REVIEW ARTICLE

Liver Fibrosis Imaging: A Clinical Review of

Ultrasound and Magnetic Resonance
Elastography
Yingzhen N. Zhang, MD,1 Kathryn J. Fowler, MD,1 Arinc Ozturk, MD,2 Chetan K. Potu, BS,1
Ashley L. Louie, BA,1 Vivian Montes, BA,1 Walter C. Henderson, BA,1 Kang Wang, MD,1
Michael P. Andre, PhD,3 Anthony E. Samir, MD,2 and Claude B. Sirlin, MD1*

Liver fibrosis is a histological hallmark of most chronic liver diseases, which can progress to cirrhosis and liver failure, and
predisposes to hepatocellular carcinoma. Accurate diagnosis of liver fibrosis is necessary for prognosis, risk stratification,
and treatment decision-making. Liver biopsy, the reference standard for assessing liver fibrosis, is invasive, costly, and
impractical for surveillance and treatment response monitoring. Elastography offers a noninvasive, objective, and quantita-
tive alternative to liver biopsy. This article discusses the need for noninvasive assessment of liver fibrosis and reviews the
comparative advantages and limitations of ultrasound and magnetic resonance elastography techniques with respect to
their basic concepts, acquisition, processing, and diagnostic performance. Variations in clinical contexts of use and com-
mon pitfalls associated with each technique are considered. In addition, current challenges and future directions to
improve the diagnostic accuracy and clinical utility of elastography techniques are discussed.
Level of Evidence: 5
Technical Efficacy Stage: 2
J. MAGN. RESON. IMAGING 2019.

L IVER FIBROSIS, a form of scarring that results from

repeated liver injury, is a common pathologic and pathogenic
process in most forms of chronic liver disease.1 Fibrosis can pro-
virus (HCV) infections and the Brunt criteria for nonalcoholic
steatohepatitis (NASH), assign ordinal scores ranging from 0–4:
0 for no fibrosis; 1 for mild fibrosis; 2 for significant fibrosis; 3 for
gress to cirrhosis, a severe stage reflecting years of cumulative advanced fibrosis; 4 for cirrhosis.3,4 The main strengths of histol-
damage and the most important risk factor for developing hepa- ogy are direct evaluation of liver collagen and concurrent assess-
tocellular carcinoma (HCC) and liver failure. Treatment of the ment of microscopic lesions other than fibrosis. However,
underlying chronic liver disease may stabilize or even reverse liver histology requires liver biopsy, which is invasive, costly, and
fibrosis.2 Accurate diagnosis and staging of liver fibrosis are essen- carries a nonnegligible complication risk.5,6 Intraobserver and
tial for establishing prognosis, monitoring progression, and guid- interobserver variability, sampling errors, and low patient accep-
ing therapy. tance are other drawbacks.7,8 These limitations have prompted
Histology is the clinical reference standard for assessing searches for alternative noninvasive methods to assess liver
liver fibrosis. Histopathologic diagnosis relies on detecting and fibrosis.
characterizing excessive extracellular matrix deposition within In the last two decades, elastography has emerged as a
liver parenchyma—the hallmark of liver fibrosis—and staging quantitative imaging approach to noninvasively assess liver fibro-
employs various semiquantitative scoring systems to categorize sis. Elastography may be performed with ultrasound (US) or
the severity. Commonly used scoring systems, such as the magnetic resonance imaging (MRI). The underlying physical
METAVIR scale for hepatitis B virus (HBV) and hepatitis C principle of elastography is that tissue stiffness and other tissue

View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.26716

Received Jan 16, 2019, Accepted for publication Feb 26, 2019.

*Address reprint requests to: C.B.S., 200 W. Arbor Dr. #8756, San Diego, CA, 92103-8756. E-mail: [email protected]

From the 1Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, California, USA; 2Center for Ultrasound Research &
Translation, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA; and 3Department of Radiology, University of California,
San Diego, La Jolla, California, USA

© 2019 International Society for Magnetic Resonance in Medicine 1

Journal of Magnetic Resonance Imaging

mechanical properties can be estimated quantitatively by analyz- different soft tissues. By comparison, shear wave speeds are three
ing the propagation of shear waves introduced into those tissues orders of magnitude slower in soft tissue, 1–6 m/s, but they can
and are biomarkers of fibrosis.9 vary greatly across different biologic tissues and this enables excel-
US elastography may be divided into vibration controlled lent contrast to distinguish soft tissue of different types.14 Shear
transient elastography (VCTE) and shear wave elastography waves are not produced in liquids or air. In addition to tissue
(SWE). MR elastography (MRE) may be divided into two types: properties, shear wave frequency also impacts propagation; all
2D MRE, the clinical standard at this time, and 3D MRE, an else being equal, higher frequencies lead to more rapid wave
emerging option mainly used in research settings. propagation and greater shear wave attenuation.15 A range of fre-
This review discusses the basic concepts; compares US and quencies is used in elastography techniques, which should be
MR-based elastography approaches with respect to acquisition, considered when comparing reported parameters between
processing, analysis, and output; and examines comparative per- platforms.
formance at diagnosing liver fibrosis, the main clinical applica- In summary, quantitative elastography techniques involve
tion of elastography in the abdomen. The last section explores the following steps: shear wave induction in tissue, visualization
future directions for the leading elastographic methods. and analysis of shear wave propagation, and conversion of this
information into an estimate of tissue stiffness. The stiffness-
related quantitative parameters reported by different elastography
Basic Concepts techniques are expressed as ratios of stress/strain, known as mod-
Many potential imaging biomarkers of fibrosis have been investi- uli, in units of kPa or shear-wave speed in m/s. The common
gated.10 All currently available techniques measure various tissue moduli reported are Young’s modulus, a measure of mechanical
properties as indirect markers of fibrosis; to date, no clinically resistance to an axially applied stress, and the complex shear mod-
available imaging method directly visualizes liver fibrosis. ulus, a measure of mechanical resistance to a shear stress. The
Elastography measures stiffness, which is a tissue property parameter “shear stiffness” frequently reported in MRE estimates
that increases with higher fibrosis stages.11 Although many physi- the magnitude of the shear modulus, which at a given frequency
ologic and pathologic processes in the liver affect stiffness— is roughly 1/3 of the Young’s modulus in biological tissues.14
inflammation, blood flow, portal pressure, hepatic-venous con-
gestion, and cholestasis are some examples—liver fibrosis is the Ultrasound
dominant factor in most patients.12 Thus, liver stiffness may Figure 1 illustrates current US elastography techniques. All utilize
serve as a proxy for liver fibrosis. Elastography techniques provide transient longitudinal mechanical (a few msec) or US (50–1000 μs)
a quantitative method to assess stiffness, which historically could impulses to induce shear waves.16 Because the longitudinal waves
be assessed by clinicians only qualitatively via manual palpation. from the impulse travel much faster through tissue than the shear
Stiffness describes a tissue’s ability to resist deformation waves they induce, longitudinal waves do not contribute to the
(strain) in response to an applied force (stress) and may be measured shear wave speed. Under simplifying assumptions, shear
expressed as the ratio of stress/strain. Stiffer materials have higher wave speed υ (m/s) may be converted into Young’s modulus
stress/strain ratios than softer materials. The stress applied in E (kPa) by E = 3ρυ2, where ρ is the density of soft tissue (approxi-
elastography is in the form of shear waves, which typically are mately equal to that of water at 1 g/cm3). A minimum of 4 hours
induced from applied longitudinal pressure waves through an of fasting is recommended prior to shear wave acquisitions to
incompletely understood process called mode conversion.13 reduce potentially confounding physiologic effects.17
Leading elastography techniques generate longitudinal waves by
applying either a transient mechanical or specialized acoustic Vibration Controlled Transient Elastography (VCTE)
“push” pulse to the tissue of interest in US elastography or con- VCTE, first introduced in France in 2003, is a 1D technique
tinuous mechanical vibrations to the skin surface in MRE. When that generates a low-frequency (50 Hz) mechanical impulse
shear waves are produced, tissue particles move back and forth at on the abdominal wall. The resulting shear waves are tracked
right angles (“shear motion”) to the direction of shear wave prop- with ultrasonic waves in a cylinder of tissue that is ~1 cm in
agation. Visualization and analysis of shear waves depend on tis- diameter by 4 cm in length, a volume ~100 times larger than
sue displacement as a function of time, which allows stiffness and that evaluated by liver biopsy but still representing a small
related mechanical tissue properties to be estimated. A detailed fraction of the total liver volume.11
description of wave physics is beyond the scope of this article. VCTE comes with three different probes: the standard M
However, as a first approximation, the shear wave speed is related probe with a frequency of 3.5 MHz, the XL probe for obese
to the tissue stress/strain; by observing propagation and capturing patients with a frequency of 2.5 MHz, and the S probe for chil-
wave information, therefore, the stiffness of tissues may be dren with a frequency of 5.0 MHz. Lower-frequency probes are
inferred. In general, the stiffer the tissue, the faster the shear wave preferred for patients with high abdominal adiposity or large skin-
travels.11 Longitudinal compressive sound wave speed in US is to-liver surface distance18 to reduce wave attenuation. As a 1D
about 1500 meters per second (m/s), varying by a few percent in method, VCTE does not generate anatomical images (B-mode);

