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MR contrast agents in hepatic cirrhosis and chronic hepatitis
MR Contrast Agents in Hepatic Cirrhosis and Chronic Hepatitis Luis Mart[-Bonmat[ Chronic liver disease alters the gross architecture of the liver and its arterial and portal blood supply. The relative proportion of regenerative hepatocytes, necrosis, extracellular interstitial space, and fibrosis is responsible for liver enhancement after the administration of a contrast agent. Because contrast agents can be directed toward either the extracellular or the intracellular spaces, knowledge of the different parenchymal enhancement alterations seen after the administration of these agents is necessary to understand how chronic liver disease pathologic changes influence contrast-enhanced magnetic resonance (MR) images. This article reviews the effect of chronic liver disease on MR contrast enhancement, as well as the effect of altered enhancement on lesion detection and characterization. Both extracellular and intracellular contrast agents are considered.
Copyright 2002, Elsevier Science (USA). All rights reserved.
HE LIVER IS a difficult organ to study because of its complex anatomy, dual blood supply, and the frequent presence of diffuse diseases. Radiologists have different challenges in analyzing liver pathology,; namely, to depict nodules and to differentiate between benign and malignant lesions. Only recently, radiologists have also become interested in the analysis of liver cell necrosis and function. Chronic hepatitis is defined as a continuous or recurrent inflammation of the liver for more than 6 months, with histologic changes of chronic liver damage, such as erosive necrosis and the production of fibroconnective tissue. Chronic hepatitis is also characterized by lymphocytic infiltration, generating liver cell injury, necrosis, and fibrosis. Chronic hepatitis, in its late stage, can progress to cirrhosis, which is a chronic and progressive diffuse process characterized by fibrosis of the liver and the formation of anatomically abnormal hepatic nodules. These nodules are surrounded by fibrous septa that bridge the spaces between the portal tracts and arrange the hepatic histology in an abnormal state of organization. Chronic liver disease may, therefore, alter the gross architecture of the liver. Liver cell necrosis is responsible for the volume loss seen in cirrhosis. Enlargement of the hilar periportal space is seen in early stages, ~ and atrophy of the left medial segment, along with the fight lobe, is seen in advanced stages. Regeneration is seen as nodularity of the liver surface and also as segmental or lobar enlargement, which mainly effects the caudate lobe and of the lateral segment of the left hepatic lobe (Fig 1). Atrophy and regeneration are principally attributed to portal blood flow alterations. Because fibrosis causes compression and irregular stenosis of the large intrahepatic
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portal vein branches, the portal flow changes according to the course of the vessels; decreasing in the right lobe and medial left lobe, while increasing (relatively) in the left lateral segment and caudate lobe. 2 Retraction of the liver surface can be seen in association with confluent hepatic fibrosis. These areas of collapse, which have a triangular shape with the apex pointing toward the hepatic hilum, show slight hyperintensity on T2-weighted magnetic resonance (MR) images. Hyperintensity is caused by invasion of the fibrous septum by inflammatory cells, as well as the presence of pseudobile ducts? Areas of confluent hepatic fibrosis can be misdiagnosed as hepatocellular carcinoma because they are hyperintense on T2-weighted images and show significant uptake of extracellular contrast agents. These areas, however, have a typical subsegmental appearance with vessels and bile ducts within them, making the differentiation from a neoplastic mass straightforward. Changes associated with portal hypertension are frequently found in cirrhotic patients. The volume of the spleen and the presence of ascites and varices are directly related to the clinical severity of cirrhosis, whereas the volume of the right hepatic lobe and the medial segment of the left lobe are inversely correlated with severity.4 Progressive atrophy of the right hepatic lobe and the medial
From the Department of Radiology, Doctor Peset University Hospital, Valencia, Spain. Address reprint requests to Luis Martf-Bonmaff, MD, PhD, Seccirn de RM, Servicio de Radiologfa, Hospital Universitario Dr Peset, [:-460]7 Valencia, Spain; e-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 0887-2171/02/'2301-0006535.00/0 doi:l O.lO53/sult.2002.29795
Seminars in Ultrasound, CT, and MRI, Vol 23, No 1 (February), 2002: pp 101-113
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Fig 1. (A) Tl-weighted and (B) STIR images in hepatic cirrhosis show liver surface nodularity and linear septa surrounding regenerative nodules. There are also collateral vessels in the gastrohepatic ligament caused by portal hypertension.
segment of the liver correlate with progression of the clinical severity of cirrhosis; however, increasing size of the caudate lobe and the lateral segment correlate with stability: In the cirrhotic liver, cell dysfunction and necrosis are responsible for the development of fibrosis and regeneration, leading to abnormal intrahepatic vascularization and abnormalities in contrast media uptake. Not only is it important to recognize these abnormalities and their clinical impact, but it is also important to realize that the evaluation of focal liver lesions in cirrhotic patients can be altered by the presence of abnormal parenchyma opacification. This article reviews the effect of chronic liver disease on MR contrast enhancement, as well as the effect of altered enhancement on lesion detection and characterization. Both extracellular and intracellular contrast agents are considered. LIVER ENHANCEMENT
Extracel[ular Contrast Agents Gadolinium chelates are the most commonly used MR contrast media. They are small hydrophilic molecules that can diffuse freely through the extracellular space, and are filtered and excreted by the kidneys. They are usually administered as a
bolus injection. They have an initial, short, intravascular phase, and pass quickly into the extravascular extracellular space. Therefore, these agents can be considered to be targeted to the intravascular space (in the first few seconds after their administration) and interstitial space (within the first few minutes). Most cirrhotic livers have inhomogeneous hepatic texture in contrast-enhanced MR images. This heterogeneous enhancement is related to the degree of liver necrosis, inflammation, and fibrosis, as well as to the dual blood supply of the liver (Fig 2). In cirrhotic livers, the increase of intrahepatic vascular resistance decreases the portal contribution to liver perfusion. This portal hypopeffusion is partially compensated by an increase in the arterial blood supply, owing to the balance between the arterial and portal supply. 6 Therefore, the arterial blood supply increases as the portal blood flow is diminished, owing to the portal hemodynamic changes associated with venous hypertension and collateral circulation. 7"8 If portal vein thrombosis occurs, the arterial fraction of liver perfusion increases even more. The inflammation associated with chronic liver disease also increases the arterial hepatic blood supply; however, the increase in the arterial perfusion is not sufficient to maintain ade-
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Fig 2. Tl-weighted, fat-suppressed, gadolinium-enhanced image shows the enhancing reticular septa within the fibrotic changes in the cirrhotic liver parenchyma.
quate liver perfusion, mainly because of a high level of extrahepatic portosystemic shunting. The net result is an overall reduction of the total liver perfusion in chronic liver diseases. Both the liver perfusion decrease and the arterial fraction changes seen in chronic liver disease are related to the severity of disease and are significantly altered in cirrhosis. 6 Liver enhancement in the first seconds after the administration of contrast media can be more prominent in cirrhotic patients than in normal subjects because the hepatic arterial perfusion is increased and there is less dilution of the contrast in the hepatic circulation than in the portal circulation. l's Early patchy enhancement of the parenchyma is associated with the presence of numerous infiltrating macrophages, necrosis, tissue collapse, and increased steatosis (Fig 3). 9 The patchy enhancement seen after gadolinium administration probably has two causes: (1) capillary density changes and damage that cause rapid contrast extravasation, and (2) increased volume of the extracellular spaces owing to hepatocellular necrosis. Additional transient hepatic intensity differences
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are frequently found in cirrhotic livers 1° consisting of focal, peripheral, subcapsular wedges of increased intensity seen only in the arterial-dominant phase. These findings are usually owing to arterioportal shunts or aberrant venous drainage, but in cirrhotic livers, large perfusion abnormalities can also be related to obstruction of the portal vein, previous percutaneous interventional procedures, and a siphon effect from a hypervascular hepatocellular carcinoma (HCC).11 Considering the latter possibility, the presence of these areas should elicit a careful search for a focal mass near the regions of increased enhancement. 1° Hepatic blood flow correlates with the severity of the liver dysfunction in cirrhosis. With dynamic, T2*-weighted MR imaging after a bolus injection of a susceptibility gadolinium chelate, it has been shown that both the portal blood flow and volume are significantly decreased in Child-Pugh B and C patients compared with Child-Pugh A patients, whereas mean transit time was prolonged in higher grades of liver dysfunction. 12 This may reflect the progressive fibrosis around the portal vein and hepatic vein branches. The decrease in mean peak liver enhancement and the delay in the time to peak liver enhancement is especially prominent in patients with portal hypertension, splenomegaly, and portosystemic shunting. Therefore, in the course of dynamic MR imaging, the portal and equilibrium phases are reached later in these patients. By analyzing the whole liver enhancement during the first 4 minutes after contrast administration, it was found that the time to peak enhancement of the
Fig 3. Tl-weighted gadolinium-enhanced image in the early portal phase shows variable enhancement of different portions of the liver. Enhancement of the caudate lobe, where regeneration is prominent, is less than other areas, and a subsegmental area of early patchy enhancement is seen in segment 6.
