Review of Hepatobiliary Contrast Agents: Current Applications and Challenges

Transcription

1 REVIEW Review of Hepatobiliary Contrast Agents: Current Applications and Challenges Alex Frydrychowicz, M.D.*, The group of hepatobiliary contrast agents comprises two gadolinium-based contrast agents (GBCAs) that show a specific amount of hepatocellular uptake and biliary excretion. Gadobenate dimeglumine (Gd-BOPTA; Bracco Diagnostics) and gadoxetic acid (Gd-EOB-DTPA; Bayer Healthcare) are US Food and Drug Administration (FDA)-approved agents for magnetic resonance imaging (MRI) and for detection and characterization of liver lesions, respectively. A third agent with hepatobiliary properties, gadofosveset trisodium, has recently been discontinued. The success of these so-called hepatobiliary contrast agents (hbgbcas) is essentially related to satisfying the fundamental motive in MRI that is, the pursuit to structurally characterize tissues or lesions. Specifically, MRI s high intrinsic soft tissue contrast with its ability to enhance specific tissue characteristics is further amended by the ability of hbgbcas to detect hepatocytes and biliary canaliculi. In combination, the use of hbgbcas in MRI is a powerful diagnostic instrument. hbgbcas carry the dual properties of acting like conventional GBCAs during the first pass and early phases of contrast enhancement, and by revealing the characteristic delayed or hepatobiliary enhancement. In the initial phases after injection, their contrast enhancement is dominated by the distribution in vessels and the extracellular space like in conventional GBCAs. However, unlike other GBCAs, hbgbcas are then taken up by functional hepatocytes. As a result, there is a persistent enhancement in hepatocytes that allows for identifying lesions of Abbreviations: EMA, European Medicines Agency; FDA, US Food and Drug Administration; FNH, focal nodular hyperplasia; GBCA, gadolinium-based contrast agent; HA, hepatic adenoma; hbgbca, hepatobiliary GBCA; MRC, magnetic resonance cholangiography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; NSF, nephrogenic systemic fibrosis. From the *University of L ubeck, Campus L ubeck, and Department of Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, Campus L ubeck, Ratzeburger Allee 160, Haus 40, 23562, L ubeck, Germany. Potential conflict of interest: Nothing to report. Received 29 September 2017; accepted 7 December 2017 View this article online at wileyonlinelibrary.com VC 2018 by the American Association for the Study of Liver Diseases 22 CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD

2 FIG 1 MRI of the liver using the hbgbca gadoxetic acid in a 23-year-old woman sent to characterize an incidental liver mass. A mass with a slight edema (A) in the right liver lobe can be appreciated. Typical hbgbca enhancement features of this histologically proven FNH (Mohajer type 1 pattern 3 ) can be recognized: hypervascularity on the arterial-phase image with a central scar (B), decreasing enhancement that is isointense to hyperintense to the liver in the portal venous and venous phases (C and D), and persistent enhancement during the delayed or hepatobiliary phase [E and F, respectively; shown are scans at 20 (E) and 30 minutes (F) after injection]. hepatocellular origin. In addition, the biliary excretion allows for both identifying lesions that contain biliary canaliculi and enhancing the biliary excretion system for magnetic resonance cholangiography (MRC). Of note, there is a relative difference in hepatobiliary excretion between both agents (gadoxetic acid: 50%, gadobenate dimeglumine: 4-5%) leading to biliary enhancement starting at 15 to 25 minutes after injection (gadoxetate acid) and 60 to 90 minutes (gadobenate dimeglumine), which has an impact on workflow considerations. Also, there are reports that add to the author s experience that there are qualitative differences in imaging properties during the early phases of contrast enhancement that are dominated by the extracellular properties of both agents related to the earlier extraction of gadoxetic acid from the extracellular space. However, the published data are not yet conclusive. Some authors have therefore suggested to increase the dose of gadoxetic acid. 1,2 Although the advantage of hbgbcas over other GBCAs in characterizing hepatocellular carcinoma and differentiating HCC from dysplastic regenerative nodules is a matter of ongoing research, their strength can truly be appreciated in the differential diagnosis of hepatic adenomas (HAs) and focal nodular hyperplasia (FNH). 3 Although both are benign tumors of hepatocellular origin, HAs show a variable appearance, may show hemorrhage, and have been associated with the risk for malignant transformation. The key for differentiating both lesions is the presence of biliary structures: Although FNHs contain often malformed biliary canaliculi, 23 CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD

