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Predicting Hepatic Steatosis in Living Liver Donors Via Controlled Attenuation Parameter
Predicting Hepatic Steatosis in Living Liver Donors Via Controlled Attenuation Parameter Y.H. Yena, F.Y. Kuob, C.C. Linc, C.L. Chenc, K.C. Changa, M.C. Tsaia, and T.H. Hua,* a
Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; bDepartment of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; and cLiver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
ABSTRACT Background. Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography. Aim. To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation. Methods. A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in >5% of hepatocytes. Results. No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91e1; P < .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP <257 dB/m, none had HS, while of the 12 candidates with CAP 257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (b ¼ 0.71, P < .001) was found to be independently associated with CAP in those without HS. Conclusions. CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.
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ONTINUOUS efforts to develop sophisticated medical teams and refine surgical techniques have greatly contributed to an increase in the availability of living donor liver transplantation (LDLT) [1e4]. In Asia, where the number of deceased donor liver transplants performed is small, the number of living donor liver transplants performed is increasing [1,2]. Among living liver donors, a residual liver with a fat content of less than 5% shows better regeneration than one with a fat content of 5% to 30%. This statistic showed the important effect of hepatic steatosis (HS) on the functional recovery of the liver. Furthermore, as the amount of donor steatosis increases from mild to moderate (30%e60%) to ª 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 230 Park Avenue, New York, NY 10169 Transplantation Proceedings, 50, 3533e3538 (2018)
severe (>60%), the possibility of renal failure and hepatic dysfunction in the recipient progressive increases [5]. The rate of ischemia-reperfusion injury and early mortality are
This study was supported by Grant CMRPG8E1301 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. *Address correspondence to Tsung-Hui Hu, Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan. Tel: þ886-7-7317123, Fax: þ8867-7322402. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.06.039
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also increased significantly in recipients of liver transplants with severe steatosis [5]. The quantitative assessment of hepatic fatty infiltration is, therefore, important in the evaluation of potential donors for LDLT. To date, there is no consensus regarding how to assess steatosis in potential liver donors. Preoperative percutaneous liver biopsy is the criterion standard. However, this procedure is accompanied by pain, potential complications, and sampling error [6,7]. The acuity of ultrasonography (US), another means of assessing liver steatosis, decreases dramatically for mild steatosis. In a study on 100 living donors for liver transplant, US could not detect steatosis when it was present in less than 10% of hepatocytes and was only capable of identifying 55% and 72% of patients with steatosis levels of 10% to 19% and 20% to 29%, respectively [8]. Computed tomography (CT) has also been used for preoperative evaluations of the fat content of donor livers. It has high diagnostic accuracy and high specificity for detecting steatosis of more than 30% in potential LDLT donors [9]. However, although there have been continuous advances in CT technology in recent years, there is still a paucity of literature validating the use of CT for the quantitative assessment of liver steatosis, particularly for lowergrade liver steatosis [10]. Magnetic resonance methods, especially magnetic resonance spectroscopy (MRS), in which the proton signals from the acyl groups in hepatocyte triglyceride stores are directly measured, have shown incredible accuracy in diagnosing and quantifying steatosis [11,12]. A recent metaanalysis reported that 1H-MRS shows high sensitivity and specificity for the detection of HS in living liver donors, especially when HS is substantial (>10%) [13]. The controlled attenuation parameter (CAP) is a technology used to measure the degree of US attenuation by hepatic fat at the central frequency of the FibroScan (Echosens, Paris, France) [14]. A recent meta-analysis showed that CAP has good sensitivity and specificity for detecting HS [15]. To date, however, only a limited number of studies have reported on the potential role of CAP in assessing steatosis in potential liver donors [16e18]. The aim of this study, therefore, was to evaluate the accuracy of CAP for the quantitative estimation of hepatic fat content in living liver donors.
YEN, KUO, LIN ET AL The requirement for informed consent was waived by the IRB. The data were analyzed anonymously.
Liver Stiffness and CAP Measurements Liver stiffness measurements (LSM) and CAP measurements were performed by FibroScan (Echosens) by 2 experienced operators, both of whom had more than 2 years of experience and had performed more than 5000 FibroScan examinations. All patients were measured using the 3.5 MHz standard M probe. The final LSM result was expressed in kPa and was the median value of 10 measurements. Only results with 10 valid shots and an interquartile range (IQR)/median LSM ratio < 30% were included. CAP has been designed to measure liver ultrasonic attenuation at 3.5 MHz on the signals acquired by the FibroScan. A given CAP value was computed only when the associated LSM was valid and using the same signals as the one used to measure LSM. Therefore, both the LSM and CAP value were obtained simultaneously. The final CAP value was the median of individual CAP values and was expressed in dB/m.
