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3D T1 relaxometry pre and post gadoxetic acid injection for the assessment of liver cirrhosis and liver function
Magnetic Resonance Imaging 33 (2015) 1075–1082
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3D T1 relaxometry pre and post gadoxetic acid injection for the assessment of liver cirrhosis and liver function Cecilia Besa a, b,⁎, Octavia Bane b, Guido Jajamovich b, Joseph Marchione a, Bachir Taouli a, b a b
Department of Radiology, Body MRI, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029
a r t i c l e
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Article history: Received 21 January 2015 Revised 9 June 2015 Accepted 20 June 2015 Keywords: T1 mapping Gadoxetic acid Cirrhosis Liver function
a b s t r a c t Purpose: To assess the diagnostic value of a 3D dual-flip-angle (DFA) T1 mapping technique with whole liver coverage before and after gadoxetic acid injection for assessment of cirrhosis and liver function, compared to blood tests (APRI: aspartate aminotransferase-to-platelet ratio index). Materials and methods: A total of 133 patients who underwent gadoxetic acid-enhanced liver MRI including a 3D FLASH DFA-T1 mapping sequence before and 20 min post-contrast (hepatobiliary phase, HBP) were included in this retrospective IRB approved study. T1 values (msec) were measured on pre-contrast and during HBP in liver parenchyma, ΔT1 (%) was calculated as [(T1 pre − T1 post)/T1 pre] × 100. T1 and ΔT1 values were compared between cirrhotic and non-cirrhotic patients and between patients stratified using Child–Pugh and Model for End-Stage Liver Disease (MELD) scores using Mann–Whitney U test. Diagnostic performance of T1 mapping parameters vs. APRI for diagnosing cirrhosis and for assessing degree of liver dysfunction was evaluated using ROC analysis. Results: Fifty non-cirrhotic and 83 cirrhotic patients [Child–Pugh A (n = 41), B (n = 31) and C (n = 11)] were included. There was no significant difference in pre-contrast T1 values between cirrhotic and non-cirrhotic patients. T1-HBP and ΔT1 values were significantly different in patients with cirrhosis (p b 0.0001) and higher MELD scores (N 17) (p = 0.003). ΔT1 showed significant strong correlations with Child–Pugh and MELD scores (r = −0.7, p b 0.0001; r = −0.56, p b 0.001 respectively). Similar AUCs (p = 0.9) for detection of liver cirrhosis were observed for T1 HBP (0.83), ΔT1 (0.86) and APRI (0.85); however APRI showed limited sensitivity (≤55%) in comparison with ΔT1 (74.7%) and T1 HBP (80.7%). Conclusion: 3D DFA-T1 mapping sequence used before and after gadoxetic acid injection is useful for the diagnosis of cirrhosis and for the assessment of liver function. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Accurate diagnosis of liver cirrhosis is essential for estimation of prognosis and management of patients with chronic liver disease. To date, liver biopsy is considered the reference standard for the assessment of liver fibrosis and cirrhosis [1]. However, it is an invasive procedure that is prone to sampling errors and to inter-observer variation [2]. Limitations of liver biopsy have led to the development of a number of non-invasive markers of liver fibrosis, ranging from serum assays to imaging techniques [3], including the use of MRI techniques [4]. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA or gadoxetic acid, Eovist/Primovist, Bayer HealthCare) is an FDA approved liver-specific gadolinium based contrast agent (GBCA) derivative of ⁎ Corresponding author at: Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029. Tel.: +1 212 824 8480; fax: +1 646 537 9689. E-mail address: [email protected] (C. Besa). http://dx.doi.org/10.1016/j.mri.2015.06.013 0730-725X/© 2015 Elsevier Inc. All rights reserved.
Gd-DTPA that produces both dynamic and liver specific hepatobiliary images [5,6]. The hepatocyte uptake of Gd-EOB-DTPA occurs mainly via the organic anion transporter polypeptides OATP1B1 and B3 [7], located at the sinusoidal membrane, whereas biliary excretion occurs via the multidrug resistance-associated proteins located at the canalicular membrane [8], pathways that may be impaired in the presence of cirrhosis [9]. Recent advances in MR technology with multichannel receiver coils with parallel imaging capabilities have allowed the use of parametric maps of magnetic relaxation properties in the clinical setting within a single breath hold. With this method, hepatic function may be interrogated by measuring changes in T1 and T2* relaxation times after gadoxetic acid injection, overcoming some of the limitations of signal intensity methods [10]. Several studies have shown the potential usefulness of gadoxetic acid liver MR to estimate liver function [11–14] and stage liver fibrosis [15–17] using direct measurements of hepatic parenchymal enhancement. To date, few studies have examined the ability of gadoxetic acid T1 relaxometry for diagnosing liver fibrosis and for prediction of liver
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function [18–21] showing good results for assessment of severity of liver cirrhosis with significant differences in T1 relaxation times of the liver after gadoxetic acid administration between patients with normal liver function and patients with Child–Pugh A, B, and C cirrhosis. These data showed that this technique might provide suitable parameters for detecting and characterizing severity of cirrhosis. However, some of these previous studies used a single slice T1 mapping technique, which allows only limited coverage of the liver parenchyma [18,19]. The objective of this study is to validate a novel T1 mapping technique using a 3D FLASH dual-flip-angle (DFA) sequence with whole liver coverage before and after gadoxetic acid for diagnosing cirrhosis and for estimation of liver function, compared to blood tests (APRI: aspartate aminotransferase-to-platelet ratio index). A new aspect of our study is also to provide in vitro validation of the T1 mapping technique and information on degree of intra-patient variability of T1 values. 2. Materials and methods 2.1. Patients This single-center retrospective study was HIPAA compliant. Our local institutional review board approved this study and waived the requirement for informed consent. Our radiological database was queried to identify patients who underwent gadoxetic acidenhanced liver MRI at 1.5 T using a 3D-DFA-T1 mapping sequence before and after gadoxetic acid administration between 6/1/2013 and 10/31/2013. The search yielded 143 consecutive patients. The following patients were excluded (n = 10, Fig. 1): hemi-hepatectomy (n = 2), infiltrative liver tumor (n = 1), severe artifact on T1 mapping technique (n = 1) and patients with chronic hepatitis (CH) without cirrhosis on imaging but lacking histopathology to document the absence of cirrhosis (n = 6). Our final cohort included patients with normal liver function (NLF) (n = 34) that included
subjects with suspected focal liver lesions in normal liver parenchyma, and patients with chronic liver disease (n = 99) secondary to chronic hepatitis C virus (HCV) infection (n = 63); hepatitis B virus (HBV) (n = 11); non-alcoholic steatohepatitis (NASH) (n = 8); alcohol abuse (n = 9); cryptogenic (n = 4); primary biliary cirrhosis (PBC) (n = 2), primary sclerosing cholangitis (PSC) (n = 1), and hemochromatosis (n = 1). Of 99 patients with chronic liver disease, 83 (83.8%) had liver cirrhosis confirmed by liver biopsy (n = 19) and/or clinical and imaging findings (n = 64) (liver surface nodularity and portal hypertension findings) [4]. Patients with chronic liver disease without cirrhosis were included in a chronic hepatitis (CH) group (n = 16). The absence of cirrhosis in the CH group was confirmed by liver biopsy [n = 13 with fibrosis staging as follows: F0 (n = 6), F1 (n = 3), F2 (n = 3), F3 (n = 1)] or transient elastography (TE, Fibroscan) (n = 3), with values ranging from 5.3 to 6.1 kPa [22]. The following laboratory values were recorded for all patients: serum albumin levels (mg/dL), serum total bilirubin (mg/dL), prothrombin time (INR), creatinine clearance (mg/dL), aspartate aminotransferase (AST) (IU/L), alanine aminotransferase (ALT) (IU/L), and platelets count (109/μL), with not more than 1 month before or after MR imaging. The aspartate aminotransferase-to-platelet ratio index (APRI) was calculated as follows: aspartate aminotransferase (/upper limit of normal) * 100/ platelet count (109/μL), which has been proposed as a noninvasive tool for the assessment of liver fibrosis [23]. Patients with cirrhosis were classified according to the Child–Pugh classification and MELD score [24,25] (Table 1). 2.2. MRI MRI was performed using a single 1.5 T system (Magnetom Aera, Siemens Healthcare) equipped with a 32-channel spine and 18-channel body coil array. Our liver MR protocol included the following sequences: axial and coronal single-shot T2-weighted
Fig. 1. Flowchart of study population.
