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Radiography (2007) 13, e54ee72

Use of contrast agents for liver MRI

Janice Ward*

Consultant Practitioner, Hepatobiliary MRI, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK

Received 15 March 2006; accepted 1 September 2006Available online 7 November 2006

KEYWORDSMRI;Contrast agents;Liver

Abstract Contrast-enhanced MRI is recognised as one of the most accurate imaging methodsfor investigating diseases of the liver. Uniquely several different types of contrast agents areavailable for liver MRI. They can be divided into non-specific extracellular fluid space (ECF),hepatocyte specific and reticulo-endothelial system (RES) specific agents. They are used to im-prove the detection of focal liver lesions by increasing normal-abnormal tissue contrast and toassist in lesion characterisation by demonstrating tissue perfusion and cellular function. ECF-gadolinium (Gd) chelates have been widely used in abdominal MRI for many years. They pro-vide valuable information regarding the vascularisation and perfusion characteristics of lesionsand assist in lesion detection, particularly of hypervascular lesions. The hepatocyte and RES-specific agents further improve lesion detection, provide important functional information andallow the distinction between hepatocellular and non-hepatocellular tumours. This article de-scribes the different MR contrast agents and discusses their current status for diagnosing focalliver lesions. The importance of optimised technique and appropriate selection of contrastagent is emphasised.ª 2006 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

Introduction

Compared with other imaging techniques MRI is regarded asthe ‘‘gold standard’’ for diagnosing liver disease. Despiteearly expectations to the contrary, contrast agents havebecome an essential part of the MRI examination and are ofcritical importance for both the detection and character-isation of focal liver lesions. Several types of contrastagents are available for liver MRI (Table 1). The non-specificextracellular fluid (ECF) space gadolinium (Gd) agents have

* Tel.: þ44 0 113 206 4037; fax: þ44 0 113 206 5092.E-mail address: janice.ward@leedsth.nhs.uk

1078-8174/$ - see front matter ª 2006 The College of Radiographerdoi:10.1016/j.radi.2006.09.002

been widely used for several years and, more recently, tis-sue-specific contrast agents have been developed to targetthe main cell populations of the liver.

The liver has two distinct cell types. Approximately 80%of the liver volume and about 60% of its total cellpopulation is made up of hepatocytes. These cells aremultifunctional and metabolically very active. They syn-thesise various proteins such as albumins and clottingfactors, eliminate many toxic substances from the bloodand are responsible for the production of bile. They alsostore and metabolise glycogen and triglycerides which arereleased into the blood as glucose and lipids when requiredfor energy production. Kupffer cells are also important forhepatic function. These are cells of the reticulo-endothelial

s. Published by Elsevier Ltd. All rights reserved.

Use of contrast agents for liver MRI e55

Table 1 Summary of contrast agents for liver MRI and their main properties

Properties Use

Extracellular Gd Chelates Intravascular and extracellularfluid enhancement. Shortens T1relaxation producing positiveT1 enhancement.

Determines vessel patency andlesion perfusion with dynamic imaging.Gadopentetate

GadoteridolGadodiamideGadoterateExtra/intracellular

T1 agentsPositive T1 enhancement. Biphasicprofile e behaves like gadopentetatein first few minutes then hepatocyteuptake and excreted in bile.

Hepatocyte phase (10e40 min)increases detection of metastasesand aids in characterisation ofhepatocellular lesions.

Gadobenate (Gd-BOPTA,Multihance)

Gadoxetic Acid(Gd-EOB-DTPA, Primovist)

Intracellular T1 agent Metabolic contrast agent. Positive T1enhancement. Taken up by tissues richin mitochondria including hepatocytes.Excreted in bile.

Optimum detection of metastases x20 min.Reliable distinction of hepatocellular andnon-hepatocellular lesions. Bile excretionallows T1-w thin slice cholangiography.

Mangafodipir Trisodium(Mn-DPDP, Teslascan)

Superparamagnetic ironoxide (SPIO) agents

Positive T1 enhancement in earlyintravascular phase, then uptake byRES cells of liver and spleen andnegative enhancement on T1 and T2*.

Improves detection of hepatic metastases,distinguishes hepatocellular and non-hepatocellulartumours and allows most hepatocellular lesionsto be characterised as benign or malignant.

Ferucarbotran (Resovist)Ferumoxides (Endorem)

system (RES) which account for approximately 2e3% of theliver cell population and are located on the endotheliallinings of the liver sinusoids. They are responsible forremoving degraded red blood cells and other waste prod-ucts from the circulation (a process know as phagocytosis).1

Contrast agents which target both cell types are avail-able. These include superparamagnetic iron oxide (SPIO)particles which are extracted by the RES cells of the liver,spleen and bone marrow and agents based on Gd ormanganese (Mn) chelates whichare taken upby hepatocytes.

In considering contrast agents for liver MRI it is impor-tant to understand why, when and how we use them andwhich of the contrast agents is most advantageous fora particular clinical problem. We use contrast agents inliver MRI for the same general aims as in other areas ofimaging. Firstly, they are used to increase the signalintensity (SI) difference between normal and abnormaltissues. Lesion visualisation depends on the differencebetween the SI of lesions and the adjacent liver paren-chyma (lesion-to-liver contrast). On unenhanced imagesmost liver lesions have a higher or lower SI than thebackground liver but some show only a minimal differenceand are relatively inconspicuous. Other lesions have SIcharacteristics similar to those of normal liver and may notbe seen at all. Following contrast administration, in manycases lesion-to-liver contrast increases dramatically solesions are more conspicuous and lesion detection eparticularly the detection of small lesions e is substantiallyimproved.2e26 Secondly, contrast agents are used to helpcharacterise abnormalities by virtue of the perfusion andextraction behaviour of tissue. Differences in the degreeand rate of contrast uptake and distribution of contrastwithin the lesion helps to distinguish benign and malignantlesions and often allows a specific diagnosis.27e44 Thirdly,they are used to provide a full assessment of the hepaticvessels which is particularly important in patients who arecandidates for liver resection or transplantation.

Essentially, contrast agents are used to improve diagnos-tic confidence. The inherent contrast of MRI is ofteninsufficient to demonstrate indistinct, or characteristicdifferences in normal and abnormal tissue so diagnosticconfidence is likely to be low when only unenhanced imagesare obtained. Moreover, with the routine use of breathholdT2-w sequences, which are relatively insensitive to solidlesions, we have become increasingly dependent on contrastenhanced imaging and, in the authors experience, the use ofcontrast agents improves diagnostic confidence in the vastmajority of patients. However, correct technique is ex-tremely important. Diagnostic efficacy depends on thetiming of image acquisition relative to contrast administra-tion and choice of pulse sequence parameters. To maximiselesion detection, images should be acquired with a pulsesequence and at the phase of enhancement that shows thegreatest difference in the SI of normal and abnormal tissue.For lesion characterisation, image acquisition should betimed to capture the different phases of enhancement inorder to demonstrate initial contrast uptake, distribution ofcontrast within the lesions interstitial space and contrastwashout. Sequences with short acquisition times and strat-egies such as test bolusing to ensure an optimum arterialphase are essential for this purpose. Choice of technique willbe discussed in more detail elsewhere in this article.

Choosing the most appropriate contrast agent to dealwith a particular clinical problem is not a simple matter. Theadvantages and attributes of each contrast agent need to beconsidered in relation to the specific clinical question.Moreover when the results of MR performed with a singlecontrast agent are equivocal it may be appropriate to usea second contrast agent to obtain the diagnosis. The contrastagent literature is extensive and helpful in this regard butrelatively few studies have compared the different contrastagents with each other.4,13,21,22,37,41,43,45e47 Nevertheless,the efficacy of individual contrast agents is now fairly wellestablished and there is extensively accumulated clinical

e56 J. Ward

experience in the use of most of these agents. Strategies fordealing with different clinical problems will be discussed.

MR imaging technique

More so than for most other applications of MRI, a successfulliver MRI examination requires careful planning and de-tailed clinical information. A thorough review of the clinicaldata is necessary to determine the appropriate protocoland provides useful pointers to a likely diagnosis. Sequenceoptimisation and choice of contrast agent are importantdeterminants of image quality and diagnostic efficacy. Weneed to achieve high lesion-to-liver contrast images, whichare free from motion artefact, and to use contrast agentsappropriately.

Assuming an acceptable level of tissue contrast, probablythe most critical issue in liver MRI is the suppression ofmotion artefact. Respiratory gating techniques are widelyused but with varied success. Although gating is effective inpatients who have a regular breathing pattern artefacts aresevere when breathing is erratic. Also, since image acquisi-tion always occurs at the same point in the respiratory cycle,acquisition times are often long. The most effective way toeliminate motion is to image during breathholding. Recentrefinements in rapid scanning techniques allow for highquality breathhold imaging with both T1 and T2-weightingand several studies have shown that breathhold versions oftraditionally used sequences achieve superior image qualityand lesion detection at least as good as non-breathholdversions.48,49 With a little encouragement, most patients areable to perform repeated 20-s breathholds. At the authorsinstitution the patients undergo a brief coaching session be-fore entering the scanner. We rehearse hyperventilationtechniques to assist breathholding and instruct the patientsto perform comparable respiratory excursions for eachbreathhold to avoid mis-registration. Wherever possible weimage during suspended end-expiration to improve repro-ducibility and we instruct the patients to breath in and outtwice before the ‘breath in, breath out, and hold’ command.In some patients we have also found that coaching them tobear down in a Valsalva-type manoeuvre is helpful. This ini-tial coaching session also allows us to identify patients witha more limited breathhold capacity. In such cases imagingparameters are adjusted to decrease acquisition timeswhilst maintaining acceptable signal-to-noise and spatialresolution. These patients often find inspiration easier tomaintain but it is important to instruct them to avoid ex-tremes in respiratory excursion or mis-registration may besevere. Oxygen administration also improves the successrate in patients whose breathholding capacity is reduced.

