ª Springer Science+Business Media New York 2015
Abdominal Imaging
Abdom Imaging (2015) DOI: 10.1007/s00261-015-0354-7
Gadoxetic acid: pearls and pitfalls Ryan B. Schwope,1,2 Lauren A. May,1 Michael J. Reiter,1 Christopher J. Lisanti,1,2 Daniel J. A. Margolis3 1
Department of Radiology, San Antonio Military Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234, USA Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA 3 David Geffen School of Medicine at UCLA, 200 Medical Plaza, #165-43, MC: 695224, Los Angeles, CA 90095-6952, USA 2
Abstract Gadoxetic acid is a hepatocyte-specific magnetic resonance imaging contrast agent with the ability to detect and characterize focal liver lesions and provide structural and functional information about the hepatobiliary system. Knowledge of the pharmacokinetics of gadoxetic acid is paramount to understanding imaging protocol and lesion appearance and facilitates identification and avoidance of undesired effects with use of this intravenous contrast agent. This article reviews the utility of gadoxetic acid in liver and biliary imaging, with emphasis on the hepatobiliary phase. Key words: Gadoxetic acid—Hepatobiliary phase—Magnetic resonance imaging
Magnetic resonance imaging (MR) is an integral instrument in the evaluation of the hepatobiliary system. The introduction of hepatocyte-specific contrast agents such as gadoxetic acid (Gd–EOB–DTPA; Eovist in the US; Primovist outside the US; Bayer HealthCare) has expanded the utility of MR in hepatobiliary evaluation. Due to the dual extracellular and hepatobiliary phases of this contrast agent, gadoxetic acid can provide information similar to that of extracellular contrast agents, in addition to functional and structural information of the hepatobiliary system. However, the unique properties of this hepatocyte-specific agent warrant a discussion of its physiology and how these properties affect MR technique, lesion appearance, and thus image interpretation. This article discusses the pharmacokinetics and technical considerations of gadoxetic acid, with emphasis on the hepatobiliary phase. The expected appearance of the liver and biliary system and the appearances of several hepatic lesions are discussed, in addition to potential Correspondence to: Ryan B. Schwope; email: [email protected]
biliary applications. The evidence supporting the use of gadoxetic acid for hepatobililary imaging is also reviewed. The pitfalls often encountered with use of gadoxetic acid are then addressed and potential solutions to help troubleshoot and decrease unwanted effects on imaging are suggested. Finally, the future directions of gadoxetic acidenhanced MR are discussed, highlighting its potential role in evaluating hepatic function and steatosis.
Pharmacokinetics of gadoxetic acid After intravenous injection, gadoxetic acid first distributes to the extracellular space. Once in the extracellular space gadoxetic acid can either be excreted by the kidneys through glomerular filtration or taken up by hepatocytes [1]. Because of this dual-elimination pathway, some authors have classified gadoxetic acid as a ‘‘combination’’ contrast agent [2]. When taken up by hepatocytes, gadoxetic acid is actively transported into hepatocytes utilizing the organic anion transporting polypeptide 1 (OATP1), the same transport protein used for bilirubin [3– 6]. Excretion of gadoxetic acid from hepatocytes into bile canaliculi is then accomplished via the canalicular multispecific organic anion transport (cMOAT) (Fig. 1) [3, 5]. In patients with normal hepatic and renal function, it can be expected that 50% of gadoxetic acid is excreted by the hepatobiliary system and 50% excreted by the kidneys [3]. Excretion of gadoxetic acid into the biliary system results in increased signal within the bile ducts, gallbladder, and duodenum on T1-weighted imaging. Biliary transit time of contrast is independent of gender, age, body mass index, gastric filling, and MR technical variations (1.5 vs. 3 T), but is dependent on liver function. In patients with normal liver function, Ringe et al. found that contrast can appear in the biliary system as early as 5 min after injection. These authors also found that gadoxetic acid refluxed into the gallbladder in 86.9% and was visualized in the duodenum in 65.5% of patients without biliary pathology. If present, reflux into the
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 1. Diagram showing the physiology and pharmacodynamics of gadoxetic acid. After intravenous injection, gadoxetic acid distributes into the extracellular space. Via organic anion transporting polypeptide 1 (OATP1), gadoxetic acid is
actively transported from extracellular space into hepatocytes, and subsequently transported from hepatocytes into bile canaliculi via canalicular multispecific organic anion transporter (cMOAT).
gallbladder and duodenal visualization typically occurred by 13–14 min and no later than 18–19 min after contrast injection in this study. The fasting state of the patient resulting in variable intraluminal gallbladder and sphincter of Oddi pressures (in theory) will affect gallbladder filling with excreted gadoxetic acid [7]. Given the aforementioned physiologic properties of gadoxetic acid, two important points can be made. First, gadoxetic acid competes with bilirubin for active transport into hepatocytes through OATP1 [6]. If bilirubin levels are elevated, hepatic parenchymal enhancement and biliary excretion of gadoxetic acid will both be decreased [2]. Second, given the dual-elimination excretion, studies have shown compensation by the remaining normally functioning elimination pathway [8, 9]. It has been suggested that this physiologic compensation may have implications for preventing nephrogenic systemic fibrosis (NSF) and that administering gadoxetic acid in a patient with diminished renal function may be safer than administering a purely extracellular agent [10]. However, no study to date presents conclusive results to demonstrate this hypothesized benefit. An additional important property of gadoxetic acid is that it has intrinsically weaker protein binding properties compared to standard gadolinium chelates, resulting in inherently increased T1 relaxivity and shortening [2, 3, 11]. This property of gadoxetic acid is important when evaluating contrast dose as the increased T1 shortening properties of gadoxetic acid allow for smaller dose administration, on the order of onefourth that of standard conventional gadolinium agents
[2]. This decreased dose also has hypothetical implications in patient safety and in decreasing the risk of NSF, although there is no conclusive evidence in the literature to demonstrate this.