C. Besa et al. / Magnetic Resonance Imaging 33 (2015) 1075–1082 Table 1 Demographic and clinical characteristics of the study population.
Age (years) Sex (F/M) BMI Albumin (mg/dL) Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) Prothrombin time (INR) Platelet count (× 109/μL) APRI MELD
NLF (n = 34)
CH (n = 16)
Cirrhosis (n = 83)
56.5 ± 16.2 21/13 26.7 ± 5.0 4.15 ± 0.5 0.5 ± 0.1 26.4 ± 16.5 25.1 ± 13.8 1.0 ± 0.1 216.8 ± 81.9 0.3 ± 0.4 –
58.8 ± 9.9 3/13 26.5 ± 6.8 4.06 ± 0.4 0.7 + 0.4 46.5 ± 38.8 51.8 ± 49.2 0.9 ± 0.08 150.7 ± 41.3 0.84 ± 0.8 –
61.8 ± 10.2 30/53 27 ± 5.2 4.13 ± 0.4 0.9 ± 0.6 52.2 ± 28.7 45.7 ± 30.1 1.0 ± 0.1 130.1 ± 52.1 1.83 ± 1.8 11.6 ± 1.8
Values indicate mean ± standard deviation. NLF: patients with normal liver function and no chronic liver disease; CH: patients with chronic hepatitis without liver cirrhosis; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; MELD: Model for End-Stage Liver Disease score, APRI: Aspartate aminotransferase-to-platelet ratio index.
imaging (T2WI) HASTE/SSFSE; axial fat-suppressed turbo spin echo T2WI; 3D T1-weighted imaging (T1WI) in- and out-of-phase, diffusion weighted (DW)-imaging and a T1WI breath-hold threedimensional fat-suppressed spoiled gradient-recalled echo sequence (VIBE) before and after administration of a fixed dose of 10 ml of gadoxetic acid (Eovist/Primovist, Bayer HealthCare) with mean weight-based dose of 0.035 mmol/kg (range 0.018–0.063 mmol/ kg) injected at a rate of 1 mL/s via a power injector followed by a 20 mL saline flush using a fixed time delay of 20 seconds. The use of a fixed dose of gadoxetic acid corresponds to our current standard of care clinical practice and is motivated by practicality and costs. For all sequences, we used parallel imaging factor 2 with a rectangular field of view of 300 × 400 mm, which was adjusted for patient body size. A breath-hold 3D FLASH dual-flip-angle (DFA) T1 mapping technique of the liver was acquired before (T1 pre) and 20 min after gadoxetic acid administration during the hepatobiliary phase (HBP) using the following parameters: repetition time (TR)/echo time (TE) 3.6/ 1.4 msec, flip angle (FA) 2-11°, slice thickness 4 mm, field of view (FOV) 260 * 260 mm, acquired matrix size 128 * 160, interpolated matrix size 256 * 320, 2 averages, GRAPPA 3, acquisition time (one breath hold of 18 s). The scanner automatically generated T1 maps of the liver using the MapIT processing tool (MapIT software, Siemens Healthcare).
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2.3. In vitro T1 mapping The sequence used for T1 mapping of the liver parenchyma in vivo was validated using a phantom consisting of 12 × 50 ml tubes containing different concentrations of gadoxetic acid in the range of 0– 2 mmol (Fig. 2). The solutions were prepared by pipetting different parts of stock solution of gadoxetic acid diluted 1:100 in distilled water from its manufacturer vial concentration of 250 mmol, and of distilled water to complete the volume. The phantom was imaged with the abdominal flexible array coil using the 3D DFA-T1 mapping sequence with same image parameters as in vivo sequence, as well as an inversion-recovery turbo spin echo sequence (IR-TSE) used as the reference T1 (flip angle 180°, slice thickness 4 mm, FOV 260 * 260 mm, matrix 256 * 256, TR 5000 msec, TE 8 msec, inversion time (TI)s: 50, 100, 150, 200, 250, 500, 600, 750, 1000, 1250, 1500, 2000, 2500, and 3000 msec). IR-TSE T1 maps were obtained by fitting the inversion recovery signal using custom software written in Matlab (MatlabR2013, The Mathworks, Natick, MA). T1 values in the vials were measured from 2.5 cm2 regions of interest (ROIs) drawn on the DFA and IR-TSE T1-maps at the same slice location. 2.4. Image analysis One observer (CB, fellowship-trained radiologist with 4 yearsexperience) placed 6 ROIs measuring 2 cm2 in the liver parenchyma at the right and left hepatic lobes at three different levels (at the level of the portal bifurcation, 2 cm above and 2 cm below) on pre-contrast and 20 min post-contrast T1 maps. ROI size and location were copied and pasted from pre- to post-contrast images, and the average signal intensity (SI) was used for analysis. For reliable ROI measurement, every effort was made to place ROIs at the same position of the liver of each patient and ROIs were drawn avoiding large vessels, liver lesions and artifacts. Osirix software (ver 4.1.2, Pixmeo) was used for processing. The reduction rate (ΔT1) of T1 relaxation time between baseline (T1 pre) and HBP (T1 HBP) was calculated as: reduction rate (ΔT1%) = [(T1 pre − T1 HBP)/T1 pre] × 100. 2.5. Statistical analysis Statistical analysis was performed using SAS 9.3 (SAS Institute, Cary, NC). A Mann–Whitney U test was used to compare T1 pre, T1 HBP relaxation times and ΔT1 between different patient subgroups. The
Fig. 2. Phantom object consisting of 12 vials of 50 ml containing saline doped with gadoxetic acid at various concentrations, imaged with a dual flip angle T1 mapping sequence (left) and an IR-TSE sequence (right). The phantoms with concentrations of gadoxetic acid in the range of 0.1–1 mmol/L (mM), corresponding to the range of T1 values seen in the liver in-vivo pre- and post-contrast (150–900 msec) were used for validation of the DFA-T1 sequence. DFA-T1: dual flip angle sequence; IR-TSE: inversion-recovery turbo spin echo sequence; FA: flip angle, TI: inversion time.
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Fig. 3. Correlation plot between T1 values measured in phantoms with the DFA sequence and the IR-TSE sequence (correlation 0.99, p b 0.001), with statistically significant slope of 1.00015 (slope p-value b 0.001) and intercept not statistically different from zero (intercept p = 0.2715).
diagnostic performance of T1 HBP, ΔT1 and blood tests (APRI) to detect liver cirrhosis and estimate liver function (based on Child–Pugh scores) was evaluated using receiver operating characteristic (ROC) curves, with optimal cutoff values estimated according to Youden index, and AUC (area under the curve) comparisons measured with DeLong nonparametric method [26]. We applied published validated cutoff values for APRI to our cohort study for prediction of liver cirrhosis (lower and higher cutoff values of 1 and 2) [23]. The relation between Child–Pugh and MELD scores and T1 relaxation times and ΔT1 was tested through Spearman correlation coefficients. Variability of T1 values across the liver was assessed with coefficient of variation (CV) test. A two-sided P value of less than 0.05 was considered statistically significant.
correlation of 0.99 (p b 0.001). The T1 values were linearly correlated with a slope of 1.0015 (p b 0.001), intercept of −25.35 msec (p = 0.27) for the range of in vitro T1 values of 150–965 msec (mean T1 = 400 msec), corresponding to in vitro gadoxetic acid concentrations in the range of 0.1–1 mmol/L. The mean CV for T1 values in this concentration range was 6.67% between the 2 sequences. This range of in vitro T1 values corresponds to expected in vivo T1 values in the liver at 1.5 T before (e.g. 400–900 msec) and after injection (e.g. 150– 400 msec) of gadoxetic acid.