3 FIG 2 MRI characteristics of a histologically proven HA in a 31-year-old woman with gadoxetic acid--enhanced MRI. Although this lesion shows similar edema (A) and intense arterial-phase enhancement (B) as compared with the lesion in Fig. 1, it is isointense to slightly hypointense during the portal venous (C) and venous phases (D), and does not exhibit contrast enhancement during the delayed or hepatobiliary phase (E and F). The asterisk (*) marks an unexplained, transient arterial enhancement of Couinaud liver segment 5. they are typically absent in HAs. As shown in Figs. 1 and 2, this leads to comparable imaging features during the early phases of contrast enhancement, but distinct differences in the delayed or hepatobiliary phase. In the delayed phase, the FNH retains contrast enhancement and will therefore reveal an isointense to hyperintense signal in comparison with the liver parenchyma. HAs, however, lack biliary structures and will typically be hypointense during the delayed phase as compared with healthy liver parenchyma. Similarly, lesions without hepatocytes such as metastases can readily be differentiated because of the lack of hepatocellular uptake. An indepth overview can be found in Frydrychowicz et al. 2 Nevertheless, care should be taken not to blindly trust hbgbca-enhanced magnetic resonance images only. The entire spectrum of MRI sequences including diffusionweight imaging should be used to narrow in on the most likely diagnosis. Especially in the presence of hemorrhage or inflammation, both FNH and HA can present with very variable MRI characteristics, and biopsy may be required. There are sparse data regarding the clinical value of hbgbca-based MRC and the comparison with threedimensional T 2 -weighted magnetic resonance cholangiopancreatography (MRCP). The available data suggest that both MRCP and MRC should be used complementary. 4 Especially in postoperative courses, the biliary excretion of hbgbcas can be advantageous in questions such as biliary leakage (see Fig. 3) or patency of biliodigestive anastomosis. In the latter, contrast enhancement in the duodenum after hbgbca application is able to confirm patency of the anastomosis, functional information that is not available by MRCP alone. Notably, when performing hbgbca-mrc, adaptation of the flip angle to the applied contrast agent and field strength has shown to be beneficial to the resulting image quality. 1,5 24 CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD

4 normal liver function from those with various stages of liver cirrhosis. With the increased availability of mapping sequences, this approach has recently been revisited by various authors and is promising for future comprehensive liver imaging protocols. Challenges potentially relevant to hbgbca MRI are associated with the clearance of each agent from the body. To one end, nephrogenic systemic fibrosis (NSF) has led to reconsideration of any indiscriminate application and dosing of GBCAs. This topic has fortunately calmed down significantly using caution in selecting patients with sufficient renal clearance. Also, the preference of so-called macrocyclic instead of linear GBCA compounds, as well as attention towards the molecular charge, may have contributed to decreased NSF incidence. 7 Although there is an ongoing debate on this complex matter, it has to be noted that even though both hbgbcas are linear compounds, they have been associated with few, if any, NSF incidents. 8 In light of reports on compensatory mechanisms regarding the excretion pathway being upscaled in restricted renal function, 9 the hepatobiliary excretion may be a decisive factor. FIG 3 Detection of biliary leakage in a 35-year-old male patient after surgery because of traumatic liver laceration. The patient returned several days after having been discharged free of symptoms with unspecific abdominal symptoms. An ultrasound survey picked up free fluid next to the liver. The patient had MRI, which confirmed prehepatic fluid (A, asterisks) adjacent to the falciform ligament where the rupture had been treated (white arrow). During delayed-phase imaging (B, 25 minutes; C, 45 minutes after injection of gadoxetic acid) biliary leakage was confirmed by extrahepatic pooling of contrast agent (1). Note the beginning of biliary contrast enhancement at 25 minutes after injection (open arrows) and a dilated bile duct in Couinaud liver segment 2 (arrowhead). The ability to exploit the functional information using hbgbcas has spurred state-of-the-art research. Under the premise that functional hepatocytes are necessary for hepatocellular uptake of these GBCAs, liver enhancement is correlated with hepatocytic function. Katsube et al. 6 have shown Look-Locker-type T 1 -mapping to evaluate T 1 -shortening as the effect of liver enhancement at different time points after gadoxetic acid injection. They were able to quantitatively differentiate patients with To the other end, the debate on linear versus macrocyclic GBCAs has just recently been revisited following reports on the deposition of gadolinium in the dentate nucleus. 10 Whereas in Europe, the European Medicines Agency (EMA) has recommended to suspend linear GBCAs to the European Commission despite no adverse health effects having been identified, 11 the FDA has stated to continue assessing all GBCAs safety and to reevaluate GBCAs pending further testing. 12 Interestingly, the EMA s recommendations to suspend linear GBCAs excluded gadoxetic acid and suggested to restrict the use of gadobenate dimeglumine to liver imaging, most likely taking into account the hbbgca s unmatched diagnostic properties and excretion pathways. Another noteworthy challenge when using gadoxetic acid is an unphysiological mechanism not yet fully understood: There are reports on shortened breathhold durations in some patients due to a transient dyspnea linked to the injection of gadoxetic acid. 13 This phenomenon has since been confirmed by other authors and can explain the deterioration of arterial-phase breathhold imaging in some cases and should be taken into account when setting up dynamic-phase imaging protocols when 25 CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD