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 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

FIGURE 1: Illustrations (a-c; all by A.L.L. and Y.N.Z.) of current quantitative ultrasound-based elastography methods (not drawn to
scale). VCTE (a) uses a probe to transmit mechanical vibrations through the skin surface and body wall (back-and-forth blue arrows).
pSWE (b) and 2D SWE (c) use a probe to generate ARFI within the liver (blue dots). The wavy blue arrows indicate the induced shear
waves and their direction. The rectangles outlined in white (a,b) indicate the interrogated cylindrical volume and the user-defined
ROI; the green-colored trapezoid and the white circle within (c) indicate the elastogram and the user-defined ROI, respectively.

the operator uses the reflected signals (A-mode) to define the best VCTE DIAGNOSTIC ACCURACY AND CLINICAL
area for reliable measurements and the only output is an estimate APPLICATIONS. VCTE has demonstrated high accuracy for
of regional liver stiffness. A pictorial example of VCTE measure- diagnosing cirrhosis (fibrosis stage 4), but diagnostic performance
ment is presented in Fig. 2. VCTE is marketed under the trade is more modest for detecting intermediate fibrosis stages. A meta-
name FibroScan (Echosens, Paris, France). analysis of patients with mixed liver diseases has shown that the
mean area under the receiver operating curve (AUROC) for the
VCTE SUCCESS RATES. In general, a VCTE examination is diagnosis of significant fibrosis (fibrosis stage ≥2), advanced fibro-
considered a technical success if at least 10 valid measurements sis (stage ≥3), and cirrhosis (stage 4) are 0.84 (95% confidence
can be made in 16 or fewer attempts (ie, ≥ 60% of attempts result interval [CI]: 0.82–0.86), 0.89 (95% CI: 0.88–0.91), and 0.94
in valid measurements). A technically successful VCTE examina- (95% CI: 0.93–0.95), respectively.26 Among patients with
tion is considered reliable if the interquartile range (IQR)-to- chronic liver diseases, summary sensitivity and specificity are
median ratio is ≤0.3.19 By these criteria, the largest prospective 0.79 (95% CI: 0.74–0.82) and 0.78 (95% CI: 0.72–0.83) for
study of VCTE on patients with chronic liver diseases found that significant fibrosis (fibrosis stage ≥2) compared with 0.83 (95%
technical failure occurred in 3.1% of patients and among the suc- CI: 0.79–0.86) and 0.89 (95% CI: 0.87–0.91) for cirrhosis
cessful examinations, a significant proportion (15.8%) were (stage 4).27 In a recent study of 16,082 healthy individuals, mean
unreliable.20 A major advantage of VCTE is that it requires little liver stiffness was 4.68 kPa.28 In a meta-analysis of VCTE in
dedicated training time. After a single training session, operators patients with HBV, the mean cutoff stiffness values have been
are able to reliably obtain results regardless of the experience reported as 7.2 kPa for stage ≥2, and 9.4 kPa for stage ≥3.29 A
level.21 VCTE examinations that meet quality criteria have excel- similar correlation between stiffness values and fibrosis stage are
lent repeatability and reproducibility. A multicenter study of seen in patients with HCV, NAFLD, and alcoholic liver
VCTE on patients with nonalcoholic fatty liver disease disease.30–32
(NAFLD) reported high reproducibility (intraobserver and inter- VCTE’s diagnostic accuracy for cirrhosis, ease of use, and
observer correlation coefficients of 0.90 and 0.84, respectively, in accessibility have led to consensus reports recommending it as a
same-day exams), while another study on patients with mixed first-line technique for assessing the severity of liver fibrosis and
liver disease reported an intraclass correlation coefficient (ICC) ruling out cirrhosis in most chronic liver diseases including
value of 0.98 for both intraobserver and interobserver NAFLD, alcoholic liver disease, and viral hepatitis.19 VCTE is
agreement.22,23 preferred by many clinicians as a point-of-care device for its por-
If the mechanical impulse fails to induce adequate shear tability, extensive validation, high patient acceptance, and rapid
wave amplitude, a technical failure results and the VCTE soft- output. It is commonly used in hepatology clinics for screening,
ware does not provide a quantitative stiffness estimate. One cause treatment monitoring, and longitudinal follow-up in most
for VCTE failure is the presence of ascites, since shear wave mode chronic liver diseases including viral hepatitis, alcoholic liver dis-
conversion does not occur in fluid.24 Morbid obesity can also ease, NAFLD, and autoimmune liver disease.33–35
lead to measurement failure owing to attenuation of the mechan-
ical pulse as it travels through the thickened body wall. The use VCTE LIMITATIONS. VCTE is subject to several technical and
of the XL probe overcomes the effects of obesity to an extent; one patient-related limitations. To ensure technical stability, VCTE
study in a cohort of overweight and obese patients with mixed needs recalibration every 6–12 months.18 Other technical chal-
liver disease found that the XL probe failed less often and was lenges include the significant proportion of unreliable measure-
more reliable than the M probe (1.15% vs. 16% fail rate, and ments and the higher technical failure rate in the presence of
73% vs. 50% reliable rate, respectively).25 confounders such as acute inflammation, narrow intercostal

