Living Donor Liver Transplantation: The Asian Perspective Chao-Long Chen, Yu-Fan Cheng, Chun-Yen Yu, Hsin-You Ou, Leo Leung-Chit Tsang, Tung-Liang Huang, Tai-Yi Chen, Allan Concejero, Chih-Chi Wang, Shih-Ho Wang, Tsan-Shiun Lin, Yueh-Wei Liu, Chin-Hsiang Yang, Chee-Chien Yong, King-Wah Chiu, Bruno Jawan, Hock-Liew Eng, See Ching Chan, William Wei Sharr, Chung-Mau Lo, Sumihito Tamura, Yasuhiko Sugawara, Norihiro Kokudo, Kwang-Woong Lee, Nam-Joon Yi, Kyung-Suk Suh, Deok-Bog Moon, Sung-Gyu Lee, Chul-Soo Ahn, Shin Huang, Ki-Hun Kim, Tae-Yong Ha, Gi-Wong Song, Dong-Hwan Jung, Gil-Chun Park, Jung-Man Namkoong, Hyung-Woo Park, Yo-Han Park, Cheon-Soo Park, Kyw-Bo Sung, Gi-Young Ko, Dong-Il Gwon, Toskimi Kaido, Kohei Ogawa, Yasuhiro Fujimoto, Takashi Ito, Koji Toniyama, Akira Mori, Yasuhiro Ogura, Shinji Uemoto, Anthony Q. Yap, Yu-Hung Lin, Chun-Yi Liu, Yuan-Cheng Chiang, Chih-Chi Lin, Milljae Shin, Jae-Won Joh, Catherine Kabiling, Tsung-Hui Hu, Sung-Hwa Kang, Bo-Hyun Jung, and Young-Rok Choi
SECTION 1. IMAGE EVALUATION OF FATTY LIVER IN LIVING DONOR LIVER TRANSPLANTATION
Yu-Fan Cheng,1 Chun-Yen Yu,1 Hsin-You Ou,1 Leo Leung-Chit Tsang,1 Tung-Liang Huang,1 Tai-Yi Chen,1 Allan Concejero,2 Chih-Chi Wang,2 Shih-Ho Wang,2 Tsan-Shiun Lin,2 Yueh-Wei Liu,2 Chin-Hsiang Yang,2 Chee-Chien Yong,2 King-Wah Chiu,3 Bruno Jawan,4 Hock-Liew Eng,5 and Chao-Long Chen2,6 Abstract. Preoperative evaluation of donors for living-donor liver transplantation aims to select a suitable donor with optimal graft quality and to ensure donor safety. Hepatic steatosis, a common finding in living liver donors, not only influences the outcome of liver transplantation for the recipient but also affects the recovery of the living donor after partial hepatectomy. Histopathologic analysis is the reference standard to detect and quantify fat in the liver, but it is invasive, and results are vulnerable to sampling error. Imaging can be repeated regularly and allows assessment of the entire liver, thus avoiding sampling error. Selection of appropriate imaging methods demands understanding of their advantages and limitations and the suitable clinical setting. This article describes potential clinical applications for liver fat quantification of imaging methods for fat detection and quantification, with an emphasis on the advantages and limitations of ultrasonography, computed tomography, and magnetic resonance imaging for quantifying liver fat. Keywords: Fatty liver, Ultrasound, CT, MR, Living donor liver transplantation.
L
iving-donor liver transplantation (LDLT) was developed to alleviate organ shortage, especially in Asian countries,
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where the cadaveric graft supply is markedly limited. The most serious ethical concern of LDLT is the risk to the healthy donor who will undergo a major operation without any potential health benefit. Therefore, preserving the health of the donors and excluding persons from donation if they are not suitable candidates, for either medical or anatomic reasons, should be the most important priority of the transplant team (1). Imaging is performed to detect liver parenchymal abnormalities that may preclude living-donor transplantation. However, in the vast majority of cases, parenchymal imaging focuses mainly on detecting hepatic steatosis, which, if present in a significant quantity, can cause postoperative graft dysfunction in the recipient and liver dysfunction or failure in the donor. Among living liver donors, the residual liver with a fat content of less than 5% shows better regeneration than one This work was supported by Grant NSC 96-231-B-182A-009 and NSC 94231-B-182A-009 from the National Science Council, Taiwan. The authors declare no conflicts of interest. 1 Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 2 Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 3 Division of Hepatogastroenterology, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 4 Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 5 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 6 Address correspondence to: Chao-Long Chen, M.D., Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Tai-Pei Road, Niao-Sung, Kaohsiung 83305, Taiwan. E-mail: [email protected] Dr. Yu-Fan Cheng and Dr. Chun-Yen Yu contributed equally to this work. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
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with a fat content of 5% to 30%. This statistic is indicative of the important effect that hepatic steatosis may have on the functional recovery of the liver. In addition, as the amount of donor hepatic steatosis increases from mild to moderate (30%) to severe (60%), the possibility of hepatic dysfunction and renal failure in the recipient escalates (2). Early mortality and the rate of ischemia-reperfusion injury also are increased significantly in recipients of liver transplants with severe steatosis (2). Quantitative assessment of hepatic fatty infiltration is, therefore, important in donor evaluation for LDLT. The next sections of the article describe the advantages and limitations of ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging (chemical shift imaging plus analysis), and MR spectroscopy for quantifying liver fat.