3. Results
Minimal intra-patient variability of T1 relaxation values was observed in the liver parenchyma, with a mean CV of 10.5% and 10.8% for T1 pre- and T1 HBP across different slices of the liver respectively. When patients with liver cirrhosis were analyzed independently, we found similarly minimal variability of T1 relaxation times across the liver (mean CV for T1 pre and T1 HBP of 11.2% and 11.3%).
3.2. Intra-patient variability of T1 relaxation times
3.1. Performance of in vitro T1 mapping The T1 values from the DFA sequence were in agreement with the reference standard values of the IR-TSE (Fig. 3), with a Pearson
Table 2 Liver T1 relaxation times (msec) before (T1 pre) and 20 min after gadoxetic acid administration (T1 HBP) and T1 reduction rate (ΔT1, %) in 133 patients. T1 pre Non-cirrhotic (n = 50) Cirrhotic (n = 83) NLF (n = 34) Chronic hepatitis without cirrhosis (n = 16) Child–Pugh A (n = 41) Child–Pugh B (n = 31) Child–Pugh C (n = 11) p (cirrhotic vs. non-cirrhotic) p (NLF vs. CH+ CPA + CPB + CPC) p (CH + CPA vs. CPB + CPC) p (CPA vs. CPB + CPC) p (CPA + CPB vs. CPC) p (CH + CPA + CPB vs. CPC) p (NLF vs. CH) p (CPB vs. CPC)
613.9 616.0 601.7 639.9 655.9 593.9 529.5 0.75 0.25 0.001 0.002 0.012 0.01 0.12 0.14
± ± ± ± ± ± ±
79.2 115.3 73.2 87.6 91.9 120.5 124.8
T1 HBP
ΔT1 (%)
200.3 ± 56.6 288.7 ± 80.5 192 ± 45.5 217.9 ± 73.5 236.7 ± 70.6 317.7 ± 79.6 300.2 ± 94.1 b0.0001 b0.0001 0.0003 0.011 0.81 0.45 0.2 0.42
67.1 ± 7.4 52.3 ± 11.6 67.8 ± 6.6 65.5 ± 9 59.6 ± 8.5 45.6 ± 10 43.6 ± 8.4 b0.0001 b0.0001 b0.0001 b0.0001 0.005 0.001 0.4 0.60
Values in boldface are statistical significant (P b0.05). Values indicate mean ± standard deviation (range). P values Mann–Whitney t test. NLF: normal liver function; CH: chronic hepatitis; CPA: Child–Pugh A; CPB: Child–Pugh B; CPC: Child–Pugh C; T1 pre: T1 relaxation time before contrast administration; T1 HBP: T1 relaxation time 20 min after contrast administration.
3.3. T1 relaxation times and ΔT1 of liver parenchyma Table 2 summarizes liver T1 relaxation times and ΔT1 in the study population. We observed no significant difference in T1 pre-contrast relaxation times between cirrhotic and non-cirrhotic patients. However, patients with worse liver function (Child–Pugh B and C) had shorter T1 pre-contrast relaxation times compared to patients with normal liver function, CH without cirrhosis and Child–Pugh A cirrhosis (p b 0.001) (Fig. 4). T1 HBP relaxation times were prolonged in patients with liver cirrhosis (p b 0.0001) and showed a constant significant increase from the normal liver function group to the Child–Pugh C group (Fig. 4). Reduction rates of T1 relaxation times (ΔT1) were significantly decreased in patients with liver cirrhosis compared to non-cirrhotic group (p b 0.0001), and showed a decrease from the normal liver function group to Child–Pugh C group (Figs. 4, 5). 3.4. Diagnostic performance of T1 mapping vs. APRI for detection of liver cirrhosis Table 3 summarizes the diagnostic performance for T1 HBP, ΔT1 and APRI with optimal cutoff values to differentiate between non-cirrhotic and cirrhotic patients and between different subgroups. We found similar AUCs for the prediction of cirrhosis by using T1 HBP [0.83, confidence intervals (CI): 0.76–0.9], ΔT1 (0.86, CI: 0.8–0.92), and APRI (0.85: 0.78–0.91), in our patient cohort. However, APRI showed limited sensitivity (30–55%) for the prediction of cirrhosis using previously validated lower and higher cutoff values of N 1 and N2 [23], in comparison with ΔT1 (74.7%) and T1 HBP (80.7%). The combination of ΔT1 and APRI did not improve accuracy (AUC of 0.86, CI: 0.78–0.92). 3.5. Assessment of liver function A strong negative correlation was observed between Child–Pugh scores in cirrhotic patients and ΔT1 (r = −0.7, p b 0.0001), with weaker correlations observed for T1 pre-contrast (r = − 0.32, p = 0.002) and T1 HBP (r = 0.29, p = 0.008). Similarly, a significant strong negative correlation was found between MELD scores (in cirrhotic patients) and ΔT1 (r = −0.56, p b 0.001) with weaker correlations observed for T1 pre (r = −0.29, p = 0.008) and T1 HBP (r = 0.21, p = 0.05). Patients with higher MELD scores (N17) had significantly prolonged T1 HBP relaxation times (p = 0.003) and reduced ΔT1 (T1 HBP = 281.9 ± 71.8 msec; ΔT1 = 54.3% ± 10.5%) in comparison with patients with lower MELD scores (≤17) (T1 HBP = 320.0 ± 103.1 msec; ΔT1 = 43.0% ± 8.9%). 4. Discussion Here we present a large comprehensive study (n = 133 patients) that validates the use of a recently introduced 3D dual flip angle T1 mapping sequence with whole liver coverage for assessment of T1 relaxation values of the liver before and after gadoxetic acid administration. Our results show that measurement of T1 relaxation values in the liver with the proposed technique is feasible and allows good discrimination between patients with normal and abnormal liver function. Two recent studies by Kamimura et al [21] and Ding et al [20] have assessed the utility of T1 relaxometry before and after gadoxetic acid administration for the assessment of liver cirrhosis and liver function using a 3D-DFA technique at a 3 T (n = 99 patients) and 1.5 T (n = 100 patients) system respectively showing that this technique has potential to serve as an MRI-based liver function test. Compared to these studies, our study provides in-vitro validation of T1 relaxation values and information on intra-patient variability of T1 values in the largest published series of patients. In
1079 Fig. 4. Pre- and post-contrast T1 relaxation times and reduction rates of T1 relaxation times (ΔT1%) of the liver. A: Boxplots showing T1 relaxation times before gadoxetic acid administration (T1 pre). B: T1 relaxation times after gadoxetic acid administration (T1 HBP). C: ΔT1% in patients with normal liver function (NLF), chronic hepatitis without cirrhosis (CH), Child–Pugh A (CPA), Child–Pugh B (CPB) and Child–Pugh C (CPC). T1 HBP increased significantly with worsening liver function, while ΔT1% showed a constant significant increase from the NLF group to the CPC group. Foot note: Top and bottom of boxes represent 25–75 percentiles of the data values. Line in box represents median value.
