3 Contrast Agents for Liver MR Imaging CONTENTS tra-hepatic abdomen [15]. However, until the ad- vent of multi-detector CT (MDCT), the value of 3.1 Introduction conventional CT for the characterization of focal 3.1.1 Non-Specific Gadolinium Chelates liver lesions was generally considered to be inferior 3.1.2 Hepatocyte-Targeted Contrast Agents to that of contrast-enhanced magnetic resonance 3.1.3 Agents with Combined Extracellular and imaging (MRI) [123]. With the recent develop- Hepatocyte-Specific Distribution ments in MDCT technology, particularly the emer- 3.1.4 RES-Specific Contrast Agents gence of 16- and 64-row scanners combined with 3.2 Injection Schemes for Liver MRI with highly concentrated iodinated contrast agents, the Different Contrast Agents impact of CT in both detection, and to a lesser ex- 3.3 Radiologic Classification of Focal Liver tent, characterization of focal liver lesions has Lesions on Unenhanced and Contrast- markedly improved [30, 61, 117]. In particular, CT Enhanced MRI has substantially shorter acquisition times, the pos- 3.4 Summary sibility to acquire thin sections on a routine basis within a single breath-hold, the opportunity to ret- rospectively calculate thinner or thicker sections from the same raw data, and improved 3D-postpro- cessing techniques. These features now permit the 3.1 acquisition of similar diagnostic information to Introduction that attainable on contrast-enhanced MRI with conventional extracellular gadolinium contrast The imaging evaluation of patients with suspected agents, where information derives from differential liver masses has three principal purposes: blood flow between the tumor and surrounding • lesion detection, normal liver parenchyma. However, unlike the situ- • lesion characterization, ation in MRI, there are as yet no hepatospecific • evaluation of the intra- and extrahepatic extent contrast agents available for CT. Hence, additional of tumor. information based on the functionality of liver le- All three of the major non-invasive imaging sions, which is attainable with MRI, is not yet at- modalities have roles to play in liver imaging. tainable with MDCT. Moreover, concern over the Ultrasound (US) has traditionally been used for nephrotoxicity of certain iodinated contrast agents the primary screening of patients with abdominal [128] and the requisite use of ionizing radiation in pain, but the advent of contrast-enhanced US tech- CT examinations are factors which should always niques now makes it a highly capable methodology be considered when referring patients for diagnos- for both the characterization and improved detec- tic evaluation of the liver. tion of liver masses [60, 93]. Computed tomogra- In contrast to the situation in CT,several differ- phy (CT) has generally been considered the imag- ent classes of contrast agent are available for rou- ing approach of choice for the detection of liver tine clinical use in MRI of the liver [39, 43, 70, 105, masses principally because of the ease of perform- 122]. These include non-specific materials that dis- ing and interpreting large numbers of examina- tribute extracellularly in a manner similar to that tions, its widespread availability, and its generally of the iodinated agents used in CT, materials that acknowledged superior ability to evaluate the ex- are taken up specifically by hepatocytes and ex- 54 MRI of the Liver creted in part through the biliary system, and ma- 147]. The four non-specific gadoliniumchelates ap- terials that are targeted specifically to the Kupffer proved in the USA are gadopentetate dimeglumine cells of the reticuloendothelial system (RES) (Ta- (Magnevist®, Gd-DTPA; Berlex Laboratories/Scher- bles 1, 2). The differential use of these agents, de- ing AG), gadoteridol (ProHance®, Gd-HP-DO3A; pending on the clinical purpose, can maximize the Bracco Diagnostics), gadodiamide (Omniscan®, Gd- diagnostic information available to the investigat- DTPA-BMA; GE Healthcare), and gadoversetamide ing radiologist. This chapter describes the proper- (Optimark®, Gd-DTPA-BMEA; Mallinckrodt). Other ties and indications for each category of contrast non-specific gadolinium agents currently approved agent for MRI of the liver. only in Europe include gadoterate meglumine (Dotarem®, Gd-DOTA; Guerbet) and gadobutrol (Gadovist®, Gd-BT-DO3A; Schering AG) (Table 2). 