Non-breathhold strategies are needed in only a smallminority of patients. In such cases we obtain sequential Truefast imaging with steady state precession (True FISP) andHalf Fourier acquisition single shot fast spin echo (HASTE)images during free breathing with navigator pulses appliedto the HASTE sequence to eliminate mis-registration. Thesesequences are followed by a stack of single slice magnet-isation-prepared GRE T1-w (Turbo Flash) images whichencompass the whole of the liver and are obtained beforeand at the arterial, portal and equilibrium phases aftergadolinium. These are single slice techniques with each sliceacquired in less than one second so motion artefacts are

consistently negligible regardless of patient co-operation.Although the magnetisation-prepared GRE T1-w sequence isextremely useful in non-compliant patients it is not recom-mended for routine use because contrast-to-noise is reducedand image contrast is less reliable than with standard multi-slice spoiled GRE techniques.

Non-contrast images

Unenhanced images are an essential part of any liver MRexamination. They are particularly important for character-ising lesions and provide a baseline marker from which thedegree of contrast enhancement can be assessed. Theyprovide a decisive diagnosis of focal or diffuse fatty changeand lesion SI often provides an indication of the type oflesion and directs the use and choice of contrast media. Forexample benign lesions of hepatocellular origin such asfocal nodular hyperplasia (FNH) and liver cell adenomastypically have a SI similar to normal liver on unenhancedT1-w and T2-w and are most reliably characterised by liver-specific contrast agents due to the presence of functioninghepatocytes and Kupffer cells. Conversely, marked hyper-intensity on T2-w and moderate hypointensity on T1-wimages points more towards a diagnosis of haemangiomawhich is best characterised by its perfusion characteristicson dynamic Gd-enhanced imaging (DGEI).

True FISP (Siemens), or balanced fast field echo (FFE,Philips) sequences have a contrast mechanism which isa function of T1/T2, but high contrast images which areessentially T2-weighted are produced.50 This is a slice selectsequence with each slice acquired in approximately one sec-ond. It provides an excellent and quick overview of the upperabdominal anatomy and is particularly useful for a rapid sur-vey of the hepatic vessels and lymph nodes. Motion artefactsare negligible so it is useful in patients who have difficultybreathholding but it is insensitive to solid liver lesions andartefacts caused by magnetic field inhomogeneities may besevere. Flow artefacts may also be seen in large vessels.

T2-w sequences are invaluable for determining the fluidcontent of lesions and distinguishing solid and non-solidtumours. We currently use HASTE imaging for this pur-pose.51 Although most solid lesions are not well seen onHASTE, cystic lesions, which have a much longer T2 andtherefore a much higher signal, are extremely well seen.Compared with other T2-w sequences, small cysts and fluidcollections are more sharply defined and more reliablycharacterised with HASTE (Fig. 1).

T1-w 2D spoiled GRE sequences produce high signal-to-noise and lesion-to-liver contrast which is often superiorto that of breathhold T2-w sequences. In-phase (IP) andopposed-phase (OP) T1-w images should be obtained in allpatients because they provide an absolute diagnosis offocal or diffuse fatty infiltration and allow the identifica-tion of fat within tumours. The fatty liver or fat containinglesions have an obviously reduced SI on OPT1-w comparedwith IPT1-w images. In patients with fatty liver, lesion-to-liver contrast is higher on IPT1-w images. The combinationof IP and OP GRE images also allows the distinction of signalloss due to fatty liver from signal loss caused by excess irondeposition. Because signal loss due to metal is caused bysusceptibility effects which become more pronounced withincreasing TE, in patients with an iron laden liver the liver

Use of contrast agents for liver MRI e57

Figure 1 Indeterminate lesions on surveillance CT in a patient with bladder cancer. (a) single shot fast spin echo sequence withhalf-Fourier reconstruction (HASTE), (b) 3D T1-w GRE arterial, (c) portal, (d) equilibrium phase Gd-enhanced images. Multiple well-defined, markedly hyperintense lesions are well seen on (a). Following Gd, the lesions in the left lobe of the liver demonstrate thecharacteristic appearance of simple cysts e they do not enhance and their appearance does not change on subsequent acquisitions.The two right lobe lesions (arrows) demonstrate rapid and persistent homogeneous enhancement (short arrow) and discontinuousnodular enhancement which progresses over time (long arrow) and both lesions show enhancement that equals that of normal ves-sels at every post contrast phase e these are specific features of haemangiomas.

has a lower SI on IPT1-w compared with OPT1-w becausethe TE of the IPT1-w sequence is longer.

Contrast-enhanced images

All commercially available contrast agents shorten both theT1 and T2 relaxation times of the tissues in which theyaccumulate. The Gd and Mn based agents predominantlyshorten T1 and produce positive enhancement on T1-wimages, but the dominant contrast effect at very highconcentrations is T2 shortening which induces signal loss.However, at the concentrations used in clinical practise,a T1 effect which is only visible on T1-w images is observed;there is no discernible effect on T2-w images. On the otherhand, SPIO is predominantly a T2 agent which producesa reduction in SI on T1-w and T2-w images but when thecontrast is distributed throughout the intra-vascular spaceand less concentrated, a T1-enhancing effect is seen on T1-w images. As the particles are taken up into the RE cellsthey become more concentrated, susceptibility effectsbecome more pronounced, T2* shortening occurs and signalloss is observed on T1-w and T2-w images.

Non-specific ECF-Gd contrast agents

Commercially available ECF agents include GadopentetateDimeglumine (Gd-DTPA, Magnevist, Schering), Gadoteridol

(Gd-HP-DO3A, Prohance, Bracco), Gadodiamide (GD-DTPA-BMA, Omniscan, Nycomed) and Gadoterate Meglumine (Gd-DOTA, Dotarem, Guerbet). They all have excellent safetyprofiles; adverse events are usually mild and transient andoccur in less then 3% of patients.52 Use of ECF-Gd is looselyanalogous to that of the iodinated contrast agents used forcontrast-enhanced computed tomography (CT). Their ef-fective use relies on dynamic imaging with rapid sequentialacquisitions obtained after bolus injection. Immediatelyafter injection ECF agents are distributed within the intra-vascular compartment. They rapidly disperse throughoutthe extracellular space and quickly equilibrate betweenthe intravascular and extracellular space after which theyare eliminated by renal excretion. In most cases lesion-to-liver contrast peaks in the first minute after injectionand then declines rapidly, so maximum lesion detection oc-curs in the first 90 s after injection. Dynamic imaging alsocaptures the distinctive perfusion and extraction featuresof different tissues at different phases of enhancement somost abnormalities are reliably characterised. Imaging atthe equilibrium phase which occurs 2e3 min after injectionis important for characterising lesions. Contrast has equili-brated within the interstitial space of the liver and tumoursby this time so many lesions are no longer visible, butlesions which have a substantial interstitial space showa gradual accumulation of contrast and become moreconspicuous.53 Haemangiomas, cholangiocarcinomas and

e58 J. Ward

peritoneal tumour deposits are examples of tumours whichhave a prominent interstitial space.54,55 Most accumulategadolinium slowly and are best seen on images acquired ap-proximately 10 min after injection (Figs. 2 and 3).

Accurate timing of image acquisition is critical. ECF-Gdis given as a rapid bolus at a dose of approximately0.1 mmol/kg bw and timed to coincide with arrival of thecontrast in the tissue or vessel of interest during acquisitionof the central lines of K-space which determine tissue con-trast within the image. Best results are obtained when thecontrast is administered by a power injector at a rate of 2e4 ml per second and a high-resolution T1-w fat suppressed3D GRE sequence is used. To enable imaging of the entireliver during suspended respiration (approximately 20 s)a T1-w GRE sequence is obtained with the shortest possibleTE to maximise the number of slices for a given TR. 3D se-quences are recommended because, compared with 2Dtechniques at a comparable voxel size, they give a highersignal-to-noise and allow a thinner effective slice thicknesswith no inter-slice gap or cross talk. Fat suppression is alsoimportant because it increases the dynamic range withinthe image and accentuates Gd enhancement. It also sup-presses the competing signal of fat adjacent to enhancinglesions on the liver surface. Appropriate commerciallyavailable 3D T1-w GRE sequences include VIBE (Siemens),WAVE (Philips) and Fame (GE). These sequences are charac-terised by a short repetition time (TR) and echo time (TE)and the use of sinc interpolation (zero-filling) in at leasttwo acquisition planes to facilitate smaller voxel sizeswith minimum time penalties. A small flip angle of approx-imately 15� is used to minimise saturation and maximise the

signal from stationary tissues for simultaneous display ofliver parenchyma and hepatic vessels. Fat suppression uni-formity is optimised by the application of a chemicallyselective fat saturation pulse before each partition loopand centric reordering of each partition.56 These high-resolution 3D sequences comfortably allow thin section cov-erage of the whole of the liver with high signal-to-noise ina 20-s breathhold but they are also extremely flexible andeasily adapted to accommodate patients with a more lim-ited breathholding capacity. Full coverage in as little as12 s can be achieved by increasing the effective slice thick-ness and reducing the number of data points in the phase en-coding direction. Conversely, if less anatomic coverage isappropriate the effective slice thickness can be reducedto as little as 1.5 mm for higher resolution breathhold imag-ing. Parameters may also be manipulated to provide isotro-pic voxels for optimal multi-planar 3D reconstruction. Withthe use of parallel imaging techniques and asymmetricecho sampling, breathhold isotropic imaging of the wholeliver can be performed in approximately 20 s in manypatients. Moreover, we no longer use dedicated magneticresonance angiography sequences to image the hepatic vas-culature since these sequences produce maximum intensityprojection (MIP) reconstructions of comparable qualitywhilst providing excellent soft tissue contrast.

For dynamic Gd-enhanced imaging to be effective, atleast three phases of enhancement (arterial, portal andequilibrium) are necessary. Delayed images acquired ap-proximately 10 min after injection may also be useful andenable a specific diagnosis to be made in many lesions. Ar-terial phase images e sometimes referred to as sinusoidal

Figure 2 Characteristic appearance of haemangioma. (a) HASTE, (b) 3D T1-w GRE arterial, (c) portal, (d) delayed phase Gd-en-hanced images. The lesion in segment VI is homogeneously hyperintense on (a) and demonstrates discontinuous peripheral nodularenhancement (b and c) which progresses to involve all of the lesion on delayed images (d). Note that lesion enhancement parallelsthe enhancement of vessels at each post-contrast phase.

