Background Magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) is a diagnostic modality for liver tumors. Three-dimensional (3D) volumetric analysis systems using EOB-MRI data are used to simulate liver anatomy for surgery. This study was conducted to investigate clinical utility of a 3D volumetric analysis system on EOB-MRI to evaluate liver function. Methods Between August 2014 and December 2015, 181 patients underwent laboratory and radiological exams as standardized preoperative evaluation for liver surgery. The liver-spleen contrast-enhanced ratio (LSR) was measured by a semi-automated 3D volumetric analysis system on EOB-MRI. First, the inter-evaluator variability of the calculated LSR was evaluated. Additionally, a subset of liver surgical specimens was evaluated histologically by using immunohisto- chemical staining. Finally, the correlations between the LSR and grading systems of liver function, laboratory data, or histological ﬁndings were analyzed. Results The inter-evaluator correlation coefﬁcient of the measured LSR was 0.986. The mean LSR was signiﬁcantly correlated with the Child–Pugh score (p = 0.014) and the ALBI score (p \ 0.001). Signiﬁcant correlations were also observed between the LSR and indocyanine green retention rate at 15 min (r = - 0.601, p \ 0.001), between the LSR and liver ﬁbrosis stage (r = - 0.556, p \ 0.001), and between the LSR and liver steatosis grade (r = - 0.396, p \ 0.001). Conclusion The LSR calculated by a 3D volumetric analysis system on EOB-MRI was highly reproducible and was shown to be correlated with liver function parameters and liver histology. These data suggest that this imaging modality can be a reliable tool to evaluate liver function. Keywords Magnetic resonance imaging Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid Three-dimensional volumetric analysis system Liver function Liver steatosis Introduction After major hepatectomy, the reported incidence of liver Electronic supplementary material The online version of this failure is 3–8%, and the reported rate of mortality associ- article (https://doi.org/10.1007/s12072-018-9874-x) contains ated with liver failure is approximately 5% . supplementary material, which is available to authorized users. Department of Pathology and Clinical Laboratory, National & Naoto Gotohda Cancer Center Hospital East, Kashiwa, Japan email@example.com Course of Advanced Clinical Research of Cancer, Juntendo 1 University Graduate School of Medicine, Tokyo, Japan Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwa-no-ha, Kashiwa, Chiba 277-8577, Japan Department of Diagnostic Radiology, National Cancer Center Hospital East, Kashiwa, Japan 123 Hepatology International (2018) 12:368–376 369 Preoperative precise assessment of liver function, extent of were used to analyze the correlations between the LSR and resection, and estimated remnant liver volume is important grading systems of liver function or laboratory data (patient to minimize the risks associated with liver surgery. cohort 2). Finally, a subgroup of all 112 patients who Gadolinium ethoxybenzyl diethylenetriamine pen- underwent liver resection was used to analyze the corre- taacetic acid (Gd-EOB-DTPA) is a liver-speciﬁc magnetic lations between the LSR and histological parameters (pa- resonance imaging (MRI) contrast agent. MRI using Gd- tient cohort 3). The patient ﬂow chart of this study is shown EOB-DTPA (EOB-MRI) is widely used to detect and in Fig. 1. characterize hepatocellular carcinoma or metastatic liver tumors . Gd-EOB-DTPA has a well-known metabolic MRI protocol pathway, and several studies have suggested that EOB- MRI is useful to evaluate liver function [3, 4]. The liver-to- All MRI studies were performed using one of the two 3.0 T spleen signal intensity ratio (LSR) on EOB-MRI has been scanners at our institution (Achieva or Ingenia, Philips used as a parameter to assess liver function [5–8], but the Medical Systems, Amsterdam, Netherlands). Contrast-en- conventional method to measure the LSR using two-di- hanced 3D fat-suppressed T1-weighted images were mensional (2D) regions of interest might be affected by obtained 20 min after intravenous administration of Gd- sampling errors or inter-evaluator variability . EOB-DTPA for hepatobiliary phase imaging, using the In a related ﬁeld, three-dimensional (3D) volumetric following parameters: repetition time (TR) 4 ms, echo time analysis systems are being used to simulate