New diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient on ultrasound B mode
New diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient on ultrasound B mode
Yohei Koizumi 0 1
Masashi Hirooka 0 1
Nobuharu Tamaki 1
Norihisa Yada 1
Osamu Nakashima 1
Namiki Izumi 1
Masatoshi Kudo 1
Yoichi HiasaID 0 1
0 Departments of Gastroenterology and Metabology, Ehime University Graduate School of Medicine , Toon City, Ehime , Japan , 2 Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital , Tokyo , Japan , 3 Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University , Osaka , Japan , 4 Pathology Division, Kurume University Hospital , Fukuoka , Japan
1 Editor: Umberto Vespasiani-Gentilucci , Policlinico Universitario Campus Bio-Medico , ITALY
We have developed a diagnostic technique to evaluate hepatic steatosis using the attenuation coefficient (ATT) in ultrasound B mode imaging. A controlled attenuation parameter (CAP) by vibration-controlled transient elastography (VCTE) has also been used to evaluate hepatic steatosis. As that method uses ultrasound A mode, visualizing the liver in real time is difficult. We designed this clinical study to evaluate the diagnostic advantage of our technique using ATT compared to CAP.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
Materials and methods
The study group included 94 patients with chronic liver disease who had undergone both
ATT and CAP assessment at the time of liver biopsy. The M-probe and XL-probe were used
for CAP measurement. Data for ATT and CAP were compared as a function of the steatosis
The area under the receiver operating characteristic curve (AUC-ROCs) for ATT and PAC
as a function of the steatosis grade were as follows: grade 1, 0.74 and 0.81; grade 2, 0.80
and 0.85; and grade 3, 0.96 and 0.98, respectively.
The accuracy of steatosis grade diagnosis using ATT was the same as that using CAP, with
no significant differences and with the added advantage of B mode ultrasound being more
convenient and rapid, compared to A mode ultrasound, particularly for patients with
subcutaneous fat thickness 2 cm.
With the increase in the obese population, liver steatosis is one of the most common chronic
liver diseases (CLDs) [
]. In addition, hepatic steatosis is also caused by alcohol
]. As hepatic steatohepatitis may progress to end-stage liver diseases, including cirrhosis
and hepatocellular carcinoma [
], early and accurate diagnosis of hepatic steatosis is
important to inform for proper management of patients with CLD [
In current clinical practice, the most used method for steatosis quantification is ultrasound
B mode examination with identification of ?bright liver,? ?deep beam attenuation,? ?vessel
blurring,? and ?liver to kidney contrast? and calculation of the Hamaguchi score [
development of non-invasive techniques, such as vibration-controlled transient elastography
(VCTE), for the diagnosis of liver fibrosis has been reported in a number of recent studies [
]. Use of the controlled attenuation parameter (CAP) as a non-invasive assessment of
hepatic steatosis has been proposed, with several recent studies having shown a significant
correlation between CAP and the steatosis grade in patients with different pathogenesis of CLD
]. However, VCTE is measured from a single shear wave based on ultrasound A mode
and, thus, the section of the liver being measured cannot be observed in real time. Moreover,
VCTE cannot be performed postoperatively (such as after right hepatic lobectomy) or in the
presence of ascites. Furthermore, as real time visualization during VCTE measurement is not
possible, it may not be clear if the region from which measurements are obtained includes
structures other than liver parenchyma, such as vessels within the liver [
]. In patients with
severe obesity, use of only one probe does not allow complete measurement of the
accumulation of steatosis, with a change to an XL-probe being necessary. Overall, it is clear that better
ultrasound-based methods of assessment of liver steatosis are needed.
One potential solution to the problems of CAP is a new diagnostic method using the
attenuation coefficient (ATT) measured on ultrasound B mode imaging [
]. Ultrasound B mode
uses multiple ultrasound wave with different frequency components for measurement. Thus,
ATT estimates hepatic steatosis from differences in attenuation of the received signals. Since
ATT is based on B mode, real time visualization of the target area for measurement is available
]. Furthermore, ATT measurements are obtained at a depth of 40?100 mm, avoiding the
influence of subcutaneous fat thickness, avoiding the need for a change in probe for obese
patients. Given these factors, we considered ATT to be potentially advantageous in terms of
reproducibility and success rate for assessing hepatic steatosis. The objectives of this
prospective study were, therefore, to compare the diagnostic accuracies of CAP and ATT for the
assessment of hepatic steatosis among patients with CLD.
