Review

Non-invasive evaluation of portal hypertension using

ultrasound elastography

Annalisa Berzigotti⇑

Summary
Keywords: Advanced chronic liver
disease; Cirrhosis; Non-invasive;
Portal hypertension (PH) leads to serious complications, such as bleeding from gastroe- Varices; Decompensation.
sophageal varices, ascites and portosystemic encephalopathy in patients with chronic liver Received 20 December 2016;
disease (CLD). Gold standard methods for assessing PH and its complications include the mea- received in revised form 4 February
surement of hepatic venous pressure gradient and endoscopy; however, these are invasive, 2017; accepted 6 February 2017
expensive and not available at all centres. Therefore, non-invasive alternatives have been
the subject of extensive investigation over the last 20 years. The present review focuses on
the role of ultrasound elastography - a novel group of non-invasive techniques used to mea-
sure stiffness in target organs. In the context of CLD these methods are used to identify the
presence of PH, its severity, and the risk of PH-related complications. The rationale,
accumulated evidence, advantages and limitations of liver and spleen stiffness measurements
evaluated by different ultrasound elastography techniques in patients with advanced CLD is
discussed. Recent data regarding the use of ultrasound elastography techniques in patients
with non-cirrhotic forms of PH are also described.
Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights
reserved.

Introduction

Portal hypertension (PH) is a common clinical syn-
drome. It is haemodynamically defined by an
increase in the venous pressure gradient across
the liver, calculated from its inflow through the
portal vein versus its outflow through the hepatic
veins.1
Like any other vascular system, portal pressure
is the product of two independent factors: resis-
tance to blood flow and the amount of flow, as sta-
ted by Ohm’s law:
Pressure ¼ Resistance  Flow
obstruction, thrombosis of the hepatic veins Swiss Liver Center, Hepatology,
(Budd-Chiari syndrome, BCS) and idiopathic PH.2 University Clinic for Visceral
Surgery and Medicine, Inselspital,
Once PH passes a critical threshold of 10 mmHg,
University of Bern, Switzerland
extrahepatic vascular changes, driven by angio-
genesis, lead to portosystemic collateral develop-
ment and splanchnic vasodilation, which in
turn contribute to further increases in portal
pressure.3
PH can remain asymptomatic for many years but
imaging and laboratory testing may suggest its pres-
ence. Splenomegaly is a very common consequence
of PH; it usually leads to thrombocytopenia due to

An increase in resistance to portal blood flow is
the initial factor that leads to a rise in portal pres-
sure. This resistance can be located at any point
in the liver circulation, i.e. at the prehepatic, intra-
hepatic or post-hepatic level. In the Western world,
ca. 90% of cases of PH are due to advanced chronic
liver disease (ACLD) or cirrhosis, which cause struc-
tural damage through fibrogenesis, parenchymal
extinction and regeneration. PH then develops at
the intrahepatic sinusoidal site.1
Other less common causes include vascular liver
diseases, such as extrahepatic portal vein
hypersplenism,4 and is often the first manifestation
to infer the presence of PH.
From the clinical point of view, PH is relevant
because of its severe complications, which include,
upper digestive bleeding caused by gastroe-
sophageal varices, ascites, spontaneous bacterial
peritonitis and hepatorenal syndrome, and hepatic
encephalopathy.5 The risk of developing clinical
complications can be effectively reduced using
appropriate non-pharmacological measures and
medical therapy to lower PH,6,7 providing strong
rationale for the early identification of at-risk
patients.
Review
⇑ Corresponding author. Address:
Swiss Liver Center, Hepatology,
University Clinic for Visceral
Surgery and Medicine, Inselspital,
University of Bern, MEM F807,
Murtenstrasse 35, CH - 3010
Berne, Switzerland. Tel.: +41 31
632 87 27; fax: +41 31 632 49 97.
E-mail address: annalisa.berzigotti@
insel.ch