liver anatomy (TE) 2 ms, ﬂip angle 10, slice thickness 4.6 mm, matrix for surgery. Using these systems, inter-evaluator variability size 512 9 512 (Achieva), and TR 3 ms, TE 2 ms, ﬂip is expected to be reduced, as signal intensity from the angle 10, slice thickness 4.6 mm, matrix size 480 9 480 whole liver can be included in a semi-automatic analysis. (Ingenia). Gd-EOB-DTPA was administered at a dose of There have been no previous clinical studies in which the about 0.1 mL/kg, by rapid intravenous bolus injection 3D volumetric analysis system was used to measure the using a power injector (SONIC SHOT GX, NEMOTO- LSR on EOB-MRI. Therefore, the objective of this study KYORINDO, Tokyo, Japan), at a rate of 2 mL/s. was to evaluate the variability of the calculated LSR of EOB-MRI using a 3D volumetric analysis system, and to MRI data analysis investigate the correlations between the LSR and liver function parameters or histological ﬁndings. The LSR was calculated using images from the 20 min- delayed hepatobiliary phase, with the 3D volumetric analysis system SYNAPSE VINCENT (Fujiﬁlm Medical, Materials and methods Tokyo, Japan), by a single investigator (Ma.Ku.), under supervision of an experienced radiologist (T.K.). First, the Patients investigator placed small operator-deﬁned volumes of interest (VOIs), one in the liver and another in the spleen Between August 2014 and December 2015, a total of 304 parenchyma, avoiding vessels and tumors (Fig. 2a). Sec- consecutive patients underwent laboratory and radiological ond, the liver and spleen parenchyma were semi-automat- examinations as preoperative evaluations in consideration ically extracted using the image-processing algorithm of liver surgery at the National Cancer Center Hospital (Fig. 2b). Finally, the LSR was calculated as the average East, Japan. Of the 304 patients, 123 were excluded for the liver parenchyma signal intensity (Fig. 2c) divided by the following reasons: contraindications to EOB-MRI average spleen parenchyma signal intensity. Using the (n = 29), inconsistent MRI acquisition technique (n = 52), patient cohort 1, the variability of the calculated LSR incomplete laboratory data (n = 3), or prior splenectomy among four evaluators (surgeons with 7–11 years of clin- (n = 1). Thirty-eight patients who had undergone portal ical experience) was analyzed. Then, since inclusion of vein embolization were also excluded because the degree extrahepatic parenchymal tissue, such as portal and hepatic of liver enhancement from Gd-EOB-DTPA could depend veins, intrahepatic bile ducts, cysts, and tumors, might considerably on the portal vein ﬂow. affect the average liver signal intensity, these structures The remaining 181 patients who underwent EOB-MRI were subtracted manually by the investigator (Fig. 2e). of the liver using a standardized imaging technique were Additionally, the vascular subtraction LSR (vsLSR) was used for the analysis in this study. Among them, 24 con- calculated, and its correlation with the LSR was analyzed secutive patients who underwent preoperative evaluation using cohort 1 (Fig. 1). from November 2015 to December 2015 were used to examine the variability of the LSR among four different evaluators (patient cohort 1). Then, all the 181 patients 123 370 Hepatology International (2018) 12:368–376 Fig. 1 Flow-diagram describing the patient cohorts in this study. Gd-EOB-DTPA gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid; LSR liver-to-spleen signal intensity ratio Grading systems of liver function and laboratory stained by hematoxylin and eosin (HE), azo carmine ani- line blue (AZAN), and smooth muscle actin (SMA) data (Fig. 3). The specimen slides were scanned using the The following laboratory parameters were obtained preop- NanoZoomer 2.0 system (Hamamatsu Photonics, Hama- matsu, Japan), and morphometric analysis was performed eratively and within a month before or after EOB-MRI were collected from the patients’ medical records: indocyanine using the WinROOF 6.5 image processing software pro- gram (MITANI Corporation, Tokyo, Japan). Histological green retention rate at 15 min (ICGR15), white blood cell count, platelet count, prothrombin activity, and serum levels analyses were performed by a single investigator (Ma.Ku.), under supervision of an experienced pathologist (Mo.Ko.). of hemoglobin, albumin, total bilirubin, aspartate amino- transferase, alanine aminotransferase, and creatinine. Grad- Liver