IMAGING EVALUATION OF FATTY LIVER Ultrasound Ultrasound is the simplest imaging method for the detection and characterization of hepatic steatosis. The quality of the US examination is highly operator dependent, and the diagnosis and characterization of fatty liver disease at US are based mainly on a subjective assessment of liver echogenicity (3, 4). Ultrasound-based evaluation of steatosis is mainly qualitative. Hepatic steatosis results in increased echogenicity (brightness) of the liver parenchyma in comparison with the renal cortex and spleen (3, 4). The grades of hepatic steatosis as depicted at US are defined qualitatively as follows: mild, characterized by mildly increased liver echogenicity and clear depiction of hepatic and portal vein walls; moderate, with increased liver echogenicity obscuring the hepatic and portal vein walls; and severe, with increased liver echogenicity and significant posterior shadowing that impairs evaluation of the deep liver parenchyma and diaphragm (3). Ultrasound-based qualitative assessment of steatosis has been reported to lack intraobserver reproducibility and interobserver reliability (3, 4). Saadeh et al. (3) reported 100% sensitivity for the detection of moderate or severe (933%) steatosis with US, but the positive predictive value was 62%, and interobserver agreement was only fair to moderate. An altered renal parenchymal echotexture with renal parenchymal disorders may affect US evaluations of the liver. Moreover, the presence of hepatic fibrosis in some patients makes the linear correlation between fatty infiltration and liver echogenicity unreliable (5, 6). Ultrasound is often useful for identifying moderate or severe hepatic steatosis but less effective for diagnosing mild hepatic steatosis. In addition, it is difficult to differentiate hepatic fibrosis from hepatic steatosis (3, 5, 6). Quantitative methods of measuring echogenicity are laborious and not always reliable (7, 8). However, qualitative assessment of steatosis at US has been found more accurate than quantitative estimation. Qualitative assessment was found to have sensitivity, specificity, and accuracy of 60% to 100%, 77% to 95%, and 96%, in comparison with 77%, 77%, and 71% for quantitative assessment (3, 8). Despite the benefits of US, such as ease of use, ready accessibility, lack of ionizing radiation, and lower cost, the method has practical limitations. Factors such as a small field
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of view, lack of reliable quantitative measurements, operator and equipment dependence, and poor sensitivity for differentiating hepatic steatosis from fibrosis and cirrhosis are impediments to the widespread use of US for evaluation of fatty liver disease (3). Ultrasound is widely used to screen for fatty liver disease, but it has low sensitivity for mild-to-moderate steatosis and thus may fail to depict the early stages of disease. Moreover, it cannot fulfill the need for more precise evaluations during screening of liver transplant donor candidates. Computed Tomography Unenhanced CT is considered the best CT method for estimation of liver fat because it involves simple measurement of liver attenuation in Hounsfield units (9). The measurement of attenuation at unenhanced CT is based on the physical characteristic of x-ray penetration of tissue. Hepatic attenuation values are inversely correlated with the amount of liver fat; thus, they decrease proportionately with increasing liver fat content. At unenhanced CT, qualitative estimation of liver fat is performed by comparing the attenuation of liver with that of spleen (9, 10). The spleen serves as a good internal control for comparison with the liver because splenic attenuation is unaffected by various diffuse pathologic processes and because the spleen is located in the same cross section as the liver. At unenhanced CT, a normal liver has higher attenuation than a normal spleen. When the liver has lower attenuation than the spleen at unenhanced CT, a diagnosis of hepatic steatosis may be considered. Several studies have confirmed that this method has a high sensitivity (88%Y95%) and specificity (90%Y99%) (10, 11). Contrast-enhanced CT, on the other hand, is not the most suitable method for determining the hepatic fat content because the attenuation characteristics depend on various factors related to the contrast material (11, 12). Contrast mediumYrelated factors such as iodine concentration, volume and rate of injection, and scanning delays influence the hepatic attenuation to varying degrees and may mask subtle differences in attenuation caused by changes in fat content (11). Computed tomography has been used for hepatic fat quantification since the appearance of the first article about the correlation of hepatic triglyceride with CT number (13). The available methods of fat quantification include hepatic attenuation measurement, calculation of the hepatic attenuation index, and measurement of the hepatic attenuation difference at dual-energy CT. Hepatic attenuation measurement: At unenhanced CT, the attenuation values measured in the normal liver (range, 50Y65 HU) typically are higher than those measured in the spleen, a fact that has been attributed to the presence of glycogen in the liver. Fatty infiltration is diagnosed when the hepatic attenuation is less than 48 HU (10). Liver attenuation values also reflect the degree of underlying fatty change. Kodama et al. (9) found that hepatic attenuation of 40 HU represents fatty change of approximately 30%. Their study showed that liver CT numbers of 64.4 HUT3.1, 59.1 HUT7.3, 41.9 HUT6.7, and 25.0 HUT15.5 at unenhanced imaging correlated with degrees of fattychange of 0%, 1% to 25%, 26% to 50%, and more than 50% (9).