Computed Tomography The CT criteria for steatosis on nonintravenous contrast scans included the following: an absolute liver attenuation of less than 40 Hounsfield units (HU), a liver-to-spleen attenuation ratio of less than 1, and a liver attenuation 10 HU less than that of the spleen attenuation [19,20]. The CT criteria for steatosis with intravenous contrast in the venous phase included a liver attenuation 20 HU less than that of the spleen attenuation [21]. The final liver attenuation value was the mean of 4 measurements in areas 5 and 6. The final spleen attenuation value was the mean of a posterior and an anterior measurement [19].
Ultrasonography Predefined criteria were used to determine the severity of HS. These included the presence of bright echoes or increased hepatorenal contrast for steatosis grade 1 (S1) (mild steatosis); the presence of both bright echoes and increased hepatorenal contrast as well as vessel blurring for steatosis grade 2 (S2) (moderate steatosis); and the presence of posterior beam attenuation and nonvisualization of the diaphragm in addition to the criteria for S2 for steatosis grade 3 (S3) (severe steatosis). The liver image was assessed to be normal if the texture was homogenous, fine level echoes were seen, the area was isoechoic compared with the renal cortex, and the hepatic vessels and diaphragm were adequately visualized (steatosis grade 0 [S0]) [22].
Biological Parameters MATERIALS AND METHODS Patients From March 2013 to October 2016, 107 healthy living liver donors underwent examinations for living donors liver transplant. Among these potential donors, 54 living donors received surgery and were enrolled. All examinations were performed within 1 month before surgery. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. This retrospective study was approved by the human research committee of Kaohsiung Chang Gung Memorial Hospital, Taiwan (IRB number: 201601367B0).
The same day the image examinations were performed, the following clinical parameters were also recorded: age, sex, body mass index (BMI), fasting lipid profile, fasting sugar level, HBsAg, anti-HCV, liver function tests, complete blood count, and creatinine level.
Donor Biopsy Zero-hour biopsy specimens were obtained by wedge resection during surgery. Histologic grading of macrovesicular steatosis was performed by 2 experienced pathologists. HS was defined by the presence of steatosis in >5% of hepatocytes [23].
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Statistical Analysis The baseline characteristics were calculated in terms of mean (SD) or median (IQR). A univariate and multivariate linear regression model was used to determine the factors influencing the CAP values for those donors without HS. Receiver operating characteristic curve analysis was used to evaluate HS using CAP. The value of the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value were calculated. A P value <.05 was considered statistically significant. Statistical analyses were performed using Stata software, version 11.0.
RESULTS Study Population Characteristics
The characteristics of the 54 donor are shown in Table 1. All the donor candidates were negative for HBsAg and antiHCV. All the liver donors were in good general health and had good liver health. Ten valid shots and an IQR/median liver stiffness ratio <30% in the FibroScan examination were obtained for all the donors. Thirty-one of the donors were male and 23 were female. Their ages ranged from 18 to 54 years, with a mean age of 32 years. Their BMIs ranged from 16.3 to 33.2 kg/m2, with a mean value of 24.0 kg/m2. The liver biopsy results showed no HS in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Diagnostic Performance of CAP for HS
Using CAP, the AUROC was 0.96 (95% CI, 0.91w1.0; P < .001) for the presence of HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%) (Fig 1). Among the 42 candidates with CAP <257 dB/m, none had HS, while among the 12 candidates with CAP 257 dB/m, 7 had HS. Associations Between Clinical and Demographic Parameters and CAP Values in Donors Without HS
In a multivariate linear regression analysis, BMI (b ¼ 0.71, P < .001) was found to be independently associated with CAP values (Table 2). Table 1. Clinical Characteristics of Donors Variables
Age, mean (SD), y Sex, No. (%) male BMI, mean (SD), kg/m2 AST, mean (SD), IU/L ALT, mean (SD), IU/L Bilirubin, mean (SD), mg/dL Glucose, mean (SD), mg/dL Cholesterol, mean (SD), mg/dL Triglyceride >150 mg/dL, No. (%) LSM, median (IQR), kPa CAP, median (IQR), dB/m Steatosis >5%, No. (%)
31.7 31 24.0 19.5 20.5 0.6 89.8 165.5 5 4 227 7
(8.3) (57.4) (4.2) (6.0) (15.1) (0.3) (8.5) (29.0) (9.3) (3.6e4.6) (205e253) (13.0)
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; IQR, interquartile range; LSM, liver stiffness measurements.
Fig 1. Receiver-operating characteristic (ROC) curves and area under the ROC curve (AUROC) for the detection of hepatic steatosis using controlled attenuation parameter.
