et IPMA, INSERM U773, Hôpital Beaujon, Université Paris Diderot, 100 Boulevard du Général Leclerc, 92110 Clichy, France. Tel.: +33 1 40 87 56 54; fax: +33 1 40 87 44 77.
    Affiliations
    Laboratoire d’Imagerie Physiologique et Moléculaire de l’Abdomen (IPMA) et Service de Radiologie, Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR 773, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, Clichy, France
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  • Catherine M. Pastor
    Affiliations
    Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Switzerland
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  • Hero K. Hussain
    Affiliations
    Department of Radiology, University of Michigan, Ann Arbor, USA
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Open AccessPublished:April 13, 2012DOI:https://doi.org/10.1016/j.jhep.2012.01.031

      Summary

      Gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA, Primovist® in Europe and Eovist® in the USA) is a liver-specific magnetic resonance imaging contrast agent that has up to 50% hepatobiliary excretion in the normal liver. After intravenous injection, Gd-EOB-DTPA distributes into the vascular and extravascular spaces during the arterial, portal venous and late dynamic phases, and progressively into the hepatocytes and bile ducts during the hepatobiliary phase. The hepatocyte uptake of Gd-EOB-DTPA mainly occurs via the organic anion transporter polypeptides OATP1B1 and B3 located at the sinusoidal membrane and biliary excretion via the multidrug resistance-associated proteins MRP2 at the canalicular membrane. Because of these characteristics, Gd-EOB-DTPA behaves similarly to non-specific gadolinium chelates during the dynamic phases, and adds substantial information during the hepatobiliary phase, improving the detection and characterization of focal liver lesions and diffuse liver disease. This information is particularly relevant for the detection of metastases, and for the detection and characterization of nodular lesions in liver cirrhosis, including early hepatocellular carcinomas. Finally, GD-EOB-DTPA-enhanced magnetic resonance imaging may provide quantitative assessment regarding liver perfusion and hepatocyte function in diffuse liver diseases. The full potential of GD-EOB-DTPA-enhanced magnetic resonance imaging has to be established further. It is already clear that GD-EOB-DTPA-enhanced magnetic resonance imaging provides anatomic and functional information in the setting of focal and diffuse liver disease that is unattainable with magnetic resonance imaging enhanced with non-specific contrast agents.

      Abbreviations:

      ABC (ATP-binding cassette), CCC (cholangiocarcinoma), CT (computed tomography), FNH (focal nodular hyperplasia), Gd-BOPTA (gadobenate dimeglumine), Gd-DO3A-butrol (gadobutrol), Gd-DOTA (gadoterate dimeglumine), Gd-EOB-DTPA (gadolinium ethoxybenzyl dimeglumine), Gd-DTPA (gadopentetate dimeglumine), HA (hepatocellular adenoma), HCC (hepatocellular carcinoma), ICG (indocyanin green), MELD (Mayo end-stage liver disease), MR (magnetic resonance), MRP (multidrug resistance protein), NTCP (sodium taurocholate-cotransporting polypeptide), OATP (organic anion transporter), SCTO (solute carrier transporter family of the OATPs), TIPS (transjugular intrahepatic portosystemic shunt)

      Keywords

      Introduction

      Magnetic resonance (MR) imaging has an important role in the detection and characterization of focal and diffuse liver diseases. Contrast agents improve the detection of focal liver lesions by increasing the lesion-to-liver contrast. Depending on their pharmacokinetics, contrast agents also improve the characterization of focal and diffuse liver diseases by showing changes in the vascular, extracellular, or intracellular volumes, and by demonstrating modifications in the transfer rates between these compartments, including perfusion, endothelial permeability, extracellular diffusion, hepatocytic uptake and biliary excretion [
      • Van Beers B.E.
      • Gallez B.
      • Pringot J.
      Contrast-enhanced MR imaging of the liver.
      ]. These volumes and transfer rates can be quantified at contrast-enhanced MR imaging, which has thus the potential to offer imaging biomarkers for the assessment of liver diseases [
      • Van Beers B.E.
      • Vilgrain V.
      Biomarkers in abdominal imaging.
      ].
      In the liver, contrast agents are categorized into non-specific agents that distribute into the vascular and extravascular extracellular spaces (such as the linear gadopentetate dimeglumine (Gd-DTPA), Magnevist®, Bayer HealthCare, Berlin, Germany; and the macrocyclic gadobutrol (Gd-DO3A-butrol), Gadovist®, Bayer HealthCare, and gadoterate dimeglumine (Gd-DOTA), Dotarem®, Guerbet, Aulnay-sous-Bois, France) and liver-specific agents taken up by liver cells. These liver-specific agents are either taken up by Kupffer cells (such as the superparamagnetic iron oxide particles ferumoxides, Endorem®, Guerbet; and ferucarbotran, Resovist®, Bayer HealthCare) or by hepatocytes (such as gadolinium ethoxybenzyl dimeglumine or gadoxetate dimeglumine (Gd-EOB-DTPA), Primovist® in Europe and Eovist® in the USA, Bayer HealthCare; and gadobenate dimeglumine (Gd-BOPTA), MultiHance®, Bracco, Milan, Italy). Gd-EOB-DTPA and Gd-BOPTA can be injected as an intravenous bolus and provide information regarding lesion vascularity in the early arterial and venous phases and regarding hepatocyte presence and function in the delayed hepatobiliary phase performed either 20 min (Gd-EOB-DTPA) or 60–120 min (Gd-BOPTA) after injection. With Gd-EOB-DTPA, approximately 50% of the administered dose in the normal human liver is transported through the hepatocytes and excreted into the bile, a proportion much higher than that of Gd-BOPTA, which only has up to 5% hepatobiliary excretion [
      • Reimer P.
      • Schneider G.
      • Schima W.
      Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications.
      ].
      The percentage of the contrast agent that is not cleared by the hepatobiliary system is excreted by glomerular filtration in the kidneys. The plasma half life of Gd-EOB-DTPA is approximately 56 min in subjects with normal hepatorenal function, which is shorter compared to extracellular contrast agents (e.g. Gd-DTPA 96 min) [
      • Ringe K.I.
      • Husarik D.B.
      • Sirlin C.B.
      • Merkle E.M.
      Gadoxetate disodium-enhanced MRI of the liver: part 1, protocol optimization and lesion appearance in the noncirrhotic liver.
      ]. A study by Gschwend et al. assessing the pharmacokinetics and safety of Gd-EOB-DTPA in patients with renal failure, hepatic failure or both showed that in patients with mild-to-moderate hepatic impairment, renal excretion was increased to compensate for hepatic impairment, and hepatic elimination was increased in the case of renal impairment [
      • Gschwend S.
      • Ebert W.
      • Schultze-Mosgau M.
      • Breuer J.
      Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment.
      ]. The pharmacokinetic parameters of Gd-EOB-DTPA were markedly altered in patients with end-stage renal disease requiring chronic hemodialysis only, and the MR imaging signal enhancement of the liver was decreased in the presence of Child C and bilirubin values >3 g/dl.