Materials and methods
Written informed consent was obtained from all study participants before enrollment, and all
study protocols were approved by our institutional ethics committee (Certified Review Board
Ehime University, permit number: 1509016). The analysis was based on a component of
multicenter research data [
]. Ninety-four patients with liver disease, who underwent liver biopsy
between July 2015 and March 2017, were enrolled into our study. All patients underwent
measurement using both CAP and ATT. The inclusion criterion was age 20 years. The exclusion
criterion was failure of VCTE measurements (n = 5). We performed a prospective
performance analysis of ATT and CAP for the diagnosis of steatosis according to the non-alcoholic
fatty liver disease (NAFLD) activity score (NAS) using a receiver operating characteristic
(ROC) analysis (Fig 1). The primary endpoint was evaluation of the diagnostic advantage of
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ATT compared to CAP, by correlating the index calculated using ATT measurement to the
Measurement of hepatic steatosis
After fasting overnight, ATT and CAP measures for hepatic steatosis were obtained on the
same day as liver biopsy. Measures were obtained using the ultrasound system (HI VISION
Ascendus; Hitachi, Tokyo, Japan), with the convex probe used for ATT (EUP-C715, 5?1 MHz,
Hitachi) and CAP (Echosen Fibroscan 502, Paris, France). A total of 10 valid measurements
were obtained for CAP in each patient. The median liver steatosis was calculated as previously
]. All measurements were recorded by two experienced gastroenterologists (Y.K.
and M.H.), who had each conducted at least 350 liver stiffness evaluations prior to this study.
ATT measurements were performed at the right intercostal space, without adding pressure
from the probe (Fig 2). Measurements were obtained from regions of interest (ROIs) on the
hepatic parenchyma, with hepatic steatosis then calculated. Ultrasound waves of different
frequencies f0,f1 (f0<f1) were transmitted along the same beam line, and ATT was determined by
calculating the slope of the received signal ratio (f0<f1). The median of five measurements was
calculated as previously described [
]. In addition, measurement time and measurement
success rate were recorded.
Histological assessment of the liver
Liver biopsy was performed within 1 week of hospitalization, using a cutting needle, 1.6 mm in
diameter and 150 mm in length [
]. As sampling error for identifying liver fibrosis may occur
from such liver biopsies, samples less than 12 mm in length were excluded [
]. All liver biopsy
samples were fixed in formalin and embedded in paraffin, and sections (4-?m-thick) were
stained with hematoxylin-eosin and impregnated with silver [
]. Except for those classified as
showing cirrhosis, liver biopsies comprising less than five portal tracts were excluded from
Fig 1. Flow chart of the study participants. VCTE, vibration-controlled transient elastography; ATT, attenuation
coefficient; CAP, controlled attenuation parameter.
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histological analysis [
]. Fibrosis and the NAFLD activity score were evaluated by an
experienced pathologist (O.N.), who was blinded to all patient characteristics. Liver steatosis was
scored according to the NAFLD activity score, as follow: S0, <5%; S1, 5?33%; S2, 33?66%; and
S3, >66% [
Data were analyzed using Student?s t test for unpaired data and the chi-squared test and
Fisher?s exact test, as appropriate for the data type. The correlation between ATT and CAP
measurement and histological findings were analyzed using Spearman rank correlation analysis.
Correlations between ATT and body mass index (BMI) were analyzed using Spearman rank
correlation analysis. ROC curves were plotted, and the area under the curve (AUC-ROCs)
were calculated using the trapezoidal rule. To maximize diagnostic accuracy, optimal cutoff
values for liver stiffness were selected. Cutoffs obtained from ROC curves were then used to
calculate sensitivity, specificity, and both positive and negative predictive values. Comparisons
of CAP and ATT AUC-ROCs for the diagnosis of steatosis were performed using the DeLong
test. The agreement between each observer?s ATT and CAP measurements was evaluated by
calculating the kappa (?) coefficient. The ? coefficient was interpreted as follows: ? <0.4, poor;
0.4 ? < 0.75, fair to good; and ? 0.75, excellent.
All data were analyzed using JMP (version 13, SAS Institute Japan, Tokyo, Japan). The
DeLong test was analyzed using XLSTAT (Addinsoft Company, Paris, France).
