Original papers

Med Ultrason 2016, Vol. 18, no. 1, 11-17

DOI: 10.11152/mu.2013.2066.181.sff

Is the spleen stiffness value acquired, using acoustic radiation force

impulse (ARFI) technology, predictive of the presence of esophageal
varices in patients with cirrhosis of various etiologies?
Jaehyung Park1, Heejin Kwon1, Jinhan Cho1, Jongyoung Oh1, Sangyun Lee1, Sangyoung Han2,
Sung Wook Lee2, Yanghyun Baek2
1Department

of Radiology, 2Department of Internal Medicine, Dong-A University Hospital, Busan, South Korea

Abstract
Aim: This studys aim was to determine the accuracy of the spleen stiffness value acquired using acoustic radiation force
impulse (ARFI) technology, to predict the presence of esophageal varices (EVs) in patients with liver cirrhosis of various
etiologies. Material and methods: Of the 366 enrolled patients, 192 had hepatitis B virus, 74 had hepatitis C virus, and 100
had alcohol-related cirrhosis. All patients underwent biochemical tests, gastrointestinal endoscopy, and liver and spleen elastography by ARFI. We evaluated the correlation between the presence of EVs and factors including liver and spleen stiffness
measured by ARFI, biochemical tests, and other noninvasive measurements, such as aspartate aminotransferase (AST), alanine
aminotransferase (ALT), platelet count (PLT), spleen diameter (SD), PLT to SD ratio, AST to ALT ratio (AAR) score, the AST
to PLT ratio index (APRI) score. Result: A univariate analysis revealed that the AAR score, APRI score, PLT, PLT/SD ratio,
and spleen elastography variables were all independently associated with EVs (p<0.05). On multivariate analysis, only spleen
elastography was associated with EVs (p=0.001). However, in cases of alcohol-induced liver cirrhosis, spleen stiffness was
not reliable for the prediction of EVs. Conclusion: Spleen elastography measured using ARFI may serve as a non-invasive
method for determining the presence of EVs. However, it is not an appropriate predictor for EVs in alcoholic cirrhosis.
Keywords: ARFI,esophageal varices, spleen,cirrhosis

Introduction
In cirrhotic patients, screening for esophageal varices
(EVs) using esophagogastroduodenoscopy (EGD) is
highly recommended in the current guidelines, as bleeding may be a serious consequence of portal hypertension
(PTH) [1]. However, the general unpleasantness and
need for sedation associated with EGD are important
limitations of the method [2]. For these reasons, noninvasive methods have been introduced to serve as markers for the evaluation of EVs. For example, the platelet
Received 25.10.2015 Accepted 23.12.2015
Med Ultrason
2016, Vol. 18, No 1, 11-17
Corresponding author: Heejin Kwon, MD,

Department of Radiology,

Dong-A University Hospital,

Dongdaesingdong 3 ga, Seo-gu,

Busan 602-715, South Korea

Phone: +82-51-2405367

Fax: +82-51-2534931

E-mail: [email protected]

count [3], the spleen diameter (SD) determined by ultrasound scan [4], and the platelet (PLT) count/SD ratio in
particular [5,6] have all been identified as noninvasive
methods to classify patients with cirrhosis and EVs. Unfortunately, these markers have not been associated with
a high sensitivity or specificity. Additionally, attempts to
use liver transient elastography (TE, Fibroscan) to indirectly evaluate the degree of PHT and the likelihood of
EVs presence [7,8], have produced disappointing results.
Acoustic radiation force impulse (ARFI) imaging
technology involves the mechanical excitation of tissue
by using short duration acoustic pulses (push pulses) in
a region of interest chosen by the operator. These pulses
produce shear waves that spread away from the region of
interest perpendicularly to the acoustic push pulse. This
process results in the generation of localized waves. By
detecting these waves, quantitative assessment of tissue
stiffness is available through the measurement of shear
wave speed [9]. The ability to measure spleen stiffness by
ARFI elastography in patients with chronic liver disease
has also been recently reported. However, these stud-