Magnetic resonance protocol and technique Gadoxetic acid is typically injected at a rate of 1–2 mL/s with a 20–25 mL normal saline chaser [5, 12]. The FDA approved dose is 0.025 mmol/kg body weight [3, 13]. Initial imaging relies on standard extracellular phase properties shared with conventional gadolinium-based intravenous contrast agents. Sequences are obtained as fat-suppressed 3D T1-weighted gradient-echo sequence with breath hold. Dynamic imaging can be acquired by bolus-tracking technique as follows: axial late arterial phase at 15 s after contrast arrives in the suprarenal aorta, axial portal venous phase at 15–30 s after arterial phase, and axial late dynamic phase at 2–3 min after arterial phase [5, 12]. The late dynamic phase of imaging acquired after the portal venous phase has also been referred to as the transitional phase as both intracellular and extracellular gadoxetic acid contribute to hepatic parenchymal enhancement [14]. Some authors advocate consecutive arterial phase acquisitions so as to optimize obtaining an ideal arterial phase [15]. Fat-suppressed 3D T1-weighted gradient-echo sequences are then obtained in the axial and coronal planes during hepatobiliary phase imaging. Hepatobiliary phase images are acquired during peak hepatocyte uptake and enhancement occurring 10–20 min after injection in patients with
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 2. Effect of the flip angle. Axial T1-weighted images with fat saturation acquired 20 min after injection of gadoxetic acid, using a flip angle of 10 (A) and a flip angle of 35 (B). Notice the increased signal of contrast within the bile ducts on the image acquired with a higher flip angle.
normal hepatocellular function [3, 12]. Hepatocyte enhancement persists for a minimum of 2 h in most patients thereby permitting repeat imaging as needed. An additional tool to optimize MR with gadoxetic acid is to increase the flip angle. Standard T1-weighted flip angles for hepatobiliary imaging range from 10 to 15. However, increasing the flip angle accentuates T1weighting and improves both signal- and contrast-tonoise ratios [16, 17]. The increase in signal- and contrastto-noise ratios will increase hepatic lesion conspicuity and accentuate contrast excreted into the biliary system (Fig. 2), although a significant increase in ghosting artifact relating to contrast in the common bile duct has been found at a higher flip angle of 40 [17]. Frydrychowicz et al. found that optimal flip angles were 25–30 for liver lesion detection and 45 for biliary system interrogation on a 3 T system [18].
Applications Knowledge of the physiologic properties of gadoxetic acid and the histology of hepatic lesions is paramount to liver and biliary imaging with gadoxetic acid, particularly during hepatobiliary phase imaging [6]. During the hepatobiliary phase, lesions that contain functional hepatocytes will take up the contrast agent and appear iso- to hyperintense relative to the hepatic parenchyma, while lesions without functioning hepatocytes will not take up contrast and appear hypointense relative to the surrounding hepatic parenchyma [4]. Many authors have utilized this finding to generate lesion-to-liver signal intensity ratios for the purposes of differentiating intrahepatic lesions [19, 20].
Focal nodular hyperplasia (FNH) FNH is composed of hepatocytes with blind-ending biliary ductules [21]. The hepatocytes are typically increased in density compared to normal liver parenchyma [2]. As a result, during hepatobiliary imaging most FNHs are isointense to hyperintense relative to the liver parenchyma (Fig. 3) [12]. One study showed that 38% of FNHs were uniformly hyperintense, 32% uniformly isointense, 28% mixed signal intensity, and 2% hypointense with respect to the surrounding parenchyma during hepatobiliary phase imaging at 20 min with gadoxetic acid [22]. It is hypothesized that this hyperintense signal may be a result of the increased density of intralesional hepatocytes in addition to the blind-ending biliary ductules precluding effective excretion of contrast [10, 19]. These hepatobiliary phase imaging characteristics of FNH allow a more confident diagnosis, especially in cases when FNH has an atypical appearance on CT or precontrast MR sequences [22]. Indeed, enough literature is now available to support the belief that FNH can be confidently diagnosed with MRI using gadoxetic acid thus precluding the need for biopsy [2]. When diagnosing FNH by MR, lesion conspicuity was superior when comparing hepatobiliary phase imaging acquired 10– 20 min after gadoxetic acid injection to hepatobiliary phase images acquired 1–3 h after gadobenate dimeglumine (another ‘‘combination’’ contrast agent with only 2%–4% uptake by functioning hepatocytes [21]) injection, also shortening MR workflow [23]. Furthermore, gadoxetic acid has been shown to be highly effective in differentiating FNH from hepatic adenomas, which are typically hypointense during hepatobiliary imaging [19,
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 3. Focal nodular hyperplasia (FNH). Axial T1-weighted images with fat saturation acquired 20 min after injection of gadoxetic acid. FNHs (arrows) are almost always iso-hyperintense with respect hepatic parenchyma during the hepatobiliary phase.
24]. Purysko et al. found that a relative signal enhancement ratio of 0.7 (comparing lesion to hepatic parenchyma signal intensity during the hepatobiliary phase) was 100% specific and 91.6% sensitive for hepatic adenomas when compared to FNHs [19].