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Journal of Magnetic Resonance Imaging

FIGURE 2: VCTE scanner (a) with the M probe (b) is used to acquire controlled attenuation parameter (CAP, c) and Time Motion
(TM) and Amplitude (A) mode shear wave propagation images (d). The CAP estimate of attenuation in units of dB/m is shown in (c).
The 5th measurement of liver stiffness in units of Young’s modulus (kPa) is shown in (d). The y-axis is distance from skin, x-axis is time.
Slope of the dashed line represents shear wave speed. Median values of these 10 measurements are calculated for stiffness and
attenuation assessment. CAP is an integrated technology that quantifies steatosis severity at the same time as liver stiffness
assessment on VCTE.

space, ascites, and obesity.20,36 Certain measures can partially Estimates of tissue stiffness are reported as shear wave speed in
overcome these confounding effects, such as waiting for liver m/s or converted into Young’s modulus in kPa.
enzymes to normalize before acquiring VCTE.37 It is well To obtain the most reliable shear wave speed estimates and
established that the degree of steatosis may influence the stiffness examine more uniform regions of the right lobe of the liver,
values in VCTE38; therefore, controlled attenuation parameter patients should be positioned in the supine or left lateral
(CAP) estimations of hepatic steatosis severity should also be decubitus position with the right arm raised above the head.
considered. CAP is integrated into VCTE on the M and XL pro- Shear wave estimation and imaging localization are best per-
bes, and indirectly indicates the degree of hepatic steatosis by formed through an intercostal acoustic window, typically the
measuring the energy loss as acoustic waves pass through the right 7th or 8th intercostal spaces, to avoid compression of the
same tissue location as that defined by VCTE to estimate tissue liver by the transducer. Ten measurements should be obtained
stiffness. This capability is especially promising in clinical assess- from the right lobe of the liver at least 2 cm beneath the liver cap-
ment of patients with NAFLD. sule (to avoid known artifacts produced by the liver edge) during
a breath-hold at shallow expiration.19 The median value of the
series of shear wave measurements is commonly used, though
Point Shear Wave Elastography (pSWE) some studies have found no performance difference between
Originally introduced by Siemens (Erlangen, Germany) on clini- mean and median values.39
cal scanners (Virtual Touch Quantification), pSWE may now be
added onto clinical scanners from other major vendors. Unlike PSWE PRECISION AND FAILURE. Excellent repeatability and
VCTE, which uses a mechanical impulse, pSWE induces shear reproducibility have been demonstrated in studies involving
waves by an excitation method known as acoustic radiation force same-day comparisons. In a cohort of patients with mixed liver
impulse (ARFI). Energy from US longitudinal waves is focused diseases who underwent pSWE by two trained hepatologists,
locally in an area of the liver by the US transducer. A fraction of pSWE had a reported intraobserver ICC of 0.89 and inter-
this acoustic energy is converted into slow-moving shear waves, observer ICC of 0.85.39,40 Evidence shows that reproducibility
which are tracked by conventional pulse echo US in a region may further improve with training.41 There is also evidence that
defined by the operator (~1 cm3). pSWE is aided by incorpora- applying an IQR-to-median ratio >30% to exclude poorly reli-
tion into a standard B-mode US acquisition, which allows the able data may improve diagnostic performance, but more studies
operator to visualize the liver tissue and select a region without are needed to determine the role of reliability indicators and the
blood vessels, rib shadows, large bile ducts, and gallbladder. optimal number of repeated measurements.42,43 Unlike VCTE,

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 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

pSWE is not limited by the presence of ascites. The failure rate is propagates laterally away from the ARFI axis. The propagation of
low for pSWE (1–2%).41 the shear waves is monitored at multiple spatial and temporal
points by conventional compressive US waves and is depicted as
PSWE DIAGNOSTIC ACCURACY AND CLINICAL a colorized elasticity map known as an elastogram.52 The size of
APPLICATIONS. Consensus reports endorse pSWE as a tool to the elastogram region varies under operator control. Within this
differentiate patients with minimal to no fibrosis from those with elastogram, the operator may place a circular region of interest
advanced fibrosis to cirrhosis.17,19 A meta-analysis of 2691 (ROI) at a location subjectively considered to be free of artifacts.
patients with chronic HBV or HCV reported AUROCs for the The mean shear wave speed (m/s) is derived from multiple mea-
diagnosis of significant fibrosis (fibrosis stage ≥2), advanced fibro- surements obtained from tissue in the ROI and can be algebrai-
sis (stage ≥3), and cirrhosis (stage 4) ranging from 0.65–0.93, cally converted to Young’s modulus (kPa).
0.85–0.97, and 0.72–0.98, respectively; summary sensitivity and First developed by SuperSonic Imagine (SSI), 2D SWE is
specificity were 0.75 (95% CI: 0.69–0.80) and 0.85 (95% CI: now available on US scanners from most major vendors. The rec-
0.81–0.89) for F ≥ 2, 0.84 (95% CI: 0.80–0.88) and 0.90 (95% ommended protocol for acquiring 2D SWE is similar to that for
CI: 0.86–0.92) for stage ≥3, and 0.86 (95% CI: 0.80–0.91) and pSWE (see above, pSWE Precision and Failure). Detailed proto-
0.84 (95% CI: 0.80–0.88) for stage 4.44 Similar performance cols may be found in recent guidelines.18 Figure 3 presents imag-
was found in patients with NAFLD, where pSWE performed ing examples of 2D SWE by various US systems and Fig. 4
well at classifying advanced fibrosis and cirrhosis (AUC 0.90 and presents imaging examples of 2D SWE over a spectrum of liver
0.86, respectively) but less well at mild fibrosis (AUC 0.66).45 fibrosis severity.
Some investigators recommend using pSWE to obtain stiffness
measurements on both the liver and the spleen, as the combina- 2D SWE PRECISION AND FAILURE. In same-day studies,
tion may perform better for staging fibrosis than liver stiffness high intraobserver (ICC values of 0.93–0.95) repeatability and
estimates alone.46 interobserver (ICC of 0.88) reproducibility have been reported.53
pSWE has been used to monitor disease progression, assess Similar to pSWE, evidence suggests operator experience impacts
treatment response, and aid in the decision to start treatment regi- repeatability. Between-day measurements acquired on the same
mens such as antiviral therapy.47 Owing to low cost and availabil- subject by an experienced operator showed significantly less vari-
ity on standard platforms, pSWE may be a cost-effective chronic ability (ICC, 0.84) than those acquired by a novice (ICC, 0.65).
liver disease screening technique. For example, a recent popula- The 2D-SWE failure rate is estimated as ~5%.54
tion-based study estimated the prevalence of significant liver fibro-
sis among Mexican Americans in a county of Texas using pSWE 2D SWE ACCURACY AND CLINICAL APPLICATIONS. As
measurements of liver stiffness.48 Other studies suggest pSWE the newest US elastography method, there is limited evidence for
may be helpful as a diagnostic and prognostic tool in the manage- 2D SWE for liver fibrosis staging. Thus far, 2D SWE has been
ment of compensated cirrhosis and its complications.49 shown to be highly accurate at diagnosing advanced fibrosis
(stage 3) and cirrhosis (stage 4). In a recent meta-analysis involv-
LIMITATIONS OF PSWE. Despite recent evidence showing
ing 2303 patients with viral hepatitis, the reported AUROC for
high diagnostic accuracy for diagnosing advanced fibrosis stages,
detecting liver fibrosis stage ≥2, ≥3, and cirrhosis were 0.87 (95%
pSWE does not perform as well at diagnosing lower liver fibrosis
CI:0.84–0.90), 0.93 (95% CI:0.91–0.95), and 0.94 (95% CI:
stages (ie, stages 0–2) due to significant overlap in shear wave
0.92–0.96), respectively.55 Similar diagnostic performance was
speed values.50 pSWE may also overestimate liver fibrosis in
reported for a subgroup of NAFLD patients in another meta-
patients with significantly elevated liver enzymes.51 pSWE mea-
analysis.56 2D SWE also shows promise as a tool for longitudinal
surements may be influenced by liver motion during inspiration/
monitoring. A recent study reported that liver stiffness measured
expiration or physiologic motion such as vascular pulsatility.
by 2D SWE decreased over time in chronic HCV patients with
Finally, pSWE is a relatively new technique compared with
sustained response to antiviral treatment.57 2D SWE may be
VCTE and most pSWE studies have focused on chronic viral
used in conjunction with clinical and laboratory findings to rule
hepatitis, with limited data for other common etiologies of liver
out cirrhosis.19 The distribution of liver fibrosis stages varies con-
fibrosis such as autoimmune liver diseases, NAFLD, and alco-
siderably in the populations the published literature was derived
holic liver disease.
from, limiting the generalizability of reported results. In one
2D Shear Wave Elastography (2D SWE) meta-analysis based on individual data from patients with mixed
liver diseases, the prevalence of significant liver fibrosis (stage ≥2),
2D SWE BASICS. 2D SWE, like pSWE, uses ARFI to induce severe fibrosis (stage ≥3), and cirrhosis were 22%, 16%, and
shear waves in liver tissue but differs in its mode of delivery and 16%, respectively; the corresponding negative predictive values
measurement. Whereas pSWE emits a single push pulse of ARFI by 2D SWE were 87%, 97%, and 95%.56
to a focal point in the liver, 2D SWE induces shear waves at mul- Liver stiffness measurement using 2D-SWE may be used
tiple points, producing a cone-shaped shear wave front that to predict the complications of advanced liver fibrosis, such as

