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Non-invasive in vivo Imaging Grading of Liver Fibrosis

  • Hanyu Jiang#,,
  • Tianying Zheng#,,
  • Ting Duan,
  • Jie Chen and
  • Bin Song*,
Journal of Clinical and Translational Hepatology 2018

DOI: 10.14218/JCTH.2017.00038

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Abstract

Liver fibrosis (LF), a common consequence of chronic liver diseases with various etiologies, is characterized by excessive accumulation of macromolecules, including collagen, glycoproteins and proteoglycans, in the liver. LF can result in hepatic dysfunction, cirrhosis, portal hypertension and, in some cases, hepatocellular carcinoma. As the current gold standard for diagnosing LF, liver biopsy, however, is invasive and prone to sampling errors and procedure-related complications. Therefore, developing noninvasive, precise and reproducible imaging tests for diagnosing and staging LF is of great significance. Conventional ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging can depict morphological alterations of advanced LF, but have relatively limited capability characterizing early-stage LF. In order to optimize the diagnostic performances of noninvasive imaging techniques for LF across its entire spectrum of severity, a number of novel methods, including US elastography, CT perfusion imaging and various MR imaging–based techniques, have been established and introduced to clinical practice. In this review, we intended to summarize current noninvasive imaging techniques for LF, with special emphasis on the possible roles, advantages and limitations of the new emerging imaging modalities.

Keywords

Liver cirrhosis, Ultrasonography, Computed tomography, Magnetic resonance imaging

Introduction

Liver fibrosis (LF) is a characteristic consequence of repetitive liver parenchymal damage triggered by various etiologies, and is typified by excessive accumulation of macromolecules, such as collagens, glycoproteins and proteoglycans, in the liver extracellular matrix1 (Fig. 1). Currently, alcoholic liver disease, chronic hepatitis B and chronic hepatitis C are the most prevalent causes of LF.2,3 LF can result in progressive hepatic dysfunction, cirrhosis, portal hypertension and, in some cases, hepatocellular carcinoma (HCC).2 Currently, although very limited treatment options beyond liver transplantation are effective for end-stage LF, early-stage LF is usually a treatable condition.4 Thus, as prognosis and patient management of chronic liver diseases (CLDs) are strongly related to LF severity, early and accurate diagnosis of LF is of great importance in clinical practice.

Mechanism of liver fibrosis.
Fig. 1.  Mechanism of liver fibrosis.

As a result of continuous liver injury, activation of vitamin A-rich quiescent hepatic stellate cells induced by necrosis and apoptosis of hepatocytes triggers accumulation of extracellular matrix. EC, endothelial cell; HSCs, hepatic stellate cells.

Liver biopsy, a standard procedure of obtaining liver tissue for histopathological assessment, is the gold standard for LF currently.5 The most widely adopted classifying system for LF triggered by chronic autoimmune and viral hepatitis is the METAVIR scoring system, where the spectrum of LF severity is divided into five stages, from no fibrosis (F0) to cirrhosis (F4).6 Accurate as it is, liver biopsy is invasive and limited by inter- and intra-observer variability, and sampling errors.5,7 Besides, liver biopsy can lead to various complications and requires considerable operator expertise. Therefore, the introduction of noninvasive diagnostic approaches is pivotal to address the above limitations of liver biopsy.

Imaging approaches comprising ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging have been playing significant roles in the assessment of LF for the past decades. The introductions of elastography and several CT and MR-based techniques have further improved the diagnostic performances for LF. In this review, we focused on noninvasive imaging evaluation of LF, with special emphasis on the roles of new emerging imaging techniques.

Noninvasive imaging evaluation of LF

Noninvasive imaging approaches allow detection, staging and monitoring of LF. Morphologic alterations of the liver and signs of portal hypertension are the most significant imaging manifestations of end-stage LF (Table 1) with high specificity. However, these signs demonstrate limited sensitivity and are visible only in advanced cases, thus not being accurate for staging LF over its entire spectrum of severity.8,9 In patients with less advanced LF, the liver parenchyma is usually normal in appearance or exhibits only subtle, nonspecific heterogeneity. In addition, extrahepatic findings, which may include ascites, splenomegaly and portosystemic varices, may be present in other conditions, hence not being specific for LF.10 Luckily, novel emerging imaging techniques are being validated to measure LF, as discussed below. Advantages and limitations of each imaging modality are documented in Table 2.

Table 1.

Imaging signs of liver fibrosis

Liver morphologyNodular liver surface (surface nodularity)
Heterogeneous parenchyma
Expanded gallbladder fossa
Altered liver size
Hypertrophy of caudate lobe and left lobe
Atrophy of the segment IV and medial segment of left hepatic lobe
Hepatic arteryIncreased diameter and tortuosity
Hepatic veinsDecreased diameter and altered straightness
Portal venous systemDilation of portal, splenic and superior mesenteric veins
SpleenSplenomegaly
Portosystemic collateral circulationFormation of gastroesophogeal, paraesophogeal, left gastric, short gastric, umbilical and abdominal wall varices with engorged and tortuous appearance
Splenorenal/gastrorenal shunts and retroperitoneal shunts
Ascites
Table 2.

