Top

Published in:

01-04-2004 | Hepatobiliary-pancreas

Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications

Authors: Peter Reimer, Günter Schneider, Wolfgang Schima

Published in: European Radiology | Issue 4/2004

Abstract

Hepatobiliary contrast agents with uptake into hepatocytes followed by variable biliary excretion represent a unique class of cell-specific MR contrast agents. Two hepatobiliary contrast agents, mangafodipir trisodium and gadobenate dimeglumine, are already clinically approved. A third hepatobiliary contrast agent, Gd-EOB-DTPA, is under consideration. The purpose of this review is to provide an overview on the properties, clinical development and application of these three hepatobiliary contrast agents. Bolus injectable paramagnetic hepatobiliary contrast agents combine established features of extracellular agents with the advantages of hepatocyte specificity. The detection and characterisation of focal liver disease appears to be improved compared to unenhanced MRI, MRI with unspecific contrast agents and contrast-enhanced CT. To decrease the total time spent by a patient in the MR scanner, it is advisable to administer the agent immediately after acquisition of unenhanced T1-w MRI. After infusion or bolus injection (with dynamic FS-T1-w 2D or 3D GRE) of the contrast agent, moderately and heavily T2w images are acquired. Post-contrast T1-w MRI is started upon completion of T2-w MRI for mangafodipir trisodium and Gd-EOB-DTPA as early as 20 min following injection, while gadobenate dimeglumine scans are obtained >60 min following injection. Post-contrast acquisition techniques with near isotropic 3D pulse sequences with fat saturation parallel the technical progress made by MSCT combined with an unparalleled improvement in tumour-liver contrast. The individual decision that hepatobiliary contrast agent one uses is partly based on personal preferences. No comparative studies have been conducted comparing the advantages or disadvantages of all three agents directly against each other.

Bellin MF, Vasile M, Morel-Precetti S (2003) Currently used non-specific extracellular MR contrast media. Eur Radiol 13:2688–2698PubMed

Brasch RC (1992) New directions in the development of MR imaging contrast media. Radiology 183:1–11PubMed

Reimer P, Balzer T (2003) Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol 13:1266–1276PubMed

Reimer P, Tombach B (1998) Hepatic MRI with SPIO: detection and characterization of focal liver lesions. Eur Radiol 8:1198–1204PubMed

Wang YX, Hussain SM, Krestin GP (2001) Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol 11:2319–2331PubMed

Schneider G et al (2001) Gadobenate dimeglumine-enhanced magnetic resonance imaging of intracranial metastases: effect of dose on lesion detection and delineation. J Magn Reson Imaging 14:525–539CrossRefPubMed

Schima W et al (1997) Contrast-enhanced MR imaging of the liver: comparison between Gd-BOPTA and Mangafodipir. J Magn Reson Imaging 7:130–135PubMed

Petersein J et al (2000) Focal liver lesions: evaluation of the efficacy of gadobenate dimeglumine in MR imaging—a multicenter phase III clinical study. Radiology 215:727–736

Bernardino ME et al (1992) Hepatic MR imaging with Mn-DPDP: safety, image quality, and sensitivity. Radiology 183:53–58PubMed

10.

Rofsky NM et al (1993) Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging. Radiology 188:53–59PubMed

11.

Ni Y et al (1994) MR imaging evaluation of liver enhancement by Gd-EOB-DTPA in selective and total bile duct obstruction in rats: correlation with serologic, microcholangiographic, and histologic findings. Radiology 190:753–758PubMed

12.

Marchal G et al (1993) Comparison between Gd-DTPA, Gd-EOB-DTPA, and Mn-DPDP in induced HCC in rats: a correlation study of MR imaging, microangiography, and histology. Magn Reson Imaging 11:665–674PubMed

13.

Toft K et al (1997) Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol 38:677–689PubMed

14.

Elizondo G et al (1991) Preclinical evaluation of Mn-DPDP: new paramagnetic hepatobiliary contrast agent for MR imaging. Radiology 178:73–78PubMed

15.

Misselwitz B, Mühler A, Weinmann H-J (1995) A toxicologic risk for using manganese complexes? A literature survey of existing data through several medical specialties. Invest Radiol 30:611–620PubMed

16.

Lim KO et al (1991) Hepatobiliary MR imaging: first human experience with Mn-DPDP. Radiology 178:79–82PubMed

17.

Wang C et al (1997) Diagnostic efficacy of MnDPDP in MR imaging of the liver. Acta Radiol 38:643–649PubMed

18.

Padovani B et al (1996) Tolerability and utility of mangafodipir trisodium injection (MnDPDP) at the dose of 5 μmol/kg body weight in detecting focal liver tumors: results of a phase III trial using an infusion technique. Eur J Radiol 23:205–211CrossRefPubMed

19.