      Characteristics of Gd-EOB-DTPA

      Gd-EOB DTPA is an amphipathic derivative of Gd-DTPA (Gd-DTPA with a covalently bound lipophilic ethoxybenzyl moiety). It has a molecular weight of 726 daltons and higher protein binding capacity than Gd-DTPA (10% vs. 1.5%). This binding increases the T1 relaxivity of Gd-EOB DTPA and resultant signal enhancement in blood and liver compared to Gd-DTPA. It has been reported that the T1 relaxivity of Gd-EOB-DTPA in water, rat blood and rat liver at 20 MHz and 39 °C is 5.3 L/mmol s, 11.2 L/mmol s and 16.6 L/mmol s respectively, compared to a relatively constant relaxivity of Gd-DTPA at 5 L/mmol s in the same conditions [
      • Schuhmann-Giampieri G.
      • Schmitt-Willich H.
      • Press W.R.
      • Negishi C.
      • Weinmann H.J.
      • Speck U.
      Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system.
      ,
      • Rohrer M.
      • Bauer H.
      • Mintorovitch J.
      • Requardt M.
      • Weinmann H.J.
      Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths.
      ]. This high relaxivity explains the lower clinical recommended dose of Gd-EOB-DTPA, 0.025 mmol/kg vs. 0.1 mmol/kg for Gd-DTPA and other non-specific gadolinium-based contrast agents.
      However, this low clinical dose of Gd-EOB-DTPA may lead to lower enhancement of the aorta, liver and portal vein during the arterial and venous phases as compared to non-specific gadolinium chelates at their recommended dose [
      • Tamada T.
      • Ito K.
      • Sone T.
      • Yamamoto A.
      • Yoshida K.
      • Kakuba K.
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging of abdominal solid organ and major vessel: comparison of enhancement effect between Gd-EOB-DTPA and Gd-DTPA.
      ]. Moreover, the injection volume of Gd-EOB-DTPA is smaller than that of non-specific gadolinium agents. This small volume can result in acquisition timing error and truncation artifacts in the arterial phase if not properly timed. Using fluoroscopic triggering with a low injection rate of 1 ml/s to stretch the bolus or diluting the contrast with normal saline to 20 ml to enable a rapid injection rate at 2 ml/s are suggested solutions [
      • Zech C.J.
      • Vos B.
      • Nordell A.
      • Urich M.
      • Blomqvist L.
      • Breuer J.
      • et al.
      Vascular enhancement in early dynamic liver MR imaging in an animal model: comparison of two injection regimen and two different doses Gd-EOB-DTPA (gadoxetic acid) with standard Gd-DTPA.
      ,
      • Haradome H.
      • Grazioli L.
      • Tsunoo M.
      • Tinti R.
      • Frittoli B.
      • Gambarini S.
      • et al.
      Can MR fluoroscopic triggering technique and slow rate injection provide appropriate arterial phase images with reducing artifacts on gadoxetic acid-DTPA (Gd-EOB-DTPA)-enhanced hepatic MR imaging?.
      ,
      • Motosugi U.
      • Ichikawa T.
      • Sou H.
      • Sano K.
      • Ichikawa S.
      • Tominaga L.
      • et al.
      Dilution method of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI).
      ]. Doubling the dose of Gd-EOB-DTPA has also been suggested. In a study of patients with cirrhosis and hepatocellular carcinomas (HCC), it has been shown that doubling the dose improves the tumor-to-liver contrast during the arterial phase in all patients and during the hepatobiliary phase in Child B patients [
      • Motosugi U.
      • Ichikawa T.
      • Sano K.
      • Sou H.
      • Onohara K.
      • Muhi A.
      • et al.
      Double-dose gadoxetic acid-enhanced magnetic resonance imaging in patients with chronic liver disease.
      ].The clinical impact of this policy in terms of lesion detection remains unknown.
      Gd-EOB-DTPA is well tolerated with adverse events similar to those reported with non-specific gadolinium chelates. Of 162 patients included in a phase III trial of Gd-EOB-DTPA injection, a total of 11 (6.8%) patients reported a total of 21 adverse events. These adverse events were assessed as: one definitely related, five probably, seven possibly, one unlikely and seven not related to the study drug. The most frequently reported adverse events of definite, possible or probable relationship to the contrast agent were nausea, vasodilatation, headache, taste perversion, and injection site pain [
      • Hammerstingl R.
      • Huppertz A.
      • Breuer J.
      • Balzer T.
      • Blakeborough A.
      • Carter R.
      • et al.
      Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions.
      ].
      Gd-EOB-DTPA is an open-chain (linear) gadolinium chelate that has a lower kinetic stability than macrocyclic gadolinium chelates [
      • Port M.
      • Idee J.M.
      • Medina C.
      • Robic C.
      • Sabatou M.
      • Corot C.
      Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review.
      ]. To the best of our knowledge, no case of nephrogenic systemic fibrosis has been reported after the injection of Gd-EOB-DTPA. However, the clinical experience with Gd-EOB-DTPA is more limited than with non-specific gadolinium chelates. As the other gadolinium chelates, Gd-EOB-DTPA should be used cautiously in patients with renal insufficiency, especially in patients with a glomerular filtration rate <30 ml/min/1.73m2 [
      • Leiner T.
      • Kucharczyk W.
      NSF prevention in clinical practice: summary of recommendations and guidelines in the United States, Canada, and Europe.
      ].
      Gd-EOB-DTPA transport in the hepatocytes is mediated by two different transport systems located at the sinusoidal and canalicular membranes of the cell [