5 using gadoxetic acid. Consequently, this may have unfavorable effects in arterial-phase imaging and especially for HCC detection and characterization, and may have influenced, at least to some extent, the published results on HCC detection rates. Also, variable signal characteristics of some HCCs in the hepatobiliary phase should be taken into account. Typically, HCCs present hypointense on T 1 -weighted fat-saturated images. In some cases, delayed-phase T 1 -weighted hyperintensity can be observed that has been attributed to different, increased expression rates of the transporters necessary for the hepatobiliary excretion pathway. 14 In summary, hepatobiliary gadolinium-based contrast agents are powerful diagnostic instruments that satisfy routine diagnostic imaging demands and can act as problem-solvers in situations such as liver lesion differentiation or biliary leakage. Their unique diagnostic potential may be further augmented by T 1 mapping of liver function. Also, the proposed compensatory excretion mechanism is potentially beneficial to patients with decreased renal function. CORRESPONDENCE Alex Frydrychowicz, M.D., University Hospital Schleswig-Holstein, Campus L ubeck, Department of Radiology and Nuclear Medicine, Ratzeburger Allee 160, Haus 40, L ubeck, Germany. alex.frydrychowicz@uksh.de REFERENCES 1) Frydrychowicz AP, Nagle SK, D Souza SL, Vigen KK, Reeder SB. Optimized high-resolution contrast-enhanced hepatobiliary imaging at 3 tesla: a cross-over comparison of gadobenate dimeglumine and gadoxetic acid. J Magn Reson Imaging 2011;34(3): ) Frydrychowicz AP, Lubner MG, Brown JJ, et al. Hepatobiliary MR imaging with gadolinium-based contrast agents. J Magn Reson Imaging 2012;35: ) Mohajer K, Frydrychowicz AP, Robbins JB, Loeffler AG, Reed TD, Reeder SB. Characterization of hepatic adenoma and focal nodular hyperplasia with gadoxetic acid. J Magn Reson Imaging 2012;36: ) Frydrychowicz AP, Jedynak AR, Kelcz F, Nagle SK, Reeder SB. Gadoxetic acid-enhanced T1-weighted MR cholangiography in primary sclerosing cholangitis. J Magn Reson Imaging 2012;36: ) Nagle SK, Busse RF, Brau ACS, et al. High resolution navigated three-dimensional T(1)-weighted hepatobiliary MRI using gadoxetic acid optimized for 1.5 Tesla. J Magn Reson Imaging 2012;36: ) Katsube T, Okada M, Kumano S, et al. Estimation of liver function using T1 mapping on Gd-EOB-DTPA-enhanced magnetic resonance imaging. Invest Radiol 2011;46: ) Altun E, Martin DR, Wertman R, Lugo-Somolinos A, Fuller ER 3rd, Semelka RC. Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy---report from two U.S. universities. Radiology 2009;253: ) Khawaja AZ, Cassidy DB, Shakarchi Al J, McGrogan DG, Inston NG, Jones RG. Revisiting the risks of MRI with gadolinium based contrast agents-review of literature and guidelines. Insights Imaging 2015;6: ) Kirchin MA, Lorusso V, Pirovano G. Compensatory biliary and urinary excretion of gadobenate ion after administration of gadobenate dimeglumine (MultiHance VR ) in cases of impaired hepatic or renal function: a mechanism that may aid in the prevention of nephrogenic systemic fibrosis? Br J Radiol 2015; 88: ) Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014; 270: ) EMA s Final Opinion Confirms Restrictions on Use of Linear Gadolinium Agents in Body Scans. European Medicines Agency EMA/457616/2017. Published July 21, europa.eu/docs/en_gb/document_library/referrals_document/gadoli nium_contrast_agents_31/opinion_provided_by_committee_for_ Medicinal_Products_for_Human_Use/WC pdf 12) Drug Safety and Availability, FDA Drug Safety Communication: FDA Identifies No Harmful Effects to Date With Brain Retention of Gadolinium-Based Contrast Agents for MRIs; Review to Continue. Published May 22, ucm htm 13) Davenport MS, Viglianti BL, Al-Hawary MM, et al. Comparison of acute transient dyspnea after intravenous administration of gadoxetate disodium and gadobenate dimeglumine: effect on arterial phase image quality. Radiology 2013;266: ) Suh YJ, Kim M-J, Choi J-Y, Park YN, Park MS, Kim KW. Differentiation of hepatic hyperintense lesions seen on gadoxetic acidenhanced hepatobiliary phase MRI. AJR Am J Roentgenol 2011;197: W44-W CLINICAL LIVER DISEASE, VOL 11, NO 1, JANUARY 2018 An Official Learning Resource of AASLD