Journal of Hepatology 2017 vol. 67 j 399–411

 Review
Portal hypertension in patients with chronic liver
Key point disease
Chronic liver disease
accounts for 90% of cases of In chronic liver disease (CLD), the liver progres-
portal hypertension in sively accumulates extracellular matrix (fibrogene-
Western countries. sis); in ACLD,8,9 fibrosis is accompanied by a more
complex derangement of intrahepatic architecture.
This includes vascular remodelling (capillarisation
of the liver sinusoids and neo-angiogenesis), forma-
tion of intrahepatic shunts and an increase in hep-
atic vascular tone (active contraction of activated
hepatic stellate cells, myofibroblasts and smooth
muscle cells). There are two distinct phases of
ACLD, characterised by different prognoses (‘com-
pensated’ and ‘decompensated’ phase). The ‘com-
pensated’, asymptomatic stage, precedes the onset
of clinical events by years, and patients’ prognosis
is only slightly worse than the general population.7
In the past, diagnosis of compensated ACLD was
difficult because it was exclusively based on liver
biopsy. Now, the availability of non-invasive meth-
ods (ultrasound elastography in particular) has
improved the clinicians’ identification of asymp-
tomatic ACLD patients, who could further progress
to clinically significant PH (CSPH) and its subse-
quent complications (decompensated phase).7,10
The development of PH drives the progression of
ACLD to the onset of complications.7
Portal hypertension in patients with cirrhosis:
Invasive diagnostic methods
Sinusoidal PH in patients with cirrhosis can be reli-
ably and safely evaluated by measuring the hepatic
venous pressure gradient (HVPG) via hepatic vein
catheterization. However, HVPG measurement
could underestimate the severity of PH in patients
with primary biliary cholangitis as they may have
a pre-sinusoidal component (especially in early
stages).4
An HVPG of up to 5 mmHg is considered
normal; subclinical PH is defined by an HVPG of
Review
Table 1. Hepatic venous pressure gradient thresholds associated with clinical risks in chronic liver
disease.
Hemodynamic Increase in the risk of the following events:
threshold
Compensated 10 mmHg Presence and development of gastroesophageal
ACLD varices;74,75 first clinical decompensation in patients
with no varices;76 postoperative decompensation in
patients undergoing resection for HCC;77,78 development
of HCC79
12 mmHg Bleeding from varices74,80
16 mmHg First clinical decompensation in patients with varices;81
mortality82
Decompensated 16 mmHg Rebleeding and mortality83
cirrhosis 20 mmHg Failure to control variceal bleeding in bleeders;84
mortality85
22 mmHg Mortality in patients with alcoholic cirrhosis and AAH86
30 mmHg Spontaneous bacterial peritonitis87
AAH, acute alcoholic hepatitis; ACLD, advanced chronic liver disease; HCC, hepatocellular carcinoma.
400 Journal of Hepatology 2017 vol. 67 j 399–411
6–9 mmHg; and an HVPG P10 mmHg represents
the ‘clinically significant’ PH threshold.4 When
HVPG reaches 10 mmHg or above, PH can become
symptomatic as patients can develop gastroe-
sophageal varices and hyperdynamic circulation,
increasing their risk of clinical decompensation.
Therefore, patients with compensated ACLD should
be screened for the presence of CSPH,7 and patients
with CSPH constitute the population that should be
screened for the presence of varices at risk of bleed-
ing. Severe PH (HVPG P12 mmHg), and very severe
PH (HVPG P16 mmHg), are associated with an
increased risk of variceal bleeding and mortality,
respectively (Table 1).1
Clinical decompensation is defined by the onset
of ascites, variceal bleeding, jaundice or hepatic
encephalopathy. It marks the symptomatic phase
of cirrhosis, which is characterised by a much higher
mortality rate. At this stage, 100% of patients have
PH and, thus, in patients who already developed
decompensation, PH does not need to be diag-
nosed.7 However, patients with decompensated
ACLD are far more likely to have varices that require
therapy, so endoscopy is always needed in this
population.7
Upper gastrointestinal endoscopy is the best
method to determine the presence of oesophageal
and gastric varices, and allows the identification of
additional signs used to stratify bleeding risk (size
of varices; presence of red colour signs and wale
marks).11 Cross-sectional imaging techniques, such
as contrast-enhanced computed tomography (CT)
scanning and contrast-enhanced magnetic reso-
nance imaging (MRI) can be used to visualise large
gastroesophageal collaterals but cannot replace
endoscopy because of their limited sensitivity.
Whenever large varices or varices with red colour
signs are diagnosed, primary prophylaxis of bleed-
ing should be initiated using non-selective beta-
blockers or endoscopic therapy (band ligation).7,12
In patients with decompensated Child-Pugh grade
C cirrhosis, even small varices can bleed, and pri-
mary prophylaxis should be initiated promptly.7,12
A need for non-invasive methods to assess portal
hypertension in patients with chronic liver disease
HVPG measurement and endoscopy are the back-
bone for the assessment of PH in CLD.7,12 However,
they are invasive and may (in rare cases) lead to
complications; in addition, a specialised clinical set-
ting and specific expertise are required to carry out
these tests, limiting their availability and increasing
the cost to health care systems. The development of
simple, non-invasive methods enabling accurate and
rapid diagnosis of patients with a low risk of both
CSPH and varices requiring treatment (who could
avoid invasive tests), and patients with CSPH (at
high risk of complications and varices, requiring
further testing), would further the advancement of
personalised medicine in this field. Patients could