Major advantages and limitations of available non-invasive imaging methods used for liver fibrosis evaluation

TestAdvantagesLimitations
UltrasoundConventional ultrasoundWidely available and inexpensive
real-time
Considerable interobserver variability
Relatively low specificity
Reproducible and without ionizing radiation
Highly sensitive in detecting portal and hepatic vein thrombosis
Interference by intestinal gas, obesity, patient respiration, fasting status, collateral pathways, hepatic steatosis and inflammation
Able to measure intrahepatic and systemic hemodynamic changes
Contrast-enhanced ultrasoundAble to measure intrahepatic and systemic hemodynamic changes with better contrast than Doppler USRequire injection of intravenous contrast agents and operator expertise
More expensive than conventional ultrasound
Ultrasound elastographyTransient elastographyWidely available and well validated in most etiologies of chronic liver diseases
Highly portable
Shear wave frequency well controlled
No anatomic images captured or the exact measurement location recorded during examination
Restricted to patients with no obesity, narrow intercostal space or ascites
Lack standardized cut-offs for each liver fibrosis stage
Point shear wave elastographyManually selected ROI allows quantitative analysis of liver stiffness and enables more reliable monitoring with less sampling variabilityMore expensive and expertise required, whereas less validated than transient elastography
Generates more robust shear waves than transient elastography
Can be applied in patients with obesity or ascites
Shear wave frequency is hard to control and therefore may introduce measurement variability
2D-shear wave elastographyUltrafast imaging allows generation of real-time quantitative elastogramsSame limitations as point shear wave elastography
Several ROIs can be placed on the elastograms
Reduced sampling variability
Computed tomographyConventional computed tomographyWidely available and well validatedIonizing radiation exposure
Allows a full cross-sectional visualizationRequire injection of intravenous contrast agents
Signs of morphologic liver alterations, cirrhosis and portal hypertension are specificNot sensitive enough to detect and stage less advanced fibrosis
Computed tomography perfusion imagingAllows quantitative measurement regional and systemic hemodynamic changesLess available or validated than conventional computed tomography
More expensive and more expertise required than conventional computed tomography
Magnetic resonance imagingConventional magnetic resonance imagingNo ionizing radiation
Liver fibrosis manifests a specific enhancement pattern
Aids in differentiation of focal fibrosis from cirrhosis-related vascular lesions
More expensive and time-consuming than conventional computed tomography
Elevated risk of nephrogenic systemic sclerosis due to gadolinium contrast agent injection
Magnetic resonance elastographyHigh diagnostic accuracy for advanced fibrosis and cirrhosis
Robust
Can be applied in patients with obesity and/or ascites
Able to assess a larger proportion of the liver than ultrasound elastography, which may reduce sampling variability for patient monitoring
High cost and time-consuming
Limited availability
Limited application in patients with iron overload, steatosis, vascular congestion or cholestasis
Acquired with inconsistent breath holds
Insufficient evidence regarding its diagnostic performances
Diffusion weighted magnetic resonance imagingWidely available and relatively easy to perform
Reproducible
Robust
Apparent diffusion coefficient well correlated with liver fibrosis stage
Intravoxel incoherent motion model can add additional diagnostic benefits
Results may be influenced by perfusion effects, hepatic steatosis, edema, iron accumulation and liver inflammation
Sensitive to susceptibility and motion-related artifacts
Acquisition relies significantly on several imaging parameters including field strength and b values
Gadoxetic acid disodiumProvides both hemodynamic information and lesion function information in a single examinationLess validated than nonspecific gadolinium chelates
Hepatobiliary phase hypointensity is not specific for hepatocellular carcinoma
High diagnostic accuracy for focal liver lesions
Early detection of hepatocellular carcinoma
Can measure preoperative liver function
Magnetic resonance perfusion imagingAllows quantitative measurement of regional and systemic hemodynamic changesTime-consuming
Less available or validated than conventional magnetic resonance imaging
Can be affected by the cardiac status, fasting state, hepatic congestion, inflammation, liver masses, and hepatic portal venous flow
Image quality not sufficient for assessing small nodules
May require a second contrast material injection

US

Conventional US: Gray-scale and Doppler US are the conventional US techniques used as first-line imaging examinations for patients with suspected LF. These methods are easy to perform, real-time, noninvasive, reproducible, inexpensive, well validated and widely available, with no ionizing radiation. Besides, they are highly sensitive in detecting portal and hepatic vein thrombosis.11 Parameters comprising liver surface nodularity, altered liver size and/or splenomegaly, bluntness of liver edge, altered liver parenchymal echogenicity with coarsened echotexture, and altered portal vein blood flow velocity and effective portal liver perfusion, have been suggested to be useful in evaluating LF.11,12

However, the diagnostic capacity of conventional US in LF can be limited due to considerable interobserver variability, low specificity, and interference by intestinal gas and obesity.13 Besides, the Doppler US can be affected by patient respiration, fasting status, collateral pathways, hepatic steatosis and inflammation.14,15

Contrast-enhanced US (CEUS): CEUS is an emerging US modality based on intravenous administration of specific contrast agents. The contrast media are gas-filled microbubbles which significantly enhance the intravascular blood flow against other tissues.8,16 It allows for the evaluation of hemodynamic changes during LF evolution. The hepatic vein arrival time (HVAT), defined as the time taken for the contrast media to reach the hepatic vein (HV) after injection, was reported to have negative correlations with the severity of LF or portal hypertension.17,18 As LF evolves, increased formation of sinusoid capillaries and arterio-/portovenous shunts can result in decreased HVAT.16 Kim et al.19 reported that, HVAT was negatively correlated with HV pressure gradient (r2 = 0.545, p < 0.001), and that with 14 seconds as a cut-off value, HVAT achieved sensitivity, specificity and the area under the receiver operating characteristic curve (AUROC) of 0.927, 0.867 and 0.973, respectively, for evaluating clinically significant portal hypertension. In addition, a shorter HVAT was significantly associated with esophageal varices and worse Child-Pugh score.

CEUS is a simple and noninvasive approach for characterizing hemodynamic changes of LF and portal hypertension. However, CEUS is more expensive than conventional US and requires injection of corresponding intravenous contrast agents and considerable operator expertise. These disadvantages may limit its application in routine clinical practice.