      • Weinmann H.J.
      • Bauer H.
      • Frenzel T.
      • Muhler A.
      • Ebert W.
      Mechanism of hepatic uptake of gadoxetate disodium.
      ]. The contrast agent enters the hepatocytes through the organic anion transporting polypeptides OATP1B1 and OATP1B3 which belong to the solute carrier transporter superfamily of the OATPs (SCTO). Following transport through the hepatocytes, it is excreted into the bile via the multidrug resistance protein 2 (MRP2), which belongs to the ATP-binding cassette C (ABCC) transporter subfamily [
      • Giacomini K.M.
      • Huang S.M.
      • Tweedie D.J.
      • Benet L.Z.
      • Brouwer K.L.
      • Chu X.
      • et al.
      Membrane transporters in drug development.
      ,
      • Leonhardt M.
      • Keiser M.
      • Oswald S.
      • Kuhn J.
      • Jia J.
      • Grube M.
      • et al.
      Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters.
      ,
      • van Montfoort J.E.
      • Stieger B.
      • Meijer D.K.
      • Weinmann H.J.
      • Meier P.J.
      • Fattinger K.E.
      Hepatic uptake of the magnetic resonance imaging contrast agent gadoxetate by the organic anion transporting polypeptide Oatp1.
      ,
      • Hagenbuch B.
      • Adler I.D.
      • Schmid T.E.
      Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X.
      ,
      • Roth M.
      • Obaidat A.
      • Hagenbuch B.
      OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies.
      ,
      • Chen Z.S.
      • Tiwari A.K.
      Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases.
      ].
      Regarding the function of MRP2, the location of the transporter within the canalicular membrane or inside the hepatocytes is important. Thus, MRP2 function is regulated by transporter retrieval from the canalicular membrane or insertion into it. It has been reported that oxidative stress induces MRP2 retrieval from the canalicular membranes and causes cholestasis [
      • Schmitt M.
      • Kubitz R.
      • Wettstein M.
      • Vom Dahl S.
      • Haussinger D.
      Retrieval of the mrp2 gene encoded conjugate export pump from the canalicular membrane contributes to cholestasis induced by tert-butyl hydroperoxide and chloro-dinitrobenzene.
      ]. In contrast, tauroursodeoxycholic acid inserts MRP2 into the canalicular membranes and stimulates organic anion secretion into bile [
      • Beuers U.
      • Bilzer M.
      • Chittattu A.
      • Kullak-Ublick G.A.
      • Keppler D.
      • Paumgartner G.
      • et al.
      Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.
      ].
      Organic acid efflux from hepatocytes may also occur through the sinusoidal membrane because the transport through OATP is bidirectional and because the sinusoidal membrane also contains multidrug resistance proteins (MRP3 and MRP4). These efflux pumps are normally expressed at low levels in normal hepatocytes but can be upregulated in pathologic conditions, such as cholestasis [
      • Kullak-Ublick G.A.
      • Stieger B.
      • Meier P.J.
      Enterohepatic bile salt transporters in normal physiology and liver disease.
      ] (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Cellular pharmacology of Gd-EOB-DTPA. Following distribution in the hepatic sinusoids and Disse spaces, GD-EOB-DTPA enters into hepatocytes through the organic anion transporting polypeptides OATP1B1 and OATP1B3. GD-EOB-DTPA exits through the ATP-dependent canalicular membrane multidrug resistance protein MRP2. MRP3 and MRP4 are transporters located in the sinusoidal membrane that may allow the efflux of GD-EOB-DTPA back to sinusoids. The OATP are bidirectional transporters (⇆). Transport through MRP2 is unidirectional (→) and MRP2 is regulated by retrieval from the membrane (decreased bile efflux) and insertion (increased bile efflux) while the localization of OATP never changes. Gd-EOB-DTPA is not metabolized within hepatocytes and is excreted unchanged into bile.
      The uptake of hepatobiliary contrast agents into hepatocytes may compete with numerous endogenous compounds and drugs. OATP1B1 and OATP1B3 transport a broad number of compounds and competition for uptake may limit Gd-EOB-DTPA uptake by hepatocytes. When rifampicin is injected before Gd-EOB-DTPA in normal rats, the antibiotic significantly prevents the increase of liver signal intensity [
      • Kato N.
      • Yokawa T.
      • Tamura A.
      • Heshiki A.
      • Ebert W.
      • Weinmann H.J.
      Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid interaction with clinical drugs in rats.
      ]. Such competition between the substrates Gd-EOB-DTPA, rifampicin, and bromosulfophthalein was also found in human embryonic kidney 293 cells injected with the human OATP1B1/B3 transporters [
      • Leonhardt M.
      • Keiser M.
      • Oswald S.
      • Kuhn J.
      • Jia J.
      • Grube M.
      • et al.
      Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters.
      ]. In humans, the first interaction to be investigated was that of erythromycin [
      • Huppertz A.
      • Breuer J.
      • Fels L.M.
      • Schultze-Mosgau M.
      • Sutter G.
      • Klein S.
      • et al.
      Evaluation of possible drug-drug interaction between gadoxetic acid and erythromycin as an inhibitor of organic anion transporting peptides (OATP).
      ]. The co-administration of erythromycin had no effect on GD-EOB-DTPA-enhanced liver MR imaging.