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The hepatic attenuation index, an objective measure of fatty liver disease, is commonly obtained by calculating the ratio of hepatic attenuation to splenic attenuation (9, 14). Park et al (14) reported that a hepatic-to-splenic attenuation ratio of less than 0.8 was highly specific (specificity, 100%) for the diagnosis of moderate to severe (930%) macrovesicular steatosis. Another method of obtaining the hepatic attenuation index involves the measurement of difference between the hepatic and splenic attenuation. In a study by Limanond et al. (15), a hepaticsplenic attenuation difference of more than 5 HU was an accurate predictor of the absence of significant macrovesicular steatosis (0%Y5%) and a difference of j10 to 5 HU was suggestive of mild-to-moderate steatosis (6%Y30%). The same authors reported a specificity of 100% for the detection of moderate-to-severe (930%) macrovesicular steatosis when the hepatic-splenic attenuation difference was less than j10 HU (15). Similarly, Park et al. (14) found a specificity of 100% for the detection of steatosis of more than 30% when the hepaticsplenic attenuation difference was less than j9HU. However, the sensitivity of the two measures (hepatic-to-splenic attenuation ratio and hepaticsplenic attenuation difference) for the diagnosis of macrovesicular steatosis of more than 30% remained between 73% and 82% (13Y15). Other factors that may alter hepatic parenchymal attenuation at CT include effects of therapeutic irradiation of the liver, toxic effects of drug therapy (e.g., amiodarone, methotrexate), acute hepatitis or acute toxic hepatic injury, cirrhosis, and depositional diseases of the liver (e.g., iron, glycogen). In the presence of acute hepatitis, the liver parenchyma has heterogeneous attenuation with periportal areas of low attenuation on CT scans. Deposition of iron has an effect on liver attenuation that is opposite to the effect of fat deposition; hence, in patients with hemochromatosis and hemosiderosis, liver attenuation values are less reliable for detecting fatty accumulation (15). Magnetic Resonance Imaging Magnetic resonance (MR) imaging is one of the most sensitive modalities for detection and characterization of fatty infiltration of the liver. The degree of fatty infiltration can be estimated by using either chemical shift imaging or MR spectroscopy. Chemical Shift Imaging The difference between the precession frequencies of fat (jCH2) and water (jOH) protons enables the use of chemical shift techniques to accurately detect and quantify fatty infiltration (16, 17). This frequency difference causes tissues containing fat and water to lose signal intensity when the proton magnetizations are opposed, in out-of phase imaging. The signal loss can be observed when out-of-phase images are compared with in-phase images, which are acquired with the fat and water proton magnetizations in phase with each other to provide additive signal (17). Whereas the normal liver parenchyma exhibits similar signal intensity on in-phase and out-ofphase images, fatty liver shows diminished signal intensity on out-of-phase images, with the reduction being more evident in the presence of severe fatty infiltration (17).
Chen et al.
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With fast SE Imaging, the fat percentage in liver (HFP) is calculated from the percent decrease in hepatic signal intensity on T2-weighted fat-saturated fast SE images in comparison with that on T2-weighted nonY fat-saturated fast SE images, as follows: HFP =[(SIT2 NF j SIT2 FS)/SIT2 NF] & 100, where SIT2 NF is the hepatic-to-splenic signal intensity ratio at T2-weighted nonYfat-saturated imaging, and SIT2 FS is the hepatic-to-splenic signal intensity ratio at T2 weighted fat-saturated imaging. A decrease in the signal intensity of liver on T2-weighted fat-saturated fast SE images in comparison with T2-weighted nonYfat-saturated fast SE images is suggestive of fatty infiltration. With the introduction of 3-T systems, the utility of MR imaging for evaluating liver fat has increased (18). The chemical shift difference between fat and water at 3 T is about 415 Hz, in comparison with 208 Hz at 1.5 T (18). With this frequency difference, TEs at in-phase and out-of-phase GRE imaging with a 3-T system are nearly half those needed to generate an echo when using a 1.5-T system. Thus, both inphase and out-of-phase images (20 axial sections) can be acquired in a single breath hold (approximately 23 seconds), helping avoid motion artifacts. The use of MR imaging with chemical shift imaging for the detection and quantification of fatty liver provides the following benefits: (a) technical simplicity, (b) coverage of the entire liver, (c) minimal vulnerability to confounding factors, and (d) absence of radiation exposure. Limitations to the routine use of MR imaging in liver fat quantification include potential variability of results