US elastography: Imaging-based elastography is an emerging technology that measures tissue stiffness and other mechanical properties noninvasively.20,21 Evaluated with elastography, share wave has particle motion perpendicular to the direction in which the wave propagates. The traveling velocity of shear waves has been validated to correlate with tissue stiffness: shear waves travel faster in stiff tissues (inflamed or fibrotic liver) and slower in soft tissues (normal or fatty liver).22,23 US elastography is able to assess liver stiffness, which increases due to fibrosis in CLDs, by tracking and measuring the speed of shear waves via liver parenchyma. Currently, shear wave imaging (SWI) is the most widely used US elastography technique for evaluating LF. SWI permits quantitative assessment of tissue stiffness and stiffness-related parameters by tracking shear waves propagating through the liver.20

Three major SWI-based techniques, including transient elastography (TE), point shear wave elastography (pSWE) and two-dimensional shear wave elastography (2D-SWE), are commercially available today.24 Among these approaches, TE is not an imaging technique, while pSWE and 2D-SWE are both imaging techniques incorporated in US scanners.

TE is the first US-based type. TE is widely available and well validated in hepatitis C virus (HCV) and chronic alcoholic liver disease-related LF, and to a lesser extent in hepatitis B virus (HBV) and nonalcoholic fatty liver disease (NAFLD) patients.2527 In TE, liver stiffness is evaluated by tracking the speed of shear waves propagating through the liver. The shear waves are generated by an ultrasound transducer, which is usually placed through an intercostal space above the right liver lobe. Propagation of the shear wave is tracked with its speed measured and the tissue stiffness reported in the form of kilopascals (kPa). A shear-wave propagation graph is displayed after each acquisition.

It has been suggested that TE is useful in discriminating no and mild fibrosis (F0-F1) from advanced fibrosis and cirrhosis (F3-F4); however, the accuracy is poor among the early stages of LF. Sporea et al.28 included 199 consecutive patients and reported that, compared with liver biopsy, an optimal cut-off value of 6.8 kPa could achieve 59.6% sensitivity and 93.3% specificity for significant fibrosis (≥ F2), with an AUROC of 0.773. Their study indicated that 6.8 kPa was the best cut-off value to distinguish significant fibrosis from no or mild fibrosis, with acceptable diagnostic accuracy.

In order to further explore the diagnostic accuracy and determine optimal cut-off values of TE for LF assessment, several meta-analyses have been conducted. Friedrich-Rust et al.29 investigated 50 studies and reported that for the detection of significant fibrosis (≥F2), TE demonstrated an AUROC of 0.84 with an optimal cut-off value of 7.6 kPa, while for cirrhosis (F4), the best cut-off value was 13 kPa with an AUROC of 0.94. However, with 40 studies analyzed, Tsochatzis et al.30 reported that, although pooled sensitivity and specificity was 0.79 and 0.78 for F2 and 0.83 and 0.89 for F4, no optimal cut-off for individual fibrosis stage was achieved because cut-offs ranged widely and presented significant overlaps within and between LF stages. Their studies implied that, for each LF stage, the best cut-off values are difficult to determine because these values are highly dependent on the etiology of CLD.

Recently, TE has been recommended by the American Gastroenterological Association, European Association for the Study of Liver and European Federation of Societies for Ultrasound in Medicine and Biology guidelines to be useful in assessing CLDs and chronic viral hepatitis-related LF.31 The American Gastroenterological Association guidelines recommended 12.5 (±1) kPa as the optimal cut-off value for diagnosis of cirrhosis (F4) in patients with chronic HCV infection and alcoholic liver disease, whereas 11.0 (±1) kPa is recommended for chronic HBV patients.32 Moreover, the European Federation of Societies for Ultrasound in Medicine and Biology guidelines issued values above 6.8–7.6 kPa as being highly correlated with the presence of significant fibrosis (≥F2) and that those ranging between 11.0–13.6 kPa may indicate cirrhosis (F4).33 Several algorithms combining TE and serum biomarkers have been proposed to increase diagnostic accuracy and reduce the number of biopsies, mainly in viral hepatitis.3436 Recently, the European Association for the Study of Liver-ALEH have suggested algorithms for noninvasive tests in first-line fibrosis staging in patients with hepatitis B and C infections37(Fig. 2).

Algorithms for noninvasive tests in first-line fibrosis staging of patients with hepatitis B (a) and C (b) infection suggested by the European Association for the Study of Liver-ALEH.
Fig. 2.  Algorithms for noninvasive tests in first-line fibrosis staging of patients with hepatitis B (a) and C (b) infection suggested by the European Association for the Study of Liver-ALEH.

Modified from EASL-ALEH Clinical Practice Guidelines.37

Abbreviations: ALT, alanine aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; TE, transient elastography.

TE is relatively inexpensive, highly portable, widely available, reproducible and easy to perform. However, the technique lacks standardized cut-offs for each fibrosis stage and may be limited in patients with ascites, obesity or narrow intercostal space. Most importantly, the exact measurement locations are not recorded because no anatomic image is captured with TE, which may introduce sampling variability for monitoring LF progress over time.

pSWE is a novel US elastography technique incorporated into conventional US scanners. In pSWE, a region of interest (ROI) of the liver is excited by a high-frequency acoustic radiation force impulse mechanically. This impulse causes tissue expansion and generates shear waves propagating perpendicular to the ultrasound beam axis.38,39 The speed of the shear wave is measured and reported in m/s, with a range between 0.5–5 m/s in different abdominal conditions.40

pSWE has been applied to assess LF of various etiologies in clinical practice. Recently, a meta-analysis of 1163 patients compared the diagnostic performances of TE and pSWE for LF. It reported that for diagnosing significant fibrosis (≥F2), the pooled sensitivity was 0.74 and specificity 0.83 for pSWE; while for TE, the summarized sensitivity and specificity was 0.78 and 0.84, respectively. In cases with cirrhosis (F4), the pooled sensitivity and specificity were 0.87 and 0.87 for pSWE, respectively, and 0.89 and 0.87 for TE. Their study demonstrated no statistically significant difference between the diagnostic accuracies of pSWE and TE for significant fibrosis (≥F2) or cirrhosis (F4).41

pSWE possesses several advantages. First, this technique permits quantitative evaluation of liver stiffness in a manually selected ROI, which enables more reliable patient monitoring and follow-up. Second, because the shear waves are generated locally within the liver, pSWE is more robust than TE and thus can be applied in patients with obesity and/or ascites. However, pSWE is more expensive, requires more expertise to perform, and is less available and validated by current studies compared with TE. Besides, the shear wave frequency is difficult to control precisely in the setting of pSWE, which is likely to introduce measurement variability.