Use of contrast agents for liver MRI e59

Figure 3 Characteristic appearance of hilar cholangiocarcinoma. (a) coronal oblique high-resolution 3D MRCP MIP image, (b) 3DT1-w GRE portal and (c) delayed phase Gd-enhanced images, (d) arterial phase and (e) portal phase MIP images. Intrahepatic biliarydilation with obstruction at the liver hilum is seen in (a). The tumour is barely visible on (b) but well seen on (c) due to delayedenhancement of the tumours larger interstitial space (arrowheads). Note the low signal intensity normal calibre CBD which is par-ticularly well seen on (c) against the high signal intensity tumour. Extension of tumour along the portal vessels is easily appreciatedwhen (b) and (c) are compared. MIP images demonstrate normal arterial anatomy (d) and patent portal veins with narrowing of thedistal main portal vein and left portal vein consistent with the tumour demonstrated in (c).

phase images e are probably the most crucial and techni-cally challenging. Optimal timing occurs during the latearterial phase of liver enhancement when there is onlyminimal enhancement of the liver parenchyma and contrast

is present in the hepatic artery and main portal veinbranches but not in the hepatic veins. At this time markedenhancement of the pancreas and renal cortex along withpatchy enhancement of the spleen is also seen. The window

e60 J. Ward

of opportunity here is extremely limited. It typically takesless than 20 s from arrival of contrast in the hepatic arteryand filling of the hepatic veins and most hypervascular le-sions are only visible during this period. Circulation timesvary from patient to patient but in most cases effective ar-terial phase enhancement occurs 15e20 s from the start ofinjection. However transit times from the ante-cubitalfossa to the hepatic artery have been shown to rangefrom 8e32 s and test bolusing has been recommended toguarantee an optimal arterial phase in every patient.57

We use a 1e2 ml test dose of Gd-DTPA followed bya 20 ml saline flush injected at a rate of 2e4 ml/sec. A mag-netisation-prepared spoiled GRE T1-w sequence with re-duced resolution is positioned over the upper abdominalaorta and a series of transverse images obtained at one sec-ond intervals is initiated at the start of injection. Usinga user defined region of interest positioned over the aortaan enhancement curve is generated to determine thetime to peak aortic enhancement. For the 3D T1-w GRE se-quence the central lines of ‘k’ space are acquired towardsthe middle of the acquisition (linear acquisition) so, at aninjection rate of 4 ml/sec, the delay between the start of

injection and data acquisition is calculated as the time topeak aortic enhancement plus the duration of Gd injectionminus the time to acquisition of the central lines of ‘k’space. At an injection rate of 2 ml/sec the calculation isbased on half the duration of the Gd injection.

Uniquely the liver has a dual blood supply receivingapproximately 75% of its blood from the portal vein and theremainder from the hepatic artery.

Consequently there is only minimal enhancement ofnormal liver at the arterial phase whilst enhancement ismaximum at the portal phase about 20 s later. Since hyper-vascular lesions are supplied almost entirely by the hepaticartery, they are best seen at the arterial phase and manyare only visible at this time. Hypovascular lesions which en-hance less than hypervascular lesions are usually best dem-onstrated at the portal phase. However, rim enhancementaround the periphery of hypovascular metastases which al-lows them to be distinguished from benign lesions may onlybe seen at the arterial phase (Fig. 4). For this reason werecommend arterial and portal phase acquisitions in all pa-tients. By the equilibrium and delayed phases (2e3 and10 min after injection) the difference in the enhancement

Figure 4 Characteristic appearance of small colorectal metastasis. (a) HASTE, (b) in-phase T1, (c) 3D T1-W GRE arterial, and (d)portal phase GD-enhanced images and (e) SPIO-enhanced T2-w GRE images. The metastasis in segment VII (arrow) is inconspicuousand difficult to distinguish from the right hepatic vein on (a) and (b). Conversely the lesion is highly conspicuous and shows a com-plete rim of enhancement on (c) which is specific for metastasis. On the subsequent portal phase acquisition (d) the lesion has lessdistinct borders and again is relatively inconspicuous. The lesion is also extremely well seen after SPIO (d).

Use of contrast agents for liver MRI e61

between normal and abnormal tissues is often poor. Al-though many lesions are no longer visible the appearanceof lesions at these times may facilitate a specific diagnosis.For example, simple cysts do not enhance and maintaintheir appearance on successive acquisitions (Fig. 1), mosthaemangiomas show discontinuous nodular enhancementwhich progresses over time to involve most or all of the

lesion (Fig. 2) and focal nodular hyperplasia shows intensearterial phase enhancement which fades to isointensity bythe portal phase with late enhancement of a central scar(Fig. 5). Most metastases exhibit a complete rim of periph-eral enhancement which is best seen on early arterial phaseimages followed by a progressive enhancement patternwhich over time renders them less conspicuous or more

Figure 5 Characteristic appearance of FNH imaged with gadobenate and SPIO. (a) HASTE, (b) In-phase T1, (c) 3D T1-w GRE ar-terial, (d) portal, (e) equilibrium and (f) hepatocyte phase gadobenate-enhanced images and (g) SPIO-enhanced T2-w GRE images.The lesion has a signal intensity similar to background liver on (a) and (b) and shows marked enhancement at the arterial phase (c).Lesion enhancement fades rapidly such that the lesion is almost isointense with the adjacent liver on (d) and (e). Although thesefeatures are entirely consistent with FNH the diagnosis is confirmed on the hepatobiliary phase images (f). The lesion shows con-trast uptake similar to background liver indicating functioning hepatocytes. The lesion also demonstrates uptake of SPIO on (g) con-sistent with functioning Kupffer cells.

e62 J. Ward

conspicuous due to delayed central enhancement resultingfrom non-specific accumulation of contrast within the le-sions interstitial space (Fig. 4). Large hepatocellular carci-nomas (HCCs) show heterogeneous enhancement anda well-defined capsule on later imaging, cholangiocarcino-mas typically show a gradual accumulation of contrastbecoming most apparent on delayed imaging (Fig. 3) andsome malignant tumours show peripheral washout on de-layed images which is a specific sign of malignancy.32

Peritoneal tumour deposits and extra-hepatic inflammatorychanges are best demonstrated on fat suppressed imagesobtained about 10 min after Gd.54,55

Tissue specific contrast agents

Liver-specific contrast agents were developed to overcomethe limitations of ECF-Gd agents and improve the diagnosticperformance of MRI further. As mentioned previously, manysmall lesions are not visible within two minutes of ECF-Gdinjection due to equilibration of contrast between theintravascular and extracellular spaces and since a minorityof lesions have perfusion characteristics similar to normaltissue they are not seen at all. It would seem reasonable toexpect that liver specific agents would be more effective insuch cases since intracellular uptake and prolonged re-tention of these agents produces greater tissue contrastand a much wider time window for image acquisition. Allliver-specific agents produce high tissue contrast andseveral studies have shown them to significantly improvethe detection of metastases compared with unenhancedimages.6e12,15,17e19,22,23,26,58 Since they also provide an as-sessment of tissue at cellular level they facilitate the dif-ferentiation of hepatocellular and non-hepatocellularlesions on the basis of cellular uptake.34e45,59,60 In termsof lesion detection, because malignant lesions lack func-tioning hepatocytes and Kupffer cells their SI is unchangedwhilst the background liver becomes hyperintense or hypo-intense depending on which agent is used. Liver-specificagents help to characterise hepatocellular lesions becausethey are taken up by functioning hepatocytes and Kupffercells in FNH, many liver cell adenomas and in the regener-ating and dysplastic nodules of cirrhosis. Well-differenti-ated HCCs may also show uptake but usually to a lesserextent.

These agents are classified by their target tissue ashepatocyte specific or superparamagnetic iron oxide parti-cles which target the RES and are taken up by Kupffer cellswithin the liver. The pharmacodynamics of each agentvaries but for most current clinical applications of liver MRIthe hepatocyte agents can be regarded as T1 agents; the SIof normal liver parenchyma is unchanged on T2-w images.In the first few minutes after injection SPIO particlesproduce an increase in T1 signal on T1-w images but theyrapidly accumulate in the Kupffer cells and become moreconcentrated after which they markedly shorten T2* anddecrease liver signal on both T1 and T2-w images.

Hepatobiliary contrast agents

Three hepatobiliary contrast agents are commercially avail-able. Mangafodipir trisodium (Mn-DPDP, Teslascan, Nycomed,Amersham) and gadobenate dimeglumine (Gd-BOPTA,

Multihance, Bracco) have been clinically approved for severalyears whilst gadoxetic acid (Gd-EOB-DTPA, Primovist, Scher-ing) has been approved only recently. All three agents areparamagnetic producing an increase in T1 shortening andpositive enhancement on T1-w images. All are well toleratedwith a very low incidence of adverse events. Relaxivity (R1 orR2) refers to the ability of a contrast agent to selectivelyshorten the relaxation time of water protons within itsimmediate vicinity. In liver tissue, all the hepatocyte agentshave a higher relaxivity than ECF-Gd so even small concen-trations produce effective liver enhancement (Table 2). Sev-eral studies have shown the enhancement effect to be morepronounced on T1-w GRE images than T1-w SE images61,62 soT1-w GRE imaging is recommended for all three agents.When the liver is fatty, IPT1-w images are recommended forhepatocyte phase imaging. The fatty liver has a reduced SIon OPT1-w images which will lessen the effect of contrast en-hancement. For improved detection of small metastases T1-w3D GRE imaging with fat suppression is recommended.

