Noruegas *et al.* published the first data regarding the use of VTQ (ARFI) elastography for non-invasive assessment of liver fibrosis in children (10 children with chronic hepatopathies, 22 children from the liver transplantation waiting list and 20 healthy controls) [68]. The reference method for liver fibrosis assessment was LB and a 4 MHz convex probe was used for VTQ (ARFI) assessment. The scans was performed by intercostal approach and/or sub-xiphoid approach. Three LS measurements by VTQ (ARFI) were performed at different positions (4-6 locations), during slow breathing. The mean LS values assessed by VTQ (ARFI) for different stages of fibrosis were: F0=1.19±0.17 m/s, F1=1.48±0.32 m/s, F2=1.66±0.43 m/s and F4=2.93±0.97 m/s. The AUROCs of VTQ (ARFI) for diagnosing F≥1, F≥2 and F=4 were: 0.834, 0.818 and 0.983 respectively.

### **66** *Hepatic Elastography Using Ultrasound Waves Bota et al.*

Marginean *et al.* evaluated by means of VTQ (ARFI) elastography 103 children divided into four categories: healthy control group (32 children), children with chronic liver disease with LB (19 subjects), overweight or obese children with NAFLD (13 children) and patients with malignancy (39 children) [69]. Ten valid LS measurements by VTQ (ARFI) were performed in the segment 8 and respectively in the liver segment 1 and median values were calculated. Global VTQ (ARFI) values were also calculated taking into consideration all the values obtained in the left and right lobe. In the healthy controls and NAFLD children the mean VTQ (ARFI) values obtained in segment 1 were significantly lower than those obtained in the liver segment 8. In the group of children with NAFLD, the mean global VTQ (ARFI) values were significantly higher than those obtained in the control group: 1.65 ± 0.49 m/s *vs.* 1.18 ± 0.27 m/s, p=0.002.

# *g. Usefulness of Spleen Stiffness Assessed by VTQ (ARFI) for Predicting Liver Cirrhosis*

In order to increase the diagnostic accuracy in liver cirrhosis, the spleen stiffness (SS) assessment by VTQ (ARFI) was evaluated. Similar with LS assessment, 10 valid measurements are performed by intercostal approach and a median value is calculated, expressed in m/s (Fig. **2**).

**Fig. (2).** VTQ (ARFI) measurement in the spleen (in a patient with splenomegaly).

### *pSWE Elastography Hepatic Elastography Using Ultrasound Waves* **67**

Our group performed a study which evaluated 82 subjects (15 healthy volunteers, 57 cirrhotic patients, 10 with chronic liver disease with various stages of liver fibrosis) [70]. The mean SS (spleen stiffness) values (m/s) were: 2.04±0.28 in healthy subjects and 3.10±0.55 in cirrhotic patients (p<0.001). For a cut-off value of >2.51 m/s, SS had 85.2% Se, 91.7% Sp, 95.8% PPV, 73.3% NPV and 87.1% accuracy (AUROC=0.91) for predicting liver cirrhosis. The optimum LS cut-off value assessed by VTQ (ARFI) for predicting the presence of cirrhosis was 1.8 m/s, with 96.4% Se, 92% Sp, 96.4% PVP, 92% NPV and 95% accuracy. If LS and SS combined values are used, when one of the parameters is higher than the proposed cut-offs, 98.1% Se, 95.8% Sp, 98.1% PPV, 95.8% NPV and 95.8% accuracy are obtained to predict cirrhosis, and when both parameters are higher than the proposed cut-offs, 94.7% Se, 96% Sp, 98.1% PPV, 88% NPV and 95.1% accuracy are obtained.

An Italian study obtained the following mean SS values in healthy subjects, noncirrhotic patients with chronic liver disease and cirrhotic patients: 2.23 m/s, 2.62 m/s and 3.36 m/s, respectively [8]. They also calculated the *spleno-hepatic index* (LS assessed by VTQ-ARFI in the right liver lobe multiplied by SS). The mean values of spleno-hepatic index in healthy subjects, patients with chronic hepatopathies and cirrhotic patients were: 2.61 m/s, 3.77 m/s and 8.13 m/s. For a cut-off value of 4.9 m/s, the spleno-hepatic index had 95.2% Se, 80.9% Sp, 81.6% PPV and 95% NPV (AUROC=0.945) for predicting the presence of liver cirrhosis.

Grgurevic *et al.* assessed LS and SS by VTQ (ARFI) in 58 subjects (20 healthy volunteers, 18 non-cirrhotic patients with chronic hepatopathies with LB and 20 patients with known liver cirrhosis) [71]. The mean SS values increased with liver fibrosis severity: 2.27±0.35 m/s in healthy subjects, 2.58±0.47 m/s in patients with chronic hepatopathies and 3.29±0.65 m/s in cirrhotic patients (p<0.001). For a cut-off value of 2.73 m/s, SS assessed by VTQ (ARFI) had 90% Se and 77.8% Sp (AUROC=0.822) for predicting F=4. The best LS cut-off value assessed by VTQ (ARFI) for predicting cirrhosis was 1.86 m/s (95% Se and 94.4% Sp, AUROC=0.989).

Cabassa *et al.* evaluated LS and SS by VTQ (ARFI) in 84 subjects (33 healthy

volunteers and 51 patients with chronic hepatopathies) [72]. Spleen stiffness assessed by VTQ (ARFI) was able to discriminate early (F1) from severe (≥F3) liver fibrosis with an optimal cut-off of 3.05 m/s (AUROC = 0.807). Liver stiffness assessed by VTQ (ARFI) was superior to SS, using a cut-off of 2.11 m/s (AUROC=0.879). Neither spleen nor liver VTQ (ARFI) was able to differentiate healthy volunteers from F1 patients.

Chen *et al.* evaluated the value of SS for predicting different stages of liver fibrosis in a cohort of 163 patients with chronic hepatitis B and C [73]. The AUROCs of SS for predicting the presence of F≥2, F≥3 and F=4 were: 0.839, 0.936 and 0.932 respectively. The optimal cut-offs of SS assessed by VTQ (ARFI) for predicting the presence of significant fibrosis, severe fibrosis and liver cirrhosis were: 2.74 m/s, 3.14 m/s and 3.32 m/s, respectively.

In conclusion, VTQ (ARFI) seems to be a useful method for liver fibrosis assessment in patients with chronic hepatopathies (especially chronic hepatitis C), non inferior as compared to TE. VTQ (ARFI) performed better for predicting severe fibrosis and cirrhosis. For patients with non-alcoholic fatty liver disease and other non-viral etiologies of chronic liver disease, post transplant patients and in children, further studies for the evaluation of VTQ (ARFI) as a predictor of liver fibrosis are required.

# **5. Usefulness of VTQ (ARFI) for Predicting Liver Cirrhosis Complications**

Liver cirrhosis is the final stage of chronic hepatopathies of diverse etiologies. It has several complications such as portal hypertension, decompensation, hepatocellular carcinoma, hepatorenal syndrome, hepatopulmonary syndrome. Invasive evaluation of hepatic vein pressure gradient (HVPG) remains the most precise method for portal hypertension assessment. A HVPG value higher than 10 mm Hg predicts the presence of clinically significant portal hypertension, while a value higher than 12mm Hg is predictive for variceal bleeding [74].

Splenomegaly is a common finding in cirrhotic patients and the spleen density is modified in these patients, due to tissue hyperplasia and fibrosis and/or due to portal and spleen congestion due to the splanchnic hyper dynamic state [75, 76].

Several non-invasive methods have been evaluated as predictors of portal hypertension and esophageal varices (EV): aspartate aminotransferase to platelet ratio index - APRI or platelet count to spleen diameter ratio [77, 78]. In the last years, another 3 methods which evaluate liver stiffness (LS) and/or spleen stiffness (SS), have demonstrated some results in this field: Magnetic Resonance Elastography (MRE) [79, 80], TE [81 - 83] and VTQ (ARFI) [70, 84, 85].

# *a. Usefulness of VTQ (ARFI) for Predicting Portal Hypertension*

Salzl *et al.* [86] presented data regarding the correlation of LS assessed by VTQ (ARFI) with HVPG in 48 patients (36 cirrhotic and 12 non-cirrhotic patients). A good correlation of LS measurements assessed by VTQ (ARFI) with HVPG measurements (r=0.709) was obtained. The authors calculated an AUROC of 0.874 for predicting the presence of clinically significant portal hypertension.

We evaluated in one study 157 patients [87]. The mean value of VTQ (ARFI) measurements in patients with large EV (at least grade 2) was not significantly different from the one in patients with no or small EV: 2.73±0.71 *vs.* 2.80±0.71m/s (p=0.49), nor in patients with or without a history of variceal bleeding: 2.78±0.81 *vs.* 2.77±0.7m/s (p=0.99).

In another study published by our group, 82 subjects were evaluated (15 healthy volunteers, 57 cirrhotic patients, 10 non-cirrhotic patients with various stages of liver fibrosis on LB) [70]. The mean SS values (m/s) were: 2.04±0.28 in healthy subjects and 3.10±0.55 in cirrhotic patients (p<0.001). For a cut-off value of >2.51 m/s, SS had 85.2% Se, 91.7% Sp, 95.8% PPV, 73.3% NPV, and 87.1% accuracy (AUROC=0.91) for predicting liver cirrhosis. No significant differences regarding SS were observed between patients with and without EV, also between those with and without a history of variceal bleeding.

In a subsequent study we tried to combine several parameters in order to increase the accuracy of VTQ (ARFI) for predicting significant EV [88]. We evaluated LS and SS by means of VTQ (ARFI) in 145 newly diagnosed cirrhotic patients who did not receive beta-blockers before LS measurements, 62 (42.7%) of them having significant EV (grade 2 and 3). The following parameters were significantly higher in patients with significant EV as compared to those without

EV or grade 1 EV: the mean SS assessed by VTQ (ARFI) (m/s) (3.28±0.50 *vs.* 3.08±0.61, p=0.04), the mean LS assessed by VTQ (ARFI) (m/s) (3.06±0.67 *vs.* 2.81±0.80, p=0.03), and the percentage of patients with ascites (70.9% *vs.* 34.9%, p=0.0001). The spleen size was similar in the 2 groups of patients. By multiple regression analysis we obtained the following formula for predicting significant EV:

**Prediction of Significant EV (Pred EV2-3**): -0.572 + 0.041 x LS (m/s) + 0.122 x SS (m/s) + 0.325 x Ascites (1-absent, 2-present).

For cut-off values > 0.395, Pred EV2-3 had 75% Se, 61.8% Sp, 61.4% PPV, 78.2% NPV and 69.6% accuracy (AUROC=0.721) for predicting significant EV. In a cohort of 24 patients, the value of PredEV2-3 score for predicting significant EV was prospectively analyzed. Using the same cut-off value, the PredEV2-3 score had 66.7% Se, 75% Sp, 72.7% PPV, 69.2% NPV and 70.8% accuracy to predict significant EV in this cohort of patients.

Rifai *et al.* evaluated SS and LS in 125 subjects (25 healthy control subjects, 70 patients with chronic hepatopathies without portal hypertension and 30 cirrhotic patients with portal hypertension) [85]. The mean SS values were higher in patients with portal hypertension *vs.* those without portal hypertension: 3.25±0.56 m/s *vs.* 2.86±0.60 m/s (p<0.008). In this study, the authors obtained a significantly better performance of LS as compared with SS for predicting significant portal hypertension (AUROC 0.90 *vs.* 0.68), but the LS cut-off value proposed for predicting significant portal hypertension (1.67 m/s), is lower than the VTQ (ARFI) cut-off values proposed by the most published studies for diagnosing liver cirrhosis [6, 9, 37, 43]. The best SS cut-off value for predicting portal hypertension was 3.29 m/s, with 47% Se, 73% Sp, 36% PPV and 81% NPV.

Vermehren *et al.* evaluated 166 cirrhotic patients by means of VTQ (ARFI) (LS and SS), TE (LS) and FibroTest [84]. In an intention-to-diagnose analysis, the AUROCs for predicting significant EV were 0.58, 0.58, 0.53 and 0.50 for VTQ (ARFI) liver, VTQ (ARFI) spleen, TE and FibroTest, respectively (p>0.20). Logistic regression analysis showed that SS assessed by VTQ (ARFI) predicted better the presence of significant EV as compared with LS assessed by VTQ (ARFI). The best SS cut-off value for predicting significant EV was 4.13 m/s

(35% Se, 83% Sp, 54% PPV and 69% NPV). The authors also calculated the SS by VTQ (ARFI) cut-off for which the Se for predicting significant EV was >90. This cut-off was 3.04 m/s (90% Se and 25% Sp).

The performance of VTQ (ARFI) for non-invasive prediction of esophageal varices reported by the Asian studies was significantly better in comparison with the one reported in studies including European population.

Ye *et al.* evaluated SS and LS by VTQ (ARFI) in a cohort of 60 healthy volunteers (classified as stage 0), 66 patients with chronic hepatitis B who had undergone liver biopsy and 138 patients with hepatitis B-related cirrhosis [89]. LS was not correlated with the varices grade, whereas a significant linear correlation (Spearman ρ = 0.65; P < .001) between SS and the varices' grade was found. The optimal SS cutoff value for predicting the presence of esophageal varices was 3.16 m/s (AUROC = 0.83).

Morishita *et al.* studied the value of SS assessed by VTQ (ARFI) for prediction of high risk esophageal varices in a cohort of 135 HCV cirrhotic patients (92 included in the training cohort und 43 in the validation group) [90]. In the training set, the SS values assessed by VTQ (ARFI) increased with the EV grade (p<0.001). The mean VTQ (ARFI) values in the group with high-risk EV was significantly higher than in the group with low-risk EVs (p < 0.001). AUROC values for diagnosis of EV presence and high-risk EVs by VTQ (ARFI) were 0.890 and 0.868. The optimal cutoff value of VTQ (ARFI) for EV presence was 2.05 m/s with good sensitivity (83%), specificity (76%), PPV (78%), and NPV (81%), and that for high-risk EV was 2.39 m/s with good sensitivity (81%), specificity (82%), PPV (69%), and NPV (89%). These cut-off values obtained in the training cohort also showed excellent performance in the validation set.