2D-SWE technique, as the currently newest SWI-based method, applies acoustic radiation force focused at successively greater depths on an axial line to stimulate microscopic tissue movements and generate shear waves.42 The entire imaging plane is scanned with high temporal resolution in one acquisition by an ultrafast imaging technique. This allows the real-time generation of quantitative elastograms.43,44 Shear wave speed (m/s) or Young’s modulus (kilopascal) are reported to depict tissue stiffness in 2D-SWE.

Much effort has been devoted to comparing the diagnostic performances of 2D-SWE and other SWI-based methods for staging LF.4448 Leung et al.46 investigated 226 patients and 171 healthy patients with liver biopsy as a reference standard. They reported the superiority of 2D-SWE over TE in diagnostic accuracy of all fibrosis stages. The AUROCs for 2D-SWE and TE, respectively, were 0.86 and 0.80 for LF ≥F1, 0.88, and 0.78 for ≥F2, 0.93 and 0.83 for ≥F3, and 0.98 and 0.92 for F4. However, another study comparing the diagnostic potential of TE, pSWE and 2D-SWE for LF found no statistically significant diagnostic difference between TE, pSWE or 2D-SWE for LF ≥F2 and F4 with 332 patients.45

2D-SWE can be applied in patients with ascites and is able to analyze multiple ROIs according to the elastograms, which reduces some of the possible sampling variability with TE and pSWE. Nevertheless, the applications of 2D-SWE in LF may have been limited due to its restricted availability and insufficient evidence concerning its diagnostic performance. Moreover, it is more expensive and requires more operator expertise. Therefore, further studies and intensive validations are encouraged to demonstrate its concrete role in LF staging and monitoring of its potential clinical superiority.

CT

CT and MR imaging are useful cross-sectional imaging modalities for LF. The diagnosis, staging and surveillance of HCC, a major consequence of CLDs and LF, are primarily established by multiphasic CT or contrast-enhanced MR imaging findings.49,50 Liver morphology changes, signs of cirrhosis and portal hypertension can be directly evaluated by CT in patients with end-stage LF, as mentioned above (Table 1) (Fig. 3). However, CT is not sensitive enough to detect and discriminate less advanced fibrosis.

Morphologic liver changes in a 51-year-old male patient diagnosed with HBV-related liver cirrhosis.
Fig. 3.  Morphologic liver changes in a 51-year-old male patient diagnosed with HBV-related liver cirrhosis.

The patient presented with anorexia and nausea for 6 years, as well as melena and fatigue for 1 year. Nonenhanced (a), arterial phase (b) and portal phase (c) CT images show surface nodularity, widening of fissures, atrophy of the right lobe, and relative enlargement of the left lobe.

CT perfusion imaging is a functional CT-based imaging technique which permits quantitative measurements of the hepatic and systemic hemodynamic changes in patients with LF.5153 One study with 21 cirrhosis patients demonstrated that two parameters—splenic arterial flow and splenic clearance—were inversely correlated with hepatic venous pressure gradient, and that a splenic clearance cut-off value of 125 ml/min/100 mL yielded 94% sensitivity and 100% specificity for severe portal hypertension.51 This study suggested that CT perfusion can be applied to quantitatively evaluate portal hypertension in patients with LF.

MR imaging

MR imaging has been widely applied and well validated to assess LF and its complications. Nevertheless, early detection and accurate grading of LF with the use of MR imaging remains one of the major challenging areas in liver imaging. Recently, several novel MR techniques have been introduced for this purpose.

Conventional MR imaging: Like CT, widely applied conventional MR imaging is able to identify liver morphology changes, signs of cirrhosis and portal hypertension in patients with advanced cirrhosis of various etiologies (Table 1). Administration of intravenous gadolinium-based contrast agents can further improve the visibility of LF and its related complications. On T1-weighted images, LF is often hyperintense.54 Moreover, LF usually displays a distinctive progressive enhancement pattern, of which the peak enhancement is usually observed during the late venous and equilibrium phases.54 However, cirrhosis-related vascular lesions, such as HCC and arterioportal shunts, can result in diagnostic confusion over focal fibrosis. Some imaging features may aid in the differential diagnosis. Presence of the specific enhancement pattern, reticular appearance and wedge-shaped configuration usually favor a diagnosis of LF.54

MR elastography: MR elastography is an emerging MR-based imaging modality which quantifies tissue stiffness noninvasively by assessing the propagation of mechanical waves through media55 (Fig. 4). As the shear waves propagate through the liver parenchyma, MR images are acquired with the use of a gradient-echo sequence. Similar to US elastography, the speed and wavelength of the shear wave through liver tissue in MR elastography is positively correlated with tissue stiffness.56 Therefore, liver stiffness can be evaluated by placing and measuring ROIs on the elastograms manually.

Illustration of the mechanical driver device in MR elastography.
Fig. 4.  Illustration of the mechanical driver device in MR elastography.

The system is composed of the active driver in the control room that generates compressions waves, which are transmitted through a plastic tube to the passive driver in the scanner room placed adjacent to the patient’s right anterior body wall that generates shear waves and the direction of shear wave propagation (curved arrows).