Among 94 patients who met the inclusion criteria, five patients were excluded because of
unreliable VCTE measurements (no successful acquisitions with the M-probe).Thus, the analysis
was based on the data of 89 patients. Characteristics of these patients at the time of biopsy are
reported in Table 1. Of note, our study sample included 7 (7.9%) obese patients, with a BMI
Fig 2. Diagnosis of fatty liver using attenuation in the B mode. Multiple ultrasound waves with different frequency
components are used when measuring in the B mode. Fat volume estimation is performed according to the difference
in the degree of attenuation of the received signal. Measurement is performed while observing the relevant part in real
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Liver steatosis as assessed by ATT and CAP
The median (95% confidence interval) ATT values (dB/cm/MHz) for each steatosis grade
(determined by histological examination of the liver biopsy) was as follows (Fig 3A): S0, 0.57
(0.54?0.60); S1, 0.63 (0.62?0.72); S2, 0.72 (0.56?0.76); and S3, 0.87 (0.74?0.97). ATT values
were significantly different between each histological steatosis grade: S0 versus S1?3, P<0.001;
S0?1 versus S2?3, P = 0.0007; and S0?2 versus S3, P<0.001. The median liver steatosis values
(dB/m) assessed using CAP M-probe for each steatosis grade, were as follows (Fig 3B): S0, 195
(187?210); S1, 253 (226?268); S2, 270 (220?301); and S3, 337 (273?401). Again, there was a
significant difference in the CAP values between each histological steatosis grade: S0 versus
S1?3, P<0.001; S0?1 versus S2?3, P = 0.0004; and S0?2 versus S3, P = 0.0009). Fig 3C shows
the median (95% confidence interval) liver steatosis values assessed using the CAP XL-probe
for each steatosis grade: S0, 207 (197?224); S1, 283 (252?302); S2, 271 (233?329); and S3, 323
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Fig 3. ATT and CAP values for each grade of steatosis. Graph shows the ATT value (A), CAP M-probe value (B) and
CAP XL-probe value (C) for each steatosis grade. Vertical axis is a logarithmic scale. Tops and bottoms of the
boxes = 1st and 3rd quartiles. Length of the box represents the interquartile range, within which 50% of values are
located. In pairwise comparisons, the ATT value and CAP M or XL-probe value for each steatosis grade differed
significantly from each other (S0 vs. S1, P<0.05; S0 vs. S2, P<0.001).ATT, attenuation coefficient; CAP, controlled
(272?378). A significant association was observed between the median CAP XL-probe (dB/m)
values and histological steatosis grade (S0 and S1?3, P<0.001; S0?1 and S2?3, P = 0.0006; and
S0?2 and S3, P = 0.0026). The ? value of S0 or S 1 was excellent for both ATT and CAP, with
a mean ?-value of 0.91?0.06 for ATT and 0.86?0.08 for CAP.
Measurement difference between ATT and CAP
ATT was measurable in all cases. In contrast, CAP with the M-probe was unmeasurable in five
cases. In these five cases, the subcutaneous fat thickness was >30 mm. Of these five cases,
measurements could be recorded using the XL-probe in four cases. However, in the remaining one
case, the measurement success rate was <60% even with the XL-probe, and this was not
considered a reliable measurement.
AUC-ROC for the diagnosis of steatosis by ATT and CAP
The AUC-ROCs for the diagnosis of steatosis using ATT and CAP are shown in Fig 4.
AUC-ROCs were 0.74, 0.81 and 0.83 for diagnosing S 1 using ATT, CAP with the M-probe
and CAP with the XL-probe, respectively, and 0.96, 0.98 and 0.91, respectively, for diagnosing
S 2, and 0.96, 0.98 and 0.91, respectively, for diagnosing S = 3 (Table 2). ATT cutoffs for
S 1, S 2, and S = 3, calculated from the AUC-ROC, were 0.68, 0.72 and 0.78 dB/cm/MHz,
respectively. For the CAP M-probe, the respective cut-offs were 230, 270 and 324 dB/m, and
267, 230 and 290 dB/m for CAP XL-probe. There was no significant difference between the
AUC-ROCs for ATT and CAP in the diagnosis of a steatosis grade 1 (ATT versus CAP
Mprobe, P = 0.125; and ATT versus CAP XL-probe, P = 0.126). Similarly, no significant
difference was evident between AUC-ROCs of ATT and CAP in the diagnosis of a steatosis
grade 2 (ATT versus CAP M-probe, P = 0.286; and ATT versus CAP XL-probe, P = 0.287) or
Fig 4. Receiver operating characteristic (ROC) curves for predicting steatosis. ROC curves for diagnosis of mild
steatosis (A; S 1), significant steatosis (B; S 2), and severe steatosis (C; S = 3). No significant differences in
AUC-ROC were found between ATT and CAP examined using the DeLong test. ATT, attenuation coefficient; CAP,
controlled attenuation parameter.
