**3. Measurement protocol and reliability criteria**

Regarding patient preparation, ultrasound-based shear wave elastography techniques including TE, pSWE, and 2D-SWE share the same recommended protocols [6, 32, 33]. Since the amount of portal flow can affect the result of liver stiffness measurement obtained by shear wave elastography, fasting for at least 4 hours before the examination is recommended for patients who undergo shear wave elastography examination to minimize the effect of portal flow. The liver stiffness measurement using shear wave elastography is usually performed in either supine or slightly left lateral decubitus position (not more than 30 degrees) with the right arm extended above the head to obtain the optimal sonic window via the stretching of the intercostal muscles [6, 34]. It has been known that both deep inspiration and deep expiration can have an influence on the result of liver stiffness measurement using shear wave elastography, and therefore, the neutral breath-hold is recommended for shear wave elastography examination to minimize the effect of breath-hold status. In addition to the aforementioned protocols for patient preparation, current guidelines for both pSWE and 2D-SWE have several recommendations for imaging acquisitions since pSWE as well as 2D-SWE provide B-mode images of the liver simultaneously, and the measurement area of pSWE and 2D-SWE can be selected under the real-time B-mode imaging guidance [6, 32, 33]. The transducer should be placed perpendicular to the liver capsule to ensure proper generation and propagation of the shear wave. The measurement box for both pSWE and 2D-SWE is placed parallel to the liver capsule, and the upper edge of the measurement box should be placed 1.5 to 2.0 cm apart from the liver capsule to minimize the effect of reverberation artifact which is generally seen in the area adjacent to the liver capsule. In most currently available ultrasound systems, the ARFI pulse reaches the maximum intensity at 4.0 to 4.5 cm apart from the transducer and is attenuated by 6.0–7.0 cm [6]. Given that, the area located at 4.0 to 4.5 cm apart from the transducer would be the optimal location for liver stiffness measurement. Since B-mode image is utilized to trace the shear wave in both pSWE and 2D-SWE, highquality B-mode images without artifacts should be acquired for accurate and reliable


*radiation force impulse.*

#### **Table 2.**

*Recommendation for patient preparation and imaging acquisition.*

#### *Evaluation of Liver Fibrosis Using Shear Wave Elastography: An Overview DOI: http://dx.doi.org/10.5772/intechopen.102853*

liver stiffness measurement. The recommended protocols for both patient preparation and imaging acquisition are summarized in **Table 2**.

Regarding the acquisition number of liver stiffness measurements using TE, ten valid measurements are recommended. In addition, the interquartile range (IQR)-tomedian ratio of ten valid measurements (subsequently referred to as IQR/M) is usually used as the quality criteria: IQR/M equal to or less than 30% indicates reliable measurement results [6, 32, 33]. According to the result of a study including 13,369 TE examinations using M probe [35], the failure rate of obtaining valid liver stiffness measurement and unreliable measurements rates was 3.1% of cases and 15.8% of cases, respectively. Regarding the contributory factors for failed and/or unreliable measurements of TE was body mass index [15, 35], and high body mass index was significantly associated with the failed and/or unreliable measurements. With the introduction of XL probe for TE examination, the reliability of liver stiffness measurements using TE has been improved, especially for NAFLD patients [36–40]. Regarding the measurement reproducibility of TE, excellent inter-reader agreement with the intraclass coefficient (ICC) of 0.98 was reported in a cohort of 188 patients having chronic HCV infection [41].