Takuma *et al.* evaluated LS and SS assessed by VTQ (ARFI) for prediction of varices in a large cohort of 340 cirrhotic patients [91]. Spleen stiffness had the greatest diagnostic accuracy for the identification of patients with EV or high-risk EV as compared with LS, independent of the etiology of cirrhosis. An SS cut-off value of 3.18 m/s identified patients with EV with 98.4% NPV, 98.5% Se and 75% accuracy. A SS cut-off value of 3.30 m/s identified patients with high-risk

EV with 99.4% NPV, 98.9% Se and 72.1% accuracy. SS values less than 3.3 m/s ruled out the presence of high-risk varices in patients with compensated or decompensated cirrhosis.

# *b. Usefulness of VTQ (ARFI) for Predicting Decompensation of Liver Cirrhosis*

A study published by our group assessed the mean LS value assessed by VTQ (ARFI) in cirrhotic patients [87]. The mean LS values were significantly lower in patients with compensated liver cirrhosis as compared with patients with decompensated liver cirrhosis (Child B and C): 2.67±0.73 *vs.* 3.05±0.8m/s (p=0.021).

In another study from our group, 211 cirrhotic patients were evaluated [92]. We found a direct, weak correlation between LS values and the Child-Pugh score (r=0.264, p<0.001) and also with MELD score (r=0.194, p=0.005). We also found a direct, weak correlation between LS measurements and total bilirubin (r=0.271, p<0.001) and an inverse, weak correlation with albumin (r= - 0.270, p<0.001), prothrombin time (r= - 0.196, p=0.006) and cholinesterase (r= - 0.241, p=0.003). The mean values of VTQ (ARFI) measurements were significantly higher in patients with Child-Pugh B *vs.* A (2.93±0.72 m/s *vs.* 2.59±0.68 m/s, p=0.002) and in Child-Pugh C *vs.* A (3.18±0.63 m/s *vs.* 2.59±0.68 m/s, p<0.001), but the values were not significantly different in patients with Child-Pugh B *vs.* C (2.93±0.72 m/s *vs.* 3.18±0.63 m/s, p=0.06). VTQ (ARFI) had 50% Se, 75% Sp, 70% PPV, 56.2% NPV, with 61.5% accuracy (AUROC - 0.65) for predicting the presence of at least B class Child-Pugh cirrhosis for a cut-off value of 3.11 m/s.

In a German study the mean SS values assessed by VTQ (ARFI) were significantly higher in patients with ascites *vs.* those without ascites: 3.33±0.59 m/s *vs.* 2.91±0.59 m/s (p<0.04) [85].

# *c. Usefulness of VTQ (ARFI) for Predicting Hepatocellular Carcinoma Occurrence*

We observed in a study performed by our group that LS values assessed by VTQ (ARFI) were similar in patients with and without hepatocellular carcinoma: 2.70±0.64 *vs.* 2.88±0.81m/s (p=0.19) [87].

### *pSWE Elastography Hepatic Elastography Using Ultrasound Waves* **73**

In a German study the AUROCs for predicting the occurrence of hepatocellular carcinoma for LS assessed by VTQ (ARFI), SS assessed by VTQ (ARFI), LS assessed by TE and FibroTest were: 0.54, 0.58, 0.56 and 0.72, respectively (p>0.20) [84]. Logistic regression analysis showed that SS assessed by VTQ (ARFI) predicted better the presence of hepatocellular carcinoma as compared with LS assessed by VTQ (ARFI). The best SS cut-off value for predicting hepatocellular carcinoma was 3.4 m/s (87% Se, 31% Sp, 11% PPV and 96% NPV). For a cut-off of 2.87 m/s the SS assessed by VTQ (ARFI) had 93% Se and 15% Sp for predicting the presence of hepatocellular carcinoma.

In conclusion, VTQ (ARFI) elastography seems to be a useful non-invasive method for predicting liver cirrhosis complications (especially portal hypertension and especially in Asian patients) and the accuracy can be increased by combining different elastographic parameters.

# **II.B. ELASTPQ ELASTOGRAPHY**

# **1. ElastPQ Technique**

ElastPQ technique is integrated into a Philips ultrasound system (iU22, Philips Medical Systems, Bothell,WA, USA, newly in Affinity 70 or in EPIC). Currently, little information is available regarding the physical principles of ElastPQ technique. According to the data provided by the manufacturer in the application for approval, submitted to the US Food and Drug Administration (FDA), ElastPQ system is relatively similar to 2D-SWE, even if this method is classified as a point SWE method [93]. The ElastPQ system generates an electronic voltage pulse, which is transmitted to the transducer. In the transducer, a piezo electric array converts the electronic pulse into an ultrasonic pressure wave. When coupled to the body, the pressure wave transmits through body tissues. The Doppler functions of the system process the Doppler shift frequencies from the echoes of moving targets, such as blood, to detect and graphically display the Doppler shift of these tissues as flow. The Doppler mode creates waves in soft tissues and estimates tissue stiffness by determining the speed at which these shear waves travel through the ROI [93]. Similar with VTQ Elastography, ROI has a predefined size, provided by the system (15 mm long and 5 mm wide). The shear wave speed is displayed on the screen (Fig. **3**). The operator can choose to display the results in m/s or in kPa.

# **2. Examination Technique**

The measurements are performed on patients in supine position, with minimal scanning pressure applied by the operator, usually the operator asking the patient to suspend their breathing in a neutral, relaxed state, in order to minimize breathing motion. According to the data provided by the manufacturer, an intercostal scanning is needed for accurate stiffness measurements and the recommended liver stiffness (LS) measurements should be taken in segment 7 or 8 of the right lobe of the liver using a sagittal view, keeping in mind to hold the transducer very still during measurements, maintaining steady pressure. On the other hand according to published data LS measurements by ElastPQ should be performed in the liver segment V, because the lowest variation of LS

### *pSWE Elastography Hepatic Elastography Using Ultrasound Waves* **75**

measurements was observed in this location [94]. The operator places the ROI in a region without large vessels and far from the heart, the diaphragm, liver/kidney interface and liver capsule. Ten valid measurements are performed and average and median value are calculated (expressed in m/s or kPa). A "0.00" value means the system did not detect liver tissue. An accurate stiffness average needs at least 10 non-zero measurements. There is no information regarding if the measurements must be made under fasting conditions. Also, there are no published studies, nor information from the manufacturer regarding the use of quality criteria parameters for LS measurements.

**Fig. (3).** ElastPQ measurement.

# **3. Feasibility of ElastPQ**

Ten valid LS measurements can be obtained in more than 95% of patients [94 - 96] or without chronic hepatopathies [97]. In our cohort reliable LS measurements were obtained in a significantly higher proportion of patients by means of ElastPQ as compared with TE, 2D-SWE and VTQ: 99.3% *vs.* 87.4% (p<0.0001), 99.3% *vs.* 87.4% (p<0.0001) and 99.3% *vs.* 92.7% (p=0.86). In another study conducted by our group we compared the performance of ElastPQ in 121 consecutive subjects with chronic hepatopathies, using TE as the reference method, since it is

### **76** *Hepatic Elastography Using Ultrasound Waves Bota et al.*

a validated method for liver fibrosis assessment [98]. Reliable LS measurements were obtained in 74.4% of patients by means of TE and in 99.3% with ElastPQ.

There is no information about the learning curve of this method, but similar with VTQ elastography, considering the excellent feasibility in the few published studies, probably a special training is not needed for physicians with basic knowledge in liver ultrasonography.

# **4. Reproducibility of ElastPQ Elastography**

Ma JJ *et al.* evaluated the inter-operator reproducibility of ElastPQ elastography in 291 successive patients with hepatitis B who underwent liver partial hepatectomy or biopsy due to liver neoplasm [95]. The ICC of 10 measurements of liver stiffness with ElastPQ technique was 0.798, which indicated a good reproducibility. Ferraioli *et al.* assessed the reproducibility of ElastPQ in 116 subjects, including 47 consecutive patients scheduled for liver biopsy (Group 1) and 69 consecutive healthy volunteers (Group 2) [99]. The intraobserver agreement ranged from 0.83 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 1 and from 0.84 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 2. The interobserver agreement yielded values from 0.83 (95%CI: 0.78-0.88) to 0.93 (95%CI: 0.91-0.95).

In a study conducted by our group we also evaluated ElastPQ reproducibility [100]. The intra and inter-operator reproducibility were studied in 33 and respectively in 50 patients. The overall intraobserver agreement was better than the interobserver one: ICC 0.92 *vs.* ICC 0.85. A strong correlation was obtained between measurements assessed by both operators (r=0.86, p<0.0001) and also between measurements assed by a single operator 0.76 (p<0.0001). For both intraand interobserver reproducibility, the ICCs were similar in patients with high body mass index (BMI) ≥25 kg/m<sup>2</sup> *vs.* <25 kg/m<sup>2</sup> (0.90 *vs.* 0.93 and 0.89 *vs.* 0.82, respectively).

# **5. Factors which Influence the Correlation of Liver Stiffness Values Assessed by ElastPQ with Fibrosis**

Ling *et al.* evaluated in 21 healthy individuals the impact of liver location

(segments I-VIII), breathing phase (end-inspiration and end-expiration), probe position (sub-costal and inter-costal position) and examiner, in what LS measurements by ElastPQ were concerned [94]. More studies were also performed in 175 healthy individuals in order to determine the influence of gender and age on LS. This study found significant impact of liver location on LSM, while the liver segment V displayed the lowest coefficient of variation (CV 21%). The liver stiffness at the end-expiration was significantly higher than that at the end-inspiration. The liver stiffness was 8% higher in men than in women (3.8 ± 0.7 kPa *vs.* 3.5 ± 0.4 kPa, p=0.0168). In contrast, the liver stiffness was comparable in the different probe positions, examiners and age groups (p>0.05).

The influence of necroinflammation on liver stiffness is controversial; some studies have found an influence [95] and others have not [99]. In a study conducted by Ma JJ *et al.* the stage of liver fibrosis and the grade of necroinflammatory activity were associated with higher values of LS by ElastPQ (*p*< 0.05) [95].

# **6. Liver Stiffness Values by ElastPQ in Healthy Volunteers**

According to available data, LS values by ElastPQ in Romanian healthy volunteers are 1.08 ± 0.12 m/s, value equivalent with 3.5 ± 0.04 kPa [96]. An Asian study showed that LS values by ElastPQ technique are significantly higher in men as compared with women and that they are not influenced by age [95].

# **7. ElastPQ Technique for Liver Fibrosis Evaluation in Chronic Hepatitis C Patients**

No information available until now.

# **8. ElastPQ Technique for Liver Fibrosis Evaluation in Chronic Hepatitis B Patients**

Published data showed a good value of ElastPQ technique for predicting the presence of significant fibrosis (F≥2) and cirrhosis (F=4), the best LS cut-off values being: 6.99 kPa (AUROC=0.94) and 9 kPa (AUROC=0.89), respectively [95].

# **9. ElastPQ Technique for Liver Fibrosis Evaluation in a Cohort of Patients with both Chronic Hepatitis B and C**

In a cohort of patients with both viral etiologies of chronic liver disease, the median LS values for different stages of liver fibrosis were: F0-1 = 4.6 kPa, F2 = 5.9 kPa, F3 = 7 kPa and F4 = 12 kPa, respectively [101]. Also, ElastPQ technique had similar value with TE for predicting different stages of liver fibrosis.

# **10. The Usefulness of ElastPQ Technique for Predicting the Complications of Liver Cirrhosis**

No information available until now.

# **11. The Usefulness of ElastPQ Technique in HCC**

Ling *et al.* evaluated the usefulness of ElastPQ in a cohort of 99 patients with pathology-proven HCC [102]. They found that *in vivo* stiffness was significantly higher than *in vitro* stiffness (20 of the 99 surgical HCC specimens). Significantly higher stiffness was observed in hyper-vascular and poorly differentiated lesions than in hypo-vascular ones (p = 0.0352) and moderately to well-differentiated lesions (p = 0.0139).

**The main advantages and weaknesses of liver fibrosis evaluation by means of ElastPQ**

# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this publication.

## **ACKNOWLEDGEMENTS**

Declared none.

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© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 3**

# **2D-ShearWaves Elastography (2D-SWE)**

#### **Alina Popescu\* , Felix Bende** and **Ioan Sporea**

*Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania*

**Abstract:** Shear waves elastography is a technique designed to overcome some of the disadvantages of other elastographic techniques. It is based on supersonic share imaging, an ultrasound-based technique used for real-time visualization of soft tissue viscoelastic properties. This technique is based on the combination of a radiation force induced into the tissues by focused ultrasonic beams and a very high frame rate ultrasound imaging sequence able to capture in real time the transient propagation of the resulting shear waves. Shear waves' propagation induces small tissue displacements which are recorded by the imaging system, and measured using tissue Doppler techniques. 2D-SWE offers as major innovations the ability to measure area and distance ratios, a high spatial resolution and real-time capabilities. The technique produces an image where true local tissue elasticity is displayed in a color map in "real time". Elasticity is displayed using a color coded image superimposed on a B-mode image. The true elasticity is assessed based on Shear Waves propagation speed into the tissue. Thus the technique permits a quantitative mapping of liver tissue viscoelasticity. The technique was first available on the Aixplorer® system (SuperSonic Imagine, France) and initially was used for the evaluation of breast nodules, of prostate elasticity, for the evaluation of muscle and tendon stiffness and for thyroid disease diagnosis. Published data showed a real value of this method for liver stiffness estimation in patients with chronic hepatitis. It has the advantage that it can be also used in patients with ascites. A similar technique is now available on the Logiq E9 system (General Electric) with promising results.

