Assessment of Hepatic Function with Gd-EOB-DTPA-Enhanced Hepatic MRIBae K.E. · Kim S.Y. · Lee S.S. · Kim K.W. · Won H.J. · Shin Y.M. · Kim P.N. · Lee M.-G.
Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
Assessment of hepatic function is essential in determining the prognosis and clinical management of a patient who has chronic liver disease or undergoes liver surgery. For a patient with locally varying hepatic parenchymal abnormalities, a regional assessment of hepatic function mapped onto hepatic anatomy is clinically more meaningful than conventional global metrics of hepatic function. Of late, hepatic magnetic resonance imaging has been increasingly used because of its superb tissue contrast and delineation of hepatic morphology and underlying abnormalities. The introduction of hepatocyte-specific contrast agents such as Gd-EOB-DTPA allows us to view not only the hepatic anatomy but also assess regional hepatic function. In this article, we review and discuss recently published studies that used Gd-EOB-DTPA-enhanced magnetic resonance imaging to evaluate hepatic function.
Copyright © 2012 S. Karger AG, Basel
Assessment of hepatic function is essential in determining the prognosis and clinical management of a patient who has chronic liver disease or undergoes liver surgery . An insufficient hepatic function of the remnant hepatic parenchyma is one of the main contributing factors to postoperative mortality in hepatic resection . Traditional methods for the measurement of hepatic function include a hepatic volumetry , indocyanine green (ICG) clearance test, and clinical scoring system such as Child-Pugh score and the Model of End Stage Liver Disease (MELD) score . However, these measurements offer the global assessment not the regional parenchymal assessment of hepatic function.
Hepatic parenchymal abnormalities are often regionally variable across the liver [5,6]. To accurately assess hepatic function in localized hepatic abnormalities, a regional mapping of hepatic function onto hepatic anatomy is likely to provide clinically more meaningful information than a global assessment. Scintigraphy was used for the evaluation of regional hepatic function [7,8]. However, scintigraphical assessment of hepatic function is limited due to poor spatial resolution of scintigraphic images.
Hepatic magnetic resonance imaging (MRI) has been increasingly used in routine clinical practice, because it provides superb tissue contrast and delineation of hepatic morphology and underlying abnormalities [9,10,11]. For instance, regional variations in hepatic parenchymal tissue composition and nodularity can be readily depicted on hepatic magnetic resonance (MR) images [12,13]. In addition, studies have reported the appropriate characterization of hepatic parenchymal properties using functional MR techniques including MR spectroscopy [14,15], MR elastography , diffusion-weighted imaging , MR relaxometry , and Gd-EOB-DTPA-enhanced MRI [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. In this article, we will review and discuss recently published studies that used Gd-EOB-DTPA-enhanced hepatic MRI to evaluate hepatic function.
Gd-EOB-DTPA-Enhanced Liver MRI
Gd-EOB-DTPA-enhanced (Primovist; Bayer HealthCare) liver MRI is increasingly used for anatomic imaging of liver in routine clinical practice to detect and characterize focal hepatic lesions [9,10,11]. Gd-EOB-DTPA is a hepatocyte-specific contrast agent that has up to 50% hepatobiliary excretion in the normal liver. After intravenous injection, Gd-EOB-DTPA distributes throughout the vascular and extravascular spaces contributing to the arterial, portal venous and late dynamic phases, and progressively into the hepatocytes and bile ducts during the hepatobiliary phase . The hepatocyte uptake of Gd-EOB-DTPA occurs mainly via the organic anion transporter polypeptides OATP1B1 and B3 located at the sinusoidal membrane and biliary excretion via the multidrug resistance-associated proteins MRP2 at the canalicular membrane . This pathway is similar to those for ICG and scintigraphic agents that were traditionally used to evaluate hepatic function. In particular, Gd-EOB-DTPA-enhanced MRI is advantageous over other imaging modalities for regional assessment of hepatic function because it offers both excellent delineation of hepatic anatomy and hepatocyte-specific function.
Evaluation of Hepatic Function with Gd-EOB-DTPA-Enhanced MRI
After Gd-EOB-DTPA is administered, MR images of the liver are acquired at different phases. The approaches of assessing hepatic function with Gd-EOB-DTPA-enhanced MR images are divided into two main directions: measurements of the biliary enhancement or hepatic parenchymal enhancement.