then be ascribed to different categories of risk and
ideally to different tests algorithms. Such a
‘‘point-of-care” non-invasive sphygmomanometer
in patients with CLD is one step closer, thanks to
the development of ultrasound elastography.
Ultrasound elastography techniques in a nutshell
Elastography techniques are all based on a com-
mon principle: all tissues have intrinsic mechani-
cal/elastic properties that can be measured by
creating a distortion in the tissue and evaluating
its response. There are several ways of creating
the distortion, detecting and then analysing the
response of the tissue. The term ‘‘ultrasound elas-
tography” groups the techniques using ultrasound
to detect the velocity of the microdisplacements
(shear waves) induced in the tissue. Comprehen-
sive technical details can be found elsewhere.13,14
The use of elastography to identify liver disease,
depends on the detection of changes in the
mechanical properties of the liver, which occur
when the structure of its tissue is modified, e.g.
when fibrosis accumulates.
Briefly, the first method that has been tested
and validated for the assessment of liver fibrosis
is vibration-controlled transient elastography (TE,
FibroScanÒ), which is a stand-alone machine. A
specific probe applied to the skin at a right inter-
costal space produces a vibration that is transmit-
ted to the liver. The measurement of the shear
wave displacement is provided by an ultrasound
beam on the tip of the probe and is reported in kilo
Pascals (kPa). The operator has very limited control
over the area of interest (monodimensional
view).15 Newer methods that are built-into high
end ultrasound devices, focus high-intensity
short-duration acoustic pulses to generate the tis-
sue displacement, either at one point (point shear
wave elastography, pSWE), or in larger, distinct
portions of the insonated area (two-dimensional
shear wave elastography, 2D-SWE).13,14,16 All these
techniques allow the real-time visualisation of the
region of interest, where elasticity can be mea-
sured, enabling both a semi-quantitative assess-
ment of elasticity by a colour-coding, and a
quantitative measurement expressed either in m/s
or in kPa. Of all the pSWE techniques, Virtual Touch
Quantification (VTQ) by acoustic radiation force
impulse (ARFI) imaging (Siemens, Germany) is the
most validated for liver fibrosis, and of 2D tech-
niqes SWE techniques, supersonic shear wave elas-
tography (SSI; Aixplorer, Supersonic Imagine,
France) is close to full validation.13,14,16 Virtually
all ultrasound device producers have now made
either pSWE or 2D-SWE available, each with differ-
ent software characteristics. Even though, similar
to TE, all ultrasound elastography techniques can
be considered point-of-care methods, the optimal
use of newer techniques requires at least a basic
knowledge of ultrasound imaging principles, and
Journal of Hepatology 2017 vol. 67 j 399–411
JOURNAL OF HEPATOLOGY
quality criteria for the correct interpretation of
results are not yet completely defined.
Liver stiffness measurement for portal hypertension:
Rationale and accuracy Key point
Liver stiffness measurement
Liver stiffness measurement (LSM) accurately (LSM) improves the non-
reflects liver fibrosis in CLD.17 In patients with invasive risk stratification
CLD, fibrosis is the major component of increased of patients with compen-
sated advanced chronic liver
intrahepatic vascular resistance leading to PH (as
disease; more than 90% of
discussed above). Therefore, LSM has been studied patients with an LSM [20-
as a possible surrogate for PH (Fig. 1). The first data 25 kPa (evaluated by tran-
reporting the close relationship between LSM and sient elastography) will have
HVPG in patients with CLD were obtained using TE clinically significant portal
in patients with post-orthotopic liver transplanta- hypertension.
tion recurrence of hepatitis C infection, and was
published about 10 years ago;18 since then, over
20 studies comparing LSM (using different elastog-
raphy techniques) and HVPG in patients with cirrho-
sis have been published. These are summarised in
Table 2.
In a study targeting patients with hepatitis C
virus (HCV)-related ACLD, Vizzutti et al. observed a
close correlation between LSM and an HVPG of up
to 10–12 mmHg. Above this haemodynamic thresh-
old, however, the strength of the correlation Key point
between the two parameters decreased markedly.19 Transient elastography is the
This is in line with the concept that once CSPH most validated ultrasound
develops, the severity of PH partially depends on elastography technique;
the increase in porto-systemic flow (splanchnic most data and proposed
cut-offs refer and apply to
vasodilatation, hyperdynamic circulation, and por-
it. Other methods utilising
tosystemic collaterals) that cannot be measured by high-end ultrasound devices
LSM. Interestingly in patients with severe PH, reduc- are now available and are
ing the blood flow-dependent component of PH using undergoing validation.
chronic non-selective beta-blocker (NSBB) therapy,
strengthens the correlation between LSM and HVPG.20
Even though LSM cannot be used to estimate
reliably an exact HVPG value (correlation (r) range:
0.59–0.70 in published series), it enables accurate
discrimination between patients with and without
CSPH;19,21 in the published data, the area under
the receiver operating characteristic curve (AUROC)
ranged between 0.82–0.94.22 A recent meta-analysis
verified these data.23 In the 11 studies included, the
Review
hierarchical summary AUROC for CSPH discrimina-
tion was 0.90, with sensitivity and specificity above
85% (sensitivity: 87.5%; 95% confidence interval [CI]:
75.8–93.9%; specificity: 85.3;%; 95% CI: 76.9–90.9%),
and the summary HVPG-LSM correlation coefficient
was 0.783 (95% CI: 0.737–0.823). A cut-off threshold
of 13.6 kPa has a high sensitivity (over 90%),19,21
whereas a threshold of 21 kPa has a high specificity
(over 90%) and can be used to confirm the presence
of CSPH.21 This cut-off maintains a high specificity
value in patients with potentially resectable hepato-
cellular carcinoma, requiring risk stratification prior
to treatment allocation.24 Given the amount and
quality of the existing data, the Baveno VI consensus
on PH agreed that values of LSM by TE [20–25 kPa
can be used to identify CSPH12 (Fig. 2). However,
most of the patients included in the studies leading
401
 Review
Key point
In patients with compen-
sated advanced chronic liver
disease of non-cholestatic
aetiology, endoscopy can be
safely avoided by using liver
stiffness measurement
(LSM) and platelet count in
combination. If such a
patient has an LSM of
\20 kPa and a platelet count
[150 g/L, it is very unlikely
(\5% risk) that on endo-
scopy he/she will have
Review
varices needing treatment.
402
LSM increases as fibrosis
accumulates in the liver and
indirectly reflects PH in patients
with ACLD
Hepatic vascular R
is mostly due
to liver fibrosis
P=R*Q
Fig. 1. Rationale for the use of liver and spleen stiffness measurements for the assessment of portal hypertension. Spleen
stiffness measurement could reflect PH more accurately, irrespective of its cause. ACLD, advanced chronic liver disease; LSM, liver
stiffness measurement; PH, portal hypertension; R, resistance. *P = R * Q: Pressure = Resistance * Flow.
to the identification of these cut-off values had a
viral aetiology, so more data regarding other dis-
ease causes are needed. The use of cut-off values
allows simple and straightforward risk stratifica-
tion in patients with compensated cirrhosis.
However, LSM provides a numerical, continuous
value, and therefore, the use of thresholds may lead
to the loss of relevant information (e.g. a value of
50 kPa holds a much higher risk compared to a
value of 21 kPa). Fine-tuning of an individual’s risk
of a specific endpoint (such as CSPH) without loss
of information, may be achieved by calibrating
the model probability, and using nomograms based
on this mathematical calculation.25
The precision of LSM for the diagnosis of CSPH
can be improved further by combining other
parameters associated with PH, such as platelet
count and spleen size.26
pSWE (ARFI technology, VTQ, Siemens, Ger-
many) has been used in three studies to date, com-
paring it to haemodynamic measurements,27–29
and describing an applicability close to 100%. The
discriminative accuracy for CSPH was very good
(AUROC 0.82–0.90).
2D-SWE (specifically using the software pro-
vided in Aixplorer, Supersonic Imagine, France)
was the subject of four studies comparing LSM to
HVPG.30–34 The accuracy of discrimination between
the presence and absence of CSPH of this method
(AUROC 0.82–0.90) was similar to the results
obtained using pSWE and TE. Two head-to-head
studies comparing 2D-SWE with TE30,32 for the
diagnosis of CSPH showed inconsistent results; in
one case 2D-SWE was more accurate than TE,30
Journal of Hepatology 2017 vol. 67 j 399–411
SSM directly reflects PH
Stiffness is due to congestion
and other changes related
directly to PH
independent of its cause
whereas in the other, no significant difference
between the techniques was observed, once quality
criteria were applied to both methods.32
Liver stiffness measurement prediction of
gastroesophageal varices and combination with
unrelated methods
The diagnostic accuracy of LSM to predict the pres-
ence and size of varices has been the subject of more
than 50 studies. LSM values are higher in patients
with esophageal varices (EV), and tend to be higher
in patients with large EV; overall, this parameter is
the most accurate single non-invasive predictor in
this field. However, LSM is less accurate for the pre-
diction of EV than for CSPH.35 In a systematic review
and meta-analysis including 18 studies with 3,644
subjects, summary AUROC was 0.84 for EV and
0.78 for large EV, with summary sensitivity and
specificity of 0.87 (95% CI: 0.80–0.92) and 0.53
(95% CI: 0.36–0.69) for EV; 0.86 (95% CI:
0.71–0.94) and 0.59 (95% CI: 0.45–0.72) for large
EV. Overall, the probability of correctly diagnosing
EV or large EV following a positive measurement
did not exceed 70%.35
Further studies were then carried out to evaluate
whether the combination of LSM with unrelated
parameters associated with portal pressure, such
as platelet count and spleen size, could improve
the probability of correctly diagnosing EV. In the ini-
tial study, which assessed patients with HBV-related
CLD, LSM, platelet count and spleen size were
combined to form the LSM-spleen diameter to
platelet ratio score (LSPS),35 which had a higher
 JOURNAL OF HEPATOLOGY
Table 2. Accuracy of liver stiffness measurement using ultrasound elastography techniques for the diagnosis of clinically significant portal hypertension.