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Journal of Magnetic Resonance Imaging

FIGURE 3: 2D-SWE technology is available in multiple devices manufactured by various vendors. Common features are colored
polygonal elastogram maps and circular ROIs. The user selects the location of the elastogram away from overlying vessels and rib
shadows and then places an ROI within a representative portion of the elastogram as described below. Mean stiffness or SWS values
from the ROIs are reported. (a) General Electric LOGIQ E9 ultrasound device. (b) Supersonic Aixplorer ultrasound device. Stiffness
value in kPa is presented at left corner of the image. Standard gray-scale image is used as a guide. Tissue stiffness (c) or shear wave
speed (d) can be presented in the same scanning session using the same device; images from Toshiba APLIO500 are presented as
examples. Manufacturers add new software into the systems to increase the accuracy of the SWE results and decrease variability.
For example, the Toshiba system calculates the (e) contour map, (f) variance map. Based on the manufacturer’s suggestions in
contour map (e), operator-located ROI in an area where propagation lines (colored lines) are parallel to each other. In the variance
map (f), operator-located ROI in an area away from “extreme” areas (yellow/red).

HCC, esophageal/gastric varices, and portal hypertension.58 A fibrosis stages.60 2D SWE implementations also vary across manu-
recent meta-analysis reported that 2D SWE can detect the pres- facturers. There is limited evidence for translating stiffness mea-
ence of clinically significant portal hypertension with summary surements from one vendor to another, which complicates
sensitivity and specificity of 0.85 (95% CI: 0.75–0.91) and 0.85 comparison of results and disease tracking when using different
(95% CI: 0.77–0.90), respectively.59 Other uses for 2D SWE systems. Finally, in contrast to VCTE, where limited training is
overlap with those of pSWE and VCTE, such as risk stratifica- required, SWE must be performed by trained sonographers or
tion and monitoring, but more studies are needed for further vali- physicians.
dation of accuracy as well as for establishing disease-specific
diagnostic thresholds. Comparison of the US Elastography Techniques
A small number of studies using large cohorts have directly com-
LIMITATIONS OF 2D SWE. Although it is an accurate and fast pared the performance of VCTE, pSWE, and 2D SWE with his-
technique that provides real-time imaging, 2D SWE has limita- topathology as the reference standard. Table 1 presents a
tions. Since shear waves are slow-moving and 2D SWE makes selection of these studies based on reporting of diagnostic accu-
more measurements over a larger tissue volume, the sampling time racy, geographic distribution, and cohort size. 2D SWE was
may be extended compared with VCTE and pSWE. Similar to found to have comparable, if not superior, diagnostic perfor-
pSWE, 2D SWE is susceptible to motion and requires breath- mance compared with pSWE and VCTE.50,56,61–66 Of the stud-
holding. Similar to other US methods, 2D SWE is more accurate ies directly comparing pSWE with VCTE, pSWE was found to
for the diagnosis of significant (stage ≥2) liver fibrosis than for the diagnose significant fibrosis and cirrhosis with similar to higher
diagnosis of mild (stage 1) liver fibrosis. An overlap in stiffness accuracy than VCTE. As for the technical success rate and reli-
values at different pathologic fibrosis stages has been reported, ability, studies suggest that pSWE may be more reliable than
which limits the capability of 2D SWE to differentiate adjacent VCTE, while 2D SWE gave mixed results.50,61–68

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 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

FIGURE 4: Transverse colorized MR elastograms (3T GE 750 scanner using 2D GRE technique, top) and ultrasound-based 2D-SWE
images with placement of ROIs filled in with colorized elasticity (GE Logiq E9 with C1-6 transducer, bottom) demonstrate increasing
stiffness estimates (kPa) or shear wave speed estimates (m/s) with increasing liver fibrosis stage as determined on histology (Brunt
system) in patients with nonalcoholic fatty liver disease. From left to right: stage 0 in a 53-year-old man, stage 1 in a 49-year-old
man, stage 2 in a 55-year-old woman, stage 3 in a 68-year-old woman, and stage 4 in a 72-year-old woman. ROIs, an automated 95%
confidence grid, and estimated magnitude of complex modulus (“shear stiffness”) values in kPa are overlain on the MR elastograms.
Shear wave speed estimates are overlain on the ultrasound images.

