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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- obstruction, thrombosis of the hepatic veins Swiss Liver Center, Hepatology,
drome. It is haemodynamically defined by an (Budd-Chiari syndrome, BCS) and idiopathic PH.2 University Clinic for Visceral
Surgery and Medicine, Inselspital,
increase in the venous pressure gradient across Once PH passes a critical threshold of 10 mmHg,
University of Bern, Switzerland
the liver, calculated from its inflow through the extrahepatic vascular changes, driven by angio-
portal vein versus its outflow through the hepatic genesis, lead to portosystemic collateral develop-
veins.1 ment and splanchnic vasodilation, which in
Like any other vascular system, portal pressure turn contribute to further increases in portal
is the product of two independent factors: resis- pressure.3
tance to blood flow and the amount of flow, as sta- PH can remain asymptomatic for many years but
ted by Ohm’s law: imaging and laboratory testing may suggest its pres-
ence. Splenomegaly is a very common consequence
Pressure ¼ Resistance Flow of PH; it usually leads to thrombocytopenia due to
Review
hypersplenism,4 and is often the first manifestation
An increase in resistance to portal blood flow is to infer the presence of PH.
the initial factor that leads to a rise in portal pres- From the clinical point of view, PH is relevant
sure. This resistance can be located at any point because of its severe complications, which include,
in the liver circulation, i.e. at the prehepatic, intra- upper digestive bleeding caused by gastroe-
⇑ Corresponding author. Address:
hepatic or post-hepatic level. In the Western world, sophageal varices, ascites, spontaneous bacterial
Swiss Liver Center, Hepatology,
ca. 90% of cases of PH are due to advanced chronic peritonitis and hepatorenal syndrome, and hepatic University Clinic for Visceral
liver disease (ACLD) or cirrhosis, which cause struc- encephalopathy.5 The risk of developing clinical Surgery and Medicine, Inselspital,
tural damage through fibrogenesis, parenchymal complications can be effectively reduced using University of Bern, MEM F807,
extinction and regeneration. PH then develops at appropriate non-pharmacological measures and Murtenstrasse 35, CH - 3010
Berne, Switzerland. Tel.: +41 31
the intrahepatic sinusoidal site.1 medical therapy to lower PH,6,7 providing strong
632 87 27; fax: +41 31 632 49 97.
Other less common causes include vascular liver rationale for the early identification of at-risk E-mail address: annalisa.berzigotti@
diseases, such as extrahepatic portal vein patients. insel.ch
Table 1. Hepatic venous pressure gradient thresholds associated with clinical risks in chronic liver A need for non-invasive methods to assess portal
disease. hypertension in patients with chronic liver disease
Hemodynamic Increase in the risk of the following events:
threshold HVPG measurement and endoscopy are the back-
Compensated 10 mmHg Presence and development of gastroesophageal bone for the assessment of PH in CLD.7,12 However,
ACLD varices;74,75 first clinical decompensation in patients they are invasive and may (in rare cases) lead to
with no varices;76 postoperative decompensation in complications; in addition, a specialised clinical set-
patients undergoing resection for HCC;77,78 development
ting and specific expertise are required to carry out
of HCC79
these tests, limiting their availability and increasing
12 mmHg Bleeding from varices74,80
the cost to health care systems. The development of
16 mmHg First clinical decompensation in patients with varices;81
mortality82 simple, non-invasive methods enabling accurate and
Decompensated 16 mmHg Rebleeding and mortality83 rapid diagnosis of patients with a low risk of both
cirrhosis 20 mmHg Failure to control variceal bleeding in bleeders;84 CSPH and varices requiring treatment (who could
mortality85 avoid invasive tests), and patients with CSPH (at
22 mmHg Mortality in patients with alcoholic cirrhosis and AAH86 high risk of complications and varices, requiring
30 mmHg Spontaneous bacterial peritonitis87 further testing), would further the advancement of
AAH, acute alcoholic hepatitis; ACLD, advanced chronic liver disease; HCC, hepatocellular carcinoma. personalised medicine in this field. Patients could
Review
sured, enabling both a semi-quantitative assess- hierarchical summary AUROC for CSPH discrimina-
ment of elasticity by a colour-coding, and a tion was 0.90, with sensitivity and specificity above
quantitative measurement expressed either in m/s 85% (sensitivity: 87.5%; 95% confidence interval [CI]:
or in kPa. Of all the pSWE techniques, Virtual Touch 75.8–93.9%; specificity: 85.3;%; 95% CI: 76.9–90.9%),
Quantification (VTQ) by acoustic radiation force and the summary HVPG-LSM correlation coefficient