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Fig 4. T1 weighted, delayed, gadolinium enhanced image shows a triangular hyperenhancing area in the intersegmental fissure due to confluent fibrosis.
liver, which may be the optimal time for imaging the liver, is obtained 54 seconds after contrast injection in patients without portal hypertension, but 84 seconds after injection in patients with cirrhosis and portal hypertension) 3 Fibrosis is mainly responsible for abnormal enhancement of the chronically damaged liver. In MR images obtained at the equilibrium and late phases after gadolinium administration, a linear enhancement pattern can be seen as an enhancing reticular network (Fig 2). Fibrosis in the septa is
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responsible for the increased enhancement of these areas, 9 and is more prominent in the periphery of the liver. Linear enhancement is seen in the fibrous septa and in the pseudocapsule around hepatomas. Triangular areas of slight and delayed enhancement, with their bases on the liver capsule, are seen in confluent fibrosis (Fig 4). 1°'14 This pattern is different from the patchy and linear patterns. Poorly marginated confluent hepatic fibrosis may be impossible to differentiate from infiltrative neoplasms. 15 In the late equilibrium and delayed phases, the contrast agent moves more slowly toward the interstitium and the fibrotic areas. Because the extracellular space is proportional to the degree of necrosis, an increase in the enhancement of the liver parenchyma in late phases is proportional to the amount of necrosis. This increase in liver enhancement can be observed (Fig 5) with appropriate tools, such as parametric images obtained on a pixel-by-pixel basis, from a dynamic series of images after bolus contrast administration. By factor analysis of dynamic structures, parenchymal enhancement has been proven to be different in healthy and cirrhotic livers. 16 The averaged enhancement and the maximum enhancement of the liver over 5 minutes after bolus injection of a gadolinium chelate, as evaluated by time-enhancement curves on a pixel-by-pixel basis, were statistically higher in cirrhotic livers (P < .05). The increase in the parenchymal enhancement is prob-
Fig 5. Parametric maps after gadolinium enhancement (left panel, representative dynamic image; right panel, averaged enhancement map over 5 minutes). A percutaneously treated, necrotic HCC without any enhancement stands out against marked enhancement of the liver parenchyma.
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ably related to an increase in the interstitial extracellular space. The decreased size and number of the hepatocytes increase the proportion of liver volume occupied by the interstitial space and vessels. a6 The increase in the liver enhancement was statistically related to the degree of chronic hepatic insufficiency, expressed as the Child-Pugh classification index (P < .05). In summary, in chronic liver disease and cirrhosis, there is an increased arterialization of the liver, resulting in areas of early transient enhancement after the administration of extracellular contrast agents. Total blood volume mad peak liver enhancement in the portal and equilibrium phases are decreased, whereas in late equilibrium and delayed phases, the enhancement is increased with respect to normal livers. These enhancement changes are related to the level of portal hypertension and the degree of liver dysfunction. Linear fibrotic septa can be observed surrounding regenerating nodules in cirrhotic livers.
Intracellular Hepatocellular Contrast Agents Mangafodipir trisodium (MnDPDP) is a specific contrast agent taken up by hepatocytes and excreted into the bile. When the liver is studied with
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Tl-weighted gradient-recalled echo (GRE) images obtained after the administration of this agent, an increase in the signal intensity of the parenchyma can easily be observed as early as 5 minutes after its administration, reaching a peak enhancement at 60 minutes with a large temporal plateau. Because this contrast media is actively incorporated inside the hepatocytes, parenchymal liver enhancement is proportional to the number of hepatocytes per unit of volume (voxel). It has been observed that the parenchymal enhancement ratio (the ratio between the signal intensity of the liver before and after the contrast administration) is statistically lower in livers with cirrhosis than in normal livers (P < .001). 17 This decrease in liver enhancement has been related, with logistic regression models, with the liver dysfunction evaluated with the ChildPugh index and also with the aspartate transaminase (AST) blood levels (P < .01). x7 By visual analysis of the enhanced images, it was also noted that all normal livers enhance with a homogeneous texture, whereas 37% of the cirrhotic livers had a heterogeneous enhancement pattern. This heterogeneity is caused by the coexistence of hyper- and hypoenhancement areas (Figs 6 and 7). Areas of lower enhancement contain fibrous zones, either
Fig 6. Tl-weighted GRE images (A) before and (B) after MnDPDP administration show heterogeneous enhancement of this cirrhotic liver caused by regeneration (posterior segments) and necrosis (anterior segments).
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Fig 7. Tl-weighted GRE images (A) before and (B) after MnDPDP administration show hypointense linear structures, more evident after contrast administration, representing the fibrous collapse bands.
confluent or diffuse, and hepatocyte necrosis, whereas areas of hepatocyte regeneration show an increase in the enhancement caused by a relatively high number of liver cells per voxel. 17'18 Hepatocytes within regenerating nodules can also have impaired bile excretion, causing increased liver enhancement owing to accumulation of the contrast in the hepatocytes. 19 In patients with liver iron overload, the liver parenchyma has a low signal intensity on T1weighted GRE images owing to the susceptibility effect of iron. In these patients, the enhancement effect of MnDPDP on liver parenchyma is masked, a8 It is not recommended, therefore, to administer this contrast agent if the precontrast Tl-weighted images show diffusely hypointense liver parenchyma. Gadobenate dimeglumine (BOPTA) is a gadolinium chelate with both nonspecific extracellular distribution and specific hepatocyte uptake and biliary excretion. Although the biliary excretion is close to 4%, in Tl-weighted images there is a prolonged enhancement of hepatic parenchyma after the intravenous administration of this compound. 2° It has been proven that for liver imaging, high-dose (0.1 mmol/Kg) Gd-BOPTA and MnDPDP provide comparable effects.21 The temporal window for this delayed liver effect is between 60 to 120 minutes after the contrast administration, which is a long delay in postcontrast imaging. 21 Surprisingly, cirrhotic livers have higher levels of signal-to-noise ratios and enhancement with Gd-BOPTA, relative to noncirrhotic liver parenchyma. This increase in enhancement can be
caused by either an additive effect of the specific hepatocytic uptake and the extracellular distribution in widely distributed fibrosis, or to the impaired hepatobiliary excretion from the hepatocytes. 22 Liver enhancement is mainly homogeneous in patients with Child-Pugh A cirrhosis, but more frequently is heterogeneous with higher grades of liver insufficiency. 2° As so happens with MnDPDP, the presence of iron overload limits the efficacy of Gd-BOPTA to enhance liver parenchyma. 22 Gd-EOB-DTPA is a paramagnetic contrast agent also with dual extracellular interstitial and intracellular hepatobiliary effects. In an animal model of liver dysfunction, the degree of liver enhancement with Gd-EOB-DTPA was decreased, probably related to a necrosis-induced decrease in the number of hepatocytes, and the washout of contrast was prolonged, probably caused by dysfunction in the energy-dependent biliary excretion. 23 Liver enhancement with this agent is reduced in fatty livers compared with normal livers. 24
Intracellular Reticuloendothelial Contrast Agents Contrast media can be targeted to the reticuloendothelial system, including the Kupffer's cells of the liver. 25-32 Contrast gents thus targeted are large, iron-oxide particles with superparamagnetic properties (SPIO). Ultra small SPIO (USPIO) particles have also been developed with similar properties regarding liver enhancement. The images obtained with a T2- or PD-weighted sequences after the administration of iron-oxide agents show signal loss of the normal liver. Most focal lesions,
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either benign or malignant, then appear as nonenhancing bright nodules. Although turbo spin echo (SE), which is caused by the multiple 180 ° radiofrequency pulses, tend to display less susceptibility effect, which is caused by iron oxides, than conventional SE sequences, 25 turbo-SE sequences perform very well with iron-oxide agents in clinical practice. Compared with a normal liver, the cirrhotic liver has a lesser number of normally functioning Kupffer's cells, in a similar proportion to the decrease in hepatocytes. Therefore, as might be expected, the loss of signal in the liver parenchyma with SPIO agents is less pronounced and more heterogeneous than in a normal liver. Therefore, the degree of SPIO enhancement of the cirrhotic liver is roughly proportional to the degree of necrosis (Fig 8). 26-28 T h e uptake of SPIO has some correlation with liver function. 26 It has been found that the signal intensity in the liver increases as the disease advances, 29 with 32% less iron-oxide (SPIO) effect in patients with Child-Pugh C than in patients with Child-Pugh B cirrhosis. 27 Another contribution to the reduced liver accumulation of SPIO is reduced hepatic extraction, which in turn results from altered hepatic perfusion related to portal hypertension (eg, intrahepatic shunts, capillarizadon of tile sinusoids with very high flow velocities, and portosystemic shunts). 28 Therefore, the decrease in the negative enhancement of the liver parenchyma in cirrhosis is also related to the degree of hepatic dysfunction and portal hyperten-
Fig 8. Proton Density SPlO-enhanced image shows decreased liver enhancement and heterogeniety in this patient with Child-Pugh B stage cirrhosis.