Mangafodipir trisodium is probably more appropriatelydescribed as a metabolic contrast agent than a hepatocyteagent. It is taken up by tissues with numerous mitochondriaand an active aerobic metabolism so the liver, pancreas,kidneys, adrenal glands, GI mucosa and myocardium allshow enhancement. Following iv injection manganese inplasma gradually dissociates from its ligand. The free man-ganese is taken up into the hepatocytes where it binds tointracellular macromolecules and is then eliminated by bil-iary and intestinal secretion in a similar way to dietary man-ganese; intact Mn-DPDP remaining in plasma is eliminatedby the kidneys.63

Whilst mangafodipir in plasma has a T1 relaxivity similarto ECF-Gd in liver tissue its T1 relaxivity is three times thatof the ECF agents (Table 2). The recommended dose is0.5 mmol/kg bw and it is administered by slow injection(over 1e2 min), or infusion (over 10e20 min) to minimiseadverse events, particularly facial flushing. Liver enhance-ment is maximum approximately 20 min from the start ofinfusion and persists for at least two hours. Althoughlesion-to-liver contrast is usually optimum at this time somemetastases and HCCs may be best seen on 24 h imageswhen the background liver has returned to baseline SI levelsand abnormal retention of the contrast agent in HCCs or de-layed washout around the periphery of metastases rendersthem more conspicuous. Mangafodipir also shows markedenhancement of bile and as such has been combined with

Table 2 Relaxivities of different contrast agents

Relaxivity

(mM�1 s�1)

R1 R2

Gd-DTPA 6.7*/5.9� 6.3�

Mn-DPDP 21.7*/2.8� 3.7þ

Gd-BOPTA 30*/9.7� 12.5�

Gd-EOB-DTPA 16.6*/8.2�/5.3þ 6.1þ

Ferumoxides 17� 82�

Ferucarbotran 24þ 190þ

*In the liver. �In human plasma. þIn aqueous solution @ 0.47 T.

Use of contrast agents for liver MRI e63

thin slice high-resolution T1-w 3D sequences to producecholangiographic images for evaluation of the biliary sys-tem.64 The technique may also be used to confirm bileduct leakage following surgery, when non-specific fluid col-lections are present on unenhanced images. When concen-trated in bile, mangafodipir produces signal loss on heavilyT2-w MR images. Conventional T2-w MR cholangiographywith mangafodipir enhancement has been identified asa way of distinguishing high SI parenchymal lesions whichretain their signal on heavily T2-w images from bile ductswith cystic dilation which show reduced signal aftermangafodipir.65

Gadobenate has combined perfusion and hepatocellularproperties.66 In the first few minutes after injection theagent has an intra-vascular distribution with subsequent dis-persal throughout the ECF space just like ECF-Gd. Most of theinjected dose is eliminated by the kidneys but 3e5% is elim-inated by the liver. In the liver gadobenate has a T1 relaxivityalmost four times that of Gd-DTPA, so even though onlya small proportion of the injected dose is incorporated intothe hepatocytes this is sufficient to induce effective andlong-lasting enhancement. The recommended dose of ga-dobenate for hepatocyte phase imaging is 0.1 mmol/kg bw.However, since the T1 relaxivity of gadobenate in plasma isalmost twice that of the standard ECF-Gd agents, compara-ble dynamic imaging is achieved at a dose of 0.05 mmol/kg.Liver enhancement peaks approximately 40 min after injec-tion and lasts for approximately two hours.

Gadoxetic acid also has a biphasic enhancement profile.67

It has an estimated T1 relaxivity in liver about half that of ga-dobenate but in this case approximately 50% of the injecteddose is taken up by the hepatocytes so liver SI is markedly in-creased at the uptake phase. Again the initial perfusionphase allows early dynamic imaging similar to that of theother ECF agents but intracellular uptake begins immedi-ately after injection. This produces a gradual increase inthe SI of normal liver during the first 20 min after injectionwhich is maintained for approximately two hours (Fig. 6).Conversely, with Gd-DTPA and its analogues, liver enhance-ment peaks in the first minute after injection and then de-clines rapidly. Consequently, while the appearance of liverlesions on early arterial and portal phase images is similarwith both agents, the typical perfusion characteristics of le-sions on delayed phase Gd-DTPA images will not be apparenton images obtained 5e10 min after gadoxetic acid. For in-stance, whilst haemangiomas and cholangiocarcinomas typ-ically have a higher SI than background liver on imagesobtained ten minutes after Gd-DTPA (Figs. 2 and 3), theywill have the same or a lower SI than normal liver on imagesacquired at the same time after gadoxetic acid (Fig. 7).

The recommended dose of gadoxetic acid is 0.1 ml/kg bwand maximum contrast between normal and abnormal tissueoccurs 20e120 min after injection. Because a substantialproportion of the injected dose is eliminated in bile, latephase images also show enhancement of the biliary tree.

RES (Kupffer cells) agents

The distribution of SPIO contrast agents is directly relatedto particle size. SPIO particles in the size range of 30e200 nm are rapidly cleared from the blood by the RES cellsof the liver (Kupffer cells), spleen and bone marrow with

about 80% of the injected dose being taken up by normalliver (ultrasmall SPIO [USPIO] agents have a particle sizeof less than 50 nm and remain within the intravascularspace for much longer; blood half-life of approximately200 min for USPIO compared with 4e10 min for SPIO). Be-cause SPIO particles are strongly paramagnetic, whenthey are clustered within the RES cells they create stronglocal field inhomogeneities which lead to rapid spin dephas-ing and signal loss in normal liver on both T1-w and T2-wimages. The effect is more pronounced on T2-w images dueto a high R2/R1 ratio (the higher the R2/R1 ratio the greaterthe T2 effect and subsequent signal loss). After SPIO the nor-mal liver loses 70%e90% of it’s signal on T2-w images.68,69

Conversely, metastases and other non-hepatocellular tu-mours lose little if any of their signal so they become highlyconspicuous after contrast.

Two SPIO agents are available for liver MRI, ferumoxides,(AMI-25, Endorem, Guerbet) and ferucarbotran (SHU555A,Resovist, Schering). Currently ferucarbotran is only li-censed in Europe but can be readily obtained in the UKon a named patient basis.

Ferumoxides contains iron oxide crystals coated withdextran which have a mean particle size of 150 nm. Unusu-ally there have been no efficacy related dose finding studiesperformed with ferumoxides (early dose finding studieswere based on toxicity data rather then efficacy data).Most studies in the USA and Japan have used a dose of10 mmol/kg bw but the recommended dose in Europe is15 mmol/kg bw. Recent studies however have shown no sig-nificant decrease in lesion to liver contrast at a dose of7.5 mmol in patients with and without diffuse liver diseaseat a field strength of 1.0 T.68,69 Whatever the dose, ferum-oxides is usually diluted in a weak glucose solution and in-fused over 30 min to minimise adverse reactions, althougha recent multicenter study showed no increase in the inci-dence or severity of adverse events when undiluted ferum-oxides was given by slow injection at a rate of 2 ml/minute.70 Minor side effects occur in approximately 10%of patients. Low back pain e the cause of which is unknown eis the most common problem but this usually abates whenthe infusion is stopped and restarted at a slower rate. Im-ages are optimum 15e120 min from the start of injectionbut since the half-life of SPIO particles in the liver andspleen is 3e4 days the useful imaging window is muchlonger.

Ferucarbotran comprises SPIO particles coated with car-boxydextran with a mean size of 60 nm. The recommendeddose of 7e10 mmol/kg bw is given by a bolus injection withrelatively few and mild side effects.71 Although this is pre-dominantly a T2 agent the preparation contains a proportionof very small particles (about 15 nm) which, in the first fewminutes after injection when the contrast is distributedthroughout the intra-vascular space and at a lower concen-tration, produce an increase in SI on T1-w images. Ferucar-botran has a blood half-life of 4e6 min and as the particlesare taken up into the RES cells their local concentration in-creases, susceptibility effects become more pronouncedand loss of signal due to T2 shortening becomes the domi-nant contrast mechanism and signal loss occurs on T1-wand T2-w images. The T1 effect of ferucarbotran is dose de-pendent. The R1 relaxivity of ferucarbotran is 4e5 timeshigher than that of Gd-DTPA but a dose of 10 mmols Fe/kg

e64 J. Ward

Figure 6 Bi-phasic imaging with gadoxetic acid in a patient with multiple hypervascular neuroendocrine metastasis. (a) 3D T1-wGRE arterial, (b) portal, (c) equilibrium and (d) and (e) hepatocyte phase gadoxetic acid-enhanced images. Numerous hyperintensemetastases (many of sub-centimetre size) are visible at the arterial phase of enhancement (a). Only the three larger lesions arevisible by the portal phase (b). Enhancement on (a) and (b) is similar to that seen with any ECF-Gd agent. On the correspondingimage acquired 2 min after injection (c) enhancement of the vascular structures is reduced and enhancement of the normal liverparenchyma due to hepatocyte uptake is already apparent. Several of the small lesions seen on (a) but not on (b) are now visible(arrows). Progressive enhancement of the normal liver is observed on successive images and maximum approximately 20 min afterinjection (d) when tumour-to-liver contrast is optimum. At this time numerous metastases in the millimetre size range are exqui-sitely seen. Combined review of all phases of enhancement allows lesions which may only be seen at the hepatocyte phase to bedistinguished from vessels which are opacified at the early vascular phase. Note marked enhancement of the biliary tree.

bw is 10 times lower than the recommended dose of0.1 mmol/kg for Gd-DTPA. Moreover, since ferucarbotranhas been marketed at only 2 pre-filled volumes, the doseto individual patients is variable. Patients weighing lessthan 60 kg receive 0.9 ml whereas patients weighing 60 kgor more receive 1.4 ml. Whilst patients weighing morethan 80 kg receive a dose of less than 8 mmol/kg, patientsweighing 50 kg receive a dose of approximately 9 mmol/kg. Although T1-w images obtained in the first 2e3 minafter injection are similar to those obtained with Gd-DTPAin some patients, T1 signal changes in most patients areconsiderably lower and liver and vessels have almost the

same SI at a lower dose (Fig. 8). Nevertheless we havefound this weak T1-effect to be extremely useful. It pro-duces a virtual ‘‘blank canvas’’ against which focal lesionsare extremely conspicuous and reliably distinguished fromadjacent vessels (Fig. 8). We now regard dynamic T1-wand delayed T2-w images after ferucarbotran as comple-mentary and obtain both in all patients with suspected met-astatic disease. T2-w GRE images are optimum 10 min afterinjection but lesion-to-liver contrast is maintained for up to1-day post injection.