Study Year Design and Population Correlation AUROC for CSPH Cut-off for CSPH Sensitivity Specificity
method used coefficient (kPa)
between LSM and
HVPG
Carrion 2006 Prospective, 129 OLT recipients with HCV- 0.840 n.a.0.930 n.a. 100% 60.8%
et al.18 TE recurrence for P6 mmHg 8.74 kPa for
HVPG [6 mmHg
Vizzutti 2007 Retrospective, 61 patients with HCV ACLD 0.781 0.990 13.6 kPa 97% 92%
et al.19 TE
Bureau 2008 Prospective, 144 patients with cirrhosis 0.858 0.945 21 kPa 89.9% 93.2%
et al.21 TE (alcohol and HCV) and varices
Lemoine 2008 Retrospective, 92 compensated patients with 0.728 0.840 all n.a. n.a. n.a.
et al.88 TE alcoholic or HCV cirrhosis 0.940 alcohol 34.9 kPa 90% 88%
Sanchez- 2011 Prospective, 38 patients with HCV 0.678 0.800 14 kPa 92.8% 50%
Conde TE cirrhosis and HIV coinfection 0.800
et al.89 for [12 mmHg
Colecchia 2012 Prospective, 100 HCV cirrhosis 0.836 0.920 24.2 kPa 52.3% 97.1%
et al.52 TE
Llop 2012 Prospective, 79 Child-Pugh A patients 0.552 0.840 Rule-out: 13.6 kPa 91% 57%
et al.24 TE (mostly viral) with potentially Rule-in: 21 kPa
resectable HCC 58% 91%
Reiberger 2012 Retrospective, 502 patients, mixed 0.794 0.871 18 kPa 82.2% 83.4%
et al.90 TE etiologies, some not
cirrhotics, some
decompensated
Hong 2013 Retrospective, 59 patients with cirrhosis 0.704 0.851 21.95 kPa 82.5% 73.7%
et al.91 TE
Augustin 2014 Prospective, 40 asymptomatic ACLD n.a. n.a. 25 kPa 65% 93%
et al.39 TE patients
Schwabl 2015 Retrospective, 188 patients with CLD 0.846 0.957 16.1 kPa 94.8% 86.9%
et al.92 TE
Kitson 2015 Prospective, 95 patients with cirrhosis n.a. 0.900 29.0 kPa 71.9% 100%
et al.93 TE
Cho 2015 Retrospective, 219 consecutive patients with n.a. 0.850 n.a. n.a. n.a.
et al.94 TE alcoholic cirrhosis (some
decompensated)
Zykus 2015 Prospective, 107 patients with cirrhosis, 0.750 0.949 17.4 88.0% 87.5%
et al.95 TE mixed etiologies (67% Child-
Pugh A)
Salzl 2014 Prospective, 88 patients with cirrhosis TE: 0.765 0.870 16.8 kPa 89.7% 75%
et al.28 TE and pSWE (half decompensated)
(VTQ) pSWE: 0.646 0.855 2.58 m/s 71.4% 87.5%
Takuma 2016 Prospective, 60 patients, viral 0.609 0.833 n.a. n.a. n.a.
et al.29 pSWE (VTQ)
Attia 2015 pSWE (VTQ) 78 patients, mixed (some 0.444 0.929 2.17 m/s 97% 89%
et al.27 decomp.; 90% CSPH; 76% EV)
Procopet 2015 Prospective, 88 consecutive patients, all All cases: 2D-SWE: 0.858 2D-SWE: 17 kPa 80.8% 82.1%
et al.32 TE and 2D- compensated 2D-SWE: 0.611 (compensated)

Review
SWE (SSI) TE: 0.699 2D-SWE reliable 2D-SWE reliable
measures: 0.948 measures: 90.9%
15.4 kPa 91.3%
Kim 2015 Prospective, 115 cirrhotic patients, mixed 0.646 0.819 15.2 kPa for CSPH 85.7% 80.0%
et al.31 2D-SWE (SSI) etiologies (some (0.587 if ascites)
decompensated); 92 analysed 0.867 for 21.6 kPa for
HVPG P12 mmHg HVPG P12 mmHg 83.3% 80.8%
Elkrief 2015 Prospective, 79 patients, mixed (55 with 0.578 (measures 2D-SWE: 0.790 2D-SWE:24.5 kPa 81% 88%
et al.30 2D-SWE (SSI) ascites; 70 with CSPH) with
and TE variable \10%) TE: 0.780 TE: 65.3 kPa
TE: n.a. 52% 100%
Jansen 2016 Prospective, 158 patients, mixed (some 0.626 0.86 24.6 kPa 68.3% 80.4%
et al.59 2D-SWE (SSI) decompensated) \16 kPa rule-out
[29.5 kPa rule-in
ACLD, advanced chronic liver disease; AUROC, area under receiver operator curve; CSPH, clinically significant portal hypertension; HBV, hepatitis B virus; HCC, hepato-
cellular carcinoma; LSM, liver stiffness measurement; n.a., not applicable; pSWE, point shear wave elastography; SSI, supersonic imagine; SWE, shear wave elastography;
TE, transient elastography; VTQ, virtual touch quantification.

Journal of Hepatology 2017 vol. 67 j 399–411 403

 Review
No
CLD: ever decompensated? Patient with compensated CLD

Yes
Advanced Chronic Liver Disease?
DECOMPENSATED CIRRHOSIS
CSPH in 100% LSM >10 kPA: No
High likelihood varices needing probable; >15 kPa Tailor need of therapy and follow-up
treatment: very probable Yes
perform endoscopy

CSPH?

