Hepatocyte-specific magnetic resonance Imaging contrast agents
Authors: Jeff Fidler, David Hough
Journal: Hepatology (2011)

A 59-year-old female with a past history of oral contraceptive use presents with right upper quadrant pain. Her physical examination and liver biochemical tests are normal. The alpha-fetoprotein level is also within normal limits. The abdominal computed tomography (CT) scan shows a small mass in the kidney that raises the suspicion of renal cell carcinoma. Images through the liver show a vague mass with some peripheral hyperenhancement in the right lobe of the liver (Fig. 1A). What is the role of magnetic resonance imaging (MRI) in the characterization of indeterminate liver masses? Is there any benefit in using newer MRI contrast agents such as Eovist? FNH: a 59-year-old woman with newly diagnosed renal cell carcinoma and a past history of oral contraceptive use. (A) CT demonstrates a vague mass with some peripheral enhancement in the right lobe of the liver (arrows). MRI with gadoxetate disodium during (B) the arterial phase, (C) the portal venous phase, and (D) the delayed hepatocyte phase shows a lobulated, hyperenhancing mass (arrows). This mass retains contrast during the delayed hepatocyte phase. The enhancement during the hepatocyte phase suggests a tumor of hepatocyte origin with normally functioning hepatocytes. According to the morphology and enhancement characteristics, this mass is consistent with FNH. CH, cavernous hemangioma; CT, computed tomography; FL-HCC, fibrolamellar hepatocellular carcinoma; FNH, focal nodular hyperplasia; HA, hepatic adenoma; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; NSF, nephrogenic systemic fibrosis. Improvements in imaging technology and more widespread utilization of imaging techniques have led to increased detection of liver masses. In many cases, a lesion can be diagnosed with certainty because of its characteristic appearance. However, the appearances may not always be typical. Hepatic masses may be enhanced more than, less than, or equally to normal hepatic parenchyma; this depends on the nature of the lesion, the timing of the scan with respect to the contrast bolus, and the attenuation of the liver during CT (e.g., normal attenuation versus low attenuation from fatty infiltration). Lesions that typically show arterial phase hyperenhancement include cavernous hemangioma (CH), focal nodular hyperplasia (FNH), hepatic adenoma (HA), hepatocellular carcinoma (HCC), fibrolamellar hepatocellular carcinoma (FL-HCC), and certain metastases (e.g., neuroendocrine tumors and breast cancer). The degree, pattern, and temporal appearance of the enhancement are all helpful in the characterization of these masses. CHs typically show nodular or globular, discontinuous peripheral enhancement with progressive centripetal filling over time. Small CHs may show more homogeneous flash filling during the early arterial phase. On MRI, the lesions are usually well defined with high signal intensity on T2-weighted images. On ultrasound, they are typically echogenic with through transmission, but they may be hypoechoic in a fatty liver. The typical appearance of FNH is a diffusely homogeneous, hyperenhancing, slightly lobulated mass during the arterial phase of imaging (Fig. 1B).1-6 The contrast enhancement quickly equilibrates with the normal liver parenchyma during the portal venous phase, and the lesion may be difficult to visualize (Fig. 1C). On MRI, FNH may have subtle, low signal intensity on T1-weighted images and minimal, high signal intensity on T2-weighted images. A central scar is usually present; however, central scars can also be seen in other tumors.1 The scar in FNH usually has high signal intensity on T2-weighted images secondary to the presence of vessels and bile ducts within the scar. Delayed scans may show enhancement of the scar. This appearance may help to differentiate the more fibrotic scar of FL-HCC, which typically is hypointense and has less enhancement.1 The visualization of a central feeding artery or draining vein can improve diagnostic specificity. On ultrasound, FNH can have variable echogenicity. FNH lesions are usually isoechoic to the normal liver and have been termed stealth lesions. Color and power Doppler may show increased central stellate vascularity. The appearance of HAs varies according to the size and complexity of the lesions. On CT and MRI, smaller lesions typically show nearly homogeneous hyperenhancement. Larger lesions may appear more heterogeneous and may contain areas of fat, hemorrhaging, necrosis, and rarely calcification. A fibrous capsule may be present in one-third of an HA. On ultrasound, the echogenicity depends on the presence of fat, hemorrhaging, or calcification.7 The detection of HCC in a cirrhotic liver is often challenging, and differentiation from regenerative nodules and perfusion abnormalities can be difficult. Multiphase imaging with CT and MRI is important for optimizing the detection and characterization of lesions. The presence of an arterial hyperenhancing mass that shows washout (low attenuation on CT or low signal intensity on MRI with respect to the normal parenchyma) on portal venous phase or delayed images is considered diagnostic. HCC may also demonstrate some peripheral delayed enhancement secondary to a pseudocapsule. FL-HCCs are hyperenhancing masses that may have a central fibrotic scar with a low density on CT and a low signal intensity on MRI. The scar usually is not enhanced on delayed images