due to differences in MR imaging systems, scanning parameters, and methods of analysis. In addition, MR imaging is relatively expensive, a factor that limits its applicability for repeated evaluations and monitoring of treatment response. Last, although MR imaging has high sensitivity for the detection of fat, it does not provide quantitation of the absolute hepatic fat concentration (19). MR Spectroscopy Magnetic resonance spectroscopy is one of the most accurate methods for noninvasive assessment of fatty liver is MR spectroscopy (20). Localized or single-voxel MR spectroscopy provides information about the chemical composition in a normal organ and chemical changes in the progression of disease (e.g., in hepatic triglyceride content). This promising technique can be used to quantify small amounts of fat, potentially eliminating the need for liver biopsy during the presurgical evaluation of liver donors and allowing closer monitoring of the response to treatment for metabolic disorders or obesity. The values obtained with spectroscopy show good correlation with the results of liver biopsy, and spectroscopy therefore has been promoted as an optimal method for estimating the hepatic triglyceride content (21). Studies have confirmed that MR spectroscopy is a promising method for quantifying liver fat and may help detect hepatic fibrosis (22, 23). The diagnostic accuracy of MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88Y1.0) (24). Furthermore, it has been found useful in evaluating necroinflammatory activity in the chronically diseased liver (22). Cho et al. (23) found that the metabolic ratios of glutamate, lipid, and glycine observed at MR spectroscopy differ in the various
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stages of chronic hepatitis. Moreover, a decrease in the lipid peak was seen at MR spectroscopy in the presence of advanced hepatitis with severe fibrosis (23). The advantages offered by MR spectroscopy for at quantification are its ability to determine the absolute liver fat concentration and its high sensitivity for detecting small amounts of hepatic triglyceride and subtle changes in hepatic triglyceride content during treatment. It is also useful for revealing a necroinflammatory response in the setting of chronic liver disease (25). However, MR spectroscopy is not widely used for these purposes. Spectral analysis methods are complex, and their complexity may lead to variability in results. The results also may vary because of differences in MR systems and acquisition parameters and because fat quantification is performed in a small volume of liver tissue.
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3. 4. 5. 6.
7. 8. 9.
USEFULNESS OF LIVER BIOPSY The use of liver biopsy remains the gold standard in determining the degree of steatosis. Some centers have even suggested routine liver biopsy for donor selection. Histopathologic analysis, in addition to providing means for grading the severity of steatosis, facilitates differentiation between steatosis and steatohepatitis (26). It helps not only confirm the diagnosis of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis but also detect clinically unsuspected processes that coexist with or mimic fatty liver disease, such as viral hepatitis (particularly that caused by chronic hepatitis C infection) (26). Despite these benefits, biopsy is an invasive technique and is fraught with potential morbidity and complications. However, lack of homogeneity in fat distribution raises the question of whether a single biopsy specimen can accurately assess steatosis. Furthermore, because hepatic steatosis is a dynamic process, monitoring progression or improvement in the disease status over time with frequent biopsy is impracticable. In our center, liver biopsy is performed only if the US or CT scan findings suggest hepatic steatosis.
CONCLUSION Imaging is not only noninvasive but also permits concomitant screening for other liver abnormalities; the entire liver can be evaluated with all modalities. In addition, imaging allows both qualitative and quantitative assessment of fat content. Ultrasound and computed tomography can be used to assess liver fat but have limited accuracy as well as other limitations. Magnetic resonance techniques can decompose the liver signal into its fat and water signal components and therefore assess liver fat more directly than CT or US. These advanced techniques show promise for accurate fat quantification and are likely to be commercially available soon. Future studies should aim at improving the sensitivity of imaging techniques in the diagnosis of steatosis.
10. 11. 12.
13. 14. 15. 16.
17. 18. 19. 20. 21.
22.
23. 24.
REFERENCES 1. 2.
Chen YS, Cheng YF, De Villa VH, et al. Evaluation of living liver donors. Transplantation 2003; 75: S16. Perez-Daga JA, Santoyo J, Suarez MA, et al. Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation. Transplant Proc 2006; 38: 2468.