Hepatocellular carcinoma (HCC) As a result of impaired expression of membrane transports, HCCs are typically hypointense compared with hepatic parenchyma on hepatobiliary phase imaging with gadoxetic acid (Fig. 4). Choi et al. showed that 90.1% of HCCs demonstrated such hypointense signal intensity during hepatobiliary phase imaging [25]. This histologic property of HCC and resultant imaging appearance has shown gadoxetic acid as an effective agent in detecting and diagnosing HCC when compared to other modalities and extracellular gadolinium contrast agents. Gadoxetic acid has been shown to be more sensitive in diagnosing HCCs when compared to CT (91.4% vs. 71.6%, respectively) and becomes even more effective than CT when the HCCs are small (£2 cm), with the sensitivities in a two reader study of 97% and 94% for gadoxetic acid and 58% and 68% for contrast-enhanced CT [26, 27]. When compared to gadopentate dimeglumine, gadoxetic acid was shown more sensitive in detecting HCC (86.4% vs. 64.4%) [28]. Additionally, MRI with gadoxetic acid has a higher sensitivity for HCC detection than MRI with superparamagnetic iron oxide (90.7% vs. 84.7%) [29]. The addition of the hepatobiliary phase to dynamic imaging is particularly useful. In identifying small (£2 cm) HCCs in cirrhotics, one study showed an
increase in both sensitivity and specificity by 11% and 7%, respectively, when utilizing both dynamic and hepatobiliary phase imaging with gadoxetic acid vs. dynamic phase imaging alone with gadoxetic acid [30]. Lesion signal intensity during hepatobiliary phase imaging after injection of gadoxetic acid has also shown useful for the detection of early HCC. In patients with cirrhosis, nodules £2 cm that are hypointense on hepatobiliary phase imaging are more likely to represent HCC or progress to HCC [27]. Sano et al. showed that hypointensity on hepatobiliary phase imaging was found as a significant imaging feature in differentiating dysplastic nodules (0% of lesions) from small HCCs (97% of lesions) [27]. In patients with cirrhosis, nodules that are hypointense with respect to hepatic parenchyma on the hepatobiliary phase and demonstrate corresponding hyperintensity on high b value diffusion-weighted imaging (800 s/mm2) are associated with progression to hypervascular HCC [31]. Motosugi et al. have shown lesions which demonstrate hypointense signal (assessed by a liver-to-lesion signal intensity) on hepatobiliary phase favor HCC over pseudolesions, especially if there is corresponding signal abnormality on diffusion-weighted imaging. These authors found that when using a hepatocyte-phase signal intensity cutoff value of less than 0.84, the sensitivity and specificity were 91% in distinguishing hypervascular HCCs from nodular pseudolesions, and that none of the pseudolesions were apparent on diffusion-weighted imaging [20]. Thus, hepatobiliary phase imaging with gadoxetic acid paired with diffusionweighted imaging is a valuable tool when assessing for small HCCs.
Metastases Metastases will appear hypointense after injection of gadoxetic acid during hepatobiliary phase imaging owing to the fact that they lack functioning hepatocytes. This functional difference between hepatocytes and metastasis will increase the lesion-to-liver contrast on hepatobiliary phase imaging improving lesion detection [3]. This is particularly true for identification of small (20% of the total functional liver volume in order to sustain postoperative liver function and enable regeneration [76]. But this future liver remnant estimate is based on healthy liver parenchyma and many patients considered for resection do not have normal hepatic function, whether secondary to cirrhosis or chemotherapy-associated parenchymal dysfunction. In this subset of patients, the volume of future liver remnant needs to be increased relative to the degree of hepatic dysfunction in order to decrease mortality and morbidity related to post-resection hepatic failure [77, 78]. Although variable worldwide and between professional organizations, liver function is typically assessed by serum laboratory analysis (bilirubin, coagulation parameters, etc.), scoring systems combining laboratory and clinical data (e.g., Model for End-Stage Liver Disease [MELD] score), and quantitative liver function tests (indocyanine green clearance, etc.) which evaluate specific parameters of function [79, 80]. Several strategies have investigated using gadoxetic acid-enhanced MR imaging to evaluate hepatic function. Conceptually, the relative enhancement of liver parenchyma ([hepatobiliary phase liver signal intensity] - [unenhanced liver signal intensity]) is decreased in the setting of hepatic dysfunction,
and correlates with degree of fibrosis, cirrhosis, and postoperative liver failure [48, 81–83]. Hepatobiliary phase hepatic parenchymal enhancement, either calculated directly as relative enhancement or corrected using the spleen or muscle as internal standards, also correlates with laboratory values, scoring systems, and quantitative functional tests used to assess liver function [48, 84–88]. One study utilizing relative enhancement during the hepatobiliary phase showed a sensitivity of 82.8% and specificity of 92.7% for differentiating normal from impaired liver function, and correlated with MELD score [84]. A more comprehensive approach, including dynamic post-contrast MR with gadoxetic acid, assesses hepatic parenchymal enhancement over multiple points in time [86–88]. From this data, perfusion and functional parameters to the segmental and subsegmental levels can be assessed quantitatively and illustrated on image maps for qualitative evaluation. A hypothetical advantage of hepatic parenchyma enhancement to assess hepatic function pertains to conditions in which the liver does not functional homogeneously. These segmental variations of hepatic dysfunction can be identified which could influence which portions of the liver are resected, whereas laboratory analysis assesses only overall liver function [89]. Disadvantages of imaging techniques to assess liver function are that they can be time consuming and require special software. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and is composed of a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Differentiating simple steatosis from NASH is important as nonalcoholic steatohepatitis is associated with an increased risk of developing cirrhosis and HCC [90]. Gadoxetic acid-enhanced MR has proved promising in differentiating these two entities based on liver