The most influential determinant of efficacy with SPIOagents is the choice of pulse sequence. Loss of signal is

Use of contrast agents for liver MRI e65

Figure 7 Multiple haemangiomas characterised with gadobenate. (a) 3D T1-w GRE portal, (b) equilibrium, (c) 10 min delayed and(d) hepatocyte phase gadobenate-enhanced images. On (a) and (b) the lesions show characteristic discontinuous peripheral nodularenhancement with central progression. On (c) and (d) lesion enhancement is about the same as the background liver and quitedifferent to the appearance of haemangiomas imaged at this time after gadopentetate (see Figs. 1 and 2). Note the areas withinthe tumour which show no enhancement are consistent with central scars which are densely hyalinised and avascular; a character-istic feature of giant haemangiomas.

more pronounced on GRE than SE sequences due to thegreater sensitivity of GRE to magnetic field inhomogene-ities. Conversely, FSE sequences are relatively insensitiveto susceptibility because their multiple 180� refocusingpulses reduce the local field inhomogeneities required toinduce spin dephasing. Magnetisation transfer (MT), whichreduces the SI of solid lesions, is also a feature of FSE butnot GRE sequences e FSE becomes increasingly insensitiveto SPIO as the echo train length is increased so lesion-to-liver contrast may be particularly poor on breathholdFSE images (Fig. 9). As discussed previously, breathhold se-quences are desirable for liver imaging because respiratoryartefacts are eliminated and scanning time is reduced. Al-though T2-w GRE imaging meets this requirement whilstmaximising the effect of SPIO, parameters must be opti-mised to minimise noise and maximise the signal from solidlesions. Ghosting artefacts from the aorta which may besevere at longer TE’s, must also be eliminated. In a recentstudy the accuracy of four SPIO-enhanced breathhold se-quences (3 GRE sequences and 1 FSE sequence) using opti-mised parameters were compared with non-contrastimages for the detection of surgically confirmed colorectalmetastases.12 All three GRE sequences achieved accuraciesbetween 90e93% and were significantly more sensitivethan non-contrast images, but enhanced-FSE was no betterthan unenhanced images with accuracies of 82% and 81%respectively. At the authors institution the best of thesesequences is used with SPIO, but it has been further re-fined by reducing the slice thickness from 10 mm to6 mm and applying fat suppression to improve the

detection of sub-centimetre and surface lesions. We alsofind this sequence extremely valuable for depicting he-patic and peritoneal tumour deposits, which are wellseen against the suppressed signal of fat and the reducedliver signal after SPIO (Fig. 10). The details of the se-quence are as follows: TR 148 msec, TE 14 msec, FA 30�,matrix 132 � 256, bandwidth 65e80 Hz/pixel, 65% phaseresolution combined with a 68e75% rectangular 280e400 mm FOV to achieve a 132 � 256 matrix and flowcompensation. The low bandwidth minimises noise and in-creases signal-to-noise ratio, whilst flow compensationgradients minimise flow artefacts. Maximum SI of any tis-sue occurs at a specific flip angle known as the Ernst angle.Since there is no competing signal from the backgroundliver after SPIO we used the Ernst angle to maximise thesignal from hepatic metastases. The flip angle of 30� wasbased on the Ernst angle for hepatic metastases at a fieldstrength of 1.5 T and a T1 of a 1000 msec. Whilst this flipangle maximises the signal from metastases the signal ofhaemangiomas and cysts tends to be reduced becausetheir T1 values are different (approximately 137 msec forhaemangiomas and approximately 143 msec for cysts);the SI of non-solid benign lesions is more reliable on non-contrast T2-w images (Fig. 10). For effective fat suppres-sion we use a technique which selectively excites waterprotons using a binomial pulse sequence. This approachis more efficient and less sensitive to magnetic field inho-mogeneities than the standard frequency selective methodof fat suppression; more slices are obtained for a givenacquisition time and fat suppression tends to be more

e66 J. Ward

Figure 8 Value of T1 enhancement with ferucarbotran. 3D T1-w GRE portal phase images obtained after ferucarbotran (a) andGd-DTPA (b) in a patient with colorectal cancer. 3D T1-w GRE portal phase (c and d) and T2-w GRE delayed phase (e and f) postferucarbotran images in two different patients (c, e) and (d, f) also with colorectal cancer. Analogous enhancement features aredemonstrated in (a) and (b) with both showing marked vascular enhancement and high tumour-to-liver contrast. On (c) and (d) theliver and vessels are almost isointense due to a relatively low dose of iron oxide and a weak T1 effect, however the metastases arehighly conspicuous and easily distinguished from adjacent vessels. The lesions are also well seen on the corresponding T2-w GREimages (e and f) obtained 10 min after (c) and (d).

homogeneous. Using these parameters 6e7 images are ob-tained during a 20 s breathhold.

Clinical value

Lesion detection

Several studies have confirmed the importance of DGEI forthe detection of hypervascular lesions, particularly smallHCCs.2e5 Whilst there is no doubt that DGEI improves the de-tection of hypervascular lesions compared with unenhancedimages, improvements in the detection of hypovascular le-sions is less clear.3 As discussed before, rapid equilibrationof ECF contrast agents into the interstitial compartment ofliver tumours may reduce their conspicuity. However, withcurrent high-resolution 3D T1-w imaging and optimised

timing of post contrast acquisitions we often see metastasesafter Gd which are invisible on unenhanced T1-w and T2-wimages. In a recent study we compared multi-slice helicalCT at a slice thickness of 3.2 mm, 3D GD-enhanced VIBEwith an effective slice thickness of 2.5 mm and SPIO-enhanced T2-w GRE images at a slice thickness of 6 mm forthe detection of metastases in 58 patients who underwenthepatic resection.13 For the detection of all lesions and le-sions 1 cm or smaller both MR techniques were significantlybetter than CT. CTwas also associated with the highest num-ber of false positive calls mostly due to benign lesions beingwrongly interpreted as metastases. Overall SPIO-enhancedMR was only marginally more accurate than Gd-enhancedMR but the detection of lesions 1 cm or smaller was substan-tially improved with SPIO.

All of the liver-specific contrast agents have been shownto improve lesion detection compared with unenhanced

Use of contrast agents for liver MRI e67

Figure 9 Importance of pulse sequence choice for effective lesion detection after SPIO. (a) unenhanced breathhold FSE, (b) in-phase T1, (c) SPIO-enhanced T2-w FSE and (d) T2-w GRE images. Although there is a substantial drop in the signal of the liver on (c)compared with (a), signal loss is greater on (d) and lesion-to-liver contrast is markedly improved. Note also that the lesions arebetter seen on (b) compared with (a).

imaging.6e12,15,17e19,22e24,58 Since the vast majority of me-tastases do not take up these agents they become consider-ably more conspicuous after contrast. In the dynamicphase, gadobenate and gadoxetic acid are similar to ECF-Gd, particularly for the depiction of hypervascular lesions,but more sensitive for the detection of small metastaseswhen dynamic and hepatocyte phase images are com-bined.23,25,45,46 Mangafodipir trisodium also improves thedetection of metastases.14e20 Although lesion-to-liver con-trast is maximum 15e120 min after injection some metas-tases are more conspicuous on 24-h images due todelayed washout around their periphery. At the time ofwriting, no comparative studies have evaluated the accu-racy of hepatocyte agents using high-resolution 3D T1-wGRE imaging but it is likely that the better spatial resolutionprovided by this sequence will improve the detection ofsub-centimetre lesions compared with 2D sequences.

There have been conflicting reports regarding the valueof mangafodipir for the detection of HCCs.20,72 In the firsttwo hours after injection lesion conspicuity may be reduceddue to contrast uptake in well-differentiated tumours.However imaging at 24-h may be more sensitive due to de-layed retention of contrast in tumours which renders themhyperintense relative to the background liver which has re-turned to its baseline SI by this time. For the detection ofHCCs smaller than 1 cm SPIO-enhanced MRI has been shownto be more accurate than mangafodipir enhanced MRI.21

SPIO-MR is also regarded as one of the most accurateimaging methods for detecting small metastases. It hasa sensitivity similar to that of CTAP but accuracy is higherbecause CTAP produces more false positives.73 Several

studies have shown SPIO-MR to be significantly more sensi-tive than non-contrast MRI and helical CT and also toimprove on DGEI for the detection of metastases.6e13

Studies comparing SPIO and dynamic Gd-enhanced imagingfor the detection of HCC have reported conflicting re-sults.4,74 In our experience, small focal lesions are oftenbest seen on arterial phase Gd images, whereas largemore diffuse, tumours are better depicted with SPIO.

Lesion characterisation

Numerous studies have confirmed the value of dynamicGd-enhanced imaging for characterising pathology on thebasis of its perfusion patterns28,29,31e33 and all of the liverspecific contrast agents have the potential to differentiatebetween hepatocellular and non-hepatocellular tu-mours.34e45,59,60 With gadobenate and gadoxetic acid,imaging at both the dynamic and delayed phases is recom-mended particularly when a hepatocellular lesion is suspec-ted.40e45 Dynamic images demonstrate the perfusionproperties of lesions whilst the uptake phase allows the dis-tinction of lesions composed of hepatocytes from thosethat are not. However, one should be aware that sincethese agents are rapidly cleared from the intravascularspace and incorporation into the hepatocytes begins shortlyafter injection, images obtained at 5e10 min may not dem-onstrate the same enhancement features that are seenwith conventional ECF-Gd agents (Fig. 7). Moreover hepato-cyte-specific enhancement at the uptake phase may be dif-ficult to distinguish from non-specific accumulation ofcontrast within the interstitial space of tumours which do

e68 J. Ward

not contain hepatocytes; non-specific enhancement maypersist for several hours in lesions which have a large inter-stitial space. Nevertheless, the combination of dynamic andhepatocyte phase imaging is advantageous and allows a spe-cific diagnosis to be reached in most patients. Mangafodipirreliably distinguishes between hepatocellular and non-hepatocellular tumours but this may have limited clinicalvalue because benign and malignant lesions of each type of-ten exhibit similar contrast behaviour.17,75 Contrast uptakeis typically seen in all tumours of hepatocellular origin in-cluding HCCs. Very rarely mangafodipir enhancement hasalso been observed in neuroendocrine metastases.76 Thereason for this is unclear but probably relates to increasedmetabolic activity in these tumours. Grazioli et al. (2005)have recently reported the ability of gadobenate to

Figure 10 Co-existent cysts and metastases after SPIO e

importance of unenhanced heavily T2-w images for lesion char-acterisation. (a) unenhanced HASTE, (b) SPIO-enhanced T2-wGRE image. On (a), a simple cyst (long arrow) is well-definedand strongly hyperintense whilst the metastasis in the leftlobe (short arrow) is poorly defined and only slightly hyperin-tense relative to the background liver. On (b) the metastasisis now highly conspicuous because of the 30� flip angle chosento maximise the signal from metastases whilst the cyst hasa relatively reduced signal intensity compared with (a). Whilstthe lesions have indistinguishable features after SPIO they arequite distinct on (a). Note also a small lymph node (arrowhead)which is well seen against the reduced signal intensity of theliver and the suppressed signal of intra-abdominal fat on (b).

distinguish FNH from hepatic adenomas.42 Whilst FNH showsmarked uptake of all of the liver-specific contrast agents(Fig. 5), most adenomas show variable uptake of mangafo-dipir, gadoxetic acid and SPIO, but no uptake of gadobenate(Fig. 11). This distinction may be crucial since FNH is almostalways left untreated whilst surgical resection is advocatedfor adenomas because they have a recognised risk of hae-morrhage and rupture.

