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JA OEN
*Ad ive Dis
Dep
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aim
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est
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73
ho
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cut-off value) bias was identified as an important cause of
heterogeneity for pooled results in both patient groups.
Conclusions: Ultrasound-based transient elastography
ap
C
Sta
vor
an
hep
dir
dat
det
den
in
tio
tat
mo
ass
tra
lar
acc
det
op
clin
ing
sys
mo
am
hig
the
eve
ma
for
sho
the
mo
rap
Tra
wh
str
the
tio
wa
acq
tion. This velocity is proportional to tissue stiffness, with faster
wave progression occurring through stiffer material. Measure-
ment of liver stiffness then is performed and measured in
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:1214–1220pears to be a clinically useful test for detecting cirrhosis.
irrhosis and its disease-related complications are respon-
sible for more than 40,000 deaths annually in the United
tes.
1
In addition, health care resource utilization for survi-
s is expected to increase based on trends in aging, obesity,
d the emergence of overt manifestations related to chronic
atitis C infection.
2,3
These clinical outcomes are related
ectly to the development of progressive hepatic fibrosis. To
e, liver biopsy has been regarded as the gold standard for
kilopascals. Ex vivo investigations have confirmed the associa-
tion between tissue elasticity and degree of fibrosis.
10
Since the initial report in 2003,
9
a number of investigations
examining ultrasound-based transient elastography in patients
with chronic liver disease have been published. With the up-
coming prospect of this technique’s expansion into the United
Abbreviation used in this paper: CI, confidence interval; I
2
, inconsis-
tency index; QUADAS, Quality Assessment of Diagnostic Accuracy
Studies; ROC, receiver operating characteristic.ltrasound-Based Transient Elastogra
brosis: Systematic Review and Meta
YANT A. TALWALKAR,* DAVID M. KURTZ,
‡
SCOTT J. SCH
vanced Liver Disease Study Group, Miles and Shirley Fiterman Center for Digest
artment of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
See CME exam on page 1123.
See editorial on page 1144.
ckground & Aims: Ultrasound-based transient elas-
raphy is a promising noninvasive alternative to liver
psy for detecting hepatic fibrosis. However, its overall
t performance in various settings remains unknown. The
s of this study were to perform a systematic review and
ta-analysis of diagnostic accuracy studies comparing ul-
sound-based transient elastography with liver biopsy for
patic fibrosis. Methods: Electronic and manual biblio-
phic searches to identify potential studies were per-
med. Selection of studies was based on reported accu-
y of ultrasound-based transient elastography compared
th liver biopsy. Data extraction was performed indepen-
ntly by 2 reviewers. Meta-analysis combined the sensitiv-
s, specificities, and likelihood ratios of individual stud-
. Extent and reasons for heterogeneity were assessed.
sults: Nine studies in full publication were identified.
r patients with stage IV fibrosis (cirrhosis), the pooled
imates for sensitivity were 87% (95% confidence interval
I], 84%–90%), specificity 91% (95% CI, 89%–92%), positive
elihood ratio 11.7 (95% CI, 7.9–17.1), and negative like-
ood ratio 0.14 (95% CI, 0.10–0.20). Among 7 investiga-
ns reporting patients with stages II–IV fibrosis, the
oled estimates for sensitivity were 70% (95% CI, 67%–
%), specificity 84% (95% CI, 80%–88%), positive likeli-
od ratio 4.2 (95% CI, 2.4–7.2), and negative likelihood
io 0.31 (95% CI, 0.23–0.43). Diagnostic threshold (orecting hepatic fibrosis. However, there continues to be evi-
ce that sampling error (up to 25%– 40%) remains a problemy for the Detection of Hepatic
nalysis
LEBER,
‡
COLIN P. WEST,
§
and VICTOR M. MONTORI
§
eases,
‡
Mayo Medical School,
§
Knowledge and Encounter Unit,
accurate fibrosis staging for individual patients.
4–6
In addi-
n, the extent of variation between histopathologist interpre-
ion for a particular stage may be as high as 20%.
4
Further-
re, the ability to procure an optimal specimen for
essment (biopsy length
25 mm with
11 complete portal
cts) is not guaranteed with either percutaneous or transjugu-
approaches.
5
Coupled with high costs and reduced patient
eptance, there remains a need for developing noninvasive
ection methods for hepatic fibrosis in addition to liver bi-
sy.
To date, the noninvasive diagnostic tests available from
ical practice are not sensitive or specific enough for detect-
occult fibrosis. In terms of novel approaches, a recent
tematic review of serum fibrosis markers was noted for only
derate performance in detecting moderate to severe fibrosis
ong patients with chronic hepatitis C after pooling results of
h-quality studies.
7
A number of serum markers representing
process of hepatic fibrosis have been studied to date. How-
r, the frequency of indeterminate results from individual
rkers or panels ranges between 25% and 40% with the need
subsequent liver biopsy for diagnosis.
7
Emerging data have
wn that a sequential algorithm-type approach to improve
posttest likelihood of detecting advanced fibrosis may be
re effective than application of a single test alone.
8
Recently, the method of ultrasound-based transient elastog-
hy was reported to identify patients with hepatic fibrosis.