LSM >21 kPA very Perform HVPG measurement

Yes LSM 13.6-21 kPA: uncertainty
likely (~90%) to assess PH

Perform endoscopic screening?

LSM >20 kPA and/or If LSM <20 kPa and platelets Safely avoid endoscopic screening
Yes >150 G/L varices needing
platelets <150 G/L Repeat LSM + platelets every year
treatment are very unlikely (<5%)*

Varices needing treatment?

Endoscopic surveillance according
No to the findings and presence or
Yes absence of ongoing exposure
to liver injury
Start NSBB or endoscopic band ligation

Fig. 2. Pragmatic use of liver stiffness measurement to guide the need of further testing in patients with compensated advanced chronic liver disease according to
the Baveno VI recommendations. LSM can improve clinical decision-making in different steps of risk stratification. *This rule should not be applied to patients with
cholestatic liver disease. ACLD, advanced chronic liver disease; CLD, chronic liver disease; CSPH, clinically significant portal hypertension; HVPG, hepatic venous pressure
gradient; LSM, liver stiffness measurement; Plt, platelet count; NSBB, non-selective beta-blockers.

performance compared to LSM alone (AUROC: 0.95
vs. 0.88, p \0.001). The use of two cut-off values,
either to rule out varices (LSPS \3.5) or to rule
them in (LSPS [5.5), allowed correct stratification
in 90% of cases, with a limited number of indeter-
minate findings.36 The higher accuracy of LSPS
compared to LSM has been confirmed in two inde-
pendent studies in patients with ACLD of different
aetiologies,26,37 showing correct classification in
over 85% of cases using LSPS. However, the cut-off
values used were different to those originally pub-
lished by Kim et al.36
Given that spleen size is not always available, a
Review
patients with cholestatic liver disease and should
not be applied in this population owing to specifici-
ties in PH in this context (i.e. the pre-sinusoidal com-
ponent that might not be properly sensed by LSM).
The successful development of non-invasive
diagnostic criteria to reduce the number of unneces-
sary endoscopy is a significant change in the man-
agement of patients with ACLD. Further studies are
needed to refine these criteria in order to reduce fur-
ther the number of unnecessary endoscopies and to
optimise costs. A tailored individual risk approach,
as postulated in a recent multicentric study (Antici-
pate study),25 could lead to a more accurate use of

simplified combination of LSM and platelet count
was also assessed,38,39 and good results were
achieved in ruling out varices needing treatment
(low false-negative rates using thresholds of
LS \20–25 kPa plus platelet count [120–150 g/L).
As a result, experts at the Baveno VI consensus
meeting on PH agreed that non-invasive tests could
be used to identify patients with ACLD that could
safely avoid screening endoscopy,12 however, a
conservative criterion to skip endoscopy was out-
lined, i.e. platelet count [150 g/L and LSM \20 kPa
(Fig. 2). Analyses of the performance of this crite-
rion in compensated ACLD are already avail-
able,25,40,41 and all confirmed that about 20% of
endoscopies could be safely avoided, missing less
than 4% of patients with varices needing treatment.
Importantly, this has not been investigated in
the LSM values in this field.
LSM by pSWE (VTQ, Siemens, Germany) has been
tested in a limited number of studies addressing the
diagnosis and severity of EV. LSM by VTQ was higher
in patients with varices, and increased in patients
with large varices,27,28 similar to results using TE.
Validated cut-off values are not available yet. This
is also the case for 2D-SWE.
Limitations of LSM
Liver stiffness is a mechanical property, and fibrosis
is the major determinant of LSM in ACLD; however,
several other tissue abnormalities can contribute to
increased liver stiffness, irrespective of fibrosis.
Inflammation, infiltrative diseases, cholestasis and

404 Journal of Hepatology 2017 vol. 67 j 399–411

 JOURNAL OF HEPATOLOGY
Table 3. Accuracy of spleen stiffness measurement using ultrasound elastography techniques for clinically significant portal hypertension and esophageal varices in
advanced chronic liver disease.

Study Year Method N included and Endpoint AUROC for the Chosen cut-off for the Sensitivity Specificity
used etiology selected endpoint selected endpoint
Stefanescu et al.51 2011 TE 174, mixed EV 0.781 46.4 kPa 83.6% 61.4%
Colecchia et al.52 2012 TE 141, HCV CSPH 0.966 Rule-out 40 kPa 98.5% 74.3%
compensated Rule-in 52.8 kPa 76.9% 97.1%

EV 0.941 Rule-out 41.3 kPa 98.1% 66.0%

Rule-in 55 kPa 71.7% 95.7%
Sharma et al.96 2013 TE 200, mixed EV 0.898 40.8 kPa 94% 76%
Calvaruso et al.54 2013 TE (modified 112, HCV LEV 0.820 54.0 kPa 80% 70%
range) compensated
Wong et al.97 2016 TE 144, HBV EV 0.685 18.9 kPa (rule-out) NPV 92.1%
PPV 56.1%
54.9 kPa (rule-in)
Vermehren et al.98 2012 pSWE (VTQ) 166, mixed LEV 0.580 3.40 m/s 87% 31%

Zykus et al.95 2015 TE 107, mixed CSPH 0.846 47.6 kPa 77.3% 79.2%
Rifai et al.99 2011 pSWE (VTQ) 100, mixed CSPH 0.680 3.29 m/s 47% 73%
Mori et al.100 2013 pSWE (VTQ) 33, HCV EV 0.800 3.41 m/s n.a. n.a.
Attia et al.27 2015 pSWE (VTQ) 78, mixed (some CSPH 0.968 2.32 m/s 96% 89%
decompensated;
90% CSPH; 76% EV)
Takuma et al.29 2016 pSWE (VTQ) 60, viral CSPH 0.943 3.10 m/s 97.1% 57.7%
HVPG P12 0.963 3.15 m/s 96.6% 61.3%
EV 0.937 3.36 m/s 95.8% 77.8%
LEV 0.955 3.51 m/s 93.8% 84.1%
Bota et al.101 2012 pSWE (VTQ) 140, mixed EV 0.578 2.55 m/s 96.7% 21.1%
Kim et al.102 2015 pSWE (VTQ) 125, mixed EV 0.768 3.16 m/s 87% 60.4%
LEV 0.786 3.40 m/s 78.9% 63.0%
Rizzo et al.103 2014 pSWE (VTQ) 54, mixed EV 0.959 3.10 m/s 96.4% 88.5%
+ controls
Takuma et al.37 2013 pSWE (VTQ) 340, mixed EV 0.937 (viral); 3.18 m/s 98.5% 60.1%
0.923 (others) 3.24 m/s 97.7% 65.2%