**Keywords:** Liver stiffness, Shear waves elastography, Viscoelasticity.

**Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Address correspondence to Alina Popescu:** Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania; Tel: +40 256 488003; Fax: +40 256 488003; E-mail<EMAIL_ADDRESS>
# **1. 2D-SHEARWAVES ELASTOGRAPHY TECHNIQUE**

2D-Shear Waves Elastography (2D-SWE) is a new technique designed to overcome some of the disadvantages of other elastographic techniques. It is based on supersonic share imaging, an ultrasound-based technique, used for real-time visualization of soft tissue viscoelastic properties. The technique is based on the combination of a radiation force induced into the tissues by focused ultrasonic beams and a very high frame rate ultrasound imaging sequence, able to capture in real time the transient propagation of resulting shear waves [1].

Thus, 2D-SWE uses transient pulses to generate shear waves into the body [2 - 4], the only approach able to provide measureable and local elastic information in "real time" [5] - a major advantage. Fully automatic generated acoustic radiation force impulses induced by ultrasound beams perturb the underlying tissues, generating mechanical waves and shear waves, which propagate transversely into the tissue. Using SonicTouch™ technology, ultrasound beams are successively focused at different depths into tissues, all resulting shear waves interfering constructively along a "Mach cone", creating two quasi-plane shear Waves fronts propagating in opposite directions through the tissue. The shear waves generated using the SonicTouch™ excitation are captured by the ultrasound system. In order to capture shear waves in sufficient detail, frame rates of a few thousand of images per second are needed, 100 times faster than the frame rates offered by current state-of-the-art ultrasound technology. This ultrafast imaging mode acquires raw radiofrequency data at a very high frame rate, up to 5000 frames/s.

Shear waves' propagation induces small tissue displacements, which are recorded by the Ultrafast™ imaging system and measured using tissue Doppler techniques. 2D-SWE offers as major innovations, the ability to measure area and distance ratios, a high spatial resolution and real-time capabilities. Fully automated shear waves generation from the ultrasound transducer also allows user-skill independent and reproducible imaging.

2D-ShearWaves™ Elastography (2D-SWE) produces an image where true local tissue elasticity is displayed in a color map in "real time". Elasticity is displayed using a color coded image superimposed on a B-mode image. Stiffer tissues are

### **90** *Hepatic Elastography Using Ultrasound Waves Popescu et al.*

coded in red and softer tissues in blue, with an image resolution of approximately 1 mm. The true elasticity is assessed based on shear Waves propagation speed into the tissue. Thus the technique permits a quantitative mapping of liver tissue viscoelasticity [1].

The 2D-SWE method was used for the evaluation of breast nodules, of prostate elasticity, for the evaluation of muscle and tendon stiffness and for thyroid disease diagnosis. Preliminary results have shown the value of this method for liver stiffness (LS) estimation in patients with chronic hepatitis.

The technique has several advantages. The elasticity estimation is performed over a large area (10 cm<sup>2</sup> ) and probably reduces sampling errors; it also allows a mapping of local stiffness heterogeneities, thus allowing a precise location of hepatic lesions. Another interesting aspect of the supersonic share imaging technique relies on its ultrafast imaging characteristics, the high frame rates up to 5000 frames/s removing the influence of low-frequency displacement artifacts, such as respiratory motion or cardiac vibrations, which are error factors for the other elastographic techniques [1]. Thus the method is proven to be rapid, easy to perform, repeatable and reproducible [1].

On the other hand, the frequency bandwidth of the generated shear Waves is large, typically ranging from 60 to 600 Hz, different from transient elastography (FibroScan® ) for example. By averaging shear Waves speed over a large bandwidth, supersonic share imaging seems to provide a more discriminator parameter for fibrosis evaluation [6] increasing the diagnosis accuracy.

The technique was first available on the *Aixplorer®system* (SuperSonic Imagine, France), integrated in an ultrasound system. The evaluation protocol requires placing the patient in supine position with the right arm in maximum abduction. The patient has to be fasted and the evaluation is recommended to be performed in normal breathing. The convex probe is placed in an intercostal space, using the best acoustic window available for liver evaluation. It is recommended to perform the acquisition on the right liver lobe and slow or no movement of the probe is preferable in order to avoid motion artifacts and to allow map stabilization. The 2D-SWE box has to be placed in vessel free parenchyma, in a uniform zone, not

### *2D-ShearWaves Elastography (2D-SWE) Hepatic Elastography Using Ultrasound Waves* **91**

close to the liver capsule. The best acquisition is performed 3 to 7 cm deep, 1-2 cm below the liver capsule [7]. The patient has to hold breath in the expiration phase for 4 sec. to acquire a stable image. The quantification box (ROI) is next placed in a homogeneous area and the elasticity value is displayed on the image (expressed as mean value and standard deviation measured either in kPa or in m/s) (Figs. **1**, **2**). The ROI size can be adjusted and allows the interrogation of a larger area of parenchyma. There is a large range of values that can be obtained (2-150 kPa), another advantage together with the possibility to use this technique also in patients with ascites (Fig. **3**). Some ultrasound experience is needed in order to obtain a high feasibility rate [8], especially in obese patients, and difficulties can also appear in patients with narrow intercostal spaces [9].

There is still no consensus regarding the number of measurements that should be performed, some authors using three [10], four [9] or five [11 - 13] valid 2D-SWE measurements. Other studies tried to see which would be the optimal number of measurements [14, 15] but the small number of patients did not allow the authors to reach a conclusion. Also, some studies used the mean value of LS measurements [9, 10], while in others the median was used [13]. In a study by Sporea *et al.* the mean LS values of three or five measurements, or the median value of five valid 2D-SWE measurements were compared. All correlated with TE showing similar results [16].

There are no quality criteria well defined yet, but some authors used the standard deviation/median liver stiffness ≤ 0.10 and measurement depth < 5.6 cm as quality technical parameters [17].

Similar to other ultrasound based elastographic methods, 2D-SWE should be performed in fasting conditions of at least 2 hours in order to avoid falsely elevated LS values [18]. There are no available data regarding the influence of elevated aminotransferases level, congestive heart failure, excessive alcohol intake or obstructive jaundice on the LS values, but in all these cases measurements can be unreliable.

**92** *Hepatic Elastography Using Ultrasound Waves Popescu et al.*

**Fig. (1).** Liver stiffness measurement by 2D-SWE using the Aixplorer® system in a patient with mild hepatitis.

**Fig. (2).** Liver stiffness measurement by 2D-SWE using the Aixplorer® system in a patient with cirrhosis.

*2D-ShearWaves Elastography (2D-SWE) Hepatic Elastography Using Ultrasound Waves* **93**

**Fig. (3).** Liver stiffness measurement by 2D-SWE using the Aixplorer® system in a patient with liver cirrhosis and ascites.

2D-SWE is proved to be a *feasible and reproducible technique*. Most published studies showed that reliable LS measurements by means of 2D-SWE can be obtained in 90-98.9% of cases [9, 10, 19, 20], but if the TE quality criteria are applied (IQR<30% and SR≥30%), the rate of reliable measurements can decrease to 71.3% [13]. The technique showed a good intra- and inter-observer reproducibility in assessing LS [19, 21, 22].

# **2. CLINICAL RESULTS**

# **a. Healthy Volunteers**

The mean LS in healthy volunteers varied from 4.1 kPa [23], to 6 ± 1.4 kPa (median 5.7 kPa), higher values being obtained in men than in women (6.6 ± 1.5 kPa *vs.* 5.7 ± 1.3 kPa, p=0.01.) [24], to values ranging from 2.6 to 6.2 kPa in another study [25].

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# **b. Chronic Liver Diseases**

# *HCV Hepatitis*

In one of the first studies, Bavu *et al.* included 133 patients with HCV chronic infection in whom 2D-SWE was compared with TE and liver biopsy (LB) [11]. Analysis of variance (ANOVA) showed a good correlation between fibrosis and elasticity assessment using 2D-SWE and TE (p<0.0001). AUROCs for elasticity values assessed by 2D-SWE were: 0.948 for F≥2, 0.962 for F≥3 and 0.968 for F=4. In this study, the AUROCs for 2D-SWE were better than those from TE performed in the same session (AUROCs for TE for F≥2, F≥3 F4 were 0.846, 0.857 and 0.940 respectively).

Another small study compared LS values in subjects with chronic C hepatitis obtained by means of ultrasound elastographic methods [26]. In a cohort of 33 patients with proven HCV hepatitis, the LS was evaluated with FibroScan® (Echosens® , XL probe, 10 valid measurements), ARFI (VTQ-Siemens, 10 valid measurements) and Aixplorer® (Supersonic, 4 valid measurements). Successful measurements were obtained with FibroScan® and ARFI in 100% and with Aixplorer® in 97% of cases. Mean values were as follows: ARFI: 1.30 m/s; FibroScan® : 8.57 kPa; Aixplorer® : 10.05 kPa. In this study, there was a significant correlation between ARFI and both FibroScan® and Aixplorer® (r2=0.6720; r2=0.5408, p<0.0001).

More recently published data proved 2D-SWE as a good, reliable method for assessing LS in chronic hepatitis C patients [9], the best cut-off values for different stages of liver fibrosis in this study being: F≥2: 7.1 kPa (AUROC=0.92), F≥3: 8.7 kPa (AUROC=0.98) and F4: 10.4 kPa (AUROC=0.98). Another study on 55 patients with HCV chronic hepatitis evaluated by 2D-SWE, FIB-4 index, aspartate aminotransferase-to-platelet ratio index (APRI) and Forns' index and liver biopsy [27] showed an AUROC for 2D-SWE for diagnosing significant liver fibrosis of 0.94, with an accuracy of 90.9%, both higher than the results for the other techniques.

# *HBV Hepatitis*

The data available regarding LS assessment by means of 2D-SWE in patients with chronic hepatitis B show almost similar values as for HCV patients: F≥1: 6.5 kPa (AUROC=0.86), F≥2: 7.1 kPa (AUROC=0.88), F≥3: 7.9 kPa (AUROC=0.93) and F4: 10.1 kPa (AUROC=0.98) [10].

In another study on 303 patients with chronic hepatitis B, in which the first 202 patients were the index cohort who were validated on the next 101 patients (validation cohort), the AUROC curves for significant fibrosis, severe fibrosis and cirrhosis were all greater than 0.90 [28]. Using the cut-off values generated from the index cohort, the validation cohort 2D-SWE had NPV of 82.6% (95% confidence interval [CI]: 68.4% - 92.3%) for significant fibrosis; 95.1% (95% CI: 86.3% - 99.0%) for severe fibrosis; and 97.4% (95% CI: 90.8% - 99.7%) for cirrhosis. The PPV were 83.6% (95% CI: 71.2% - 92.2%); 65.0% (95% CI: 48.1 -  79.5%); and 60.0% (95% CI: 38.7% - 78.9%), respectively, proving that the method is better to rule out the diagnosis of cirrhosis.

# *NAFLD*

Even if data are still limited, 2D-SWE seems to be also accurate for the evaluation of LS in NAFLD patients. Thus, 291 NAFLD patients were evaluated by 2D-SWE, TE (M probe), and ARFI (VTQ) using liver biopsy as reference method. The AUROCs for 2D-SWE, TE, and ARFI (VTQ) were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively [29]. Also the cut-off values for 2D-SWE and TE for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4.

# *Various Etiologies of Liver Disease*

In a preliminary study performed by Bavu and al, evaluation of hepatic elasticity with 2D-SWE was performed in 104 patients with chronic hepatitis, in comparison with liver biopsy, serum tests and TE [6]. Sensitivity and specificity of 2D-SWE for F≥2 were 0.72 and 0.86; for F≥3 were 0.69 and 0.82 and for F=4 were 0.90 and 0.91.

### **96** *Hepatic Elastography Using Ultrasound Waves Popescu et al.*

Ulterior studies seemed to confirm the good value of 2D-SWE for liver fibrosis assessment. Thus, in a cohort of 79 patients with chronic hepatitis, Ferraioli *et al.* compared 2D-SWE with TE and liver biopsy [30]. The cut-off value found for F≥2 was 7.4 kPa (Se=80%, Sp=83%), for F≥3 it was 8.7 kPa (Se=100%, Sp=95%) and for F=4 it was 9.2 kPa (Se=100%, Sp=87%). The AUROCs for prediction of F≥2, F≥3 and F4 were 0.91, 0.99 and 0.97 respectively. In cases in which 2D-SWE was compared to TE, the two methods showed similar diagnostic performance.

In a study on Romanian patients with various etiologies of chronic liver disease, the cut-off values for predicting each stage of fibrosis were the following: F≥1: 7.1 kPa (AUROC=0.825), F≥2: 7.8 kPa (AUROC=0.859), F≥3: 8 kPa (AUROC=0.897) and for F=4: 11.5 kPa (AUROC=0.914) [31]. In another study on a cohort of 127 consecutive patients with chronic liver diseases, the optimal 2D-SWE cut-off values for predicting significant fibrosis and cirrhosis were slightly higher: 8.03 kPa for F≥2 (AUROC=0.832) and 13.1 kPa for F=4 (AUROC=0.915), respectively [32].

Good results were also obtained in a study that compared 2D-SWE, TE and ARFI (VTQ) in 349 consecutive patients with chronic liver diseases who underwent liver biopsy [33]. 2D-SWE performed better then TE and ARFI (VTQ): AUROCs of 2D-SWE, TE, and ARFI (VTQ) were 0.89, 0.86, and 0.84 for the diagnosis of mild fibrosis; 0.88, 0.84, and 0.81 for the diagnosis of significant fibrosis; 0.93, 0.87, and 0.89, for the diagnosis of severe fibrosis; 0.93, 0.90, and 0.90 for the diagnosis of cirrhosis, respectively. Another similar study on 132 patients with chronic hepatopathies, in whom LS was evaluated using TE, ARFI (VTQ) and 2- D SWE, with liver biopsy as the reference method for liver fibrosis assessment (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31), showed no significant differences between the three elastographic methods for diagnosing significant fibrosis, advanced fibrosis and cirrhosis [34].

The good accuracy of 2D-SWE for liver fibrosis assessment was also proved in overweight and obese patients with chronic liver disease, including HCV patients [35].