MR elastography has been validated for the assessment of LF since its introduction.5759 A prospective study58 demonstrated that the diagnostic performance of MR elastography for LF was significantly better than that of ultrasound elasticity, pSWE, or the combination of ultrasound elasticity and pSWE. Other prospective studies59,60 reported that the frequency-independent cut-off values of MR elastography were 2.84 kPa for LF ≥F1, 3.18 kPa for ≥F2, 3.32 kPa for ≥F3 and 4.21 kPa for F4. The AUROCs were 0.9128, 0.9244, 0.9744 and 0.9931 for LF ≥F1, ≥F2, ≥F3 and F4, respectively. In a retrospective study, Venkatesh et al.61 demonstrated that MR elastography performed significantly better than conventional MR imaging for staging significant fibrosis (≥F2) (AUROC: 0.98.9 vs. 0.71–0.82, p < 0.001) and cirrhosis (F4) (AUROC: 0.93.5 vs. 0.61–0.80.5, p < 0.01).

The pooled diagnostic performances of MR elastography for LF staging, as reported by several meta-analyses, were good to excellent. Singh et al.62 conducted a meta-analysis of 12 retrospective studies and reported that, with liver biopsy as the gold standard, MR elastography demonstrated mean AUROCs of 0.84, 0.88, 0.93 and 0.92 for LF stage ≥F1, ≥F2, ≥F3 and F4, respectively. Their results suggested that MR elastography yielded excellent diagnostic accuracy for staging advanced fibrosis (≥F3) to cirrhosis (F4) and good performance regarding significant (≥F2) and mild fibrosis (≥F1) independent of sex, obesity, and etiology of CLD.

Using NAFLD cohorts, two cross-sectional prospective studies established head-to-head comparisons between MR elastography and TE for LF diagnosis in sequential patients. Park et al.63 consecutively enrolled 104 patients who underwent MR elastography, TE and liver biopsy in the United States. They demonstrated superior performance of MR elastography over TE in detecting any fibrosis (≥F1 vs. F0) (AUROC: 0.82 vs. 0.67, p = 0.0116), with cut-off values of 2.65 kPa for MR elastography and 6.10 kPa for TE, respectively. However, MR elastography did not increase accuracy for diagnosing other LF stages. This finding was not consistent with those of the other study, conducted by Imajo et al.64 in a Japanese cohort. Imajo et al.64 revealed that MR elastography was significantly more accurate than TE in diagnosing significant fibrosis (≥F2 vs. F0–1), advanced fibrosis (≥F3 vs. F0–2) and cirrhosis (F4 vs. F0–3), but not in any fibrosis (≥F1 vs. F0). This variation may have been attributed to the geographic heterogeneity of the included subjects and different cut-off values applied for each LF stage. Hence, further large scale prospective studies are encouraged to determine the optimal cut-off values of each LF stage for Western and Asian NAFLD populations.

Another prospective cross-sectional study was performed to compare the diagnostic accuracies between MR elastography and pSWE for LF in NAFLD patients. Cui et al.65 reported significantly higher accuracy of MR elastography than pSWE in detecting any fibrosis (≥F1 vs. F0) (AUROC: 0.799 vs. 0.644, p = 0.012), especially in patients with class II obesity (p = 0.007), but the differences were not significant for other LF stages.

MR elastography is highly accurate for diagnosing advanced fibrosis (≥F3) and cirrhosis (F4). This technique is robust, and therefore is feasible in obese patients and those with ascites. MR elastography is more sensitive for staging LF compared with other MR techniques. When compared with the US-based elastography techniques, MR elastography allows evaluation of a larger proportion of the liver, which is likely to reduce the sampling variability for patient monitoring over time.

However, MR elastography is limited on account of its high cost, long examination time, restricted product availability and its reliance on patient cooperation for breath-holds. Moreover, liver stiffness measurement with MR elastography may be affected in cases with hepatic iron overload, steatosis, vascular congestion or cholestasis. Therefore, further efforts are required to address the above limitations of MR elastography in liver imaging.

Diffusion-weighted MR imaging (DWI): DWI is a MR technique quantitatively assessing the random thermal diffusion ability of protons within the tissue, which is characterized by the parameter apparent diffusion coefficient (ADC).66 Fibrotic liver tissue usually manifests restricted diffusion; hence, the ADC value of the fibrotic tissue is significantly lower than that of the normal liver parenchyma. Therefore, ADC values are found to be negatively correlated with LF stages in most cases67,68 (Fig. 5).

Diffusion-weighted MR imaging in a 29-year-old female with normal liver (a-d) and a 44-year old male with liver cirrhosis (e-h).
Fig. 5.  Diffusion-weighted MR imaging in a 29-year-old female with normal liver (a-d) and a 44-year old male with liver cirrhosis (e-h).

Images obtained with increasing b values of 0 (a, e), 50 (b, f), and 1000 (c, g) sec/mm2 at 3T show a progressive reduction in signal intensity of the liver; however, the reduction is more significant in cirrhotic liver. (d, h) Corresponding ADC maps generated under the monoexponential model show that the mean ADC values of the circular regions of interest of the normal and cirrhotic liver are about 0.93 10−3 mm2/sec and 0.54 10−3 mm2/sec, respectively.