12

Jaehyung Park et al

Is the spleen stiffness value acquired, using acoustic radiation force impulse...

ies focused primarily on the simple correlation between

spleen stiffness and EVs without consideration of cirrhosis etiology [10-12].
The aim of the current study was to evaluate the reliability of ARFI elastography-measured liver and spleen
stiffness in patients with liver cirrhosis, as well as to investigate whether liver and spleen stiffness values, along
with several other non-invasive tests, may be suitable
predictors for the presence of EVs. Additionally, the
utility of cirrhosis etiology for prediction of esophageal
varices by ARFI elastography-measured liver or spleen
stiffness was also assessed.
Materials and methods
This prospective, single institution study was Health
Insurance Portability and Accountability Act compliant,
and the study protocol was approved by the Institutional
Review Board of Dong A University Hospital, Busan,
Republic of Korea. Written informed consent was obtained from each patient.
Patient Population
From June 2014 to April 2015, 614 participants, previously diagnosed with liver cirrhosis were enrolled. To
meet inclusion criteria, patients had to have hepatic cirrhosis resulting from an infection with a hepatitis virus
or heavy alcohol consumption. The exclusion criteria
included patients with autoimmune disease, carcinoma,
ascites, portal vein thrombosis, expected survival <3
months, and refusal to participate in the study. Of the
initial 614 patients, 488 met the inclusion criteria. The
origins of cirrhosis among these patients were chronic
hepatitis B virus (HBV)-related in 262 patients, chronic
hepatitis C virus (HCV)-related in 96 patients, and alcohol-related in 130 patients.
To recruit patients, we used our patient information
system to identify those scheduled for an upper endoscopy EVs assessment and serologic tests up to two weeks
prior to ARFI elastography.
Liver and spleen stiffness measurement by ARFI
After overnight fasting, patients underwent an upper abdomen ultrasound. ARFI was performed in the left
lateral decubitus position for the liver (right lobe) and
the right lateral decubitus position for the spleen, with
the contralateral side of the arm in maximum reduction.
The scanning was done in the best visualized area between the intercostal spaces. The size of the region of
interest (ROI) was fixed at 10x5 mm and positioned in
the parenchyma free of vascular or biliary structure. The
standard ROI measurement depth was 3 cm below the
liver and spleen capsule. During the procedure, patients
were asked to stop breathing for a moment in order to

minimize motion. Previous reports demonstrated that >5

successful measurements should be collected for reliability [13,14]. Therefore, the mean values of 5 successful
measurements were taken from the liver and from the
spleen, and were expressed in kPa. A 3-5 MHz convex
transducer and sonographic equipment (XMatrix iU22,
iU22; Philips, Seattle, WA, USA) were used. All measurements were performed independently and blindly by
a board-certified and fellowship-trained abdominal radiologist with 10 years of experience. For the best correlation between ARFI and stiffness, the interquartile range
(IQR) interval had to be <30% [15].
Upper gastrointestinal endoscopy
All patients underwent upper endoscopy using flexible video gastroscopy (GIF-XQ-2400 endoscope, Olympus Optical CT, Ltd, Tokyo, Japan) in the maximum 14
days before ultrasonography. EVs were evaluated according to the published criteria [16].
Spleen diameter
Maximum spleen bipolar diameter expressed in cm
[17] was estimated by means of an ultrasound scan using the same machine in the same session as the ARFI
measurement. All examinations were performed by the
same individual.
Other non-invasive measurements
Laboratory tests including serum aspartate aminotransferase (AST), alanine aminostransferase (ALT),
albumin, and PLT count were performed for all patients
within 2 weeks of study initiation. To evaluate the influence of other known non-invasive measurements for
liver cirrhosis, the AST/ALT ratio (AAR) [18], PLT/SD
[5,6], and AST to PLT ratio index (APRI) score were
calculated. The APRI score was calculated as follows:
APRI=(sample AST/reference AST)100/PLT, where
reference is the upper limit of normal for AST (34 IU/L)
and the PLT count is assessed as x109 cells/L [19].
Statistical Analysis
All statistical analyses were conducted using a computer software package (SPSS version 21.0; Inc., Chicago, IL, USA), and a medical statistician reviewed all
data. These results were expressed as the mean standard deviation. The data were analyzed by comparing the
eminence of EVs at EGD and the stiffness of the liver and
spleen using ARFI. The Levene test was used to investigate the homogeneity of variance. Analysis of variance
and the least significant difference t-tests were used to
compare the differences in mean liver and spleen stiffness values in the cirrhosis patients according to the presence of varices in endoscopy. The independent t-test was
used to compare the other non-invasive measurements
between cirrhotic patients with and without varices. In
each test, p<0.05 was considered statistically significant.