and may have areas of calcification Although the classic appearance of the aforementioned hepatic masses is well known, atypical appearances are not uncommon and can lead to uncertainty in diagnosis. Atypical findings may occur in 10% to 50% of FNH cases.2 Several atypical findings have been reported; they include a high T1 signal (fat, hemorrhaging, or copper), a low T2 signal (iron), less intense arterial enhancement, tumor heterogeneity, an unusual appearance of the central scar such as no enhancement or an absence (up to 50%), and the presence of a pseudocapsule (10%-37%).1, 2 In such situations, it may be difficult to differentiate FNH from adenoma, HCC, or metastases. Therefore, in these inconclusive cases, further imaging or biopsy is usually performed. Currently, MRI offers several advantages over other techniques, including improved soft tissue contrast and the ability to use different contrast agents to improve lesion detection and characterization. There are two main categories of gadolinium contrast agents used for hepatic imaging: extracellular agents and hepatocyte-specific agents (Table 1).8, 9 The most widely used are the extracellular gadolinium agents, which are used for routine imaging throughout the body. These agents circulate in the vascular system, are distributed into the extracellular space, and are excreted by the kidneys. The enhancement characteristics of hepatic lesions are similar to those seen on CT. However, in some cases, the enhancement may be more conspicuous on MRI because of the increased soft tissue contrast. There are two liver-specific contrast agents: gadobenate dimeglumine (MultiHance, Bracco) and gadoxetate disodium (Eovist from Bayer HealthCare, which is also known as Primovist in Europe).8, 9 These agents are taken up by normally functioning hepatocytes and are excreted into the biliary system. Therefore, these agents may be able to differentiate tumors that have normally functioning hepatocytes and biliary excretion from those that do not. Both gadobenate dimeglumine and gadoxetate disodium are injected dynamically and are circulated and distributed in the extracellular space similarly to extracellular gadolinium agents. Therefore, similarly to the extracellular agents, imaging can be performed during the arterial and portal venous phases. However, the ability to allow delayed hepatocyte-specific imaging provides additional information. Gadobenate dimeglumine is taken up by hepatocytes and is excreted into the biliary system by anion transport. Delayed imaging, also known as the hepatocyte phase, is usually performed at 60 to 90 minutes. Delayed imaging allows the differentiation of lesions that have normally functioning hepatocytes, which show some degree of contrast uptake, from lesions without normally functioning hepatocytes, which have lower intensity in comparison with normal parenchyma. Gadoxetate disodium is transported from the extracellular space into the hepatocytes by adenosine triphosphate–dependent organic anion transporting polypeptide 1. It is subsequently excreted into the biliary canaliculi by the canalicular multispecific organic anion transporter.8 Fifty percent of this agent is excreted by the biliary system, whereas only 5% of gadobenate dimeglumine is. Therefore, there is more intense enhancement of the liver with gadoxetate disodium. In addition, the hepatocyte phase scans can be performed at only 20 minutes, and this improves efficiency. A limitation of gadoxetate disodium is that the recommended dose of 0.025 mmol/kg (0.1 mL/kg) is only one-quarter of the dose of gadobenate dimeglumine and various other extracellular agents (0.1 mmol/kg or 0.2 mL/kg). The volume of contrast administered to a 70-kg patient is one-half or 7 mL. This may lead to diminished arterial phase hepatic enhancement, and achieving the optimal scan delay to capture peak arterial enhancement is technically challenging. The main role of the hepatic-specific agents is to improve both the detection and characterization of lesions. These agents may be helpful in improving the detection of small or subtle masses.10-12 By increasing the contrast between the markedly enhanced normal parenchyma and hypoenhanced or unenhanced masses, they may improve the detection of smaller lesions. This may be helpful in the preoperative assessment of patients who are being evaluated for surgical resection of malignant hepatic masses such as metastases from colorectal cancer. These agents may also increase the conspicuity of subtle or ill-defined masses such as treated malignancies or intrahepatic cholangiocarcinomas. However, further studies are needed to compare these agents to the conventional extracellular agents. Lesions of hepatocellular origin (FNH, HA, and well-differentiated HCC) may show uptake and retention of these contrast agents, and this can help to differentiate them from nonhepatocellular tumors (e.g., CH and metastases).9 Understanding the histology of these tumors helps us to explain their appearance during the delayed phase when hepatic-specific agents are used. FNH consists of normally functioning, densely packed hepatocytes and abnormal, blind-ending bile ductules, which result in contrast retention and delayed biliary excretion. This combination of findings produces the high signal intensity seen in these lesions during the delayed hepatocyte phase (Fig. 1D).8 However, the degree of enhancement of FNH during the delayed hepatocyte phase can vary. In a study of 59 cases of FNH using