In a more recent individual patient data based meta-analysis that included 1340 patients and which compared 2D-SWE with liver biopsy, the overall performance of 2D-SWE was good to excellent in patients with HCV, HBV and NAFLD with AUROCs of 86.3%, 91.6%, 85.9% for diagnosing significant fibrosis and 96.1%, 97.1% and 95.5% for diagnosing cirrhosis, respectively [36]. The optimal cut-off for diagnosing significant fibrosis in all patients was 7.1 kPa, while for diagnosing liver cirrhosis the cut-offs were 13.5 kPa in HCV and NAFLD patients, and 11.5 kPa in HBV patients.

# **c. Liver Cirrhosis Complications Estimation**

This technique is rather new and there are limited data regarding its place in predicting liver cirrhosis complications. Kim *et al.* showed that for a cut-off value of 15.2 kPa, the sensitivity and specificity of 2D-SWE for predicting clinically significant portal hypertension were 85.7% and 80% respectively (AUROC 0.819) (HVPG > 10 mmHg) [37]. Procopet *et al.* [17] used as quality technical parameters the standard deviation/median liver stiffness ≤ 0.10 and measurement depth < 5.6 cm, and when applying them, for the optimal cut-off value of 15.4 kPa, 2D-SWE showed a very good accuracy in predicting clinically significant portal hypertension (AUROC =0.948, with both sensitivity and specificity higher than 90%).

In another study on 79 patients with liver cirrhosis in whom LS and spleen stiffness (SS) were measured by 2D-SWE, TE and in whom HVPG measurements were also performed, the technical success rate of 2D-SWE was significantly better than that of TE for both LS and SS (97% and 97% *vs.* 44% and 42%, respectively; P < .001) [38]. 2D-SWE LS of more than 24.6 kPa had 81% sensitivity, 88% specificity, and 82% accuracy for clinically significant portal hypertension, the diagnostic performance of LS being better than of SS (AUROC of 0.87 *vs.* 0.64, P = .003).

In a larger study, on 401 consecutive cirrhotic patients, the liver stiffness cut-offs values for a NPV≥90% to exclude high-risk esophageal varices, history of ascites, Child-Pugh B/C, variceal bleeding and clinical decompensation were 12.8, 19, 21.4, 30.5, and 39.4 kPa, respectively [39]. The AUROCs for SS and LS (2D-

SWE), and LS (TE) were 0.80, 0.77 and 0.73 respectively for detection of esophageal varices.

All these papers concerning 2D-SWE in patients with chronic hepatopathies showed very good accuracies for LS evaluation (similar or slightly superior diagnostic performance as compared to TE, but with the advantage that with 2D-SWE, valid measurements are obtained in a high proportion of cases), placing it as a reliable alternative of LS evaluation, with further advantages that that require more research.

## *2D-SWE.GE*

Another system that implemented the 2D-ShearWaves Elastography (2D-SWE) technique is the **LOGIQ E9** ultrasound system from General Electric. The examination protocol requires the subjects to lie supine with their right arm raised over their head. Through the inter-costal space, the right liver lobe is scanned and the Shear Waves elastography region of interest (ROI) is placed below the liver capsule, in a region free of vessels (if possible). Once a suitable image window is found, the subject is asked to suspend breathing and afterwards the Shear Waves acquisition is initiated. After approximately five seconds, during which usually 2 or 3 Shear Waves frames are acquired, the subject is asked to resume breathing. The acquisition process needs to be repeated until at least 10 Shear Waves frames are acquired. The measurements are than performed by placing a circular measurement region of interest over each saved Shear Waves elastographic image (Figs. **4**, **5**). The measurement regions are chosen to exclude obvious artifacts.

The average stiffness expressed in terms of Young's Modulus within each measurement region is automatically recorded by the system in a worksheet. The ten measurement regions are typically placed on different Shear Waves image frames or at non-overlapping locations on the same frame, so that ten independent measurements of liver stiffness are obtained for each subject. The system automatically calculates the median value and the interquartile range of the valid measurements [40].

*2D-ShearWaves Elastography (2D-SWE) Hepatic Elastography Using Ultrasound Waves* **99**

**Fig. (4).** Liver stiffness measurement by 2D SWE using Logiq E9 system in a mild hepatitis.

**Fig. (5).** Liver stiffness measurement by 2D SWE using the Logiq E9 system in a patient with cirrhosis.

### **100** *Hepatic Elastography Using Ultrasound Waves Popescu et al.*

**Main advantages and weaknesses of liver fibrosis evaluation by means of 2D-SWE.**

# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this publication.

# **ACKNOWLEDGEMENTS**

Alina Popescu received speaker fees from Philips.

Felix Bende has no conflict of interest to declare.

Ioan Sporea participated in an Advisory Board for Siemens and received speaker fees from Philips, Siemens and General Electric.

# **REFERENCES**

[1] Muller M, Gennisson J-L, Deffieux T, Tanter M, Fink M. Quantitative viscoelasticity mapping of human liver using supersonic shear imaging: preliminary *in vivo* feasibility study. Ultrasound Med Biol 2009; 35(2): 219-29. [http://dx.doi.org/10.1016/j.ultrasmedbio.2008.08.018] [PMID: 19081665]

[2] Sarvazyan AP, Rudenko OV, Swanson SD, Fowlkes JB, Emelianov SY. Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics. Ultrasound Med Biol 1998; 24(9): 1419- 35.

[http://dx.doi.org/10.1016/S0301-5629(98)00110-0] [PMID: 10385964]

*2D-ShearWaves Elastography (2D-SWE) Hepatic Elastography Using Ultrasound Waves* **101**

[http://dx.doi.org/10.11152/mu.2013.2066.153.ogt1is2] [PMID: 23979612]

[9] Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012; 56(6): 2125-33.

[http://dx.doi.org/10.1002/hep.25936] [PMID: 22767302]

[http://dx.doi.org/10.1016/j.ultrasmedbio.2011.05.016] [PMID: 21775051]

[12] Yoon JH, Lee JM, Woo HS, *et al.* Staging of hepatic fibrosis: comparison of magnetic resonance elastography and shear wave elastography in the same individuals. Korean J Radiol 2013; 14(2): 202- 12.

[http://dx.doi.org/10.3348/kjr.2<IP_ADDRESS>] [PMID: 23483022]

[13] Sporea I, Bota S, Jurchis A, *et al.* Acoustic radiation force impulse and supersonic shear imaging *versus* transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39(11): 1933- 41.

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[40] GE Healthcare LOGIQ E9 Shear Waves Elastography Whitepaper recommendations. Available at: http://www3.gehealthcare.com

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Real-Time Strain Elastography (HI-RTE)**

**Larisa Săndulescu<sup>1</sup> , Ioan Sporea<sup>2</sup>** and **Alina Popescu2,\***

*1 Department of Internal Medicine - Gastroenterology, Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy Craiova, 66, 1 Mai Bv, 200638 Craiova, Romania*

*2 Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania*

**Abstract:** Real-Time Strain Elastography performed by the Hitachi System (HI-RTE) uses a conventional ultrasound probe to compare and analyze echo signals before and under slight compression. Initially, HI-RTE offers only qualitative results. To overcome this limitation several quantitative methods in RTE have been developed, such as Elastic Ratio, Elastic Index, Elasticity Score and Liver Fibrosis Index (LFI). Despite being the first ultrasound-based elastography technique, HI-RTE has not yet yielded the desired results in the evaluation of liver fibrosis. This lack of performance is a consequence of inconsistency between the ultrasound-systems, methods and data analysis among different research teams. In the past few years, it seems that the technique has become more standardized and the elastographic assessment parameters are already established. The overall results of a meta-analysis suggested that LFI was excellent in diagnosing F≥3 and has moderate accuracy for F≥2 and F=4. However, LFI could not be applied to accurately differentiate F2 *versus* F0-1 and F=4 *versus* F0-3. HI-RTE is readily available with the ultrasound machine, is feasible in patients with ascites and inflammation and has promising results for non-invasive liver fibrosis evaluation in patients with chronic viral hepatitis and fatty liver diseases. In the future, a large, prospective, international multicenter study is essential to obtain a further evaluation of the potential diagnostic value of HI-RTE.

**Keywords:** Elasticity index, Liver stiffness, Real Time Elastography.

\* **Address correspondence to Alina Popescu:** Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania; Tel: +40 256 488003; Fax: +40 256 488003; E-mail<EMAIL_ADDRESS>
> **Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

As mentioned in the previous chapters, there is a current trend towards replacing liver biopsy with ultrasound-based elastography in the evaluation of liver fibrosis in chronic diffuse liver diseases. In all elastographic methods mechanical stress acted upon the liver induces a tissue displacement. Measuring tissue displacement offers an estimation of the elastic properties of the liver, which in turn allows a reliable assessment of liver fibrosis severity.

## **1. REAL-TIME STRAIN ELASTOGRAPHY TECHNIQUE**

Real-Time Strain Elastography (RTE) is an add-on module that can be incorporated, similar to acoustic radiation force impulse (ARFI) technology, in standard ultrasound devices; this represents an advantage when compared with transient elastography (TE), for example, where a new unit must be purchased. On the other hand, both Real-Time Elastography and ARFI use conventional ultrasound transducers for the examination, allowing a direct visualization of liver parenchyma while performing a liver stiffness (LS) evaluation. Thus, the examiner is able to avoid the liver capsule, to adjust the transducer's position, and thus to obtain the best acoustic window, even in difficult patients, such as overweight ones. The method is also reliable and reproducible in patients with ascites [1].

Real-Time Strain Elastography was performed for the first time with Hitachi systems (EUB-8500 and EUB-900) [2]. It uses a conventional ultrasound probe to compare and analyze echo signals before and under slight compression [3]. To perform free-hand HI-RTE, usually with the patient in supine position, the transducer is placed in the intercostal space and the examiner must apply stress by moving the transducer [4]. The examination is usually performed in the right liver lobe. The Hitachi Real-Time Elastography (HI-RTE) module uses an extended combined autocorrelation method to produce a real-time elasticity image, by using a freehand approach and compressing the tissues with the ultrasound transducer. The relative tissue elasticity is calculated and displayed as a color overlay on the conventional B-mode image. Stiffer structures are displayed in blue, while the more easily deformed tissues are displayed in red.

Initially, HI-RTE offered only qualitative results. To overcome this limitation

several quantitative methods in RTE have been developed, such as **Elastic Ratio, Elastic Index, Elasticity Score and Liver Fibrosis Index (LFI).**

Despite being the first ultrasound-based elastography technique, HI-RTE has not yet yielded the desired results in the evaluation of liver fibrosis. This lack of performance is a consequence of inconsistency between the ultrasound-systems, methods and data analysis among different research teams. In the past few years, though, along with the development of the new HI-RTE systems (HI VISION Avius, Preirus, Ascendus systems - Hitachi Medical Systems Europe Holding AG), it seems that the technique has become more standardized and the elastographic assessment parameters are already established. The examination is performed using a linear probe (3.5-7 MHz), positioned in the intercostal space, without compressing, seeing that the device already uses the internal pressure generated by the heart beats on the liver parenchyma. In this fashion, the sampling errors produced by the examiner compression are avoided. A well trained examiner with sufficient experience is needed in order to keep clear of any artifacts related to obesity, ROI setting, avoidance of large vessels and costal shades, as well as adjustment of the probe position in order to obtain a reliable image of the liver parenchyma, where compression/relaxation is homogeneous and axial to the probe.

# **1. Feasibility and Reproducibility**

Ultrasound examinations are operator-dependent techniques and different levels of training and experience could influence the results of the HI-RTE as well. A prospective study in which patients were examined by two doctors with different levels of experience in ultrasound obtained good intra- and inter-observer variability values [5]. The authors did not find significant differences between the two physicians, regardless of the patients' real status (cirrhosis, chronic hepatitis, steatosis, or healthy subjects). In a study published by Koizumi *et al.*, elastography was performed at four liver locations by two independent observers. The authors found no difference in reproducibility for the four measurement positions, while the interobserver agreement was very good (k=95%) [6].

# **2. Clinical Results**

# *a. Liver Stiffness Values in Healthy Volunteers*

Very little information is available to date. Hu *et al.* conducted a study in adults without liver disease, in order to investigate normal liver stiffness evaluated by RTE. The mean LFI in healthy participants with a normal BMI was 1.31 ± 0.25. The optimal LFI threshold value for discriminating normal liver from noncirrhotic chronic liver disease was 2.12 in participants with a normal BMI. The authors found no significant differences in the mean LFI between sexes or among different age groups, but only a positive correlation between BMI and the liver fibrosis index [7].

# *b. RTE for Liver Fibrosis Evaluation in Chronic Viral Hepatitis*

The first report [2] regarding chronic viral hepatitis evaluated by HI-RTE (Hitachi EUB-8500 and EUB-900) included 79 patients with chronic HCV or HBV hepatitis (all of them had had a liver biopsy), 20 patients with proven cirrhosis and a control group of 20 healthy volunteers. In those participants, the amount of displacement of the reflected ultrasound echoes before and under compression were measured (stress field). A strain field was then reconstructed from the measured displacements (strain image).

The calculation of tissue elasticity distribution was performed in real-time and the examination results were represented as color-coded images with a conventional B-mode image in the background. 10 valid measurements were performed. The investigators attempted to find a new elasticity score using a specially developed Matlab computer program.

This *German Elasticity Score* was generated as follows: numerical values were determined from 0 – 10, according to color mapping from blue (1) to red (0), followed by the calculation of mean, median, minimum, maximum, frequency of pixel values above 0.75 of a single measurement, and descriptive statistics of all measurements. The elasticity score was then calculated by the following formula, which was developed by stepwise multivariate logistic regression analysis:

**Elasticity score** = 177 + 50 × Log10 (Median [Freq(pixel 3 0.75)] –

13000 ×Min [Min (pixel with values above 0)]).