The recommended acquisition number of liver stiffness measurements using pSWE is also ten valid measurements. The same as the TE, the result with IQR/M equal to or less than 30% for measurement given in kilopascals is considered a reliable result. Regarding the 2D-SWE, the area for liver stiffness measurement is larger than pSWE, and thus, each liver stiffness measurement value is actually an average value of several measurements [6]. In addition, several manufacturers provide quality assessment methods for their 2D-SWE systems such as propagation map, stability index, and reliable measurement index [6]. Given that, the current guideline recommends five measurements for 2D-SWE when a quality assessment method is provided by the manufacturer. However, when a quality assessment method is not available, ten measurements for 2D-SWE are recommended, the same as the TE or pSWE [6]. IQR/M for measurement given in kilopascals is also used as the quality criteria for 2D-SWE, the same as the TE or pSWE. Result with IQR/M equal to or less than 30% of five or ten measurements given in kilopascals indicates reliable measurement results. It has been reported that when IQR/M for measurement given in kilopascals was higher than 30%, the accuracy of liver stiffness value obtained from shear wave elastography was reduced [33, 42, 43]. According to the result of a study comparing pSWE and 2D-SWE in 79 patients at the same day [44], the failure rate was 1.3% for pSWE and 5.1% for 2D-SWE, respectively. The overall intra-reader agreement was higher for pSWE than 2D-SWE (ICC of 0.915 for pSWE vs. ICC of 0.829 for 2D-SWE, P < 0.001). In addition, intra-reader reproducibility between liver stiffness measurements by using 2D-SWE performed in the same participant on different days was higher for the experienced operator than novice operator (ICC of 0.84 for experienced reader vs. 0.65 for novice reader) [45], indicating that reader experience has an influence on the measurement reliability. Ferraioli et al. also reported that the liver stiffness measurement by using pSWE was affected by operator experience [46]. Given that, operators doing pSWE and/or 2D-SWE examinations need to be properly trained and to follow the recommendations for patient preparation and imaging acquisition [15].

## **4. Diagnostic performance for staging liver fibrosis**

Liver fibrosis is the result of chronic liver injury and is defined as an abnormal and excessive deposition of collagen and other extracellular matrix components in the

liver [9, 47]. Essentially, any kind of chronic liver disease caused by HBV or HCV infection, alcohol abuse, and NAFLD lead to steatosis, inflammation with necrosis in response to an injury [9]. Without appropriate management, these liver cell injury continuously progresses, eventually developing liver cirrhosis. Information regarding the liver fibrosis stage is beneficial for the prediction of prognosis, personalized followup, and treatment decisions. For example, antiviral therapy for HBV or HCV infection might be guided by the information regarding the liver fibrosis stage [48, 49]. Therefore, an accurate assessment of the liver fibrosis stage is an important step for chronic liver disease management. For this purpose, liver biopsy with histopathologic examinations using various staging systems including Ishak, METAVIR, and Batts-Ludwig systems has been traditionally used as the standard reference method [18, 50]. However, liver biopsy is limited for widespread application in clinical practice, mainly due to its invasive nature. To overcome the limitation of liver biopsy, ultrasound-based shear wave elastography techniques including TE, pSWE, and 2D-SWE have been emerged as noninvasive methods for the evaluation of liver fibrosis and reported a good diagnostic performance.

#### **4.1** *Transient elastography*

Since TE was the first approved and commercially available ultrasound-based elastography technique for the liver, there have been a lot of studies including meta-analyses reporting the diagnostic performance of TE in assessing liver fibrosis stage for chronic liver disease patients with various etiologies. Currently, TE is the most widely used and extensively validated elastography technique for liver stiffness measurement. Regarding the detection of advanced fibrosis and liver cirrhosis originated from HBV or HCV infection by using TE, early studies reported an excellent diagnostic performance with areas under the receiver operating characteristic curve (AUROCs) of 0.88–0.99 [51–57]. Several meta-analyses also reported the excellent diagnostic capability of TE to detect liver cirrhosis with AUROCs of 0.93–0.96, better than those for diagnosing moderate fibrosis (F2-F4) with AUROCs ranging from 0.83 to 0.88 [58–62]. The reported cut-off liver stiffness value was 7.0–7.9 kPa for the detection of moderate fibrosis (F2-F4) and 11.3–15.6 kPa for the diagnosis of cirrhosis (F4) [58–60, 63]. In addition to the HBV and HCV infection, TE also showed a good diagnostic performance in assessing liver fibrosis for NAFLD patients. However, the application of TE for NAFLD patients is challenging, mainly due to the high failure rate and poor measurement reliability in obese patients, especially when standard M probe is used. The reported rate of unreliable and/ or failed measurement of TE for NAFLD patients ranged from 3.8% to 50.0% [38, 64, 65]. According to the result of a meta-analysis including 854 NAFLD patients with individual data, the reported pooled sensitivity and specificity of TE using the standard M probe was 79% and 75% to detect F2-F4, 85% and 82% to detect F3–4, and 92% and 92% to detect F4, respectively [66]. The AUROCs of TE ranged from 0.79–0.87 for detection of F2-F4, 0.76–0.98 for detection of F3-F4, and 0.91–0.99 for the diagnosis of F4, respectively, in NAFLD patients [15]. The introduction of XL probe for obese patients has improved the measurement reliability of TE [67].