gadoxetate disodium, the pattern of enhancement during the hepatocyte phase was homogeneous in 36% to 41%, heterogeneous in 31% to 36%, mainly in the rim in 17% to 19%, and absent in 10% to 12%.13 HAs lack biliary ductules; therefore, no biliary excretion is seen in these tumors.7, 8 Thus, many adenomas appear hypointense during the hepatocyte phase (Fig. 2); however, there have been some reports of enhancement with gadoxetate disodium.8 Hepatic adenomatosis: a 34-year-old woman with a history of oral contraceptive use. CT shows multiple liver masses. MRI with gadoxetate disodium shows (A) during the arterial phase hyperenhancing masses (arrows) that rapidly wash out with peripheral rim enhancement (B) during the portal venous phase. (C) During the delayed hepatocyte phase, the masses are hypointense to the normal liver. The lack of contrast retention during the hepatocyte phase suggests a tumor lacking normally functioning hepatocytes. According to the age, history, and multiplicity, this is consistent with adenomatosis. Because these agents are excreted into the biliary system, they can also be used to image the bile ducts. This may be helpful for better demonstrating the biliary anatomy or function or evidence of a bile duct leak. Even though these agents are taken up by hepatocytes and are excreted into the biliary system, the appearance of lesions during the portal venous phase and delayed phase differs between these two agents. Gadoxetate disodium is rapidly extracted from the blood pool. Therefore, the blood vessels and CHs may begin to lose contrast during the portal venous phase and have lower signals during the hepatocyte phase. A lack of familiarity with these properties can result in the misdiagnosis of common lesions such as CHs. Because of the longer delay in biliary excretion with gadobenate dimeglumine, the blood vessels and CHs have an enhancement appearance similar to that of extracellular agents during the portal venous phase. HCC may behave differently according to the degree of differentiation of the tumor. Well-differentiated tumors may show some uptake and retention of these contrast agents (Fig. 3), whereas poorly differentiated tumors usually will not. Therefore, before using these agents, one should have a thorough understanding of the pharmacokinetics in the setting of cirrhosis. HCC: an 83-year-old man with biopsy-proven, well-differentiated HCC. MR with gadoxetic disodium during the delayed hepatocyte phase shows a large mass (arrows); portions of the mass are enhanced to the same degree as the normal liver parenchyma. Well-differentiated HCC may have some normally functioning hepatocytes retaining contrast during the delayed hepatocyte phase. A common problem that arises in clinical practice is the differentiation of FNH and HA. There are limited data on the use of these agents in differentiating these two masses. Using gadobenate dimeglumine, Grazioli et al.7 showed that 96.9% of 128 FNHs were hyperintense or isointense during the delayed hepatocyte phase, whereas 100% of 107 adenomas were hypointense. In a smaller study assessing several types of tumors with gadoxetate disodium, Hupperts et al.14 found in three cases that FNH showed heterogeneous enhancement during the delayed hepatic phase. Both adenomas in the study showed hyperenhancement; one was heterogeneous, and the other was homogeneous. Therefore, further studies are needed to understand why gadoxetate disodium uptake occurs in some adenomas. Poorly functioning hepatocytes, which appear during cirrhosis and biliary obstruction (bilirubin level > 3 mg/dL), may lead to limitations in the usefulness of these agents due to poor hepatic uptake and excretion. Thus, these contrast agents may not be helpful in detecting tumors in deeply jaundiced patients and in many patients with cirrhosis. The role of these agents in the diagnosis of cholangiocarcinoma is also unclear. Frequently, intrahepatic cholangiocarcinoma may be ill defined and difficult to detect or quantitate because of poorly marginated borders. The ability of gadoxetate disodium to provide intense hepatic enhancement provides a theoretical advantage over conventional contrast agents for improving the conspicuity of cholangiocarcinoma. However, because hilar cholangiocarcinoma frequently causes biliary obstruction, there may be many cases in which the obstruction and the elevated bilirubin level limit the use of gadoxetate disodium. All of the gadolinium agents have similar side effects that rarely occur, including nausea, headache, and allergic reactions. The administration of gadolinium should be avoided in individuals with impaired renal function and a low estimated glomerular filtration rate to reduce the risk of nephrogenic systemic fibrosis (NSF). Theoretically, gadolinium agents that have more stability or have biliary excretion may be less likely to induce NSF. Both gadoxetate disodium and gadobenate dimeglumine are more stable than the extracellular agents and are excreted through the biliary system. However, there are currently no scientific data to confirm that these agents reduce the risk of development of NSF. In this case, MRI with either gadobenate dimeglumine or gadoxetate disodium would be recommended to help in differentiating between FNH and adenoma (Fig. 1B-D). In the rare situation in which these lesions cannot be differentiated because of atypical findings, percutaneous biopsy may be considered. If the lesion appears to be an HA, serial follow-up would be indicated.