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
parenchymal enhancement [91–97]. Bastati et al. showed that patients with NASH have a significantly lower relative enhancement than those with simple steatosis, with a sensitivity and specificity of differentiating these two processes of 97% and 63%, respectively [91]. Another study compared T1 mapping on gadoxetic acid-enhanced MR imaging with semi-quantitative scoring of steatosis, activity, and fibrosis in rabbits [92]. By using T1 mapping to measure the T1 relaxation time and reduction rate of T1 relaxation of the liver parenchyma during the HBP (i.e., T1 shortening effect of gadoxetic acid), differentiating NASH from NAFLD without NASH and normal liver could be achieved with high diagnostic accuracy, with areas under the receiver operating characteristic curves (AUCs) of 0.87 and 0.86, respectively. In addition, theses imaging parameters showed potential value for staging fibrosis with AUCs of 0.86–0.93. Advantages of using T1 mapping is that a quantitative evaluation of gadoxetic acid uptake by the liver parenchyma can be achieved, and T1 relaxation time is an absolute value and less unaffected by technical factors [98– 102]. MR utilizing gadoxetic acid as a method for assessment of liver function and NAFLD requires further validation before its implantation into routine practice. However, given these potential uses and the aforementioned applications of gadoxetic acid, it may be possible for complete liver assessment from one imaging study when imaging with this contrast agent, providing both anatomical and functional information, as well as detection and characterization of focal liver lesions. Additional research and consensus amongst experts is needed to determine whether this comprehensive MR approach is feasible logistically and economically, and influences clinical decisions.
Summary In conclusion, gadoxetic acid is a newer gadolinium contrast agent with a dual capacity for imaging during dynamic and hepatobiliary phases. This contrast agent has the potential to evaluate the hepatic vasculature, hepatic parenchyma, biliary system, and hepatic function in one comprehensive MR exam. However, in order to effectively utilize gadoxetic acid, a strong understanding of its pharmacokinetics and lesion histopathology is necessary as they dictate lesion appearance. Moreover, knowledge of the unwanted effects and pitfalls of gadoxetic acid are imperative for accurate image interpretation and troubleshooting. Acknowledgments. Christopher J. Lisanti receives royalties from Lippincott, Williams and Wilkins.
References 1. Lee NK, Kim S, Lee JW, Lee SH, et al. (2009) Biliary MR imaging with Gd-EOB-DTPA and its clinical applications. Radiographics 29:1707–1724
2. Seale MK, Catalano OA, Saini S, et al. (2009) Hepatobiliaryspecific MR contrast agents: role in imaging the liver and biliary tree. Radiographics 29(6):1725–1748 3. Ringe KI, Husarik DB, Sirlin CB, et al. (2010) Gadoxetate disodium-enhanced MRI of the Liver: Part 1. Protocol optimization and lesion appearance in the noncirrhotic liver. AJR 195:13–28 4. Huppertz A, Haraida S, Kraus A, et al. (2005) Enhancement of focal liver lesions at gadoxetic acid-enhanced mr imaging: correlation with histopathologic findings and spiral CT-initial observations. Radiology 234(2):468–478 5. Cruite I, Schroeder M, Merkle EM, et al. (2010) Gadoxetate disodium-enhanced MRI of the liver: Part 2. Protocol optimization and lesion appearance in the cirrhotic liver. AJR 195:29–41 6. Goodwin MD, Dobson JE, Sirlin CB, et al. (2011) Diagnostic challenges and pitfalls in MR imaging with hepatocyte-specific contrast agents. Radiographics 31(6):1547–1568 7. Ringe KI, Husarik DB, Gupta RT, et al. (2011) Hepatobiliary transit times of gadoxetate disodium (Primovist) for protocol optimization of comprehensive MR imaging of the biliary system—what is normal? Eur J Radiol 79:201–205 8. Mu¨hler A, Heinzelmann I, Weinmann H (1994) Elimination of gadolinium-ethoxybenzyl-DTPA in a rat model of severely impaired liver and kidney excretory function: an experimental study in rats. Invest Radiol 29:213–216 9. Gschwend S, Ebert W, Schultze-Mosgau M, et al. (2011) Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment. Invest Radiol 46:556– 566 10. Fidler J, Hough D (2011) Hepatocyte-specific magnetic resonance imaging contrast agents. Hepatology 53(2):678–682 11. Van Beers BE, Pastor CM, Hussain HK (2012) Primovist, Eovist: what to expect? J Hepatol 57:421–429 12. Zech CJ, Bartolozzi C, Bioulac-Sage P, et al. (2013) Consensus report of the fifth international forum for liver MRI. AJR 201:97– 107 13. Karam AR, Shankar S, Surapaneni P, et al. (2010) Focal nodular hyperplasia: central scar enhancement pattern using gadoxetate disodium. J Magn Reson Imaging 32(2):341–344 14. American College of Radiology (2014) Liver imaging reporting and data system (LI-RADS). Washington, DC: American College of Radiology. http://www.acr.org/quality-safety.resources/lirads. Accessed 