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Fig. 5. T1 parametric maps pre-contrast (A–C) and 20 min post-contrast (B–D) (at hepatobiliary phase) in a non-cirrhotic patient (upper row) and a Child–Pugh C cirrhotic patient (lower row) demonstrate prolonged T1 HBP relaxation values and lower ΔT1 in the cirrhotic (323 msec, ΔT1 44%) versus non-cirrhotic liver (167 msec, ΔT1 67%).
addition, the diagnostic capability of T1 relaxometry was compared with a previously validated blood test (APRI) for diagnosing cirrhosis. Pre-contrast T1 relaxation time for non-cirrhotic livers (610 ± 81.6 msec) was comparable to previously published data at 1.5 T [27– 29]. Assessment of liver fibrosis and cirrhosis and liver function is important for diagnosis and for assessing the prognosis of patients with chronic liver diseases, and is particularly required in cirrhotic patients to determine the optimal timing for liver transplantation and before liver resection for hepatocellular carcinoma to minimize the risk of post-operative liver failure. To date, several imaging techniques using functional MRI have been proposed with variable success rates for detection of liver fibrosis [4]. Recently, the use of parametric maps has been investigated for assessment of infiltrative liver disease [18,19,30,31]. In our study, we tested the hypothesis that fibrotic remodeling of the liver parenchyma in patients with liver cirrhosis and impaired liver function exerts an influence on T1 relaxation times before and after gadoxetic acid contrast administration as measured by MR relaxometry. We found no significant differences in pre-contrast T1 relaxation times of the liver parenchyma between cirrhotic and non-cirrhotic
patients in our study. However, shorter T1 pre relaxation values in patients with more impaired liver function (Child–Pugh B and C groups) in comparison with chronic hepatitis and Child–Pugh A groups (p = 0.002) were noted. Prior reports have shown conflicting results. Heye et al [28] and Katsube et al [18] found prolonged pre-contrast T1 relaxation values in cirrhotic livers compared with controls, while the study by Haimerl et al [19] showed no significant difference between patients with normal and abnormal liver functions. These conflicting findings question the role of non-contrast T1 relaxometry for liver fibrosis detection. Pre-contrast T1 relaxation times of the liver parenchyma could be affected by several factors other than the degree of liver fibrosis, such as iron deposition and steatosis among others, which are commonly present in patients with chronic liver disease [32]. Significantly prolonged T1 HBP and lower ΔT1 were observed in cirrhotic patients in comparison with non-cirrhotic patients in our study. In addition, patients with impaired liver function (Child–Pugh B and C and lower MELD scores) had significantly prolonged post-contrast T1 relaxation times and lower ΔT1 in comparison with patients with normal liver function, chronic hepatitis and Child–Pugh A cirrhosis, in agreement with recent publications [18,19]. These findings are likely explained by reduced hepatocyte intracellular
Table 3 ROC analysis assessing diagnostic performance of T1 reduction rate (ΔT1%), T1 relaxation time 20 min after gadoxetic acid administration (T1 HBP) and APRI (aspartate aminotransferase-to-platelet ratio index) to differentiate between non-cirrhotic and cirrhotic patients. AUC (95% CI)
Cutoff value
Sensitivity (95% CI)
Specificity (95% CI)
T1 HBP (msec) ΔT1 (%) APRI
0.83 (0.76–0.9) 0.86 (0.8–0.92) 0.85 (0.78–0.91)
p T1 HBP vs. APRI p T1 ΔT1 vs. APRI p T1 ΔT1 vs. T1 HBP
0.5 0.9 0.2
224 59% N1.0 N2.0 – –
80.7% (70.5–88.5) 74.7% (63.9–83.6) 55% (43.4–66.1) 30% (20.2–41.2) – –
78.5% (65.5–88.4) 85.7% (73.7–93.6) 88.1% (74.3–96) 92% (80.5–98.5) – –
P values between AUCs were measured with DeLong nonparametric method. T1 pre: T1 relaxation time before contrast administration; T1 HBP: T1 relaxation time 20 min after contrast administration.
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gadoxetic acid uptake due to a decreased number of normal functioning hepatocytes or disturbed transporting system present in advanced liver cirrhosis as showed in a recent animal model [9]. Good diagnostic performance for detection of liver cirrhosis was found for T1 HBP (AUC = 0.83) and ΔT1 (AUC = 0.86) in our patient cohort. APRI was measured in our study on account of its simplicity and because it is a fairly effective tool for assessing liver fibrosis [23]. However, APRI was found to be less sensitive than T1 mapping parameters (T1 HBP and ΔT1) for detection of liver cirrhosis. Moreover, the main drawback of these blood-based tests is that they can be influenced by extra-hepatic conditions [3]. Motosugi et al [33] showed that APRI has a greater reliability for predicting severe fibrosis and cirrhosis in comparison with direct measurements of hepatic parenchymal enhancement after gadoxetic acid. However, APRI was not compared against T1 gadoxetic acid T1 relaxometry in their study. Liver failure is the most serious complication after liver resection in patients with liver disease and can be life-threatening [34]. Current available clinical liver function tests such as the indocyanine green clearance test (ICG) [35] and Child–Pugh or MELD clinical scoring systems offer only a global assessment of liver function without taking into account heterogeneous function distribution in the liver. Gadoxetic acid liver MRI offers a unique opportunity to combine qualitative and quantitative morphological and functional information that may improve the assessment of diffuse liver diseases and liver function, and is routinely performed in many centers as part of the evaluation of complications of chronic liver disease. Hence, gadoxetic acid T1 relaxometry could be easily incorporated routinely as part of the multiparametric assessment of focal and infiltrative liver disease with only minimal addition of scanning time to the routine clinical protocol. This imaging tool can also facilitate assessment of total and regional liver functions in patients being considered for liver resection. We acknowledge several limitations to our study. First, because of the retrospective nature of the present study there might have been a potential selection bias in the patient sample. However, our enrolled population included all consecutive patients who underwent gadoxetic acid MRI including T1 mapping technique in a 3-month period at our center who met eligibility criteria, which limits the possibility of sampling bias and reflects the most common clinical scenario in a tertiary referral center. Second, one of the major limitations of the study was that histopathologic diagnosis of liver cirrhosis was not available for all cases, and clinical and consensus reading of MR images was used as the reference standard in the absence of pathology data. However, the absence of advanced liver fibrosis/cirrhosis in CH group was confirmed by liver biopsy in 81% (n = 13/16) of the patients. Also, correlation between T1 mapping parameters and different fibrosis stages was not performed in the current study. Third, we compared hepatic uptake of gadoxetic acid with most widely used clinical parameters to evaluate liver function (Child–Pugh and MELD scoring systems); however, more sophisticated tests for liver function assessment, such as the IGG test or hepatobiliary scintigraphy were not used in our study. Fourth, we use of a fixed dose of gadoxetic acid (mean dose of 0.035 mmol/kg in our patient cohort) in accordance to our current standard of care clinical practice, which is lower to the recommended dose (0.05 mmol/kg). This could potentially affect T1 HBP values; however, it should not have influenced ΔT1 values. Finally, despite the good diagnostic performance of T1 HBP and ΔT1 for detection of liver cirrhosis and differentiating patients with impaired liver function (based on Child–Pugh scores), there was an overlap of T1 values among cirrhotic patients with different stages of liver dysfunction. In addition, cutoff values that were used to calculate sensitivity and specificity were derived retrospectively from the same population, and therefore, likely overestimate the diagnostic
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performance of the method. Thus, the use of these parameters for prediction of liver cirrhosis and liver function in individual patients with chronic liver disease must be confirmed in a prospective study. In conclusion, a 3D DFA-T1 mapping sequence with whole liver coverage used before and after gadoxetic acid injection can help detect cirrhosis and assess liver function. We showed that gadoxetic acid liver uptake measured by T1 mapping is strongly affected by presence of liver cirrhosis and liver function, and provides good discriminatory ability for the detection of cirrhosis (T1 HBP AUC = 0.81; ΔT1 AUC = 0.84). The present study provides the basis for potential new algorithms to assess diffuse liver disease. Future studies will need to assess prospectively the diagnostic performance of gadoxetic acid enhanced-T1 mapping technique of the liver as a quantitative marker of liver fibrosis and liver dysfunction.