SPIO is probably the best discriminator of benign andmalignant hepatocellular lesions. Benign cirrhotic nodules,most nodules of FNH and some adenomas show a substantialdegree of uptake of SPIO whereas the great majority ofHCCs show no uptake. A percentage SI loss (PSIL) of greaterthan 40% on T2-w post contrast images appears to reliablyindicate benign disease.77 The same imaging sequence withidentical parameters must be acquired before and aftercontrast to measure PSIL. Benign non-hepatocellular lesionsare often indistinguishable from metastases on SPIO-enhanced T2-w images because cysts, haemangiomas andmetastases may all be highly hyperintense against the re-duced SI of the background liver after SPIO. However,most lesions can be correctly characterised by combinedreview of pre- and post-contrast T2-w images e cysts andhaemangiomas are well defined and markedly hyperintenseon HASTE whilst most metastases are moderately hyperin-tense and less well-defined (Fig. 10).

Dual contrast MR (DCMR)

In selected patients the combination of SPIO and DGEIprovides important additional information.78 Although theextra cost and increased examination time requires the care-ful selection of patients, the elimination of other tests morethan outweighs the increased cost of a second contrast agentprovided DCMR is performed only in patients whose clinicalmanagement is likely to be altered by the additional informa-tion. Since the mechanisms that establish contrast with SPIOand Gd are different it would seen reasonable to expect thatused in combination they may be more effective than eitheragent used alone. In a single examination the high sensitivityof SPIO for lesion detection is combined with the attributes ofDGEI for lesion characterisation.

Lesion characterisation is as important as lesion de-tection in patients with liver metastases. Even in patientswith established malignancy as many as 50% of small lesionsmay be benign. It is particularly important to distinguishbenign and malignant lesions in surgical patients. Whilstfailure to detect benign lesions does not alter patientmanagement the incorrect interpretation of benign lesionsas malignant may lead to an inappropriate surgical ap-proach or even preclude surgery as an option. DCMRcombines the high sensitivity of SPIO for lesion detectionwith the lesion characterisation ability of DGEI. Thedifferent magnetic properties of the two agents may alsolead to a synergistic increase in contrast between thereduced SI of background liver after SPIO and the increasedSI of enhancing lesions after Gd. Small hypervasculartumours are particularly conspicuous on arterial phase Gdimages following prior injection of SPIO.

The combined effects of SPIO and Gd also improve thecharacterisation of many lesions, particularly nodules incirrhosis which often show overlapping enhancement

Use of contrast agents for liver MRI e69

Figure 11 Hepatocellular adenoma reliably characterised with gadobenate and SPIO. (a) HASTE, (b) in-phase T1-w, (c) 3D T1-wGRE arterial, (d) portal and (e) hepatocyte phase gadobenate-enhanced images and (f) SPIO-enhanced T2-w GRE images. Multiplelesions with signal intensity characteristics similar to normal liver are seen on (a) and (b). The lesions showed marked enhancementat the arterial phase (c) followed by rapid washout and isointensity with background liver on (d). On images obtained 40 min laterat the hepatocyte phase (e) the lesions are hypointense relative to normal liver indicating that there is no intracellular uptake ofgadobenate. However the lesions show uptake of SPIO similar to that of normal liver and are isointense on (e). This confirms thepresence of functioning Kupffer cells and the benign hepatocellular nature of the lesions. This spectrum of findings is consistentwith a diagnosis of hepatocellular adenoma.

characteristics when a single contrast agent is used.Although most HCCs are hypervascular they are occasion-ally hypovascular, dysplastic nodules are typically hypovas-cular but may be hypervascular and well-differentiatedHCCs may show some uptake of SPIO. Uncertainty due tothese overlapping features is generally overcome whenSPIO and Gd are used in combination. In recent studiesusing SPIO immediately followed by DGEI in patients withlate stage cirrhosis,60,79 significantly more HCCs (particu-larly lesions less than 1 cm) were detected with SPIO andGd images combined, compared with unenhanced or SPIO-enhanced images alone. A small number of lesions howeverwere only visible with SPIO enhancement. The combined

effects of SPIO and DGEI also improved the characterisationof dysplastic nodules and HCCs.60

With this DCMR technique the second agent is injectedimmediately after acquisition of the first agent images. Theorder of contrast administration is determined by theclinical indication. Whilst prior injection of Gd has noeffect on subsequent SPIO-enhanced T2-w images, SPIOinjected before Gd produces a prolonged reduction in liversignal on both T1-w and T2-w images and may havea significant effect on subsequent Gd-enhancement. Weuse a ‘Gd-first’ approach to detect benign hepatocellularlesions which may be isointense with adjacent liver onunenhanced and SPIO images. Conversely, Gd lesion

e70 J. Ward

enhancement is more pronounced after prior injection ofSPIO due to the reduced signal of background liver sohypervascular lesions are particularly conspicuous with an‘SPIO-first’ approach. Hypovascular lesions on the otherhand, may be isointense when SPIO is injected before Gdbecause liver enhancement after Gd appears less pro-nounced against the reduced signal induced by SPIO.Although many lesions are correctly characterised byunenhanced images and DGEI in combination, some lesionsexhibit atypical enhancement and in such cases subsequentSPIO-enhanced images may be valuable. Both ‘SPIO-first’ and ‘Gd-first’ approaches are effective for character-ising such lesions. In our experience prior uptake of SPIOwithin a lesion does not adversely effect Gd lesionenhancement.

A practical approach

The authors’ experience has evolved in a centre whichprovides a supra-regional service for liver surgery and hasa high throughput of patients referred for hepatobiliaryMRI. There is no single protocol using contrast agents whichis applicable to all patients. Different imaging strategiesare needed to answer different clinical questions. All ourprotocols include unenhanced True FISP, IP and OP T1-wGRE and HASTE sequences. Our choice of contrast agentdepends on the particular clinical scenario and the imagingappearance on unenhanced images. In the non-cirrhoticliver, patients referred for characterisation of an incidentalliver lesion on routine ultrasound (the vast majority ofwhich are benign) or an indeterminate lesion on surveil-lance CT, are examined with DGEI in the first instance. Ifthese images indicate a hepatocellular lesion we obtain T2-w GRE images before and after SPIO to measure lesion PSILand confirm the diagnosis. We also use DGEI with imagesobtained 10 min after injection to characterise and deter-mine tumour extent in hilar cholangiocarcinomas and otherprimary liver tumours. If, on the basis of clinical data orprior imaging, a hepatic adenoma is suspected we use Gd-BOPTA in place of Gd-DTPA and obtain dynamic and delayedhepatocyte phase images. Whilst lesion enhancement atthe hepatocyte phase is consistent with FNH, the diagnosisis less clear if the lesion does not show hepatocyte uptake.Both adenomas and non-hepatocellular tumours show neg-ligible intracellular uptake of BOPTA. To distinguish thetwo we administer SPIO immediately after BOPTA-enhanced imaging and obtain a measure of lesion PSIL. Thecombination of arterial phase enhancement, no intracellularuptake of BOPTA and decreased signal intensity after SPIOdue to the presence of functioning Kupffer cells appears toreliably indicate hepatocellular adenoma (Fig. 11).

In patients with metastatic disease who are candidatesfor hepatic resection, our current practise is to obtaindynamic SPIO-enhanced 3D FS T1-w GRE imaging anddelayed T2-w GRE sequences to maximise lesion detection.If any lesion has benign characteristics on unenhancedimages and a location which may influence the surgicalapproach we perform DGEI immediately after SPIO-enhanced imaging for more reliable characterisation. In non-surgical patients or patients with rising tumour markers,unenhanced imaging followed by either high-resolution

DGEI or bi-phasic imaging with gadoxetic acid is performed.In patients with cirrhosis at high risk of developing HCC weperform DCMR with SPIO-enhanced images obtained imme-diately before DGEI. This approach improves the detectionof HCC and provides a more rigorous approach to lesioncharacterisation. DGEI also allows a full assessment of theportal venous anatomy which is essential in patients whoare candidates for liver transplantation. DCMR is alsoperformed in non-cirrhotic patients when lesion character-isation is inconclusive after a single-contrast-agent andwhen the vascular relationship of lesions that are best seenon SPIO-enhanced images is uncertain and may influencethe surgical approach.

References

1. Wiliam PL, Warwick R, Dyson M, Bannister LH, editors. Gray’sanatomy. 37th ed. London, New York: Churchill Livingstone;1989.

2. Oi H, Murakami T, Kim T, Matsushita M, Kishimoto H,Nakamura H. Dynamic MR imaging and early-phase CT for de-tecting small intrahepatic metastases of hepatocellular carci-noma. AJR 1996;166:369e74.

3. Peterson MS, Baron RL, Murakami T. Hepatic malignancies: use-fulness of acquisition of multiple arterial and portal venousphase images at dynamic gadolinium-enhanced MR imaging.Radiology 1996;201:337e45.