Med Ultrason 2016; 18(1): 11-17

Table I. Analysis of non-invasive measurements for predicting EVs
All etiologies
(n=366)
Gender
Male
Female
Age
Liver SWV (kPa)
Spleen SWV (kPa)
AST (IU/L)
ALT (IU/L)
AST/ALT (AAR)
PLT (x 103)
AST/PLT (APRI)
Spleen diameter (cm)
ALB (g/dL)
PLT/SD

Varices (-)
(n=172)
92
80
55.778.73
8.785.4
16.1911.93
47.9155.66
25.4722.28
1.920.76
166.6562.05
0.360.52
9.681.53
4.350.39
17.787.56

Varices (+)
(n=194)
140
54
56.329.24
10.865.52
36.9918.62
49.6625.42
20.556.79
2.51.14
123.6894.22
0.790.98
11.72.61
3.990.69
11.247.71

p-Value
0.064
0.772
0.075
<0.001
0.846
0.153
0.006
0.013
0.012
<0.001
0.004
<0.001

Multivariate analysis
OR (95% CI)
1.098(1.041-1.157)
1.696(0.79-3.641)
0.98(0.949-1.011)
0.805(0.167-3.868)
1.867(0.894-3.897)
0.472(0.09-2.46)
1.257(0.888-1.78)

p-Value
0.001
0.175
0.208
0.786
0.096
0.372
0.198

The values are presented as the mean standard deviation; CI- confidence interval, SWV- shear wave velocity, AST- aspartate aminotransferase, ALT- alanine aminotransferase, AAR- AST/ALT ratio, PLT- platelet count, APRI- AST/PLT ratio index, ALB- albumin, SD- spleen
diameter

Spearman correlation coefficients were used to assess

the correlation between the EVs and elastography values.
The Spearman correlation coefficient, Rho(), is a value
that ranges between +1 to -1. The closer the is to 1, the
more correlated the factors are likely to be. Similarly, the
closer the is to -1, the less correlated the factors are
likely to be.
The diagnostic performance of the spleen elastography in the distinction of the EVs was assessed by receiver operating characteristic (ROC) analysis to determine the best cut-off values. The best cut-off value was
determined while balancing the best sensitivity with the
lowest false-positive rate. The area under the ROC curve
(AUC) was also calculated.
Results
In 122 of 488 patients (25%) with valid ARFI measurements, the technical parameters were unsatisfactory (IQR>30%). Of these individuals who could not
be further evaluated, 117 cases were unreliable cases
regarding splenic stiffness and 43 cases were unreliable cases regarding liver stiffness. Additionally, 38
of these cases were unreliable regarding both organs.
These figures exceed 100%;, however, cases could exist in multiple categories. The final study population
of evaluated cases with good quality technical parameters obtained consisted of 366 patients (232 men, 134
women), 192 of whom had HBV-related cirrhosis, 74
with HCV-related cirrhosis, and 100 with alcohol-related cirrhosis. The mean age of study participants was
55.9212.8 years.