29 Dec 2014 15. Zech CJ, Vos B, Nordell A, et al. (2009) Vascular enhancement in early dynamic liver MR imaging in an animal model: comparison of two injection regimen and two different doses of Gd-EOBDTPA (gadoxetic acid) with standard Gd-DTPA. Invest Radiol 44:305–310 16. Nagle SK, Busse RF, Brau AC, et al. (2012) High resolution navigated three-dimensional T1-weighted hepatobiliary MRI using gadoxetic acid optimized for 1.5 Tesla. J Magn Reson Imaging 36(4):890–899 17. Kim S, Mussi TC, Lee LJ, et al. (2013) Effect of flip angle for optimization of image quality of gadoxetate disodium-enhanced biliary imaging at 1.5 T. AJR 200(1):90–96 18. Frydrychowicz A, Nagle SK, D’Souza SL, et al. (2011) Optimized high-resolution contrast-enhanced hepatobiliary imaging at 3 tesla: a cross-over comparison of gadobenate dimeglumine and gadoxetic acid. J Magn Reson Imaging 34:585–594 19. Purysko AS, Remer EM, Coppa CP, et al. (2012) Characteristics and distinguishing features of hepatocellular adenoma and focal nodular hyperplasia on gadoxetate disodium-enhanced MRI. AJR 198:115–123 20. Motosugi U, Ichikawa T, Sou H, et al. (2010) Distinguishing hypervascular pseudolesions of the liver from hypervascular hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging. Radiology 256(1):151–158 21. Grazioli L, Morana G, Federle MP, et al. (2001) Focal nodular hyperplasia: morphologic and functional information from MR Imaging with gadobenate dimeglumine. Radiology 221(3):731–739 22. Zech CJ, Grazioli L, Breuer J, et al. (2008) 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. Invest Radiol 43(7):504–511
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23. Gupta RT, Iseman CM, Leyendecker JR, et al. (2012) Diagnosis of focal nodular hyperplasia with MRI: multicenter retrospective study comparing gadobenate dimeglumine to gadoxetate disodium. AJR 199(1):35–43 24. Grazioli L, Bondioni MP, Haradome H, et al. (2012) Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis. Radiology 262:520–529 25. Choi JW, Lee JM, Kim SJ, et al. (2013) Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced mr images and their value as an imaging biomarker. Radiology 267:776–786 26. Kim YK, Kim CS, Han YM, et al. (2009) Detection of hepatocellular carcinoma: gadoxetic acid-enhanced 3-dimensional magnetic resonance imaging versus multi-detector row computed tomography. J Comput Assist Tomogr 33(6):844–850 27. Sano K, Ichikawa T, Motosugi U, et al. (2011) Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 261(3):834–844 28. Park G, Kim YK, Kim CS, et al. (2010) Diagnostic efficacy of gadoxetic acid-enhanced MRI in the detection of hepatocellular carcinomas: comparison with gadopentetate dimeglumine. Br J Radiol 82:1010–1016 29. Kim YK, Kim CS, Han YM, et al. (2010) Comparison of gadoxetic acid-enhanced MRI and superparamagnetic iron oxideenhanced MRI for the detection of hepatocellular carcinoma. Clin Radiol 65(5):358–365 30. Golfieri R, Renzulli M, Lucidi V, et al. (2011) Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (
Abdominal Imaging
Abdom Imaging (2015) DOI: 10.1007/s00261-015-0354-7
Gadoxetic acid: pearls and pitfalls Ryan B. Schwope,1,2 Lauren A. May,1 Michael J. Reiter,1 Christopher J. Lisanti,1,2 Daniel J. A. Margolis3 1
Department of Radiology, San Antonio Military Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234, USA Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA 3 David Geffen School of Medicine at UCLA, 200 Medical Plaza, #165-43, MC: 695224, Los Angeles, CA 90095-6952, USA 2
Abstract Gadoxetic acid is a hepatocyte-specific magnetic resonance imaging contrast agent with the ability to detect and characterize focal liver lesions and provide structural and functional information about the hepatobiliary system. Knowledge of the pharmacokinetics of gadoxetic acid is paramount to understanding imaging protocol and lesion appearance and facilitates identification and avoidance of undesired effects with use of this intravenous contrast agent. This article reviews the utility of gadoxetic acid in liver and biliary imaging, with emphasis on the hepatobiliary phase. Key words: Gadoxetic acid—Hepatobiliary phase—Magnetic resonance imaging
Magnetic resonance imaging (MR) is an integral instrument in the evaluation of the hepatobiliary system. The introduction of hepatocyte-specific contrast agents such as gadoxetic acid (Gd–EOB–DTPA; Eovist in the US; Primovist outside the US; Bayer HealthCare) has expanded the utility of MR in hepatobiliary evaluation. Due to the dual extracellular and hepatobiliary phases of this contrast agent, gadoxetic acid can provide information similar to that of extracellular contrast agents, in addition to functional and structural information of the hepatobiliary system. However, the unique properties of this hepatocyte-specific agent warrant a discussion of its physiology and how these properties affect MR technique, lesion appearance, and thus image interpretation. This article discusses the pharmacokinetics and technical considerations of gadoxetic acid, with emphasis on the hepatobiliary phase. The expected appearance of the liver and biliary system and the appearances of several hepatic lesions are discussed, in addition to potential Correspondence to: Ryan B. Schwope; email: [email protected]
biliary applications. The evidence supporting the use of gadoxetic acid for hepatobililary imaging is also reviewed. The pitfalls often encountered with use of gadoxetic acid are then addressed and potential solutions to help troubleshoot and decrease unwanted effects on imaging are suggested. Finally, the future directions of gadoxetic acidenhanced MR are discussed, highlighting its potential role in evaluating hepatic function and steatosis.