This elasticity score ranged from 65 to 122. The comparison of histological liver fibrosis with HI-RTE showed a good correlation; the increasing elasticity scores corresponded to increasing stages of fibrosis. Spearman's correlation coefficient between elasticity scores and histological fibrosis stages was highly significant, with a value of 0.48 (p<0.001). The accuracy was 0.75 for significant fibrosis (F≥2), 0.73 for severe fibrosis (F≥3) and 0.69 for cirrhosis (F=4). In this study, 80% of patients with significant fibrosis (F≥2) could be correctly identified with HI-RTE and the elasticity score was not influenced by the severity of liver steatosis.

Tatsumi *et al.* [8] performed HI-RTE in 119 patients with chronic liver disease, who had had a liver biopsy and compared the results with TE and serum fibrotic markers. Tissue elasticity was calculated using real-time tissue elastography, in which numerical values from 0–255 (256 stepwise grading) were determined according to color mapping from blue (0) to red (255). The percentage of blue areas in the ROI was then calculated. The authors elaborated the *Japanese Elasticity Score*: numerical values were determined from 0 – 255 according to color mapping from blue (0) to red (255), followed by the calculation of means ± SD in the "region of interest" (ROI), the percentage of blue area in the ROI, the complexity (length squared divided by blue area), skewness, as well as image features using a co-occurrence matrix: inverse difference moment, angular second moment (ASM), and entropy. In this study, HI-RTE showed a negative correlation with fibrotic stages and FibroScan® findings, suggesting that real-time tissue elastography is a better test than FibroScan® .

The group of Friedrich-Rust who published the first study using HI-RTE for the evaluation of liver fibrosis [2], performed a validation study of their own elasticity score and the elasticity score developed in Japan and compared the results of HI-RTE with TE [9]. They evaluated a cohort of 134 patients with histological evaluated chronic hepatitis (n=112) or proven liver cirrhosis (n=20) and showed that HI-RTE, in its present form, cannot replace TE for non-invasive assessment

# **110** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

of liver fibrosis.

In the study performed by Koizumi *et al.*, 70 patients with chronic HCV hepatitis were evaluated through HI-RTE, biological tests, liver biopsy and the Elastic Ratio [6]. The Elastic ratio was calculated (ratio of the value in the intrahepatic venous small vessels, divided by the value in the hepatic parenchyma) and compared with the histological stage of fibrosis on liver biopsy. HI-RTE cut-off values were: 2.73 for F ≥ 2; 3.25 for F ≥ 3 and 3.93 for F4. The AUROCs for elastic ratio (HI-RTE), hyaluronic acid, type IV collagen, aspartate aminotransferase-to-platelet ratio index, FibroIndex, Forns score and Hepascore were: 0.95, 0.32, 0.73, 0.76, 0.76, 0.87, and 0.70, respectively. In this study, the Elastic Ratio performed better than the serum fibrosis markers and the AUROCs for this method are promising (0.95).

Another study conducted by Hu *et al.* evaluated the utility of the Elastic Ratio for assessing liver fibrosis in ninety-six patients with chronic hepatitis B, compared with histological fibrosis stage on liver biopsy [10]. Using the optimal cut-off value of 2.62 for liver fibrosis S > 2; 3.20 for S >3; and 3.86 for S≥ 4, the corresponding area under the ROC curves were 0.91, 0.93, and 0.94, respectively. These findings are consistent with the study of Koizumi *et al.* in patients with chronic hepatitis C.

In the study of Tatsumi *et al.* that evaluated HI-RTE + Strain Histogram in 44 patients with chronic HCV infection as compared to liver biopsy and TE, HI-RTE was better at detecting the differences between milder stages of fibrosis: F1/F2, and F2/F3 as well [11]. On the other hand, Hi-RTE was more successful than FibroScan® in diagnosing the severity of fibrosis.

Gheonea *et al.* [5] performed a study on 97 patients diagnosed with chronic viral B and C hepatitis, liver cirrhosis, fatty alcoholic liver disease, as well as healthy volunteers. A Hitachi EUB 8500 ultrasound system was used, with an embedded elastography module (Hitachi Medical Systems Europe Holding AG, Zug, Switzerland) using a 6.5-MHz linear probe. Three 10 seconds long movie clips were captured in each patient by each of the 2 operators. Each recorded elastography movie was then evaluated by computer-enhanced dynamic analysis

using a public domain Java-based image processing tool (Image J) with a special plug-in, developed by the authors. The study showed a good inter-observer variability and there were no significant differences between the two physicians, regardless of the patients' real status.

The group of Fujimoto evaluated the effectiveness of HI-RTE for liver fibrosis assessment in a cohort of 310 patients with chronic C hepatopathies [12]. Nine image features were extracted from each RTE image and multiple regression analysis was performed to obtain an equation for the *Liver Fibrosis Index* (LF Index), which had 78.4% accuracy to discriminate between F0-1/F3-4 and 80.3% accuracy to discriminate between F0-3/F4.

Further improvements were developed in analyzing the elastographic images. Thus, in another Japanese study, the authors used for image evaluation a novel software developed by Hitachi Medical, Elasto ver. 1.5.1 [13]. They demonstrated the utility of Mean, SD, Area and Complexity as RTE parameters, speculating that Mean and Area may directly represent liver elasticity, while SD and Complexity may imply the collapse of the uniform architecture of liver parenchyma, concomitant with progressing hepatic fibrosis.

Another improvement in this technique was the development of the new HI VISION Preirus (Hitachi Medical Systems Europe Holding AG) system with embedded an elastography module. The probe (3.5-7MHz linear probe) is applied in an intercostal space without compression, with the patient lying supine. The strain graph displayed is used as a quality control of the procedure. The device automatically captures the internal compression transmitted to the liver parenchyma by the heart beats. Practically, this examination technique accredited in the last years includes several steps [14 - 16]:

### **112** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

spaces, between the anterior and middle axillary line, with the transducer towards the direction of heart, while the patient is holding his breath, with constant compression on the probe. The strain induced into the liver tissues is dependent on the heart beats.

The quantitative software elaborated by Hitachi provides many parameters from which two are the most important: Liver Fibrosis Index and mean strain histogram (mean of relative strain value within the ROI) (Fig. **2b**).

**D**

*)LJ contd.....*

#### *Real-Time Strain Elastography (HI-RTE) Hepatic Elastography Using Ultrasound Waves* **113**

**Fig. (1).** Examination technique of HI-RTE. ROI is placed 1 cm under the liver capsule in order to avoid artifacts generated by vessels (**a**), rib shadows (**b**), capsular proximity or remoteness (**c**).

The *new Hitachi Preirus system* was used by Colombo *et al.* in a study including 45 patients with chronic liver diseases and 27 normal subjects, in whom they compared transient elastography (TE), HI-RTE and ARFI for liver fibrosis diagnosis [17].

**114** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

**Fig. (2).** Examination technique of HI-RTE. The displayed image is induced by internal compression of the heart beats (**a**). Parameters recorded in HI-RTE were Liver Fibrosis Index and mean strain histogram (**b**).

Ten static images were analyzed using the Elasto vers. 1.5.1 software, provided by Hitachi. The pixel distribution was represented by a histogram, from which eleven parameters were derived and analyzed by the software. Four main functions (Z1–Z4) were calculated and included in an integrative function, from which the common elastic index of RT-E was calculated, according to the formula: I =

(5.174Z1 + 2.154Z2 + 1.366Z3 + 0.985Z4). Results were expressed as the mean elastic index of all measurements.

**D**

**E**

*)LJ contd.....*

#### **116** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

**Fig. (3).** HI-RTE images reflecting different stages of liver fibrosis in chronic viral hepatitis patients. From F1 to F4 fibrosis stage, color variation of the strain elastogram increases, from relatively low strain regions to a patched image pattern. F1 stage (**a**), F2 stage (**b**), F3 stage (**c**), F4 stage (**d**).

In this study, the performances of TE, HI-RTE and ARFI, expressed as AUROCs,

### *Real-Time Strain Elastography (HI-RTE) Hepatic Elastography Using Ultrasound Waves* **117**

for predicting various stages of fibrosis were as follows: for predicting any fibrosis: TE 0.878, RTE 0.834 and ARFI 0.807 (no significant difference between the three curves); for predicting significant fibrosis: TE 0.897, RTE 0.751 and ARFI 0.815 (TE better than RTE with p<0.01, no significant difference between TE and ARFI, nor between ARFI and RTE); for predicting cirrhosis: TE 0.922, RTE 0.852, ARFI 0.934 (no significant difference between the three curves). The authors also specified that RTE and ARFI were feasible in all patients, while TE was unsuccessful (no valid measurements) in 15% of patients. Figs. (**3a**, **b**, **c** and **d**) represent strain elastograms for F1, F2, F3 and F4 respectively.

In another study performed on the same system by Wang *et al.* in patients with HBV chronic hepatitis, the Spearman's correlation coefficient between the elasticity index and the histological fibrosis stage was 0.81, which is highly significant (p<0.001) [18]. The AUROCs indicating diagnostic accuracy were 0.93 for F≥F1 (p<0.001), 0.92 for F≥F2 (p<0.001), 0.84 for F≥F3 (p<0.05) and 0.66 for F=F4 (p>0.05), respectively. These data are surprising since the accuracy seems to decrease with fibrosis severity (contrary to other elastographic methods).

Seventy-four patients with chronic liver diseases who had undergone a liver biopsy were analyzed in a study performed with Hitachi HI-Visions Preirus system by Chung *et al.* [19]. Ten valid measurements were performed in each patient and the elasticity score was determined on a scale of 0 to 5. TE, ARFI and RTE showed good correlations with histological fibrotic stages. The optimal cutoff values for significant fibrosis (≥F2) were 7.5 kPa for TE (AUROC=0.727), 1.19 m/s for ARFI (AUROC=0.715) and 2.54 for RTE (AUROC=0.507) (p=0.0069, P=0.0277). The optimal cut-off values for cirrhosis were 8.6 kPa for TE (AUROC=0.786), 1.39 m/s for ARFI (AUROC=0.807) and 2.79 for RTE (AUROC=0.767). TE, ARFI and RTE for predicting cirrhosis did not show significant differences from each other, while TE and ARFI had a better predictive value than RTE for predicting significant fibrosis (≥F2).

**Liver Fibrosis Index** (LFI), one of the most important parameters provided by Hitachi HI VISION Preirus software, was analyzed in many studies based in Asia, where the real-time elastography system is widely spread and LB is still a reference method for liver fibrosis assessment. Thus, Kim *et al.* found good AUCs of LFI obtained by RTE: 0.683 and 0.744 for predicting advanced fibrosis (stage ≥ F3) and cirrhosis (stage F4), respectively, in a cohort of eighty-three patients with chronic hepatitis B or C [20]. The cut-off LFI value of >3.51 had 82.4% sensitivity and a 68.2% specificity for predicting cirrhosis (stage F4). In this study, RTE could discriminate between advanced fibrosis (F3) and cirrhosis (F4) more effectively than other serologic markers.

Fujimoto *et al.* studied 310 subjects with chronic hepatitis C and liver biopsy used as the gold standard [21]. In 15% of cases no valid measurements were obtained. LFI was calculated from image features of HI-RTE images, using multiple regression analysis performed on clinical data of 310 cases as the training data set. LFI highly correlated with fibrosis stages (r=0.68 with p<0.001). AUROC of LFI for F0-1 *vs.* F2-4 was 0.82. LFI seemed not to be correlated with inflammation in this study [21].

LFI was developed and validated initially in chronic hepatitis C patients. A large, multicenter study confirmed that LFI obtained through RTE is valuable for the diagnosis of hepatic fibrosis also in patients with chronic hepatitis B [22]. The AUROC of LFI for predicting significant fibrosis was 0.858, while for cirrhosis, it was 0.862.

Another study was conducted by Yada *et al.* on 245 patients with HCV and HBV chronic infection with liver biopsy used as the gold standard. The researchers used 9 parameters from the histogram and LFI. AUROC of LFI was 0.800 to discriminate between F0-1 *vs.* F2-4 and 0.846 between F0-3 *vs.* F4 [23].

Moreover, in 2014 the first *meta-analysis* regarding RTE was published, which included thirteen published studies [24]. The overall results suggested that LFI was excellent in diagnosing F≥3 and had moderate accuracy for F≥2 and F=4. However, LFI could not be applied to accurately differentiate F2 *versus* F0-1 and F=4 *versus* F0-3.

Another *meta-analysis* published by Kobayashi *et al.* in 2015 included 15 studies evaluating the diagnostic performance of RTE for staging liver fibrosis [25]. This meta-analysis demonstrated that RTE is not highly accurate for any cut-off stage of fibrosis; both summary sensitivity and specificity are roughly 0.80. Compared with findings of meta-analyses on TE and ARFI, the overall accuracy of RTE seems to be nearly identical for the diagnosis of significant fibrosis (F≥2), but less accurate for the diagnosis of cirrhosis (F≥4).

Recently, two studies made on the phantoms showed that the quantitative techniques are superior to qualitative visual scoring in order to assess target stiffness by RTE [26, 27].

# *c. RTE for Liver Fibrosis Evaluation in Patients with Non-alcoholic Fatty Liver Disease (NAFLD)*

Very little information is available to date. The group of Ochi evaluated the effectiveness of elastic ratio by RTE for liver fibrosis and portal hypertension assessment in a cohort of 187 patients with non-alcoholic liver disease [28]. Elastic ratio cut-off values by stage were: 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut-off values, the diagnostic accuracies for fibrosis diagnosis were: 82.6% (F0 *versus* F1-F4), 92.3% (F0-F1 *versus* F2-F4), 94.7% (F0-F2 *versus* F3-F4) and 96.0% (F0-F3 *versus* F4), respectively. RTE could also be a useful tool for evaluating portal hypertension, but only 8 patients with NAFLD also had portal hypertension in this study.

# *d. RTE for Predicting Liver Cirrhosis Complications*

Only one study was published regarding this topic to the best of our knowledge. Hirooka M *et al.* included 277 consecutive patients with chronic liver disease who underwent RTE of the spleen and correlated spleen elasticity and severity of portal hypertension with the hepatic venous pressure gradient (HVPG). The correlation between the two parameters was high (*R* = 0.855; 95% confidence interval: 0.767 - 0.911; *P*>0.0001) and the accuracy of diagnosing gastroesophageal varices was 90% when a cut-off value of 8.24 for splenic elasticity was used for predicting HVPG of more than 10 mm Hg [29].