Diagnostic Performance of US and CT for HS
Using US, the AUROC was 0.733 (0.530e0.935) for the presence of HS (sensitivity: 57.14%, specificity: 89.36%, positive predictive value: 44.44%, negative predictive value: 93.33%). Among the 9 candidates with US-identified HS, 4 (44.4%) had histologically defined HS. Among the 45 candidates without US-identified HS, 42 (93.3%) did not have histologically defined HS. Using CT, the AUROC was 0.865 (0.717e1.000) for the presence of HS (sensitivity: 85.71%, specificity: 87.23%, positive predictive value: 50.00%, negative predictive value: 97.62%). Among the 12 candidates with CT-identified HS, 6 (50%) had histologically defined HS. Among the 43 candidates without CT-identified HS, 42 (97.62%) did not have histologically defined HS. DISCUSSION
In previous studies, fatty liver grafts have been reported to be associated with poor graft function or primary nonfunction, resulting in poor graft survival [24e26]. The acceptable level of HS in living donors varies depending on the transplant Table 2. Factors Influencing Controlled Attenuation Parameter Values Using Univariate and Multivariate Linear Regression Analysis in Those Without HS Univariate
Multivariate
Variables
b
P
b
P
Age, y Male BMI, kg/m2 AST, IU/L ALT, IU/L Bilirubin, mg/dL Glucose, mg/dL Cholesterol, mg/dL Triglyceride, mg/dL LSM, kPa
0.17 0.09 0.74 0.23 0.27 0.09 0.13 0.42 0.14 0.35
.25 .56 <.001 .13 .07 .53 .39 .003 .34 .02
0.12 0.20 0.71 0.26 0.15 0.11 0.13 0.09 0.12 0.17
.39 .23 <.001 .29 .52 .40 .37 .59 .42 .19
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI: body mass index; HS, hepatic steatosis; LSM, liver stiffness measurements.
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program. Most transplantation centers do not perform transplants using donor livers with HS or carefully select donors with low levels of HS [27]. There is, however, no consensus on the acceptable degree of steatosis for live liver donation; some centers only use livers with an HS level of less than 10%, whereas others allow the use of livers with an HS level as high as 30% for selected graft types [28e30]. In our hospital, we only use graft livers with an HS level of less than 10%. Noninvasive studies, such as BMI, US, or CT scans are only sensitive enough to predict moderate to severe HS [31e33]. Therefore, these modalities are not suitable for transplantation centers that only use livers with a low level of HS (<10%) for grafts, such as our hospital. Our results also showed that the diagnostic accuracy levels of US and CT are inferior to the diagnostic accuracy of CAP. MRS is the most accurate noninvasive measure of steatosis [34,35]. A recent meta-analysis reported that MRS shows high sensitivity and specificity for the detection of HS, especially when HS is substantial (>10%) [13]. However, MRS also shows sampling errors due to the heterogeneity of steatosis in liver biopsy specimens [36]. CAP has some advantages over other methods of measurement such as being noninvasive, nonionizing, quantitative, inexpensive, and easy to perform. Several reports have suggested cutoff CAP values for determining the presence of HS (either > 5% or > 10% of hepatic fat depending on the study) in patients with chronic liver disease (CLD) of various etiologies [14,37e43]. However, those values were mostly assessed in patients with CLD, while those for healthy living liver donors have only been investigated in a few studies [16,17]. In this study, we found that the optimal cutoff CAP value for the diagnosis of HS is 257 dB/m, as this cutoff had a high negative predictive value (100%). In a multivariate linear regression analysis, BMI (b ¼ 0.71, P < .001) was found to be independently associated with CAP values in those without HS in our study. A previous study measured CAP values in a cohort of healthy subjects who were screened as living liver transplant donors and other subjects who underwent health checkups. Subjects with current CLD or a history of CLD, abnormalities on liver-related laboratory tests, or fatty liver on US or biopsy were excluded. A total of 76 potential liver donors and 188 subjects who had undergone health checkups were included in the analysis. The normal range of CAP values was from 174.5 to 266.3 dB/m in the potential liver donors [16], which was compatible with the results of the present study. In a multivariate linear regression analysis, both BMI and triglyceride levels were found to be independently associated with CAP values in this cohort [15]. In contrast, only BMI was found to be independently associated with CAP values in those without HS in our study. This discrepancy between the previous study and our study may be because of the fact that the previous study enrolled subjects who had undergone health checkups, with no liver biopsies having been performed in these subjects. For these subjects, any diagnosis of steatosis was made by US.
