Clinical value of MRI liver-specific contrast agents: a tailored examination for a confident non-invasive diagnosis of focal liver lesions

Screening of the liver for hepatic lesion detection and characterization is usually performed with either ultrasound or CT. However, both techniques are suboptimal for liver lesion characterization and magnetic resonance (MR) imaging has emerged as the preferred radiological investigation. In addition to unenhanced MR imaging techniques, contrast-enhanced MR imaging can demonstrate tissue-specific physiological information, thereby facilitating liver lesion characterization. Currently, the classes of contrast agents available for MR imaging of the liver include non-tissue-specific extracellular gadolinium chelates and tissue-specific hepatobiliary or reticuloendothelial agents. In this review, we describe the MR features of the more common focal hepatic lesions, as well as appropriate imaging protocols. A special emphasis is placed on the clinical use of non-specific and liver-specific contrast agents for differentiation of focal liver lesions. This may aid in the accurate diagnostic workup of patients in order to avoid invasive procedures, such as biopsy, for lesion characterization. A diagnostic strategy that considers the clinical situation is also presented.     

Focal liver lesions: role of contrast-enhanced ultrasound

The introduction of microbubble contrast agents and the development of contrast-specific techniques have opened new possibilities in liver imaging. Initially, only intermittent imaging with Doppler detection was available. Second-generation contrast agents and low mechanical index real-time scanning techniques are decisive advances that enable convenient liver examinations with high sensitivity and specificity. Hepatic lesions usually show typical perfusion and enhancement patterns through the various contrast phases, which help their characterization. Several published studies and the daily clinical routine show that, as opposed to conventional ultrasound (US), contrast-enhanced US can substantially improve detection and differentiation of focal liver lesions. Today, contrast-enhanced US is the dynamic imaging modality of choice for differentiation of focal liver lesions. Contrast uptake patterns of the most relevant liver lesions, as well as important clinical indications are presented and discussed.     

Use of contrast agents for liver MRI

Contrast-enhanced MRI is recognised as one of the most accurate imaging methods for investigating diseases of the liver. Uniquely several different types of contrast agents are available 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 improve the detection of focal liver lesions by increasing normal-abnormal tissue contrast and to assist 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 provide valuable information regarding the vascularisation and perfusion characteristics of lesions and assist in lesion detection, particularly of hypervascular lesions. The hepatocyte and RES-specific agents further improve lesion detection, provide important functional information and allow the distinction between hepatocellular and non-hepatocellular tumours. This article describes the different MR contrast agents and discusses their current status for diagnosing focal liver lesions. The importance of optimised technique and appropriate selection of contrast agent is emphasised.     

Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents

Ultrasonography (US) is the first choice for screening patients with suspected liver lesions. However, due to a lack of contrast agents, US used to be less sensitive and specific compared with computed tomography (CT) and magnet resonance imaging (MRI). The advent of microbubble contrast agents increased both sensitivity and specificity dramatically. Rapid developments of the contrast agents as well as of special imaging techniques were made in recent years. Today numerous different US imaging methods exist which based either on Doppler or on harmonic imaging. They are using the particular behaviour of microbubbles in a sound field which varies depending on the energy of insonation (low/high mechanical index, MI) as well as on the properties of the agent themselves. Apart from just blood pool enhancement some agents have a hepatosplenic specific late phase. US imaging during this late phase using relatively high MI in phase inversion mode (harmonic imaging) or stimulated acoustic emission (SAE; Doppler method) markedly improves the detection of focal liver lesions and is also very helpful for lesion characterisation. With regards to detection, contrast enhanced US performs similarly to CT as shown by recent studies. Early results of studies using low MI imaging and the newer perfluor agents are also showing promising results for lesion detection. Low MI imaging with these agents has the advantage of real time imaging and is particularly helpful for characterisation of focal lesions based on their dynamic contrast behaviour. Apart from the techniques which based on the morphology of liver lesions there were some attempts for the detection of occult metastases or micrometastases by means of liver blood flow changes. Also in this field the use of US contrast agents appears to have advantages over formerly used non contrast-enhanced methods although no conclusive results are available yet.     

Contrast agents for MR imaging of the liver

Imaging of the liver is performed most often to detect and characterize focal liver lesions. MR imaging has been the method of choice to assess focal liver lesions accurately. Nonspecific intravenous contrast agents have been used for routine abdominal MR imaging protocols including liver imaging. Over the last 10 to 15 years new contrast agents have been developed that combine the excellent contrast resolution of MR imaging with improved tissue specificity. This article reviews various contrast agents that are in clinical use for liver MR imaging and discusses their potential clinical role.     