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3D T1 relaxometry pre and post gadoxetic acid injection for the assessment of liver cirrhosis and liver function Cecilia Besa a, b,⁎, Octavia Bane b, Guido Jajamovich b, Joseph Marchione a, Bachir Taouli a, b a b
Department of Radiology, Body MRI, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029 Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029
a r t i c l e
i n f o
Article history: Received 21 January 2015 Revised 9 June 2015 Accepted 20 June 2015 Keywords: T1 mapping Gadoxetic acid Cirrhosis Liver function
a b s t r a c t Purpose: To assess the diagnostic value of a 3D dual-flip-angle (DFA) T1 mapping technique with whole liver coverage before and after gadoxetic acid injection for assessment of cirrhosis and liver function, compared to blood tests (APRI: aspartate aminotransferase-to-platelet ratio index). Materials and methods: A total of 133 patients who underwent gadoxetic acid-enhanced liver MRI including a 3D FLASH DFA-T1 mapping sequence before and 20 min post-contrast (hepatobiliary phase, HBP) were included in this retrospective IRB approved study. T1 values (msec) were measured on pre-contrast and during HBP in liver parenchyma, ΔT1 (%) was calculated as [(T1 pre − T1 post)/T1 pre] × 100. T1 and ΔT1 values were compared between cirrhotic and non-cirrhotic patients and between patients stratified using Child–Pugh and Model for End-Stage Liver Disease (MELD) scores using Mann–Whitney U test. Diagnostic performance of T1 mapping parameters vs. APRI for diagnosing cirrhosis and for assessing degree of liver dysfunction was evaluated using ROC analysis. Results: Fifty non-cirrhotic and 83 cirrhotic patients [Child–Pugh A (n = 41), B (n = 31) and C (n = 11)] were included. There was no significant difference in pre-contrast T1 values between cirrhotic and non-cirrhotic patients. T1-HBP and ΔT1 values were significantly different in patients with cirrhosis (p b 0.0001) and higher MELD scores (N 17) (p = 0.003). ΔT1 showed significant strong correlations with Child–Pugh and MELD scores (r = −0.7, p b 0.0001; r = −0.56, p b 0.001 respectively). Similar AUCs (p = 0.9) for detection of liver cirrhosis were observed for T1 HBP (0.83), ΔT1 (0.86) and APRI (0.85); however APRI showed limited sensitivity (≤55%) in comparison with ΔT1 (74.7%) and T1 HBP (80.7%). Conclusion: 3D DFA-T1 mapping sequence used before and after gadoxetic acid injection is useful for the diagnosis of cirrhosis and for the assessment of liver function. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Accurate diagnosis of liver cirrhosis is essential for estimation of prognosis and management of patients with chronic liver disease. To date, liver biopsy is considered the reference standard for the assessment of liver fibrosis and cirrhosis [1]. However, it is an invasive procedure that is prone to sampling errors and to inter-observer variation [2]. Limitations of liver biopsy have led to the development of a number of non-invasive markers of liver fibrosis, ranging from serum assays to imaging techniques [3], including the use of MRI techniques [4]. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA or gadoxetic acid, Eovist/Primovist, Bayer HealthCare) is an FDA approved liver-specific gadolinium based contrast agent (GBCA) derivative of ⁎ Corresponding author at: Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029. Tel.: +1 212 824 8480; fax: +1 646 537 9689. E-mail address: [email protected] (C. Besa). http://dx.doi.org/10.1016/j.mri.2015.06.013 0730-725X/© 2015 Elsevier Inc. All rights reserved.
Gd-DTPA that produces both dynamic and liver specific hepatobiliary images [5,6]. The hepatocyte uptake of Gd-EOB-DTPA occurs mainly via the organic anion transporter polypeptides OATP1B1 and B3 [7], located at the sinusoidal membrane, whereas biliary excretion occurs via the multidrug resistance-associated proteins located at the canalicular membrane [8], pathways that may be impaired in the presence of cirrhosis [9]. Recent advances in MR technology with multichannel receiver coils with parallel imaging capabilities have allowed the use of parametric maps of magnetic relaxation properties in the clinical setting within a single breath hold. With this method, hepatic function may be interrogated by measuring changes in T1 and T2* relaxation times after gadoxetic acid injection, overcoming some of the limitations of signal intensity methods [10]. Several studies have shown the potential usefulness of gadoxetic acid liver MR to estimate liver function [11–14] and stage liver fibrosis [15–17] using direct measurements of hepatic parenchymal enhancement. To date, few studies have examined the ability of gadoxetic acid T1 relaxometry for diagnosing liver fibrosis and for prediction of liver
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function [18–21] showing good results for assessment of severity of liver cirrhosis with significant differences in T1 relaxation times of the liver after gadoxetic acid administration between patients with normal liver function and patients with Child–Pugh A, B, and C cirrhosis. These data showed that this technique might provide suitable parameters for detecting and characterizing severity of cirrhosis. However, some of these previous studies used a single slice T1 mapping technique, which allows only limited coverage of the liver parenchyma [18,19]. The objective of this study is to validate a novel T1 mapping technique using a 3D FLASH dual-flip-angle (DFA) sequence with whole liver coverage before and after gadoxetic acid for diagnosing cirrhosis and for estimation of liver function, compared to blood tests (APRI: aspartate aminotransferase-to-platelet ratio index). A new aspect of our study is also to provide in vitro validation of the T1 mapping technique and information on degree of intra-patient variability of T1 values. 2. Materials and methods 2.1. Patients This single-center retrospective study was HIPAA compliant. Our local institutional review board approved this study and waived the requirement for informed consent. Our radiological database was queried to identify patients who underwent gadoxetic acidenhanced liver MRI at 1.5 T using a 3D-DFA-T1 mapping sequence before and after gadoxetic acid administration between 6/1/2013 and 10/31/2013. The search yielded 143 consecutive patients. The following patients were excluded (n = 10, Fig. 1): hemi-hepatectomy (n = 2), infiltrative liver tumor (n = 1), severe artifact on T1 mapping technique (n = 1) and patients with chronic hepatitis (CH) without cirrhosis on imaging but lacking histopathology to document the absence of cirrhosis (n = 6). Our final cohort included patients with normal liver function (NLF) (n = 34) that included
subjects with suspected focal liver lesions in normal liver parenchyma, and patients with chronic liver disease (n = 99) secondary to chronic hepatitis C virus (HCV) infection (n = 63); hepatitis B virus (HBV) (n = 11); non-alcoholic steatohepatitis (NASH) (n = 8); alcohol abuse (n = 9); cryptogenic (n = 4); primary biliary cirrhosis (PBC) (n = 2), primary sclerosing cholangitis (PSC) (n = 1), and hemochromatosis (n = 1). Of 99 patients with chronic liver disease, 83 (83.8%) had liver cirrhosis confirmed by liver biopsy (n = 19) and/or clinical and imaging findings (n = 64) (liver surface nodularity and portal hypertension findings) [4]. Patients with chronic liver disease without cirrhosis were included in a chronic hepatitis (CH) group (n = 16). The absence of cirrhosis in the CH group was confirmed by liver biopsy [n = 13 with fibrosis staging as follows: F0 (n = 6), F1 (n = 3), F2 (n = 3), F3 (n = 1)] or transient elastography (TE, Fibroscan) (n = 3), with values ranging from 5.3 to 6.1 kPa [22]. The following laboratory values were recorded for all patients: serum albumin levels (mg/dL), serum total bilirubin (mg/dL), prothrombin time (INR), creatinine clearance (mg/dL), aspartate aminotransferase (AST) (IU/L), alanine aminotransferase (ALT) (IU/L), and platelets count (109/μL), with not more than 1 month before or after MR imaging. The aspartate aminotransferase-to-platelet ratio index (APRI) was calculated as follows: aspartate aminotransferase (/upper limit of normal) * 100/ platelet count (109/μL), which has been proposed as a noninvasive tool for the assessment of liver fibrosis [23]. Patients with cirrhosis were classified according to the Child–Pugh classification and MELD score [24,25] (Table 1). 2.2. MRI MRI was performed using a single 1.5 T system (Magnetom Aera, Siemens Healthcare) equipped with a 32-channel spine and 18-channel body coil array. Our liver MR protocol included the following sequences: axial and coronal single-shot T2-weighted
Fig. 1. Flowchart of study population.
