Ultrasound-based Hepatic Elastography
Origins, Limitations, and Applications
Eric B. Cohen, MD* and Nezam H. Afdhal, MDw
Abstract: A reliable, noninvasive marker to help clinicians evaluate
hepatic fibrosis is urgently needed. The liver biopsy, an imperfect
gold standard, has recognized limitations including sampling error
and interobserver variability. Hepatic elastography (HE) is a novel
sonographic method for assessing liver stiffness and has excellent
accuracy in making the diagnosis of minimal fibrosis and cirrhosis.
Several conditions intrinsic to the pathology of the liver
compromise the positive predictive value of HE for fibrosis alone
including acute hepatitis, obstructive cholestasis, and passive
congestion. Technical considerations that hinder the performance
of elastography include an advanced body mass index, the presence
of ascites and narrow intercostal spaces. Despite these limitations,
elastography has a role in staging fibrosis, prognosis of disease
outcome, surveillance, and treatment decisions. HE is now being
used in lieu of liver biopsy to investigate the natural history of
chronic liver diseases. Additional studies are required to better
define the appropriate role of HE in clinical practice.
Key Words: hepatic elastography, transient elastography, Fibroscan,
noninvasive markers of fibrosis, cirrhosis
(J Clin Gastroenterol 2010;44:637–645)
Liver fibrogenesis is the wound-healing response and “final”pathway of chronic liver disease.1 Accurate staging of
fibrosis is valuable for prognosis, treatment decisions, and
surveillance of disease progression or regression.2,3 Liver
biopsy, currently the gold standard4 has several recognized
limitations including sampling error and interobserver varia-
bility in interpretation and staging.5 Furthermore, the
dynamic process of fibrosis resulting from progression and
regression is difficult to capture with biopsy alone.6 The
hepatology community is actively researching noninvasive
methods of fibrosis quantification.
Hepatic elastography (HE), which uses the novel
method of transient elastography (TE), has been extensively
evaluated in many different forms of liver disease as a tool
to measure liver stiffness as a surrogate for fibrosis.
However, as it is not widely available in the United States
and is awaiting FDA approval, there is considerable
uncertainty about elastometry’s niche within the day-
to-day practice of hepatology.7 Perhaps the most critical
question for clinicians, as multiple methods develop for the
evaluation of fibrosis, is how to cost effectively and safely
incorporate this multimodality approach into clinical care.
The aim of this review is 3-fold: (1) to provide background
that sets the stage for the emergence of HE as a leading
noninvasive marker candidate, (2) to identify the strengths
and weaknesses of HE, and (3) to describe how it is being
applied to the clinical and research setting.
A NEED FOR NONINVASIVENESS
Our understanding of liver fibrogenesis has led to new
insights that liver fibrosis is not a relentless and progressive
condition. Gone is the dogma of fibrosis following a single,
common pathway. New insights dictate that clinically
significant histologic improvement can occur even in a
cirrhotic liver.8 Pathways favoring fibrogenesis include
stellate cell activation, the process of epithelial-to-mesenchy-
mal transition (EMT) of hepatocytes and cholangiocytes,
activation of resident portal fibroblasts and bone marrow-
derived fibrocytes.9 There is additional variability within
pathways, with the composition of extracellular matrix
(ECM) changing over time. At the earliest stages of
fibrogenesis, elements such as collagen-type IV, heparin-
sulfate proteoglycans, and laminin predominate, whereas
the ECM of more established fibrosis is dominated by fibril
forming collagens type I and III.9 There is, however, a
definite inability to accurately measure fibrogenesis and
fibrosis regression in vivo using any of our currently
available technologies. To really look at these dynamic
changes, we will probably need to advance molecular
imaging of the cells involved in liver fibrosis and regression.
Thus it is essential to have an accurate method to
quantify the amount of fibrosis regardless of stage, under-
lying pathway or disease etiology. To this end liver biopsy
has been the clinician and investigator’s gold standard for
decades. Beyond its diagnostic capability, liver biopsy is an
invaluable tool for clinical prognostication as it relates
to the stage of fibrosis. For a clinician, defining the stage
of liver fibrosis provides a general estimation of disease
chronicity and severity. Clinically relevant outcomes in liver
disease are often a result of advanced fibrosis or cirrhosis,
with eventual development of portal hypertension and
hepatocellular carcinoma. In fact, septal thickness and
small nodularity are 2 histologic features independently
predictive of clinically significant portal hypertension
(HVPG Z10).10 In addition, HCC occurs primarily in the
setting of cirrhosis and one can argue that the major role of
biopsy is in diagnosing or excluding advanced fibrosis and
cirrhosis so that appropriate screening can be undertaken.
In addition, the fibrosis stage has been used to
determine the relative urgency for disease treatment, espe-
cially with highly prevalent, indolent conditions such as
hepatitis C virus infection and nonalcoholic steatohepatitis.
Valid recognition of the extreme ends of the fibrosisCopyright r 2010 by Lippincott Williams & Wilkins
From the *Yale University School of Medicine, Department of
Digestive Diseases; and wLiver Center, Beth Israel Deaconess
Medical Center.
There are no grants or financial support to declare.
There are no conflicts of interest for either investigators.
Reprints: Eric Cohen, MD, Beth Israel Deaconess Medical Center, 110
Frances Street, LMOB Ste 4, Boston, MA 02215 (e-mail: ebcohen@
bidmc.harvard.edu).