Contrast agents for MR imaging of the liver

A variety of different categories of contrast agents, and within each category a number of individual agents, are currently available for clinical use in magnetic resonance (MR) imaging of the liver. In this review, the use of nonspecific extracellular gadolinium chelates, reticuloendothelial system-specific iron oxide particulate agents, hepatocyte-selective agents, and combined perfusion and hepatocyte-selective agents are described. Most clinical experience is with nonspecific extracellular gadolinium chelates. The relatively low cost, safety, good patient tolerance, and ability to help detect and characterize a wide range of liver diseases have rendered gadolinium chelates as commonly used agents. Reticuloendothelial system-specific agents improve lesion detection by decreasing the signal intensity of background liver on T2-weighted MR images, which increases the conspicuity of focal hepatic lesions with negligible reticuloendothelial cells (eg, metastases). Hepatocyte-selective agents increase the signal intensity of background liver on T1-weighted images, which increases the conspicuity of focal lesions that do not contain hepatocytes (eg, metastases). The clinical application of the different categories of contrast agents, techniques for their administration, sequences to be used, and appearances of common entities on contrast agent-enhanced studies are described.     

MultiHance in the dynamic phase of contrast enhancement: a pictorial assessment

The present article demonstrates pictorially the use of MultiHance (gadobenate dimeglumine, Gd-BOPTA) in dynamic magnetic resonance imaging and is aimed at ensuring that the product is not misconceived as solely a hepatobiliary agent for use in delayed, static magnetic resonance imaging for the improved detection of focal liver lesions. The enhancement patterns of three malignant (hepatocellular carcinoma, cholangiocarcinoma and metastasis) and three benign (hemangioma, focal nodular hyperplasia and adenoma) lesion types are demonstrated. Each was imaged during the dynamic phase of contrast enhancement immediately following the intravenous bolus administration of 0.05 mmol/kg MultiHance. The article demonstrates that the enhancement patterns observed for these relatively common lesions are similar to those reported in the literature after the intravenous bolus administration of conventional, non-specific 'extracellular fluid' contrast agents, and concludes by inferring that MultiHance behaves in the liver as a conventional gadolinium-based agent in the first minutes after administration.     

Ultrasound contrast agents for hepatic imaging with nonlinear modes

The continuing development of nonlinear imaging, as well as a whole new generation of contrast agents, holds out great prospects in improving liver imaging. Optimization of the equipment settings for different classes of contrast agents is essential in the detection and characterization of focal liver lesions. On the basis of the preliminary results of multicenter clinical trials, it is reasonable to assume that their application in specific clinical settings will impact favorably on patient management.     

Magnetic resonance imaging of the liver: New imaging strategies for evaluating focal liver lesions

The early detection of focal liver lesions, particularly those which are malignant, is of utmost importance. The resection of liver metastases of some malignancies (including colorectal cancer) has been shown to improve the survival of patients. Exact knowledge of the number, size, and regional distribution of liver metastases is essential to determine their resectability. Almost all focal liver lesions larger than 10 mm are demonstrated with current imaging techniques but the detection of smaller focal liver lesions is still relatively poor. One of the advantages of magnetic resonance imaging (MRI) of the liver is better soft tissue contrast (compared to other radiologic modalities), which allows better detection and characterization of the focal liver lesions in question. Developments in MRI hardware and software and the availability of novel MRI contrast agents have further improved the diagnostic yield of MRI in lesion detection and characterization. Although the primary modalities for liver imaging are ultrasound and computed tomography, recent studies have suggested that MRI is the most sensitive method for detecting small liver metastatic lesions, and MRI is now considered the pre-operative standard method for diagnosis. Two recent developments in MRI sequences for the upper abdomen comprise unenhanced diffusion-weighted imaging (DWI), and keyhole-based dynamic contrast-enhanced (DCE) MRI (4D THRIVE). DWI allows improved detection (b = 10 s/mm(2)) of small (< 10 mm) focal liver lesions in particular, and is useful as a road map sequence. Also, using higher b-values, the calculation of the apparent diffusion coefficient value, true diffusion coefficient, D, and the perfusion fraction, f, has been used for the characterization of focal liver lesions. DCE 4D THRIVE enables MRI of the liver with high temporal and spatial resolution and full liver coverage. 4D THRIVE improves evaluation of focal liver lesions, providing multiple arterial and venous phases, and allows the calculation of perfusion parameters using pharmacokinetic models. 4D THRIVE has potential benefits in terms of detection, characterization and staging of focal liver lesions and in monitoring therapy.     