impulse (ARFI) imaging (Siemens, Germany) is the was 0.783 (95% CI: 0.737–0.823). A cut-off threshold
most validated for liver fibrosis, and of 2D tech- of 13.6 kPa has a high sensitivity (over 90%),19,21
niqes SWE techniques, supersonic shear wave elas- whereas a threshold of 21 kPa has a high specificity
tography (SSI; Aixplorer, Supersonic Imagine, (over 90%) and can be used to confirm the presence
France) is close to full validation.13,14,16 Virtually of CSPH.21 This cut-off maintains a high specificity
all ultrasound device producers have now made value in patients with potentially resectable hepato-
either pSWE or 2D-SWE available, each with differ- cellular carcinoma, requiring risk stratification prior
ent software characteristics. Even though, similar to treatment allocation.24 Given the amount and
to TE, all ultrasound elastography techniques can quality of the existing data, the Baveno VI consensus
be considered point-of-care methods, the optimal on PH agreed that values of LSM by TE [20–25 kPa
use of newer techniques requires at least a basic can be used to identify CSPH12 (Fig. 2). However,
knowledge of ultrasound imaging principles, and most of the patients included in the studies leading
Hepatic vascular R
is mostly due SSM directly reflects PH
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 whereas in the other, no significant difference
viral aetiology, so more data regarding other dis- between the techniques was observed, once quality
ease causes are needed. The use of cut-off values criteria were applied to both methods.32
allows simple and straightforward risk stratifica-
tion in patients with compensated cirrhosis. Liver stiffness measurement prediction of
Key point
However, LSM provides a numerical, continuous gastroesophageal varices and combination with
In patients with compen- value, and therefore, the use of thresholds may lead unrelated methods
sated advanced chronic liver to the loss of relevant information (e.g. a value of
disease of non-cholestatic 50 kPa holds a much higher risk compared to a The diagnostic accuracy of LSM to predict the pres-
aetiology, endoscopy can be
value of 21 kPa). Fine-tuning of an individual’s risk ence and size of varices has been the subject of more
safely avoided by using liver
stiffness measurement of a specific endpoint (such as CSPH) without loss than 50 studies. LSM values are higher in patients
(LSM) and platelet count in of information, may be achieved by calibrating with esophageal varices (EV), and tend to be higher
combination. If such a the model probability, and using nomograms based in patients with large EV; overall, this parameter is
patient has an LSM of on this mathematical calculation.25 the most accurate single non-invasive predictor in
\20 kPa and a platelet count The precision of LSM for the diagnosis of CSPH this field. However, LSM is less accurate for the pre-
[150 g/L, it is very unlikely
can be improved further by combining other diction of EV than for CSPH.35 In a systematic review
(\5% risk) that on endo-
scopy he/she will have parameters associated with PH, such as platelet and meta-analysis including 18 studies with 3,644
Review
varices needing treatment. count and spleen size.26 subjects, summary AUROC was 0.84 for EV and
pSWE (ARFI technology, VTQ, Siemens, Ger- 0.78 for large EV, with summary sensitivity and
many) has been used in three studies to date, com- specificity of 0.87 (95% CI: 0.80–0.92) and 0.53
paring it to haemodynamic measurements,27–29 (95% CI: 0.36–0.69) for EV; 0.86 (95% CI:
and describing an applicability close to 100%. The 0.71–0.94) and 0.59 (95% CI: 0.45–0.72) for large
discriminative accuracy for CSPH was very good EV. Overall, the probability of correctly diagnosing
(AUROC 0.82–0.90). EV or large EV following a positive measurement
2D-SWE (specifically using the software pro- did not exceed 70%.35
vided in Aixplorer, Supersonic Imagine, France) Further studies were then carried out to evaluate
was the subject of four studies comparing LSM to whether the combination of LSM with unrelated
HVPG.30–34 The accuracy of discrimination between parameters associated with portal pressure, such
the presence and absence of CSPH of this method as platelet count and spleen size, could improve
(AUROC 0.82–0.90) was similar to the results the probability of correctly diagnosing EV. In the ini-
obtained using pSWE and TE. Two head-to-head tial study, which assessed patients with HBV-related
studies comparing 2D-SWE with TE30,32 for the CLD, LSM, platelet count and spleen size were
diagnosis of CSPH showed inconsistent results; in combined to form the LSM-spleen diameter to
one case 2D-SWE was more accurate than TE,30 platelet ratio score (LSPS),35 which had a higher
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.