Bernhard C et al (2002) Safety of mangafodipir administration at abdominal MR imaging: bolus injection vs. slow infusion. Eur Radiol 12 [Suppl 1]:291

20.

Rummeny E et al (1991) Manganese-DPDP as a hepatobiliary contrast agent in the magnetic resonance imaging of liver tumors. Results of clinical phase 2 trials in Germany including 141 patients. Invest Radiol 26:S142–S145PubMed

21.

Watson A (1992) Theory and mechanisms of contrast-enhancing agents. In: CB H, H H, CA H (eds) Magnetic resonance imaging of the body. Raven Press, New York

22.

de Haen C, Lorusso V, Tirone P (1996) Hepatic transport of gadobenate dimeglumine in TR-rats. Acad Radiol 3 [Suppl 2]:S452–S454

23.

Kirchin MA, Pirovano GP, Spinazzi A (1998) Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol 33:798–809PubMed

24.

Spinazzi A et al (1999) Safety, tolerance, biodistribution, and MR imaging enhancement of the liver with gadobenate dimeglumine: results of clinical pharmacologic and pilot imaging studies in nonpatient and patient volunteers. Acad Radiol 6:282–291PubMed

25.

de Haen C, Gozzini L (1993) Soluble-type hepatobiliary contrast agents for MR imaging. J Magn Reson Imaging 3:179–186PubMed

26.

de Haen C, La Ferla R, Maggioni F (1999) Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) as contrast agent for magnetic resonance imaging of the liver: mechanistic studies in animals. J Comput Assist Tomogr 23 [Suppl 1]:S169–S179

27.

Cavagna FM et al (1997) Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging. Invest Radiol 32:780–796PubMed

28.

Schuhmann-Giampieri G (1993) Liver contrast media for magnetic resonance imaging. Interrelations between pharmacokinetics and imaging. Invest Radiol 28:753–761PubMed

29.

Spinazzi A et al (1998) Multihance clinical pharmacology: biodistribution and MR enhancement of the liver. Acad Radiol 5 [Suppl 1]:S86–S89 (discussion S93–S94)

30.

Kirchin MA et al (2001) Safety assessment of gadobenate dimeglumine (MultiHance): extended clinical experience from phase I studies to post-marketing surveillance. J Magn Reson Imaging 14:281–294CrossRefPubMed

31.

Weinmann HJ et al (1991) A new lipophilic gadolinium chelate as a tissue-specific contrast medium for MRI. Magn Reson Med 22:233–237 (discussion 242)PubMed

32.

Schuhmann-Giampieri G et al (1992) Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology 183:59–64PubMed

33.

Muehler A et al (1993) Gadolinium-ethoxybenzyl-DTPA, a new liver-directed magnetic resonance contrast agent. Absence of acute hepatotoxic, cardiovascular, or immunogenic effects. Invest Radiol 28:26–32PubMed

34.

Hamm B et al (1995) Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: safety, pharmacokinetics, and MR imaging. Radiology 195:785–792PubMed

35.

Reimer P et al (1996) Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology 199:177–183PubMed

36.

Shamsi K et al (2002) Gd-EOB-DTPA (Eovist), a liver specific contrast agent for MRI: results of a placebo controlled, double blind dose ranging study in patients with focal liver lesions. Tenth scientific meeting and exhibition of the International Society for Magnetic Resonance in Medicine. ISMRM, Honolulu, HI, USA

37.

Huppertz A et al (2004) Improved detection of focal liver lesions in MRI—a multicenter comparison of Gd-EOB-DTPA with intraoperative findings. Radiology 230:266–275PubMed

38.

Aicher KP et al (1993) Mn-DPDP-enhanced MR imaging of malignant liver lesions: efficacy and safety in 20 patients. J Magn Reson Imaging 3:731–737PubMed

39.

Gehl H-B et al (1991) Pancreatic enhancement after low-dose infusion of Mn-DPDP. Radiology 180:337–339PubMed

40.

Gehl H-B et al (1993) Mn-DPDP in MR imaging of pancreatic adenocarcinoma: initial clinical experience. Radiology 186:795–798PubMed

41.

Romijn MG et al (2000) MRI with mangafodipir trisodium in the detection and staging of pancreatic cancer. J Magn Reson Imaging 12:261–268PubMed

42.

Schima W, Függer R (2002) Evaluation of focal pancreatic masses: comparison of mangafodipir-enhanced MR imaging and contrast-enhanced helical CT. Eur Radiol 12:2998–3008PubMed

43.

King LJ et al (2002) MnDPDP enhanced magnetic resonance imaging of focal liver lesions. Clin Radiol 57:1047–1057PubMed

44.

Federle MP et al (2000) Efficacy and safety of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the US multicenter phase III clinical trials. Efficacy of early imaging. J Magn Reson Imaging 12:689–701PubMed

45.