C. Besa et al. / Magnetic Resonance Imaging 33 (2015) 1075–1082 Table 1 Demographic and clinical characteristics of the study population.
Age (years) Sex (F/M) BMI Albumin (mg/dL) Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) Prothrombin time (INR) Platelet count (× 109/μL) APRI MELD
NLF (n = 34)
CH (n = 16)
Cirrhosis (n = 83)
56.5 ± 16.2 21/13 26.7 ± 5.0 4.15 ± 0.5 0.5 ± 0.1 26.4 ± 16.5 25.1 ± 13.8 1.0 ± 0.1 216.8 ± 81.9 0.3 ± 0.4 –
58.8 ± 9.9 3/13 26.5 ± 6.8 4.06 ± 0.4 0.7 + 0.4 46.5 ± 38.8 51.8 ± 49.2 0.9 ± 0.08 150.7 ± 41.3 0.84 ± 0.8 –
61.8 ± 10.2 30/53 27 ± 5.2 4.13 ± 0.4 0.9 ± 0.6 52.2 ± 28.7 45.7 ± 30.1 1.0 ± 0.1 130.1 ± 52.1 1.83 ± 1.8 11.6 ± 1.8
Values indicate mean ± standard deviation. NLF: patients with normal liver function and no chronic liver disease; CH: patients with chronic hepatitis without liver cirrhosis; BMI: body mass index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; MELD: Model for End-Stage Liver Disease score, APRI: Aspartate aminotransferase-to-platelet ratio index.
imaging (T2WI) HASTE/SSFSE; axial fat-suppressed turbo spin echo T2WI; 3D T1-weighted imaging (T1WI) in- and out-of-phase, diffusion weighted (DW)-imaging and a T1WI breath-hold threedimensional fat-suppressed spoiled gradient-recalled echo sequence (VIBE) before and after administration of a fixed dose of 10 ml of gadoxetic acid (Eovist/Primovist, Bayer HealthCare) with mean weight-based dose of 0.035 mmol/kg (range 0.018–0.063 mmol/ kg) injected at a rate of 1 mL/s via a power injector followed by a 20 mL saline flush using a fixed time delay of 20 seconds. The use of a fixed dose of gadoxetic acid corresponds to our current standard of care clinical practice and is motivated by practicality and costs. For all sequences, we used parallel imaging factor 2 with a rectangular field of view of 300 × 400 mm, which was adjusted for patient body size. A breath-hold 3D FLASH dual-flip-angle (DFA) T1 mapping technique of the liver was acquired before (T1 pre) and 20 min after gadoxetic acid administration during the hepatobiliary phase (HBP) using the following parameters: repetition time (TR)/echo time (TE) 3.6/ 1.4 msec, flip angle (FA) 2-11°, slice thickness 4 mm, field of view (FOV) 260 * 260 mm, acquired matrix size 128 * 160, interpolated matrix size 256 * 320, 2 averages, GRAPPA 3, acquisition time (one breath hold of 18 s). The scanner automatically generated T1 maps of the liver using the MapIT processing tool (MapIT software, Siemens Healthcare).
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2.3. In vitro T1 mapping The sequence used for T1 mapping of the liver parenchyma in vivo was validated using a phantom consisting of 12 × 50 ml tubes containing different concentrations of gadoxetic acid in the range of 0– 2 mmol (Fig. 2). The solutions were prepared by pipetting different parts of stock solution of gadoxetic acid diluted 1:100 in distilled water from its manufacturer vial concentration of 250 mmol, and of distilled water to complete the volume. The phantom was imaged with the abdominal flexible array coil using the 3D DFA-T1 mapping sequence with same image parameters as in vivo sequence, as well as an inversion-recovery turbo spin echo sequence (IR-TSE) used as the reference T1 (flip angle 180°, slice thickness 4 mm, FOV 260 * 260 mm, matrix 256 * 256, TR 5000 msec, TE 8 msec, inversion time (TI)s: 50, 100, 150, 200, 250, 500, 600, 750, 1000, 1250, 1500, 2000, 2500, and 3000 msec). IR-TSE T1 maps were obtained by fitting the inversion recovery signal using custom software written in Matlab (MatlabR2013, The Mathworks, Natick, MA). T1 values in the vials were measured from 2.5 cm2 regions of interest (ROIs) drawn on the DFA and IR-TSE T1-maps at the same slice location. 2.4. Image analysis One observer (CB, fellowship-trained radiologist with 4 yearsexperience) placed 6 ROIs measuring 2 cm2 in the liver parenchyma at the right and left hepatic lobes at three different levels (at the level of the portal bifurcation, 2 cm above and 2 cm below) on pre-contrast and 20 min post-contrast T1 maps. ROI size and location were copied and pasted from pre- to post-contrast images, and the average signal intensity (SI) was used for analysis. For reliable ROI measurement, every effort was made to place ROIs at the same position of the liver of each patient and ROIs were drawn avoiding large vessels, liver lesions and artifacts. Osirix software (ver 4.1.2, Pixmeo) was used for processing. The reduction rate (ΔT1) of T1 relaxation time between baseline (T1 pre) and HBP (T1 HBP) was calculated as: reduction rate (ΔT1%) = [(T1 pre − T1 HBP)/T1 pre] × 100. 2.5. Statistical analysis Statistical analysis was performed using SAS 9.3 (SAS Institute, Cary, NC). A Mann–Whitney U test was used to compare T1 pre, T1 HBP relaxation times and ΔT1 between different patient subgroups. The
Fig. 2. Phantom object consisting of 12 vials of 50 ml containing saline doped with gadoxetic acid at various concentrations, imaged with a dual flip angle T1 mapping sequence (left) and an IR-TSE sequence (right). The phantoms with concentrations of gadoxetic acid in the range of 0.1–1 mmol/L (mM), corresponding to the range of T1 values seen in the liver in-vivo pre- and post-contrast (150–900 msec) were used for validation of the DFA-T1 sequence. DFA-T1: dual flip angle sequence; IR-TSE: inversion-recovery turbo spin echo sequence; FA: flip angle, TI: inversion time.
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Fig. 3. Correlation plot between T1 values measured in phantoms with the DFA sequence and the IR-TSE sequence (correlation 0.99, p b 0.001), with statistically significant slope of 1.00015 (slope p-value b 0.001) and intercept not statistically different from zero (intercept p = 0.2715).
diagnostic performance of T1 HBP, ΔT1 and blood tests (APRI) to detect liver cirrhosis and estimate liver function (based on Child–Pugh scores) was evaluated using receiver operating characteristic (ROC) curves, with optimal cutoff values estimated according to Youden index, and AUC (area under the curve) comparisons measured with DeLong nonparametric method [26]. We applied published validated cutoff values for APRI to our cohort study for prediction of liver cirrhosis (lower and higher cutoff values of 1 and 2) [23]. The relation between Child–Pugh and MELD scores and T1 relaxation times and ΔT1 was tested through Spearman correlation coefficients. Variability of T1 values across the liver was assessed with coefficient of variation (CV) test. A two-sided P value of less than 0.05 was considered statistically significant.
correlation of 0.99 (p b 0.001). The T1 values were linearly correlated with a slope of 1.0015 (p b 0.001), intercept of −25.35 msec (p = 0.27) for the range of in vitro T1 values of 150–965 msec (mean T1 = 400 msec), corresponding to in vitro gadoxetic acid concentrations in the range of 0.1–1 mmol/L. The mean CV for T1 values in this concentration range was 6.67% between the 2 sequences. This range of in vitro T1 values corresponds to expected in vivo T1 values in the liver at 1.5 T before (e.g. 400–900 msec) and after injection (e.g. 150– 400 msec) of gadoxetic acid.