Hepatic Function from Biliary Gd-EOB-DTPA Enhancement
For normal subjects with normal hepatic function and no bile duct obstruction, the intrahepatic and extrahepatic bile ducts enhance intensely at 20 min after the administration of Gd-EOB-DTPA  (fig. 1). Several studies reported that the time and degree of Gd-EOB-DTPA biliary enhancement is affected by hepatic function [21,22,23,24,25]. Tamada et al.  showed that the biliary enhancement was significantly delayed and weaker in patients with liver cirrhosis than in normal subjects. Takao et al.  measured the relative signal intensity of bile duct normalized by that of muscle. They revealed that the relative signal intensity of the bile duct for the chronic liver disease group was significantly lower than that of the normal liver function group. ICG retention rate at 15 min was also a significant predictor for the relative signal intensity of bile duct.
|Fig. 1. Bile duct visualization after Gd-EOB-DTPA injection. a, b In a patient with normal hepatic function, coronal T1-weighted images with fat suppression demonstrate a sufficient visualization of the biliary tree. The intrahepatic (a, arrowhead) and extrahepatic ducts (a, b, arrow) are well seen. c In contrast, in a patient with poor liver function (Child-Pugh class C, bilirubin 2.7 mg/dl), contrast is not visualized in the bile duct (arrow) at the same time delay after the contrast injection. Liver cirrhosis is also noted.|
Advantages and Limitations
This approach is simple and easy to implement in clinical practice because it is based on a routine clinical imaging protocol and does not require additional imaging or sophisticated image analysis. However, the biliary enhancement is influenced not only by hepatic function but also by bile duct flow [25,26]. When the biliary fluid dynamics is impaired, the measurement of biliary enhancement alone does not assure accurate assessment of hepatic function.
Hepatic Function from Hepatic Parenchymal Enhancement
Patients with severe hepatic dysfunction often present with reduced hepatic parenchymal enhancement in clinical Gd-EOB-DTPA-enhanced liver MRI (fig. 2). The hepatic parenchymal enhancement likely reflects the function of hepatocytes in the liver. Therefore, the differential degree of hepatic parenchymal enhancement can be measured from Gd-EOB-DTPA-enhanced liver MRI and interpreted to assess hepatic function. Three different approaches were reported: direct measurement of hepatic parenchymal signal intensity; measurement of T1 or T2* relaxation time changes on the basis of MR relaxometry, and dynamic contrast-enhanced MRI (DCE-MRI) technique.
|Fig. 2. Hepatic parenchymal enhancement after Gd-EOB-DTPA injection. a Axial T1-weighted image with fat suppression at 20 min after Gd-EOB-DTPA injection shows a homogeneous and well-enhanced pattern of liver parenchyma in a patient with normal hepatic function. b In a patient with liver cirrhosis the degree of parenchymal enhancement is markedly decreased and heterogeneous, in contrast to that in a patient with normal hepatic function.|
This is the most common approach used to assess hepatic function from Gd-EOB-DTPA-enhanced hepatic MRI, because of its simplicity. Studies reported methods ranging from purely qualitative to more sophisticated quantitative methods, including visual assessment of hepatic enhancement , measurement of the signal-to-noise ratio (SNR) of the hepatic parenchyma in the hepatobiliary phase , and corrected measurement of hepatic parenchymal signal intensity using internal tissue standards such as the spleen and skeletal muscles [29,30,31,32,33,34,35,36].
Tajima et al.  measured the hepatic parenchymal SNR in the hepatobiliary phase of Gd-EOB-DTPA-enhanced liver MRI. They demonstrated that hepatic parenchymal signal intensity is significantly lower in patients with chronic liver disease than in those with normal liver function. In that study, ICG-R15 was proven to be a significant contributor to hepatic signal intensity in the hepatobiliary phase. More recent studies reported the use of hepatic parenchymal enhancement corrected by muscle or spleen signal intensity to assess hepatic function [29,30,31,32,33,34,35,36]. Motosugi et al.  used a corrected liver-to-muscle enhancement ratio in 100 patients who underwent liver biopsy or surgery, and claimed that the corrected liver-enhancement ratio strongly predicted liver fibrosis stage. Watanabe et al.  computed a ‘contrast enhancement index’ that corresponded to the degree of hepatic parenchymal enhancement corrected by splenic signal intensity. They published that the contrast enhancement index strongly correlated with fibrosis stage (R = –0.79). Yamada et al.  introduced yet a new index, ‘hepatocellular uptake index (HUI)’. This index was computed from the volume and signal intensity of the liver and spleen, and stated that the HUI correlated significantly with ICG clearance rate (R = 0.87).