## **4.2 Point shear wave elastography (pSWE) and two-dimensional shear wave elastography (2D-SWE)**

Since both pSWE and 2D-SWE have become commercially available more lately than TE, the number of studies and the amount of data are less than those of TE.

#### *Evaluation of Liver Fibrosis Using Shear Wave Elastography: An Overview DOI: http://dx.doi.org/10.5772/intechopen.102853*

Thus, the level of evidence for the diagnostic performance of pSWE or 2D-SWE in assessing the liver fibrosis stage is usually lower than that for TE.

Regarding the pSWE, several early studies reported a high accuracy for liver fibrosis staging in both HBV patients [68–71] and HCV patients [72–75]. For example, a study using pSWE done by Sporea et al. reported an AUROCs of 0.91 for detecting F3-F4 stage fibrosis and 0.94 for detecting cirrhosis (F4), respectively, in 274 patients having chronic HCV infection [72]. A meta-analysis including 21 studies containing 2691 individual data with chronic HBV or HCV infections showed an AUROCs of 0.88 for the detection of F2-F4, and 0.91 for the diagnosis of cirrhosis, respectively [76]. pSWE also provides a good diagnostic performance in diagnosing liver fibrosis stage for NAFLD patients, and the reported AUROCs of pSWE to detect liver cirrhosis (F4) was greater than 0.97 [77–80]. When pSWE was compared to TE for NAFLD patients in assessing liver fibrosis stage, there was no significant difference in diagnostic capability between the two elastography methods, although pSWE provided a significantly higher rate of reliable measurement [81].

In addition to pSWE, 2D-SWE also provides excellent diagnostic performance in assessing the liver fibrosis stage for patients having chronic HBV or HCV infection [20, 82–84]. However, since 2D-SWE is the newest elastography method, it has been less validated than TE or pSWE. A meta-analysis including seven studies using 2D-SWE in assessing liver fibrosis stage showed an AUROCs of 0.91 for detection of F2-F4 stage fibrosis and 0.95 for the diagnosis of liver cirrhosis (F4) [85]. In addition, recent studies reported that 2D-SWE showed a significant better diagnostic capability in detecting both F3-F4 stage fibrosis and cirrhosis (F4) than TE [86, 87]. The same as the chronic HBV or HCV patients, 2D-SWE is less well-validated for NAFLD patients than TE or pSWE. Several prospective studies showed a good diagnostic performance of 2D-SWE in detecting liver cirrhosis for NAFLD patients with AUROCs ranging from 0.88 to 0.95 [88–90].

#### **5. Limitation of ultrasound-based shear wave elastography for the liver**

Although currently available ultrasound-based shear wave elastography systems including TE, pSWE, and 2D-SWE provide an excellent diagnostic capability in assessing liver fibrosis stage and are widely used in clinical practice, ultrasound-based shear wave elastography systems have some limitations. Operators should be aware of the limitations of current ultrasound-based shear wave elastography techniques for accurate measurement of liver stiffness value as well as for the appropriate interpretation of the results. After the introduction of pSWE and 2D-SWE that can be incorporated into commercial ultrasound systems for routine B-mode imaging, many of manufacturers provide their own SWE systems for liver stiffness measurement. Therefore, inter-platform variability among the different SWE systems from the various vendors may be an issue [15]. In the view of physics, the liver stiffness measurement values obtained by different SWE systems from different vendors can not be interchangeable. Thus, vendor-specific cut-off values for the assessment of the liver fibrosis stage are needed since the frequencies of shear wave generated within the liver tissue are different among the various SWE systems from different vendors: 50 Hz for TE and wideband ranging from 100 to 500 Hz for pSWE and 2D-SWE [31, 91, 92]. However, the application of vendor-specific cut-off might be infeasible in clinical practice and it is hardly possible to follow up patients with the same SWE system during the disease course. According to the result of the study evaluating