A notable limitation to all three US-based elastography variability. The Radiological Society of North America Quantita-
methods is their lower rate of success and reliability in the set- tive Imaging Biomarkers Alliance (RSNA-QIBA) has formed a
ting of obesity, which affects a significant proportion of committee to investigate the effects of these variables on shear wave
NAFLD patients. Cassinotto et al reported that failure rates elastography accuracy and reproducibility.72,73
of 2D SWE, pSWE, and VCTE increased with increasing
body mass index (BMI) in a cohort of NAFLD patients.61
Another common confounder is the presence of acute liver MRE
inflammation, which increases liver stiffness. Different liver MRE may be performed on a clinical scanner with the addition
stiffness thresholds adapted to normal and abnormally ele- of commercially available software and hardware. Currently,
vated liver transaminase levels for the detection of significant MRE is available on three major manufacturers of MR scanners
fibrosis and cirrhosis have been proposed and successfully (General Electric, Milwaukee, WI; Philips Medical Systems,
implemented in studies involving patients with HBV, HCV, Best, Netherlands; Siemens Healthineers, Erlangen, Germany)
and alcoholic liver disease.69,70 Other biological confounders at 1.5 T and 3T field strengths. One of two sequences is usually
that increase liver stiffness without fibrosis include hepatic used: a 2D gradient-recalled echo-based (GRE) sequence or a 2D
venous congestion, cholestasis, right heart failure, and infiltra- spin-echo-based echo-planar imaging (SE-EPI) sequence. Both
tive diseases such as amyloidosis. Performance of shear wave sequences provide similar estimates of stiffness, although the SE-
imaging in these conditions is not well understood, and fur- EPI variant is less susceptible to technical failure caused by iron
ther studies are needed to examine their effects. deposition due to its decreased sensitivity to T2* transverse relax-
Overall, each US-based elastography method has its ation time decay.74–77 Since T2* relaxation time in the liver is
advantages and disadvantages and no single method is best shorter at higher field strengths, SE-EPI is generally the preferred
suited for all clinical scenarios. Table 2 compares the main sequence at 3T even in the absence of iron overload.78 To bal-
clinical and technical advantages and drawbacks of VCTE, ance between acquisition time and volume of liver sampled, usu-
pSWE, 2D SWE, and MRE. ally four axial slices of about 10 mm thickness each are acquired
Regardless of the method used, the availability of a reliable through the widest portion of the liver for clinical applications of
option for quantifying liver stiffness is important for monitoring, GRE and SE-EPI, and the number of breath-holds range from
assessing treatment response, and establishing endpoints in clinical one (SE-EPI) to four (GRE).79 The liver dome and inferior tip of
trials. Few studies have compared the various proprietary systems the right liver lobe should be avoided.
and their cross-platform reproducibility and repeatability; Piscaglia The hardware requirements for MRE consist of an active
et al reported only moderate concordance in liver stiffness mea- acoustic driver, which generates vibrations via an audio device,
surements acquired on seven different pSWE and 2D SWE plat- and a passive pneumatic driver, which is placed on the patient’s
forms and VCTE, with significant variability even between body wall. The active driver is located outside the scanner room
different versions of pSWE.71 Technical factors including scanner and connects via plastic tubing through a small hole (known as a
calibration, software version, measured parameters’ units (m/s or wave guide) in the MR scanner wall to the passive driver. The
kPa), frequency, and operator experience may all contribute to the driver system can generate vibrations at frequencies ranging from

7
8
TABLE 1. Selection of Prospective Studies

AUROC for liver fibrosis stage:

No. of Any significant
Study Etiology Patients Method Success (%) ≥2 ≥3 4 differences, P < 0.05
Studies directly comparing VCTE, pSWE, and 2D SWE
Cassinotto et al, 2014 Mixed 349 VCTE 92% 0.83 0.86 0.90 AUROC: 2D SWE > pSWE for
stage ≥2; 2D SWE > VCTE and
pSWE for stage ≥3, 2D
SWE > pSWE for stage 4
Success:
Journal of Magnetic Resonance Imaging

• % with stiffness estimates:

VCTE >2D SWE; pSWE >2D
SWE, pSWE >VCTE;
• % reliable results: VCTE
> pSWE
pSWE 84% 0.81 0.85 0.84
2D SWE 91% 0.89 0.92 0.92
Gerber et al, 2015 Mixed 132 VCTE (M and XL probe) 86% 0.95 0.95 0.96 None
pSWE 95% 0.91 0.94 0.92
2D SWE 100% 0.90 0.93 0.92
a
Cassinotto et al, 2016 NAFLD 291 VCTE 77% 0.82 0.86 0.87 AUROC: 2D SWE > pSWE for
stage ≥2
Success: pSWE > VCTE for
BMI < 30 kg/m2
pSWE 81% 0.77 0.84 0.84
2D SWE 80% 0.86 0.89 0.88
Studies directly comparing VCTE and 2D SWE
Leung et al, 2013 HBV 454 VCTE 90% 0.78 0.83 0.92 AUROC: 2D SWE > VCTE for
stage ≥2, ≥3, and 4
Success: 2D SWE > VCTE
2D SWE 99% 0.88 0.93 0.98
 TABLE 1. Continued

AUROC for liver fibrosis stage:

No. of Any significant
Study Etiology Patients Method Success (%) ≥2 ≥3 4 differences, P < 0.05
Yoneda, Thomas, Sclair, HCV 102 VCTE (XL probe) 92%b 0.91 0.95 0.91 None
Grant, & Schiff, 2015
2D SWE 0.87 0.95 0.91
Paul et al, 2017 HBV, HCV 240 VCTE 98% 0.84 0.90 0.97 AUROC: 2D SWE > VCTE for
stage ≥2
Success: none
2D SWE 99% 0.76 0.90 0.93
Gao et al, 2018 HBV 402 VCTE NA 0.62 NA 0.80 AUROC: 2D SWE > VCTE for
stage 4
Success: NA
2D SWE 99% 0.75 0.87
Studies directly comparing VCTE and pSWE
Rizzo et al, 2011 HCV 139 VCTE 94% 0.78 0.83 0.80 AUROC: pSWE > VCTE for stage
≥2 and ≥ 3
Success: pSWE > VCTE
pSWE 100% 0.86 0.94 0.89
Cassinotto et al, 2013 Mixed 321 VCTE (M and XL probe) 89% 0.80–0.88 0.86–0.89 0.90–0.91 AUROC: None
Success: None
pSWE 91% 0.77 0.82 0.84

With large cohorts (n > 100 patients) directly comparing the performances of VCTE, pSWE, and 2D SWE at diagnosing significant fibrosis (fibrosis stage ≥2), advanced fibrosis (stage ≥3),
and cirrhosis (stage 4), using histopathology as the reference standard.
a
VCTE measurements made with standard M probe unless otherwise noted.
b
Combined failure rate for both VCTE and 2D SWE; separate failure rates are not reported.
NAFLD, nonalcoholic fatty liver disease; HBV, hepatitis B virus; NA, not available; HCV, hepatitis C virus; BMI, body mass index
Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

9
10
TABLE 2. Comparison Between Quantitative Elastography Techniques for Assessing Liver Fibrosis
Accuracya

Cirrhosis Practical Anatomic Training required Training required

Modality (stage 4) Stage ≥2 Stage ≥1 Challenges Advantages Size of liver sampled imaging for operator for analysis

VCTE Excellent Good Poor Obesity Point-of-care ~3 cm3 None A single session Not applicable
Inflammation Access
Ascites Rapid output
Journal of Magnetic Resonance Imaging

No visual guidance Well-validated

Optional quantitative
assessment of fat (CAP)

pSWE Excellent Good, may be better than VCTE Poor-fair Obesity Access ~1 cm3 Clinical US exam Experience with clinical Not applicable
Inflammation Visual guidance US imaging plus some
Simultaneous US exam additional training