ﬁbrosis was assessed in three ways. First, using HE-stained slides, the ﬁbrosis stage was morphologically ing systems of liver function, such as the Child–Pugh score and the albumin-bilirubin (ALBI) score, were analyzed for categorized by the METAVIR scoring system as follows: F0, no ﬁbrosis; F1, portal ﬁbrosis without septa; F2, few the correlation with the LSR. The Child–Pugh score was graded into A, B, or C, using ﬁve variables, including septa; F3, numerous septa without cirrhosis; F4, cirrhosis bilirubin, albumin, prothrombin, ascites status, and degree of . Second, the ratio of ﬁbrosis (ROF) on AZAN-stained slides (ROFazan) was quantiﬁed using morphometric encephalopathy. The ALBI score was calculated as follows: analysis from a color-detecting algorithm (Fig. 3b), using 0:085 ðalbumin g/lÞþ 0:66 the same technique as reported in a previous study . logðtotal bilirubin lmol/lÞ; Third, the ROF on SMA-stained slides (ROFsma) was and categorized into the following three grades: quantiﬁed in a similar manner (Fig. 3d). Liver steatosis was also assessed in two ways. First, the \ 2:60; ALBI 1; [ 2:06 to 1:39; ALBI 2; steatosis grade was morphologically categorized as in [ 1:39; ALBI 3: Kleiner et al. : grade 0, \ 5%; grade 1, 5–33%; grade 2, 34–66%; grade 3, [ 67%. Second, the ratio of droplet Using patient cohort 2, the correlations between the LSR steatosis (ROS) was quantiﬁed using morphometric anal- and grading systems of liver function or other laboratory ysis from the color-detecting algorithm (Fig. 3f). data were analyzed (Fig. 1). Statistical analysis Histological analysis of the surgical specimen Statistical analyses were performed using JMP (version From the 181 studied patients, 112 patients underwent liver 12.0.10; SAS Institute, Cary, NC). Ebel’s intraclass cor- resection (patient cohort 3) (Fig. 1). Their surgical speci- relation coefﬁcients were used to evaluate the inter-eval- mens of non-tumoral liver tissues were ﬁxed in formalin uator variability of the LSR and the correlation between the and embedded in parafﬁn. Then, 4-lm-thick sections were 123 Hepatology International (2018) 12:368–376 371 Fig. 2 Image analysis using the three-dimensional volumetric system. calculated semi-automatically. d Liver parenchyma extracted before a The investigator placed a small volume of interest (VOI) in the liver subtracting vascular structures. e Liver parenchyma after subtracting parenchyma. b The liver parenchyma was semi-automatically vascular structures, such as portal veins and hepatic veins, and extracted from the initial VOI seed. c The three-dimensional liver intrahepatic bile ducts volume was extracted, and the average liver signal intensity was LSR and vsLSR in patient cohort 1. Correlations between hepatocellular carcinoma in 94 patients (50%), metastatic the LSR and the clinicopathological factors were assessed liver cancer in 76 patients (42%), perihilar cholangiocar- by the standard Pearson’s correlation coefﬁcient or cinoma in ﬁve patients (3%), cholangiocellular carcinoma Spearman’s rank correlation coefﬁcient in patient cohorts 2 in four patients (2%), and other disease in six patients and 3. The correlations between the LSR and ﬁbrosis stage (3%). The primary lesion of metastatic liver cancer was or steatosis grade were evaluated using pairwise compar- colon in 71 patients, stomach in two patients, pancreas in isons with the Mann–Whitney test in patient cohort 3. Two- one patient, lung in one patient, and biliary tract in one sided p values of less than 0.05 were considered indicative patient, respectively. There was an underlying liver infec- of signiﬁcance. tion of the hepatitis C virus in 44 patients (24%) and of the hepatitis B virus in nine patients (5%). Of the 181 patients undergoing EOB-MRI of the liver in this study, 177 Results (97.8%) patients were classiﬁed as having the Child–Pugh grade A and four (2.2%) patients as having the Child–Pugh Patients’ demographics grade B. The median value of ICGR15 was 13.1% (range, 2.9–58.9%). The therapies provided for the liver tumors The median age was 70 (range, 39–90), and 130 (72%) of were as follows: surgical resection in 112 patients (62%), 181 patients were male. The diagnoses were as follows: chemotherapy in 26 patients (14%), radiofrequency 123 372 Hepatology International (2018) 12:368–376 Fig. 3 Areas of ﬁbrosis and steatosis were calculated using morphometric analysis of color- detecting algorithm (WinROOF