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AUC-ROC, area under the receiver operating characteristic curve; ATT, attenuation coefficient; CAP, controlled attenuation parameter.
Sensitivity (%) Specificity (%)
Correlation between ATT and CAP
The correlation between the ATT and CAP M-probe value was significant (r = 0.549, P<0.0001,
Fig 5A), as was the correlation between the ATT and CAP XL-probe value (r = 0.526, P<0.0001,
Measurement time and success rate in each method
ATT was successfully measured in all cases (success rate, 100%). The mean measurement time
for ATT was 40.6?10.9 s. By contrast, CAP measurement was successfully performed in 89 of
the 94 cases (success rate, 94.7%), with a mean measurement time of 196.4?128.1 s (which
includes the time for cases in which CAP was not successfully measured). Although there was
a wide variability in measurement time for both ATT and CAP, overall, the measurement time
was significantly shorter for ATT than CAP (P<0.0001, Fig 6A). CAP measurement time was
significantly extended in cases where the subcutaneous fat thickness was >2 cm (P = 0.0085,
Fig 6B). In contrast, the measurement time for ATT was unaffected by subcutaneous fat
thickness (P = 0.9713, Fig 6C).
Factors affecting ATT measurement
The median ATT value (dB/cm/MHz) for each fibrosis stage was as follows: F0, 0.51; F1, 0.59;
F2, 0.66; F3, 0.63; and F4, 0.63. The median ATT value (dB/cm/MHz) for each activity grade
Fig 5. Correlation between ATT and CAP. ATT measurements were significantly correlated with CAP M-probe
measurements (r = 0.549, P<0.0001) and CAP XL-probe measurements (r = 0.526, P<0.0001). ATT, attenuation
coefficient; CAP, controlled attenuation parameter.
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Fig 6. Measurement times for CAP and ATT. A) Measurement time is significantly shorter for ATT than for CAP
M-probe (P<0.0001). Measurement times for CAP M-probe (B) and ATT (C), grouped by subcutaneous fat thickness,
showing a significantly increased CAP M-probe measurement time when the subcutaneous fat thickness is >2 cm
(P = 0.0085), with no effect of subcutaneous fat thickness on ATT measurements (P = 0.9713).
was as follows: A0, 0.50; A1, 0.60; A2, 0.64; and A3, 0.74. There was no correlation between the
ATT value and either the fibrosis stage and activity grade. However, the ATT value did
increase as a function of increasing BMI (Spearman?s ? = 0.31, p = 0.0032). Furthermore, the
AUC-ROCs for the diagnosis of steatosis using ATT and CAP by liver etiology are shown in
Fig 7. The AUC-ROCs for diagnosing S 1 using ATT, CAP with the M-probe, and CAP with
the XL-probe were 0.69, 0.86, and 0.82, respectively, in patients with HBV and HCV; 0.94,
0.88, and 0.88, respectively, in those with alcoholic liver disease; 0.84, 0.81, and 0.66,
respectively, in those with NASH and NAFLD; and 0.56, 0.63, and 0.80, respectively, in those with
other liver diseases.