4. Tang Y, Yamashita Y, Arakawa A, Namimoto T, Mitsuzaki K,Abe Y, et al. Detection of hepatocellular carcinomas arisingin cirrhotic livers: comparison of gadolinium-and ferumox-ides-enhanced MR imaging. AJR 1999;172:1547e54.

5. Yamashita Y, Mitsuzaki K, Yi T, Ogata I, Nishiharu T, Urata J,et al. Small hepatocellular carcinoma in patients with chronicliver damage: prospective comparison of detection with dy-namic MR imaging and helical CT of the whole liver. Radiology1996;200:79e84.

6. Blakeborough A, Ward J, Wilson D, Griffith M, Kajiya Y,Guthrie JA, et al. Hepatic lesion detection at MR imaging:a comparative study with four sequences. Radiology 1997;203:759e65.

7. Hagspiel KD, Neidl KFW, Eichenberger AC, Weder W,Marincek B. Detection of liver metastases: comparison ofsuperparamagnetic iron oxide-enhanced MR imaging at 1.5 Twith dynamic CT, intraoperative US and percutaneous US.Radiology 1995;196:471e8.

8. Muller RD, Vogel K, Neumann K, Hirche H, Barkhausen J,Stoblen F, et al. SPIO-MR imaging versus double-phase spiralCT in detecting malignant lesions of the liver. Acta Radiol1999;40:628e35.

9. Reimer P, Jahnke N, Fiebich M, Schima W, Deckers F, Marx C,et al. Hepatic lesion detection and characterization: value ofnon-enhanced MR imaging, superparamagnetic iron oxide-enhanced MR imaging and spiral CT-ROC analysis. Radiology2000;217:152e8.

10. Ward J, Chen F, Guthrie JA, Wilson D, Lodge JP, Wyatt JI, et al.Hepatic lesion detection after superparamagnetic iron oxideenhancement: comparison of five T2-Weighted sequences at1.0 T by using alternative-free response receiver operatingcharacteristic analysis. Radiology 2000;214:159e66.

11. Ward J, Naik KS, Guthrie JA, Wilson D, Robinson PJ. Hepatic le-sion detection: comparison of MR imaging after the administra-tion of superparamagnetic iron oxide with dual-phase CT byusing alternative-free response receiver operating characteris-tic analysis. Radiology 1999;210:459e566.

12. WardJ,GuthrieJA,WilsonD,ArnoldP,LodgeJP,ToogoodGJ,etal.Colorectal hepatic metastases, detection with SPIO-enhanced

Use of contrast agents for liver MRI e71

breathhold imaging: comparison of optimised sequences at 1.5 T.Radiology 2003;228(3):709e18.

13. Ward J, Robinson PJ, Guthrie JA, Downing S, Wilson D,Lodge JP, et al. Liver metastases in candidates for hepatic re-section: comparison of thin-slice helical CT, high-resolution 3Ddynamic gadolinium-enhanced MR and SPIO-enhanced T2Wgradient echo imaging. Radiology 2005;237:170e80.

14. Reimer P, Schneider G, Schima W. Hepatobiliary contrastagents for contrast-enhanced MRI of the liver: properties,clinical development and applications. Eur Radiol 2004;14:559e78.

15. King LJ, Burkill GJ, Scurr ED, Vlavianos P, Murrary-Lyons I,Healy JC. MnDPDP enhanced magnetic resonance imaging offocal liver lesions. Clin Radiol 2002;57:1047e57.

16. Padovani B, Lecesne R, Raffaelli C, Chevallier P, Drouillard J,Bruneton JN, et al. Tolerability and utility of mangafodipir tri-sodium injection (MnDPDP) at the dose of 5 mmmol/kg bodyweight in detecting focal liver tumors: results of phase III trialusing an infusion technique. Eur J Radiol 1996;23:205e11.

17. Federle MP, Chezmar JL, Rubin DL, Weinreb JC, Freeny PC,Semelka RC, et al. Efficacy and safety of mangafodipir triso-dium (MnDPDP) injection for hepatic MRI in adults: results ofthe U.S. multicenter phase III clinical trials. J Magn Reson Im-aging 2000;12:186e97.

18. Braga HJ, Choti MA, Lee VS, Paulson EK, Siegelman ES,Bluemke DA. Liver lesions: manganese-enhanced MR anddual-phase helical CT for preoperative detection and charac-terization comparison with receiver operator characteristicanalysis. Radiology 2002;223:525e31.

19. Mann GN, Marx HF, Lai LL, Wagman LD. Clinical and cost effec-tiveness of a new hepatocellular MRI contrast Agent, mangafo-dipir trisodium, in the preoperative assessment of liverresectability. Ann Surg Oncol 2001;8:573e9.

20. Bartolozzi C, Donati F, Cioni D, Crocetti L, Lencioni R. MnDPDP-enhanced MRI vs dual-phase spiral CT in the detection of hepato-cellular carcinoma in cirrhosis. Eur Radiol 2000;120:1697e702.

21. Kim SK, Kim SH, Lee WJ, Kim H, Seo JW, Choi D, et al. Pre-operative detection of hepatocellular carcinoma: ferumox-ides-enhanced versus mangafodipir trisodium-enhanced MRimaging. AJR 2002;179:741e50.

22. Kuwatsuru R, Kadoya M, Ohtomo K, Tanimoto A, Hirohashi S,Murakami T, et al. Comparison of gadobenate dimegluminewith gadopentetate dimeglumine for magnetic resonance im-aging of liver tumors. Invest Radiol 2001;36:632e41.

23. Petersein J, Spinazzi A, Giovagnoni A, Soyer P, Terrier F,Lencioni R, et al. Focal liver lesions: evaluation of the efficacyof gadobenate dimeglumine in MR imaging e a multicenterphase III clinical study. Radiology 2000;215:727e36.

24. Schneider G, Maas R, Schultze Kool L, Rummeny E, Gehl HB,Lodemann KP, et al. Low-dose gadobenate dimeglumine versusstandard dose gadopentetate dimeglumine for contrast-en-hanced magnetic resonance imaging of the liver: an intra-indi-vidual crossover comparison. Invest Radiol 2003;38:85e94.

25. Stern W, Schick F, Kopp AF, Reimer P, Shamsi K, Claussen CD,et al. Dynamic MR imaging of liver metastases with Gd-EOB-DTPA. Acta Radiologica 2000;41:255e62.

26. Huppertz A, Balzer T, Blakeborough A, Breuer J, Giovagnoni A,Heinz-Peer G, et al. Improved detection of focal liver lesions inMRI: multicenter comparison of gadoxetic acid-enhanced MRimages with intraoperative findings. Radiology 2004;230:266e75.

27. Reimer P, Rummeny EJ, Daldrup HE, Hesse T, Balzer T,Tombach B, et al. Enhancement characteristics of liver metas-tases, hepatocellular carcinomas and haemangiomas with Gd-EOB-DTPA: preliminary results with dynamic MR imaging.Euro Radiol 1997;7(2):275e80.

28. Hamm B, Thoeni RF, Gould RG, Bernardino ME, Luning M,Saini S, et al. Focal liver lesions: characterisation with non-

enhanced and dynamic contrast material-enhanced MR imag-ing. Radiology 1994;190:417e23.

29. Hawighorst H, Schoenberg SO, Knopp MV, Essig M, Miltner P, vanKaick G,etal.Hepatic lesions:morphologic andfunctionalcharac-terisation with multiphase breath-hold 3D gadolinium-enhancedMR angiography-initial results. Radiology 1999;210:89e96.

30. Larson RE, Semelka RC, Bagley AS, Molina PL, Brown ED,Lee JK, et al. Hypervascular malignant liver lesions: compari-son of various MR imaging pulse sequences and dynamic CT.Radiology 1994;192:393e9.

31. Mahfouz A-E, Hamm B, Taupitz M, Wolf KJ. Hypervascular liverlesions differentiation of focal nodular hyperplasia from malig-nant tumours with dynamic gadolinium-enhanced MR imaging.Radiology 1993;186:133e8.

32. Mahfouz AE, Hamm B, Wolf KJ. Peripheral washout: a sign ofmalignancy on dynamic gadolinium-enhanced MR images offocal liver lesions. Radiology 1994;190:49e52.

33. Mitchell DG, Saini S, Weinreb J, De Lange EE, Runge VM,Kuhlman JE, et al. Hepatic metastases and cavernous hemangi-omas: distinction with standard- and triple-dose gadoteridol-enhanced MR imaging. Radiology 1994;193:49e57.

34. Grandin C, Van Beers BE, Robert A, Gigot JF, Geubel A,Pringot J, et al. Benign hepatocellular tumors: MRI after super-paramagnetic iron oxide administration. J Comput AssistTomogr 1995;19(3):412e8.

35. Poeckler-Schoeniger C, Koepke J, Gueckel F, Sturm J,Georgi M. MRI with superparamagnetic iron oxide: efficacy inthe detection and characterisation of focal hepatic lesions.Magn Reson Imaging 1999;17:383e92.

36. Precetti-Morel S, Bellin MF, Ghebontni L, Zaim S, Opolon P,Poynard T, et al. Focal nodular hyperplasia of the liver on fer-umoxides-enhanced MR imaging: features on conventionalspin-echo, fast spin-echo and gradient-echo pulse sequences.Eur Radiol 1999;9:1535e42.

37. Ba-Ssalamah A, Schima W, Schmook MT, Linnau KF, Schibany N,Helbich T, et al. Atypical focal nodular hyperplasia of the liver:imaging features of non-specific and liver-specific MR contrastagents. AJR 2002;179:1447e56.

38. Oudkerk M, Torres CG, Song B, Konig M, Grimm J, Fernandez-Cuadrado J, et al. Characterization of liver lesions with manga-fodipir trisodium-enhanced MR imaging: multicenter studycomparing MR and dual-phase spiral CT. Radiology 2002;223:517e24.

39. Helmberger TK, Laubenberger J, Rummeny E, Jung G,Sievers K, Dohring W, et al. MRI characteristics in focal hepaticdisease before and after administration of MnDPDP: discrimi-nant analysis as a diagnostic tool. Eur Radiol 2002;12:62e70.