A recent meta-analysis68 demonstrated DWI to have good diagnostic accuracy for staging LF, and the AUROC was 0.8554 for LF ≥F1, 0.8770 for ≥F2, 0.8836 for ≥F3 and 0.8596 for F4, respectively. Additional diagnostic benefits could be achieved when incorporating the novel DWI-derived intravoxel incoherent motion model into the conventional DWI for patients with LF.68,69

DWI is robust, reproducible, widely available and relatively easy to perform compared with other emerging MR techniques in LF evaluation. However, several challenges stand in the way of using diffusion parameters as surrogate markers for LF assessment. First, perfusion, iron overload, hepatic steatosis, liver inflammation and edema can confound the interpretation of diffusion parameters.54 Second, DWI is sensitive to motion-related artifacts and susceptibility, thus it may be challenging to obtain images with enough quality to conduct reliable quantitative analyses.54 Most importantly, the acquisition standardization of the ADC is of great value but challenging to achieve because DWI relies significantly on several imaging parameters such as field strength and b values. Therefore, intensive large-scale prospective studies are encouraged to focus on standardization of DWI and search for the best cut-offs of ADC value for each LF stage.68

Gadoxetic acid disodium (Gd-EOB-DTPA): Gd-EOB-DTPA is an emerging hepatocyte-specific hepatobiliary MR contrast material capable of, in a single examination, providing both the hemodynamic information during dynamic phases and good lesion characterization concerning hepatocyte function in the hepatobiliary phase (HBP) of the lesion.70

Gd-EOB-DTPA-enhanced MR imaging can optimize detection and differentiation of focal liver lesions, especially HCCs, in cirrhotic patients. During hepatocarcinogenesis, the uptake of Gd-EOB-DTPA by hepatocytes decreases progressively as a result of hepatic dysfunction. Therefore, most HCCs appear as hypointense foci in HBP.70 This enhancement pattern helps to differentiate HCCs, especially early HCCs with diagnostic confusions, from the hyper- or isointense dysplastic and regenerative nodules in HBP.7174 However, HBP hypointensity is not specific for HCC because it can be found in some iron-rich dysplastic nodules75 and nonhepatocyte containing lesions, such as hemangioma, cholangiocarcinoma and metastases.76

MR imaging with Gd-EOB-DTPA can be applied to measure preoperative liver function in patients with cirrhosis. Quantitative analysis of Gd-EOB-DTPA uptake can help evaluate liver function, determine the optimal timing for liver resection, transplantation or invasive procedures, such as transjugular intrahepatic portosystemic shunt insertion, and predict postoperative liver failure risk.7779

MR perfusion imaging: During the process of fibrosis, as liver parenchymal blood flow velocity and portal venous flow decrease progressively, hepatic arterial flow and formation of intrahepatic shunts usually increase over time.54 These hemodynamic alterations can be tracked with MR perfusion imaging. Several previous studies in patients with CLDs have demonstrated its feasibility in LF staging.80,81

Nevertheless, liver perfusion can be affected by systemic factors, such as the cardiac status and fasting state, or regional factors, including hepatic congestion, inflammation and space-occupying lesions. Therefore, liver perfusion may not correlate exclusively with LF stage. Moreover, image analysis of MR perfusion imaging is a time-consuming procedure and the image quality of small hepatic nodules is often poor, leading to the need of a second contrast agent injection.

Conclusions

Early diagnosis and accurate staging of LF can facilitate timely patient care and optimize prognoses. In order to address the limitations of liver biopsy, imaging approaches comprising US-, CT- and MR imaging-based techniques are applied to assess LF noninvasively. Conventional US, CT and MR imaging can detect morphologic liver changes and signs of LF-related complications in patients with end-stage fibrosis, but they have limited diagnostic capacity in less advanced fibrosis. Novel imaging techniques have significantly improved LF diagnosis and staging since their introductions. Among them, TE is most widely available and extensively validated with good reproducibility and reasonable cost, and hence is the modality preferred for LF staging in the setting of routine clinical practice. MR elastography is another modality which is gaining increasing popularity, especially in academic medical centers. Nevertheless, future studies are warranted to further explore these novel imaging techniques over the entire etiology and severity spectrum of LF, before they can be widely implemented in routine clinical practice.

Abbreviations

2D-SWE: 

Two-dimensional shear wave elastography

ADC: 

apparent diffusion coefficient

AUROC: 

area under the receiver operating characteristic curve

CLD: 

chronic liver disease

CT: 

computed tomography

CEUS: 

contrast-enhanced US

DWI: 

diffusion-weighted MR imaging

Gd-EOB-DTPA: 

gadoxetic acid disodium

HBP: 

hepatobiliary phase

HBV: 

hepatitis B virus

HCC: 

hepatocellular carcinoma

HCV: 

hepatitis C virus

HV: 

hepatic vein

HVAT: 

hepatic vein arrival time

LF: 

liver fibrosis

MR: 

magnetic resonance

NAFLD: 

nonalcoholic fatty liver disease

pSWE: 

point shear wave elastography

ROI: 

region of interest

SWI: 

shear wave imaging

TE: 

transient elastography

US: 

ultrasound

Declarations

Acknowledgement

This study was funded by the National Natural Science Foundation of China (Grant Number 81471658).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Contributed to manuscript writing (HJ, TZ), material support (TD, JC) and critical revision and funding of the article (BS).