3. Results
Minimal intra-patient variability of T1 relaxation values was observed in the liver parenchyma, with a mean CV of 10.5% and 10.8% for T1 pre- and T1 HBP across different slices of the liver respectively. When patients with liver cirrhosis were analyzed independently, we found similarly minimal variability of T1 relaxation times across the liver (mean CV for T1 pre and T1 HBP of 11.2% and 11.3%).
3.2. Intra-patient variability of T1 relaxation times
3.1. Performance of in vitro T1 mapping The T1 values from the DFA sequence were in agreement with the reference standard values of the IR-TSE (Fig. 3), with a Pearson
Table 2 Liver T1 relaxation times (msec) before (T1 pre) and 20 min after gadoxetic acid administration (T1 HBP) and T1 reduction rate (ΔT1, %) in 133 patients. T1 pre Non-cirrhotic (n = 50) Cirrhotic (n = 83) NLF (n = 34) Chronic hepatitis without cirrhosis (n = 16) Child–Pugh A (n = 41) Child–Pugh B (n = 31) Child–Pugh C (n = 11) p (cirrhotic vs. non-cirrhotic) p (NLF vs. CH+ CPA + CPB + CPC) p (CH + CPA vs. CPB + CPC) p (CPA vs. CPB + CPC) p (CPA + CPB vs. CPC) p (CH + CPA + CPB vs. CPC) p (NLF vs. CH) p (CPB vs. CPC)
613.9 616.0 601.7 639.9 655.9 593.9 529.5 0.75 0.25 0.001 0.002 0.012 0.01 0.12 0.14
± ± ± ± ± ± ±
79.2 115.3 73.2 87.6 91.9 120.5 124.8
T1 HBP
ΔT1 (%)
200.3 ± 56.6 288.7 ± 80.5 192 ± 45.5 217.9 ± 73.5 236.7 ± 70.6 317.7 ± 79.6 300.2 ± 94.1 b0.0001 b0.0001 0.0003 0.011 0.81 0.45 0.2 0.42
67.1 ± 7.4 52.3 ± 11.6 67.8 ± 6.6 65.5 ± 9 59.6 ± 8.5 45.6 ± 10 43.6 ± 8.4 b0.0001 b0.0001 b0.0001 b0.0001 0.005 0.001 0.4 0.60
Values in boldface are statistical significant (P b0.05). Values indicate mean ± standard deviation (range). P values Mann–Whitney t test. NLF: normal liver function; CH: chronic hepatitis; CPA: Child–Pugh A; CPB: Child–Pugh B; CPC: Child–Pugh C; T1 pre: T1 relaxation time before contrast administration; T1 HBP: T1 relaxation time 20 min after contrast administration.
3.3. T1 relaxation times and ΔT1 of liver parenchyma Table 2 summarizes liver T1 relaxation times and ΔT1 in the study population. We observed no significant difference in T1 pre-contrast relaxation times between cirrhotic and non-cirrhotic patients. However, patients with worse liver function (Child–Pugh B and C) had shorter T1 pre-contrast relaxation times compared to patients with normal liver function, CH without cirrhosis and Child–Pugh A cirrhosis (p b 0.001) (Fig. 4). T1 HBP relaxation times were prolonged in patients with liver cirrhosis (p b 0.0001) and showed a constant significant increase from the normal liver function group to the Child–Pugh C group (Fig. 4). Reduction rates of T1 relaxation times (ΔT1) were significantly decreased in patients with liver cirrhosis compared to non-cirrhotic group (p b 0.0001), and showed a decrease from the normal liver function group to Child–Pugh C group (Figs. 4, 5). 3.4. Diagnostic performance of T1 mapping vs. APRI for detection of liver cirrhosis Table 3 summarizes the diagnostic performance for T1 HBP, ΔT1 and APRI with optimal cutoff values to differentiate between non-cirrhotic and cirrhotic patients and between different subgroups. We found similar AUCs for the prediction of cirrhosis by using T1 HBP [0.83, confidence intervals (CI): 0.76–0.9], ΔT1 (0.86, CI: 0.8–0.92), and APRI (0.85: 0.78–0.91), in our patient cohort. However, APRI showed limited sensitivity (30–55%) for the prediction of cirrhosis using previously validated lower and higher cutoff values of N 1 and N2 [23], in comparison with ΔT1 (74.7%) and T1 HBP (80.7%). The combination of ΔT1 and APRI did not improve accuracy (AUC of 0.86, CI: 0.78–0.92). 3.5. Assessment of liver function A strong negative correlation was observed between Child–Pugh scores in cirrhotic patients and ΔT1 (r = −0.7, p b 0.0001), with weaker correlations observed for T1 pre-contrast (r = − 0.32, p = 0.002) and T1 HBP (r = 0.29, p = 0.008). Similarly, a significant strong negative correlation was found between MELD scores (in cirrhotic patients) and ΔT1 (r = −0.56, p b 0.001) with weaker correlations observed for T1 pre (r = −0.29, p = 0.008) and T1 HBP (r = 0.21, p = 0.05). Patients with higher MELD scores (N17) had significantly prolonged T1 HBP relaxation times (p = 0.003) and reduced ΔT1 (T1 HBP = 281.9 ± 71.8 msec; ΔT1 = 54.3% ± 10.5%) in comparison with patients with lower MELD scores (≤17) (T1 HBP = 320.0 ± 103.1 msec; ΔT1 = 43.0% ± 8.9%). 4. Discussion Here we present a large comprehensive study (n = 133 patients) that validates the use of a recently introduced 3D dual flip angle T1 mapping sequence with whole liver coverage for assessment of T1 relaxation values of the liver before and after gadoxetic acid administration. Our results show that measurement of T1 relaxation values in the liver with the proposed technique is feasible and allows good discrimination between patients with normal and abnormal liver function. Two recent studies by Kamimura et al [21] and Ding et al [20] have assessed the utility of T1 relaxometry before and after gadoxetic acid administration for the assessment of liver cirrhosis and liver function using a 3D-DFA technique at a 3 T (n = 99 patients) and 1.5 T (n = 100 patients) system respectively showing that this technique has potential to serve as an MRI-based liver function test. Compared to these studies, our study provides in-vitro validation of T1 relaxation values and information on intra-patient variability of T1 values in the largest published series of patients. In
1079 Fig. 4. Pre- and post-contrast T1 relaxation times and reduction rates of T1 relaxation times (ΔT1%) of the liver. A: Boxplots showing T1 relaxation times before gadoxetic acid administration (T1 pre). B: T1 relaxation times after gadoxetic acid administration (T1 HBP). C: ΔT1% in patients with normal liver function (NLF), chronic hepatitis without cirrhosis (CH), Child–Pugh A (CPA), Child–Pugh B (CPB) and Child–Pugh C (CPC). T1 HBP increased significantly with worsening liver function, while ΔT1% showed a constant significant increase from the NLF group to the CPC group. Foot note: Top and bottom of boxes represent 25–75 percentiles of the data values. Line in box represents median value.