Pharmacokinetics of gadoxetic acid After intravenous injection, gadoxetic acid first distributes to the extracellular space. Once in the extracellular space gadoxetic acid can either be excreted by the kidneys through glomerular filtration or taken up by hepatocytes [1]. Because of this dual-elimination pathway, some authors have classified gadoxetic acid as a ‘‘combination’’ contrast agent [2]. When taken up by hepatocytes, gadoxetic acid is actively transported into hepatocytes utilizing the organic anion transporting polypeptide 1 (OATP1), the same transport protein used for bilirubin [3– 6]. Excretion of gadoxetic acid from hepatocytes into bile canaliculi is then accomplished via the canalicular multispecific organic anion transport (cMOAT) (Fig. 1) [3, 5]. In patients with normal hepatic and renal function, it can be expected that 50% of gadoxetic acid is excreted by the hepatobiliary system and 50% excreted by the kidneys [3]. Excretion of gadoxetic acid into the biliary system results in increased signal within the bile ducts, gallbladder, and duodenum on T1-weighted imaging. Biliary transit time of contrast is independent of gender, age, body mass index, gastric filling, and MR technical variations (1.5 vs. 3 T), but is dependent on liver function. In patients with normal liver function, Ringe et al. found that contrast can appear in the biliary system as early as 5 min after injection. These authors also found that gadoxetic acid refluxed into the gallbladder in 86.9% and was visualized in the duodenum in 65.5% of patients without biliary pathology. If present, reflux into the
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 1. Diagram showing the physiology and pharmacodynamics of gadoxetic acid. After intravenous injection, gadoxetic acid distributes into the extracellular space. Via organic anion transporting polypeptide 1 (OATP1), gadoxetic acid is
actively transported from extracellular space into hepatocytes, and subsequently transported from hepatocytes into bile canaliculi via canalicular multispecific organic anion transporter (cMOAT).
gallbladder and duodenal visualization typically occurred by 13–14 min and no later than 18–19 min after contrast injection in this study. The fasting state of the patient resulting in variable intraluminal gallbladder and sphincter of Oddi pressures (in theory) will affect gallbladder filling with excreted gadoxetic acid [7]. Given the aforementioned physiologic properties of gadoxetic acid, two important points can be made. First, gadoxetic acid competes with bilirubin for active transport into hepatocytes through OATP1 [6]. If bilirubin levels are elevated, hepatic parenchymal enhancement and biliary excretion of gadoxetic acid will both be decreased [2]. Second, given the dual-elimination excretion, studies have shown compensation by the remaining normally functioning elimination pathway [8, 9]. It has been suggested that this physiologic compensation may have implications for preventing nephrogenic systemic fibrosis (NSF) and that administering gadoxetic acid in a patient with diminished renal function may be safer than administering a purely extracellular agent [10]. However, no study to date presents conclusive results to demonstrate this hypothesized benefit. An additional important property of gadoxetic acid is that it has intrinsically weaker protein binding properties compared to standard gadolinium chelates, resulting in inherently increased T1 relaxivity and shortening [2, 3, 11]. This property of gadoxetic acid is important when evaluating contrast dose as the increased T1 shortening properties of gadoxetic acid allow for smaller dose administration, on the order of onefourth that of standard conventional gadolinium agents
[2]. This decreased dose also has hypothetical implications in patient safety and in decreasing the risk of NSF, although there is no conclusive evidence in the literature to demonstrate this.
Magnetic resonance protocol and technique Gadoxetic acid is typically injected at a rate of 1–2 mL/s with a 20–25 mL normal saline chaser [5, 12]. The FDA approved dose is 0.025 mmol/kg body weight [3, 13]. Initial imaging relies on standard extracellular phase properties shared with conventional gadolinium-based intravenous contrast agents. Sequences are obtained as fat-suppressed 3D T1-weighted gradient-echo sequence with breath hold. Dynamic imaging can be acquired by bolus-tracking technique as follows: axial late arterial phase at 15 s after contrast arrives in the suprarenal aorta, axial portal venous phase at 15–30 s after arterial phase, and axial late dynamic phase at 2–3 min after arterial phase [5, 12]. The late dynamic phase of imaging acquired after the portal venous phase has also been referred to as the transitional phase as both intracellular and extracellular gadoxetic acid contribute to hepatic parenchymal enhancement [14]. Some authors advocate consecutive arterial phase acquisitions so as to optimize obtaining an ideal arterial phase [15]. Fat-suppressed 3D T1-weighted gradient-echo sequences are then obtained in the axial and coronal planes during hepatobiliary phase imaging. Hepatobiliary phase images are acquired during peak hepatocyte uptake and enhancement occurring 10–20 min after injection in patients with
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 2. Effect of the flip angle. Axial T1-weighted images with fat saturation acquired 20 min after injection of gadoxetic acid, using a flip angle of 10 (A) and a flip angle of 35 (B). Notice the increased signal of contrast within the bile ducts on the image acquired with a higher flip angle.
normal hepatocellular function [3, 12]. Hepatocyte enhancement persists for a minimum of 2 h in most patients thereby permitting repeat imaging as needed. An additional tool to optimize MR with gadoxetic acid is to increase the flip angle. Standard T1-weighted flip angles for hepatobiliary imaging range from 10 to 15. However, increasing the flip angle accentuates T1weighting and improves both signal- and contrast-tonoise ratios [16, 17]. The increase in signal- and contrastto-noise ratios will increase hepatic lesion conspicuity and accentuate contrast excreted into the biliary system (Fig. 2), although a significant increase in ghosting artifact relating to contrast in the common bile duct has been found at a higher flip angle of 40 [17]. Frydrychowicz et al. found that optimal flip angles were 25–30 for liver lesion detection and 45 for biliary system interrogation on a 3 T system [18].