Advantages and Limitations
Methods based on the direct measurement of hepatic parenchymal signal intensity are simple and do not require a sophisticated mathematical modeling or analysis of MR signal characteristics. For this reason, it is most commonly used. However, it also has several limitations. First, the signal intensity measurement is subjected to data sampling errors, since the observers place regions of interest over limited portions of the liver. Second, the MR signal intensity is confounded by numerous technical factors and highly variable depending on MR scanners and scanning parameters [37,38]. For these reasons, signal intensity measurements may not be reproducible. Third, the relationship between signal intensity and gadolinium concentration is not linear . Thus, signal intensity measurement may not directly correlate with gadolinium concentration. Finally, the signal intensity measurement at a single time point may not sufficiently reflect serial hepatic responses over time. One remedy to this problem is by the application of the analysis of area under the time-signal intensity curve .
In order to overcome some of the limitations associated with the direct hepatic parenchymal signal intensity measurement method, researchers proposed the MR relaxometry method [37,38]. In this method, hepatic function is evaluated from measurement of changes in T1 or T2* relaxation time that is affected by Gd-EOB-DTPA uptake. Katsube et al.  reported that the postcontrast T1 relaxation time of liver was significantly longer with lower reduction rates in Child-Pugh B cirrhosis group than in control group. With the knowledge that Gd-EOB- DTPA has the ability to shorten not only T1 values but also T2* values, another study published a method based on T2* relaxation time . In this study, T2* reduction rate was significantly lower in the Child-Pugh B group than in the control group.
Advantages and Limitations
The T1 or T2* relaxation times measured on the basis of MR relaxometry were directly correlated with the concentration of Gd-EOB-DTPA. Therefore, MR relaxometry appears more reliable and less subjective than the direct hepatic signal intensity method to assess hepatic function. Two MR relaxometry studies [37,38] also presented segmental hepatic function maps. Compared to the direct hepatic signal intensity method, the MR relaxometry method requires additional scan sequences and dedicated software to calculate relaxation times [37,38]. In addition, the uptake of ICG and Gd-EOB-DTPA into hepatocytes is influenced by both the hepatocyte function and hepatic blood flow .
DCE-MRI has been widely used for evaluation of brain perfusion. DCE-MRI of the liver is a relatively new approach to determine perfusion parameters and quantify the microcirculatory status of hepatic parenchyma . DCE-MRI data consist of one T1-weighted signal-time curve for every voxel in the field of view. Using a dedicated software, the data can be analyzed descriptively or quantitatively to parameterize the physiological state of the tissue .
Studies proposed to measure a time intensity curve over portal vein and hepatic parenchyma from dynamic Gd-EOB-DTPA-enhanced hepatic MRI and compute ‘hepatic extraction fraction (HEF)’ using a deconvolution method [42,43]. HEF represents the proportion of a tracer extracted by the liver from the system. Compared to normal subjects, patients with primary biliary cirrhosis demonstrated significantly lower HEF values. These studies also provided hepatic function maps to depict the anatomic distribution of hepatic function. A more recent study adopting a dual-input single compartment model suggested that the arterial blood flow was a good predictor for mild fibrosis .
Advantages and Limitations
The DCE-MRI method has advantages over other methods because it takes into consideration not only the serial event of hepatic uptake of Gd-EOB-DTPA according to the hepatic function but also hepatic blood flow. However, DCE-MRI requires a dedicated software and complex mathematical modeling. Additional challenges in the current state of DCE-MRI of the liver include (1) the liver has dual blood supplies and is subject to breathing motion during imaging acquisition compared to the brain, (2) there is lack of uniformity in measurement and analysis methods, and (3) no data is available for reproducibility of this method . Further technical developments and validation studies are required to overcome these challenges Table 1.
|Table 1. Summary of studies assessing hepatic function with Gd-EOB-DTPA-enhanced hepatic MRI|
In conclusion, assessment of hepatic function with Gd-EOB-DTPA-enhanced liver MRI is a relatively new technique with a great potential for clinical applications. It allows us to obtain both hepatic anatomical and functional information in a single imaging acquisition setting. In particular, for a patient with locally varying hepatic parenchymal abnormalities, a regional assessment of hepatic function mapped onto hepatic anatomy may be clinically more meaningful than conventional global metrics of hepatic function. A number of promising studies for assessing hepatic function were developed and published. However, the technique is still evolving and requires more development and validation to be standardized and accepted in routine clinical practice.
This study was supported by grant #2012-546 from the Asan Institute for Life Science, Seoul, Korea.
The authors declare that no financial or other conflict of interest exists in relation to the content of the article.
So Yeon Kim, MD
Department of Radiology and Research Institute of Radiology
University of Ulsan College of Medicine, Asan Medical Center
88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736 (Korea)
Published online: December 13, 2012
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 1, Number of References : 44
Digestive Diseases (Clinical Reviews)
Vol. 30, No. 6, Year 2012 (Cover Date: December 2012)
Journal Editor: Malfertheiner P. (Magdeburg)
ISSN: 0257-2753 (Print), eISSN: 1421-9875 (Online)
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