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sion. Although cirrhotic livers show less response to iron-oxide particles than normal liver tissue, this has no influence in HCC detection. 31'32 Because the fibrous septa have fewer Kupffer's cells than the regenerating liver, these septae stand out against the reduced signal of the hepatic parenchyma on SPIO images. The prominence of these septa gives a reticular appearance to the cirrhotic liver, and produces an inhomogeneous decrease in liver signal intensity (Fig 8). Geometric hyperintense areas, without SPIO negative enhancement, can be seen in cases of confluent fibrosis. Embedded within these hyperintense regions are focal areas of low signal intensity that presumably correspond to residual functioning liver parenchyma.3° LESION DETECTION AND CHARACTERIZATION
Hepatic cirrhosis is a condition leading to the development of HCC. The relative risk of HCC for patients with cirrhosis caused by the hepatitis virus is much higher than the risk for patients with cirrhosis who are not infected. Hepatic fibrosis and nodule development in cirrhosis cause architectural distortion. HCC develops in a background of cirrhosis by means of a multistep dedifferentiation process that progresses from regenerative nodule to dysplastic nodule and then to HCC. 33 Dysplastic nodes are found in 15% to 28% of explanted cirrhotic livers. 34 With sufficient time, these neoplastic, premalignant nodules may turn into HCC. Early diagnosis and liver transplantation offers the most effective treatment for HCC because transplantation can cure both the cancer and the underlying cirrhosis.11 Early HCC detection is also important in nonsurgical patients because small and well-defined tumors are more effectively treated with percutaneous procedures (thermal and radiofrequency ablation, alcohol injection, chemoembolization) than are large and infiltrating tumors. MR contrast media are effective for enhancement of liver tissue, improving contrast for detection of focal liver lesions. These agents also help with tumor characterization. However, hepatic enhancement and resulting tumor-to-liver contrast are negatively influenced by the existence of diffuse liver diseases. The type of contrast agent selected and the type of liver disease (steatosis, chronic hepatitis, cirrhosis, and iron overload) influence the impairment of enhancement because
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Fig 9. Liver cirrhosis with iron overload, (A) Regenerating nodules are hyperintense in this patient before gadolinium administration because iron deposition predominates outside the nodes. (B) in the portal phase, after gadolinium administration, there is little difference in enhancement between the regenerative nodules and the surrounding parenchyma.
diffuse liver disease may not affect all hepatocyte functions similarly. 24 Therefore, the choice as to which MR contrast agent should be used is a complex matter and depends on many factors, including the diagnostic goal, enhancement performance, underlying diffuse liver disease, required pulse sequences, the temporal enhancement window, and cost. Regenerating nodes are isointense or slightly hypointense to the surrounding liver on most nonenhanced MR sequences. Although they can rarely be hyperintense on Tl-weighted images (Fig 9), they are almost never hyperintense on T2-weighted images. They have a predominantly portal venous blood supply, with minimal contribution from the hepatic artery. Some contain iron and are named syderotic nodes. These are hypointense on MR images (mainly on GRE pulse sequences). 35 Dysplastic nodes are hyperintense on nonenhanced T 1-weighted images and hypoisointense on T2-weighted images. They are almost never hyperintense on T2-weighted images.11 A central area of hyperintensity within a regenerating node on T2-
weighted images suggest early malignant transformation. Dysplastic nodules usually have a blood supply from the portal venous system, 1°'36 but a minority of low-grade nodules, and some highgrade nodules, can have preferential arterial perfusion. 37 HCCs are isointense or hyperintense on nonenhanced Tl-weighted images and hyperintense, isointense, or hypointense on T2-weighted images. Hyperintensity on Tl-weighted images correlates with a more highly differentiated histologic grade than does iso- or hypointensity. 3s Hyperintensity on T2-weighted images is characteristic of HCC, and is related to more clear-cell content within the tumor and a lower degree of histologic differentiation. 3s On contrast-enhanced images (Gd chelates), HCCs reveal predominantly arterial perfusion, and can have a peripheral pseudocapsule as seen on delayed images after enhancement. Most small HCCs exhibit diffuse, homogeneous enhancement during the hepatic arterial phase, with rapid washout during the portal venous phase. 11 Larger HCCs tend to display a heterogeneous,
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mosaic pattern of enhancement. Although these imaging features are helpful in a clinical setting, they are not specific, and it must be acknowledged that there are nodules with atypical findings in which MR characterization must be interpreted with caution. 39
Extracellular Contrast Agents MR is accurate in the detection and characterization of large HCC lesions. However, its sensitivity for tumor detection is close to 53% to 62% with respect to small lesions found in explanted livers. 15 The use of contrast media increases the accuracy of lesion characterization with MR imaging, and MR findings can predict the nature of the nodules in the cirrhotic liver with a higher degree of accuracy than any other imaging test. Contrast-enhanced (Gd chelates), dynamic MR images, obtained in the arterial, portal, and equilibrium phases, are invaluable for the detection of HCC, and for the differential diagnosis of benign and malignant nodules, 4° but MR signal intensity characteristics alone cannot differentiate benign nodules from HCC with absolute certainty. Gadolinium enhancement, on the other hand, is a very sensitive and specific characteristic of H C C . 41 Most HCCs are hypervascular in the arterial phase with progressive wash out of contrast in the portal and delayed phases. By receiver-operator characteristic analysis, it has been noted that arterial phase dynamic MR imaging is significantly better than arterial-phase helical CT for tumor detection. 42 Although in the equilibrium phase most tumors are hypovascular, some HCCs have a dis-
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cemible capsule during this phase. Regenerative and dysplastic nodules should not have this finding. A lesion with a peripheral capsule, hyperintensity on T2-weighted images, and hypervascularity after gadolinium administration is almost certainly an HCC; nevertheless, benignity is not inferred with certainty by the converse MR findings. A lesion that is hyperintense on Tl-weighted images and hypoisointense on T2-weighted images, even if hypervascular in the arterial phase of gadolinium administration, can correspond to either a dysplastic nodule or an HCC] 5 The vascular behavior of a liver mass must be considered in the diagnosis of HCC, 43 even though there are cases of hypervascular dysplastic nodules, 15 and hypovascular HCCs. 44
Intracellular Hepatocellular Contrast Agents Hepatobiliary MR contrast agents are designed to be incorporated into the hepatocytes; therefore, tumors containing hepatocytes can take up these contrast media. Regenerating nodules, which contain normal hepatocytes, will take up MnDPDP in a way similar to normal liver parenchyma, and may enhance to an even greater degree than the normal liver. Neoplastic nodules in liver cirrhosis also show a tendency to accumulate MnDPDP, and may have either a homogeneous or heterogeneous enhancement pattern (Figs 10 and 11). The degree of tumor enhancement, however, correlates with the tumor histologic grade. 45 Dysplastic nodules and well-differentiated HCCs frequently display stronger enhancement than the surrounding liver (Fig 10). MnDPDP accumulates in damaged hepatocytes to a greater degree than normal cells because
Fig 10. Tl-weighted images (AI before and (B) after MnDPDP administration show this well-differentiated HCC as a hyperenhancing, encapsulated mass.
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Fig 11, Tl-weighted images (A) before and (B) after MnDPDP administration show a poorly differentiated HCC with portal invasion. Tumor enhancement is present, but the lesion becomes less well seen after contrast administration.
of intrahepatic cholostasis (a lower clearance of the contrast media to the bile canaliculi). This is probably the reason why dysplastic nodules and welldifferentiated HCC may show higher enhancement than the normal liver with MnDPDP. 19'46 On the contrary, cells in poorly differentiated HCC lack the normal transport system for these contrast agents, and do not enhance. Therefore, they become more conspicuous and easily appreciated after MR contrast injection. The enhancement of HCCs with hepatobiliary agents can result in previously identifiable tumors enhancing to become isointense with the liver, and not identifiable, on postcontrast images (Fig 11). Despite the possibility of postcontrast images obscuring some HCCs, MnDPDP is of value in the detection of small tumors. 45 Furthermore, the presence of hepatic cirrhosis does not influence tumor characterization. As is the case with MnDPDP, regenerating nodules may enhance to a greater degree than the surrounding liver parenchyma after Gd-BOPTA administration. Well-differentiated HCCs will also enhance after the administration of this agent; therefore, it can be difficult to differentiate small benign lesions from small HCCs unless T2-weighted images and dynamic contrast imaging after bolus contrast administration are used before the hepatobiliary phase is reached. 22 Delayed (60-120 minutes) enhanced images provide additional information for the characterization of HCC, which shows diffuse or partial enhancement in this phase. 47 Gd-EOB-DTPA is a biphasic contrast agent with
a perfusion phase and a hepatobiliary phase, and a peak liver signal intensity that occurs 20 minutes after injection. 48 In an animal model, Gd-EOBDTPA produces positive contrast enhancement (intensity greater than normal liver) in some HCC tumors. 49 This enhancement occurs in well- and moderately differentiated HCC, implying that some degree of cellular maturity may be required for tumor enhancement. The enhancement is probably related to the inability of the tumor hepatocytes to excrete the agent to the bile canaliculi because of histochemical abnormalities within the tumor. It has also been shown that Tl-weighted
Fig 12. Proton density-weighted SPIO-enhanced image shows heterogeneous liver enhancement caused by cirrhosis, and a hyperintense nonenhancing HCC in segment 7.