Applications Knowledge of the physiologic properties of gadoxetic acid and the histology of hepatic lesions is paramount to liver and biliary imaging with gadoxetic acid, particularly during hepatobiliary phase imaging [6]. During the hepatobiliary phase, lesions that contain functional hepatocytes will take up the contrast agent and appear iso- to hyperintense relative to the hepatic parenchyma, while lesions without functioning hepatocytes will not take up contrast and appear hypointense relative to the surrounding hepatic parenchyma [4]. Many authors have utilized this finding to generate lesion-to-liver signal intensity ratios for the purposes of differentiating intrahepatic lesions [19, 20].
Focal nodular hyperplasia (FNH) FNH is composed of hepatocytes with blind-ending biliary ductules [21]. The hepatocytes are typically increased in density compared to normal liver parenchyma [2]. As a result, during hepatobiliary imaging most FNHs are isointense to hyperintense relative to the liver parenchyma (Fig. 3) [12]. One study showed that 38% of FNHs were uniformly hyperintense, 32% uniformly isointense, 28% mixed signal intensity, and 2% hypointense with respect to the surrounding parenchyma during hepatobiliary phase imaging at 20 min with gadoxetic acid [22]. It is hypothesized that this hyperintense signal may be a result of the increased density of intralesional hepatocytes in addition to the blind-ending biliary ductules precluding effective excretion of contrast [10, 19]. These hepatobiliary phase imaging characteristics of FNH allow a more confident diagnosis, especially in cases when FNH has an atypical appearance on CT or precontrast MR sequences [22]. Indeed, enough literature is now available to support the belief that FNH can be confidently diagnosed with MRI using gadoxetic acid thus precluding the need for biopsy [2]. When diagnosing FNH by MR, lesion conspicuity was superior when comparing hepatobiliary phase imaging acquired 10– 20 min after gadoxetic acid injection to hepatobiliary phase images acquired 1–3 h after gadobenate dimeglumine (another ‘‘combination’’ contrast agent with only 2%–4% uptake by functioning hepatocytes [21]) injection, also shortening MR workflow [23]. Furthermore, gadoxetic acid has been shown to be highly effective in differentiating FNH from hepatic adenomas, which are typically hypointense during hepatobiliary imaging [19,
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
Fig. 3. Focal nodular hyperplasia (FNH). Axial T1-weighted images with fat saturation acquired 20 min after injection of gadoxetic acid. FNHs (arrows) are almost always iso-hyperintense with respect hepatic parenchyma during the hepatobiliary phase.
24]. Purysko et al. found that a relative signal enhancement ratio of 0.7 (comparing lesion to hepatic parenchyma signal intensity during the hepatobiliary phase) was 100% specific and 91.6% sensitive for hepatic adenomas when compared to FNHs [19].
Hepatocellular carcinoma (HCC) As a result of impaired expression of membrane transports, HCCs are typically hypointense compared with hepatic parenchyma on hepatobiliary phase imaging with gadoxetic acid (Fig. 4). Choi et al. showed that 90.1% of HCCs demonstrated such hypointense signal intensity during hepatobiliary phase imaging [25]. This histologic property of HCC and resultant imaging appearance has shown gadoxetic acid as an effective agent in detecting and diagnosing HCC when compared to other modalities and extracellular gadolinium contrast agents. Gadoxetic acid has been shown to be more sensitive in diagnosing HCCs when compared to CT (91.4% vs. 71.6%, respectively) and becomes even more effective than CT when the HCCs are small (£2 cm), with the sensitivities in a two reader study of 97% and 94% for gadoxetic acid and 58% and 68% for contrast-enhanced CT [26, 27]. When compared to gadopentate dimeglumine, gadoxetic acid was shown more sensitive in detecting HCC (86.4% vs. 64.4%) [28]. Additionally, MRI with gadoxetic acid has a higher sensitivity for HCC detection than MRI with superparamagnetic iron oxide (90.7% vs. 84.7%) [29]. The addition of the hepatobiliary phase to dynamic imaging is particularly useful. In identifying small (£2 cm) HCCs in cirrhotics, one study showed an
increase in both sensitivity and specificity by 11% and 7%, respectively, when utilizing both dynamic and hepatobiliary phase imaging with gadoxetic acid vs. dynamic phase imaging alone with gadoxetic acid [30]. Lesion signal intensity during hepatobiliary phase imaging after injection of gadoxetic acid has also shown useful for the detection of early HCC. In patients with cirrhosis, nodules £2 cm that are hypointense on hepatobiliary phase imaging are more likely to represent HCC or progress to HCC [27]. Sano et al. showed that hypointensity on hepatobiliary phase imaging was found as a significant imaging feature in differentiating dysplastic nodules (0% of lesions) from small HCCs (97% of lesions) [27]. In patients with cirrhosis, nodules that are hypointense with respect to hepatic parenchyma on the hepatobiliary phase and demonstrate corresponding hyperintensity on high b value diffusion-weighted imaging (800 s/mm2) are associated with progression to hypervascular HCC [31]. Motosugi et al. have shown lesions which demonstrate hypointense signal (assessed by a liver-to-lesion signal intensity) on hepatobiliary phase favor HCC over pseudolesions, especially if there is corresponding signal abnormality on diffusion-weighted imaging. These authors found that when using a hepatocyte-phase signal intensity cutoff value of less than 0.84, the sensitivity and specificity were 91% in distinguishing hypervascular HCCs from nodular pseudolesions, and that none of the pseudolesions were apparent on diffusion-weighted imaging [20]. Thus, hepatobiliary phase imaging with gadoxetic acid paired with diffusionweighted imaging is a valuable tool when assessing for small HCCs.