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However, US has limited sensitivity and does not reliably detect steatosis of <20% [44,45], which could explain the discrepancy between the 2 studies. Recently, a meta-analysis of CAP data for individual patients was published [46]. That analysis established a CAP cutoff value of 248 dB/m for the presence of steatosis and found that the CAP values were influenced by several covariates, including nonalcoholic fatty liver disease status, diabetes status, and BMI. The authors of the study thus suggested deducting 10 dB/m from the CAP value for patients with nonalcoholic fatty liver disease. In this study, the optimal cutoff CAP value for the diagnosis of HS was found to be 257 dB/m. After deducting 10 dB/m from that cutoff CAP value, the resulting cutoff value for diagnosing the presence of steatosis would be compatible with that reported by the aforementioned meta-analysis [46]. The present study has some limitations. First, our study population of 54 living liver donors was relatively small. Second, the study population included a large portion of donors with normal BMI, while a significant number of patients were excluded predominantly based on US or CT evaluation results. Potential liver donors with a high level of steatosis were excluded, and only 7 patients (13.0%) with HS were included. Therefore, the study population consisted of selected candidates. Third, it should be noted that we are only suggesting an optimized CAP cutoff value for HS in an East Asian population, because Western populations have, on average, a higher BMI, which was independently associated with the CAP value, than East Asians [43]. The normal CAP values in Western populations should thus be determined separately. Fourth, although this study was a retrospective study, there were no missing data because the data were collected through routine clinical examinations for living liver donors in our center. Fifth, although fatty liver grafts have previously been reported to be associated with poor graft function or primary nonfunction, resulting in poor graft survival [24e26], we did not follow up the participants in the present study to see if CAP could be used as a predictor of post liver transplant outcomes. CONCLUSIONS
In summary, our results suggest that CAP might be a promising tool to exclude HS in East Asian living liver donors, with preoperative percutaneous liver biopsies reserved only for those with CAP 257dB/m. We also found that BMI was associated with CAP values in those without HS. A future study involving a greater number of cases will be required, however, in order to confirm whether or not CAP can effectively screen East Asian living liver donors and identify subpopulations at high risk of HS. REFERENCES [1] Chen CL, Fan ST, Lee SG, Makuuchi M, Tanaka K. Livingdonor liver transplantation: 12 years of experience in Asia. Transplantation 2003;75:S6e11.
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[2] Sugawara Y, Makuuchi M. Advances in adult living donor liver transplantation: a review based on reports from the 10th anniversary of the adult-to-adult living donor liver transplantation meeting in Tokyo. Liver Transpl 2004;10:715e20. [3] Freeman Jr RB, Steffick DE, Guidinger MK, Farmer DG, Berg CL, Merion RM. Liver and intestine transplantation in the United States, 1997-2006. Am J Transplant 2008;8:958e76. [4] Settmacher U, Theruvath T, Pascher A, Neuhaus P. Livingdonor liver transplantationdEuropean experiences. Nephrol Dial Transplant 2004;19(Suppl. 4):iv16e21. [5] Perez-Daga JA, Santoyo J, Suárez MA, et al. Influence of degree of hepatic steatosis on graft function and postoperative complications of liver transplantation. Transplant Proc 2006;38: 2468e70. [6] Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2:165e73. [7] Gunneson TJ, Menon KV, Wiesner RH, et al. Ultrasoundassisted percutaneous liver biopsy performed by a physician assistant. Am J Gastroenterol 2002;97:1472e5. [8] Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002;8:1114e22. [9] 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;244:479e85. [10] van Werven JR, Marsman HA, Nederveen AJ, et al. Assessment of hepatic steatosis in patients undergoing liver resection: comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1HMR spectroscopy. Radiology 2010;256:159e68. [11] Fierbinteanu-Braticevici C, Dina I, Petrisor A, Tribus L, Negreanu L, Carstoiu C. Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis. World J Gastroenterol 2010;16:4784e91. [12] Chiang HJ, Chang WP, Chiang HW, et al. Magnetic resonance spectroscopy in living-donor liver transplantation. Transplant Proc 2016;48:1003e6. [13] Zheng D, Guo Z, Schroder PM, et al. Accuracy of MR imaging and MR spectroscopy for detection and quantification of hepatic steatosis in living liver donors: a meta-analysis. Radiology 2017;282:92e102. [14] Sasso M, Beaugrand M, de Ledinghen V, et al. Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol 2010;36: 1825e35. [15] Shi KQ, Tang JZ, Zhu XL, et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy. J Gastroenterol Hepatol 2014;29:1149e58. [16] Chon YE, Jung KS, Kim KJ, et al. Normal controlled attenuation parameter values: a prospective study of healthy subjects undergoing health checkups and liver donors in Korea. Dig Dis Sci 2015;60:234e42. [17] Kim JM, Ha SY, Joh JW, et al. Predicting hepatic steatosis in living liver donors via noninvasive methods. Medicine (Baltimore) 2016;95:e2718. [18] Mancia C, Loustaud-Ratti V, Carrier P, et al. Controlled attenuation parameter and liver stiffness measurements for steatosis assessment in the liver transplant of brain dead donors. Transplantation 2015;99:1619e24. [19] Dendl LM, Schreyer AG. Steatohepatitis–a challenge? Radiologe 2012;52:745e52 [in German]. [20] Lawrence DA, Oliva IB, Israel GM. Detection of hepatic steatosis on contrast-enhanced CT images: diagnostic accuracy of identification of areas of presumed focal fatty sparing. AJR Am J Roentgenol 2012;199:44e7.