Ultrasound of focal liver lesions

This paper gives a comprehensive overview of ultrasound of focal liver lesions. Technical aspects such as examination technique and the use of Doppler modes as well as recent developments such as tissue harmonic imaging and microbubble contrast agents are discussed. The clinical significance and sonographic features of various liver lesions such as haemangioma, focal nodular hyperplasia, adenoma, regenerative nodule, metastasis, hepatocellular carcinoma and various types of focal infections are described. With the exception of cysts and typical haemangiomas, definitive characterisation of a liver lesion is often not possible on conventional ultrasound. This situation has changed with the recent advent of ultrasound contrast agents, which permit definitive diagnosis of most lesions. Contrast-enhanced sonography using recently developed contrast-specific imaging modes dramatically extends the role of liver ultrasound by improving its specificity in the detection and characterisation of focal lesions to rival CT and MRI.     

Contrast material for computed tomography and magnetic resonance imaging of the gastrointestinal tract

Various contrast agents are applied in both CT and MR imaging to improve the detection as well as the differentiation of focal liver lesions. In detecting hepatocellular carcinoma, the accuracy of Lipiodol-enhanced CT is comparable to that of CT during arterial portography. Tissue-specific contrast agents for the liver are superparamagnetic iron oxide particles, which are characterized by uptake in the reticuloendothelial system, and the paramagnetic hepatobiliary contrast agent manganese (II)-N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate). Both substances have the potential for markedly improving the detection of malignant liver tumors. The already good differentiation of focal hepatic lesions on plain MR images can be further improved by dynamic gadolinium diethylenetriamine penta-acetic acid-enhanced MR imaging. In the diagnosis of bile duct disorders, contrast-enhanced CT continues to be the method of choice. Water applied as a gastrointestinal contrast agent improves the staging of rectal carcinoma by CT. The development of suitable orally applied gastrointestinal contrast agents has now also improved the differentiation of the intestine from other abdominal structures on MR images, and this will lead to a general improvement of abdominal MR imaging.     

Impact of European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines on the use of contrast agents in liver ultrasound

The introduction of microbubble contrast agents and the development of contrast-specific techniques have opened new prospects in liver ultrasound. Over the past few years several reports have shown that contrast ultrasound can substantially improve detection and characterization of focal liver lesions with respect to baseline studies. The advent of second-generation agents and low mechanical index real-time scanning techniques has been instrumental in improving the easiness and the reproducibility of the examination. With the publication of the guidelines for the use of contrast agents in liver ultrasound by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), contrast ultrasound enters into clinical practice. The guidelines define the indications and recommendations for the use of contrast ultrasound in focal liver lesion detection, characterization, and follow-up after tumor ablation procedures. We discuss the impact of EFSUMB guidelines on diagnostic protocols currently adopted in liver imaging.     

The value of magnetic resonance tomography in the detection and differential diagnosis of focal liver lesions]

Magnetic resonance imaging (MRI) of the liver has made considerable progress due to improvements in the examination technique. Sensitivity for the detection of focal liver lesions is higher for MRI than for CT. In the differential diagnosis of liver tumors MRI is remarkably accurate. This is particularly true for hemangiomas, liver cell carcinomas and focal nodular hyperplasias. From a clinical view point differentiation between hemangiomas and metastases is of utmost importance. Future improvements in MR diagnosis of liver diseases are expected due to fast imaging techniques and liver-specific contrast agents.     

Contrast agents for MR imaging of the liver: a clinical overview

Different contrast agents have been clinically used in MR imaging of the liver including extracellular gadolinium chelates, contrast agents targeted to the macrophage-monocytic phagocytic system (MMPS), hepatobiliary contrast agents, and blood-pool contrast agents. Extracellular gadolinium chelates are optimally used for characterization of focal hepatic lesions, whereas hepatobiliary and MMPS-targeted contrast agents are optimally used for detection and preoperative evaluation. The present review portrays these contrast agents and discusses their advantages and shortcomings. Received 14 June 1996; Revision received 14 August 1996; Accepted 16 August 1996     

Magnetic resonance imaging: Review of imaging techniques and overview of liver imaging

Magnetic resonance imaging (MRI) of the liver is slowly transitioning from a problem solving imaging modality to a first line imaging modality for many diseases of the liver. The well established advantages of MRI over other cross sectional imaging modalities may be the basis for this transition. Technological advancements in MRI that focus on producing high quality images and fast imaging, increasing diagnostic accuracy and developing newer function-specific contrast agents are essential in ensuring that MRI succeeds as a first line imaging modality. Newer imaging techniques, such as parallel imaging, are widely utilized to shorten scanning time. Diffusion weighted echo planar imaging, an adaptation from neuroimaging, is fast becoming a routine part of the MRI liver protocol to improve lesion detection and characterization of focal liver lesions. Contrast enhanced dynamic T1 weighted imaging is crucial in complete evaluation of diseases and the merit of this dynamic imaging relies heavily on the appropriate timing of the contrast injection. Newer techniques that include fluoro-triggered contrast enhanced MRI, an adaptation from 3D MRA imaging, are utilized to achieve good bolus timing that will allow for optimum scanning. For accurate interpretation of liver diseases, good understanding of the newer imaging techniques and familiarity with typical imaging features of liver diseases are essential. In this review, MR sequences for a time efficient liver MRI protocol utilizing newer imaging techniques are discussed and an overview of imaging features of selected common focal and diffuse liver diseases are presented.     

