Fibrosis or cirrhosis of the liver is a manifestation of end-stage liver disease, which is a common outcome of various chronic liver diseases in children. As hepatic fibrosis can be lethal and can induce various complications in children, the precise evaluation of liver fibrosis is very important in patient management and prognosis [1,2]. Even though liver biopsy has been considered the standard for evaluating the degree of hepatic fibrosis, there are several restrictions on the use of liver biopsy in children due to its invasiveness, potential complications, sampling variations, and related interobserver and intraobserver variability [3]. Therefore, liver biopsy is generally conducted in children in limited circumstances, and there is a constant need to search for a noninvasive method to measure liver stiffness such as ultrasound (US) or magnetic resonance elastography techniques [4,5]. Among such techniques, US-based elastography has been very promising in children because of its noninvasiveness, easy accessibility, and real-time nature [5,6]. US-based elastography techniques have made it possible to acquire quantitative measurements of liver fibrosis [7] within a short time period in routine sonographic examinations, even during free breathing [8]. Several real-time US-based elastography techniques have been introduced, and studies have demonstrated a high correlation between US-based elastography and the severity of liver fibrosis in children [2,9].

Shear wave elastography (SWE; Aixplorer, SuperSonic Imagine SA, Aix-en-Provence, France), one of several real-time US-based elastography techniques, provides quantitative tissue elasticity maps. With SWE, shear waves are generated from acoustic pulses forced at five different tissue depth levels [8,10] and the shear wave velocity is estimated by ultrafast Doppler-like acquisition of 5,000 frames per second. Then, the shear wave speed is converted to tissue stiffness as kilopascals using the formula E=3 ρ v² , where E represents the elasticity of the tissue, ρ represents the density of the tissue, and v represents shear wave velocity. Although several studies have been conducted regarding the reproducibility and reliability of SWE in measuring liver fibrosis in adults [11,12], not much is known about the reproducibility of SWE in pediatric patients. Furthermore, most studies have analyzed data obtained using the breath-holding technique during the measurement of liver stiffness with SWE. Using breath-holding techniques can potentially minimize artifacts and disturbances in shear wave velocity acquisition caused by movement during breathing [13]. Since it can be difficult to achieve adequate breath-holding during the acquisition of US-based elastography in young children, it is necessary to compare liver stiffness measurements during breath-holding and free-breathing and to investigate methods that can assist in the acquisition of adequate measurements of hepatic fibrosis in children. The stability index (SI) is a new technique that provides temporal stability when placing a region of interest (ROI) box during SWE examinations, in order to ensure a high-quality assessment of liver stiffness by analyzing the temporal and spatial reproducibility of the last three to five images to create a SI value. An SI value over 90% is considered a good result, and indicates adequate acquisition of data within the ROI. We hypothesized that using this new technique would improve the reproducibility of liver SWE measurements in children. To our knowledge, no study has evaluated the clinical application of the SI in measuring liver stiffness using SWE.

Therefore, the purpose of our study was to evaluate the usefulness of the SI for decreasing the variability of liver stiffness measurements and the number of measurements required for adequate data acquisition free-breathing and breath-holding conditions in children.

Failure of acquisition of SI values over 90% was observed in five of 29 patients (17%) in the free-breathing group and in two of 29 patients (7%) in the breath-holding group.

Comparison of the mean elasticity value revealed no significant difference between free-breathing and breath-holding (6.31±3.98 kPa vs. 6.47±4.09 kPa, P=0.354, n=29). There was no significant difference in the mean elasticity value between the FBeye and FBSI groups (6.31±3.98 kPa vs. 6.38±4.39 kPa, P=0.694, n=24) or between the BHeye and BHSI groups (6.47±4.09 kPa vs. 6.72±4.70 kPa, P=0.101, n=27) (Table 1).

Table 2 summarizes the differences in the variability of SWE measurements between the groups that utilized the SI and the groups that did not. In the comparison of the acquired standard deviation values with and without utilization of the SI in both the free-breathing and breath-holding groups, the groups that utilized SI showed significantly lower standard deviation values than those that did not (P<0.01).

In both the free-breathing and breath-holding groups, the coefficient of variation was significantly lower when using the SI than when not using the SI (free-breathing group, 0.055±0.230 vs. 0.182±0.022, P<0.01; breath-holding group, 0.037±0.223 vs. 0.198±0.125, P<0.01).

Four of the 24 SWE measurements (16.7%) were considered unreliable in the free-breathing group. When the SI was used, the number of patients with unreliable results decreased to two of the 24 SWE measurements (8.3%). In the breath-holding group, the number of unreliable results was four out of 27 patients (14.8%) and there were no unreliable results when the SI was used.

An ICC value of 0.87 (95% CI, 0.74 to 0.94) was found in the free-breathing group, and it increased to 0.99 (95% CI, 0.97 to 0.99) when the SI was used. In the breath-holding group, the ICC value was 0.95 (95% CI, 0.90 to 0.98), and it increased to 0.99 (95% CI, 0.99 to 0.99) when the SI was used.

