Chronic liver disease: Quantitative MRI vs CEUS-based microperfusion

Abstract

PURPOSE: To compare the diagnostic performance of MRI-based T1 relaxometry with dynamic contrast-enhanced ultrasound (CEUS)-based liver microcirculation for evaluation of liver function.

MATERIALS AND METHODS: 22 patients underwent Gd-EOB-DTPA-enhanced MRI with T1 relaxometry and previous or consecutive CEUS examinations. A transverse 3D VIBE sequence with an inline T1 calculation was acquired and the reduction rate of T1 relaxation time (rrT1) was evaluated. For CEUS measurements (1–6 MHz), a bolus injection of 1.4 ml sulfur hexafluoride microbubbles were administered and both cine loops and single images from arterial phase up to late phase were stored.

Quantification of time to peak (TTP), rise time (RT), Wash- In Area Under the Curve (WiAUC), mean transit time (mTTI), the wash- in rate (WiR) and Wash-in perfusion index (WIPI)) was performed using a novel quantification software (VueBox^TM). To compare quantification parameters, patients were classified in patients representing a healthy population (rrT1 > 50%, n = 8) and those representing patients with liver disease (rrT1 < 50%, n = 14).

RESULTS: Comparing perfusion parameters TTP, mTTI, and WiR were higher in patients without liver disease compared to patients with impaired liver function (p = 0.10–0.21). RT, WiAUC and WIPI were significantly lower in patients with impaired liver function (RT, 14.8±1.5 s; WiAUC, 17288±6179 a.u., WIPI, 1243±423) compared to patients without liver disease (RT, 21.2±2.6 s, p = 0.032; WiAUC, 71534±25600, p = 0.034; WIPI, 4286±1748, p = 0.04). In a simple linear regression model, none of the perfusion parameters correlated significantly with rrT1 (p = 0.08–0.63).

CONCLUSION: Within the framework of this study, CEUS-based perfusion parameters were not able to assess severity of liver disease, however, WiAUC, RT and WIPI were significant perfusion parameters to make a rough assessment of liver function.

Keywords

Chronic liver disease CEUS microcirculation liver function

1 Introduction

Appropriate evaluation of liver function is important for both preoperative assessment of hepatic functional reserve in patients scheduled for liver resection and monitoring patients with chronic liver disease, i.e. oncologic patients, intensive care patients or patients with diffuse liver disease. In clinical routine, the evaluation of clinical scoring systems like the Child- Pugh Score or the Model for End-Stage Liver Disease (MELD) score as well as continuous measurement of biochemical blood parameters is used for estimating liver function and for selecting therapeutic approaches [17, 25].

In the last few years, hepatocyte- specific contrast agents are increasingly being evaluated with respect to their ability to be used for an imaging based liver function test [2]. Gadoxetic acid (Gd-EOB-DTPA; Primovist^®, Bayer Healthcare, Berlin) is a paramagnetic hepatobiliary magnetic resonance (MR)contrast agent that shares several pharmacokinetic properties with both scintigraphic agents like ⁹⁹Tm mebrofenin and indocyanin green (ICG), considered to be the goldstandard of liver function. Here, the hepatocyte uptake of Gd-EOB-DTPA occurs mainly via the organic anion transporter polypeptides OATP1B1/B3 located at the sinusoidal membrane and biliary excretion via the multidrug resistance-associated proteins MRP2 at the canalicular membrane [51]. Therefore, similar to ICG clearance and mebrofenin uptake, gadoxetate disodium-enhanced MR imaging should provide information for quantitative evaluation of liver function and moreover allows for anatomic delineation of hepatic function in one single examination [11, 29]. As an alternative approach to the direct measurement of signal intensities after Gd-EOB-DTPA administration, the evaluation of T1 relaxation has recently received augmented attention as a diagnostic tool for quantitative evaluation of MRI-based liver function and few studies have demonstrated that Gd-EOB-DTPA-enhanced MR imaging using T1 Relaxometry can estimate liver function according to the ICG-test, the Child-Pugh score, MELD score, or in patients with cirrhosis or chronic liver disease [19–21 , 57].