Ultrasound B mode is a simple and useful method for diagnosing fatty liver, but is limited by
the inability to determine, in real time, if only liver parenchyma is included in the
]. As a solution to this problem, the usefulness of a scoring system adopting the
findings of ultrasound B mode images has been reported [
]. The use of CAP as a non-invasive
assessment of hepatic steatosis has been proposed [
]. However, CAP measurements are
influenced by subcutaneous fat thickness, with an XL-probe required in obese patients [
Since the transmission frequencies for these two probes differ, numerical values also differ
and, thus, values obtained by the M-probe and XL-probe cannot be directly compared. As
such, a distinct advantage of ATT is that measurements of hepatic steatosis can be obtained
with the same probe, regardless of subcutaneous tissue thickness. Moreover, ATT allows for
real time visualization of the target region of measurement, with no additional equipment
required. Of note, Jung et al. [
] reported that CAP was unaffected by the state of liver
inflammation or liver fibrosis, confirming the utility of CAP for diagnosing steatosis independently
of the disease stage or inflammatory activity. Furthermore, in the present study, ATT was
measurable in a case (not included in the analysis target) wherein reliable results were not obtained
by CAP measurement using the XL-probe. In our own work, we reported similar results for
ATT, noting a correlation between ATT values and the grade of fibrosis or inflammatory
activity determined by histology [
]. Moreover, ATT values also correlated with the hepatic fat
content in the target area of measurement, further underlining the usefulness of ATT for the
diagnosis of liver steatosis [
In the present study, ATT performed well as a noninvasive method for quantifying hepatic
steatosis, providing a good diagnostic accuracy for hepatic steatosis, with AUC-ROCs of 0.80
and 0.96 for steatosis S 2 and S = 3, respectively. Furthermore, ATT was successfully
performed in all cases, and required a significantly shorter time than CAP. Of clinical importance,
both ATT and CAP measurements showed high inter-observer agreement.
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Fig 7. Receiver operating characteristic (ROC) curves by liver etiology. A) ROC curves for hepatitis C virus
(HCV)positive patients and hepatitis B virus (HBV)-positive patients. B) ROC curves for alcoholic liver disease patients. C)
ROC curves for nonalcoholic fatty liver disease (NAFLD) patients and nonalcoholic steatohepatitis (NASH) patients.
D) ROC curves for other liver disease patients. The AUC-ROC results for each background liver disease varied.
ATT performance was relatively lower for the diagnosis of S 1, with an AUC-ROC of
0.74. This finding is consistent with a previous report for CAP, in which the AUC-ROCs
ranged from 0.79 for the diagnosis of S1, and increasing to 0.84 for the diagnosis of S2 and S3
]. Similarly, other studies have also reported on the better diagnostic performance of
CAP for more severe steatosis grades [
]. We do note that two studies reported the
diagnostic performance of CAP as being suboptimal for severe steatosis, and further considered
the differentiation of steatosis grades 0 and 1 by CAP as being unsatisfactory [
of mild liver steatosis is important for delineating individuals at risk for NASH and subsequent
hepatocellular carcinoma. Further studies are needed to establish optimal diagnostic methods
for mild liver steatosis (S<1).
There are several important limitations of the study. First, the number of cases was limited.
In particular, few cases of significant or severe liver steatosis (S2 or S3) were included, such
that the sample size for S2 and S3 diagnosis may have been insufficient. As a result, the S3 ATT
and CAP AUROC (0.96 and 0.98, respectively) and the S1 and S2 AUROC are not comparable
(0.74 versus 0. 81 and 0.80 versus 0. 85, respectively). Third, the target cases in this study had
mixed etiologies of liver steatosis. In addition, the AUC-ROC results for each background liver
disease varied. Therefore, ATT measurements might be affected by liver etiology. Investigation
in a greater number of cases is thus needed to verify the diagnostic accuracy of ATT. We also
note that, although we determined inter-observer agreement in measurement, we did not
evaluate the variability in inter- and intra-observer measurement for either ATT or CAP.
In conclusion, measurements obtained with the newly developed ATT correlated with CAP
values. ATT offers distinct advantages over CAP; hence, it is potentially more clinically useful
than CAP. Analysis using ATT allows real time visualization without the requirement for
special equipment; ATT measurement is simple and quick to perform and is are not affected by
subcutaneous tissue thickness. Therefore, ATT should be considered for the assessment of
liver steatosis, in particular, when CAP measurements cannot be obtained.
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S1 Checklist. TREND checklist.
S1 Dataset. Sets of data, median value of ATT and CAP.
S2 Dataset. Sets of data, measurement time of ATT and CAP.
S1 Protocol. Trial study protocol in original language (Japanese).
S2 Protocol. Translated trial study protocol.
Conceptualization: Masashi Hirooka, Yoichi Hiasa.
Data curation: Yohei Koizumi, Masashi Hirooka.
Formal analysis: Yohei Koizumi, Osamu Nakashima.
Supervision: Nobuharu Tamaki, Norihisa Yada, Namiki Izumi, Masatoshi Kudo.
Writing ? original draft: Yohei Koizumi.
Writing ? review & editing: Yoichi Hiasa.
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