2D SWE Excellent Good, may be better than VCTE Fair Obesity Access Variable; sampled Clinical US exam Experience with clinical Not applicable
Inflammation Visual guidance volume typically US imaging plus some
Simultaneous US exam ≥20 cm3 additional training

MRE Excellent Excellent Good Iron Low technical failure rate ≥250 cm3 Clinical MRI exam Experience with MRI Training in ROI
Access Simultaneous MR exam Up to 1/3 of the liver plus some additional placement
MR contraindications Optional quantitative assessment of volume training required
other MR biomarkers (automated ROI
placement under
development)

a
Classifying diagnostic accuracy by area under an ROC curve (AUROC) as reported in published literature: 0.90–1.00, excellent; 0.80–0.90, good, 0.70–0.80, fair; 0.60–0.70, poor.
VCTE, vibration-controlled transient elastography; pSWE, point shear wave elastography; 2D SWE, two-dimensional shear wave elastography; MRE, magnetic resonance elastography; US, ultrasound; MRI, magnetic resonance imaging.
 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

20–200 Hz, although 60 Hz is usually used for liver applica- prior hepatectomy, the driver should be placed over the remnant
tions. Vibrations enter the patient as fast longitudinal pressure left lobe of the liver.
waves. A fraction of the wave energy is converted into slower
shear waves through mode conversion.13 The shear waves, but MRE Hardware
not the longitudinal waves, are imaged by MR sequences modi- Different types of drivers have been developed to transmit longi-
fied with motion-encoding gradients. Processing of the MR tudinal waves into the patient, including pneumatic, piezoelectric,
image involves an inversion algorithm, as detailed below. The and electromagnetic systems.82 In commercial implementations,
basic schematic of an MRE acquisition is presented in Fig. 5. an active driver delivers acoustic compressions set to a single fre-
Four or more hours of fasting is recommended prior to a quency, usually 60 Hz, to a passive pneumatic driver chosen for
clinical MRE for hepatic evaluation, as postprandial portal blood its simple design, low cost, and MR compatibility.82 The passive
flow in patients with liver diseases may lead to an increase in esti- driver consists of a semirigid membrane mounted on a drum-like
mated liver stiffness.80 Administration of intravenous gadolinium circular paddle that is in direct physical contact with the patient.
contrast does not affect liver stiffness estimates, so MRE may be Once the center of the liver has been determined, the pas-
acquired pre- or postcontrast. Acquisition parameters that can be sive driver is secured to the anterior abdominal wall by an elastic
altered include passive driver vibration frequency (usually band, which can prevent the common pitfall of detachment dur-
60 Hz), field of view (FOV) (usually 30–48 cm, although the ing the acquisition. The band should be tightened to achieve a
QIBA MRE profile recommends that FOV be kept the same on snug fit with the patient in relaxed expiration; this prevents the
longitudinal exams in the same patient), phase offsets (usually driver from shifting in position during the respiratory cycle.
four), slice thickness (usually 10 mm, but slice thicknesses as Once in position, the phased array coil is placed over the top of
small as 6 mm can be used), and paddle position.81 The vibra- the driver and secured. The output in a clinical 2D MRE is an
tion frequency affects the repetition time (TR), which is adjusted estimate of the magnitude of the complex shear modulus, often
automatically to be a multiple of the wave period. With a typical described colloquially as “shear stiffness,” in units of kPa.
vibration frequency of 60 Hz, the GRE variant usually has a
50 msec TR while the SE-EPI variant usually has a 1000 msec MRE Sequence
TR. The echo times (TEs) are usually set at default values (rang- MRE uses a phase-contrast sequence modified with motion-
ing 18.4–26 msec for the GRE variant and 58–59 msec for the encoding gradients (MEG) to image shear wave propagation.
SE-EPI variant), although they can be modified slightly by the The clinical version of MRE images an axial slice of the liver and
user. The paddle on the passive driver is commonly positioned at encodes motion from shear waves perpendicular to this axial slice,
the level of the xiphoid along the right mid-clavicular line, which ie, in one direction, the z-direction. The driver system generates
approximates the location of the center of the liver. Patients with shear waves that propagate in a largely transverse direction within
unusual anatomy or who have colonic interposition may require the target region of the liver, which allows analysis of wave
the driver to be moved to the mid-axillary line. In patients with motion in a single 2D plane. The investigational 3D MRE

FIGURE 5: MRE involves several steps. A driver system generates and transmits longitudinal waves into the patient. Some of the
wave energy is converted into shear waves via “mode conversion” (not shown). A phase-contrast pulse sequence with motion-
encoding gradients images the shear waves at several (typically three or four) “phase offsets” to capture different phases of the
wave cycle; one phase cycle is shown. Four or more slices are usually acquired; one slice is shown. Raw phase and magnitude images
are generated. Postprocessing produces wave images and colorized magnitude-of-complex-shear-modulus (“shear stiffness”) maps
known as elastograms for each acquired slice. An analyst places an ROI on each elastogram. A mean “shear stiffness” value in units
of kPa is calculated from all pixels contained in all ROIs in all slices.

11
Journal of Magnetic Resonance Imaging

acquires the wave field in a 3D volume and encodes displacement that may disrupt wave propagation such as lesions, blood vessels,
in the x, y, and z directions.83,84 gallbladder, and the outer 1 cm of the liver.81 The typical ROI
As a 2D projection on a 3D shear wave field, 2D MRE varies in size depending on factors that affect wave amplitude and
analysis suffices for estimating stiffness but yields limited propagation. In general, the size of the ROIs that can be drawn
information on wave complexity, obliquity, and interference. increases with SE-EPI sequence and stiffer livers and decreases
These limitations lead to a tendency in 2D MRE to over- with GRE, softer livers, and iron overload.88
estimate the upper bounds of the magnitude of the complex Due to differences in techniques, analyst experience, and
shear modulus.85 This overestimation is corrected in 3D software used, the final reading of MRE images can vary even with
MRE through the application of a 3D vector-based inversion the same analyst.87 The variability in manual analysis of MRE has
algorithm to a 3D wave field, which requires fewer assump- prompted the creation of more objective and automated
tions and allows additional mechanical properties to be processing of MRE wave field data. For example, software to auto-
assessed.86 These advances in 3D MRE enable analysis of matically identify pixels with invalid data has been implemented
subtle wave motion in deep tissue, improved robustness on 2D MRE and is being developed for 3D MRE.87,89 For 2D
against artifacts, and greater technical success. MRE, this software uses statistical methods to select high-quality
wave information with good signal-to-noise ratio. A polynomial is
Postprocessing selected to fit the stiffness data as calculated by the inversion
Raw data on shear waves acquired from the phase-contrast algorithm in predefined pixel windows, and goodness-of-fit
sequence is postprocessed by an inversion algorithm into a color- R2 from individual windows are combined into a confidence
scaled representation of tissue stiffness known as an elastogram. map. R2 values greater than 0.95 are considered reliable stiffness
Although the elastogram covers the entire abdomen, not all por- measurements.87
tions contain valid data. In particular, parts of the image in which
the wave propagation is weak (ie, low signal-to-noise) or where MRE Precision and Failure
there is significant wave interference or obliquity (ie, interface MRE has demonstrated excellent repeatability and reproducibility
between two media where the stiffness is artificially elevated) are for individual vendors, with reported intraobserver ICC of 0.95
invalid and should be excluded from analysis.87 In the past, a radi- and interobserver ICC ranging from 0.83–0.95.77,90 Yasar et al
ologist or a member of the radiology team would visually inspect also demonstrated excellent same-day cross-platform reproduc-
the elastogram and manually delineate ROIs around areas of the ibility of phantom stiffness measurements on GRE-based 2D
liver with planar wave propagation, high signal-to-noise wave MRE, with a reported ICC of 0.98.75 Current QIBA guidelines
information, and good wave quality. Figure 6 presents an imaging recommend that a change in stiffness of 19% or greater at the
example of this process. The analyst would also examine the MR same site using the same protocol be considered a true change in
magnitude image to avoid placing ROIs over anatomical regions stiffness with 95% confidence.91,92