3.1.1 Although the safety profiles of these agents are all Non-Specific Gadolinium Chelates extremely attractive, especially in comparison to io- dinated x-ray contrast agents [39, 54, 70, 79, 80, 82, Chelates of the paramagnetic gadolinium ion that 105, 107, 127, 132], possible problems associated distribute solely to the extracellular space (i.e. do with the least stable of these agents (gadodiamide not have any tissue-specific biodistribution) have and gadoversetamide) [54] have recently come to been commercially available since 1986 [113, 136, light. Specifically, both gadodiamide and gadoverse- Table 1. Contrast agent type Manufacturer Principal Mechanism Extracellular Gd agents Gadopentetate dimeglumine; Gd-DTPA (Magnevist®) Schering1 / Berlex2 T1 shortening Gadoteridol; Gd-HP-DO3A (ProHance®) Bracco3 ,4 T1 shortening Gadodiamide; Gd-DTPA-BMA (Omniscan®) GE Healthcare5 T1 shortening Gadoversetamide; Gd-DTPA-BMEA (OptiMARK®) Tyco Healthcare6 T1 shortening Gadoterate meglumine; Gd-DOTA (Dotarem®) Guerbet7 T1 shortening Gadobutrol; Gd-BT-DO3A (Gadovist®) Schering1 T1 shortening Hepatobiliary agent Mangafodipir trisodium; Mn-DPDP (Teslascan®) GE Healthcare5 T1 shortening Combined extracellular / hepatobiliary agents Gadobenate dimeglumine; Gd-BOPTA (MultiHance®) Bracco3 ,4 T1 shortening Gadoxetate; Gd-EOB-DTPA (Primovist®) Schering1 / Berlex2 T1 shortening SPIO agent AMI-25; Ferumoxides (Feridex®; Endorem®) Berlex8 / Guerbet7 T2 shortening USPIO agents SH U 555 A (Resovist®) Schering1 T1 & T2 shortening AMI-227 (Combidex®; Sinerem®) Advanced Magnetics8 / T1 & T2 shortening Guerbet7 1 = Berlin, Germany; 2 = Wayne NJ, USA; 3 = Milano, Italy; 4 = Princeton NJ, USA; 5 = Chalfont St. Giles, UK; 6 = St. Louis MO, USA; 7 = Aulnay- Sous-Bois, France; 8 = Cambridge MA, USA Table 2. Physicochemical characteristics of commercially-available T1-shortening MR contrast agents Characteristic Extracellular agents Combined extracellular / Hepatobiliary hepatobiliary agents agent Magnevist ProHance Omniscan OptiMARK Dotarem Gadovist MultiHance Primovist Teslascan (0.5 mol/L) (0.5 mol/L) (0.5 mol/L) (0.5 mol/L) (0.5 mol/L) (1.0 mol/L) (0.5 mol/L) (0.2 5 mol/L) (0.0 5 mol/L) Molecular structure Linear, Cyclic, Linear, Linear, Cyclic, Cyclic, Linear, Linear, Not applicable ionic non-ionic non-ionic non-ionic ionic non-ionic ionic ionic Thermodynamic stability 22.123.816.916.625.821.822.623.4 Not applicable constant (log Keq) Conditional stability 18.117.114.915.018.8 N/A 18.418.7 Not applicable constant at pH 7.4 Osmolality (Osm/kg) 1.96 0.63 0.65 1.11 1.35 1.61.97 0.69 0.30 3 • Contrast Agents for Liver MRImaging Liver for Agents 3 •Contrast 55 Viscosity (mPa•s at 37°C) 2.91.31.42.02.04.96 5.31.19 0.8 r1 relaxivity 0.2 T 4.7a NA NA NA NA 5.5 a 10.9a NA NA in plasma 0.47 T 4.8b, 3.8c, 4.9d 4.9b , 4.8c 4.4b , 4.4c 5.7c 4.3c 5.6b , 6.1c 9.2c, 9.7d 8.7c, 8.7e 3.6c (L/mmol•s–1) 1.5 T 3.9a, 4.1c 4.1c 4.3c 4.7c 3.6c 4.7a, 5.2c 8.1a, 6.3c 6.9c 3.6c 3 T 3.3a, 3.7c 3.7c 4.0c 4.5c 3.5c 3.6a, 5.0c 6.3a, 5.5c 6.2c 2.7c r2 relaxivity 0.2 T 9.6a NA NA NA NA 10.1 a 18.9a NA NA in plasma 0.47 T 4.1c, 6.3d 6.1c 4.6c 5.7c 5.5c 7.4c 12.9c, 12.5d 13.0c, 8.7e 4.3c (L/mmol•s–1) 1.5 T 5.3a, 4.6c 5.0c 5.2c 6.6c 4.3c 6.8a, 6.1c 18.7a, 8.7c 8.7c 7.1c 3 T 5.2a, 5.2c 5.7c 5.6c 5.9c 4.9c 6.3a, 7.1c 17.5a, 11.0c 11.0c 9.3c NA = not available ; a = Pintaske et al [88].; b = Vogler et al [141]; c = Rohrer et al.[100]; d = De Haen et al.[20], e = Schuhmann-Giampieri [119] n.b. r1 and r2 relaxivity values from Rohrer et al. were determined from curves of relaxation rate versus concentration for just two concentrations of contrast agent and hence are subject to variability. Values from Pintaske et al. were determined for a minimum of eight contrast agent concentrations. 56 MRI of the Liver tamide, but none of the other approved gadolinium since most focal lesions, especially primary liver agents, have been shown to cause spurious hypocal- tumors like hepatocellular carcinoma (HCC) and cemia as a result of interference with laboratory metastases are supplied primarily via the hepatic tests for serum calcium [25, 54, 71, 90, 91]. The issue arteries [41, 72, 148]. Enhancement during the ar- of gadolinium chelate stability in the case of gado- terial dominant phase is important in order to de- diamide has also been raised in a study to deter- tect perfusion abnormalities. For example, tran- mine the extent to which gadolinium is deposited in sient increased segmental enhancement in liver bone following intravenous injection of this agent segments may indicate that portal-venous flow is [33]. compromised due to compression or thrombosis As paramagnetic compounds, gadolinium [114, 152]. This can be of value in patients where chelates shorten T1 tissue relaxation times when findings on unenhanced images are equivocal. injected intravenously. At recommended doses of Typically, maximal enhancement of the hepatic 0.1-0.3 mmol/kg their principal effect is to shorten parenchyma is seen in the portal-venous phase. In the T1 relaxation time resulting in an increase in this phase, hypovascular lesions such as cysts, hy- tissue signal intensity.