Using conventional B-mode ultrasound, the progression of chronic liver disease is detected through characteristic macroscopic changes such as a non-homogenous appearance of the liver parenchyma, hepatomegaly, hepatic surface nodularity, splenomegaly, and caudate lobe hypertrophy [13, 15]. Moreover, structural changes of liver parenchyma in chronic liver disease come along with certain hemodynamic disruptions in microscopic liver vessels [6]. Therefore, the study of the hepatic microcirculation could provide information on the degree of structural progression of liver disease and may thus allow for the evaluation of liver function. With the development of dynamic contrast-enhanced ultrasound (CEUS) technology using contrast agents of the second generation, such as sulfur-hexafluoride microbubbles (SonoVue^®, Bracco, Italy), a valuable imaging modality has been established in the evaluation of liver perfusion quantification [16], which may mirror the changes in microcirculation and hemodynamics in early-stage of liver disease. Only few studies have shown the utility of CEUS for fibrosis/cirrhosis assessment using time intensity curve analysis [1 , 45].

The purpose of this study was to compare the diagnostic performance of Gd-EOB-DTPA-enhanced T1 relaxometry and CEUS with consecutive perfusion quantification - two imaging-based approaches for evaluation of liver function.

2 Material and methods

2.1 Patients

This retrospective analysis covered the period of time between March 2015 and September 2015 and included patients who underwent CEUS examination and a Gd-EOB-DTPA-enhanced MRI at 3.0 Tesla with T1 relaxometry. Patients underwent imaging modalities either because of suspected chronic liver disease, as part of a scheduled follow-up examination in the case of known liver disease or because of the presence of a suspicious liver lesion detected during previous imaging based examinations. To be included in the study, patients had to have undergone a Gd-EOB-DTPA-enhanced MR imaging examination with prototype T1 relaxometry sequences using variable flip angles that was performed within 24–72 h of CEUS examination. All patients had no history of previous reaction to SonoVue or Gd.EOB-DTPA, or contraindication to both MRI (e.g., claustrophobia, pacemaker) and Gd-EOB-DTPA administration in terms of no renal failure (defined as a glomerular filtration rate of less than 30 mL/min), respectively.

A total of 22 patients underwent CEUS examination and Gd-EOB-DTPA-enhanced MRI, Informed consent was obtained from all participating patients and the study was conducted in full accordance with the ethical guidelines of the journal [14].

Patients were classified as follows: patients with a reduction rate of T1 relaxation time (rrT1) <50% (n = 14, representing patients with liver disease) and patients with rrT1 > 50% (n = 8, representing a healthy population).

2.2 Contrast enhanced ultrasound

One experienced examiner (more than 3000 ultrasound examinations per year for more than 10 years) performed CEUS examination and, for purpose of analysis, a modified scan with optimized visualization of liver parenchyma was used. High-resolution contrast-enhanced ultrasound examination (1–6 MHz, LOGIQ E9/GE Healthcare, Chalfont St.Giles - UK) was performed using a multiple-frequency convexe probe. 1.4 ml sulfur hexafluoride microbubbles (SonoVue^®, Bracco, Italy) were administered through a cubital vein, followed by 10 ml NaCl. The “lowMI technique” could be used with a reduced mechanical index (MI; <0.16). True Agent detection mode enabled simultaneous data acquisition in B-scan mode and CEUS. Both raw data and digital DICOM and were stored as cine loops up to portal venous phase (60–70 s) and single images were stored up to late phase (3–5 min). Contrast agent inflow and wash-out were observed in the liver parenchyma without changing the position of the probe and patients had to pay attention to relaxed breathing in order to avoid motion artifacts.

Perfusion-quantification was performed using a novel quantification software (VueBox^TM, Bracco Suisse SA –Software Applications, Genève – Suisse), after respective DICOM loops have been generated [49]. After uploading the clip-sequences, a calibration of the software (based on ultrasound system, probe, presets, gain used) and motion compensation are required to achieve sufficient reproducibility independent of the used ultrasound equipment. Regions of interest (ROI) were defined manually in all clip sequences and did not change throughout the whole clip. The ROI was placed in the liver parenchyma as large as possible.

The time-intensity curves (TIC) generated by VueBox^TM were automatically analyzed to determine the CEUS perfusion parameters using a curve fitting process that adjusts the parameters of a mathematical model function to match the experimental linearized signal in an ideal manner. Here, the linearized signal represents the echo-power data as a function of time.