[21] Jacobs JE, Birnbaum BA, Shapiro MA, et al. Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. AJR Am J Roentgenol 1998;171:659e64. [22] Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, Mc-Cullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol 2009;51:1061e7. [23] European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASLEASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388e402. [24] Imber CJ, St Peter SD, Handa A, Friend PJ. Hepatic steatosis and its relationship to transplantation. Liver Transpl 2002;8:415e23. [25] Todo S, Demetris AJ, Makowka L, et al. Primary nonfunction of hepatic allografts with preexisting fatty infiltration. Transplantation 1989;47:903e5. [26] Verran D, Kusyk T, Painter D, et al. Clinical experience gained from the use of 120 steatotic donor livers for orthotopic liver transplantation. Liver Transpl 2003;9:500e5. [27] Brown Jr RS, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med 2003;348:818e25. [28] Trotter JF, Campsen J, Bak T, et al. Outcomes of donor evaluations for adult-to-adult right hepatic lobe living donor liver transplantation. Am J Transplant 2006;6:1882e9. [29] Valentín-Gamazo C, Malagó M, Karliova M, et al. Experience after the evaluation of 700 potential donors for living donor liver transplantation in a single center. Liver Transpl 2004;10: 1087e96. [30] Hwang S, Lee SG, Lee YJ, et al. Lessons learned from 1000 living donor liver transplantations in a single center: how to make living donation safe. Liver Transpl 2006;12:920e7. [31] Iwasaki M, Takada Y, Hayashi M, et al. Noninvasive evaluation of graft steatosis in living donor liver transplantation. Transplantation 2004;78:1501e5. [32] 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;23:105e12. [33] Lee JY, Kim KM, Lee SG, et al. Prevalence and risk factors of nonalcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47:239e44. [34] Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol 2009;51:433e45. [35] McPherson S, Jonsson JR, Cowin GJ, et al. Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered. J Hepatol 2009;51:389e97. [36] Hines CD, Frydrychowicz A, Hamilton G, et al. T(1) independent, T(2) (*) corrected chemical shift based fat-water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis. J Magn Reson Imaging 2011;33:873e81. [37] Wang CY, Lu W, Hu DS, Wang GD, Cheng XJ. Diagnostic value of controlled attenuation parameter for liver steatosis in patients with chronic hepatitis B. World J Gastroenterol 2014;20: 10585e90. [38] Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2014;29:1470e6. [39] Kumar M, Rastogi A, Singh T, et al. Controlled attenuation parameter for non-invasive assessment of hepatic steatosis: does etiology affect performance? J Gastroenterol Hepatol 2013;28: 1194e201.
3538 [40] Jung KS, Kim BK, Kim SU, et al. Factors affecting the accuracy of controlled attenuation parameter (CAP) in assessing hepatic steatosis in patients with chronic liver disease. PLoS One 2014;9:e98689. [41] de Lédinghen V, Vergniol J, Foucher J, Merrouche W, le Bail B. Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liver Int 2012;32:911e8. [42] Chon YE, Jung KS, Kim SU, et al. Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population. Liver Int 2014;34:102e9.
YEN, KUO, LIN ET AL [43] Ferraioli G, Tinelli C, Lissandrin R, et al. Controlled attenuation parameter for evaluating liver steatosis in chronic viral hepatitis. World J Gastroenterol 2014;20:6626e31. [44] Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745e50. [45] Fishbein M, Castro F, Cheruku S, et al. Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol 2005;39:619e25. [46] Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol 2017;66:1022e30.
Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; bDepartment of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; and cLiver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
ABSTRACT Background. Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography. Aim. To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation. Methods. A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in >5% of hepatocytes. Results. No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91e1; P < .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP <257 dB/m, none had HS, while of the 12 candidates with CAP 257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (b ¼ 0.71, P < .001) was found to be independently associated with CAP in those without HS. Conclusions. CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.