The ICC values and 95% CIs calculated from comparing the mean of eight subsets of two to nine consecutive measurements and the reference values (median liver stiffness of the 10 measurements in each dataset) are summarized in Table 3. An ICC value over 0.95 implies that the measurement error due to the sampling number was less than 5%, which is within the accepted error range [11]. In the free-breathing group, the first eight and nine repeated measurements showed ICC values over 0.95 compared with the reference values. With the use of SI, the first five measurements and above had ICC values over 0.95 in comparison with the reference values. This means that the minimal number of repeated measurements with an acceptable error range decreased from eight to five repeated measurements when the SI was used. In the breath-holding group, the first six repeated measurements compared with the reference values had ICC values over 0.95 when the SI was not used, whereas the first two repeated measurements demonstrated an ICC value of 0.99. Using the SI reduced the minimal number of repeated measurements with an acceptable error range from six to two measurements in the breath-holding group.

When measuring liver elasticity with US, issues related to the variability and reliability of elasticity measurements are quite important, especially in children who tend to be uncooperative and cannot hold their breath. Therefore, any technique that can decrease measurement variability is valuable. The SI is a newly introduced technique for reducing the number of unreliable results due to poor image acquisition and suboptimal Q-box positioning when SWE is performed to assess the degree of fibrosis within the liver. This tool, based on SWE coding conditions and temporal stability, automatically calculates the quality of each acquired image in order to obtain an SI value. Taking into consideration temporal, spatial, and noise information before calculating the IQR, the SI calculation helps users to rule out a poor-quality signal. When the SI is lower than 90%, manufacturers recommend locating the Q-Box elsewhere in the 2-dimensional SWE box or performing the SWE acquisition again to reduce the number of poor SWE acquisitions and incorrect Q-Box locations.

Our study showed that variability in liver stiffness measurements could be reduced by using SI values. The standard deviation of SWE measurements and the coefficient of variation were reduced by applying SI values, which could be interpreted as a decreased spread of the variability of measurements relative to the mean, thereby providing more consistent and reliable measurements in both the free-breathing and breath-holding groups. Additionally, using SI not only decreased the number of unreliable results, but also increased intraobserver agreement in both the free-breathing and breath-holding groups. Reliable measurements of liver stiffness are critical for determining and observing liver fibrosis and planning future treatment in clinical practice. Liver stiffness could be adequately measured with increased reliability and reduced inconsistency using the SI, even when acquiring measurements during free breathing.

It is very important to reduce the scan time as much as possible in children, because it is particularly difficult to obtain adequate cooperation from patients to hold their breath or remain in the same position while measuring liver stiffness. Therefore, several previous studies have tried to identify the minimum number of acquisitions needed to obtain the optimal elasticity value in both adults and children [16,18-20]. In addition to these efforts, we speculate that we could further reduce the optimal minimal number of repeated measurements of SWE in both the free-breathing and breath-holding groups by using SI. Considering a sampling error range of less than 5% as acceptable, our results showed that the minimal number of repeated measurements decreased from eight to five repeated measurements by using the SI in the free-breathing group, and from six to two repeated measurements in the breath-holding group. Our hope is to reduce the number of repeated SWE measurements by utilizing the SI, and eventually, reducing the scan time in children. In particular, referring to the SI, we can expect not only decreased variability of liver stiffness measurements, but also a decreased scan time for adequate liver stiffness measurements, which can be very helpful when performing SWE in children. Since the optimal number of liver stiffness measurements can vary according to children’s age [18], further investigation is needed to establish the role of the SI in reducing the number of liver stiffness measurements needed for an adequate assessment of liver stiffness in children.

However, our study also showed that acquiring SI values over 90% was not always possible because of significant temporal and spatial instability observed in some cases. In particular, the failure rate increased to 17% during free breathing due to respiratory movement. We suggest that vigorous breathing movements and underlying liver parenchymal heterogeneity may have contributed to this phenomenon. Therefore, we think that further investigation should be conducted into the cause of failure to obtain a sufficient SI value and that technical improvements should be made in order for this technique to be utilized consistently. With regard to the effect of breathing status on the liver SWE value, the study by Pellot-Barakat et al. [21] showed that the mean SWE value was higher in the measurements obtained during breath-holding than in those obtained during free breathing. They hypothesized that the hemodynamic changes during the different stages of breathing may lead to variability in SWE in the same patient [21]. Our study revealed a similar tendency for a higher stiffness value during free breathing, but without statistical significance.

There are several limitations in our study. First, our study cohort was rather small, and older children and young adults (with mean age of 16.1 years) were recruited, because our intention was to evaluate the effect of breathing status on utilization of SI. Even though we believe that our results could be applicable to young children who cannot hold their breath, a further study would be helpful to validate our results in young children. Second, patients with a variety of underlying diseases and a wide range of liver SWE values were included in our study. However, our study cohort reflects the normal patient distribution in routine clinical practice. Third, a single operator performed the SWE examinations. Therefore, interoperator variability could not be evaluated in our study. Lastly, due to limited patient cooperation in pediatric patients, it might be difficult to obtain images and precise measurements of SWE values during the free-breathing and breath-holding phases with strict control of respiration. However, we performed a large number of repeated measurements to acquire mean SWE values to overcome this shortcoming.

In conclusion, utilizing the SI in the measurement of liver SWE in children and young adults reduced measurement variability in both free-breathing and breath-holding conditions, and it may reduce the scan time by decreasing the number of repeated measurements in children and young adults.