Parameters for perfusion quantification of bolus kinetics were time to peak (TTP), rise time (RT), Wash- In Area Under the Curve (WiAUC), mean transit time (mTTI), the wash- in rate (WiR) and Wash-in perfusion index (WIPI), defined as WiAUC/RT. WiAUC, WiR and WIPI were given in arbitrary units, TTP, mTTI, and RT were given in seconds.

2.3 MR imaging

A clinical whole body 3 T system (Magnetom Skyra, Siemens Healthcare, Erlangen; Germany) was used for imaging and a combination of spine and body array coils (18-channel body matrix coil, 32-channel spine matrix coil) was used for signal reception. Before and 20 min after Gd-EOB-DTPA (Primovist; Bayer Schering Pharma AG, Berlin, Germany) administration a T1-weighted volume-interpolated breath-hold examination (VIBE) sequence with fat suppression (repetition time (TR), 3.09 ms; echo time (TE), 1.16 ms; flip angle, 9°; parallel imaging factor, 2; slices, 64; reconstructed voxel size, 1.3×1.3×3.0 mm) was acquired during breath-hold. Every sequence covered the entire liver before Gd-EOB-DTPA administration and in hepatobiliary phase after 20 min (HBP). Gd-EOB-DTPA dose (0.025 mmol/kg body weight) was adapted to patients’ body weight and contrast media was administered via bolus injection with a flow rate of 1 mL/s and followed by 20 mL NaCl.

In addition to the routine imaging protocol, additional T1 relaxometry sequences of the liver were performed before Gd-EOB-DTPA administration and in HBP 20 min after contrast media administration using a prototypical VIBE sequence with variable flip angles (1°, 7°, 14°). To improve the homogeneity of respective T1 maps, a B1 map of the entire liver was acquired before T1 mapping and color-coded T1 maps were calculated inline. The whole liver was covered during breath-hold using an acceleration factor of 4 and CAIPIRINHA (Controlled Aliasing In Parallel Imaging Results in Higher Acceleration) as a parallel imaging technique.

2.4 Image analysis

At the MR scanner workstation (Skyra, Siemens, Erlangen, Germany), 4 regions of interest (ROIs; liver: 3 in right lobe, 1 in left lobe) were located in T1 maps with reasonable care before and after administration of Gd-EOB-DTPA. We avoided focal solid hepatic lesions, imaging artifacts and major branches of the portal or hepatic veins. The mean T1 values for the 4 ROIs were regarded as the representative T1 value of the liver. Each ROI was a circle (the size of the ROI ranged between 0.9 cm² and 3.8 cm²) that was chosen as large as possible. ROIs were placed at the same imaging sequence in the T1 maps before and after Gd-EOB-DTPA administration.

The reduction rate of T1 relaxation times (rrT1) between pre- and post-Gd-EOB-DTPA enhancement was calculated as follows: $Reduction rate of T 1 relaxation time = \frac{{T 1}_{pre} - {T 1}_{post}}{{T 1}_{pre}} \times 100 %$ (1) where T1_pre is the T1 relaxation time before Gd-EOB-DTPA administration and T1_post is the T1 relaxation time 20 min after Gd-EOB-DTPA administration.

2.5 Statistical analysis

Data are expressed as mean±standard error of the mean (SEM). We used the non-parametric Mann-Whitney test to analyze differences between patients with normal liver function and patient group with impaired liver function. Simple linear regression model were calculated to assess the predictive power of the reduction rate of the T1 relaxation times (rrT1) and CEUS based perfusion parameters.

All tests were two-sided, and values of p < 0.05 indicate a significant difference. Statistical analysis was performed with IBM SPSS Statistics (version 23, Chicago, IL).

3 Results

Twenty-two patients (mean age: 62.0±11.9; 16 men, 8 women) underwent Gd-EOB-DTPA-enhanced 3T MRI with T1 relaxometry and previous or consecutive CEUS examinations. Patients were classified as patients with a reduction rate of T1 relaxation time (rrT1) <50% (n = 14; mean rrT1 (%)=38.1±7.6) representing patients with liver disease and patients with rrT1 > 50% (n = 8; mean rrT1 = 65.0±4.4) representing a healthy population. Age, weight and hight was not significantly different in healthy patients compared to patients with impaired liver function (age (years); 66.4±12.3 vs. 59.4±11.4, p = 0.18; weight (kg); 75.6±11.3 vs. 78.5±9.9, p = 0.44; height (m); 1.80±0.08 vs. 1.70±0.06, p = 0.27).