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Fig 13. Tl-weighted GRE SPIO- and gadolinium-enhanced image shows a heterogeneous liver with 2 large nodules of HCC as well as small enhancing metastases in the left hepatic lobe.
Gd-EOB-DTPA enhanced images showed the same performance in tumor detection as SPIOenhanced, T2-weighted images. 5°
Intracellular Reticuloendothelial Contrast Agents SPIO is a tissue-specific MR contrast agent that produces decreased signal intensity of the liver parenchyma on P D - a n d T2-weighted !mages. Its biodistribution to the reticuloendothelial system improve the contrast between liver lesions and normal liver because most tumors lack Kupffer cells. Reticuloendothelial cells are seen in regenerating and dysplastic nodules, but they are rarely seen in hepatocellular carcinoma. 51 With T2- and DP-weighted images, ferrite particles decreased the signal intensity of regenerating and dysplastic
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nodules, in contrast to the signal of HCC, which remains hyperintense with these sequences (Fig 12). The inability of a lesion to accumulate SPIO must be considered a HCC finding, 43 though there have been cases of well-differentiated HCC taking up SPIO. 32'52 A small number of Kupffer cells are found in well-differentiated HCC, 36'51 but the decrease of signal intensity in these tumors is very slight. 52'53 This signal intensity loss can be seen in well-differentiated HCC, whereas undifferentiated HCC has no appreciable decrease in signal intensity after SPIO is administered. 52 SPIO-enhanced PD-weighted images are more accurate than unenhanced images in the detection and localization of HCC in cirrhotic livers. 32 Because of its high accuracy, ferumoxides-enhanced MR imaging can be used successfully in place of computed tomography (CT) arterial portography and CT hepatic arteriography for the preoperative evaluation of patients with HCC. 54 Although controversy exists, dynamic gadolinium-enhanced MR imaging has been shown to be more sensitive than SPIO-enhanced MR imaging in the depiction of HCC in patients with varying degrees of hepatic cirrhosis. 4° Because well-differentiated HCC may contain functioning Kupffer's cells, negative enhancement of these tumors with SPIO may account for some of the false-negative results. However, these findings must be analyzed cautiously because histologic correlation after transplantation was not routinely available in most series comparing different techniques and contrast agents in the detection and characterization of HCC. This fact may artificially
Fig 14. STIR images (A) before and (B) after SPIO administration show a large HCC with peripheral satellite nodules and nontumor arterioportal shunt. SPIO images show the difference between nontumor abnormal signal intensity and tumor nodules.
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increase the sensitivity of the techniques for HCC detection. When lesions dedifferentiate from regenerative nodules to dysplasfic nodules and then to HCCs, the portal venous blood supply decreases, the arterial blood supply increases, and the uptake of SPIO is reduced. Because of these changes, the combination of SPIO with rapid sequential imaging after gadolinium administration has been shown to statistically improve the detection of HCC in patients with hepatic cirrhosis (Fig 13). 43 This double-contrast MR approach may be superior to dynamic gadolinium-enhanced Tl-weighted images because the signal intensity of the background liver is lower than on nonenhanced images after the S P I t administration, but before gadolinium injection.
In cirrhotic livers, a nontumorous arterioportal shunt can be difficult to differentiate from HCC. These shunts appear as hyperenhancing foci during the arterial phase of dynamic MR studies. When they occur adjacent to a HCC, the hyperenhancing areas may hide satellite nodules. SPIO can differentiate between nontumorous artefioportal shunts and tumors, as shown in Figure 14. Artefioportal shunts caused by tumors are seen as areas of reduced signal loss. On the contrary, most nontumorous artefioportal shunts are seen as areas of normal signal loss, similar to the nonaffected liver parenchyma. 55 This impairment in the uptake of SPIO corresponds to the injury of the liver parenchyma (edema, Kupffer cell and hepatocytes depletion, and fibrosis) that occurs in tumor-related shunts in which the associated portal branches are obstructed. 55
REFERENCES 1. Ito K, Mitchell DG, Gabata T: Enlargement of hilar periportal space: A sign of early cirrhosis at MR imaging. J Magn Reson Imaging 11:136-140, 2000 2. Ito K, Mitchell DG: Hepatic morphologic changes in cirrhosis: MR imaging findings: Abdom Imaging 25:456-461, 2000 3. Murakami T, Kim T, Nakamura H: Hepatitis, cirrhosis, and hepatoma. J Magn Reson Imaging 8:346-358, 1998 4. Ito K, Mitchell DG, Hann HW, et al: Viral-induced cirrhosis: Grading of severity using MR imaging. AJR Am J Roentgenol 173:591-596, 1999 5. Ito K, Mitchell DG, Harm HW, et al: Progressive viralinduced cirrhosis: Serial MR imaging findings and clinical correlation. Radiology 207:729-735, 1998 6. Van Beers BE, Leconte I, Materne R, et al: Hepatic perfusion parameters in chronic liver disease: Dynamic CT measurements correlated with disease severity. AJR Am J Roentgenol 176:667-673, 2001 7. Mitchell DG: Focal manifestations of diffuse liver disease at MR imaging. Radiology 185:1-11, 1992 8. Miles KA, Hayball MP, Dixon AK: Functional images of hepatic perfusion obtained with dynamic CT. Radiology 188: 405-411, 1993 9. Semelka RC, Chung JJ, Hussain SM, et al: Chronic hepatitis: Correlation of early patchy and late finear enhancement patterns on gadolinium-enhanced MR images with histopathology initial experience. J Magn Reson Imaging 13:385-391, 2001 10. Brown JJ, Naylor MJ, Yagan N: Imaging of hepatic cirrhosis. Radiology 202:1-16, 1997 11. Krinsky GA, Lee VS: MR imaging of cirrhotic nodules. Abdom Imaging 25:471-482, 2000 12. Uematsu H, Yamada H, Sadato N, et al: Assessment of hepatic portal perfusion using T2 measurements of Gd-DTPA. J Magn Reson Imaging 8:650-654, 1998 13. Soyer P, Dufresne AC, Somveille E, et al: MR imaging of the liver: Effect of portal hypertension on hepatic parenchymal enhancement using a gadolinium chelate. J Magn Resort Imaging 7:142-146, 1997
14. Ohtomo K, Baron RL, Dodd GD III, et al: Confluent hepatic fibrosis in advanced cirrhosis: Evaluation with MR imaging. Radiology 189:871-874, 1993 15. Krinsky GA, Lee VS, Theise ND, et al: Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: Prospective diagnosis with MR imaging and explantation correlation. Radiology 219: 445-454, 2001 16. Martf-Bonmati L, Masifi L, Casillas C, et al: Differentiation of healthy from cirrhotic livers: Evaluation of parametric images after contrast administration in MR imaging. Invest Radiol 31:768-773, 1996 17. Martf-Bonmaff L, Lonjedo E, Poyatos C, et al: MnDPDP enhancement characteristics and differentiation between cirrhotic and noncirrhotic livers. Invest Radiol 33:717-722, 1998 18. Murakami T, Baron RL, Federle MP, et al: Cirrhosis of the liver: MR imaging with Mangafodipir trisodium (MnDPDP). Radiology 198:567-572, 1996 19. Marchal GM, Ni Y, Yu J, et al: Mn-DPDP enhanced MRI in experimental bile duct obstruction. J Comput Assist Tomogr 17:290-296, 1993 20. Vogl TJ, Pegios W, McMahon C, et al: Gadobenate dimeglumine a new contrast agent for MR imaging: Preliminary evaluation in healthy volunteers. AJR Am J Roentgenol 158: 887-892, 1992 21. Schima W, Petersein J, Hahn PF, et al: Contrast-enhanced MR imaging of the liver: Comparison between GdBPTA and Mangafodipir. J Magn Reson Imaging 7:130-135, 1997 22. Manfredi R, Maresca G, Baron RL, et al: Gadobenate dimeglumine (BOPTA) enhanced MR imaging: Patterns of enhancement in normal liver and cirrhosis. J Magn Reson Imaging 8:862-867, 1998 23. Kim T, Murakami T, Hasuike Y, et al: Experimental hepatic dysfunction: Evaluation by MRI with Gd-EOB-DTPA. J Magn Reson Imaging 7:683-688, 1997 24. Kuwatsuru R, Brasch RC, Muhler A, et al: Definition of liver tumors in the presence of diffuse liver disease: Compari-