      Liver tumor detection

      Liver-specific contrast agents such as Gd-EOB-DTPA were first developed to improve the contrast-to-noise ratio between metastases and liver parenchyma. Lesions with no hepatocytes, such as metastases, or with less functioning hepatocytes, such as most HCCs, do not accumulate Gd-EOB-DTPA and appear as low signal intensity foci against the enhancing high signal parenchyma in the hepatobiliary phase, thus improving tumor detection. Several studies have shown that GD-EOB-DTPA-enhanced MR imaging has a higher sensitivity compared to dynamic contrast-enhanced CT and MR imaging enhanced with non-specific contrast agents for the detection of liver metastases and HCC [
      • Hammerstingl R.
      • Huppertz A.
      • Breuer J.
      • Balzer T.
      • Blakeborough A.
      • Carter R.
      • et al.
      Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions.
      ,
      • Reimer P.
      • Rummeny E.J.
      • Shamsi K.
      • Balzer T.
      • Daldrup H.E.
      • Tombach B.
      • et al.
      Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence.
      ,
      • Vogl T.J.
      • Kummel S.
      • Hammerstingl R.
      • Schellenbeck M.
      • Schumacher G.
      • Balzer T.
      • et al.
      Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA.
      ,
      • Ichikawa T.
      • Saito K.
      • Yoshioka N.
      • Tanimoto A.
      • Gokan T.
      • Takehara Y.
      • et al.
      Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.
      ,
      • Ahn S.S.
      • Kim M.J.
      • Lim J.S.
      • Hong H.S.
      • Chung Y.E.
      • Choi J.Y.
      Added value of gadoxetic acid-enhanced hepatobiliary phase MR imaging in the diagnosis of hepatocellular carcinoma.
      ,
      • Di Martino M.
      • Marin D.
      • Guerrisi A.
      • Baski M.
      • Galati F.
      • Rossi M.
      • et al.
      Intraindividual comparison of gadoxetate disodium-enhanced MR imaging and 64-section multidetector CT in the detection of hepatocellular carcinoma in patients with cirrhosis.
      ,
      • Kim M.J.
      Current limitations and potential breakthroughs for the early diagnosis of hepatocellular carcinoma.
      ]. Recently, the detection of small liver metastases has also been improved by unenhanced diffusion-weighted MR imaging. This last imaging sequence tends to have lower spatial resolution than the hepatobiliary phase of Gd-EOB-DTPA, and a combination of the two imaging sequences has been recommended for improved diagnostic efficacy [
      • Lowenthal D.
      • Zeile M.
      • Lim W.Y.
      • Wybranski C.
      • Fischbach F.
      • Wieners G.
      • et al.
      Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and GD-EOB-DTPA-enhanced MR imaging.
      ]. Regarding therapeutic efficacy, it has been shown in a large multicenter trial that GD-EOB-DTPA-enhanced MR imaging changed the surgical strategy in 19 of 131 patients (14.5%) [
      • Hammerstingl R.
      • Huppertz A.
      • Breuer J.
      • Balzer T.
      • Blakeborough A.
      • Carter R.
      • et al.
      Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions.
      ].
      It should be noted that the time-efficiency of GD-EOB-DTPA-enhanced MR imaging can be improved by performing T2-weighted and diffusion-weighted MR imaging during the time period of more than 15 min between the completion of the dynamic series and the acquisition of the hepatocyte phase images [
      • Lowenthal D.
      • Zeile M.
      • Lim W.Y.
      • Wybranski C.
      • Fischbach F.
      • Wieners G.
      • et al.
      Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and GD-EOB-DTPA-enhanced MR imaging.
      ]. This policy is justified because it has been shown that the lesion-to-liver contrast was significantly higher on T2-weighted and diffusion-weighted MR images after Gd-EOB-DTPA and that the apparent diffusion coefficients of focal liver lesions did not change significantly [
      • Kim Y.K.
      • Kwak H.S.
      • Kim C.S.
      • Han Y.M.
      Detection and characterization of focal hepatic tumors: a comparison of T2-weighted MR images before and after the administration of gadoxectic acid.
      ,
      • Choi J.S.
      • Kim M.J.
      • Choi J.Y.
      • Park M.S.
      • Lim J.S.
      • Kim K.W.
      Imaging of liver on 3.0-Tesla system: effect of intravenous administration of gadoxetic acid disodium.
      ].
      The improved diagnostic efficacy of Gd-EOB-DTPA relative to non-specific gadolinium chelates has to be balanced against its increased cost. The cost of gadolinium chelates varies among countries. In several European countries, the cost of Gd-EOB-DTPA is about three times higher than that of non-specific gadolinium chelates [
      • Zech C.J.
      • Grazioli L.
      • Jonas E.
      • Ekman M.
      • Niebecker R.
      • Gschwend S.
      • et al.
      Health-economic evaluation of three imaging strategies in patients with suspected colorectal liver metastases: GD-EOB-DTPA-enhanced MRI vs. extracellular contrast media-enhanced MRI and 3-phase MDCT in Germany, Italy and Sweden.
      ]. Very few health-economic studies about Gd-EOB-DTPA are available. In an economic evaluation in patients with metachronous colorectal liver metastasis, it was reported that a strategy starting with GD-EOB-DTPA-enhanced MR imaging was cost saving compared to non-specific gadolinium chelate MR imaging by improving pre-operative planning and decreasing intra-operative changes [
      • Zech C.J.
      • Grazioli L.
      • Jonas E.
      • Ekman M.
      • Niebecker R.
      • Gschwend S.
      • et al.
      Health-economic evaluation of three imaging strategies in patients with suspected colorectal liver metastases: GD-EOB-DTPA-enhanced MRI vs. extracellular contrast media-enhanced MRI and 3-phase MDCT in Germany, Italy and Sweden.
      ]. More cost-effectiveness studies based on clinical trial data rather than on expert opinion are needed in the future.

      Liver tumor characterization

      At MR imaging, tumor characterization is a complex process based on the analysis of the morphology and signal intensity of the lesion on the various imaging sequences. Dynamic contrast-enhanced MR imaging during the arterial, portal venous, and equilibrium phases has an important role in this context by showing differences of contrast agent distribution between the vascular and extravascular spaces of tumors and liver parenchyma [
      • Van Beers B.E.
      • Gallez B.
      • Pringot J.
      Contrast-enhanced MR imaging of the liver.
      ]. GD-EOB-DTPA provides similar information to that provided by non-specific gadolinium chelates during the arterial and venous phases, but enhancement in the equilibrium phase has contribution from hepatic cellular uptake and contrast in bile ducts, in addition to contrast in the intravascular and extracellular spaces. This phase is therefore better referred to as “late dynamic phase” [
      • Ringe K.I.
      • Husarik D.B.
      • Sirlin C.B.
      • Merkle E.M.
      Gadoxetate disodium-enhanced MRI of the liver: part 1, protocol optimization and lesion appearance in the noncirrhotic liver.
      ]. Because of increased parenchymal enhancement in this phase, the delayed enhancement traditionally used to diagnose lesions such as hemangioma and cholangiocarcinoma (CCC) is altered and may no longer be discernable [
      • Husarik D.B.
      • Gupta R.T.
      • Ringe K.I.
      • Boll D.T.
      • Merkle E.M.
      Contrast enhanced liver MRI in patients with primary sclerosing cholangitis: inverse appearance of focal confluent fibrosis on delayed phase MR images with hepatocyte specific versus extracellular gadolinium based contrast agents.
      ]. The high parenchymal enhancement at Gd-EOB-DTPA enhancement explains that hemangiomas may appear hypointense during the equilibrium and hepatobiliary phases [

      Gupta RT, Marin D, Boll DT, Husarik DB, Davis DE, Feuerlein S, et al. Hepatic hemangiomas: difference in enhancement pattern on 3T MR imaging with gadobenate dimeglumine versus gadoxetate disodium. Eur J Radiol, 2011 [Epub ahead of print].