Contrast agents for MR imaging of the liver

The evolution of contrast agents for MR imaging of the liver has proceeded along several different paths with the common goal of improving liver-lesion contrast. These contrast agents are used to accentuate the inherent differences in liver-lesion signal intensity through differential enhancement of proton relaxation within adjacent tissues. Contrast agents used for hepatic MR imaging can be broadly categorized into those that target the extracellular space, the hepatobiliary system, and the reticuloendothelial system. Although only a small number of liver contrast agents are currently available, others are rapidly proceeding through clinical trials and may soon be added to our clinical armamentarium. This article will briefly review the current clinical experience with these agents, discussing their mechanism of contrast enhancement, pharmacokinetics, and efficacy in the evaluation of focal liver lesions.     

Focal liver lesion detection and characterization with GD-EOB-DTPA

Superior soft-tissue contrast affords magnetic resonance imaging (MRI) some advantages compared to computed tomography (CT) in both detection and characterization of focal liver lesions. Because of its relatively recently introduction into clinical practice, a growing number of articles in the literature have demonstrated the usefulness of the hepatobiliary-specific MRI contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in liver imaging. The purpose of this review is to demonstrate the typical enhancement patterns of the most common liver lesions using Gd-EOB-DTPA in daily clinical scenarios and briefly describe its mechanism of action. Radiologists interpreting liver MRI studies with this agent must be familiar with the appearance of focal lesions in the hepatocyte phase to avoid misinterpretation.     

Looking into the future: iotrolan and beyond

The modern classes of contrast agents in the diagnostic areas of X-ray, magnetic resonance and ultrasound imaging offer safety and tolerance on a level which is difficult to further improve. The thrust of research is, therefore, now focused on efficacy, which basically means the development of organ and tissue-specific contrast agents. These new substance classes promise to open up faseinating possibilities and are represented in this review by specific agents that are currently undergoing preclinical or clinica evaluation. Reficulo-endothelial systems and hepatocyte-targeted agents enhance the tissue contrast of the liver and spleen, reducing the detection threshold and facilitating further characterization of focal liver lesions. With blood pool contrast agetns it is possible to delincate blood vessesl and obtain an angiographic effect for detection of areas of increased capillary permeability and occult bleeding.     

Invited MRI of the liver

MRI of the liver is a powerful imaging modality for detection and characterization of liver pathology. MRI technology continues to evolve with developments in scanner hardware performance and refinements in imaging sequences, particularly in respect to fast imaging techniques, improving the quality of images that can be routinely achieved. Fast imaging techniques allow dynamic contrast-enhanced scanning to assist in lesion detection and characterization. An array of tissue-specific contrast agents are also becoming available; the clinical utility of some of these agents is yet to be fully established. An overview of scanning technique, contrast media, and the role of MRI in liver lesion detection and characterization is presented, with a review of the typical imaging characteristics of common focal and diffuse hepatic diseases. Where possible, emphasis has been placed on features that allow distinction between the various pathologic entities described.     

Detection and characterization of benign focal liver lesions with multislice CT

MDCT is a rapidly evolving technique that significantly improves CT imaging for several indications including depiction of focal benign lesions. Imaging mainly profits from improved longitudinal spatial resolution allowing high-quality non-axial reformations and 3D reconstructions and CT angiography as well as rapid accurate multiphase imaging with short breath-holding periods. This review provides an overview of the current status of MDCT with respect to liver imaging and the implications for characterizing benign focal liver lesions. MDCT currently allows the acquisition of thin slices in daily routine diagnostics providing an improved detection rate of small liver lesions. Whereas large benign focal liver lesions exhibit typical patterns of morphology, attenuation and perfusion, which also may be assessed with single-slice scanners, small lesions remain challenging even with MDCT, since the specific criteria for confident diagnosis become more ambiguous. Here, MR imaging provides more detailed information about tissue components and the availability of liver-specific contrast agents, adding further impact to this technique. With respect to dose considerations, the number of necessary multiphase scans as well as the application of very thin collimation should be strictly checked for each patient undergoing MDCT based on the individual clinical situation and question.