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son of findings at MR imaging with positive and negative contrast agents. Radiology 202:131-138, 1997 25. Schwartz LH, Seltzer SE, Adams DF, et al: Effects of superparamagnetic iron oxide (AMI-25) on liver and spleen imaging using spin-echo and fast spin-echo magnetic resonance pulse sequence. Invest Radiol 29:21-23, 1994 26. Yamashita Y, Yamamoto H, Hirai A, et al: MR imaging enhancement with superparamagnetic iron oxide in chronic liver disease: Influence of liver dysfunction and parenchymal pathology. Abdom Imaging 21:318-323, 1996 27. Hundt W, Petsch R, Helmberger T, et al: Signal changes in liver and spleen after Endorem administration in patients with and without liver cirrhosis. Eur Radiol 10:409-416, 2000 28. Elizondo G, Weissleder R, Stark DD, et al: Hepatic cirrhosis and hepatitis: MR imaging enhanced with superparamagnetic iron oxide. Radiology 174:797-801, 1990 29. Tang Y, Yamashita Y, Arakawa A, et al: Detection of hepatocellular carcinoma arising in cirrhotic livers: Comparison of gadolinium- and ferumoxides-enhanced MR imaging. AJR Am J Roentgenol 172:1547-1554, 1999 30. Matsuo M, Kanematsu M, Kondo H, et al: Confluent hepatic fibrosis in cirrhosis: Ferumoxides-enhanced MR imaging findings. ,Abdom Imaging 26:146-148, 2001 31. Clement O, Frija G, Chambon C, et al. Liver tumors in cirrhosis: Experimental study with SPit-enhanced MR imaging. Radiology 180:31-36, 1991 32. Yamamoto H, Yamashita Y, Yoshimatsu S, et al: Hepatocellular carcinoma in cirrhotic livers: Detection with unenhanced and iron oxide-enhanced MR imaging. Radiology 195: i06-I 12, 1995 33. Ferrell L, Wright T, Lake J, et al: Incidence and diagnostic features of macroregenerative nodules vs small hepatocellular carcinoma in cirrhotic rivers. Hepatology 16:1372-1381, 1992 34. Hytiroglou P, Tlieise ND, Schwartz M, et al: Macroregenerative nodules in a series of adult cirrhotic liver explants: Issues of classification and nomenclature. Hepatology 21:703708, 1995 35. Ito K, Mitchell DG, Gabata T, et al: Hepatocellular carcinoma: Association with increased iron deposition in the cirrhotic liver at MR imaging. Radiology 212:235-240, 1999 36. Earls JP, Theise ND, Weinreb JC, et al: Dysplastic nodules and hepatocellular carcinoma: Thin-section MR imaging of explanted cirrhotic livers with pathologic correlation. Radiology 201:207-214, 1996 37. Hayashi M, Matsui O, Ueda K, et al: Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: Evaluation by CT during intraarterial injection of contrast medium. AJR Am J Roentgenol 172:969-976, 1999 38. Ebara M, Fukuda H, Kojima Y, et al: Small hepatocellular carcinoma: Relationship of signal intensity to liistopathologic findings and metal content of the tumor and surrounding hepatic parenchyma. Radiology 210:81-88, 1999 39. Haratake J, Scheuer PJ: An immunohistochemical and ultrastructural study of the sinusoids of hepatocellular carcinoma. Cancer 65:1985-1993, 1990 40. Choi D, Kim SH, Lim JH, et al: Detection of hepatocelIular carcinoma: Combined T2-weighted and dynamic gadolinium-enhanced MRI versus combined CT during arterial portog-
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raphy and CT hepatic arteriography. J Comput Assist Tomogr 25:777-785, 2001 41. Rode A, Bancel B, Douek P, et al: Small nodule detection in cirrhotic livers: Evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver. J Comput Assist Tomogr 25:327-336, 2001 42. Yamashita Y, Mitsuzaki M, Yi T, et al: Small hepatocellular carcinoma in patients with chronic liver damage: Prospective comparison of detection with dynamic MR imaging and helical CT of the whole liver. Radiology 200:79-84, 1996 43. Ward J, Guthrie JA, Scott DJ, et al: Hepatocellular carcinoma in the cirrhotic liver: Double-contrast MR imaging for diagnosis. Radiology 216:154-162, 2000 44. Lencioni R, Macalchi M, Caramella D, et al: Small hepatocellular carcinoma: Differentiation from adenomatous hyperplasia with color Doppler US and dynamic Gd-DTPAenhanced MR imaging. Abdom Imaging 21:41-48, 1996 45. Murakami T, Baron RL, Peterson MS, et al: Hepatocellular carcinoma: MR imaging with mangafodipir trisodium (Mn-DPDP). Radiology 200:69-77, 1996 46. Liou J, Lee JK, Borrello JA, et al: Differentiation of hepatomas from nonhepatomatous masses: Use of MnDPDPenhanced MR images. Magn Reson Imaging 12:71-79, 1994 47. Pirovano G, Vanzulli A, Marti-Bonmati L, et al: Evaluation of the accuracy of gadobenate dimeglumine-enhanced MR imaging in the detection and characterization of focal liver lesions. AJR Am J Roentgenol 175:1111-1120, 2000 48. Vogl T, Ktimmel S, Hammerstingl R, et al: Liver tumors: Comparison of MR imaging with Gd-EOB-DTPA and GdDTPA. Radiology 200:59-67, 1996 49. FujitaM, YamamotoR, Takahashi M, et al: Paradoxicuptake of Gd-EOB-DTPAby hepatocellularcarcinomain mice: Quantitative image analysis. J Magn Reson Imaging 7:768-770, 1997 50. Tanimoto A, Satoh Y, Yuasa Y, et al: Performance of Gd-EOB-DTPA and superparamagnetic iron oxide particles in the detection of primary liver cancer: A comparative study by alternative free-response receiver operating characteristic analysis. J Magn Reson Imaging 7:120-124, 1997 51. Kawamori Y, Matsui O, Kadoya M, et al: Differentiation of hepatocellular carcinomas from hyperplastic nodules induced in rat liver with ferrite-enhanced MR imaging. Radiology 183: 65-72, 1992 52. Vogl TJ, Hammerstingl R, Schwarz W, et al: Superparamagnetic iron oxide-enhanced versus gadolinium-enhanced MR imaging for differential diagnosis of focal liver lesions. Radiology 198:881-887, 1996 53. Paley MR, Mergo PJ, Torres GM, et al: Characterization of focal hepatic lesions with ferumoxides-enhanced T2-weighted MR imaging. AJR Am J Roentgenol 175:159-163, 2000 54. Choi D, Kim S, Lim J, et al: Preoperative detection of hepatocellular carcinoma: Femmoxides-enhanced MR imaging versus combined helical CT during arterial portography and CT hepatic arteriography. AJR Am J Roentgenol 176:475-482, 2001 55. Mori K, Yoshioka H, Itai Y, et al: Arterioportal shunts in cirrhotic patients: Evaluation of the difference between tumorous and nontumorous arterioportal shunts on MR imaging with superparamagnetic iron oxide. AJR Am J Roentgenol 175: 1659-1664, 2000
Copyright 2002, Elsevier Science (USA). All rights reserved.
HE LIVER IS a difficult organ to study because of its complex anatomy, dual blood supply, and the frequent presence of diffuse diseases. Radiologists have different challenges in analyzing liver pathology,; namely, to depict nodules and to differentiate between benign and malignant lesions. Only recently, radiologists have also become interested in the analysis of liver cell necrosis and function. Chronic hepatitis is defined as a continuous or recurrent inflammation of the liver for more than 6 months, with histologic changes of chronic liver damage, such as erosive necrosis and the production of fibroconnective tissue. Chronic hepatitis is also characterized by lymphocytic infiltration, generating liver cell injury, necrosis, and fibrosis. Chronic hepatitis, in its late stage, can progress to cirrhosis, which is a chronic and progressive diffuse process characterized by fibrosis of the liver and the formation of anatomically abnormal hepatic nodules. These nodules are surrounded by fibrous septa that bridge the spaces between the portal tracts and arrange the hepatic histology in an abnormal state of organization. Chronic liver disease may, therefore, alter the gross architecture of the liver. Liver cell necrosis is responsible for the volume loss seen in cirrhosis. Enlargement of the hilar periportal space is seen in early stages, ~ and atrophy of the left medial segment, along with the fight lobe, is seen in advanced stages. Regeneration is seen as nodularity of the liver surface and also as segmental or lobar enlargement, which mainly effects the caudate lobe and of the lateral segment of the left hepatic lobe (Fig 1). Atrophy and regeneration are principally attributed to portal blood flow alterations. Because fibrosis causes compression and irregular stenosis of the large intrahepatic
T
portal vein branches, the portal flow changes according to the course of the vessels; decreasing in the right lobe and medial left lobe, while increasing (relatively) in the left lateral segment and caudate lobe. 2 Retraction of the liver surface can be seen in association with confluent hepatic fibrosis. These areas of collapse, which have a triangular shape with the apex pointing toward the hepatic hilum, show slight hyperintensity on T2-weighted magnetic resonance (MR) images. Hyperintensity is caused by invasion of the fibrous septum by inflammatory cells, as well as the presence of pseudobile ducts? Areas of confluent hepatic fibrosis can be misdiagnosed as hepatocellular carcinoma because they are hyperintense on T2-weighted images and show significant uptake of extracellular contrast agents. These areas, however, have a typical subsegmental appearance with vessels and bile ducts within them, making the differentiation from a neoplastic mass straightforward. Changes associated with portal hypertension are frequently found in cirrhotic patients. The volume of the spleen and the presence of ascites and varices are directly related to the clinical severity of cirrhosis, whereas the volume of the right hepatic lobe and the medial segment of the left lobe are inversely correlated with severity.4 Progressive atrophy of the right hepatic lobe and the medial
From the Department of Radiology, Doctor Peset University Hospital, Valencia, Spain. Address reprint requests to Luis Martf-Bonmaff, MD, PhD, Seccirn de RM, Servicio de Radiologfa, Hospital Universitario Dr Peset, [:-460]7 Valencia, Spain; e-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 0887-2171/02/'2301-0006535.00/0 doi:l O.lO53/sult.2002.29795
Seminars in Ultrasound, CT, and MRI, Vol 23, No 1 (February), 2002: pp 101-113
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Fig 1. (A) Tl-weighted and (B) STIR images in hepatic cirrhosis show liver surface nodularity and linear septa surrounding regenerative nodules. There are also collateral vessels in the gastrohepatic ligament caused by portal hypertension.