Patient characteristics are shown in Table 1.

The examined perfusion parameters generated by VueBox using ROI analysis (ROI_liver) were TTP, WiAUC, mTTI, RT, WiR, and WIPI Fig. 1.

Comparing perfusion parameters derived from ROI _liver TTP, mTTI, and WiR were higher in patients without liver disease (rrT1 > 50%) compared to patients with impaired liver function (rrT1 < 50%; p = 0.10–0.21) (Table 2, Fig. 2). RT, WiAUC and WIPI were significantly lower in patients with impaired liver function (RT, 14.8±1.5 s; WiAUC, 17288±6179 a.u., WIPI, 1243±423) compared to patients without liver disease (RT, 21.2±2.6 s, p = 0.032; WiAUC, 71534±25600, p = 0.034; WIPI, 4286±1748, p = 0.04).

In a simple linear regression model, none of the perfusion parameters correlated significantly with rrT1 (p = 0.08–0.63, Table 3).

4 Discussion

In clinical routine several scoring systems (Meld score, Child-Pugh score) and clinical bedside tests (ICG test, LiMax test) are widely accepted for assessing hepatic dysfunction and have been established as non-invasive valuable tools for estimating true global liver function [20 , 56]. Here, the ICG plasma clearance test is now the most widely used quantitative liver function test in a clinical setting as it is removed from the blood stream exclusively by the liver, has no reported toxicity and undergoes neither intrahepatic conjugation nor enterohepatic circulation [7 , 18].

However, these methods only provide a global assessment of liver function and are limited when liver function is distributed inhomogeneously. A more convenient, imaging-based tool that would allow for both providing anatomical information and estimating segmental liver function would therefore be desirable. Reflecting the metabolic activity of different areas of liver parenchyma such imaging-based liver function tests were first developed in nuclear medicine using tracers such as ⁹⁹mTc galactosyl and ⁹⁹mTc mebrofenin [4, 12]. However, the need for a radioactive tracer as well as low temporal and spatial resolution are limitations of this expensive and time-consuming method.

ICG and Mebrofenin undergo an OATP1B1/B3-mediated uptake at the basolateral membrane of hepatocytes and a MRP2-mediated biliary excretion at the canalicular membrane - this is a common property these acid compounds share with gadoxetic acid (Gd-EOB-DTPA, Eovist, Primovist; Bayer Health Care, Berlin, Germany), a paramagnetic hepatobiliary magnetic resonance (MR) contrast agent for T1- weighted imaging [11 , 29]. Therefore, in recent years, increasing evidence has emerged to suggest that Gd-EOB-DTPA- enhanced MRI can be used for evaluation of global and remnant liver function [10 , 57].

Gd-EOB-DTPA-enhanced MRI is already used in an increasing number of patients scheduled for liver surgery allowing both delineation of tumors from liver parenchyma as well as assessment of topography with regards to parenchymal liver vessels. In addition to presenting morphological information, Gd-EOB-DTPA-enhanced MRI could therefore provide functional information of the liver parenchyma in a single examination.

In this context both signal intensity (SI)-based indices and T1 relaxometry have been proposed for evaluation of liver function. Here, the evaluation of the T1 relaxation time is an alternative and possibly superior approach to the direct measurement of SI and has recently received augmented attention [20 , 57]. While SI measurements, which depend on many technical parameters like the used receiver coils and radiofrequency amplifier, can neither be compared between repeated examinations of the same patient, nor between different patients due to the relative character on an arbitrary scale, absolute values derived from T1 relaxometry can be measured in a defined unit (ms), providing comparable parameters.

However, cross sectional imaging techniques such as dynamic Gd-EOB-DTPA-enhanced magnetic resonance imaging are time- consuming and cost-intensive methods and, in some clinical settings, lack of availability and safety.

Therefore, in the work- up process of patients with chronic liver disease, B-mode ultrasonography with consecutive Color-Coded Duplex sonography (CCDS) of the major hepatic vessels is often the first-line imaging study. While characteristic liver disease-induced changes of liver parenchyma can be detected with B-mode ultrasonography, CCDS is used to analyze hemodynamic changes in macroscopic liver vessels, i.e. waveforms in hepatic veins, resistance indices in hepatic artery and blood velocity in the portal vein [6, 15]. These changes result from both the development of intrahepatic shunts in the context of liver damage-induced angiogenesis and ongoing fibrogenesis with augmentation of the hepatic vascular tone and consecutive increase of the mechanical resistance to the portal blood flow [3 , 48].