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 >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%)*
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 patients with cholestatic liver disease and should
vs. 0.88, p \0.001). The use of two cut-off values, not be applied in this population owing to specifici-
either to rule out varices (LSPS \3.5) or to rule ties in PH in this context (i.e. the pre-sinusoidal com-
them in (LSPS [5.5), allowed correct stratification ponent that might not be properly sensed by LSM).
in 90% of cases, with a limited number of indeter- The successful development of non-invasive
minate findings.36 The higher accuracy of LSPS diagnostic criteria to reduce the number of unneces-
compared to LSM has been confirmed in two inde- sary endoscopy is a significant change in the man-
pendent studies in patients with ACLD of different agement of patients with ACLD. Further studies are
aetiologies,26,37 showing correct classification in needed to refine these criteria in order to reduce fur-
over 85% of cases using LSPS. However, the cut-off ther the number of unnecessary endoscopies and to
values used were different to those originally pub- optimise costs. A tailored individual risk approach,
lished by Kim et al.36 as postulated in a recent multicentric study (Antici-
Given that spleen size is not always available, a pate study),25 could lead to a more accurate use of
Review
simplified combination of LSM and platelet count the LSM values in this field.
was also assessed,38,39 and good results were LSM by pSWE (VTQ, Siemens, Germany) has been
achieved in ruling out varices needing treatment tested in a limited number of studies addressing the
(low false-negative rates using thresholds of diagnosis and severity of EV. LSM by VTQ was higher
LS \20–25 kPa plus platelet count [120–150 g/L). in patients with varices, and increased in patients
As a result, experts at the Baveno VI consensus with large varices,27,28 similar to results using TE.
meeting on PH agreed that non-invasive tests could Validated cut-off values are not available yet. This
be used to identify patients with ACLD that could is also the case for 2D-SWE.
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 Limitations of LSM
(Fig. 2). Analyses of the performance of this crite-
rion in compensated ACLD are already avail- Liver stiffness is a mechanical property, and fibrosis
able,25,40,41 and all confirmed that about 20% of is the major determinant of LSM in ACLD; however,
endoscopies could be safely avoided, missing less several other tissue abnormalities can contribute to
than 4% of patients with varices needing treatment. increased liver stiffness, irrespective of fibrosis.
Importantly, this has not been investigated in Inflammation, infiltrative diseases, cholestasis and
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%
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%
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 Obesity used to be a limiting factor for LSM by
possible confounders of the relationship between TE;46 however, a specifically designed extra-large
LSM and portal pressure, irrespective of the elas- (XL) probe is now available, overcoming this prob-
tography method used.16 LSM (measured by any lem. Nonetheless, LSM values measured by XL probe
of the available ultrasound techniques) increases are lower than those measured by the standard M
after meal ingestion in ACLD and in patients with probe, and there is currently no data regarding XL
PH.42–45 Therefore, liver elastography should be probe cut-off values for the diagnosis of CSPH and
always performed in fasting state.17 varices. Further data on this topic are required.
presence of EV (ten studies using TE, three using concept for PH-related events. In another study,
pSWE-VTQ, and three using 2D-SWE-SSI) has shown both LSM and SSM predicted clinical decompensation
that SSM was significantly superior to LSM.53 How- in patients with HCV-related cirrhosis;62 however,
ever, most of the published data were obtained in only SSM and MELD score remained associated with
heterogeneous populations of patients, with either occurrence of first decompensation in multivariate
compensated (correct target) or decompensated cir- analysis (cut-off value for discrimination: 54 kPa).
rhosis, and therefore, the superiority of SSM versus Table 4 summarises the results of longitudinal stud-
LSM for the diagnosis of PH in compensated ACLD ies using LSM or SSM to predict PH-related events.