segment of the liver correlate with progression of the clinical severity of cirrhosis; however, increasing size of the caudate lobe and the lateral segment correlate with stability: In the cirrhotic liver, cell dysfunction and necrosis are responsible for the development of fibrosis and regeneration, leading to abnormal intrahepatic vascularization and abnormalities in contrast media uptake. Not only is it important to recognize these abnormalities and their clinical impact, but it is also important to realize that the evaluation of focal liver lesions in cirrhotic patients can be altered by the presence of abnormal parenchyma opacification. This article reviews the effect of chronic liver disease on MR contrast enhancement, as well as the effect of altered enhancement on lesion detection and characterization. Both extracellular and intracellular contrast agents are considered. LIVER ENHANCEMENT
Extracel[ular Contrast Agents Gadolinium chelates are the most commonly used MR contrast media. They are small hydrophilic molecules that can diffuse freely through the extracellular space, and are filtered and excreted by the kidneys. They are usually administered as a
bolus injection. They have an initial, short, intravascular phase, and pass quickly into the extravascular extracellular space. Therefore, these agents can be considered to be targeted to the intravascular space (in the first few seconds after their administration) and interstitial space (within the first few minutes). Most cirrhotic livers have inhomogeneous hepatic texture in contrast-enhanced MR images. This heterogeneous enhancement is related to the degree of liver necrosis, inflammation, and fibrosis, as well as to the dual blood supply of the liver (Fig 2). In cirrhotic livers, the increase of intrahepatic vascular resistance decreases the portal contribution to liver perfusion. This portal hypopeffusion is partially compensated by an increase in the arterial blood supply, owing to the balance between the arterial and portal supply. 6 Therefore, the arterial blood supply increases as the portal blood flow is diminished, owing to the portal hemodynamic changes associated with venous hypertension and collateral circulation. 7"8 If portal vein thrombosis occurs, the arterial fraction of liver perfusion increases even more. The inflammation associated with chronic liver disease also increases the arterial hepatic blood supply; however, the increase in the arterial perfusion is not sufficient to maintain ade-
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Fig 2. Tl-weighted, fat-suppressed, gadolinium-enhanced image shows the enhancing reticular septa within the fibrotic changes in the cirrhotic liver parenchyma.
quate liver perfusion, mainly because of a high level of extrahepatic portosystemic shunting. The net result is an overall reduction of the total liver perfusion in chronic liver diseases. Both the liver perfusion decrease and the arterial fraction changes seen in chronic liver disease are related to the severity of disease and are significantly altered in cirrhosis. 6 Liver enhancement in the first seconds after the administration of contrast media can be more prominent in cirrhotic patients than in normal subjects because the hepatic arterial perfusion is increased and there is less dilution of the contrast in the hepatic circulation than in the portal circulation. l's Early patchy enhancement of the parenchyma is associated with the presence of numerous infiltrating macrophages, necrosis, tissue collapse, and increased steatosis (Fig 3). 9 The patchy enhancement seen after gadolinium administration probably has two causes: (1) capillary density changes and damage that cause rapid contrast extravasation, and (2) increased volume of the extracellular spaces owing to hepatocellular necrosis. Additional transient hepatic intensity differences
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are frequently found in cirrhotic livers 1° consisting of focal, peripheral, subcapsular wedges of increased intensity seen only in the arterial-dominant phase. These findings are usually owing to arterioportal shunts or aberrant venous drainage, but in cirrhotic livers, large perfusion abnormalities can also be related to obstruction of the portal vein, previous percutaneous interventional procedures, and a siphon effect from a hypervascular hepatocellular carcinoma (HCC).11 Considering the latter possibility, the presence of these areas should elicit a careful search for a focal mass near the regions of increased enhancement. 1° Hepatic blood flow correlates with the severity of the liver dysfunction in cirrhosis. With dynamic, T2*-weighted MR imaging after a bolus injection of a susceptibility gadolinium chelate, it has been shown that both the portal blood flow and volume are significantly decreased in Child-Pugh B and C patients compared with Child-Pugh A patients, whereas mean transit time was prolonged in higher grades of liver dysfunction. 12 This may reflect the progressive fibrosis around the portal vein and hepatic vein branches. The decrease in mean peak liver enhancement and the delay in the time to peak liver enhancement is especially prominent in patients with portal hypertension, splenomegaly, and portosystemic shunting. Therefore, in the course of dynamic MR imaging, the portal and equilibrium phases are reached later in these patients. By analyzing the whole liver enhancement during the first 4 minutes after contrast administration, it was found that the time to peak enhancement of the
Fig 3. Tl-weighted gadolinium-enhanced image in the early portal phase shows variable enhancement of different portions of the liver. Enhancement of the caudate lobe, where regeneration is prominent, is less than other areas, and a subsegmental area of early patchy enhancement is seen in segment 6.
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Fig 4. T1 weighted, delayed, gadolinium enhanced image shows a triangular hyperenhancing area in the intersegmental fissure due to confluent fibrosis.
liver, which may be the optimal time for imaging the liver, is obtained 54 seconds after contrast injection in patients without portal hypertension, but 84 seconds after injection in patients with cirrhosis and portal hypertension) 3 Fibrosis is mainly responsible for abnormal enhancement of the chronically damaged liver. In MR images obtained at the equilibrium and late phases after gadolinium administration, a linear enhancement pattern can be seen as an enhancing reticular network (Fig 2). Fibrosis in the septa is
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responsible for the increased enhancement of these areas, 9 and is more prominent in the periphery of the liver. Linear enhancement is seen in the fibrous septa and in the pseudocapsule around hepatomas. Triangular areas of slight and delayed enhancement, with their bases on the liver capsule, are seen in confluent fibrosis (Fig 4). 1°'14 This pattern is different from the patchy and linear patterns. Poorly marginated confluent hepatic fibrosis may be impossible to differentiate from infiltrative neoplasms. 15 In the late equilibrium and delayed phases, the contrast agent moves more slowly toward the interstitium and the fibrotic areas. Because the extracellular space is proportional to the degree of necrosis, an increase in the enhancement of the liver parenchyma in late phases is proportional to the amount of necrosis. This increase in liver enhancement can be observed (Fig 5) with appropriate tools, such as parametric images obtained on a pixel-by-pixel basis, from a dynamic series of images after bolus contrast administration. By factor analysis of dynamic structures, parenchymal enhancement has been proven to be different in healthy and cirrhotic livers. 16 The averaged enhancement and the maximum enhancement of the liver over 5 minutes after bolus injection of a gadolinium chelate, as evaluated by time-enhancement curves on a pixel-by-pixel basis, were statistically higher in cirrhotic livers (P < .05). The increase in the parenchymal enhancement is prob-
Fig 5. Parametric maps after gadolinium enhancement (left panel, representative dynamic image; right panel, averaged enhancement map over 5 minutes). A percutaneously treated, necrotic HCC without any enhancement stands out against marked enhancement of the liver parenchyma.
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ably related to an increase in the interstitial extracellular space. The decreased size and number of the hepatocytes increase the proportion of liver volume occupied by the interstitial space and vessels. a6 The increase in the liver enhancement was statistically related to the degree of chronic hepatic insufficiency, expressed as the Child-Pugh classification index (P < .05). In summary, in chronic liver disease and cirrhosis, there is an increased arterialization of the liver, resulting in areas of early transient enhancement after the administration of extracellular contrast agents. Total blood volume mad peak liver enhancement in the portal and equilibrium phases are decreased, whereas in late equilibrium and delayed phases, the enhancement is increased with respect to normal livers. These enhancement changes are related to the level of portal hypertension and the degree of liver dysfunction. Linear fibrotic septa can be observed surrounding regenerating nodules in cirrhotic livers.
Intracellular Hepatocellular Contrast Agents Mangafodipir trisodium (MnDPDP) is a specific contrast agent taken up by hepatocytes and excreted into the bile. When the liver is studied with
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Tl-weighted gradient-recalled echo (GRE) images obtained after the administration of this agent, an increase in the signal intensity of the parenchyma can easily be observed as early as 5 minutes after its administration, reaching a peak enhancement at 60 minutes with a large temporal plateau. Because this contrast media is actively incorporated inside the hepatocytes, parenchymal liver enhancement is proportional to the number of hepatocytes per unit of volume (voxel). It has been observed that the parenchymal enhancement ratio (the ratio between the signal intensity of the liver before and after the contrast administration) is statistically lower in livers with cirrhosis than in normal livers (P < .001). 17 This decrease in liver enhancement has been related, with logistic regression models, with the liver dysfunction evaluated with the ChildPugh index and also with the aspartate transaminase (AST) blood levels (P < .01). x7 By visual analysis of the enhanced images, it was also noted that all normal livers enhance with a homogeneous texture, whereas 37% of the cirrhotic livers had a heterogeneous enhancement pattern. This heterogeneity is caused by the coexistence of hyper- and hypoenhancement areas (Figs 6 and 7). Areas of lower enhancement contain fibrous zones, either
Fig 6. Tl-weighted GRE images (A) before and (B) after MnDPDP administration show heterogeneous enhancement of this cirrhotic liver caused by regeneration (posterior segments) and necrosis (anterior segments).