inter-observer variability of liver stiffness measurements among seven different SWE systems including TE, four pSWE methods, and two 2D-SWE methods, the overall agreement among the liver stiffness measurements performed with different SWE systems was good to excellent having ICCs ranging from 0.74 to 0.97 [93]. There would be an approximately 10% variability of the liver stiffness measurements among the different vendor SWE systems [93]. Therefore, these inter-platform variabilities should be taken into account in the application of various SWE systems from different vendors for the assessment of liver fibrosis staging.

To calculate the liver stiffness value from the measured shear wave propagation velocity, the current SWE systems assume that the tissue in that a stress is applied is purely elastic, and neglect the tissue viscosity. However, in some clinical situations, the assumption of pure tissue elasticity does not work well, leading to errors in the liver stiffness measurements. These conditions include acute hepatitis, liver inflammation with necrosis, obstructive cholangitis, hepatic congestion, and infiltrative disease such as amyloidosis or lymphoma [15], and have been known to increase tissue viscosity. When the tissue viscosity is increased by various causes, the liver stiffness values measured by SWE systems are usually higher than without those conditions, leading to the over-estimation of the liver fibrosis stage [94]. Therefore, current guidelines for liver elastography examination do not recommend the liver stiffness measurement for the assessment of liver fibrosis stage when the serum level of aspartate aminotransaminase (AST) and/or alanine aminotransaminase (ALT) is elevated greater than five times upper normal limits [15]. The assessment of the liver fibrosis stage by using liver SWE can be performed after the normalization of AST and/or ALT level to minimize the effect of liver inflammation on the results of liver stiffness measurement. In addition, tissue viscosity introduces a dependency of shear wave propagation velocity on excitation frequencies [23, 95]. Given that, more complex modeling taking tissue viscoelasticity into account is warranted to overcome the current limitation of ultrasound-based shear wave elastography for the liver.

## **6. Conclusion**

Many studies reported an excellent diagnostic performance of ultrasound-based shear wave elastography in the evaluation of liver fibrosis and detection of liver cirrhosis. Among the various shear wave elastography techniques, TE has been the most widely used and extensively validated method for the assessment of liver fibrosis, subsequently having a higher level of evidence compared to the other elastography methods. In addition to TE, pSWE, and 2D-SWE have emerged as another noninvasive methods for the assessment of liver fibrosis. Since both pSWE and 2D-SWE utilize the conventional ultrasound probe for routine B-mode imaging equipped in standard diagnostic ultrasound machines, pSWE, and 2D-SWE can provide B-mode images of the liver simultaneously during the examination, enabling the liver stiffness measurement under the real-time B-mode image guidance. Although current ultrasound-based shear wave elastography techniques including TE, pSWE, and 2D-SWE provide an excellent diagnostic capability in assessing liver fibrosis stage, interchangeability of liver stiffness measurement results among the different SWE systems from different vendors may be an issue. In addition, the presence of concurrent liver inflammation with/without necrosis, hepatic congestion, obstructive cholestasis, and diffuse infiltrative disease in the liver, which can increase the tissue viscosity, is another limitation of the current liver elastography technique for the

*Evaluation of Liver Fibrosis Using Shear Wave Elastography: An Overview DOI: http://dx.doi.org/10.5772/intechopen.102853*

diagnosis of liver fibrosis and cirrhosis, leading to over-estimation of liver fibrosis stage. Therefore, operators should be aware of the limitations of current SWE systems for proper use of SWE technique in assessing liver fibrosis stage as well as for the accurate interpretation of the liver stiffness measurement results.