      ].

      Hepatocellular carcinomas

      At dynamic, contrast-enhanced imaging with non-specific gadolinium contrast, hepatocellular carcinomas (HCC) are diagnosed when arterial hypervascularity and portal venous and/or late dynamic phase hypointensity or “washout” are demonstrated [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ]. Arterial hypervascularity manifests as increased tumor enhancement relative to hepatic parenchyma during the arterial-dominant phase, and washout as hypointense tumor relative to hepatic parenchyma during the venous and/or late dynamic phases. These characteristic features are observed in most HCCs and are related to features such as the development of unpaired arteries, absence of portal vein supply and nodular growth. However, it has been reported that in nodules 20 mm or smaller, the sensitivity of MR imaging for the diagnosis of HCC based on these criteria is only 62% and it is even lower for contrast-enhanced ultrasound [
      • Forner A.
      • Vilana R.
      • Ayuso C.
      • Bianchi L.
      • Sole M.
      • Ayuso J.R.
      • et al.
      Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.
      ]. This low sensitivity is explained by the fact that early HCCs often lack the characteristic features of HCC. Indeed, early HCCs often are not hypervascular, have persistent portal venous blood supply and replacing growth [
      • International Consensus Group for Hepatocellular Neoplasia
      Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.
      ].
      Interestingly, during the hepatobiliary phase at GD-EOB-DTPA-enhanced MR imaging, most HCCs, including hypovascular, early HCC, appear hypointense (Fig. 2, Fig. 3) [
      • Kudo M.
      Will Gd-EOB-MRI change the diagnostic algorithm in hepatocellular carcinoma?.
      ]. Thus, GD-EOB-DTPA-enhanced MR imaging appears useful for the characterization of small HCCs and for their differentiation from dysplastic nodules and vascular pseudolesions, which usually do not show this delayed hypointensity [
      • Kogita S.
      • Imai Y.
      • Okada M.
      • Kim T.
      • Onishi H.
      • Takamura M.
      • et al.
      GD-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow.
      ,
      • Motosugi U.
      • Ichikawa T.
      • Sou H.
      • Sano K.
      • Tominaga L.
      • Muhi A.
      • et al.
      Distinguishing hypervascular pseudolesions of the liver from hypervascular hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging.
      ,
      • Sano K.
      • Ichikawa T.
      • Motosugi U.
      • Sou H.
      • Muhi A.M.
      • Matsuda M.
      • et al.
      Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging.
      ,
      • Lee J.M.
      • Zech C.J.
      • Bolondi L.
      • Jonas E.
      • Kim M.J.
      • Matsui O.
      • et al.
      Consensus report of the 4th international forum for gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging.
      ]. In a recent imaging study including 12 dysplastic nodules, 30 early HCCs and 66 progressed HCCs, Sano et al. showed that low signal intensity at hepatobiliary phase GD-EOB-DTPA-enhanced MR imaging had an area under the receiver operating characteristic curve of 0.98 for the diagnosis of HCC. This area was significantly larger than that of contrast-enhanced CT and combined CT during arterial portography and CT during hepatic arteriography [
      • Sano K.
      • Ichikawa T.
      • Motosugi U.
      • Sou H.
      • Muhi A.M.
      • Matsuda M.
      • et al.
      Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging.
      ].
      Figure thumbnail gr2
      Fig. 2Classification of nodules in liver cirrhosis. (A) Pathological classification of nodules into low grade dysplastic nodules (LGDN), high grade dysplastic nodules (HGDN), early HCC, and progressed HCC. Early HCCs show a vaguely nodular appearance and are well differentiated. Progressed HCCs grow in an expansile fashion with formation of a fibrous capsule and are moderately differentiated. The differentiation between HGDN and early HCC may be difficult at histopathological examination. The presence of stromal invasion is a useful criterion of malignancy. (B) Vascularity of nodules in liver cirrhosis and contrast-enhanced MR imaging features during the dynamic phase. Unpaired arteries (red dots) appear in HGDN and more extensively in early HCC. The increase of unpaired arteries is paralleled by a decrease of portal tracts (diamonds containing portal venous branch in blue, arterial branch in red and bile duct in orange). Progressed HCCs only contain unpaired arteries. This evolution explains that progressed HCCs typically appear hyperintense (Hyper) relative to the liver parenchyma during the arterial phase at MR imaging (MRIHA) and hypointense (Hypo) during the portal venous and/or the late dynamic phase (MRIPVE). In contrast, LGDN appear iso-intense (Iso), whereas HGDN and early HCC have a variable enhancement (V) depending on their arterial and portal venous supply. (C) Transporters in nodules of liver cirrhosis and MR imaging features during the hepatobiliary phase. In early and progressed HCC, OATP1B1/B3 expression is often decreased (or absent) relative to that of the liver parenchyma (O−), whereas MRP2 expression is often increased (M+). These HCC appear hypointense during the hepatobiliary phase (MRIHB). In some HCC, OATP expression is increased (O+). In these HCC, the signal intensity will depend on MRP2 expression. When MRP2 expression is high, the HCCs usually appear hypointense. Hyperintense (or isointense) HCCs during the hepatobiliary phase are HCCs having high expression of OATP and low expression of MRP2 (M−) or HCCs having high expression of OATP and MRP2 with Gd-EOB-DTPA excretion in pseudoglands. This figure illustrates the superiority of GD-EOB-DTPA-enhanced MR imaging relative to MR imaging enhanced with non-specific gadolinium chelates in the differentiation between dysplastic nodules and early HCC because early HCC appear hypointense during the hepatobiliary phase at GD-EOB-DTPA-enhanced MR imaging, whereas the enhancement of dysplastic nodules and early HCC does not differ at MR imaging enhanced with with non-specific gadolinium chelates.