Braga HJ et al (2002) Liver lesions: manganese-enhanced MR and dual-phase helical CT for preoperative detection and characterization comparison with receiver operating characteristic analysis. Radiology 223:525–531PubMed

46.

Mann GN et al (2001) Clinical and cost effectiveness of a new hepatocellular MRI contrast agent, mangafodipir trisodium, in the preoperative assessment of liver resectability. Ann Surg Oncol 8:573–579CrossRefPubMed

47.

Hamm B et al (1992) Focal liver lesions: MR imaging with Mn-DPDP—initial clinical results in 40 patients. Radiology 182:167–174PubMed

48.

Mathieu D et al (1999) Unexpected MR-T1 enhancement of endocrine liver metastases with mangafodipir. J Magn Reson Imaging 10:193–195CrossRefPubMed

49.

Marti-Bonmati L et al (1998) MnDPDP enhancement characteristics and differentiation between cirrhotic and noncirrhotic livers. Invest Radiol 33:717–722CrossRefPubMed

50.

Murakami T et al (1996) Cirrhosis of the liver: MR imaging with mangafodipir trisodium (Mn-DPDP). Radiology 198:567–572PubMed

51.

Vogl TJ et al (1993) Mn-DPDP enhancement patterns of hepatocellular lesions on MR images. J Magn Reson Imaging 3:51–58PubMed

52.

Liou J et al (1994) Differentiation of hepatomas from nonhepatomatous masses: use of Mn-DPDP-enhanced MR images. Magn Reson Imaging 12:71–79PubMed

53.

Murakami T et al (1996) Hepatocellular carcinoma: MR imaging with mangafodipir trisodium (Mn-DPDP). Radiology 200:69–77PubMed

54.

Bartolozzi C et al (2000) MnDPDP-enhanced MRI vs dual-phase spiral CT in the detection of hepatocellular carcinoma in cirrhosis. Eur Radiol 10:1697–1702CrossRefPubMed

55.

Kim SK et al (2002) Preoperative detection of hepatocellular carcinoma: ferumoxides-enhanced versus mangafodipir trisodium-enhanced MR imaging. AJR 179:741–750

56.

Ba-Ssalamah A et al (2002) Atypical focal nodular hyperplasia of the liver: imaging features of nonspecific and liver-specific MR contrast agents. AJR 179:1447–1456

57.

Oudkerk M et al (2002) Characterization of liver lesions with mangafodipir trisodium-enhanced MR imaging: multicenter study comparing MR and dual-phase spiral CT. Radiology 223:517–524PubMed

58.

Coffin CM et al (1999) Benign and malignant hepatocellular tumors: evaluation of tumoral enhancement after mangafodipir trisodium injection on MR imaging. Eur Radiol 9:444–449CrossRefPubMed

59.

Helmberger TK et al (2002) MRI characteristics in focal hepatic disease before and after administration of MnDPDP: discriminant analysis as a diagnostic tool. Eur Radiol 12:62–70CrossRefPubMed

60.

Saini S (1992) Contrast-enhanced MR imaging of the liver. Radiology 182:12–14PubMed

61.

Hamm B, Taupitz M (1995) Use of contrast agents in the detection and differentiation of focal liver lesions by MR imaging: Gd-DTPA, Mn-DPDP and iron oxide. In: Balzer T, Hamm B, Niendorf H-P (eds) Contrast agents in liver imaging. Kluwer, Dordrecht

62.

Nakamura H et al (1994) 3DFT-FISP MRI with gadopentetate dimeglumine in differential diagnosis of small liver tumors. J Comput Assist Tomogr 18:49–54PubMed

63.

Powers C et al (1994) Primary liver neoplasms: MR imaging with pathologic correlation. Radiographics 14:459–482PubMed

64.

Mahfouz AE, Hamm B, Wolf KJ (1994) Peripheral washout: a sign of malignancy on dynamic gadolinium-enhanced MR images of focal liver lesions. Radiology 190:49–52PubMed

65.

Semelka RC et al (1994) Hepatic hemangiomas: a multi-institutional study of appearance on T2-weighted and serial gadolinium-enhanced gradient-echo MR images. Radiology 192:401–406PubMed

66.

Hamm B et al (1994) Focal liver lesions: characterization with nonenhanced and dynamic contrast material-enhanced MR imaging. Radiology 190:417–423PubMed

67.

Hamm B et al (1997) Liver metastases: improved detection with dynamic gadolinium-enhanced MR imaging? Radiology 202:677–682PubMed

68.

Cavagna FM et al (1990) Hepatobiliary contrast agents for MRI. In: Ferrucci J, Stark D (eds) Liver imaging: current trends and new techniques. Andover Medical Publishers Inc., Boston

69.

Kuwatsuru R et al (2001) Comparison of gadobenate dimeglumine with gadopentetate dimeglumine for magnetic resonance imaging of liver tumors. Invest Radiol 36):632–641CrossRefPubMed

70.