40. Morana G, Grazioli L, Schneider G, Testoni M, Menni K,Chiesa A, et al. Hypervascular hepatic lesions: dynamic andlate enhancement pattern with Gd-BOPTA. Acta Radiol 2002;9(Suppl. 2):476e9.

41. Grazioli L, Morana G, Kirchin MA, Caccia P, Romanini L,Bondioni MP, et al. MRI of focal nodular hyperplasia (FNH)with gadobenate dimeglumine (Gd-BOPTA) and SPIO (ferumox-ides): an intra-individual comparison. J Magn Reson Imaging2003;17:593e602.

42. Grazioli L, Morana G, Kirchin MA, Schneider G. Accurate differ-entiation of focal nodular hyperplasia from hepatic adenomaat gadobenate dimeglumine-enhanced MR imaging: prospec-tive study. Radiology 2005;236:166e77.

43. Vogl T. Enhancement of malignant and benign focal liver lesionsusing Gd-EOB-DTPA and Gd-DTPA enhanced MRI in the same pa-tient, International conferenceofMRIof theabdomenandpelvis.Bremen, Munich, Germany: H.M. Hauschild Ltd; 1995.

44. Huppertz A, Haraida S, Kraus A, Zech CJ, Scheidler J, Breuer J,et al. Enhancement of focal liver lesions at gadoxetic acid-en-hanced MR imaging: correlation with histopathologic findingsand spiral CT e initial observations. Radiology 2005;234:468e78.

e72 J. Ward

45. Vogl TJ, Kummel S, Hammerstingl R, Schellenbeck M,Schumacher G, Balzer T, et al. Liver tumors: comparison of MR im-aging withGd-EOB-DTPAandGd-DTPA.Radiology1996;200:59e67.

46. Runge VM. A comparison of two MR hepatobiliary gadoliniumchelates: Gd-BOPTA and Gd-EOB-DTPA. J Comp Assist Tomogr1998;22:643e50.

47. Tanimoto A, Satoh Y, Yuasa Y, Jinzaki M, Hiramatsu K. Perfor-mance of Gd-EOB-DTPA and superparamagnetic iron oxide par-ticles in the detection of primary liver cancer: a comparativestudy by alternative free-response receiver operating charac-teristic analysis. J Magn Reson Imaging 1997;7:120e4.

48. Gaa J, Hatabu H, Jenkins RL, Finn JP, Edelman RR. Liver masses:replacement of conventional T2-weighted spin-echo MR imagingwith breath-hold MR imaging. Radiology 1996;200:459e64.

49. Hittmair K, Trattnig S, Herold CJ, Breitenseher M, Kramer J.Comparison between conventional and fast spin-echo STIR se-quences. Acta Radiol 1996;37:943e9.

50. Duerk JL, Lewin JS, Wendt M, Petersilge C. Remember trueFISP? A high SNR, near 1-second imaging method for T2-likecontrast in interventional MRI at .2 T. J Magn Reson Imaging1998;8:203e8.

51. Kiefer B, Grassner J, Hausmann R. Image acquisition in a secondwith Half-Fourier single shot turbo spin-echo. J Magn ResonImagin 1994;4P:486e9.

52. Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA.Clinical safety of gadopentetate dimeglumine. Radiology1996;196:439e43.

53. Low RN, Sigeti JS, Francis IR, WeinmanD, Bower B, Shimakawa A,et al. Evaluation of malignant biliary obstruction: efficacyof fastmultiplanar spoiled gradient-recalled MR imaging vs spin-echoMR, CT and cholangiography. AJR 1994;162:315e23.

54. Low RN, Barone RM, Lacey C, Sigeti JS, Alzate GD,Sebrechts CP. Peritoneal tumor: MR imaging with dilute oralbarium and intravenous gadolinium-containing contrast agentscompared with unenhanced MR imaging and CT. Radiology1997;204:513e20.

55. Low RN, Francis IR, Politoske D, Bennett M. Crohn’s diseaseevaluation: comparison of contrast-enhanced MR imaging andsingle phase helical CT scanning. J Magn Reson Imaging 2000;11:127e35.

56. RofskyNM,LeeVS, LaubG, PollackMA,KrinskyGA, ThomassonD,et al. Abdominal MR imaging with a volumetric interpolatedbreath-hold examination. Radiology 1999;212:876e84.

57. Earls JP, Rofsky NM, DeCorato DR, Krinsky GA, Weinreb JC.Hepatic arterial-phase dynamic gadolinium-enhanced MRimaging: optimization with a test examination and a powerinjector. Radiology 1997;202:268e73.

58. Rummeny EJ, Torres CG, Kurdziel JC, Nilsen G, Op de Beeck B,Lundby B. MnDPDP for MR imaging of the liver. Results of an in-dependent image evaluation of the European phase III studies.Acta Radiol 1997;38(4 pt 2):638e42.

59. Rofsky NM, Weinreb JC, Bernardino ME, Young SW, Lee JK,Noz ME. Hepatocellular tumors: characterization with Mn-DPDP-enhanced MR imaging. Radiology 1993;188(1):53e9.

60. WardJ,Guthrie JA,ScottDJ,AtchleyJ,WilsonD,DaviesMH,etal.Hepatocellular carcinoma in the cirrhotic liver: double-contrastMR imaging for diagnosis. Radiology 2000;216(1):154e62.

61. Schima W, Petersein J, Hahn PF, Harisinghani M, Halpern E,Saini S. Contrast-enhanced MR imaging of the liver: comparisonbetween Gd-BOPTA and Mangafodipir. J Magn Reson Imaging1997;7:130e5.

62. Aicher KP, Laniado M, Kopp AF, Gronewaller E, Duda SH,Claussen CD. Mn-DPDP-enhanced MR imaging of malignant liverlesions: efficacy and safety in 20 patients. J Magn Reson Imag-ing 1993;3:731e7.

63. Gallez B, Baudelet C, Adline J, Charbon V, Lambert DM. Theuptake of Mn-DPDP by hepatocytes is not medicated by the fa-cilitated transport of pyridoxine. Magn Reson Imaging 1996;14:1191e5.

64. Lee VS, Rofsky NM, Morgan GR, Teperman LW, Krinsky GA,Berman P, et al. Volumetric mangafodipir-trisodium-enhancedcholangiography to define intrahepatic biliary anatomy. AJR2001;176(4):906e8.

65. Mitchell DG, Alam F. Mangafodipir trisodium: effects on T2- andT1-weighted MR cholangiography. J Magn Reson Imaging 1999;9:366e8.

66. Spinazzi A, Lorusso V, Pirovano G, Kirchin A. Safety, tolerance,biodistribution, and MR imaging enhancement of the liver withgadobenate dimeglumine: results of clinical, pharmacologicand pilot imaging studies in non-patient and patient volun-teers. Acad Radiol 1999;6(5):282e91.

67. Hamm B, Staks T, Muhler A, Bollow M, Taupitz M, Frenzel T,et al. Phase I clinical evaluation of Gd-EOB-DTPA as a hepato-biliary MR contrast agent: safety, pharmacokinetics, and MRimaging. Radiology 1995;195(3):785e92.

68. Scott J, Ward J, Guthrie JA, Wilson D, Robinson PJ. MRI of theliver: a comparison of CNR enhancement using high dose andlow dose ferumoxide infusion in patients with colorectal livermetastases. Magn Reson Imaging 2000;18:297e303.

69. Arnold P, Ward J, Wilson D, Guthrie JA, Robinson PJ. Superpar-amagnetic iron oxide (SPIO) enhancement in the cirrhotic liver:a comparison of two doses of ferumoxides in patients with ad-vanced disease. Magn Reson Imaging 2003;21:695e700.

70. Bluemke DA, Weber TM, Rubin D, de Lange EE, Semelka R,Redvanly RD, et al. Hepatic MR imaging with ferumoxides: mul-ticenter study of safety and effectiveness of direct injectionprotocol. Radiology 2003;228(2):457e64.

71. Reimer P, Balzer T. Ferucarbotran (Resovist): a new clinicallyapproved RES-specific contrast agent for contrast-enhancedMRI of the liver: properties, clinical development, and applica-tions. Eur Radiol 2003;13:1266e76.

72. Murakami T, Baron RL, Peterson MS, Oliver 3rd JH, Davis PL,Confer SR, et al. Hepatocellular carcinoma: MR imagingwith mangafodipir trisodium (Mn-DPDP). Radiology 1996;200:69e77.

73. Seneterre E, Taourel P, Bouvier Y, Pradel J, Van Beers B,Daures JP, et al. Detection of hepatic metastases: ferumox-ides-enhanced MR imaging versus unenhanced MR imaging andCT during arterial portography. Radiology 1996;200:785e92.

74. Helmberger TK, Holzknecht NG, Gregor MM. Unenhanced, Gd-DTPA- and ferumoxides-enhanced MRI in focal hepatic disease:a comparison in over 900 patients. Radiology 2000;217(p):280.

75. Coffin CM, Diche T, Mahfouz A, Alexandre M, Caseiro-Alves F,Rahmouni A, et al. Benign and malignant hepatocellular tu-mors: evaluation of tumoral enhancement after mangafodipirtrisodium injection on MR imaging. Eur Radiol 1999;9:444e9.

76. Mathieu D, Coffin C, Kobeiter H, Caseiro-Alves F, Mahfouz A.Rahmouni A et al. Unexpected MR-T1 enhancement of endo-crine liver metastases with mangafodipir. J Magn Reson Imag-ing 1999;10:193e5.

77. Hahn PF, Stark DD, Weissleder R, Elizondo G, Saini S,Ferrucci JT. Clinical application of superparamagnetic ironoxide to MR imaging of tissue perfusion in vascular liver tumors.Radiology 1990;174:361e6.

78. Ward J, Robinson PJ. Combined use of MR contrast agents forevaluating liver disease. MRI Clinics N Am 2001;9(4):767e83.

79. Bhartia B, Ward J, Guthrie JA, Robinson PJ. Hepatocellular car-cinoma in cirrhotic livers: double-contrast thin-section MR im-aging with pathologic correlation of explanted tissue. Am JRoentgenol 2003;180(3):577e84.