Among the 366 patients with valid measurements,

172 patients (47%) had no EVs at EGD. On univariate
analysis, spleen shear wave velocity (SWV), spleen diameter, PLT, albumin, AAR, PLT/SD and APRI score
were independently associated with EVs. On multivariate analysis, spleen SWV was independently associated
with EVs (p<0.001; Table I). According to these results,
spleen SWV was the most reliable test that could be used
to predict EVs not only on univariate, but also on multivariate analysis.
The AUC of spleen elastography and the presence
of EVs was 0.859 (CI: 0.781-0.938). With the Younden index, a cut-off value for detecting the presence of
EVs using spleen elastography was determined. By
setting the spleen elastography cut off value as 29.9
kPa, the sensitivity, specificity, positive predictive value, and negative predictive value were 85.1%, 79.1%,
81.6% (67.98-91.25%), and 82.94% (67.96-92.85%),
respectively.
Liver and Spleen stiffness Measurements for
Predicting EVs according to different etiologies
Among the 192 cirrhotic patients with HBV, EVs
were found in 100 patients. On univariate analysis a statistically significant correlation between liver stiffness
and the presence EVs was established (p=0.022). However, on multivariate analysis, statistical differences were
not observed between the mean liver stiffness values in
patients with and without EVs (p=0.495). Unlike liver
stiffness, a significant correlation was observed between
spleen stiffness and EVs on univariate (p<0.001) and
multivariate analyses (p=0.022; Table II). If the cutoff
value applied to hepatitis B virus induced liver cirrho-

13

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Jaehyung Park et al

Is the spleen stiffness value acquired, using acoustic radiation force impulse...

Table II. Analysis of non-invasive measurements for predicting EVs in HBV patients.
HBV
Varices (-)
Varices (+)
p-Value
(n=192)
(n=92)
(n=100)
Gender
0.077
Male
48
74
Female
44
26
Age
53.048.22
56.448.3
0.162
0.009
Liver SWV (kPa)
7.533.79
11.285.55
<0.001
Spleen SWV (kPa)
16.469.4
4015.59
0.005
AST (IU/L)
31.439.96
40.8811.91
ALT (IU/L)
20.439.85
20.26.96
0.924
AST/ALT (AAR)
1.720.65
2.150.67
0.03
PLT (x 103)
170.8756.89
128.08112.77
0.108
0.001
AST/PLT (APRI)
0.20.09
0.540.47
<0.001
Spleen diameter (cm)
9.781.55
12.72.74
0.002
ALB (g/dL)
4.450.22
4.110.45
<0.001
PLT/SD
17.65.21
10.166.86

Multivariate analysis
OR (95% CI)
0.89(0.637-1.244)
1.22(1.029-1.447)
0.684(0.457-1.025)
1.158(0.077-17.483)
2.615(0.952-7.183)
14.952(0.02-11440.378)
1.568(0.912-2.696)

p-Value
0.495
0.022
0.066
0.915
0.066
0.062
0.425
0.104

*The values are presented as the mean standard deviation; HBV hepatitis B virus, CI confidence interval, SWV shear wave velocity,
AST aspartate aminotransferase, ALT alanine aminotransferase, AAR AST/ALT ratio, PLT platelet count, APRI AST/PLT ratio
index, ALB albumin, SD spleen diameter