LEV 3.30 m/s 98.9% 62.9%

Ye et al.104 2012 pSWE (VTQ) 204, HBV EV 0.830 3.16 m/s 84.1% 81%
Elkrief et al.30 2015 2D-SWE 79, mixed (most CSPH 0.630 34.7 kPa 40% 100%
(SSI) decompensated; LEV 0.580 32.3 kPa 48% 71%
89% CSPH; 69%
TE Child-Pugh B-C; 34 CSPH 0.640 56.3 kPa 73% 67%
with LEV) LEV 0.650 73.5 kPa 54% 78%
Procopet et al.32 2015 2D-SWE 55, mixed CSPH 0.725 22.7 kPa (rule-out) 90% n.a.
(SSI) Compensated 40 kPa (rule-in) n.a. 90%

TE
Cassinotto et al.57 2015 2D-SWE 401, mixed (some LEV 0.80 25.6 kPa (chosen to 94% 36%
(SSI) decompensated) maximise sensitivity)

Review
Jansen et al.59 2016 2D-SWE 158, mixed (some CSPH 0.84 26.3 kPa 79.7% 84.2%
(SSI) decompensated) 621.7 kPa rule-out
[35.6 kPa rule-in
CSPH, clinically significant portal hypertension; EV, esophageal varices; HBV, hepatitis B virus; LEV, large esophageal varices; n.a., not applicable; PPV, positive predictive
value; SSI, supersonic imagine; pSWE, point shear wave elastography; SWE, shear wave elastography; TE, transient elastography; VTQ, virtual touch quantification.

venous congestion should always be considered as
possible confounders of the relationship between
LSM and portal pressure, irrespective of the elas-
tography method used.16 LSM (measured by any
of the available ultrasound techniques) increases
after meal ingestion in ACLD and in patients with
PH.42–45 Therefore, liver elastography should be
always performed in fasting state.17
Obesity used to be a limiting factor for LSM by
TE;46 however, a specifically designed extra-large
(XL) probe is now available, overcoming this prob-
lem. Nonetheless, LSM values measured by XL probe
are lower than those measured by the standard M
probe, and there is currently no data regarding XL
probe cut-off values for the diagnosis of CSPH and
varices. Further data on this topic are required.

Journal of Hepatology 2017 vol. 67 j 399–411 405

 Review
Key point
Spleen stiffness measure-
ment (SSM) is closely
associated with portal
hypertension. SSM is
increased in pre-hepatic
portal hypertension (PH),
suggesting that it could be
used as a surrogate for PH,
irrespective of its cause.
Key point
SSM is a promising parame-
ter for use in predicting both
the presence of varices, and
varices needing treatment.
Review
Key point
Liver stiffness measurement
can be used to predict
clinical decompensation in
patients with compensated
advanced chronic liver
disease. Spleen stiffness
measurement requires fur-
ther evaluation in this field.
406
Technique-specific limitations for pSWE and
2D-SWE include the need of a basic knowledge of
ultrasound to position the probe correctly, and
interpret the possible artefacts leading to non-
reliable results.15
Despite a good correlation with each other, the
values measured by the different ultrasound
elastography techniques and ultrasound devices
are not identical, and also differ from those pro-
vided by TE.16,47,48 Therefore, technique-specific
and machine-specific experience is required to gen-
erate appropriate results, and specific knowledge
and clinical experience is needed to interpret the
findings correctly.
Elastography for portal hypertension beyond liver
stiffness measurement: Spleen stiffness measurement
The spleen undergoes parenchymal remodelling in
patients with PH. This is partly attributable to pas-
sive congestion and increased arterial inflow, and
partly because of increased hyperactive splenic lym-
phoid tissue and enhanced angiogenesis and fibro-
genesis,49 leading to the progressive development
of splenomegaly in most patients. Ultrasound stud-
ies in the 1980s and 1990s showed that spleen vas-
cular resistance (estimated by Doppler pulsatility
and resistance indexes) is increased in patients with
PH, and correlates with PH severity and complica-
tions.50 Therefore, it has been postulated that spleen
stiffness measurement (SSM) by ultrasound elastog-
raphy could be an accurate non-invasive surrogate
for PH, and devoid of the limitations of LSM
(Fig. 1). Studies comparing LSM and SSM (measured
by TE in an adequate left intercostal space using
technical conditions similar to those used for LSM)
showed that the spleen is substantially stiffer than
the liver in both healthy subjects and patients with
CLD.51 In some studies, SSM showed a closer corre-
lation with HVPG,52 CSPH and presence and size of
EV when compared to LSM;51,52 in other studies,
SSM had similar or less accuracy (Table 3). A meta-
analysis of the 16 studies that compared the
accuracy of SSM with LSM for use in predicting the
presence of EV (ten studies using TE, three using
pSWE-VTQ, and three using 2D-SWE-SSI) has shown
that SSM was significantly superior to LSM.53 How-
ever, most of the published data were obtained in
heterogeneous populations of patients, with either
compensated (correct target) or decompensated cir-
rhosis, and therefore, the superiority of SSM versus
LSM for the diagnosis of PH in compensated ACLD
patients, has not been definitively proven.
TE applicability for SSM is limited to about 70%
of cases and, for technical reasons, it is closely
dependent on the presence of increased spleen size.
Additionally, measurement of stiffness by TE cur-
rently reaches a maximum of 75 kPa. As the spleen
is significantly stiffer than the liver, most patients
with severe PH show maximal values of SSM, above
which, risk cannot be stratified. Widening the mea-
Journal of Hepatology 2017 vol. 67 j 399–411
surement range up to 150 kPa with appropriate soft-
ware modifications has been proposed and tested,
and showed that patients with large varices, or
varices which had already bled, often had an SSM
well above 75 kPa.54 pSWE29,37,55 and 2D-SWE32,56
have been used more recently, and do not have the
ceiling effect of TE. Assessment of SSM using
2D-SWE (SSI), like TE, is limited to patients with
enlarged spleen.32,56,57 However, SSM can be mea-
sured using pSWE (VTQ) in about 95% of cases.37
Higher variability has been observed in the mea-
surement of this parameter compared to LSM using
the same technique.58
SSM is not yet used routinely in clinical practice
because of the limitations described above. Future
studies should clarify to what extent it adds to
LSM for the diagnosis of CSPH (as proposed by a
recent study59), whether it allows patients who do
not meet the Baveno criteria to safely avoid endo-
scopy, and if it enables a2 correct risk stratification
of EV in patients with cholestatic liver disease.
Technical improvements, such as dedicated probes
for SSM using TE would facilitate these studies in
centres using this ultrasound elastography
technique.
Prediction of clinical decompensation by liver and
spleen stiffness measurement, and use of ultrasound
elastography in the follow-up of patients with portal
hypertension
Several studies, mostly using TE, showed that LSM
has prognostic value when examining hard
endpoints (clinical decompensation, hepatocellular
carcinoma and death) in patients with CLD; this
was confirmed by a meta-analysis.60 In patients
with compensated ACLD undergoing both LSM and
HVPG measurement and followed-up for two years
showed that HVPG and LSM presented a similar
accuracy for predicting a first decompensating epi-
sode; all decompensating events occurred in
patients with LSM P21.1 kPa (using TE; a value with
a high specificity for identifying patients with
CSPH).61 This study provided an important proof of
concept for PH-related events. In another study,
both LSM and SSM predicted clinical decompensation
in patients with HCV-related cirrhosis;62 however,
only SSM and MELD score remained associated with
occurrence of first decompensation in multivariate
analysis (cut-off value for discrimination: 54 kPa).
Table 4 summarises the results of longitudinal stud-
ies using LSM or SSM to predict PH-related events.
Most of the published data only include small-to-
medium size cohorts with a limited follow-up.
Limited data are available on changes in LSM in
relation to changes in portal pressure or clinical risk.
A recommendation was formed at the Baveno con-
sensus conference on PH in 2015, suggesting that
patients not requiring screening endoscopy accord-
ing to non-invasive criteria on the first observation,
should undergo yearly LSM and platelet count to
 Table 4. Liver stiffness measurement and spleen stiffness measurement using ultrasound elastography techniques for the prediction of portal hypertension-related outcomes in longitudinal studies.