FIGURE 6: MR elastography performed on a 3T GE 750 scanner by using a 2D GRE sequence (top row) and a 2D SE-EPI sequence
(bottom row) in a 54-year-old man with NAFLD and fibrosis stage 0 on histology (Brunt system). Shown from left to right for each
sequence: magnitude image, transverse colorized wave image, and transverse colorized elastogram. Using magnitude images as
reference, ROIs are drawn over the right liver lobe by an analyst on the wave images. Areas with poor wave propagation, blood
vessels, and inhomogeneous liver parenchyma are avoided. The ROIs are propagated to the elastograms for mean “shear stiffness”
estimates (kPa). An automated 95% confidence grid, appearing as a cross-hatched pattern within the ROIs, is placed over areas of
unreliable data that do not contribute to the mean stiffness estimates on the elastograms.

12
 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

The MRE failure rate is low; in 1377 consecutive MRE the effects of rapid T2* decay in mild to moderate cases but can-
examinations performed for clinical indications on a 2D GRE not overcome extreme iron overload.
scanner, the rate of technical failure was less than 5.6%.93 Iron Other limitations are technical- or patient-related. The con-
deposition is responsible for most of these failures (71%). ventional driver system uses semirigid membranes, which can
result in nonuniform delivery of mechanical excitation to the
patient, leading to region-dependent accuracy in liver stiffness
MRE Diagnostic Accuracy and Clinical Applications
estimates.13 Flexible, ergonomic drivers are being developed to
Due to its recent development and narrower availability, data on
improve patient tolerance and provide a more symmetric interface
MRE diagnostic performance in clinical settings are more limited
with the anterior chest wall.99 Since MRE is a motion-sensitive
than US. Most studies on MRE have been performed in research
technique, a fraction of the failure rates is due to motion artifacts;
settings and have demonstrated excellent performance at detecting
free-breathing 3D MRE is in development.100 Finally, a minority
fibrosis using a shear stiffness cutoff value of 3 kPa (sensitivity and
of patients cannot tolerate MR exams due to claustrophobia, MR-
specificity of 0.98 and 0.99, respectively).94,95 In a meta-analysis
incompatible implantable devices, discomfort related to the MR
comprising 697 patients with mixed chronic liver diseases, the
driver system, or inability to fit into the MR scanner bore.
AUROCs of 2D MRE for detecting fibrosis stages ≥1, ≥2, ≥3, and
cirrhosis were 0.84 (95% CI: 0.76–0.92), 0.88 (95% CI:
0.84–0.91), 0.93 (95% CI: 0.90–0.95), and 0.92 (95% CI: Comparative Performance of US Elastography
0.90–0.94), respectively.96 This meta-analysis reported optimal and MRE
cutoffs of 3.45, 3.66, 4.11, and 4.71 kPa for detecting fibrosis
MRE has demonstrated many advantages over US elastography at
stages ≥1, ≥2, ≥3, and 4, respectively. Kim et al found no signifi-
assessing liver fibrosis. Table 3 summarizes comparative advantages
cant differences between the pooled sensitivity and specificity of
and clinical uses for the techniques. In direct comparisons between
2D MRE using GRE vs. SE-EPI sequences.76 More studies are
MRE and US elastography methods using histopathology as the
needed to establish diagnostic thresholds for 3D MRE.
reference standard, MRE is more accurate for staging liver
Only three prospective studies have examined the perfor-
fibrosis45,101–105 (Table 3). MRE provides a larger volume of
mance of 3D MRE in patients: one found that 3D MRE out-
assessment than US, which can be useful for assessing advanced
performed 2D MRE at diagnosing advanced fibrosis in a
disease where there may be more spatial heterogeneity.106 US tech-
cohort of NAFLD patients (difference in AUROC within 95%
niques perform less well in obese patients, whereas MRE is not
CI: 0.001–0.223), while the other two found similar diagnostic
meaningfully impacted by obesity as long as the patient can fit into
performance between the two methods in patients with mixed
an MR scanner with the passive driver in place.45,107 Emerging
chronic liver diseases.77,83,97 These promising results require
versions of MRE, such as 3D MRE, may provide higher technical
further validation prior to recommending 3D MRE over 2D
precision than 2D MRE and assess multiple tissue mechanical
MRE for routine clinical use.
properties that may be sensitive to pathologic changes other than
Currently, 2D MRE may be useful in practice for iden-
fibrosis (ie, inflammation).97 In comparison, current US elas-
tifying significant fibrosis or cirrhosis in patients with
tography techniques on human subjects provide a single output
NAFLD or HCV to help direct therapy. The MRE exam
designed to assess overall tissue stiffness.
may be included as part of a liver protocol MRI, which can
Despite the strengths of MRE, US elastography remains a
assess other morphologic features of chronic liver disease and
valuable tool, with broad clinical use and greater availability. US
complications like HCC. There is little data on the longitudi-
elastography techniques are relatively inexpensive and easy to per-
nal use of MRE for therapeutic response in clinical practice.
form, can be incorporated into a standard liver assessment, utilize
MRE by itself is a short exam requiring ~2 minutes of
widely available platforms, do not require offline postprocessing
acquisition time.79 The CPT code for MRE has recently been
or analysis, and, in the case of VCTE, have been extensively vali-
accepted and will become operational in 2019, allowing reim-
dated and available at the point of service. In comparison, MR is
bursement for abbreviated MRIs that include only MRE in the
less accessible in many practice settings. The charges associated
clinical setting.98 This development is expected to increase the uti-
with MR tend to be higher than its actual operating cost. US has
lization of MRE.
virtually no contraindications, whereas MR cannot be performed
in a minority of patients.
MRE Limitations
The one notable exception to MRE’s high rate of technical success
is the presence of excessive hepatic iron. Although an uncommon Current Challenges
finding, iron overload is especially problematic when GRE Both US and MR elastography methods show significant
sequences are used. Iron causes T2* shortening and signal loss, overlap in liver stiffness estimates between adjacent liver fibro-
which diminishes the visibility of shear waves on phase contrast sis stages, especially in the range of no to mild disease,
images.78 The development of newer SE-EPI sequences mitigates although there tends to be less overlap with MRE.45

13
14
TABLE 3. Prospective, Head-to-Head Comparisons of VCTE, pSWE, or 2D SWE vs. 2D MRE

AUROC for liver fibrosis stage:

Any significant
Study Population No. of patients Comparison Success (%) ≥2 ≥3 4 differences, P < 0.05
Studies directly comparing VCTE and 2D MRE
Chen et al, Mixed 111 VCTE 81% 0.91 0.87 0.92 2D MRE higher rate of success and
Journal of Magnetic Resonance Imaging

2017 reliability than VCTE

2D MRE 96% 0.93 0.92 0.95
Park et al, NAFLD 104 VCTE 93% 0.86 0.80 0.69 2D MRE more accurate at
2017 diagnosing stage ≥1 than VCTE
(0.82 vs. 0.67)
2D MRE 100% 0.89 0.87 0.87
Imajo et al, NAFLD 142 VCTE 89% 0.82 0.88 0.92 2D MRE more accurate at
2016 diagnosing stage ≥2 than VCTE
2D MRE 100% 0.89 0.89 0.97
Studies directly comparing pSWE and 2D MRE
Chou, Chen, HCC (mixed etiology) 82 pSWE 100% 0.81 0.86 0.86 2D MRE more accurate at
Wu, Lin, & diagnosing stage ≥2, ≥3, and
Chen, 2017 4 than pSWE
2D MRE 98% 0.93 0.96 0.99
Cui et al, NAFLD 125 pSWE 98% 0.85 0.90 0.86 2D MRE more accurate at
2016 diagnosing stage ≥1 than pSWE
2D MRE 99% 0.89 0.93 0.88

for the diagnosis of significant fibrosis (stage ≥2), advanced fibrosis (stage ≥3), and cirrhosis (stage 4), with histopathology as the reference standard.
VCTE, vibration-controlled transient elastography; pSWE, point shear wave elastography; 2D SWE, two-dimensional shear wave elastography; 2D MRE, two-dimensional magnetic resonance
elastography; NAFLD, nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma.
 Zhang et al.: Liver Fibrosis Imaging: A Clinical Review

The biological basis of liver fibrosis may partially needed to establish and validate potential clinical decision-making
account for this overlap. Increased liver stiffness in the con- algorithms.
text of liver fibrosis is thought to be caused by the fibrotic tis- The application of artificial intelligence to imaging has
sue acting as a rigid scaffold on the liver parenchyma. Liver garnered much interest in recent years and is another area of
fibrosis is mainly composed of collagen, and staging depends active investigation in US and MRE. In US elastography,
on total collagen content as well as its location and associated machine-learning and deep-learning-enhanced image analysis
structural remodeling. Thus, total collagen content does not techniques show promise for improving the accuracy of the
track linearly with liver fibrosis stage. In fact, studies have measurements and reducing the effect of the operator. Com-
shown that total collagen content in the liver rises slowly bined mathematical models or machine-learning models—
between no fibrosis (stage 0) to significant fibrosis (stage 2), which include imaging and circulating biomarkers, demo-
then increases exponentially once the patient progresses to graphic variables, and other patient-related variables—can also
advanced fibrosis (stage 3).108 Since liver stiffness estimates be developed to improve the accuracy of the elastography
may directly reflect total collagen content rather than fibrosis technique and contribute to risk stratification.
stage, liver stiffness unsurprisingly demonstrates more overlap In MRE, active areas of research include automated analysis
at lower stages of liver fibrosis. employing machine-learning methods and development of hard-
Another factor that contributes to the overlap in liver ware and software to predict pathologic changes other than fibro-
stiffness estimates may be the imprecision of histology as a sis. Automated analysis of 2D MRE has been shown to have
reference standard. Evidence suggests considerable overlap in comparable performance to that of human analysts and may
the histological classification of low-intermediate stages of become available in clinical practice in the near future, and auto-
fibrosis.7,8 Reasons for this imprecision include interreader mated analysis of 3D MRE is also in progress.87
variability, fibrosis heterogeneity, and sampling error. Given Future studies may explore whether elastography can mea-
the overlap in the reference standard, some overlap in fibrosis sure factors other than liver stiffness, such as inflammation, which
stage classification by all elastography methods is unavoidable. are important in the pathogenesis of NAFLD/NASH or viral hep-
In addition to decreased discriminative power at lower atitis. Finally, one question that needs to be addressed for all
stages of fibrosis, the lack of standardization in reported modalities involving elastography is the significance of tissue
parameters to enable comparisons across techniques also com- mechanical properties as standalone predictors of clinical out-
plicates liver fibrosis staging and follow-up. Currently, custom come. Until now, elastography has been designed as an indirect
conversions are needed for measurements obtained from dif- marker of fibrosis. Given the multifactorial contributors to tissue
ferent institutions and even between different platforms in stiffness other than fibrosis and the imperfect histological stan-
the same institution. This lack of uniformity in reported dard, there is a need to move beyond fibrosis as a relative scale for
parameters prevents the widespread adoption of elastography imaging measured stiffness. Future studies are needed to gauge
techniques and the establishment of disease-specific thresh- the predictive power of imaging-measured stiffness using markers
olds for diagnosis, staging, and monitoring. of clinical outcome, which might include progression to cirrhosis,
More fundamentally, there is the issue of accuracy verifica- portal hypertension, hepatic decompensation, development of
tion. Tissue stiffness is inferred from assessing shear wave propaga- HCC, and death. Understanding the significance of longitudinal
tion in biological systems, but no quantitative, in vivo method changes in imaging measured stiffness—for instance, the associa-
exists to directly verify these stiffness estimates. Although investi- tion between reductions in stiffness and clinical improvement—
gators have demonstrated the accuracy of stiffness measurements would also be invaluable to determining treatment response and
in phantoms with known stiffness, phantom models cannot repli- endpoints for clinical trials. Establishing direct associations
cate the complexity of livers in vivo.109 between imaging-measured stiffness and clinical outcomes and
prolonged survival would make liver stiffness measurements
standalone indicators of liver disease status, similar to the diagnos-
Future Directions tic and prognostic roles served by measurements of blood pressure
As the two clinically available and FDA-approved imaging modali- and hemoglobin A1C for cardiovascular and metabolic outcomes.
ties for estimating liver stiffness, US and MRE are mostly com-
pared in a competitive context. However, the strengths and
limitations of the two modalities may yield a better screening and Summary
diagnostic model when used in combination than independently. Liver fibrosis is a defining characteristic of chronic liver disease
For instance, US elastography may be used to screen certain at-risk and a target for therapy. Histology has served as the clinical refer-
populations using lower cutoff values with high sensitivity, while ence standard for the evaluation of liver fibrosis but is invasive,
MRE may be used to confirm US findings and identify patients costly, and impractical for widespread screening and longitudinal
for further testing and intervention. For such purposes, prospec- surveillance. Elastography offers a quantitative and noninvasive
tive, multicenter clinical trials involving multiple platforms are alternative that utilizes shear waves as a probe for liver stiffness,

15
Journal of Magnetic Resonance Imaging

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Acknowledgment An update to the World Federation for Ultrasound in Medicine and Biol-
Contract grant sponsor: NIBIB of the National Institutes of Health ogy Guidelines and Recommendations. Ultrasound Med Biol 2018;44:
2419–2440.
(NIH); Contract grant number: K23 EB020710 (to A.E.S.). is
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The authors report no conflicts of interest.
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