Unlike other Ultrasound Societies, *The Japan Society of Ultrasonics in Medicine* (JSUM) state the importance of HI-RTE in the evaluation of liver fibrosis in the *JSUM ultrasound elastography practice guidelines*, published in 2013 [14]. In these guidelines, the authors believe that the liver fibrosis progression can be

### **120** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

easily observed visually or quantitatively by the use of the liver fibrosis index, elastic ratio, or strain ratio. In Japanese experts' opinion, HI-RTE accurately measures liver fibrosis with no regard to the adverse effects of ascites accumulation, inflammation, jaundice, and liver congestion.

*In conclusion*, RTE can find its applicability in the non-invasive assessment of liver fibrosis. RTE is readily available with the ultrasound machine, is easy to use, cost-effective and, moreover, painless. In the future, a large, prospective, international multi-center study is essential to achieve a further evaluation of the potential diagnostic value of HI-RTE.

**Main advantages and weaknesses of liver fibrosis evaluation by means of HI-RTE:**

# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this publication.

# **ACKNOWLEDGEMENTS**

Larisa Săndulescu has no conflict of interest to declare.

Ioan Sporea participated in an Advisory Board for Siemens and received speaker fees from Philips, Siemens and General Electric.

Alina Popescu received speaker fees from Philips.

## **REFERENCES**

[http://dx.doi.org/10.1016/j.crad.2013.10.003] [PMID: 24290780]

#### **122** *Hepatic Elastography Using Ultrasound Waves Săndulescu et al.*

[http://dx.doi.org/10.2957/kanzo.51.539]

meta-analysis. PLoS One 2014; 26: e115702.

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Combined Methods for Liver Fibrosis Evaluation**

#### **Ioan Sporea1,\*** and **Simona Bota<sup>2</sup>**

*1 Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timișoara, Romania*

*2 1st Medical Department, Klinikum Klagenfurt, Austria, 11, Feschnigstrasse, 9020 Klagenfurt am Wörthersee, Austria*

**Abstract:** Biological tests, elastographic methods alone or in combination can be used for the non-invasive evaluation of chronic liver diseases, in order to increase their value.

Combinations of non-invasive tests were searched for in order to improve the diagnostic performance of significant fibrosis (F≥2) and severe fibrosis/cirrhosis (F3–F4) the most promising being *TE and serologic tests*. In chronic hepatitis C a clinical management algorithm was proposed, using the combination of TE (FibroScan® ) and FibroTest as the first-line tests in the work-up strategy, thus avoiding liver biopsy in most patients (77%). In HBV inactive carriers, the combination of TE and FibroTest allowed the exclusion of significant fibrosis (F≥2) in nearly 80% of cases.

Another useful combination is of *two elastographic methods [TE and VTQ (ARFI)]*, which proved to be highly specific for predicting significant fibrosis (F≥2 Metavir). When both TE and VTQ (ARFI) values were higher than the proposed cut-offs, their combination had 93.3% Sp and 96.8% PPV for predicting F≥2, so that liver biopsy could be avoided in 60.5% of cases. For predicting cirrhosis (F4), the results were also very good, with 94.4% Sp, 94.4% NPV and 91.8% accuracy, so that the combination of TE and VTQ was able to confirm, and also to exclude the presence of liver cirrhosis.

**Keywords:** Combination methods, Elastography, Liver fibrosis, Serological tests.

\* **Address correspondence to Ioan Sporea:** Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timișoara, Romania; Tel: +40 256 488003; Fax: +40 256 488003; E-mail<EMAIL_ADDRESS>
> **Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

Since both serological tests and elastographic techniques are available for the non-invasive assessment of fibrosis severity in chronic liver diseases, many authors have tried to combine them to increase their diagnostic accuracy.

# **1. COMBINATION OF ELASTOGRAPHIC METHODS WITH SEROLOGICAL TESTS**

FibroTest (a serological test that combines six biologic parameters) has been proved to be an accurate test to predict the presence of significant fibrosis (F≥2) as well as of severe fibrosis/cirrhosis (F3–F4) [1 - 3]. If TE and FibroTest results agreed (70 - 80% of cases), there was also a great similarity with liver biopsy results: 84% concordance in patients with significant fibrosis (F≥2); 95% concordance in patients with severe fibrosis (F≥3); and 94% concordance in cirrhotics (F=4).

Castera *et al.* evaluated the accuracy of two algorithms using non-invasive tests to predict liver fibrosis severity using liver biopsy (LB) as the gold standard: one including TE and FibroTest and the other including APRI and FibroTest (SAFE biopsy) [2]. The combination of TE and FibroTest saved 23% more liver biopsies than SAFE biopsy for predicting F≥2 Metavir (71.9% *vs.* 48.3%, p<0.0001), but its accuracy was significantly lower (87.7% *vs.* 97.0%, p<0.0001). The situation was reversed for predicting liver cirrhosis, where the accuracy of TE + FibroScan was significantly better than of SAFE biopsy (95.7% *vs.* 88.7% p<0.0001), while the number of saved biopsies was similar (78.8% *vs.* 74.8%; p>0.05).

Cross *et al.* performed a study that evaluated by TE and King score 187 patients with chronic hepatitis C, with LB considered as the reference method (Ishak score was used for staging liver fibrosis) [4]. The AUROCs for TE, King score and the combination of King score and TE for the diagnosis of significant fibrosis (F≥3 Ishak) were 0.83, 0.82 and 0.85, respectively, while for the diagnosis of cirrhosis (F≥5 Ishak) they were 0.96, 0.89 and 0.93, respectively. NPVs higher than 90% were obtained for the diagnosis of cirrhosis for the following cut-off values: 10 kPa for TE (NPV 98%); 24.3 for King score (NPV 91%); and 26.1 for the two combined (NPV 94%).

The combination of TE with FibroTest showed promising results in chronic

hepatitis C patients [5, 6] and also in HBV inactive carriers, in whom it allowed exclusion of at least significant fibrosis (F≥2) in approximately 80% of cases [7].

A number of 212 patients with chronic hepatitis C were evaluated in our department by means of LB, TE and serological tests (APRI score, Lok score, Forns score, FIB-4 score, Fibrosis Index score, King score, Bonacini score) [8]. The strongest correlation with liver fibrosis severity was observed for TE (r=0.62), King score (r=0.57) and APRI score (r=0.56). By multiple regression analysis, the following formula was obtained:

**Prediction liver fibrosis score (PLF score)** = 0.956 + 0.084 x TE – 0.004 x King score + 0.124 x Forns score + 0.202 x APRI score

The AUROCs of PLF score for predicting F≥1, F≥2, F≥3 and F=4 were 0.76, 0.78, 0.86, and 0.97 respectively. The PLF score had a better predictive value than TE for F≥2 Metavir (AUROCs 0.78 *vs.* 0.74, p=0.02); also for F≥3 Metavir (AUROCs 0.86 *vs.* 0.81, p=0.003), while for diagnosing cirrhosis the performance was similar (AUROCs 0.97 *vs.*0.97, p=0.28).

Liu *et al.* evaluated 111 subjects (95 with chronic hepatitis B and 16 healthy volunteers), by means of VTQ (ARFI), TE and APRI score [9]. Strong correlations were observed between fibrosis stage and ARFI (r=0.85, p <0.001), between fibrosis stage and TE (r=0.81, p <0.001) while only a moderate correlation was found between fibrosis stage and APRI (r=0.63, p <0.001). An optimal linear combination (LC) of the three methods was developed, and its diagnostic performance was evaluated by a 10-fold cross-validation:

**LC**: For F≥2: ARFI + 0.034 TE – 0.084 APRI

For F4: ARFI + 0.044 TE – 0.135 APRI

The calculated accuracies of LC for significant fibrosis (≥F2 Metavir) and cirrhosis (F4) were 83.86% and 91.88%, respectively, better than those of VTQ (ARFI) (83.50% and 88.76%, respectively); of TE (75.27% and 87.61%, respectively); and also than those of APRI score (73.29% and 81.67%, respectively) [9].

Takaki *et al.* evaluated 176 patients with chronic hepatitis by means of liver biopsy, VTQ (ARFI) and simple serological tests [10]. In the training set (120 subjects), LS expressed as Shear Waves Velocity (SWV) assessed by VTQ (ARFI), the INR and ALT independently and significantly correlated with liver fibrosis severity. Based on this data *VIA* index score was calculated.

*VIA* **index** = - 1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT

In the training set, an AUROC of 0.838 was calculated for *VIA* index as a predictor of significant fibrosis (F≥2); 0.904 for prediction of severe fibrosis (F≥3) and 0.958 for prediction of cirrhosis (F4). In the validation set (56 subjects), the AUROCs were 0.917 for F≥2, 0.906 for F≥3 and 1.000 for F4, respectively.

# **2. COMBINATION OF ELASTOGRAPHIC METHODS**

In a study comprising 197 HCV patients, our group evaluated the *combination of TE and VTQ (ARFI)* [11]. This combination was highly specific for predicting significant fibrosis (F≥2 Metavir). If LS values obtained by both elastographic techniques were higher than the cut-off values of 6.7 kPa for TE and 1.2 m/s for VTQ (ARFI) (currently used for predicting F≥2), the combination had 93.3% Se and 96.8% PPV for F≥2, so that liver biopsy cold be avoided in those patients (60.5% of cases). Also, by combining the two elastographic methods for predicting cirrhosis (F4) (TE ≥12.2 kPa and VTQ (ARFI) ≥1.8 m/s), the results were very good, with 94.4% Sp, 94.4% NPV and 91.8% accuracy, so the combined methods are not only able to confirm, but also to exclude the presence of cirrhosis.

TE has been recommended in France - by the Hâute Autorité de Santé, as a first line method for liver fibrosis assessment in patients with chronic hepatitis C and no co-morbidities [12]. With regard to the other elastographic methods, such as VTQ (ARFI), studies have demonstrated its non-inferiority in comparison with TE [13, 14]. Probably, by combining different non-invasive methods for LS evaluation, the accuracy of those methods will improve.

# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this

**128** *Hepatic Elastography Using Ultrasound Waves Sporea and Bota*

publication.

# **ACKNOWLEDGEMENTS**

Simona Bota has no conflict of interest to declare.

Ioan Sporea participated in an Advisory Board for Siemens and received speaker fees from Philips, Siemens and General Electrics

# **REFERENCES**

[1] Poynard T, Munteanu M, Ngo Y, *et al.* Appropriate evidence-based overviews shown on the diagnosis and prognosis of performances in patients with chronic hepatitis fibroTest C. Aliment Pharmacol Ther 2009; 30: 1183-5.

[http://dx.doi.org/10.1111/j.1365-2036.2009.04115.x] [PMID: 19888919]

[http://dx.doi.org/10.1111/j.1365-2893.2009.01210.x] [PMID: 19874477]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 6**

# **Comparison of Elastographic Techniques**

#### **Ioan Sporea\*** and **Roxana Şirli**

*Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania*

**Abstract:** Several elastographic techniques for liver fibrosis assessment are available (on different machines) and practitioners are interested in comparing these techniques with regard to feasibility but also with regard to accuracy in staging fibrosis. Comparative studies including at least three methods are presented in this chapter. Regarding feasibility, the most feasible technique seems to be ElastPQ (approximately 99%), followed by VTQ (approximately 93%) and TE and 2D-SWE (approximately 87%). VTQ, ElastPQ and 2D-SWE had similar accuracies for diagnosing at least significant fibrosis (F≥2) and cirrhosis (F4) considering TE as the reference method.

**Keywords:** ARFI elastography, Comparative studies, Liver elastography, Transient elastography, 2D-SWE elastography.

At this moment, when many elastographic techniques for liver fibrosis assessment are available (on different machines), practitioners are interested in published data comparing these techniques not only with regard to feasibility but also with regard to accuracy when compared to liver biopsy. Not so many comparative studies have been published to date. We will present in this chapter studies comparing at least three elastographic techniques.

In a study performed in France, 349 consecutive patients with chronic liver diseases underwent liver biopsy and liver stiffness assessment by 2D-SWE (Aixplorer® - Supersonic Imagine), ARFI technology (VTQ - Siemens) and TE

**Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Address correspondence to Ioan Sporea:** Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania; Tel: +40 256 488003; Fax: +40 256 488003; E-mail<EMAIL_ADDRESS>
### *Comparison of Elastographic Techniques Hepatic Elastography Using Ultrasound Waves* **131**

(FibroScan® - Echosens® ) (M probe for patients with BMI < 30kg/m<sup>2</sup> and XL probe for patients with BMI > 30kg/m<sup>2</sup> ) [1]. AUROCs were calculated and compared for each stage of fibrosis. 2D-SWE, TE, and VTQ correlated significantly with histological fibrosis score (r=0.79, p<.00001; r=0.70, p<.00001; r=0.64, p<.00001, respectively). In this study, AUROCs of 2D-SWE, TE and VTQ were 0.89, 0.86, and 0.84 for mild fibrosis; 0.88, 0.84, and 0.81 for significant fibrosis (F*≥*2); 0.93, 0.87, and 0.89, for severe fibrosis (F*≥*3) and 0.93, 0.90, and 0.90 for the diagnosis of cirrhosis, respectively. 2D-SWE had a higher accuracy than FibroScan® for the diagnosis of severe fibrosis (*≥*F3) (p=0.0016), and a higher accuracy than VTQ for the diagnosis of significant fibrosis (*≥*F2) (p=0.0003). Finally, no significant differences were observed for the diagnosis of mild fibrosis and cirrhosis using the three elastographic methods.