software, version 6.5; MITANI Corporation, Tokyo, Japan). a Azo carmine aniline blue (AZAN) and c smooth muscle actin (SMA) stain. The AZAN/ SMA-positive area was determined using a color- detecting algorithm and is represented as bright green in b and d. The ratio of ﬁbrosis (ROF) was calculated as the percentage area of the entire ﬁeld and the AZAN/SMA- positive area. Hematoxylin– eosin stain of fatty liver (e). Fat droplets were determined using a color-detecting algorithm and are represented as bright green in image (f). The ratio of steatosis (ROS) was calculated as the percentage area of the entire ﬁeld and the fat droplets area ablation in 11 patients (6%), transcatheter arterial Correlation between the LSR and grading chemoembolization in 13 patients (7%), proton beam systems of liver function (patient cohort 2, radiation therapy in 12 patients (7%), and supportive care n = 181) in seven patients (4%). Correlations between the LSR and grading systems of liver Inter-evaluator variability of the LSR function were summarized in Table 1. The mean LSR was and correlation between the LSR and vsLSR lower in the patients with the Child–Pugh grade B than (patient cohort 1, n = 24) those with the Child–Pugh grade A (1.57 vs 1.97, p = 0.014). The mean LSR was lower in the patients with The intraclass correlation coefﬁcient of the LSR amongst the ALBI score 2 than those with the ALBI score 1 (1.64 vs the four evaluators calculated using the 3D volumetric 2.05, p \ 0.001). analysis system, was 0.986. The intraclass correlation coefﬁcient between the LSR and vsLSR, evaluated by a single investigator, was 0.987. 123 Hepatology International (2018) 12:368–376 373 Table 1 Correlations between the liver-to-spleen ratio (LSR) and aminotransferase (r = - 0.422, p \ 0.001), and alanine grading systems of liver function (patient cohort 2, n = 181) aminotransferase (r = - 0.287, p \ 0.001). n = 181 LSR (mean) p Correlations between the LSR and histological Child–Pugh score findings (patient cohort 3, n = 112) A 177 (97.8%) 1.97 = 0.014 B 4 (2.2%) 1.57 Correlations between the LSR and histological ﬁndings, ALBI score including liver ﬁbrosis and steatosis, are summarized in 1 142 (78.5%) 2.05 \ 0.001 Table 2 and Fig. 4. In terms of liver ﬁbrosis, negative 2 39 (21.5%) 1.64 correlations were observed between the LSR and the METAVIR score (r = - 0.556, p \ 0.001), between the LSR and ROFazan (r = - 0.424, p \ 0.001), and between the LSR and ROFsma (r = - 0.592, p \ 0.001) (Table 2). Correlations between the LSR and laboratory The LSR value was signiﬁcantly greater for ﬁbrosis stages data (patient cohort 2, n = 181) F0 and F1 than for stages F2, F3, or F4 (each pairwise comparison, p \ 0.001) (Fig. 4a). In terms of liver Correlations between the LSR and laboratory data are steatosis, negative correlations were observed between the summarized in Table 2. Positive correlations were LSR and the Kleiner’s grade (r = - 0.396, p \ 0.001) and observed between the LSR and the following parameters: between the LSR and ROS (r = - 0.428, p \ 0.001). The platelet count (r = 0.307, p \ 0.001), serum level of LSR value was signiﬁcantly greater for steatosis grade 0 albumin (r = 0.453, p \ 0.001), and prothrombin activity than for grade 1 (p \ 0.001), grade 2 (p \ 0.001), or grade (r = 0.426, p \ 0.001). Negative correlations were 3 (each pairwise comparison, p = 0.001) (Fig. 4b). observed between the LSR and the following parameters: ICGR15 (r = - 0.601, p \ 0.001) and serum levels of total bilirubin (r = - 0.370, p \ 0.001), aspartate Discussion Table 2 Correlations between the liver-to-spleen ratio (LSR) and In this study, the clinical utility of the LSR, calculated as laboratory data or histological ﬁndings the signal intensity of the liver parenchyma divided by that rp of the spleen on EOB-MRI, was evaluated using a 3D volumetric analysis system. The reproducibility of the Laboratory data (patient cohort 2, n = 181) calculated LSR amongst the different evaluators was very ICGR15 - 0.601 \ 0.001 high. The LSR was shown to be correlated with grading White blood cell 0.067 0.368 systems of liver function, such as the Child–Pugh score and Platelet count 0.307 \ 0.001 the ALBI score. In addition, signiﬁcant correlations Prothrombin activity 0.426 \ 0.001 between the LSR and ICGR15 and between the LSR and Hemoglobin 0.021 0.783 histological ﬁndings of liver ﬁbrosis or steatosis were Albumin 0.453 \ 0.001 observed. This