sis, the sensitivity, specificity, positive predictive value,

negative predictive value and AUC were 96.0%, 82.6%,
64.8%(39.0%-85.5%), 98.4%(85.7%-10.0%), 0.920 (CI:
.805-.979), respectively.
Among the 74 cirrhotic patients with HCV, EVs were
found in 34 patients. No correlation between liver stiffness and EVs on univariate or multivariate analyses was
found (all p0.05). However, a significant direct correlation (p=0.015) was found between spleen stiffness and
EVs on univariate analysis, although this correlation was
lost on multivariate analysis (p=0.288; Table III).
Among the 100 patients with alcoholic cirrhosis, EVs
were found in 60 patients. No correlation between spleen
stiffness and the presence of EVs was found (Table IV)
Association between splenic diameter and EVs
No correlation between the spleen diameter and EV
on multivariate analysis was obtained. On univariate
analysis, only the patients of HBV related liver cirrhosis
showed significant correlation between spleen diameter
and EV (p<0.001).
Association between other non-invasive
measurement and EVs
Significant correlations between EVs and albumin
(p=0.004) and PLT (p=0.013) were detected on univariate analysis. However, the correlations were not significant on multivariate analysis with alcoholic cirrhosis.
ALT and AST levels were not statistically different
between the groups with and without EVs. The AAR
ratio (p=0.006) and APRI score (p=0.012) were significantly higher in patients with EVs when compared with
the group without EVs on univariate analysis, with the
exception of alcoholic liver cirrhosis patients)

The PLT/SD ratio was a relatively good predictive

factor for EVs (p<0.001) in HBV-related cirrhosis on
univariate analysis, but no significant relationships were
found on multivariate analysis or with other origin-related cirrhosis.
Discussions
Increased resistance to portal blood flow is the key
factor for portal hypertension (PTH) in liver cirrhosis.
There are many PTH-related complications, and EVs is
one of the most severe. As hepatic fibrosis progresses,
hemodynamic and pathologic changes can be concomitantly found in the spleen, especially in the stages of hepatic fibrosis. The results of a previous study demonstrated that the size of the spleen increased as liver fibrosis
progressed and was more apparent in the late stages. The
density of the spleen changes in patients with splenomegaly due to tissue hyperplasia, angiogenesis, and fibrogenesis, as well as portal and splenic congestion [20]. Such
changes of spleen stiffness are mechanical properties that
can be quantified by ARFI elastography.
Recently, several reports have been published regarding the use of spleen ARFI elastography as a noninvasive
diagnostic tool for the detection of EVs. Ye et al have
reported a significant correlation between spleen elastography and EVs in patients with chronic HBV (sensitivity
84.1%, specificity 81%) [10]. Colecchia et al found significant correlation between spleen elastography and EV
in patients with chronic hepatitis C related liver cirrhosis
(sensitivity 98.5%, specificity 60.1%, negative predictive
value 98.4%) [11]. Bota et al detected a positive associa-

Med Ultrason 2016; 18(1): 11-17

Table III. Analysis of non-invasive measurements for predicting EVs in HCV patients.
HCV
Varices (-)
Varices (+)
p-Value
(n=74)
(n=40)
(n=34)
Gender
0.419
Male
16
20
Female
24
14
Age
60.45.66
57.1414.75
0.531
Liver SWV (kPa)
8.185.39
10.986.06
0.331
0.015
Spleen SWV (kPa)
12.18.08
34.0823.82
AST (IU/L)
43.522.73
69.8633.6
0.072
ALT (IU/L)
218.42
19.865.27
0.756
0.009
AST/ALT (AAR)
2.060.68
3.481.25
PLT (x 103)
156.743.64
104.4372.22
0.082
AST/PLT (APRI)
0.310.21
1.211.31
0.046
Spleen diameter (cm)
9.171.48
10.842.21
0.073
0.036
ALB (g/dL)
4.410.2
3.631.06
PLT/SD
18.128.34
10.89.18
0.107

Multivariate analysis
OR (95% CI)
1.299(0.801-2.107)
-

p-Value
0.288
0.368
0.388
0.217
-

The values are presented as the mean standard deviation; HCV hepatitis C virus, CI confidence interval, SWV shear wave velocity,
AST aspartate aminotransferase, ALT alanine aminotransferase, AAR AST/ALT ratio, PLT platelet count, APRI AST/PLT ratio
index, ALB albumin, SD spleen diameter

Table IV. Analysis of non-invasive measurements for predicting EVs in alcholic cirrhosis.
Alcohol
(n=100)
Gender
Male
Female
Age
Liver SWV(kPa)
Spleen SWV(kPa)
AST(IU/L)
ALT(IU/L)
AST/ALT(AAR)
PLT(x 103)
AST/PLT(APRI)
Spleen diameter(cm)
ALB(g/dL)
PLT/SD