CLINICAL REVIEW
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spectrum, therefore, would either allow for a cautious, cost-
effective delay of treatment or herald imminent treatment and
surveillance for the complications of cirrhosis. This paradigm
helps define the utility we seek in noninvasive biomarkers. In
effect, categorizing an established diagnosis as early or late in
its natural history can add efficiency to treatment algorithms
and provide important prognostic information for both the
patient and clinician.
However, the need for staging disease is also depen-
dant on the outcome of treatment; as treatment becomes
more effective the need for staging disease precisely
becomes less necessary and the need to exclude cirrhosis
more important. For example, in genotype 2 and 3 HCV,
biopsy is not necessary as over 80% of patients achieve a
sustained virologic response that is independent of disease
stage. In such cases, biopsy can be reserved for those that
fail to respond.
A biopsy is said to represent 1/50,000 of the liver,11,12
and therefore it is not surprising that sampling error
frequently occurs. The actual frequency is an area of
debate; 25% to 30% is commonly ascribed, with under-
staging occurring especially at the lower strata of fibro-
sis.13,14 In a recent paper by Robert et al,15 the percentage
of disagreement between hepatopathologist and community
pathologist assessments for staging hepatitis C ranged
between 22 and 58% depending on the stage of fibrosis,
and was augmented in biopsy samples less than 1.5 cm. In
addition to the propensity for sample error and inter-
observer interpretation, liver biopsy suffers from poor
patient acceptance because it is invasive and sometimes
painful.16 Furthermore, there is a small but significant risk
for serious complications and death,4 even when carried out
transjugularly. Toward the future, as more clinical trials of
antifibrotics are designed, serial biopsy will unlikely be the
sole evaluator of regression, and therefore, noninvasive
methods are paramount.
Mehta et al evaluated a critical aspect in the search for
the ideal noninvasive marker of fibrosis.17 Assuming a
conservative error rate for biopsy staging of 10% to 20%,
how is it possible to validate a perfect alternative when
it is compared with an imperfect standard? Their model
suggested that the area under the ROC curve for a
surrogate marker for fibrosis compared with liver biopsy
could not exceed 0.9. In effect, biopsy error causes the true
validity of surrogate tests to be underestimated. This will in
turn lead a clinician to falsely misperceive the test as
inaccurate, when in fact it is possible that a perfect
surrogate marker could already exist.
The ideal noninvasive marker should have certain
characteristics for practical application. For an imaging
modality such as elastometry, salient features should include:
ability to accurately determine fibrosis stage; reliability
unaffected by the underlying disease and conditions intrinsic
to hepatopathology; ease of performance and reproducibility.
These characteristics are similar to ones earlier described for
serologic markers of fibrosis.18 Studies thus far suggest that
HE possesses many of the characteristics of an ideal marker,
and will be elaborated in this review.
ELASTOGRAPHY AND FIBROSIS STAGING
The evolution of elastography in the field of hepato-
logy took many forms over nearly 2 decades before finding
success in HE.19 The methods of static, dynamic and
remote elastography were all first attempted without
success. The primary reason was the boundary effect, or
motion artifact from respiration that interferes with hepatic
imaging. Those methods proved more successful with
breast19,20 and prostate19 evaluation.
A sentinel study by Yeh et al21 from China, published
in Ultrasound and Medical Biology in 2002, laid the
foundation for HE when it was shown that liver stiffness
positively correlated with fibrosis. Partial hepatectomy
specimens were sectioned into blocks and placed on an
electronic balance. This balance was connected to a
personal computer and acrylic compressor, which was
lowered on to the tissue. The compressor then applied
intervals of increasing pressure (in kPa), allowing for
measurement of the internal displacement of liver tissue.
In effect, healthier livers allowed for greater internal
displacement whereas cirrhotic livers, stiffer by nature,
had less internal displacement. Interestingly, this correla-
tion was greatest at the ends of the fibrosis spectrum, and
suffered from poor discriminatory ability at the middle
strata of fibrosis. This dilemma would prove to haunt HE’s
applicability throughout subsequent clinical investigations.
This technology was initially used in the cheese
industry as a way to evaluate the internal stiffness of large
blocks of cheese. Echosens (Paris, France) capitalized on
the shear elasticity of another soft solid material and
developed the now widely used FibroScan unit. The hand-
held probe is placed in the intercostal space overlying the
right, lateral lobe of the liver. It sends out 2 types of waves.
The first, a shear, mechanical wave, propagates through
firm tissue quickly, and through healthy tissue more slowly.
The second type of wave emitted by the probe is an
ultrasound wave. At a depth between 2.5 and 5.5 cm from
the skin, successive ultrasound waves reach a propagating
shear wave at a given distance apart, depending on the
velocity of that initial shear wave (Fig. 1). The distance
between the 2 points can then be used to calculate the shear
wave velocity, and in turn, through a mathematical model
using Young modulus, the stiffness is determined.19 The
FIGURE 1. The probe is placed between ribs overlying the liver.
It emits 2 types of waves (mechanical, ultrasound) and gathers
information from a field that is roughly 100 times larger than that
explored by a liver biopsy.
Cohen and Afdhal J Clin Gastroenterol  Volume 44, Number 9, October 2010
638 | www.jcge.com r 2010 Lippincott Williams & Wilkins