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Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liverdisease. Gastroenterology 2002; 123: 745. Strauss S, Gavish E, Gottlieb P, et al. Interobserver and intraobserver variability in the sonographic assessment of fatty liver. AJR Am J Roentgenol 2007; 189: W320. Joseph AE, Saverymuttu SH, al-Sam S, et al. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol 1991; 43: 26. Mathiesen UL, Franzen LE, Aselius H, et al. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases. Dig Liver Dis 2002; 34: 516. Hamer OW, Aguirre DA, Casola G, et al. Fatty liver: imaging patterns and pitfalls. RadioGraphics 2006; 26: 1637. Graif M, Yanuka M, Baraz M, et al. Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease. Invest Radiol 2000; 35: 319. Kodama Y, Ng CS, Wu TT, et al. Comparison of CT methods for determining the fat content of the liver. AJR Am J Roentgenol 2007; 188: 1307. Lee SW, Park SH, Kim KW, et al. Unenhanced CT for assessment of macrovesicular hepatic steatosis in living liver donors: comparison of visual grading with liver attenuation index. Radiology 2007; 244: 479. Panicek DM, Giess CS, Schwartz LH. Qualitative assessment of liver for fatty infi ltration on contrastenhanced CT: is muscle a better standard of reference than spleen? J Comput Assist Tomogr 1997; 21: 699. Johnston RJ, Stamm ER, Lewin JM, et al. Diagnosis of fatty infiltration of the liver on contrast enhanced CT: limitations of liverminus-spleen attenuation difference measurements. Abdom Imaging 1998; 23: 409. Ducommun JC, Goldberg HI, Korobkin M, et al. The relation of liver fat to computed tomography numbers: a preliminary experimental study in rabbits. Radiology 1979; 130: 511. Park SH, Kim PN, Kim KW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology 2006; 239: 105. Limanond P, Raman SS, Lassman C, et al. Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings. Radiology 2004; 230: 276. Qayyum A, Goh JS, Kakar S, et al. Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradientecho and fat-saturated fast spin-echo techniquesVinitial experience. Radiology 2005; 237: 507. Pilleul F, Chave G, Dumortier J, et al. Fatty infi ltration of the liver: detection and grading using dual T1 gradient echo sequences on clinical MR system. Ramalho M, Altun E, Heredia V, et al. Liver MR imaging: 1.5T versus 3T. Magn Reson Imaging Clin N Am 2007; 15: 321, vi. Xiaozhou Ma, Nagaraj-Setty Holalkere, Avinash Kambadakone R. Imaging-based Quantification of Hepatic Fat: Methods and Clinical Applications. Radiographics 2009; 29: 1253. Cassidy FH, Yokoo T, Aganovic L, et al. Fatty liver disease: MR imaging techniques for the detection and quantifi cation of liver steatosis. Radiographics 2009; 29: 231. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462. Orlacchio A, Bolacchi F, Cadioli M, et al. Evaluation of the severity of chronic hepatitis C with 3-T 1H-MR spectroscopy. AJR Am J Roentgenol 2008; 190: 1331. Cho SG, Kim MY, Kim HJ, et al. Chronic hepatitis: in vivo proton MR spectroscopic evaluation of the liver and correlation with histopathologic findings. Radiology 2001; 221: 740. Georgoff P, Thomasson D, Louie A, et al. Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis. AJR Am J Roentgenol 2012; 199: 2. Bonekamp S, Kamel I, Solga S, et al. Can imaging modalities diagnose and stage hepatic fi brosis and cirrhosis accurately? J Hepatol 2009; 50: 17. Hubscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathology 2006; 49: 450.
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SECTION 1. IMAGE EVALUATION OF FATTY LIVER IN LIVING DONOR LIVER TRANSPLANTATION
Yu-Fan Cheng,1 Chun-Yen Yu,1 Hsin-You Ou,1 Leo Leung-Chit Tsang,1 Tung-Liang Huang,1 Tai-Yi Chen,1 Allan Concejero,2 Chih-Chi Wang,2 Shih-Ho Wang,2 Tsan-Shiun Lin,2 Yueh-Wei Liu,2 Chin-Hsiang Yang,2 Chee-Chien Yong,2 King-Wah Chiu,3 Bruno Jawan,4 Hock-Liew Eng,5 and Chao-Long Chen2,6 Abstract. Preoperative evaluation of donors for living-donor liver transplantation aims to select a suitable donor with optimal graft quality and to ensure donor safety. Hepatic steatosis, a common finding in living liver donors, not only influences the outcome of liver transplantation for the recipient but also affects the recovery of the living donor after partial hepatectomy. Histopathologic analysis is the reference standard to detect and quantify fat in the liver, but it is invasive, and results are vulnerable to sampling error. Imaging can be repeated regularly and allows assessment of the entire liver, thus avoiding sampling error. Selection of appropriate imaging methods demands understanding of their advantages and limitations and the suitable clinical setting. This article describes potential clinical applications for liver fat quantification of imaging methods for fat detection and quantification, with an emphasis on the advantages and limitations of ultrasonography, computed tomography, and magnetic resonance imaging for quantifying liver fat. Keywords: Fatty liver, Ultrasound, CT, MR, Living donor liver transplantation.