References

  1. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004;1:98-105 View Article
  2. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838-851 View Article
  3. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 2015;386:1546-1555 View Article
  4. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468-475 View Article
  5. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500 View Article
  6. The French METAVIR Cooperative Study Group. Hepatology 1994;20:15-20 View Article
  7. Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449-1457 View Article
  8. Procopet B, Berzigotti A. Diagnosis of cirrhosis and portal hypertension: imaging, non-invasive markers of fibrosis and liver biopsy. Gastroenterol Rep (Oxf) 2017;5:79-89 View Article
  9. Kim MY, Jeong WK, Baik SK. Invasive and non-invasive diagnosis of cirrhosis and portal hypertension. World J Gastroenterol 2014;20:4300-4315 View Article
  10. Ito K, Mitchell DG. Imaging diagnosis of cirrhosis and chronic hepatitis. Intervirology 2004;47:134-143 View Article
  11. Colli A, Fraquelli M, Andreoletti M, Marino B, Zuccoli E, Conte D. Severe liver fibrosis or cirrhosis: accuracy of US for detection--analysis of 300 cases. Radiology 2003;227:89-94 View Article
  12. Aubé C, Oberti F, Korali N, Namour MA, Loisel D, Tanguy JY. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol 1999;30:472-478 View Article
  13. Chen CH, Lin ST, Yang CC, Yeh YH, Kuo CL, Nien CK. The accuracy of sonography in predicting steatosis and fibrosis in chronic hepatitis C. Dig Dis Sci 2008;53:1699-1706 View Article
  14. Bernatik T, Strobel D, Hahn EG, Becker D. Doppler measurements: a surrogate marker of liver fibrosis?. Eur J Gastroenterol Hepatol 2002;14:383-387 View Article
  15. Colli A, Cocciolo M, Mumoli N, Cattalini N, Fraquelli M, Conte D. Hepatic artery resistance in alcoholic liver disease. Hepatology 1998;28:1182-1186 View Article
  16. Grier S, Lim AK, Patel N, Cobbold JF, Thomas HC, Cox IJ. Role of microbubble ultrasound contrast agents in the non-invasive assessment of chronic hepatitis C-related liver disease. World J Gastroenterol 2006;12:3461-3465 View Article
  17. Blomley MJ, Lim AK, Harvey CJ, Patel N, Eckersley RJ, Basilico R. Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study. Gut 2003;52:1188-1193 View Article
  18. Lim AK, Taylor-Robinson SD, Patel N, Eckersley RJ, Goldin RD, Hamilton G. Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C. Gut 2005;54:128-133 View Article
  19. Kim MY, Suk KT, Baik SK, Kim HA, Kim YJ, Cha SH. Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis. Hepatology 2012;56:1053-1062 View Article
  20. Talwalkar JA. Elastography for detecting hepatic fibrosis: options and considerations. Gastroenterology 2008;135:299-302 View Article
  21. Muthupillai R, Lomas DJ, Rossman PJ, Greenleaf JF, Manduca A, Ehman RL. Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 1995;269:1854-1857 View Article
  22. Yoneda M, Suzuki K, Kato S, Fujita K, Nozaki Y, Hosono K. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010;256:640-647 View Article
  23. Tang A, Cloutier G, Szeverenyi NM, Sirlin CB. Ultrasound elastography and MR elastography for assessing liver fibrosis: Part 1, principles and techniques. AJR Am J Roentgenol 2015;205:22-32 View Article
  24. Sigrist RMS, Liau J, Kaffas AE, Chammas MC, Willmann JK. Ultrasound elastography: review of techniques and clinical applications. Theranostics 2017;7:1303-1329 View Article
  25. Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-350 View Article
  26. Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48-54 View Article
  27. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835-847 View Article
  28. Sporea I, Sirli R, Deleanu A, Tudora A, Curescu M, Cornianu M. Comparison of the liver stiffness measurement by transient elastography with the liver biopsy. World J Gastroenterol 2008;14:6513-6517 View Article
  29. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-974 View Article
  30. Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011;54:650-659 View Article
  31. virus infection. J Hepatol 2011;55:245-264 View Article
  32. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association institute technical review on the role of elastography in chronic liver diseases. Gastroenterology 2017;152:1544-1577 View Article
  33. Cosgrove D, Piscaglia F, Bamber J, Bojunga J, Correas JM, Gilja OH. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: Clinical applications. Ultraschall Medx 2013;34:238-253 View Article
  34. Castéra L, Sebastiani G, Le Bail B, de Lédinghen V, Couzigou P, Alberti A. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010;52:191-198 View Article
  35. Boursier J, de Ledinghen V, Zarski JP, Fouchard-Hubert I, Gallois Y, Oberti F. Comparison of eight diagnostic algorithms for liver fibrosis in hepatitis C: new algorithms are more precise and entirely noninvasive. Hepatology 2012;55:58-67 View Article
  36. Sebastiani G, Vario A, Guido M, Alberti A. Sequential algorithms combining non-invasive markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B. World J Gastroenterol 2007;13:525-531 View Article
  37. Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J. Hepatol 2015;63:237-264 View Article
  38. Nightingale K, Soo MS, Nightingale R, Trahey G. Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Ultrasound Med Biol 2002;28:227-235 View Article
  39. Nightingale K. Acoustic radiation force impulse (ARFI) imaging: a review. Curr Med Imaging Rev 2011;7:328-339 View Article
  40. Srinivasa Babu A, Wells ML, Teytelboym OM, Mackey JE, Miller FH, Yeh BM. Elastography in chronic liver disease: modalities, techniques, limitations, and future directions. Radiographics 2016;36:1987-2006 View Article
  41. Bota S, Herkner H, Sporea I, Salzl P, Sirli R, Neghina AM. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int 2013;33:1138-1147 View Article
  42. Bercoff J, Tanter M, Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE Trans Ultrason Ferroelectr Freq Control 2004;51:396-409 View Article
  43. Muller M, Gennisson JL, Deffieux T, Tanter M, Fink M. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary in vivo feasibility study. Ultrasound Med Biol 2009;35:219-229 View Article
  44. Sirli R, Bota S, Sporea I, Jurchis A, Popescu A, Gradinaru-Tascău O. Liver stiffness measurements by means of supersonic shear imaging in patients without known liver pathology. Ultrasound Med Biol 2013;39:1362-1367 View Article