9
nsient elastography is based on the principle of Hooke’s law,
ich characterizes a material’s strain response to external
ess. By using an ultrasound transducer probe mounted on
axis of a vibrator, the transmission of low-frequency vibra-
ns from the right intercostal space creates an elastic shear
ve that propagates into the liver. A pulse-echo ultrasound
uisition then is used to detect the velocity of wave propaga-© 2007 by the AGA Institute
1542-3565/07/$32.00
doi:10.1016/j.cgh.2007.07.020

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October 2007 ULTRASOUND–BASED TRANSIENT ELASTOGRAPHY 1215tes, we sought to conduct a systematic review and meta-
alysis to characterize the diagnostic performance of ultra-
nd-based transient elastography as compared with the ref-
nce standard of liver biopsy for the detection of hepatic
rosis.
Methods
Literature Search
A computer-aided literature search of PubMed
EDLINE), EMBASE, the Cochrane Library, Database of Ab-
acts of Reviews of Effects, Web of Science, SCOPUS, Ameri-
College of Physicians Journal Club, and Google Scholar
abases was conducted from database inception through Jan-
ry 29, 2007. Initial search strategy using free-text words
epatic fibrosis AND elastography”) was conducted. We also
d a sensitive and precise search strategy in the PubMed
abase for locating any existing systematic reviews on ultra-
nd-based transient elastography (to identify additional
dies missed by our search), of which none were identified.
11
nual searching of reference lists from primary studies then
s performed to locate any potential studies missed by elec-
nic search strategies. Abstracts and proceedings from the
erican Association for the Study of Liver Disease, European
ociation for the Study of the Liver, and Digestive Disease
ek annual meetings between 2003 and 2006 also were re-
wed. This time period is noted for an increased submission
d acceptance rate for investigations examining ultrasound-
ed transient elastography to detect hepatic fibrosis. Consul-
ion with experts in the field also was performed to identify
itional published and unpublished primary studies.
Study Selection
Two independent reviewers (D.M.K. and S.J.S.) read all
tracts of candidate articles and retrieved the full text of
blished manuscripts that could not be narrowed down based
title and abstract alone. These articles were read and checked
inclusion criteria independently, with disagreements re-
ved through consensus with a third reviewer (J.A.T.). Primary
dies that reported data required for meta-analysis were iden-
ed and included.
Study Inclusion/Exclusion Criteria
Inclusion criteria for primary studies required the fol-
ing features: (1) detailed description of human subjects
der study, (2) description of ultrasound-based transient elas-
raphy as the index test, and (3) description of liver biopsy as
reference standard. The inclusion of non–English language
dies was allowed. Studies in which transient elastography
s compared with other noninvasive methods of hepatic fi-
sis (ie, serum markers) were allowed if discrete information
transient elastography alone could be extracted from the
a. Exclusion criteria were limited to duplicate publications
a primary study that contained all or some of the original
a. In this situation, the updated manuscript was to be
sen, assuming the relevant data for meta-analysis were avail-
e.Quality Assessment of Primary Studies
Each of the studies meeting inclusion criteria was ana-
ed in duplicate by independent reviewers (D.M.K. and S.J.S.)
per
det
0 –
bioquality using the Quality Assessment of Diagnostic Accu-
y Studies (QUADAS) checklist
12,13
(Table 1). This tool is a
-item instrument that allows for the identification of impor-
t design elements in diagnostic accuracy studies such as
ient spectrum, the presence or absence of observer blinding
d verification bias, handling of indeterminate results, and
orting of patient loss to follow-up evaluation. Where there
re discrepancies between the reviewers, a consensus reviewer
.T.) resolved the differences.
Data Extraction
Two reviewers (D.M.K. and S.J.S.) independently ex-
cted the required information from primary studies. Pre-
cified data elements for collection included patient age, sex,
d body mass index; underlying chronic liver disease etiology,
ails of test and reference standards, histologic fibrosis stage,
rage liver biopsy size, average number of portal tracts per
r biopsy, and duration of time between biopsy and ultra-
nd-based transient elastography. Other variables that were
ght included diagnostic threshold (or cut-off) values used
detecting hepatic fibrosis, test performance characteristics,
sons for participant exclusion, and methods for handling
eterminate or missing data.
Data Analysis/Synthesis
The primary outcome for analysis was diagnostic test
ble 1. QUADAS Assessment Items
s the spectrum of patients representative of the patients who
ill receive the test in practice? (Generalizability item)
re selection criteria clearly described? (Clarity item)
he reference standard likely to correctly classify the target
ondition? (Validity item)
he time between reference standard and index test short
nough to be reasonably sure that the target condition did not
hange between the two tests? (Validity item)
the whole sample or a random selection of the sample receive
erification using a reference standard of diagnosis? (Validity
tem)
patients receive the same reference standard regardless of the
ndex test result? (Validity item)
s the reference standard independent of the index test (ie, the
ndex test did not form part of the reference standard)? (Validity
tem)
s the execution of the index test described in sufficient detail to
ermit replication of the test? (Clarity item)
s the execution of the reference standard described in sufficient
etail to permit its replication? (Clarity item)
re the index test results interpreted without knowledge of the
esults of the reference standard? (Validity item)
re the reference standard results interpreted without knowledge
f the results of the index test? (Validity item)
re the same clinical data available when test results were
nterpreted as would be available when the test is used in
ractice? (Validity item)
re uninterpretable/intermediate test results reported? (Clarity
tem)
re withdrawals from the study explained? (Clarity item)formance of ultrasound-based transient elastography for the
ection of cirrhosis (stage IV) fibrosis vs no cirrhosis (stages
III fibrosis) compared with the reference standard of liver
psy. Assessing the diagnostic test performance of ultra-