L
iving-donor liver transplantation (LDLT) was developed to alleviate organ shortage, especially in Asian countries,
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& Volume 97, Number 8S, April 27, 2014
where the cadaveric graft supply is markedly limited. The most serious ethical concern of LDLT is the risk to the healthy donor who will undergo a major operation without any potential health benefit. Therefore, preserving the health of the donors and excluding persons from donation if they are not suitable candidates, for either medical or anatomic reasons, should be the most important priority of the transplant team (1). Imaging is performed to detect liver parenchymal abnormalities that may preclude living-donor transplantation. However, in the vast majority of cases, parenchymal imaging focuses mainly on detecting hepatic steatosis, which, if present in a significant quantity, can cause postoperative graft dysfunction in the recipient and liver dysfunction or failure in the donor. Among living liver donors, the residual liver with a fat content of less than 5% shows better regeneration than one This work was supported by Grant NSC 96-231-B-182A-009 and NSC 94231-B-182A-009 from the National Science Council, Taiwan. The authors declare no conflicts of interest. 1 Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 2 Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 3 Division of Hepatogastroenterology, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 4 Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 5 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Taiwan. 6 Address correspondence to: Chao-Long Chen, M.D., Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, 123 Tai-Pei Road, Niao-Sung, Kaohsiung 83305, Taiwan. E-mail: [email protected] Dr. Yu-Fan Cheng and Dr. Chun-Yen Yu contributed equally to this work. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9708-00 DOI: 10.1097/TP.0000000000000060
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with a fat content of 5% to 30%. This statistic is indicative of the important effect that hepatic steatosis may have on the functional recovery of the liver. In addition, as the amount of donor hepatic steatosis increases from mild to moderate (30%) to severe (60%), the possibility of hepatic dysfunction and renal failure in the recipient escalates (2). Early mortality and the rate of ischemia-reperfusion injury also are increased significantly in recipients of liver transplants with severe steatosis (2). Quantitative assessment of hepatic fatty infiltration is, therefore, important in donor evaluation for LDLT. The next sections of the article describe the advantages and limitations of ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging (chemical shift imaging plus analysis), and MR spectroscopy for quantifying liver fat.
IMAGING EVALUATION OF FATTY LIVER Ultrasound Ultrasound is the simplest imaging method for the detection and characterization of hepatic steatosis. The quality of the US examination is highly operator dependent, and the diagnosis and characterization of fatty liver disease at US are based mainly on a subjective assessment of liver echogenicity (3, 4). Ultrasound-based evaluation of steatosis is mainly qualitative. Hepatic steatosis results in increased echogenicity (brightness) of the liver parenchyma in comparison with the renal cortex and spleen (3, 4). The grades of hepatic steatosis as depicted at US are defined qualitatively as follows: mild, characterized by mildly increased liver echogenicity and clear depiction of hepatic and portal vein walls; moderate, with increased liver echogenicity obscuring the hepatic and portal vein walls; and severe, with increased liver echogenicity and significant posterior shadowing that impairs evaluation of the deep liver parenchyma and diaphragm (3). Ultrasound-based qualitative assessment of steatosis has been reported to lack intraobserver reproducibility and interobserver reliability (3, 4). Saadeh et al. (3) reported 100% sensitivity for the detection of moderate or severe (933%) steatosis with US, but the positive predictive value was 62%, and interobserver agreement was only fair to moderate. An altered renal parenchymal echotexture with renal parenchymal disorders may affect US evaluations of the liver. Moreover, the presence of hepatic fibrosis in some patients makes the linear correlation between fatty infiltration and liver echogenicity unreliable (5, 6). Ultrasound is often useful for identifying moderate or severe hepatic steatosis but less effective for diagnosing mild hepatic steatosis. In addition, it is difficult to differentiate hepatic fibrosis from hepatic steatosis (3, 5, 6). Quantitative methods of measuring echogenicity are laborious and not always reliable (7, 8). However, qualitative assessment of steatosis at US has been found more accurate than quantitative estimation. Qualitative assessment was found to have sensitivity, specificity, and accuracy of 60% to 100%, 77% to 95%, and 96%, in comparison with 77%, 77%, and 71% for quantitative assessment (3, 8). Despite the benefits of US, such as ease of use, ready accessibility, lack of ionizing radiation, and lower cost, the method has practical limitations. Factors such as a small field
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of view, lack of reliable quantitative measurements, operator and equipment dependence, and poor sensitivity for differentiating hepatic steatosis from fibrosis and cirrhosis are impediments to the widespread use of US for evaluation of fatty liver disease (3). Ultrasound is widely used to screen for fatty liver disease, but it has low sensitivity for mild-to-moderate steatosis and thus may fail to depict the early stages of disease. Moreover, it cannot fulfill the need for more precise evaluations during screening of liver transplant donor candidates. Computed Tomography Unenhanced CT is considered the best CT method for estimation of liver fat because it involves simple measurement of liver attenuation in Hounsfield units (9). The measurement of attenuation at unenhanced CT is based on the physical characteristic of x-ray penetration of tissue. Hepatic attenuation values are inversely correlated with the amount of liver fat; thus, they decrease proportionately with increasing liver fat content. At unenhanced CT, qualitative estimation of liver fat is performed by comparing the attenuation of liver with that of spleen (9, 10). The spleen serves as a good internal control for comparison with the liver because splenic attenuation is unaffected by various diffuse pathologic processes and because the spleen is located in the same cross section as the liver. At unenhanced CT, a normal liver has higher attenuation than a normal spleen. When the liver has lower attenuation than the spleen at unenhanced CT, a diagnosis of hepatic steatosis may be considered. Several studies have confirmed that this method has a high sensitivity (88%Y95%) and specificity (90%Y99%) (10, 11). Contrast-enhanced CT, on the other hand, is not the most suitable method for determining the hepatic fat content because the attenuation characteristics depend on various factors related to the contrast material (11, 12). Contrast mediumYrelated factors such as iodine concentration, volume and rate of injection, and scanning delays influence the hepatic attenuation to varying degrees and may mask subtle differences in attenuation caused by changes in fat content (11). Computed tomography has been used for hepatic fat quantification since the appearance of the first article about the correlation of hepatic triglyceride with CT number (13). The available methods of fat quantification include hepatic attenuation measurement, calculation of the hepatic attenuation index, and measurement of the hepatic attenuation difference at dual-energy CT. Hepatic attenuation measurement: At unenhanced CT, the attenuation values measured in the normal liver (range, 50Y65 HU) typically are higher than those measured in the spleen, a fact that has been attributed to the presence of glycogen in the liver. Fatty infiltration is diagnosed when the hepatic attenuation is less than 48 HU (10). Liver attenuation values also reflect the degree of underlying fatty change. Kodama et al. (9) found that hepatic attenuation of 40 HU represents fatty change of approximately 30%. Their study showed that liver CT numbers of 64.4 HUT3.1, 59.1 HUT7.3, 41.9 HUT6.7, and 25.0 HUT15.5 at unenhanced imaging correlated with degrees of fattychange of 0%, 1% to 25%, 26% to 50%, and more than 50% (9).