Varices (-)
(n=40)

Varices (+)
(n=60)

28
12
57.410.62
12.277.34
19.6718.73
90.2104.86
41.540.46
2.230.97
166.989.41
0.780.96
9.941.55
4.070.65
17.8511.44

44
16
55.738.28
10.15.52
33.3421.08
54.8732.03
21.477.43
2.631.45
125.3370.08
1.021.34
10.451.93
3.970.81
13.268.49

p-Value
0.601
0.664
0.408
0.111
0.23
0.071
0.454
0.206
0.635
0.497
0.756
0.261

The values are presented as the mean standard deviation; SWV shear wave velocity, AST aspartate aminotransferase, ALT alanine
aminotransferase, AAR AST/ALT ratio, PLT platelet count, APRI AST/PLT ratio index, ALB albumin, SD spleen diameter

tion between grade 2-3 EV and spleen elastography in

patients with various etiologies (sensitivity 96.7%, specificity 47.6%) [12]. However, there was not any reports
assessing diagnostic performance according to the differences of the etiologies resulting in cirrhosis.
The results from the current study indicated a significant correlation between spleen stiffness detected by
ARFI and the presence of EVs, especially in cirrhosis resulting from HBV. However, spleen stiffness and other
non-invasive tests were not reliable for prediction of EVs
in cases of alcoholic-induced liver cirrhosis. Therefore,
application of spleen elastography for detecting EVs
should be avoided in patients with alcohol induced liver
cirrhosis.

We have no explanation for the lack of correlation between spleen stiffness and EV in alcoholic liver cirrhosis.
There are reports about various spleen sizes in cirrhosis
of different etiologies. In alcoholic cirrhosis, the mean
spleen size was significantly smaller than in the hepatitis C and nonalcoholic steatohepatitis [21]. In addition,
splenomegaly resulted more in primary biliary cirrhosis,
in HBV-related cirrhosis and in cryptogenic cirrhosis
than in the alcoholic form [22]. These results show that
pathophysiological features of spleen in liver cirrhosis
may differ according to its varied etiology. Further studies may be necessary.
The data from the current study demonstrated that
other noninvasive tests for detecting EVs (AAR, APRI

15

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Jaehyung Park et al

Is the spleen stiffness value acquired, using acoustic radiation force impulse...

test, PLT count, spleen diameter, albumin, and PLT/SD

ratio) were independently related to the presence of EVs
on univariate analysis. These results corresponded well
with the results of previous published studies [5,6,18,19].
However, in multivariate analysis, only spleen elastography remained as a reliable predictor for EVs.
There are several limitations to the current study.
Firstly, for comparison purposes, we assessed only singular etiology among HBV, HCV, and alcohol-induced
liver cirrhosis, meaning that those with multiple viral infections or combined causes for liver cirrhosis were not
assessed. Secondly, there may have been other possible
related causes resulting in EVs which were not excluded
from our study. Therefore, the results may not be generalizable. Thirdly, among the 488 patients, spleen elastography was not reliable in 117 patients (24%) due to
their interquartile range (>30%). This could result in poor
reliability in a subsequent follow-up study. Additionally,
its unreliable rate is relatively higher, as compared with
Fibroscan, in which the inconclusive measurement rates
were reported to be 14.3% [23] and 13% [24].
Conclusions
Spleen stiffness as measured by ARFI may have the
potential for use as a non-invasive method for determining the presence of EVs. However, the evidence supporting a similar role for replacing endoscopy is lacking.
Furthermore, it is not an appropriate predictor for EVs
in alcoholic cirrhosis. A larger study with an increased
number of prospective cohort members with different
cirrhosis etiologies will be necessary for a more accurate
evaluation of the true utility of this method in clinical
practice.
Acknowledgement: This work was supported by the
Dong-A University research fund.
Conflict of interest: none
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