is the ﬁrst report using a 3D volumetric Total bilirubin - 0.370 \ 0.001 analysis system of EOB-MRI to evaluate liver function. Aspartate aminotransferase - 0.422 \ 0.001 Conventionally, signal intensity of the liver parenchyma Alanine aminotransferase - 0.287 \ 0.001 on EOB-MRI has been measured by ROIs arbitrarily Creatinine - 0.116 0.120 selected on a few 2D MRI slices. However, such systems Histological ﬁndings (patient cohort 3, n = 112) might include a certain degree of selection bias of the Liver ﬁbrosis ROIs. On the other hand, 3D volumetric analysis systems, METAVIR score - 0.556 \ 0.001 which extract the entire volume of speciﬁc internal organs ROF (AZAN stain) - 0.424 \ 0.001 based on high-precision image processing algorithm, have ROF (SMA stain) - 0.592 \ 0.001 been introduced in clinical settings in recent years. The Liver steatosis beneﬁts of preoperative simulation of liver anatomy with Kleiner grade - 0.396 \ 0.001 the use of 3D image visualization technologies have been ROS - 0.428 \ 0.001 shown in several papers [13, 14]. Takamoto et al. showed a high correlation between estimated liver volume on pre- ICGR15 indocyanine green retention rate at 15 min; ROF ratio of ﬁbrosis; ROS ratio of steatosis; AZAN azo carmine aniline blue; SMA operative computed tomography and the weight of the smooth muscle actin resected specimens . Ogawa et al. reported the utility of a 3D volumetric analysis system on computed tomography 123 374 Hepatology International (2018) 12:368–376 Fig. 4 Box plots of the liver-to-spleen ratio (LSR) according to the ﬁbrosis stage (a) and steatosis grade (b). *Signiﬁcant differences in pairwise comparisons using the Mann–Whitney test images to predict the area of the liver that is embolized the strongest correlation between the LSR and ICGR15, after transcatheter arterial chemoembolization . The compared to the other laboratory data analyzed. advantage of 3D volumetric analysis systems compared to There are several studies showing a signiﬁcant correla- 2D ones is that they enable the calculation of the average tion between signal intensity of the liver on 2D analysis whole liver signal intensity automatically, from only a systems on EOB-MRI and liver ﬁbrosis [6, 20–22]. These small VOI drawn in the liver parenchyma. The present studies evaluated liver ﬁbrosis using either the METAVIR study showed that the inter-evaluator correlation coefﬁ- score or the New INUYAMA classiﬁcation as categorical cient of the LSR values was 0.986. This means that the variables assessed by pathologists. In this study, morpho- LSR, calculated using a 3D volumetric analysis system of metric analysis, using image processing software, enabled EOB-MRI, is an objective, precise, and quantitative index the quantiﬁcation of ﬁbrosis or steatosis in the liver, and to measure liver signal intensity. showed a signiﬁcantly inverse correlation between the LSR There are several studies that used 2D analysis systems and ﬁbrosis or steatosis. These data suggest that inﬁltration on EOB-MRI to evaluate liver function. These studies in the liver parenchyma of stromal tissues, such as ﬁbrosis indicated that liver signal intensity, measured from ROIs, or steatosis, decreases the relative area of hepatocytes and was correlated with liver functional reserve markers, such leads to the reduction of signal intensity of the whole liver as ICGR15, prothrombin activity, or liver ﬁbrosis on EOB-MRI. Interestingly, as shown in the Supplemen- [3–5, 17]. The present study showed that the LSR calcu- tary Table, ICGR15 was not signiﬁcantly correlated with lated using a 3D volumetric analysis system on EOB-MRI ﬁbrosis or steatosis in the liver. These results suggest that was correlated with grading systems of liver function and the function of the liver that was affected by ﬁbrosis or laboratory data, such as platelet count, serum levels of steatosis was not reﬂected accurately by ICGR15 but by the albumin, total bilirubin, aspartate aminotransferase, alanine signal intensity of the whole liver on EOB-MRI. Therefore, aminotransferase, prothrombin activity, and ICGR15. the LSR, calculated by a 3D volumetric analysis system on ICGR15 is one of the well-known biochemical indices used EOB-MRI, may indicate liver function more accurately to predict post-hepatectomy remnant liver function. In than the other liver function parameters. There might be principle, ICG is taken up to hepatocytes via the organic concerns