Key point patients, has not been definitively proven. Most of the published data only include small-to-
Liver stiffness measurement TE applicability for SSM is limited to about 70% medium size cohorts with a limited follow-up.
can be used to predict of cases and, for technical reasons, it is closely Limited data are available on changes in LSM in
clinical decompensation in dependent on the presence of increased spleen size. relation to changes in portal pressure or clinical risk.
patients with compensated Additionally, measurement of stiffness by TE cur- A recommendation was formed at the Baveno con-
advanced chronic liver sensus conference on PH in 2015, suggesting that
rently reaches a maximum of 75 kPa. As the spleen
disease. Spleen stiffness
is significantly stiffer than the liver, most patients patients not requiring screening endoscopy accord-
measurement requires fur-
ther evaluation in this field. with severe PH show maximal values of SSM, above ing to non-invasive criteria on the first observation,
which, risk cannot be stratified. Widening the mea- should undergo yearly LSM and platelet count to
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 detected (e.g. idiopathic PH, schistosomiasis, amyloi-
This recommendation awaits validation. dosis, lymphoma, tuberculosis, hepatic myeloid
LSM using TE did not reflect the HVPG response metaplasia due to extramedullary haematopoiesis in
to NSBB in one study.20 Conversely, another study patients with myeloproliferative neoplasms). Liver
using 2D-SWE (SSI) in a small group of patients, biopsy remains crucial in patients without evident
showed a strong correlation between changes in causes of ACLD, although LSM and SSM may help the
LSM and HVPG (r = 0.863).63 clinician in this initial assessment (Fig. 3). LSM is usu-
Data regarding SSM in relation to NSBB therapy ally only moderately increased in idiopathic PH (mean
are lacking. However, after transjugular intrahep- value of 8.4 ± 3.3 kPa),67 showing a clear mismatch
atic portosystemic shunt (TIPS) placement, SSM with the values expected in patients with cirrhosis;
using pSWE (Philips iU22 in one study; VTQ in one however, SSM in this population is elevated to values
study) decreased,64,65 suggesting that this parame- similar or even higher than those observed in patients
ter might have potential for monitoring the effects with cirrhotic PH.68 Cirrhotic and idiopathic PH often
of therapy on PH, and deserves further investiga- appear similar when imaged, and therefore, the ratio
tion. There is little evidence to suggest whether between LSM and SSM could improve the clinicians’
LSM or SSM could be useful in identifying patients ability to identify idiopathic PH and avoid an incorrect
remaining at risk of PH-related complications after diagnosis of cryptogenic cirrhosis.
successful treatment of HCV in patients with cirrho- In patients with extrahepatic portal vein obstruc-
sis. Nevertheless, one recent study showed that LSM tion (EHPVO) spleen stiffness is increased,67,69 and
rapidly decreased after virus clearance, but this was SSM values are higher in patients who had already
probably the result of decreased liver inflamma- bled from varices, versus patients whose varices
tion,66 thus making interpretation of post-therapy had not bled.69 Therefore, SSM might be a valuable
Review
values difficult. In the same study SSM did not tool used to stratify the severity of PH in patients
change significantly, possibly indicating persistence with EHPVO, in whom HVPG is not reliable (pre-
of PH in this population.66 Further studies with long hepatic PH).
follow-up and longitudinal assessment of these No data are available in patients with BCS;
parameters are needed in this field. however, in this author’s experience, LSM is often
markedly increased in patients with BCS, likely due
Elastography in patients with suspected portal to hepatic congestion.70 In a study using a mouse
hypertension of unknown cause, and in patients model of congestive hepatopathy,71 chronic venous
with non-cirrhotic portal hypertension2 stasis led to an increase in LSM (measured by mag-
netic resonance elastography) in the absence of
When PH is suspected, the first step towards its fibrosis, probably because of the mechanical tension
correct characterisation is to identify its cause. This generated by vascular strain in congestion. Using an
requires excluding the presence of thrombosis in in vitro approach, the authors demonstrated that
the portal vein and/or the hepatic veins by ultra- mechanical cyclic strain increases fibronectin
sound, so that the differential diagnosis is restricted secretion from hepatic stellate cells, and increased
to intrahepatic forms of PH. ACLD accounts for over extracellular matrix fibril assembly, suggesting
90% of cases, but other uncommon forms can be that mechanical forces, such as sinusoidal stretch
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