For daily practice, feasibility of ultrasound based elastography is crucial, so as to be able to evaluate a vast majority of patients that enter an elastography laboratory. In a comparative study performed by our team [2] we aimed to compare the feasibility of four elastographic methods used for liver fibrosis evaluation (Transient Elastography - TE; point Shear Waves Elastography (pSWE) using ARFI technique - VTQ and ElastPQ techniques, respectively; and 2D-SWE).We included in our study 151 consecutive subjects with or without chronic hepatopathies (excluding patients with ascites), in which liver stiffness (LS) was evaluated in the same session by means of 4 elastographic methods: TE (FibroScan® , Echosens®®), VTQ (Siemens Acuson S2000TM), ElastPQ (Philips, Affinity) and 2D-SWE (Aixplorer® , SuperSonic Imagine S.A). Reliable LS measurements were defined as follows: for TE and VTQ – the median value of 10 LS measurements with a success rate ≥ 60% and an interquartile range < 30%, for 2D-SWE – the median value of 3 LS measurements acquired in an homogenous area and for ElastPQ - the median value of 10 LS measurements. For TE, M and XL probes were used. LS was expressed in kPa for TE, 2D-SWE, ElastPQ and in m/s for VTQ. All elastographic measurements were performed by experienced operators. In this study, reliable LS measurements were obtained in a significantly higher proportion of patients by means of ElastPQ as compared with TE, 2D-SWE and VTQ: 99.3% *vs.* 87.4% (p<0.0001), 99.3% *vs.* 87.4% (p<0.0001) and 99.3% *vs.* 92.7% (p=0.08). TE and 2D-SWE had similar rates of reliable LS

### **132** *Hepatic Elastography Using Ultrasound Waves Sporea and Şirli*

measurements 87.4% *vs.* 87.4% (p=0.86). Reliable LS measurements by all four shear waves ultrasound elastographic methods were obtained only in 72.2% (109/151) subjects. For TE and VTQ we used technical quality criteria (IQR and SR), but for the other two methods (ElastPQ and 2D-SWE) no quality criteria were used since none were published.

In another comparative study performed by our group [3] we compared the performances of point Shear Waves Elastography using ARFI technique (VTQ and ElastPQ, respectively) and 2D-SWE (SuperSonic Shear Imaging) considering Transient Elastography (TE) as the reference method. We included in this study 151 consecutive subjects (with or without chronic hepatopathies, none with ascites), who were evaluated in the same session by means of 4 elastographic methods: TE (FibroScan® , Echosens®®), VTQ (Siemens, Acuson S2000TM), ElastPQ (Philips, Affinity) and 2D-SWE (Aixplorer® , SuperSonic Imagine S.A). For differentiating between stages of liver fibrosis we used the following cut-off values: for TE - significant fibrosis (F≥2) – 7.2 kPa and for liver cirrhosis (F4) - 14.5kPa [4]; for VTQ: F≥2 – 1.35m/s, F4=1.84m/s [5]; for 2D-SWE: F≥2 – 7.1 kPa, and F4=13.5 kPa (HCV,NAFLD) and 11.5 kPa in HBV [6]; and for ElastPQ F≥2-5.9 kPa, F4=12kPa [7]. In this study, considering TE as the reference method, the diagnostic accuracy of VTQ, 2D-SWE and ElastPQ for the diagnosis of absence or mild fibrosis (F<2) was similar: VTQ *vs.* 2D-SWE (86.2% *vs.* 82.5% p=0.57); VTQ *vs.* ElastPQ (86.2% *vs.* 84.4% p=0.85), 2D-SWE *vs.* ElastPQ (82.5% vs. 84.4% p=0.84). For significant fibrosis (F≥2) the values obtained were: VTQ vs. 2D-SWE (84% vs. 76.1% p=0.19); VTQ vs. ElastPQ (84% vs. 80.7% p=0.64), 2D-SWE vs. ElastPQ (76.1% vs. 80.7% p=0.50). For diagnosing cirrhosis we also obtained similar diagnostic accuracies: VTQ *vs.* 2D-SWE (96.3% *vs.* 93.6% p=0.54); VTQ *vs.* ElastPQ (96.3% *vs.* 94.5% p=0.75), 2D-SWE *vs.* ElastPQ (93.6% *vs.* 94.5% p=0.99). In this study, similar to previously published papers, the accuracy of elastographic methods increased with the severity of fibrosis, producing the best results in patients with liver cirrhosis. Finally, the conclusion of this study was VTQ, ElastPQ and 2D-SWE had similar accuracies for diagnosing at least significant fibrosis (F≥2) and cirrhosis (F4).

In another comparative study performed by our group [8] we aimed to compare

#### *Comparison of Elastographic Techniques Hepatic Elastography Using Ultrasound Waves* **133**

the performance of several ultrasound elastographic techniques and FibroTest in diagnosing compensated HCV liver cirrhosis (LC). At this moment, expensive treatments for HCV patients are prioritized considering the severity of fibrosis, and patients with compensated LC are the first to be treated. In this prospective study which included 40 consecutive patients diagnosed with LC by means of liver biopsy, TE (LS > 12.5 kPa [9]) or by clinical, biologic, ultrasonography and endoscopic criteria, all were evaluated with five elastographic techniques in the same session, while FibroTest was performed within a month of the elastographic methods. LS as a marker for fibrosis was assessed by: TE - FibroScan® , Echosens®®; by Point shear Waves elastography techniques: VTQ - Acuson S2000, Siemens and by ElastPQ technique - Affinity, Philips; and by 2D-SWE - Aixplorer® , Supersonic Imagine (SSI) and with the LogiqE9, General Electric (2D-SWE GE) system. In each patient we performed 10 valid measurements (VM) for TE, VTQ, ElastPQ and 2D-SWE.GE, and 3 valid measurements for SSI. For each elastographic technique the median value of VM was calculated. The following published cut-offs were used to diagnose cirrhosis: TE-12.5 kPa [9]; VTQ-1.81 m/s [5]; ElastPQ-12 kPa [7]; SSI-13.5 kPa [6]; 2D-SWE.GE-11.9 kPa [10]. In this study we compared the proportion of correctly classified patients by all non-invasive tests. In all patients, we obtained VM by all five elastographic methods. Subjects were correctly classified by: TE in 97% of cases, VTQ-97%, ElastPQ-82%, SSI-90%, 2D-SWE.GE-90% and FibroTest-85%. There were no significant differences between FibroTest - TE (85% *vs.* 97%, p=0.13), FibroTest - VTQ (85% *vs.* 97%, p=0.13), FibroTest - ElastPQ (85% *vs.* 82%, p=0.95), FibroTest - SSI (85% *vs.* 90%, p=0.73), FibroTest - 2D-SWE.GE (85% *vs.* 90%, p=0.73) respectively. The conclusion of this study was that all ultrasound based elastographic methods performed well for the diagnosis of compensated liver cirrhosis and thus can be used in daily practice.

All the studies presented in this chapter show the necessity of head to head comparison of different ultrasound based elastographic method for daily practice. For practitioners, a question has arisen: should one or more elastographic methods be used in daily practice [11]. And our answer is that many elastographic methods have proved their value for liver fibrosis assessment and very soon will be validated for daily practice.

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# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this publication.

# **ACKNOWLEDGEMENTS**

Ioan Sporea participated in an Advisory Board for Siemens and received speaker fees from Philips, Siemens and General Electric.

Roxana Șirli received speaker fees from Philips.

# **REFERENCES**

[1] Cassinotto C, Lapuyade B, Mouries A, *et al.* Non-invasive assessment of liver fibrosis with impulse elastography: comparison of supersonic shear imaging with ARFI and fibroScan® . J Hepatol 2014; 61(3): 550-7.

[http://dx.doi.org/10.1016/j.jhep.2014.04.044] [PMID: 24815876]

*Comparison of Elastographic Techniques Hepatic Elastography Using Ultrasound Waves* **135**

APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128(2): 343-50.

[http://dx.doi.org/10.1053/j.gastro.2004.11.018] [PMID: 15685546]

[http://dx.doi.org/10.11152/mu.2013.2066.172.isp1] [PMID: 26052561]

© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Elastography in Focal Liver Lesions**

#### **Mirela Dănilă\*** and **Ana Jurchiş**

*Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania*

**Abstract:** The accurate characterization and the differential diagnosis between different types of focal liver lesions (FLL) are important aims that all imaging modalities available today should satisfy. Elastographic methods aim to exploit the elasticity differences between FLL and liver parenchyma in order to make the differential diagnosis between malignant and benign lesions. Currently, three elastographic methods have been evaluated and showed their applicability in this area: Acoustic Radiation Force Impulse (ARFI) Elastography, Real-time Elastography (RT-E) and Shear Waves Elastography (SWE). Many studies have shown that using one of the elastographic methods, for a chosen cut-off, the differentiation between malignant and benign nodules is possible. Other studies demonstrated that elastographic techniques are helpful to detect recurring hepatocellular carcinomas (HCCs), or to evaluate HCC or liver metastases after local or systemic treatment.

**Keywords:** Benign or malignant, Elastography, Focal liver lesions.

A focal liver lesion (FLL) refers to an area of damaged tissue identified into the hepatic tissue, with varying significance, depending on the patient's health condition and a variety of other factors. The differential diagnosis of a FLL can be narrowed down by several factors, including age, gender, use of birth control pills or hormone medications, travel history and the presence of cirrhosis, hepatitis or other chronic liver diseases. In many cases, FLLs are detected incidentally, during a routine abdominal ultrasound examination.

**Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**

<sup>\*</sup> **Address correspondence to Mirela Dănilă:** Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania; Tel: +40 256 488003; Fax: +40 256 488003; E-mail<EMAIL_ADDRESS>
# FLLs are classified as *benign* or *malignant*.

*Benign* (noncancerous) FLLs can be *solid* or *cystic* (meaning that the lesions are fluid filled). Within these types, the subtypes include hemangiomas (the most common), focal nodular hyperplasia (FNH), hepatic adenoma, focal fatty changes, and hydatid cysts and bile duct cysts.

*Malignant* liver tumors can be *primary* liver cancers or *secondary* liver lesions (metastases).

The most common *primary* malignant liver tumor is hepatocellular carcinoma (HCC) and the second most common type of liver malignancy is cholangiocarcinoma. Other rare liver cancers are: angiosarcomas and hepatoblastomas.

The liver is one of the most often affected organs in advanced cancers and most types of malignant tumors may spread into the liver in the late stages. The most common *secondary* liver tumor is colon cancer metastasis, but other cancers (such as pancreatic, gastric, thyroid, skin and kidney cancer) often spread into the liver.

The accurate characterization and the differential diagnosis between different types of FLLs are important aims, that all imaging modalities available today should satisfy [1].

**Conventional ultrasonography** (US) is often the first imaging modality performed to screen for, or to study hepatic lesions because of its low cost and wide availability. Color-Doppler, Tissue Harmonic Imaging and more recently, microbubble contrast agents (Contrast Enhanced Ultrasound-CEUS), have significantly improved the characterization of solid FLL. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are second line imaging methods able to accurately characterize previously detected lesions, but they are more expensive and less available. Contrast enhanced imaging modalities, such as contrast-enhanced US, contrast enhanced-CT and contrast-MRI, assess lesion morphology and vascularization, with a high diagnostic accuracy owing to their specific features, well described in the literature. Nevertheless, invasive studies are sometimes required to make a definite diagnosis [1].

Neoplastic and inflammatory diseases can change the tissue's

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composition/structure, and thus parenchyma stiffness of an organ. Elastography aims to assess these elasticity differences in order to be able to identify malignant transformation [2].

Many elastographic methods have tried to assess liver tumors' stiffness.

# **1. POINT SWE USING ACOUSTIC RADIATION FORCE IMPULSE (ARFI) TECHNOLOGY**

Point SWE using Acoustic Radiation Force Impulse (ARFI) technology is an elastomeric technique incorporated into a conventional ultrasound (US) system, which permits real-time non-invasive quantification of tissue elasticity during US B-mode examination.

In order to evaluate such a lesion by VTQ (ARFI) technology, the FLL has to be visualized in abdominal US. After that the measurement box is placed in the lesion (Fig. **1**) and VTQ (ARFI) measurements are performed (median value of 10 acquisitions expressed in m/s). VTQ (ARFI) measurements should also be performed in the surrounding tissue.

**Fig. (1).** VTQ (ARFI) measurement in hemangioma.

# **a. VTQ (ARFI) in Benign FLL**

*Hemangiomas* are the most frequent benign FLLs. Imaging methods are very sensitive in the diagnosis of hemangiomas, starting with standard US, followed by CEUS, CE-CT or CE-MRI. In VTQ (ARFI) evaluation, a high variability of Virtual Touch Quantification (VTQ) values was observed for this type of lesion: **2.30 m/s**-Gallotti *et al.* [1], **1.30 m/s**-Zhang *et al.* [3], **1.83 m/s-**Park *et al.* [4]. Its stiffness depends on the amount of fibrotic septa which divide the dilated vascular spaces.

*Focal Nodular Hyperplasias (FNH)* was reported to be *the stiffest* lesions after metastases and cholangiocarcinomas, regardless of their dimensions and of the presence or absence of central scar (due to the presence of fibrotic content) (Fig. **2**).

**Fig. (2).** VTQ (ARFI) measurement in Focal Nodular Hyperplasia.

*Adenomas* showed similar VTQ values to those observed in the surrounding liver (mean VTQ value of the lesion 1.25 m/s; mean VTQ value of the surrounding

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parenchyma 1.40 m/s) [1].

In a multicenter prospective study performed by Gallotti *et al.*, 40 lesions were evaluated and a total of 400 measurements were obtained [1]. The lesions were: 6 HCCs (15%), 7 hemangiomas (17.5%), 5 adenomas (12.5%), 9 metastases (22.5%) and 13 focal nodular hyperplasias (32.5%). A significant difference (p<0.05) was found by comparing tissue stiffness in adenomas *vs.* other lesions. Their conclusion was that VTQ (ARFI) could provide significant information regarding tissue stiffness, useful for FLL differential diagnosis.

# **b. VTQ (ARFI) in Malignant FLL**

Almost all *HCCs* evaluated *appeared as softer lesions* compared to the surrounding cirrhotic liver [1, 5] (mean VTQ value 2.17 m/s *vs.* 2.99 m/s respectively) (Fig. **3**).