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Fig 7. Tl-weighted GRE images (A) before and (B) after MnDPDP administration show hypointense linear structures, more evident after contrast administration, representing the fibrous collapse bands.
confluent or diffuse, and hepatocyte necrosis, whereas areas of hepatocyte regeneration show an increase in the enhancement caused by a relatively high number of liver cells per voxel. 17'18 Hepatocytes within regenerating nodules can also have impaired bile excretion, causing increased liver enhancement owing to accumulation of the contrast in the hepatocytes. 19 In patients with liver iron overload, the liver parenchyma has a low signal intensity on T1weighted GRE images owing to the susceptibility effect of iron. In these patients, the enhancement effect of MnDPDP on liver parenchyma is masked, a8 It is not recommended, therefore, to administer this contrast agent if the precontrast Tl-weighted images show diffusely hypointense liver parenchyma. Gadobenate dimeglumine (BOPTA) is a gadolinium chelate with both nonspecific extracellular distribution and specific hepatocyte uptake and biliary excretion. Although the biliary excretion is close to 4%, in Tl-weighted images there is a prolonged enhancement of hepatic parenchyma after the intravenous administration of this compound. 2° It has been proven that for liver imaging, high-dose (0.1 mmol/Kg) Gd-BOPTA and MnDPDP provide comparable effects.21 The temporal window for this delayed liver effect is between 60 to 120 minutes after the contrast administration, which is a long delay in postcontrast imaging. 21 Surprisingly, cirrhotic livers have higher levels of signal-to-noise ratios and enhancement with Gd-BOPTA, relative to noncirrhotic liver parenchyma. This increase in enhancement can be
caused by either an additive effect of the specific hepatocytic uptake and the extracellular distribution in widely distributed fibrosis, or to the impaired hepatobiliary excretion from the hepatocytes. 22 Liver enhancement is mainly homogeneous in patients with Child-Pugh A cirrhosis, but more frequently is heterogeneous with higher grades of liver insufficiency. 2° As so happens with MnDPDP, the presence of iron overload limits the efficacy of Gd-BOPTA to enhance liver parenchyma. 22 Gd-EOB-DTPA is a paramagnetic contrast agent also with dual extracellular interstitial and intracellular hepatobiliary effects. In an animal model of liver dysfunction, the degree of liver enhancement with Gd-EOB-DTPA was decreased, probably related to a necrosis-induced decrease in the number of hepatocytes, and the washout of contrast was prolonged, probably caused by dysfunction in the energy-dependent biliary excretion. 23 Liver enhancement with this agent is reduced in fatty livers compared with normal livers. 24
Intracellular Reticuloendothelial Contrast Agents Contrast media can be targeted to the reticuloendothelial system, including the Kupffer's cells of the liver. 25-32 Contrast gents thus targeted are large, iron-oxide particles with superparamagnetic properties (SPIO). Ultra small SPIO (USPIO) particles have also been developed with similar properties regarding liver enhancement. The images obtained with a T2- or PD-weighted sequences after the administration of iron-oxide agents show signal loss of the normal liver. Most focal lesions,
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either benign or malignant, then appear as nonenhancing bright nodules. Although turbo spin echo (SE), which is caused by the multiple 180 ° radiofrequency pulses, tend to display less susceptibility effect, which is caused by iron oxides, than conventional SE sequences, 25 turbo-SE sequences perform very well with iron-oxide agents in clinical practice. Compared with a normal liver, the cirrhotic liver has a lesser number of normally functioning Kupffer's cells, in a similar proportion to the decrease in hepatocytes. Therefore, as might be expected, the loss of signal in the liver parenchyma with SPIO agents is less pronounced and more heterogeneous than in a normal liver. Therefore, the degree of SPIO enhancement of the cirrhotic liver is roughly proportional to the degree of necrosis (Fig 8). 26-28 T h e uptake of SPIO has some correlation with liver function. 26 It has been found that the signal intensity in the liver increases as the disease advances, 29 with 32% less iron-oxide (SPIO) effect in patients with Child-Pugh C than in patients with Child-Pugh B cirrhosis. 27 Another contribution to the reduced liver accumulation of SPIO is reduced hepatic extraction, which in turn results from altered hepatic perfusion related to portal hypertension (eg, intrahepatic shunts, capillarizadon of tile sinusoids with very high flow velocities, and portosystemic shunts). 28 Therefore, the decrease in the negative enhancement of the liver parenchyma in cirrhosis is also related to the degree of hepatic dysfunction and portal hyperten-
Fig 8. Proton Density SPlO-enhanced image shows decreased liver enhancement and heterogeniety in this patient with Child-Pugh B stage cirrhosis.
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sion. Although cirrhotic livers show less response to iron-oxide particles than normal liver tissue, this has no influence in HCC detection. 31'32 Because the fibrous septa have fewer Kupffer's cells than the regenerating liver, these septae stand out against the reduced signal of the hepatic parenchyma on SPIO images. The prominence of these septa gives a reticular appearance to the cirrhotic liver, and produces an inhomogeneous decrease in liver signal intensity (Fig 8). Geometric hyperintense areas, without SPIO negative enhancement, can be seen in cases of confluent fibrosis. Embedded within these hyperintense regions are focal areas of low signal intensity that presumably correspond to residual functioning liver parenchyma.3° LESION DETECTION AND CHARACTERIZATION
Hepatic cirrhosis is a condition leading to the development of HCC. The relative risk of HCC for patients with cirrhosis caused by the hepatitis virus is much higher than the risk for patients with cirrhosis who are not infected. Hepatic fibrosis and nodule development in cirrhosis cause architectural distortion. HCC develops in a background of cirrhosis by means of a multistep dedifferentiation process that progresses from regenerative nodule to dysplastic nodule and then to HCC. 33 Dysplastic nodes are found in 15% to 28% of explanted cirrhotic livers. 34 With sufficient time, these neoplastic, premalignant nodules may turn into HCC. Early diagnosis and liver transplantation offers the most effective treatment for HCC because transplantation can cure both the cancer and the underlying cirrhosis.11 Early HCC detection is also important in nonsurgical patients because small and well-defined tumors are more effectively treated with percutaneous procedures (thermal and radiofrequency ablation, alcohol injection, chemoembolization) than are large and infiltrating tumors. MR contrast media are effective for enhancement of liver tissue, improving contrast for detection of focal liver lesions. These agents also help with tumor characterization. However, hepatic enhancement and resulting tumor-to-liver contrast are negatively influenced by the existence of diffuse liver diseases. The type of contrast agent selected and the type of liver disease (steatosis, chronic hepatitis, cirrhosis, and iron overload) influence the impairment of enhancement because
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Fig 9. Liver cirrhosis with iron overload, (A) Regenerating nodules are hyperintense in this patient before gadolinium administration because iron deposition predominates outside the nodes. (B) in the portal phase, after gadolinium administration, there is little difference in enhancement between the regenerative nodules and the surrounding parenchyma.