Many reports have shown that CCDS may be a valuable non-invasive method to evaluate the hemodynamics in macroscopic liver vessels emphasizing the value of Doppler sonography in assessing the diagnosis of portal hypertension and progression of liver cirrhosis [9 , 59]. However, especially regarding the grading of liver disease, the clinical impact of Doppler measurements in the setting of chronic liver disease is discussed controversially due to limited data, contradictory results and lack of reproducibility [5 , 34].

As a valuable addition to B- mode ultrasound and CCDS, Contrast-enhanced ultrasonography (CEUS) has been established. CEUS is performed after intravenous administration of a suspension of gas-filled microbubbles, which remain entirely within the intravascular space and thus act as a blood pool tracer. This allows for both improved detection and characterization of focal liver lesions and imaging of functional aspects of microvascularization in biological tissues in real-time [24 , 55], which might mirror the early hemodynamic changes in fibrogenesis and thus provide information on the degree of structural progression of liver disease.

CEUS can be performed on different high-end ultrasound units allowing for time intensity curve (TIC) analysis. However, to use different data sets from different units and to improve reproducibility, a dedicated perfusion software is required for advanced perfusion analysis.

We examined patients with (rrT1 < 50%) and without (rrT1 > 50%) chronic liver disease using CEUS with novel perfusion software VueBox^TM to analyse hepatic parenchymal perfusion, which might mirror the changes in microcirculation and hemodynamics.

In our study, comparing the two patient groups, the examined perfusion parameters RT, WiAUC, and WiPI were significantly higher in patients without liver disease (p = 0.032–0.04).

Decreasing wash-in indices (WiAUC, WiPI) in patients with liver disease might be the result of an ongoing architectural distortion of the microvascularization of the liver parenchyma leading to an increased vascular resistance and a consecutive kinetic wash-in.

However, the time to reach the peak of enhancement (TTP) was lower (p = 0.17) and RT significantly lower (p = 0.03), respectively, in patients with liver disease (TTP, 18.0±1.6 s vs. 26.0±3.4 s; RT, 14.8±1.5 s vs. 21.2±2.6). This might reflect the development of intrahepatic shunts that allow branches of hepatic arteries and portal veins to skip cirrhotic areas of liver parenchyma, leading into the central venous compartment immediately. In the literature, the mTTI has been shown to decrease in the case of liver disease [31 , 45]. Here, the hepatic vein arrival time and the transit time between the artery and the hepatic vein has been shown to be significantly shorter in patients with severe fibrosis or cirrhosis, most likely due to the development of intrahepatic venous shunts. Our results also revealed a reduced mTTi in patients with liver disease (173±35 s vs. 205±37 s), however, there was no significant difference (p = 0.21) between the two patients groups.

Including all patients and calculating a simple linear regression model of CEUS-based perfusion parameters on rrT1, we could not find a significant correlation (p = 0.08–0.63) with the best correlation coefficient for WIPI (r = 0.43).

The main limitation of our study is the small number of patients included. Studies in much larger populations are needed to make conclusions on the value of Vuebox analysis of CEUS data in diagnosing chronic liver disease. Moreover the acquisition and analysis of CEUS cine loops requires dedicated software and equipment, however, the use of a perfusion software may increase the reproducibility of CEUS findings, being useful for standardizing CEUS protocols, which may help to compare different findings obtained by different operators.

In conclusion, within the framework of this study, our experience with VueBox-assisted CEUS studies of the liver revealed that CEUS-based perfusion parameters were not able to assess severity of liver disease in the frame of grading liver function. However, significant differences of perfusion parameters (RT, WiAUC, WIPI) between healthy patients and patients with chonic liver disease, characterized by the reduction rate of T1 relaxation time using Gd-EOB-DTPA-enhanced MRI, could be observed. This may allow for making a rough assessment regarding liver function. Further investigations need to be made to assess in which extend perfusion-assisted CEUS may represent a valuable non-invasive tool to evaluate liver disease severity on the one hand and monitor the progression of chronic liver diseases on the other hand.

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