regarding other components in the liver than anion transporting polypeptide or Na -taurocholate co- normal parenchyma, ﬁbrosis, and steatosis. Majority of transporting polypeptides located in the sinusoidal mem- previous studies reported no signiﬁcant correlations brane, and is excreted into the biliary system via the ATP- between ﬁbrosis or steatosis and iron deposition dependent export pump multidrug resistance-associated histopathologically or radiographically [23–25]. Moreover, protein 2 without biotransformation . Gd-EOB-DTPA there were no patients with hemosiderosis or hemochro- is also taken up to hepatocytes via the organic anion matosis clinically in our patient cohort. Therefore, liver transporting polypeptides, and is excreted into the biliary ﬁbrosis or steatosis was considered to be evaluated using system via the multidrug resistance-associated protein 2 EOB-MRI regardless of the iron deposition. . Therefore, in the light of the metabolic mechanism In this study, there were ﬁve patients with perihilar theory, the signal intensity of the liver on EOB-MRI would cholangiocarcinoma who developed obstructive jaundice at be expected to reﬂect ICGR15. The present study showed presentation. However, we consider that the inﬂuence of 123 Hepatology International (2018) 12:368–376 375 obstructive jaundice on evaluating liver function using In conclusion, the LSR calculated using a 3D volumetric EOB-MRI was expected to be minimal, because all the analysis system on EOB-MRI were highly reproducible, patients who had obstructive jaundice were re-examined by and were correlated with grading systems of liver function, EOB-MRI for operative indication after biliary drainage laboratory data, and histological ﬁndings. EOB-MRI using and resolution of jaundice. However, evaluation of liver a 3D volumetric analysis system may be a reliable modality function using EOB-MRI for the patients with obstructive to evaluate liver function. jaundice may be a subject of future study. Acknowledgements The authors would like to thank Ryo Morisue, Our study has several limitations. First, there was a Toshiyuki Suzuki and Hidetoshi Aizawa for assisting with data col- considerable number of patients (52/304, 17%) that had to lection, and Kenichi Ikejima M.D. (Department of Gastroenterology, be excluded due to a different EOB-MRI acquisition pro- Juntendo University Graduate School of Medicine, Tokyo, Japan) for tocol (mostly due to a different slice thickness). During the his technical support. This research did not receive any speciﬁc grant from funding agencies in the public, commercial, or not-for-proﬁt study period, the slice thickness of 4.6 mm might be rel- sectors. atively thick for 3D volumetric analysis. The MRI protocol was determined to diagnose liver tumors but not to evaluate Compliance with ethical standards liver function in this study. However, our study showed that the LSR was correlated with the Child–Pugh grade, the Conflict of interest Masashi Kudo, Naoto Gotohda, Motokazu Sugi- ALBI score, ICGR15 and other laboratory data, and his- moto, Tatsushi Kobayashi, Motohiro Kojima, Shinichiro Takahashi, Masaru Konishi, and Ryuichi Hayashi declare that they have no tological ﬁndings, although the MRI conditions were set to conflicts of interest. diagnose liver tumors. These results suggest that EOB-MRI would be applied for evaluating liver function in the clin- Ethical approval This study protocol conformed to the ethical ical situation. Furthermore, the MRI protocol in the pre- guidelines of the 1975 Declaration of Helsinki and was approved by vious studies that evaluated liver function using EOB-MRI the institutional review board of the National Cancer Center, Japan. did not differ widely from that in our study: the slice Informed consent Informed consent was obtained from each patient thickness was 5.0 mm in the study by Okada et al. , included in the study. 4.0 mm by Nishie et al. , and 3.8 mm by Matsushima et al. . Second, in the 3D volumetric analysis, extra- Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creative hepatic-parenchymal tissues such as portal vein or hepatic commons.org/licenses/by/4.0/), which permits unrestricted use, dis- vein were included in the whole liver signal intensity cal- tribution, and reproduction in any medium, provided you give culation: the LSR was the metric primarily used. 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Published: Jun 2, 2018