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ONTINUOUS efforts to develop sophisticated medical teams and refine surgical techniques have greatly contributed to an increase in the availability of living donor liver transplantation (LDLT) [1e4]. In Asia, where the number of deceased donor liver transplants performed is small, the number of living donor liver transplants performed is increasing [1,2]. Among living liver donors, a residual liver with a fat content of less than 5% shows better regeneration than one with a fat content of 5% to 30%. This statistic showed the important effect of hepatic steatosis (HS) on the functional recovery of the liver. Furthermore, as the amount of donor steatosis increases from mild to moderate (30%e60%) to ª 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 230 Park Avenue, New York, NY 10169 Transplantation Proceedings, 50, 3533e3538 (2018)
severe (>60%), the possibility of renal failure and hepatic dysfunction in the recipient progressive increases [5]. The rate of ischemia-reperfusion injury and early mortality are
This study was supported by Grant CMRPG8E1301 from the Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan. *Address correspondence to Tsung-Hui Hu, Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung Dist. 833, Kaohsiung City, Taiwan. Tel: þ886-7-7317123, Fax: þ8867-7322402. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.06.039
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also increased significantly in recipients of liver transplants with severe steatosis [5]. The quantitative assessment of hepatic fatty infiltration is, therefore, important in the evaluation of potential donors for LDLT. To date, there is no consensus regarding how to assess steatosis in potential liver donors. Preoperative percutaneous liver biopsy is the criterion standard. However, this procedure is accompanied by pain, potential complications, and sampling error [6,7]. The acuity of ultrasonography (US), another means of assessing liver steatosis, decreases dramatically for mild steatosis. In a study on 100 living donors for liver transplant, US could not detect steatosis when it was present in less than 10% of hepatocytes and was only capable of identifying 55% and 72% of patients with steatosis levels of 10% to 19% and 20% to 29%, respectively [8]. Computed tomography (CT) has also been used for preoperative evaluations of the fat content of donor livers. It has high diagnostic accuracy and high specificity for detecting steatosis of more than 30% in potential LDLT donors [9]. However, although there have been continuous advances in CT technology in recent years, there is still a paucity of literature validating the use of CT for the quantitative assessment of liver steatosis, particularly for lowergrade liver steatosis [10]. Magnetic resonance methods, especially magnetic resonance spectroscopy (MRS), in which the proton signals from the acyl groups in hepatocyte triglyceride stores are directly measured, have shown incredible accuracy in diagnosing and quantifying steatosis [11,12]. A recent metaanalysis reported that 1H-MRS shows high sensitivity and specificity for the detection of HS in living liver donors, especially when HS is substantial (>10%) [13]. The controlled attenuation parameter (CAP) is a technology used to measure the degree of US attenuation by hepatic fat at the central frequency of the FibroScan (Echosens, Paris, France) [14]. A recent meta-analysis showed that CAP has good sensitivity and specificity for detecting HS [15]. To date, however, only a limited number of studies have reported on the potential role of CAP in assessing steatosis in potential liver donors [16e18]. The aim of this study, therefore, was to evaluate the accuracy of CAP for the quantitative estimation of hepatic fat content in living liver donors.
YEN, KUO, LIN ET AL The requirement for informed consent was waived by the IRB. The data were analyzed anonymously.
Liver Stiffness and CAP Measurements Liver stiffness measurements (LSM) and CAP measurements were performed by FibroScan (Echosens) by 2 experienced operators, both of whom had more than 2 years of experience and had performed more than 5000 FibroScan examinations. All patients were measured using the 3.5 MHz standard M probe. The final LSM result was expressed in kPa and was the median value of 10 measurements. Only results with 10 valid shots and an interquartile range (IQR)/median LSM ratio < 30% were included. CAP has been designed to measure liver ultrasonic attenuation at 3.5 MHz on the signals acquired by the FibroScan. A given CAP value was computed only when the associated LSM was valid and using the same signals as the one used to measure LSM. Therefore, both the LSM and CAP value were obtained simultaneously. The final CAP value was the median of individual CAP values and was expressed in dB/m.
Computed Tomography The CT criteria for steatosis on nonintravenous contrast scans included the following: an absolute liver attenuation of less than 40 Hounsfield units (HU), a liver-to-spleen attenuation ratio of less than 1, and a liver attenuation 10 HU less than that of the spleen attenuation [19,20]. The CT criteria for steatosis with intravenous contrast in the venous phase included a liver attenuation 20 HU less than that of the spleen attenuation [21]. The final liver attenuation value was the mean of 4 measurements in areas 5 and 6. The final spleen attenuation value was the mean of a posterior and an anterior measurement [19].
Ultrasonography Predefined criteria were used to determine the severity of HS. These included the presence of bright echoes or increased hepatorenal contrast for steatosis grade 1 (S1) (mild steatosis); the presence of both bright echoes and increased hepatorenal contrast as well as vessel blurring for steatosis grade 2 (S2) (moderate steatosis); and the presence of posterior beam attenuation and nonvisualization of the diaphragm in addition to the criteria for S2 for steatosis grade 3 (S3) (severe steatosis). The liver image was assessed to be normal if the texture was homogenous, fine level echoes were seen, the area was isoechoic compared with the renal cortex, and the hepatic vessels and diaphragm were adequately visualized (steatosis grade 0 [S0]) [22].
Biological Parameters MATERIALS AND METHODS Patients From March 2013 to October 2016, 107 healthy living liver donors underwent examinations for living donors liver transplant. Among these potential donors, 54 living donors received surgery and were enrolled. All examinations were performed within 1 month before surgery. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. This retrospective study was approved by the human research committee of Kaohsiung Chang Gung Memorial Hospital, Taiwan (IRB number: 201601367B0).