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The hepatic attenuation index, an objective measure of fatty liver disease, is commonly obtained by calculating the ratio of hepatic attenuation to splenic attenuation (9, 14). Park et al (14) reported that a hepatic-to-splenic attenuation ratio of less than 0.8 was highly specific (specificity, 100%) for the diagnosis of moderate to severe (930%) macrovesicular steatosis. Another method of obtaining the hepatic attenuation index involves the measurement of difference between the hepatic and splenic attenuation. In a study by Limanond et al. (15), a hepaticsplenic attenuation difference of more than 5 HU was an accurate predictor of the absence of significant macrovesicular steatosis (0%Y5%) and a difference of j10 to 5 HU was suggestive of mild-to-moderate steatosis (6%Y30%). The same authors reported a specificity of 100% for the detection of moderate-to-severe (930%) macrovesicular steatosis when the hepatic-splenic attenuation difference was less than j10 HU (15). Similarly, Park et al. (14) found a specificity of 100% for the detection of steatosis of more than 30% when the hepaticsplenic attenuation difference was less than j9HU. However, the sensitivity of the two measures (hepatic-to-splenic attenuation ratio and hepaticsplenic attenuation difference) for the diagnosis of macrovesicular steatosis of more than 30% remained between 73% and 82% (13Y15). Other factors that may alter hepatic parenchymal attenuation at CT include effects of therapeutic irradiation of the liver, toxic effects of drug therapy (e.g., amiodarone, methotrexate), acute hepatitis or acute toxic hepatic injury, cirrhosis, and depositional diseases of the liver (e.g., iron, glycogen). In the presence of acute hepatitis, the liver parenchyma has heterogeneous attenuation with periportal areas of low attenuation on CT scans. Deposition of iron has an effect on liver attenuation that is opposite to the effect of fat deposition; hence, in patients with hemochromatosis and hemosiderosis, liver attenuation values are less reliable for detecting fatty accumulation (15). Magnetic Resonance Imaging Magnetic resonance (MR) imaging is one of the most sensitive modalities for detection and characterization of fatty infiltration of the liver. The degree of fatty infiltration can be estimated by using either chemical shift imaging or MR spectroscopy. Chemical Shift Imaging The difference between the precession frequencies of fat (jCH2) and water (jOH) protons enables the use of chemical shift techniques to accurately detect and quantify fatty infiltration (16, 17). This frequency difference causes tissues containing fat and water to lose signal intensity when the proton magnetizations are opposed, in out-of phase imaging. The signal loss can be observed when out-of-phase images are compared with in-phase images, which are acquired with the fat and water proton magnetizations in phase with each other to provide additive signal (17). Whereas the normal liver parenchyma exhibits similar signal intensity on in-phase and out-ofphase images, fatty liver shows diminished signal intensity on out-of-phase images, with the reduction being more evident in the presence of severe fatty infiltration (17).
Chen et al.