Metastases Metastases will appear hypointense after injection of gadoxetic acid during hepatobiliary phase imaging owing to the fact that they lack functioning hepatocytes. This functional difference between hepatocytes and metastasis will increase the lesion-to-liver contrast on hepatobiliary phase imaging improving lesion detection [3]. This is particularly true for identification of small (20% of the total functional liver volume in order to sustain postoperative liver function and enable regeneration [76]. But this future liver remnant estimate is based on healthy liver parenchyma and many patients considered for resection do not have normal hepatic function, whether secondary to cirrhosis or chemotherapy-associated parenchymal dysfunction. In this subset of patients, the volume of future liver remnant needs to be increased relative to the degree of hepatic dysfunction in order to decrease mortality and morbidity related to post-resection hepatic failure [77, 78]. Although variable worldwide and between professional organizations, liver function is typically assessed by serum laboratory analysis (bilirubin, coagulation parameters, etc.), scoring systems combining laboratory and clinical data (e.g., Model for End-Stage Liver Disease [MELD] score), and quantitative liver function tests (indocyanine green clearance, etc.) which evaluate specific parameters of function [79, 80]. Several strategies have investigated using gadoxetic acid-enhanced MR imaging to evaluate hepatic function. Conceptually, the relative enhancement of liver parenchyma ([hepatobiliary phase liver signal intensity] - [unenhanced liver signal intensity]) is decreased in the setting of hepatic dysfunction,
and correlates with degree of fibrosis, cirrhosis, and postoperative liver failure [48, 81–83]. Hepatobiliary phase hepatic parenchymal enhancement, either calculated directly as relative enhancement or corrected using the spleen or muscle as internal standards, also correlates with laboratory values, scoring systems, and quantitative functional tests used to assess liver function [48, 84–88]. One study utilizing relative enhancement during the hepatobiliary phase showed a sensitivity of 82.8% and specificity of 92.7% for differentiating normal from impaired liver function, and correlated with MELD score [84]. A more comprehensive approach, including dynamic post-contrast MR with gadoxetic acid, assesses hepatic parenchymal enhancement over multiple points in time [86–88]. From this data, perfusion and functional parameters to the segmental and subsegmental levels can be assessed quantitatively and illustrated on image maps for qualitative evaluation. A hypothetical advantage of hepatic parenchyma enhancement to assess hepatic function pertains to conditions in which the liver does not functional homogeneously. These segmental variations of hepatic dysfunction can be identified which could influence which portions of the liver are resected, whereas laboratory analysis assesses only overall liver function [89]. Disadvantages of imaging techniques to assess liver function are that they can be time consuming and require special software. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and is composed of a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Differentiating simple steatosis from NASH is important as nonalcoholic steatohepatitis is associated with an increased risk of developing cirrhosis and HCC [90]. Gadoxetic acid-enhanced MR has proved promising in differentiating these two entities based on liver
R. B. Schwope et al.: Gadoxetic acid: pearls and pitfalls
parenchymal enhancement [91–97]. Bastati et al. showed that patients with NASH have a significantly lower relative enhancement than those with simple steatosis, with a sensitivity and specificity of differentiating these two processes of 97% and 63%, respectively [91]. Another study compared T1 mapping on gadoxetic acid-enhanced MR imaging with semi-quantitative scoring of steatosis, activity, and fibrosis in rabbits [92]. By using T1 mapping to measure the T1 relaxation time and reduction rate of T1 relaxation of the liver parenchyma during the HBP (i.e., T1 shortening effect of gadoxetic acid), differentiating NASH from NAFLD without NASH and normal liver could be achieved with high diagnostic accuracy, with areas under the receiver operating characteristic curves (AUCs) of 0.87 and 0.86, respectively. In addition, theses imaging parameters showed potential value for staging fibrosis with AUCs of 0.86–0.93. Advantages of using T1 mapping is that a quantitative evaluation of gadoxetic acid uptake by the liver parenchyma can be achieved, and T1 relaxation time is an absolute value and less unaffected by technical factors [98– 102]. MR utilizing gadoxetic acid as a method for assessment of liver function and NAFLD requires further validation before its implantation into routine practice. However, given these potential uses and the aforementioned applications of gadoxetic acid, it may be possible for complete liver assessment from one imaging study when imaging with this contrast agent, providing both anatomical and functional information, as well as detection and characterization of focal liver lesions. Additional research and consensus amongst experts is needed to determine whether this comprehensive MR approach is feasible logistically and economically, and influences clinical decisions.
Summary In conclusion, gadoxetic acid is a newer gadolinium contrast agent with a dual capacity for imaging during dynamic and hepatobiliary phases. This contrast agent has the potential to evaluate the hepatic vasculature, hepatic parenchyma, biliary system, and hepatic function in one comprehensive MR exam. However, in order to effectively utilize gadoxetic acid, a strong understanding of its pharmacokinetics and lesion histopathology is necessary as they dictate lesion appearance. Moreover, knowledge of the unwanted effects and pitfalls of gadoxetic acid are imperative for accurate image interpretation and troubleshooting. Acknowledgments. Christopher J. Lisanti receives royalties from Lippincott, Williams and Wilkins.
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