The same day the image examinations were performed, the following clinical parameters were also recorded: age, sex, body mass index (BMI), fasting lipid profile, fasting sugar level, HBsAg, anti-HCV, liver function tests, complete blood count, and creatinine level.
Donor Biopsy Zero-hour biopsy specimens were obtained by wedge resection during surgery. Histologic grading of macrovesicular steatosis was performed by 2 experienced pathologists. HS was defined by the presence of steatosis in >5% of hepatocytes [23].
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Statistical Analysis The baseline characteristics were calculated in terms of mean (SD) or median (IQR). A univariate and multivariate linear regression model was used to determine the factors influencing the CAP values for those donors without HS. Receiver operating characteristic curve analysis was used to evaluate HS using CAP. The value of the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value were calculated. A P value <.05 was considered statistically significant. Statistical analyses were performed using Stata software, version 11.0.
RESULTS Study Population Characteristics
The characteristics of the 54 donor are shown in Table 1. All the donor candidates were negative for HBsAg and antiHCV. All the liver donors were in good general health and had good liver health. Ten valid shots and an IQR/median liver stiffness ratio <30% in the FibroScan examination were obtained for all the donors. Thirty-one of the donors were male and 23 were female. Their ages ranged from 18 to 54 years, with a mean age of 32 years. Their BMIs ranged from 16.3 to 33.2 kg/m2, with a mean value of 24.0 kg/m2. The liver biopsy results showed no HS in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Diagnostic Performance of CAP for HS
Using CAP, the AUROC was 0.96 (95% CI, 0.91w1.0; P < .001) for the presence of HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%) (Fig 1). Among the 42 candidates with CAP <257 dB/m, none had HS, while among the 12 candidates with CAP 257 dB/m, 7 had HS. Associations Between Clinical and Demographic Parameters and CAP Values in Donors Without HS
In a multivariate linear regression analysis, BMI (b ¼ 0.71, P < .001) was found to be independently associated with CAP values (Table 2). Table 1. Clinical Characteristics of Donors Variables
Age, mean (SD), y Sex, No. (%) male BMI, mean (SD), kg/m2 AST, mean (SD), IU/L ALT, mean (SD), IU/L Bilirubin, mean (SD), mg/dL Glucose, mean (SD), mg/dL Cholesterol, mean (SD), mg/dL Triglyceride >150 mg/dL, No. (%) LSM, median (IQR), kPa CAP, median (IQR), dB/m Steatosis >5%, No. (%)
31.7 31 24.0 19.5 20.5 0.6 89.8 165.5 5 4 227 7
(8.3) (57.4) (4.2) (6.0) (15.1) (0.3) (8.5) (29.0) (9.3) (3.6e4.6) (205e253) (13.0)
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; IQR, interquartile range; LSM, liver stiffness measurements.
Fig 1. Receiver-operating characteristic (ROC) curves and area under the ROC curve (AUROC) for the detection of hepatic steatosis using controlled attenuation parameter.
Diagnostic Performance of US and CT for HS
Using US, the AUROC was 0.733 (0.530e0.935) for the presence of HS (sensitivity: 57.14%, specificity: 89.36%, positive predictive value: 44.44%, negative predictive value: 93.33%). Among the 9 candidates with US-identified HS, 4 (44.4%) had histologically defined HS. Among the 45 candidates without US-identified HS, 42 (93.3%) did not have histologically defined HS. Using CT, the AUROC was 0.865 (0.717e1.000) for the presence of HS (sensitivity: 85.71%, specificity: 87.23%, positive predictive value: 50.00%, negative predictive value: 97.62%). Among the 12 candidates with CT-identified HS, 6 (50%) had histologically defined HS. Among the 43 candidates without CT-identified HS, 42 (97.62%) did not have histologically defined HS. DISCUSSION
In previous studies, fatty liver grafts have been reported to be associated with poor graft function or primary nonfunction, resulting in poor graft survival [24e26]. The acceptable level of HS in living donors varies depending on the transplant Table 2. Factors Influencing Controlled Attenuation Parameter Values Using Univariate and Multivariate Linear Regression Analysis in Those Without HS Univariate
Multivariate
Variables
b
P
b
P
Age, y Male BMI, kg/m2 AST, IU/L ALT, IU/L Bilirubin, mg/dL Glucose, mg/dL Cholesterol, mg/dL Triglyceride, mg/dL LSM, kPa
0.17 0.09 0.74 0.23 0.27 0.09 0.13 0.42 0.14 0.35
.25 .56 <.001 .13 .07 .53 .39 .003 .34 .02
0.12 0.20 0.71 0.26 0.15 0.11 0.13 0.09 0.12 0.17
.39 .23 <.001 .29 .52 .40 .37 .59 .42 .19
Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI: body mass index; HS, hepatic steatosis; LSM, liver stiffness measurements.