diffuse liver disease may not affect all hepatocyte functions similarly. 24 Therefore, the choice as to which MR contrast agent should be used is a complex matter and depends on many factors, including the diagnostic goal, enhancement performance, underlying diffuse liver disease, required pulse sequences, the temporal enhancement window, and cost. Regenerating nodes are isointense or slightly hypointense to the surrounding liver on most nonenhanced MR sequences. Although they can rarely be hyperintense on Tl-weighted images (Fig 9), they are almost never hyperintense on T2-weighted images. They have a predominantly portal venous blood supply, with minimal contribution from the hepatic artery. Some contain iron and are named syderotic nodes. These are hypointense on MR images (mainly on GRE pulse sequences). 35 Dysplastic nodes are hyperintense on nonenhanced T 1-weighted images and hypoisointense on T2-weighted images. They are almost never hyperintense on T2-weighted images.11 A central area of hyperintensity within a regenerating node on T2-
weighted images suggest early malignant transformation. Dysplastic nodules usually have a blood supply from the portal venous system, 1°'36 but a minority of low-grade nodules, and some highgrade nodules, can have preferential arterial perfusion. 37 HCCs are isointense or hyperintense on nonenhanced Tl-weighted images and hyperintense, isointense, or hypointense on T2-weighted images. Hyperintensity on Tl-weighted images correlates with a more highly differentiated histologic grade than does iso- or hypointensity. 3s Hyperintensity on T2-weighted images is characteristic of HCC, and is related to more clear-cell content within the tumor and a lower degree of histologic differentiation. 3s On contrast-enhanced images (Gd chelates), HCCs reveal predominantly arterial perfusion, and can have a peripheral pseudocapsule as seen on delayed images after enhancement. Most small HCCs exhibit diffuse, homogeneous enhancement during the hepatic arterial phase, with rapid washout during the portal venous phase. 11 Larger HCCs tend to display a heterogeneous,
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mosaic pattern of enhancement. Although these imaging features are helpful in a clinical setting, they are not specific, and it must be acknowledged that there are nodules with atypical findings in which MR characterization must be interpreted with caution. 39
Extracellular Contrast Agents MR is accurate in the detection and characterization of large HCC lesions. However, its sensitivity for tumor detection is close to 53% to 62% with respect to small lesions found in explanted livers. 15 The use of contrast media increases the accuracy of lesion characterization with MR imaging, and MR findings can predict the nature of the nodules in the cirrhotic liver with a higher degree of accuracy than any other imaging test. Contrast-enhanced (Gd chelates), dynamic MR images, obtained in the arterial, portal, and equilibrium phases, are invaluable for the detection of HCC, and for the differential diagnosis of benign and malignant nodules, 4° but MR signal intensity characteristics alone cannot differentiate benign nodules from HCC with absolute certainty. Gadolinium enhancement, on the other hand, is a very sensitive and specific characteristic of H C C . 41 Most HCCs are hypervascular in the arterial phase with progressive wash out of contrast in the portal and delayed phases. By receiver-operator characteristic analysis, it has been noted that arterial phase dynamic MR imaging is significantly better than arterial-phase helical CT for tumor detection. 42 Although in the equilibrium phase most tumors are hypovascular, some HCCs have a dis-
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cemible capsule during this phase. Regenerative and dysplastic nodules should not have this finding. A lesion with a peripheral capsule, hyperintensity on T2-weighted images, and hypervascularity after gadolinium administration is almost certainly an HCC; nevertheless, benignity is not inferred with certainty by the converse MR findings. A lesion that is hyperintense on Tl-weighted images and hypoisointense on T2-weighted images, even if hypervascular in the arterial phase of gadolinium administration, can correspond to either a dysplastic nodule or an HCC] 5 The vascular behavior of a liver mass must be considered in the diagnosis of HCC, 43 even though there are cases of hypervascular dysplastic nodules, 15 and hypovascular HCCs. 44
Intracellular Hepatocellular Contrast Agents Hepatobiliary MR contrast agents are designed to be incorporated into the hepatocytes; therefore, tumors containing hepatocytes can take up these contrast media. Regenerating nodules, which contain normal hepatocytes, will take up MnDPDP in a way similar to normal liver parenchyma, and may enhance to an even greater degree than the normal liver. Neoplastic nodules in liver cirrhosis also show a tendency to accumulate MnDPDP, and may have either a homogeneous or heterogeneous enhancement pattern (Figs 10 and 11). The degree of tumor enhancement, however, correlates with the tumor histologic grade. 45 Dysplastic nodules and well-differentiated HCCs frequently display stronger enhancement than the surrounding liver (Fig 10). MnDPDP accumulates in damaged hepatocytes to a greater degree than normal cells because
Fig 10. Tl-weighted images (AI before and (B) after MnDPDP administration show this well-differentiated HCC as a hyperenhancing, encapsulated mass.
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Fig 11, Tl-weighted images (A) before and (B) after MnDPDP administration show a poorly differentiated HCC with portal invasion. Tumor enhancement is present, but the lesion becomes less well seen after contrast administration.
of intrahepatic cholostasis (a lower clearance of the contrast media to the bile canaliculi). This is probably the reason why dysplastic nodules and welldifferentiated HCC may show higher enhancement than the normal liver with MnDPDP. 19'46 On the contrary, cells in poorly differentiated HCC lack the normal transport system for these contrast agents, and do not enhance. Therefore, they become more conspicuous and easily appreciated after MR contrast injection. The enhancement of HCCs with hepatobiliary agents can result in previously identifiable tumors enhancing to become isointense with the liver, and not identifiable, on postcontrast images (Fig 11). Despite the possibility of postcontrast images obscuring some HCCs, MnDPDP is of value in the detection of small tumors. 45 Furthermore, the presence of hepatic cirrhosis does not influence tumor characterization. As is the case with MnDPDP, regenerating nodules may enhance to a greater degree than the surrounding liver parenchyma after Gd-BOPTA administration. Well-differentiated HCCs will also enhance after the administration of this agent; therefore, it can be difficult to differentiate small benign lesions from small HCCs unless T2-weighted images and dynamic contrast imaging after bolus contrast administration are used before the hepatobiliary phase is reached. 22 Delayed (60-120 minutes) enhanced images provide additional information for the characterization of HCC, which shows diffuse or partial enhancement in this phase. 47 Gd-EOB-DTPA is a biphasic contrast agent with
a perfusion phase and a hepatobiliary phase, and a peak liver signal intensity that occurs 20 minutes after injection. 48 In an animal model, Gd-EOBDTPA produces positive contrast enhancement (intensity greater than normal liver) in some HCC tumors. 49 This enhancement occurs in well- and moderately differentiated HCC, implying that some degree of cellular maturity may be required for tumor enhancement. The enhancement is probably related to the inability of the tumor hepatocytes to excrete the agent to the bile canaliculi because of histochemical abnormalities within the tumor. It has also been shown that Tl-weighted
Fig 12. Proton density-weighted SPIO-enhanced image shows heterogeneous liver enhancement caused by cirrhosis, and a hyperintense nonenhancing HCC in segment 7.
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Fig 13. Tl-weighted GRE SPIO- and gadolinium-enhanced image shows a heterogeneous liver with 2 large nodules of HCC as well as small enhancing metastases in the left hepatic lobe.
Gd-EOB-DTPA enhanced images showed the same performance in tumor detection as SPIOenhanced, T2-weighted images. 5°
Intracellular Reticuloendothelial Contrast Agents SPIO is a tissue-specific MR contrast agent that produces decreased signal intensity of the liver parenchyma on P D - a n d T2-weighted !mages. Its biodistribution to the reticuloendothelial system improve the contrast between liver lesions and normal liver because most tumors lack Kupffer cells. Reticuloendothelial cells are seen in regenerating and dysplastic nodules, but they are rarely seen in hepatocellular carcinoma. 51 With T2- and DP-weighted images, ferrite particles decreased the signal intensity of regenerating and dysplastic
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nodules, in contrast to the signal of HCC, which remains hyperintense with these sequences (Fig 12). The inability of a lesion to accumulate SPIO must be considered a HCC finding, 43 though there have been cases of well-differentiated HCC taking up SPIO. 32'52 A small number of Kupffer cells are found in well-differentiated HCC, 36'51 but the decrease of signal intensity in these tumors is very slight. 52'53 This signal intensity loss can be seen in well-differentiated HCC, whereas undifferentiated HCC has no appreciable decrease in signal intensity after SPIO is administered. 52 SPIO-enhanced PD-weighted images are more accurate than unenhanced images in the detection and localization of HCC in cirrhotic livers. 32 Because of its high accuracy, ferumoxides-enhanced MR imaging can be used successfully in place of computed tomography (CT) arterial portography and CT hepatic arteriography for the preoperative evaluation of patients with HCC. 54 Although controversy exists, dynamic gadolinium-enhanced MR imaging has been shown to be more sensitive than SPIO-enhanced MR imaging in the depiction of HCC in patients with varying degrees of hepatic cirrhosis. 4° Because well-differentiated HCC may contain functioning Kupffer's cells, negative enhancement of these tumors with SPIO may account for some of the false-negative results. However, these findings must be analyzed cautiously because histologic correlation after transplantation was not routinely available in most series comparing different techniques and contrast agents in the detection and characterization of HCC. This fact may artificially
Fig 14. STIR images (A) before and (B) after SPIO administration show a large HCC with peripheral satellite nodules and nontumor arterioportal shunt. SPIO images show the difference between nontumor abnormal signal intensity and tumor nodules.
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increase the sensitivity of the techniques for HCC detection. When lesions dedifferentiate from regenerative nodules to dysplasfic nodules and then to HCCs, the portal venous blood supply decreases, the arterial blood supply increases, and the uptake of SPIO is reduced. Because of these changes, the combination of SPIO with rapid sequential imaging after gadolinium administration has been shown to statistically improve the detection of HCC in patients with hepatic cirrhosis (Fig 13). 43 This double-contrast MR approach may be superior to dynamic gadolinium-enhanced Tl-weighted images because the signal intensity of the background liver is lower than on nonenhanced images after the S P I t administration, but before gadolinium injection.
In cirrhotic livers, a nontumorous arterioportal shunt can be difficult to differentiate from HCC. These shunts appear as hyperenhancing foci during the arterial phase of dynamic MR studies. When they occur adjacent to a HCC, the hyperenhancing areas may hide satellite nodules. SPIO can differentiate between nontumorous artefioportal shunts and tumors, as shown in Figure 14. Artefioportal shunts caused by tumors are seen as areas of reduced signal loss. On the contrary, most nontumorous artefioportal shunts are seen as areas of normal signal loss, similar to the nonaffected liver parenchyma. 55 This impairment in the uptake of SPIO corresponds to the injury of the liver parenchyma (edema, Kupffer cell and hepatocytes depletion, and fibrosis) that occurs in tumor-related shunts in which the associated portal branches are obstructed. 55
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