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Fig. 5. T1 parametric maps pre-contrast (A–C) and 20 min post-contrast (B–D) (at hepatobiliary phase) in a non-cirrhotic patient (upper row) and a Child–Pugh C cirrhotic patient (lower row) demonstrate prolonged T1 HBP relaxation values and lower ΔT1 in the cirrhotic (323 msec, ΔT1 44%) versus non-cirrhotic liver (167 msec, ΔT1 67%).
addition, the diagnostic capability of T1 relaxometry was compared with a previously validated blood test (APRI) for diagnosing cirrhosis. Pre-contrast T1 relaxation time for non-cirrhotic livers (610 ± 81.6 msec) was comparable to previously published data at 1.5 T [27– 29]. Assessment of liver fibrosis and cirrhosis and liver function is important for diagnosis and for assessing the prognosis of patients with chronic liver diseases, and is particularly required in cirrhotic patients to determine the optimal timing for liver transplantation and before liver resection for hepatocellular carcinoma to minimize the risk of post-operative liver failure. To date, several imaging techniques using functional MRI have been proposed with variable success rates for detection of liver fibrosis [4]. Recently, the use of parametric maps has been investigated for assessment of infiltrative liver disease [18,19,30,31]. In our study, we tested the hypothesis that fibrotic remodeling of the liver parenchyma in patients with liver cirrhosis and impaired liver function exerts an influence on T1 relaxation times before and after gadoxetic acid contrast administration as measured by MR relaxometry. We found no significant differences in pre-contrast T1 relaxation times of the liver parenchyma between cirrhotic and non-cirrhotic
patients in our study. However, shorter T1 pre relaxation values in patients with more impaired liver function (Child–Pugh B and C groups) in comparison with chronic hepatitis and Child–Pugh A groups (p = 0.002) were noted. Prior reports have shown conflicting results. Heye et al [28] and Katsube et al [18] found prolonged pre-contrast T1 relaxation values in cirrhotic livers compared with controls, while the study by Haimerl et al [19] showed no significant difference between patients with normal and abnormal liver functions. These conflicting findings question the role of non-contrast T1 relaxometry for liver fibrosis detection. Pre-contrast T1 relaxation times of the liver parenchyma could be affected by several factors other than the degree of liver fibrosis, such as iron deposition and steatosis among others, which are commonly present in patients with chronic liver disease [32]. Significantly prolonged T1 HBP and lower ΔT1 were observed in cirrhotic patients in comparison with non-cirrhotic patients in our study. In addition, patients with impaired liver function (Child–Pugh B and C and lower MELD scores) had significantly prolonged post-contrast T1 relaxation times and lower ΔT1 in comparison with patients with normal liver function, chronic hepatitis and Child–Pugh A cirrhosis, in agreement with recent publications [18,19]. These findings are likely explained by reduced hepatocyte intracellular
Table 3 ROC analysis assessing diagnostic performance of T1 reduction rate (ΔT1%), T1 relaxation time 20 min after gadoxetic acid administration (T1 HBP) and APRI (aspartate aminotransferase-to-platelet ratio index) to differentiate between non-cirrhotic and cirrhotic patients. AUC (95% CI)
Cutoff value
Sensitivity (95% CI)
Specificity (95% CI)
T1 HBP (msec) ΔT1 (%) APRI
0.83 (0.76–0.9) 0.86 (0.8–0.92) 0.85 (0.78–0.91)
p T1 HBP vs. APRI p T1 ΔT1 vs. APRI p T1 ΔT1 vs. T1 HBP
0.5 0.9 0.2
224 59% N1.0 N2.0 – –
80.7% (70.5–88.5) 74.7% (63.9–83.6) 55% (43.4–66.1) 30% (20.2–41.2) – –
78.5% (65.5–88.4) 85.7% (73.7–93.6) 88.1% (74.3–96) 92% (80.5–98.5) – –
P values between AUCs were measured with DeLong nonparametric method. T1 pre: T1 relaxation time before contrast administration; T1 HBP: T1 relaxation time 20 min after contrast administration.
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gadoxetic acid uptake due to a decreased number of normal functioning hepatocytes or disturbed transporting system present in advanced liver cirrhosis as showed in a recent animal model [9]. Good diagnostic performance for detection of liver cirrhosis was found for T1 HBP (AUC = 0.83) and ΔT1 (AUC = 0.86) in our patient cohort. APRI was measured in our study on account of its simplicity and because it is a fairly effective tool for assessing liver fibrosis [23]. However, APRI was found to be less sensitive than T1 mapping parameters (T1 HBP and ΔT1) for detection of liver cirrhosis. Moreover, the main drawback of these blood-based tests is that they can be influenced by extra-hepatic conditions [3]. Motosugi et al [33] showed that APRI has a greater reliability for predicting severe fibrosis and cirrhosis in comparison with direct measurements of hepatic parenchymal enhancement after gadoxetic acid. However, APRI was not compared against T1 gadoxetic acid T1 relaxometry in their study. Liver failure is the most serious complication after liver resection in patients with liver disease and can be life-threatening [34]. Current available clinical liver function tests such as the indocyanine green clearance test (ICG) [35] and Child–Pugh or MELD clinical scoring systems offer only a global assessment of liver function without taking into account heterogeneous function distribution in the liver. Gadoxetic acid liver MRI offers a unique opportunity to combine qualitative and quantitative morphological and functional information that may improve the assessment of diffuse liver diseases and liver function, and is routinely performed in many centers as part of the evaluation of complications of chronic liver disease. Hence, gadoxetic acid T1 relaxometry could be easily incorporated routinely as part of the multiparametric assessment of focal and infiltrative liver disease with only minimal addition of scanning time to the routine clinical protocol. This imaging tool can also facilitate assessment of total and regional liver functions in patients being considered for liver resection. We acknowledge several limitations to our study. First, because of the retrospective nature of the present study there might have been a potential selection bias in the patient sample. However, our enrolled population included all consecutive patients who underwent gadoxetic acid MRI including T1 mapping technique in a 3-month period at our center who met eligibility criteria, which limits the possibility of sampling bias and reflects the most common clinical scenario in a tertiary referral center. Second, one of the major limitations of the study was that histopathologic diagnosis of liver cirrhosis was not available for all cases, and clinical and consensus reading of MR images was used as the reference standard in the absence of pathology data. However, the absence of advanced liver fibrosis/cirrhosis in CH group was confirmed by liver biopsy in 81% (n = 13/16) of the patients. Also, correlation between T1 mapping parameters and different fibrosis stages was not performed in the current study. Third, we compared hepatic uptake of gadoxetic acid with most widely used clinical parameters to evaluate liver function (Child–Pugh and MELD scoring systems); however, more sophisticated tests for liver function assessment, such as the IGG test or hepatobiliary scintigraphy were not used in our study. Fourth, we use of a fixed dose of gadoxetic acid (mean dose of 0.035 mmol/kg in our patient cohort) in accordance to our current standard of care clinical practice, which is lower to the recommended dose (0.05 mmol/kg). This could potentially affect T1 HBP values; however, it should not have influenced ΔT1 values. Finally, despite the good diagnostic performance of T1 HBP and ΔT1 for detection of liver cirrhosis and differentiating patients with impaired liver function (based on Child–Pugh scores), there was an overlap of T1 values among cirrhotic patients with different stages of liver dysfunction. In addition, cutoff values that were used to calculate sensitivity and specificity were derived retrospectively from the same population, and therefore, likely overestimate the diagnostic
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performance of the method. Thus, the use of these parameters for prediction of liver cirrhosis and liver function in individual patients with chronic liver disease must be confirmed in a prospective study. In conclusion, a 3D DFA-T1 mapping sequence with whole liver coverage used before and after gadoxetic acid injection can help detect cirrhosis and assess liver function. We showed that gadoxetic acid liver uptake measured by T1 mapping is strongly affected by presence of liver cirrhosis and liver function, and provides good discriminatory ability for the detection of cirrhosis (T1 HBP AUC = 0.81; ΔT1 AUC = 0.84). The present study provides the basis for potential new algorithms to assess diffuse liver disease. Future studies will need to assess prospectively the diagnostic performance of gadoxetic acid enhanced-T1 mapping technique of the liver as a quantitative marker of liver fibrosis and liver dysfunction.
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