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With fast SE Imaging, the fat percentage in liver (HFP) is calculated from the percent decrease in hepatic signal intensity on T2-weighted fat-saturated fast SE images in comparison with that on T2-weighted nonY fat-saturated fast SE images, as follows: HFP =[(SIT2 NF j SIT2 FS)/SIT2 NF] & 100, where SIT2 NF is the hepatic-to-splenic signal intensity ratio at T2-weighted nonYfat-saturated imaging, and SIT2 FS is the hepatic-to-splenic signal intensity ratio at T2 weighted fat-saturated imaging. A decrease in the signal intensity of liver on T2-weighted fat-saturated fast SE images in comparison with T2-weighted nonYfat-saturated fast SE images is suggestive of fatty infiltration. With the introduction of 3-T systems, the utility of MR imaging for evaluating liver fat has increased (18). The chemical shift difference between fat and water at 3 T is about 415 Hz, in comparison with 208 Hz at 1.5 T (18). With this frequency difference, TEs at in-phase and out-of-phase GRE imaging with a 3-T system are nearly half those needed to generate an echo when using a 1.5-T system. Thus, both inphase and out-of-phase images (20 axial sections) can be acquired in a single breath hold (approximately 23 seconds), helping avoid motion artifacts. The use of MR imaging with chemical shift imaging for the detection and quantification of fatty liver provides the following benefits: (a) technical simplicity, (b) coverage of the entire liver, (c) minimal vulnerability to confounding factors, and (d) absence of radiation exposure. Limitations to the routine use of MR imaging in liver fat quantification include potential variability of results due to differences in MR imaging systems, scanning parameters, and methods of analysis. In addition, MR imaging is relatively expensive, a factor that limits its applicability for repeated evaluations and monitoring of treatment response. Last, although MR imaging has high sensitivity for the detection of fat, it does not provide quantitation of the absolute hepatic fat concentration (19). MR Spectroscopy Magnetic resonance spectroscopy is one of the most accurate methods for noninvasive assessment of fatty liver is MR spectroscopy (20). Localized or single-voxel MR spectroscopy provides information about the chemical composition in a normal organ and chemical changes in the progression of disease (e.g., in hepatic triglyceride content). This promising technique can be used to quantify small amounts of fat, potentially eliminating the need for liver biopsy during the presurgical evaluation of liver donors and allowing closer monitoring of the response to treatment for metabolic disorders or obesity. The values obtained with spectroscopy show good correlation with the results of liver biopsy, and spectroscopy therefore has been promoted as an optimal method for estimating the hepatic triglyceride content (21). Studies have confirmed that MR spectroscopy is a promising method for quantifying liver fat and may help detect hepatic fibrosis (22, 23). The diagnostic accuracy of MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88Y1.0) (24). Furthermore, it has been found useful in evaluating necroinflammatory activity in the chronically diseased liver (22). Cho et al. (23) found that the metabolic ratios of glutamate, lipid, and glycine observed at MR spectroscopy differ in the various
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stages of chronic hepatitis. Moreover, a decrease in the lipid peak was seen at MR spectroscopy in the presence of advanced hepatitis with severe fibrosis (23). The advantages offered by MR spectroscopy for at quantification are its ability to determine the absolute liver fat concentration and its high sensitivity for detecting small amounts of hepatic triglyceride and subtle changes in hepatic triglyceride content during treatment. It is also useful for revealing a necroinflammatory response in the setting of chronic liver disease (25). However, MR spectroscopy is not widely used for these purposes. Spectral analysis methods are complex, and their complexity may lead to variability in results. The results also may vary because of differences in MR systems and acquisition parameters and because fat quantification is performed in a small volume of liver tissue.
Transplantation
3. 4. 5. 6.
7. 8. 9.
USEFULNESS OF LIVER BIOPSY The use of liver biopsy remains the gold standard in determining the degree of steatosis. Some centers have even suggested routine liver biopsy for donor selection. Histopathologic analysis, in addition to providing means for grading the severity of steatosis, facilitates differentiation between steatosis and steatohepatitis (26). It helps not only confirm the diagnosis of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis but also detect clinically unsuspected processes that coexist with or mimic fatty liver disease, such as viral hepatitis (particularly that caused by chronic hepatitis C infection) (26). Despite these benefits, biopsy is an invasive technique and is fraught with potential morbidity and complications. However, lack of homogeneity in fat distribution raises the question of whether a single biopsy specimen can accurately assess steatosis. Furthermore, because hepatic steatosis is a dynamic process, monitoring progression or improvement in the disease status over time with frequent biopsy is impracticable. In our center, liver biopsy is performed only if the US or CT scan findings suggest hepatic steatosis.
CONCLUSION Imaging is not only noninvasive but also permits concomitant screening for other liver abnormalities; the entire liver can be evaluated with all modalities. In addition, imaging allows both qualitative and quantitative assessment of fat content. Ultrasound and computed tomography can be used to assess liver fat but have limited accuracy as well as other limitations. Magnetic resonance techniques can decompose the liver signal into its fat and water signal components and therefore assess liver fat more directly than CT or US. These advanced techniques show promise for accurate fat quantification and are likely to be commercially available soon. Future studies should aim at improving the sensitivity of imaging techniques in the diagnosis of steatosis.
10. 11. 12.
13. 14. 15. 16.
17. 18. 19. 20. 21.
22.
23. 24.
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Chen YS, Cheng YF, De Villa VH, et al. Evaluation of living liver donors. Transplantation 2003; 75: S16. Perez-Daga JA, Santoyo J, Suarez MA, et al. Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation. Transplant Proc 2006; 38: 2468.
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