Schneider G et al (2003) Low-dose gadobenate dimeglumine versus standard dose gadopentetate dimeglumine for contrast-enhanced magnetic resonance imaging of the liver: an intra-individual crossover comparison. Invest Radiol 38:85–94CrossRefPubMed

71.

Morana G et al (2002) Hypervascular hepatic lesions: dynamic and late enhancement pattern with Gd-BOPTA. Acad Radiol 9 [Suppl 2]:476–479

72.

Grazioli L et al (2003) MRI of focal nodular hyperplasia (FNH) with gadobenate dimeglumine (Gd-BOPTA) and SPIO (ferumoxides): an intra-individual comparison. J Magn Reson Imaging 17:593–602CrossRefPubMed

73.

Reimer P et al (1997) Enhancement characteristics of liver metastases, hepatocellular carcinomas, and hemangiomas with Gd-EOB-DTPA: preliminary results with dynamic MR imaging. Eur Radiol 7:275–280CrossRefPubMed

74.

Stern W et al (2000) Dynamic MR imaging of liver metastases with Gd-EOB-DTPA. Acta Radiol 41:255–262CrossRefPubMed

75.

Vogl T et al (1995) Enhancement of malignant and benign focal liver lesions using Gd-EOB-DTPA and Gd-DTPA enhanced MRI in the same patient. In: International conference of MRI of the abdomen and pelvis. H.M. Hauschild Ltd, Bremen, Munich, Germany

76.

Kuehnen J, Schering AG (2003) Results of European Phase 3 Clinical trials on Gd-EOB-DTPA. Personal communication, Berlin, Germany

77.

Kane PA et al (1997) MnDPDP-enhanced MR imaging of the liver. Correlation with surgical findings. Acta Radiol 38:650–654PubMed

78.

Petersein J et al (2000) Comparison of in-phase and out-of-phase gradient recalled echo T1-weighted pulse sequences for MR imaging of malignant liver masses following administration of paramagnetic gadolinium-chelate. Abdom Imaging 25:159–163PubMed

79.

Bollow M et al (1997) Gadolinium-ethoxybenzyl-DTPA as a hepatobiliary contrast agent for use in MR cholangiography: results of an in vivo phase-I clinical evaluation. Eur Radiol 7:126–132CrossRefPubMed

80.

Hirohashi S et al (1998) Optimal dose of hepatobiliary contrast agent for MR cholangiography: experimental study in rats. J Magn Reson Imaging 8:847–852PubMed

81.

Schmitz SA et al (1996) Functional hepatobiliary imaging with gadolinium-EOB-DTPA. A comparison of magnetic resonance imaging and 153 gadolinium-EOB-DTPA scintigraphy in rats. Invest Radiol 31:154–160CrossRefPubMed

82.

Schuhmann-Giampieri G et al (1993) Biliary excretion and pharmacokinetics of a gadolinium chelate used as a liver-specific contrast agent for magnetic resonance imaging in the rat. J Pharm Sci 82:799–803PubMed

83.

Lee VS et al (2001) Volumetric mangafodipir trisodium-enhanced cholangiography to define intrahepatic biliary anatomy. AJR 176:906–908PubMed

84.

Vitellas KM et al (2001) Detection of bile duct leaks using MR cholangiography with mangafodipir trisodium (Teslascan). J Comput Assist Tomogr 25:102–105PubMed

85.

Vogl TJ et al (1996) Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology 200:59–67PubMed

86.

Hammerstingl R et al (2002) Contrast-enhanced MRI of focal liver tumors using a hepatobiliary MR contrast agent: detection and differential diagnosis using Gd-EOB-DTPA-enhanced versus Gd-DTPA-enhanced MRI in the same patient. Acad Radiol 9 [Suppl 1]:S119–S120

Title: Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications
Authors: Peter Reimer
Günter Schneider
Wolfgang Schima
Publication date: 01-04-2004
Publisher: Springer-Verlag
Published in: European Radiology / Issue 4/2004
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI: https://doi.org/10.1007/s00330-004-2236-1

At a glance: The STEP trials

Springer Medicine

Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2004

Mn-DPDP-enhanced 24-h delayed-scan MRI of hepatocellular carcinoma is correlated with histology

Cerebral vasculitis due to Treponema pallidum infection: MRI and MRA findings

Potential clinical relevance of digital radiogrammetry for quantification of periarticular bone demineralization in patients suffering from rheumatoid arthritis depending on severity and compared with DXA

Contrast-enhanced MR angiography vs intra-arterial digital subtraction angiography for carotid imaging: activity-based cost analysis

Current trends in treatment of osteoid osteoma with an emphasis on radiofrequency ablation

Drug smuggling by body packing: what radiologists should know about it