      Figure thumbnail gr3
      Fig. 3GD-EOB-DTPA-enhanced MR images of HCC in two patients. (A) In the first patient, no lesion is seen during the arterial phase at Gd-EOB-DTPA MR imaging because of lack of hypervascularity in small HCC. (B) Two small HCCs (arrow) are seen as hypointense nodules in the right hepatic lobe during the hepatobiliary phase. (C) In another patient, a HCC of the right liver lobe is isointense relative to the liver on unenhanced T1-weighted MR image. (D) The progressed HCC is hypervascular during the arterial phase. (E) The tumor is hyperintense during the hepatobiliary phase at GD-EOB-DTPA-enhanced MR imaging.
      Because of its high sensitivity in the diagnosis of HCC, GD-EOB-DTPA-enhanced MR imaging has been recommended in a recent consensus conference as a method for characterizing a nodule that has been detected in the cirrhotic liver using ultrasonography [
      • Lee J.M.
      • Zech C.J.
      • Bolondi L.
      • Jonas E.
      • Kim M.J.
      • Matsui O.
      • et al.
      Consensus report of the 4th international forum for gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging.
      ]. However, more data should be obtained about the specificity of the hepatobiliary hypointensity sign in prospective studies that should include patients with other nodules than HCC and dysplastic nodules. Meanwhile, a hypointense nodule in the hepatobiliary phase of Gd-EOB-DTPA that is non-hypervascular in the arterial phase should be regarded as intermediate risk, whereas one that is hypervascular in the arterial phase is high risk [
      • Lee J.M.
      • Zech C.J.
      • Bolondi L.
      • Jonas E.
      • Kim M.J.
      • Matsui O.
      • et al.
      Consensus report of the 4th international forum for gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging.
      ].
      The enhancement pattern during the hepatobiliary phase at GD-EOB-DTPA-enhanced MR imaging has been explained by OATP and MRP expression. Most HCCs appear hypointense during that phase because the expression of OATP1B1/B3 is decreased. When OATP1B1/B3 expression is maintained, the intensity of HCC depends on the expression of MRP2. In most HCCs, the expression of MRP2 is high and located on the canalicular membrane of hepatocytes. These HCCs are hypointense. In contrast, 5 – 10% of HCCs are iso- or hyperintense relative to the liver. This has been related to low MRP2 expression or high MRP2 expression at the luminal membrane of pseudoglands [
      • Tsuboyama T.
      • Onishi H.
      • Kim T.
      • Akita H.
      • Hori M.
      • Tatsumi M.
      • et al.
      Hepatocellular carcinoma: hepatocyte-selective enhancement at gadoxetic acid-enhanced MR imaging – correlation with expression of sinusoidal and canalicular transporters and bile accumulation.
      ,
      • Lee S.A.
      • Lee C.H.
      • Jung W.Y.
      • Lee J.
      • Choi J.W.
      • Kim K.A.
      • et al.
      Paradoxical high signal intensity of hepatocellular carcinoma in the hepatobiliary phase of GD-EOB-DTPA-enhanced MRI: initial experience.
      ] (Fig. 2, Fig. 3).
      MRP3 is usually decreased in HCC [
      • Zollner G.
      • Wagner M.
      • Fickert P.
      • Silbert D.
      • Fuchsbichler A.
      • Zatloukal K.
      • et al.
      Hepatobiliary transporter expression in human hepatocellular carcinoma.
      ]. It has been observed that the expression of MRP3 is increased rather than decreased in hyperintense vs. hypointense HCC [
      • Kitao A.
      • Zen Y.
      • Matsui O.
      • Gabata T.
      • Kobayashi S.
      • Koda W.
      • et al.
      Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imaging – correlation with molecular transporters and histopathologic features.
      ]. This suggests that MRP3 expression has little influence on HCC signal intensity at GD-EOB-DTPA-enhanced MR imaging.
      It has been recently reported that the OATP1B1/B3 expression is progressively lost in HCCs that gain a biliary phenotype with worse prognosis [
      • Vasuri F.
      • Golfieri R.
      • Fiorentino M.
      • Capizzi E.
      • Renzulli M.
      • Pinna A.D.
      • et al.
      OATP 1B1/1B3 expression in hepatocellular carcinomas treated with orthotopic liver transplantation.
      ]. Moreover, it has been shown that MR imaging hypointensity during the hepatobiliary phase increases with increasing HCC grade [
      • Kitao A.
      • Matsui O.
      • Yoneda N.
      • Kozaka K.
      • Shinmura R.
      • Koda W.
      • et al.
      The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging.
      ]. However, the correlation between Gd-EOB-DTPA enhancement and tumor grade remains controversial [
      • Choi J.Y.
      • Kim M.J.
      • Park Y.N.
      • Lee J.M.
      • Yoo S.K.
      • Rha S.Y.
      • et al.
      Gadoxetate disodium-enhanced hepatobiliary phase MRI of hepatocellular carcinoma: correlation with histological characteristics.
      ]. Further studies are needed to correlate the enhancement pattern in HCC to the expression of hepatic transporters in the various subtypes of HCC, according to molecular classification [
      • Zucman-Rossi J.
      Molecular classification of hepatocellular carcinoma.
      ].
      Finally, it has been reported that soranenib, in contrast to sunitinib, is a substrate for MRP2 [
      • Shibayama Y.
      • Nakano K.
      • Maeda H.
      • Taguchi M.
      • Ikeda R.
      • Sugawara M.
      • et al.
      Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib.
      ]. The relationship between the signal intensity of HCC at GD-EOB-DTPA-enhanced MR imaging and resistance to sorafenib is currently unknown.