  45. Sporea I, Bota S, Jurchis A, Sirli R, Grădinaru-Tascău O, Popescu A. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013;39:1933-1941 View Article
  46. Leung VY, Shen J, Wong VW, Abrigo J, Wong GL, Chim AM. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology 2013;269:910-918 View Article
  47. Bavu E, Gennisson JL, Couade M, Bercoff J, Mallet V, Fink M. Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients. Ultrasound Med Biol 2011;37:1361-1373 View Article
  48. Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012;56:2125-2133 View Article
  49. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022 View Article
  50. Clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol 2012;56:908-943 View Article
  51. Talakić E, Schaffellner S, Kniepeiss D, Mueller H, Stauber R, Quehenberger F. CT perfusion imaging of the liver and the spleen in patients with cirrhosis: Is there a correlation between perfusion and portal venous hypertension?. Eur Radiol 2017;27:4173-4180 View Article
  52. Guan S, Zhao WD, Zhou KR, Peng WJ, Mao J, Tang F. CT perfusion at early stage of hepatic diffuse disease. World J Gastroenterol 2005;11:3465-3467 View Article
  53. Van Beers BE, Leconte I, Materne R, Smith AM, Jamart J, Horsmans Y. Hepatic perfusion parameters in chronic liver disease: dynamic CT measurements correlated with disease severity. AJR Am J Roentgenol 2001;176:667-673 View Article
  54. Faria SC, Ganesan K, Mwangi I, Shiehmorteza M, Viamonte B, Mazhar S. MR imaging of liver fibrosis: current state of the art. Radiographics 2009;29:1615-1635 View Article
  55. Manduca A, Oliphant TE, Dresner MA, Mahowald JL, Kruse SA, Amromin E. Magnetic resonance elastography: non-invasive mapping of tissue elasticity. Med Image Anal 2001;5:237-254 View Article
  56. Talwalkar JA, Yin M, Fidler JL, Sanderson SO, Kamath PS, Ehman RL. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 2008;47:332-342 View Article
  57. Huwart L, Sempoux C, Salameh N, Jamart J, Annet L, Sinkus R. Liver fibrosis: noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index. Radiology 2007;245:458-466 View Article
  58. Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008;135:32-40 View Article
  59. Asbach P, Klatt D, Schlosser B, Biermer M, Muche M, Rieger A. Viscoelasticity-based staging of hepatic fibrosis with multifrequency MR elastography. Radiology 2010;257:80-86 View Article
  60. Wang Y, Ganger DR, Levitsky J, Sternick LA, McCarthy RJ, Chen ZE. Assessment of chronic hepatitis and fibrosis: comparison of MR elastography and diffusion-weighted imaging. AJR Am J Roentgenol 2011;196:553-561 View Article
  61. Venkatesh SK, Yin M, Takahashi N, Glockner JF, Talwalkar JA, Ehman RL. Non-invasive detection of liver fibrosis: MR imaging features vs. MR elastography. Abdom Imaging 2015;40:766-775 View Article
  62. Singh S, Venkatesh SK, Loomba R, Wang Z, Sirlin C, Chen J. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol 2016;26:1431-1440 View Article
  63. Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology 2017;152:598-607.e2 View Article
  64. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2016;150:626-637.e7 View Article
  65. Cui J, Heba E, Hernandez C, Haufe W, Hooker J, Andre MP. Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease: A prospective study. Hepatology 2016;63:453-461 View Article
  66. Taouli B, Koh DM. Diffusion-weighted MR imaging of the liver. Radiology 2010;254:47-66 View Article
  67. Wang QB, Zhu H, Liu HL, Zhang B. Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of hepatic fibrosis: A meta-analysis. Hepatology 2012;56:239-247 View Article
  68. Jiang H, Chen J, Gao R, Huang Z, Wu M, Song B. Liver fibrosis staging with diffusion-weighted imaging: a systematic review and meta-analysis. Abdom Radiol (NY) 2017;42:490-501 View Article
  69. Luciani A, Vignaud A, Cavet M, Nhieu JT, Mallat A, Ruel L. Liver cirrhosis: intravoxel incoherent motion MR imaging--pilot study. Radiology 2008;249:891-899 View Article
  70. Van Beers BE, Pastor CM, Hussain HK. Primovist, Eovist: what to expect?. J Hepatol 2012;57:421-429 View Article
  71. Kierans AS, Kang SK, Rosenkrantz AB. The diagnostic performance of dynamic contrast-enhanced MR imaging for detection of small hepatocellular carcinoma measuring up to 2 cm: a meta-analysis. Radiology 2016;278:82-94 View Article
  72. Kitao A, Matsui O, Yoneda N, Kozaka K, Kobayashi S, Koda W. Hypervascular hepatocellular carcinoma: correlation between biologic features and signal intensity on gadoxetic acid-enhanced MR images. Radiology 2012;265:780-789 View Article
  73. Narita M, Hatano E, Arizono S, Miyagawa-Hayashino A, Isoda H, Kitamura K. Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 2009;44:793-798 View Article
  74. Lee MH, Kim SH, Park MJ, Park CK, Rhim H. Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease. AJR Am J Roentgenol 2011;197:W868-W875 View Article
  75. Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part I. Development, growth, and spread: key pathologic and imaging aspects. Radiology 2014;272:635-654 View Article
  76. Seale MK, Catalano OA, Saini S, Hahn PF, Sahani DV. Hepatobiliary-specific MR contrast agents: role in imaging the liver and biliary tree. Radiographics 2009;29:1725-1748 View Article
  77. Yamada A, Hara T, Li F, Fujinaga Y, Ueda K, Kadoya M. Quantitative evaluation of liver function with use of gadoxetate disodium-enhanced MR imaging. Radiology 2011;260:727-733 View Article
  78. Cho SH, Kang UR, Kim JD, Han YS, Choi DL. The value of gadoxetate disodium-enhanced MR imaging for predicting posthepatectomy liver failure after major hepatic resection: a preliminary study. Eur J Radiol 2011;80:e195-e200 View Article
  79. Zipprich A, Kuss O, Rogowski S, Kleber G, Lotterer E, Seufferlein T. Incorporating indocyanin green clearance into the Model for End Stage Liver Disease (MELD-ICG) improves prognostic accuracy in intermediate to advanced cirrhosis. Gut 2010;59:963-968 View Article
  80. Hagiwara M, Rusinek H, Lee VS, Losada M, Bannan MA, Krinsky GA. Advanced liver fibrosis: diagnosis with 3D whole-liver perfusion MR imaging--initial experience. Radiology 2008;246:926-934 View Article
  81. Chen BB, Hsu CY, Yu CW, Wei SY, Kao JH, Lee HS. Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients. Eur Radiol 2012;22:171-180 View Article
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