Endpoint Study Year Parameter N included and etiology Cumulative AUROC for the Chosen cut-off Notes
and method incidence of selected for the
the endpoint endpoint selected
endpoint
Clinical decompensation Robic 2011 LSM by TE 96 patients with cirrhosis 41% 0.815 21.1 kPa 100% Sens and NPV; 41% Spec
et al.61 (mixed etiology) followed up HVPG based AUROC: 0.837
in mean for 245 ± 244 days
Kitson 2015 LSM by TE 95 patients with cirrhosis 29.5% 0.730 34.5 kPa LSM: Sens 75.0%, Spec 69.4% HVPG:
et al.93 followed up in mean for Sens 100%, Spec 40.3%
15.1 months
Merchante 2012 LSM by TE 239 HIV/HCV coinfected 12.9% n.a. 40 kPa LSM had borderline significance as
et al.105 patients with cirrhosis predictor (HR 1.03; p = 0.08)
followed up in median for
20 months
Journal of Hepatology 2017 vol. 67 j 399–411

Colecchia 2014 SSM 92 patients with HCV cirrhosis 32.6% 0.678 54 kPa NPV 97.5%
et al.62 by TE followed up in mean for HVPG based AUROC: 0.830
24 months
Grgurevic 2015 LSM and SSM 44 patients with compensated 40.9% n.a. LSM: 21.5 kPa Risk of decompensation 3.4-fold
et al.106 by 2D-SWE cirrhosis followed up in mean higher over the cut-off value
(SSI) for 28 months SSM: 31.7 kPa Both LSM and SSM were associated to
decompensation, but LSM was
superior
Clinical worsening defined as Wang 2014 LSM by TE 220 patients with viral 12.8% at Progression of 17 kPa LSM measured every 6–12 months, but
progression of endoscopic et al.107 cirrhosis; median follow-up 3 years varices: 0.744 unclear if changes improve the
signs, decompensation or HCC 36.9 months prediction
Clinical 21.1 kPa
decompensation:
0.929

JOURNAL OF HEPATOLOGY
No value for HCC
Variceal bleeding Kim 2011 LSM by TE 577 HBV cirrhosis patients; 4.3% (16.7% of 0.929 LSPS [6.5 LSPS independent predictor, alongside
et al.108 + spleen size 150 with VNT, followed up for those with large variceal size and Child-Pugh B/C
and Plt (LSPS) in median 29 months VNT)
Merchante 2016 LSM by TE 446 HIV/HCV coinfected 3.4% n.a. 21 kPa NPV 100%
et al.109 patients with cirrhosis
followed up in median for
49 months
Takuma 2016 SSM by pSWE 446 patients with cirrhosis 7.4% 0.857 overall 3.64 m/s MELD score, red colour signs on
et al.55 (VTQ) followed up in mean for overall varices and SS independent predictors
32.7 months of EV bleeding; SSM best parameter
0.911 in 3.48 m/s in
compensated compensated
HCC, hepatocellular carcinoma; LSM, liver stiffness measurement; LSPS, LSM-spleen diameter to platelet ratio score; MELD, model for end-stage liver disease; n.a., not applicable; NPV, negative predictive value; pSWE,
point shear wave elastography; Sens, sensitivity; Spec, specificity; SSI, supersonic imagine; SSM, spleen stiffness measurement; SWE, shear wave elastography; TE, transient elastography; VNT, varices needing treatment;
Plt, platelet count; VTQ, virtual touch quantification.
407

Review
 Review

Site of increased resistance to portal flow Liver stiffness Spleen stiffness HVPG
Pre-hepatic PH Normal Increased Normal
(EHPVO)
Pre-sinusoidal PH Normal or slightly Increased Normal or slightly
(idiopathic PH) elevated elevated (<10 mmHg)
(<12 kPa) Often veno-venous
Intrahepatic PH communications
Sinusoidal PH Increased >13.6 kPa Increased Increased:
(cirrhosis; others) LSM ≥21 kPa: HVPG ≥10 mmHg
Spec >90% for CSPH defines CSPH
Post-hepatic PH No published data; No published data; Normal or increased,
(Budd-Chiari syndrome) likely increased due likely increased due with high free hepatic
to venous congestion to PH venous P