      Benign hepatocellular tumors

      The expression of OATP1B1/B3 and MRP2, MRP3 has also been investigated in focal nodular hyperplasia (FNH) and hepatocellular adenomas (HA) [
      • Vander Borght S.
      • Libbrecht L.
      • Blokzijl H.
      • Faber K.N.
      • Moshage H.
      • Aerts R.
      • et al.
      Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver.
      ]. Typical FNH is associated with chronic cholestasis, ductular reaction, and fibrosis. Bile canaliculi are not connected to bile ducts and bile compounds accumulate within the lesion. In FNH, OATP1B1/B3 expression is increased, MRP2 expression is similar to that in the normal liver, while MRP3 has a low expression. In HA, the OATP1B1/B3 expression is typically low, MRP2 expression is similar to that in the normal liver, while MRP3 has a diffuse and high expression.
      In clinical studies, FNHs show enhancement during the hepatobiliary phase either similar to or more than liver parenchyma with low signal intensity of the central scar (Fig. 4) [
      • Zech C.J.
      • Grazioli L.
      • Breuer J.
      • Reiser M.F.
      • Schoenberg S.O.
      Diagnostic performance and description of morphological features of focal nodular hyperplasia in GD-EOB-DTPA-enhanced liver magnetic resonance imaging: results of a multicenter trial.
      ]. A case of FNH-like nodule in liver cirrhosis with lesion hypointensity during the hepatobiliary phase has been recently reported [
      • Doi N.
      • Tomiyama Y.
      • Kawase T.
      • Nishina S.
      • Yoshioka N.
      • Hara Y.
      • et al.
      Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis.
      ]. This lesion also showed arterial hyperintensity and was misdiagnosed as HCC.
      Figure thumbnail gr4
      Fig. 4GD-EOB-DTPA-enhanced MR images in a patient with FNH and HA. (A) On diffusion-weighted MR image, both HA (short arrow) in the right lobe and FNH (long arrow) in the left lobe are slightly hyperintense. (B) The two lesions are hypervascular during the arterial phase after Gd-EOB-DTPA injection and cannot be differentiated. (C and D) Two MR images obtained during the hepatobiliary phase show that the FNH is isointense (C), whereas the HA is hypointense (D, slightly lower section).
      The enhancement of HA is variable [
      • Fidler J.
      • Hough D.
      Hepatocyte-specific magnetic resonance imaging contrast agents.
      ,
      • Sakamoto A.
      • Hayashi H.
      • Sakamoto I.
      • Isomoto I.
      • Eguchi S.
      • Takatsuki M.
      • et al.
      Multiple hepatocellular adenomas in a patient with glycogen storage disease type I: various enhancement patterns in MRI with Gd-EOB-DTPA.
      ,
      • Huppertz A.
      • Haraida S.
      • Kraus A.
      • Zech C.J.
      • Scheidler J.
      • Breuer J.
      • et al.
      Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: correlation with histopathologic findings and spiral CT – initial observations.
      ]. Most HA are hypointense during the hepatobiliary phase (Fig. 4). However, some HA may also take up the contrast agent and appear hyperintense. As for HCC, further studies are needed to correlate the enhancement pattern in HA to the expression of hepatic transporters in the various subtypes [
      • Ronot M.
      • Bahrami S.
      • Calderaro J.
      • Valla D.C.
      • Bedossa P.
      • Belghti J.
      • et al.
      Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification.
      ]. Currently, the added value of GD-EOB-DTPA-enhanced MR imaging relative to dynamic contrast-enhanced MR imaging with a non-specific gadolinium chelate in the differentiation of benign hepatocellular tumors remains to be proven. The enhancement characteristics of the most frequent liver tumors are shown in Table 1.
      Table 1Enhancement characteristics of the most frequent liver tumors.

      Bile duct diseases

      GD-EOB-DTPA-enhanced cholangiography can be performed during the hepatobiliary phase. While the intrahepatic and extrahepatic ducts are well seen at 20 min [
      • Ringe K.I.
      • Husarik D.B.
      • Gupta R.T.
      • Boll D.T.
      • Merkle E.M.
      Hepatobiliary transit times of gadoxetate disodium (Primovist) for protocol optimization of comprehensive MR imaging of the biliary system – what is normal?.
      ], a delay of 30 min after the injection of Gd-EOB-DTPA is suggested by some authors to ensure sufficient enhancement of the bile ducts and demonstrate gallbladder enhancement [
      • Lee N.K.
      • Kim S.
      • Lee J.W.
      • Lee S.H.
      • Kang D.H.
      • Kim G.H.
      • et al.
      Biliary MR imaging with Gd-EOB-DTPA and its clinical applications.
      ,
      • Smith A.D.
      • Veniero J.C.
      Gd-EOB-DTPA as a functional MR cholangiography contrast agent: imaging gallbladder filling in patients with and without hepatobiliary dysfunction.
      ]. Biliary enhancement is affected by hepatic function and has been shown to be weaker and delayed in the cirrhotic liver [

      Tamada T, Ito K, Sone T, Kanki A, Sato T, Higashi H. GD-EOB-DTPA-enhanced MR imaging: evaluation of biliary and renal excretion in normal and cirrhotic livers. Eur J Radiol, 2010 [Epub ahead of print].

      ].
      T1-weighted GD-EOB-DTPA-enhanced cholangiography may add functional information to unenhanced T2-weighted MR cholangiography. This may potentially be useful for the detection of bile duct leaks, the grading of bile duct obstruction, the differentiation between Caroli disease and peribiliary cysts, and the differentiation between parenchymal and small bile duct diseases [
      • Lee N.K.
      • Kim S.
      • Lee J.W.
      • Lee S.H.
      • Kang D.H.
      • Kim G.H.
      • et al.
      Biliary MR imaging with Gd-EOB-DTPA and its clinical applications.
      ]. However, the visualization of the bile ducts may be poor or even absent at GD-EOB-DTPA-enhanced cholangiography in patients with advanced diffuse parenchymal disease or bile duct obstruction [
      • Tschirch F.T.
      • 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.
      ]. T2-weighted MR cholangiography should be performed before Gd-EOB-DTPA administration due to the T2 shortening effect of enhanced bile which renders the biliary system invisible [
      • Ringe K.I.
      • Gupta R.T.
      • Brady C.M.
      • Massey C.M.
      • Hahn A.
      • Galanski M.
      • et al.
      Respiratory-triggered three-dimensional T2-weighted MR cholangiography after injection of gadoxetate disodium: is it still reliable?.
      ].