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program. Most transplantation centers do not perform transplants using donor livers with HS or carefully select donors with low levels of HS [27]. There is, however, no consensus on the acceptable degree of steatosis for live liver donation; some centers only use livers with an HS level of less than 10%, whereas others allow the use of livers with an HS level as high as 30% for selected graft types [28e30]. In our hospital, we only use graft livers with an HS level of less than 10%. Noninvasive studies, such as BMI, US, or CT scans are only sensitive enough to predict moderate to severe HS [31e33]. Therefore, these modalities are not suitable for transplantation centers that only use livers with a low level of HS (<10%) for grafts, such as our hospital. Our results also showed that the diagnostic accuracy levels of US and CT are inferior to the diagnostic accuracy of CAP. MRS is the most accurate noninvasive measure of steatosis [34,35]. A recent meta-analysis reported that MRS shows high sensitivity and specificity for the detection of HS, especially when HS is substantial (>10%) [13]. However, MRS also shows sampling errors due to the heterogeneity of steatosis in liver biopsy specimens [36]. CAP has some advantages over other methods of measurement such as being noninvasive, nonionizing, quantitative, inexpensive, and easy to perform. Several reports have suggested cutoff CAP values for determining the presence of HS (either > 5% or > 10% of hepatic fat depending on the study) in patients with chronic liver disease (CLD) of various etiologies [14,37e43]. However, those values were mostly assessed in patients with CLD, while those for healthy living liver donors have only been investigated in a few studies [16,17]. In this study, we found that the optimal cutoff CAP value for the diagnosis of HS is 257 dB/m, as this cutoff had a high negative predictive value (100%). In a multivariate linear regression analysis, BMI (b ¼ 0.71, P < .001) was found to be independently associated with CAP values in those without HS in our study. A previous study measured CAP values in a cohort of healthy subjects who were screened as living liver transplant donors and other subjects who underwent health checkups. Subjects with current CLD or a history of CLD, abnormalities on liver-related laboratory tests, or fatty liver on US or biopsy were excluded. A total of 76 potential liver donors and 188 subjects who had undergone health checkups were included in the analysis. The normal range of CAP values was from 174.5 to 266.3 dB/m in the potential liver donors [16], which was compatible with the results of the present study. In a multivariate linear regression analysis, both BMI and triglyceride levels were found to be independently associated with CAP values in this cohort [15]. In contrast, only BMI was found to be independently associated with CAP values in those without HS in our study. This discrepancy between the previous study and our study may be because of the fact that the previous study enrolled subjects who had undergone health checkups, with no liver biopsies having been performed in these subjects. For these subjects, any diagnosis of steatosis was made by US.
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However, US has limited sensitivity and does not reliably detect steatosis of <20% [44,45], which could explain the discrepancy between the 2 studies. Recently, a meta-analysis of CAP data for individual patients was published [46]. That analysis established a CAP cutoff value of 248 dB/m for the presence of steatosis and found that the CAP values were influenced by several covariates, including nonalcoholic fatty liver disease status, diabetes status, and BMI. The authors of the study thus suggested deducting 10 dB/m from the CAP value for patients with nonalcoholic fatty liver disease. In this study, the optimal cutoff CAP value for the diagnosis of HS was found to be 257 dB/m. After deducting 10 dB/m from that cutoff CAP value, the resulting cutoff value for diagnosing the presence of steatosis would be compatible with that reported by the aforementioned meta-analysis [46]. The present study has some limitations. First, our study population of 54 living liver donors was relatively small. Second, the study population included a large portion of donors with normal BMI, while a significant number of patients were excluded predominantly based on US or CT evaluation results. Potential liver donors with a high level of steatosis were excluded, and only 7 patients (13.0%) with HS were included. Therefore, the study population consisted of selected candidates. Third, it should be noted that we are only suggesting an optimized CAP cutoff value for HS in an East Asian population, because Western populations have, on average, a higher BMI, which was independently associated with the CAP value, than East Asians [43]. The normal CAP values in Western populations should thus be determined separately. Fourth, although this study was a retrospective study, there were no missing data because the data were collected through routine clinical examinations for living liver donors in our center. Fifth, although fatty liver grafts have previously been reported to be associated with poor graft function or primary nonfunction, resulting in poor graft survival [24e26], we did not follow up the participants in the present study to see if CAP could be used as a predictor of post liver transplant outcomes. CONCLUSIONS
In summary, our results suggest that CAP might be a promising tool to exclude HS in East Asian living liver donors, with preoperative percutaneous liver biopsies reserved only for those with CAP 257dB/m. We also found that BMI was associated with CAP values in those without HS. A future study involving a greater number of cases will be required, however, in order to confirm whether or not CAP can effectively screen East Asian living liver donors and identify subpopulations at high risk of HS. REFERENCES [1] Chen CL, Fan ST, Lee SG, Makuuchi M, Tanaka K. Livingdonor liver transplantation: 12 years of experience in Asia. Transplantation 2003;75:S6e11.
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