Fig. 3. Findings at liver and spleen stiffness measurements, and hepatic venous pressure gradient measurement in patients
with portal hypertension, classified according to the increased site of resistance to portal blood flow. The combined use of liver
and spleen stiffness measurements can improve the characterisation of patients with portal hypertension of unknown cause. The
final diagnosis remains, however, to be confirmed by liver biopsy. CSPH, clinically significant portal hypertension; EHPVO,
extrahepatic portal vein obstruction; HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement; P, pressure; PH,
portal hypertension.

pin-point the optimum time for first endoscopy.12
This recommendation awaits validation.
LSM using TE did not reflect the HVPG response
to NSBB in one study.20 Conversely, another study
using 2D-SWE (SSI) in a small group of patients,
showed a strong correlation between changes in
LSM and HVPG (r = 0.863).63
Data regarding SSM in relation to NSBB therapy
are lacking. However, after transjugular intrahep-
atic portosystemic shunt (TIPS) placement, SSM
using pSWE (Philips iU22 in one study; VTQ in one
study) decreased,64,65 suggesting that this parame-
ter might have potential for monitoring the effects
of therapy on PH, and deserves further investiga-
tion. There is little evidence to suggest whether
LSM or SSM could be useful in identifying patients
remaining at risk of PH-related complications after
successful treatment of HCV in patients with cirrho-
sis. Nevertheless, one recent study showed that LSM
rapidly decreased after virus clearance, but this was
probably the result of decreased liver inflamma-
tion,66 thus making interpretation of post-therapy
Review
detected (e.g. idiopathic PH, schistosomiasis, amyloi-
dosis, lymphoma, tuberculosis, hepatic myeloid
metaplasia due to extramedullary haematopoiesis in
patients with myeloproliferative neoplasms). Liver
biopsy remains crucial in patients without evident
causes of ACLD, although LSM and SSM may help the
clinician in this initial assessment (Fig. 3). LSM is usu-
ally only moderately increased in idiopathic PH (mean
value of 8.4 ± 3.3 kPa),67 showing a clear mismatch
with the values expected in patients with cirrhosis;
however, SSM in this population is elevated to values
similar or even higher than those observed in patients
with cirrhotic PH.68 Cirrhotic and idiopathic PH often
appear similar when imaged, and therefore, the ratio
between LSM and SSM could improve the clinicians’
ability to identify idiopathic PH and avoid an incorrect
diagnosis of cryptogenic cirrhosis.
In patients with extrahepatic portal vein obstruc-
tion (EHPVO) spleen stiffness is increased,67,69 and
SSM values are higher in patients who had already
bled from varices, versus patients whose varices
had not bled.69 Therefore, SSM might be a valuable

values difficult. In the same study SSM did not
change significantly, possibly indicating persistence
of PH in this population.66 Further studies with long
follow-up and longitudinal assessment of these
parameters are needed in this field.
Elastography in patients with suspected portal
hypertension of unknown cause, and in patients
with non-cirrhotic portal hypertension2
When PH is suspected, the first step towards its
correct characterisation is to identify its cause. This
requires excluding the presence of thrombosis in
the portal vein and/or the hepatic veins by ultra-
sound, so that the differential diagnosis is restricted
to intrahepatic forms of PH. ACLD accounts for over
90% of cases, but other uncommon forms can be
tool used to stratify the severity of PH in patients
with EHPVO, in whom HVPG is not reliable (pre-
hepatic PH).
No data are available in patients with BCS;
however, in this author’s experience, LSM is often
markedly increased in patients with BCS, likely due
to hepatic congestion.70 In a study using a mouse
model of congestive hepatopathy,71 chronic venous
stasis led to an increase in LSM (measured by mag-
netic resonance elastography) in the absence of
fibrosis, probably because of the mechanical tension
generated by vascular strain in congestion. Using an
in vitro approach, the authors demonstrated that
mechanical cyclic strain increases fibronectin
secretion from hepatic stellate cells, and increased
extracellular matrix fibril assembly, suggesting
that mechanical forces, such as sinusoidal stretch

408 Journal of Hepatology 2017 vol. 67 j 399–411


secondary to congestion lead to early steps of
matrix development.71 This may mean that the
prognostic value of LSM in ACLD might be partially
ascribed to the accelerated fibrogenesis in patients
with stiffer livers.
Data regarding the pediatric population with PH
due to biliary atresia, suggest that liver and spleen
elastography (measured either by TE or pSWE)
could be valuable tools to help predict outcomes
before surgery, and might be used after the Kasai
operation to monitor liver disease and PH.72,73
Conclusions
Ultrasound elastography is now an established and
useful tool for hepatologists. It enables a point-of-
care and quantitative assessment of liver and
spleen stiffness, which relate to PH and its compli-
cations, thus allowing rapid risk stratification and
identification of patients requiring further testing
(i.e. invasive assessment). TE remains the most val-
idated technique. LSM using TE cannot provide the
exact value of HVPG, nor identify with high cer-
tainty which patients carry EV, but it can confirm
the presence of CSPH. Even more importantly,
LSM combined with platelet count has now entered
in the decision algorithm for patients with compen-
sated ACLD, allowing patients at very low risk of
varices needing treatment, to avoid endoscopy.
JOURNAL OF HEPATOLOGY
LSM cannot replace HVPG for monitoring the
haemodynamic response to NSBB. Further research
is needed to establish whether the dynamics of
SSM over time or in response to treatment could
be a better indicator of HVPG changes.
The field of ultrasound elastography is rapidly
evolving, and newer techniques are becoming
widely available; their diagnostic performance for
PH remains to be established, but it is likely to be
similar to TE. Clinical hepatologists are required to
understand the specificities of each method, and
have the technical skills and knowledge of the val-
ues, pitfalls and limitations, which is a challenge.
Head-to-head comparisons to select the best
method for each clinical scenario in PH is certainly
a field for future research.
Financial support
Interdisciplinary Grant 2015 of the University of
Bern (UniBe-ID 2015).
Conflict of interest
The author declared that she does not have anything
to disclose regarding funding or conflict of interest
with respect to this manuscript.

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