      Assessment of liver function

      Assessment of liver function is important to determine the prognosis of patients with chronic liver diseases, and is particularly required in patients with cirrhosis to determine the optimal timing for transplantation or transjugular intrahepatic portosystemic shunt (TIPS) insertion [
      • Zipprich A.
      • Kuss O.
      • Rogowski S.
      • Kleber G.
      • Lotterer E.
      • Seufferlein T.
      • et al.
      Incorporating indocyanin green clearance into the Model for End Stage Liver Disease (MELD-ICG) improves prognostic accuracy in intermediate to advanced cirrhosis.
      ]. Evaluation of total and regional liver function is also important before major liver resection to minimize the risk of post-operative liver failure, especially in patients with cirrhosis or even less advanced diseases such as steatosis, cholestasis, or chemotherapy toxicity [
      • Belghiti J.
      • Ogata S.
      Assessment of hepatic reserve for the indication of hepatic resection.
      ,
      • Bennink R.J.
      • de Graaf W.
      • van Gulik T.M.
      Toward a total and regional scintigraphic liver function test enabling assessment of future remnant liver function.
      ]. Indocyanin green (ICG) clearance and hepatic scintigraphy with technetium-99m mebrofenin (99mTc-mebrofenin) have been proposed for assessing liver function. The organic anion 99mTc-mebrofenin is a substrate of OATP1B1/B3, whereas ICG is a substrate of OATP1B3 and sodium taurocholate-cotransporting polypeptide (NTCP). Both ICG and mebrofenin are excreted in the bile by MRP2 without undergoing biotransformation [
      • Hendrikse N.H.
      • Kuipers F.
      • Meijer C.
      • Havinga R.
      • Bijleveld C.M.
      • van der Graaf W.T.
      • et al.
      In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein.
      ,
      • de Graaf W.
      • Hausler S.
      • Heger M.
      • van Ginhoven T.M.
      • van Cappellen G.
      • Bennink R.J.
      • et al.
      Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green.
      ].
      Assessment of liver function at GD-EOB-DTPA-enhanced MR imaging may be an alternative to ICG clearance and hepatic scintigraphy with 99mTc-mebrofenin. Hepatic extraction fraction of Gd-EOB-DTPA has been shown to correlate with ICG clearance in rabbits and liver-spleen contrast to noise ratio at GD-EOB-DTPA-enhanced MR imaging has been shown to correlate with ICG clearance in patients [
      • Ryeom H.K.
      • Kim S.H.
      • Kim J.Y.
      • Kim H.J.
      • Lee J.M.
      • Chang Y.M.
      • et al.
      Quantitative evaluation of liver function with MRI using Gd-EOB-DTPA.
      ,
      • Motosugi U.
      • Ichikawa T.
      • Sou H.
      • Sano K.
      • Tominaga L.
      • Kitamura T.
      • et al.
      Liver parenchymal enhancement of hepatocyte-phase images in GD-EOB-DTPA-enhanced MR imaging: which biological markers of the liver function affect the enhancement?.
      ]. The advantages of GD-EOB-DTPA-enhanced MR imaging include absence of radiation, combined anatomical and functional assessment, and the ability to quantitatively assess hepatic perfusion and function [
      • Nilsson H.
      • Nordell A.
      • Vargas R.
      • Douglas L.
      • Jonas E.
      • Blomqvist L.
      Assessment of hepatic extraction fraction and input relative blood flow using dynamic hepatocyte-specific contrast-enhanced MRI.
      ]. A preliminary study in rats to evaluate liver fibrosis showed a good correlation between advanced fibrosis and the signal-intensity time course of GD-EOB-DTPA-enhanced MR imaging [
      • Tsuda N.
      • Okada M.
      • Murakami T.
      New proposal for the staging of nonalcoholic steatohepatitis: evaluation of liver fibrosis on GD-EOB-DTPA-enhanced MRI.
      ]. Decreased enhancement and increased enhancement time are attributed to slower hepatocyte uptake due to lower OATP1 activity, and rapid elimination due to increased MRP2 activity which is upregulated in the cirrhotic liver [
      • Tsuda N.
      • Matsui O.
      Cirrhotic rat liver: reference to transporter activity and morphologic changes in bile canaliculi – gadoxetic acid-enhanced MR imaging.
      ].
      Several issues need to be taken into account when performing pharmacokinetic analysis of liver enhancement at GD-EOB-DTPA-enhanced MR imaging. These include the lack of linear relationship between signal intensity of liver and contrast agent concentration, and the differing relaxivity of Gd-EOB-DTPA in water, blood and liver [
      • Materne R.
      • Smith A.M.
      • Peeters F.
      • Dehoux J.P.
      • Keyeux A.
      • Horsmans Y.
      • et al.
      Assessment of hepatic perfusion parameters with dynamic MRI.
      ]; the need to incorporate all factors that influence hepatic clearance of contrast agents such as blood flow, transmembrane barriers and the presence of other drugs metabolized in the liver [
      • Van Beers B.E.
      • Materne R.
      • Annet L.
      • Hermoye L.
      • Sempoux C.
      • Peeters F.
      • et al.
      Capillarization of the sinusoids in liver fibrosis: noninvasive assessment with contrast-enhanced MRI in the rabbit.
      ,
      • Liu L.
      • Pang K.S.
      An integrated approach to model hepatic drug clearance.
      ]; and lastly the complexity of transporter regulation in hepatocytes including the inter-individual variability of transporter expression and the saturation of the transport systems at high concentrations of the contrast agents [
      • Van Beers B.E.
      • Grandin C.
      • Pauwels S.
      • Mottet I.
      • Goudemant J.F.
      • Delos M.
      • et al.
      Gd-EOB-DTPA enhancement pattern of hepatocellular carcinomas in rats: comparison with Tc-99m-IDA uptake.
      ,
      • Millet P.
      • Moulin M.
      • Stieger B.
      • Daali Y.
      • Pastor C.M.
      How organic anions accumulate in hepatocytes lacking Mrp2: evidence in rat liver.
      ,
      • Stieger B.
      • Heger M.
      • de Graaf W.
      • Paumgartner G.
      • van Gulik T.
      The emerging role of transport systems in liver function tests.
      ].

      Conflict of interest

      Pr. Hero Hussain has served as occasional consultant for Bayer in 2010 and 2011. The other authors have no conflict of interest to disclose.

      Acknowledgements

      The authors thank Pr. Celso Matos from the Department of Radiology, Erasme Hospital, Free University of Brussels, Belgium for providing Fig. 3, Fig. 4.

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