Definition

• Gadobenate dimeglumine (Gd-BOPTA) and gadoxetate disodium (Gd-EOB-DTPA) are liver-specific gadolinium-based MR contrast agents.  Liver specific contrast agents have both an extracellular phase and a hepatobiliary phase (HBP) because a portion of the administered dose is taken up by hepatocytes and excreted through the biliary system. HBAs provide information not only about arterial and portal venous phase enhancement, but also about the presence of functioning hepatocytes. These hepatocytes may show variable degrees of expression of the uptake transporter of these contrast agents. 
• Gadobenate dimeglumine and gadoxetate disodium possess different pharmacokinetic properties, which result in different timing of peak hepatic enhancement (hepatobiliary phase). The percentages of hepatobiliary excretion and the temporal windows for hepatobiliary phase imaging are.
  •  Gadobenate dimeglumine:
    • Hepatobiliary excretion: approximately 5% of the administered dose
    • Window for HBP imaging: approximately 1-3 hours (typically 1 hour)
  • Gadoxetate disodium:
    • Hepatobiliary excretion: approximately 50% of the administered dose
    • Window for HBP imaging: approximately 10 minutes - several hours (typically 15-20 minutes) 

Comments:

• Although there is a broad temporal window for hepatobiliary phase imaging, most available data suggest that in non-cirrhotic livers a delay of 15-20 minutes for gadoxetate disodium and a delay of 1 hour for gadobenate dimeglumine consistently provide high-quality hepatobiliary phase imaging.
• The cirrhotic liver may have diminished parenchymal enhancement during the hepatobiliary phase and the time to peak enhancement may be delayed, possibly due to reduced number of functional hepatocytes or dysfunctional cellular transport mechanisms.
• In the setting of cirrhosis and severe hepatic dysfunction, increasing the delay for hepatobiliary phase imaging to 30 minutes or more for gadoxetate disodium and 2-3 hours for gadobenate dimeglumine may improve parenchymal enhancement somewhat; however, it is difficult to predict which patients will have diminished and/or delayed hepatic parenchymal enhancement.
• Enhancement of the hepatic parenchyma during the hepatobiliary phase should be considered suboptimal if the hepatic parenchyma is not unequivocally hyperintense relative to hepatic blood vessels.
• If hepatobiliary phase parenchymal enhancement is suboptimal, characterization of liver observations may be difficult. If an observation is hypointense in the hepatobiliary phase despite suboptimal hepatobiliary phase parenchymal enhancement, the observation may be characterized as hypointense. If an observation is iso- or hyperintense, characterization of hepatobiliary phase intensity may be unreliable.  

Pitfalls:

• Characterization of some masses of non-hepatocellular origin (e.g., hemangiomas and small metastases) may be more difficult with gadoxetic acid. If further characterization of an observation identified on an MR examination with gadoxetate disodium is needed, an examination with an extracellular contrast agent or gadobenate dimeglumine can be performed.
• Some major features of HCC may be more difficult to identify on gadoxetate disodium enhanced examinations.
• Capsule appearance may be more difficult to identify. It may be obscured by the higher signal intensity of the surrounding liver during the transitional phase. It may be less apparent due to reduced extracellular distribution of gadoxetate disodium in the fibrous pseudocapsule.
• Washout appearance may be more difficult to characterize with certainty because hypoenhancement of an observation during the transitional phase may be due to relative hyperenhancement of the surrounding liver parenchyma rather than “washout” of the observation. In individuals with normal hepatic function, some hepatocellular uptake of gadoxetate disodium may be evident during the portal venous phase; therefore, in at risk patients with relatively preserved hepatic function, hepatocyte uptake during the portal venous phase could potentially result in a pseudo-washout appearance, although no studies to date have documented this potential pitfall. 
  • Therefore, on gadoxetate disodium enhanced studies, if an observation demonstrates "washout" during portal venous phase, confident assessment can be made. If an observation becomes hypointense only during transitional phases, caution is advised in assessing "washout". The rationale for this caution is that many observations (metastases, hemangiomas, cholangiocarcinomas) may be hypointense during the hepatobiliary and transitional phases due to the above described enhancement of the liver parenchyma and lack of transporter expression.   
• A small percentage of HCCs may demonstrate iso- or hyperintensity in the hepatobiliary phase.Tumor in vein may be more difficult to identify with gadoxetate disodium due to more rapid venous clearance of contrast in the portal venous, delayed, and transitional phases with resulting decreased vein to tumor contrast.
  • Such HCCs may be misinterpreted as non-malignant nodules (e.g., FNHs and dysplastic nodules). Ancillary imaging features reported to favor the diagnosis of HCC include HBP hypointense rim, nodule-in-nodule architecture, and focal defect in HBP uptake.
• Infiltrative HCC may be difficult to identify and delineate from background cirrhotic liver in the hepatobiliary phase after administration of HBA, due to ill-defined margins and frequent low lesion to parenchyma contrast.
• Locoregional treatment (TACE, RF ablation and local radiation therapy) for HCC may result in geographic areas of reduced hepatic parenchymal enhancement in the hepatobiliary phase, which can limit evaluation for residual or recurrent HCC.  Poor arterial phase image quality, seen in a small minority of patients who receive gadoxetate disodium (see next slide), also could limit early detection of recurrent disease.
• Distinction between HCC and intrahepatic cholangiocarcinoma (ICC), hypervascular metastasis, and hemangioma may be more difficult with hepatobiliary agents. Poor arterial phase image quality has been observed in up to 14% of patients undergoing MRI with gadoxetate disodium and has been attributed to transient dyspnea; however, the cause is not well understood and may be multifactorial.
  • All may show arterial phase hyperenhancement and hepatobiliary phase hypointensity.
  • T2-weighted imaging may be helpful in making the distinction between HCC and hemangioma, as hemangioma often demonstrates marked T2 hyperintensity, whereas HCC usually is less T2 hyper-intense.
  • DWI “target appearance” (central hypointensity surrounded by peripheral hyperintensity) favors ICC over HCC.
  • Hepatobiliary phase “target appearance” (central hyperintensity surrounded by peripheral hypointensity) also favors ICC over HCC.
• High-grade dysplatic nodules and sometimes low-grade dysplastic nodules may be hypointense in the hepatobiliary phase due to underexpression of uptake transporters; thus, not all cirrhotic nodules with HBP hypointensity are HCC.
• Siderotic nodules may be hypointense in the hepatobiliary phase. The mechanism has not yet been determined but may be related to T2* shortening effects of iron and/or underexpression of uptake transporters.
• Focal steatosis may be hypointense in the hepatobiliary phase. The mechanism has not yet been determined but may be related to suppression of fat containing voxels on fat-suppressed T1w images and/or underexpression of uptake transporters.

Additional Information:

• Gadoxetate disodium is transported from the extracellular space into hepatocytes by the organic anion transporting polypeptide 1B3 (OATP1B3), which also has been referred to in the medical literature as OATP8.  The specific OATP that transports gadobenate dimeglumine into hepatocytes has not yet been established.  Both agents subsequently are excreted into the biliary canaliculi by the canalicular multispecific organic anion transporter (cMOAT) (also known as the multidrug resistance protein 2 [Mrp2]).
• Genetic polymorphism of transporters and drug-drug interactions may affect hepatocyte uptake of hepatobiliary agents. Other factors associated with reduced hepatobiliary phase enhancement include high bilirubin, AST and MELD score and Child-Pugh class C functional status. The degree of morphologic changes of cirrhosis alone do not appear to correlate with the degree of hepatocyte enhancement.
• Most HCCs appear hypo-intense to liver during the hepatobiliary phase, but HCC with overexpression of uptake transporter OATP1B3/OATP8 may demonstrate iso- or hyperintensity in the hepatobiliary phase.