**Fig. (3).** VTQ (ARFI) measurement in HCC.

All *metastatic lesions* (Fig. **4**) *and cholangiocarcinomas were stiffer* than the surrounding liver: mean VTQ value of the lesion 2.87 m/s; mean VTQ value of the surrounding parenchyma 1.63 m/s) [1].

**Fig. (4).** VTQ (ARFI) measurement in liver metastasis.

Cho at all showed that in 72% of cases metastatic lesions and cholangiocarcinomas were stiffer than the surrounding liver [6]. In the same study which included 51 patients with 60 FLLs (17 hemangiomas, 25 HCCs, 15 metastases and three cholangiocarcinomas) a cut-off value of 2 m/s was obtained for malignancy, with an 89% positive predictive value and 81% specificity. Images obtained with VTQ (ARFI) elastography helped in tumor characterization regarding the stiffness and margins of liver tumors. By measuring shear Waves velocity it was possible to differentiate malignant hepatic tumors from hepatic hemangiomas.

Our group [7] evaluated 59 FLL: 40 HCCs, 10 liver metastases, 7 hemangiomas, 1 adenoma and 1 focal fatty lesion. Tumor stiffness (TS) was significantly lower in

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HCCs than in the surrounding liver parenchyma (2.26±0.98m/s *vs.* 2.71±0.68m/s, p=0.01), but significantly higher in metastases (Fig. **2**) than in the liver parenchyma (2.82±1.11m/s *vs.* 1.69±0.64m/s, p=0.01). TS was significantly higher in metastases than in hemangiomas (2.82±1.11m/s *vs.* 1.47±0.67m/s, p=0.01) and in HCCs *vs.* hemangiomas (2.26±0.98m/s *vs.* 1.47±0.67m/s, p=0.04), but not significantly different in HCCs *vs.* metastases (2.26±0.98m/s *vs.* 2.82±1.11m/s, p=0.12). Using VTQ for ARFI measurements we found significant differences between the surrounding liver parenchyma and malignant FLLs, but this method cannot distinguish malignant from benign FLL.

Shuang-Ming *et al.* demonstrated in a study on 116 consecutive patients with 128 liver lesions (60 benign, 68 malignant) that VTQ (ARFI) can differentiate benign and malignant liver lesions [8]. For a cut-off value of 2.22 m/sec, 89.7% sensitivity, 95% specificity and 92.2% accuracy were observed for the diagnosis of malignancy.

Yu *et al.* evaluated by VTQ (ARFI) 89 patients with 105 FLL (28 HCCs, 13 metastasis, 35 hemangiomas, 15 focal nodular hyperplasias, 8 focal fatty sparing, 4 focal fatty deposits and 2 adenomas [9]. VTQ (ARFI) values showed significant differences between benign (1.73 ± 0.8 m/s) and malignant FLL (2.57 ±1.01 m/s) (P<0.001). For differentiation of malignant from benign nodules, TS measurements had 68% sensitivity, 69% specificity, 58% positive predictive value and 77% negative predictive value, if 1.9 m/s was chosen as a cutoff value. If the cut off chosen value was 2.72 m/s the sensitivity, specificity, positive predictive value and negative predictive value were 69%, 89%, 56%, and 93%, respectively.

Kapoor *et al.* performed a study designed to evaluate the role of VTQ (ARFI) in differentiating metastatic from non-metastatic liver nodules [10]. The study comprised 48 patients with liver nodules. Nodule stiffness was determined by real-time elastography (ES) using color maps and shear Waves velocity (SWV) (ARFI measurements). Nodules with marked stiffness or SWV higher than 2.5 m/s were diagnosed as metastatic. Fine needle aspiration cytology was used for the final diagnosis. There were no significant differences seen on elasto-maps in the stiffness of metastatic and non metastatic nodules (p=0.16), while SWV showed significant differences in the strain velocities of benign, metastatic and

hepatocellular carcinoma nodules p <0.0001 and p <0.008 respectively. If a cut off value of 2.5 m/s was chosen for SWV, the sensitivity, specificity and false positive to detect metastatic nodules by ES were 88%, 83% and 16%, respectively. When the SWV cut off value was set at 2.0 m/s, the sensitivity, specificity and false positive were 94%, 70% and 29%, respectively. The study showed that SWV was a useful tool in diagnosing both solid and necrotic metastatic liver nodules as compared with the color stiffness maps alone.

# **c. VTQ (ARFI) Ratio**

VTQ (ARFI) Ratio the ratio between the median VTQ (ARFI) value in the liver and in the lesion seems to be more accurate in the evaluation of FLL. Lu *et al.* demonstrated that *diagnostic performance with stiffness values was significantly lower than that with stiffness ratio for discrimination of metastasis from primary liver cancers* [11].

VTQ (ARFI) seems to be a useful method in the following scenarios:

Further studies are required in order to find the correct place of VTQ (ARFI) elastography in everyday clinical practice.

# **2. REAL-TIME ELASTOGRAPHY (RTE)**

Real-time Elastography (RTE) has proven its utility in differentiating between benign and malignant pancreatic lesions and lymph nodes [13 - 15]. It was also proved to be useful in differentiating solid tumors located in the wall or nearby the gastrointestinal tract which can be also visualized and characterized by endoscopic ultrasound elastography [15]. There are several studies showing the usefulness of RTE in FLL characterization.

Gheorghe *et al.* performed a study in which it was demonstrated that US elastography is a promising method for the non-invasive diagnosis of early HCC

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[16]. The study included 42 cirrhotic patients with 58 nodules (1-3 cm) which were evaluated by means of real-time elastography (Hitachi EUB-6500) - the mean colors intensity (red, blue, green) were measured using a semi-quantitative method. Histograms analysis for each color was performed in order to quantify the nodule elasticity as compared with the surrounding cirrhotic liver tissue. Mean intensity of blue color proved to be a good diagnostic tool for HCC (AUROC=0.94); for a cut-off value>128.9, 92.2% sensitivity, 78.9% specificity, 95.4% PPV and 68% NPV were observed.

Kato *et al.* studied the intra-operative application of RTE for the diagnosis of liver tumors [17]. Fifty-five liver tumors in 44 patients were examined with RT-E, concomitantly with routine intra-operative ultrasonography. Elasticity images were classified into four types: type A (even strain) to type D (no strain), according to the distribution and the strain level contrasted with that of the surrounding liver (*elasticity type of liver tumor* (ETLT)). Twenty-one of 22 HCCs were classified as type B (with a sensitivity of 95.5%, a specificity of 90.9% and an accuracy of 92.7%), while all 24 metastatic adenocarcinomas were classified as either type C or type D (with a sensitivity of 100%, a specificity of 80.6% and an accuracy of 89.1%). Using a new criterion, ETLT, RTE was able to distinguish rather accurately between HCC and metastatic adenocarcinoma.

Fukuda *et al.* showed that common liver tumors had their own strain patterns which could help to make a differential diagnosis [18]. The study included 47 liver tumors (14 HCCs, 12 metastatic liver tumors and 21 hemangiomas). The strain images obtained by RTE were classified into five groups in contrast to the surrounding liver: category 1 (even strain pattern), category 2 (less strain area in the tumor <50%), category 3 (less strain area = about 50%), category 4 (50% <less strain area <90%) and category 5 (less strain area >90%). Of 14 HCCs, 12 were category 4. Of 12 metastatic liver tumors, 11 were category 4 or 5. Of 21 hemangiomas, 17 were category 1 or 2. RT-E revealed that HCC or metastatic liver tumors had less strain than the surrounding liver; in contrast, most hemangiomas did not.

Inoue Y studied the usefulness of RTE for the intra-operative characterization of small FLL [19]. In this study, 27 adenocarcinomas, 18 HCCs and 11 benign

lesions were included. Elasticity images were also classified into 4 types, from type A (more, or comparable strain relative to the background) to type D (no strain). Fourteen of the 18 HCCs were type B or C (with 83% sensitivity, 76% specificity and 61% accuracy), while 22 of the 26 adenocarcinomas were type D (with 85% sensitivity, 86% specificity, and 86% accuracy). For 15 lesions, clear images in B-mode intra-operative US (IOUS) were difficult to obtain, whereas RTE clearly visualized the elasticity differences. His conclusion was that the new RTE system serves as a supportive modality for B-mode IOUS.

*Strain Elastography in the Evaluation of FLL*: the strain index value (strain ratio of liver parenchyma *vs.* focal lesions) of each lesion was calculated. Mean strain index values of benign and malignant liver lesions were compared. The mean strain index value of malignant liver lesions ± SD (2.82 ± 1.82) was significantly higher than that of benign liver lesions (1.45 ± 1.28; P< .0001). Hemangiomas had a significantly lower mean strain index value than other benign lesions (P < .00 34). There was *no significant difference between strain index values of different types of malignant lesions* (P > .05) [23].

# **3. 2D-SHEAR WAVES ELASTOGRAPHY (2D-SWE)**

2D-Shear Waves Elastography (2D-SWE) is another new elastographic technique used in FLL characterization.

In the study of Guibal *et al.* [20] whose purpose was to describe elastic map characteristics for FLLs assessed by 2D-Shear Waves Elastography (2D-SWE), 106 hepatic lesions in 85 patients were included (41 benign and 65 malignant): 17 hemangiomas (Fig. **5**), 14 focal nodular hyperplasias (FNHs), 10 adenomas, 16 HCCs including 2 HCCs in normal liver, 43 metastases (Fig. **6**), 6 cholangiocarcinomas. Tumor heterogeneity was assessed on elasticity 2D maps and tumor and parenchyma elasticity values were also quantified. Significant differences in stiffness were observed in:

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**Fig. (5).** 2D-SWE measurement in a hemangioma.

**Fig. (6).** 2D-SWE measurement in a liver metastasis.

Parenchyma elasticity values were 7.7 kPa in normal liver and 28.5 kPa in cirrhotic liver (p<0.001). On 2D elasticity maps, FNH had high central elasticity values.

Ronot *et al.* evaluated 73 patients with 105 FLLs and observed no significant differences in stiffness between benign *vs.* malignant FLLs (p=0.64); FNHs were significantly stiffer than adenomas (p=0.014) [21].

Also, the study of Brunel *et al.* [22] showed the usefulness of shear Waves elastography (2D-SWE) during ultrasound for differentiating between focal nodular hyperplasias (FNHs) and hepatic adenomas (HAs).

In conclusion SWE can provide additional information regarding FLLs.

# **4. ELASTOGRAPHIC METHODS USED FOR THE EVALUATION OF LIVER TUMORS TREATMENT EFFICIENCY**

Many studies have demonstrated that for small HCCs, treatment efficacy of radio frequency ablation (RFA) is comparable to that of surgical resection [24 - 26]. MR and CT are considered 'gold standard' methods for post-therapy assessment of nodule viability and procedure's success [27, 28]. Contrast-enhanced US can be also an alternative for follow-up assessment of RFA procedures [29 - 31].

Fahey *et al.* suggested that Virtual Touch Imaging (VTI) by ARFI can be useful in RFA therapy [32]. US in combination with VTI (ARFI) imaging may be useful during several stages of RFA procedures since boundary definition is improved in VTI. Comparison of pre- and post-treatment VTI may provide information regarding the success of RFA. Large displacement contrast was observed in VTI of both pre-ablation malignancies (mean 7.5 dB, range 5.7 –11.9 dB) and postablation thermal lesions (mean 6.2 dB, range 5.1 – 7.5 dB) in the Fahey study.

Kwon *et al.* demonstrated that the VTI technique is helpful in detecting more easily recurred HCCs in patients with liver cirrhosis [33]. The study included 38 patients with HCC including recurred HCCs after RFA. They all had undergone VTI elastography. The tumor brightness was assessed and the shear Waves velocity was measured for stiffness quantification. According to the brightness, the tumors were classified as brighter, the same color or darker as compared with

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the surrounding parenchyma. Using the same methods, 8 patients with recurred HCCs after RFA were evaluated regarding the brightness as compared with adjacent RFA ablation area. From the 38 patients with HCCs, in 20 (52.6%) cases the HCCs were brighter than surrounding cirrhotic parenchyma. Another 13 (34.2%) were darker. The others (5 cases, 13.2%) were seen as the same color as the adjacent liver parenchyma. Post-RFA lesions were darker than the previous tumor and the surrounding parenchyma in all 38 cases. However, recurring HCCs were brighter than the treated site in all 8 cases.

The study of Xiaohong Xu *et al.* explored VTI elastography in assessing residual tumors after radiofrequency ablation (RFA) in 83 HCC lesions [34]. All patients were examined with VTI, contrast enhanced ultrasound (CEUS), and CT or MRI. For all lesions virtual touch tissue imaging (VTI) and shear Waves velocity (SWV) were assessed before and at one month after RFA procedure. After RFA there were 14 lesions with residual tumors detected by CT or MRI, but VTI was not able to detect residual tumors in these cases. This study concluded that VTI technique cannot demonstrate residual tumor post RFA and also that VTQ (ARFI) elastography cannot replace imaging methods with contrast (CEUS, CT or MRI) in assessing response to ablation therapy.

In a study performed by Leen *et al.*, 22 patients with colorectal liver metastases undergoing radiofrequency ablation (RFA), were evaluated by 2D-SWE, using the Aixplorer® ultrasound system [35]. The lesions' elasticity (kPa) was quantified using the on-board quantification software, following placement of regions of interest over the whole lesion before, during and immediately after RFA. The size of the ablation zone was measured using the parametric image of the RFA zone. The reference method used was CEUS, performed before and after each RFA, to assess the size of lesions and of the ablation zones. There was a significant increase in the elasticity of the ablated zone as compared with the pre-RFA tumor measurements (21.5±5.8 *vs.* 4.6±2.7; p<0.0001). The elasticity was maximal towards the end of the ablation procedure.

The size (cm) of the ablated zone based on both CEUS and 2D-SWE (4.5±0.75 & 4.9±0.80) was significantly increased as compared with that of the pre-RFA (3.1±1.0) (p<000.1), without a significant difference in the size of the ablation zones as determined with either 2D-SWE or CEUS. Using the parametric imaging of 2D-SWE, the margins of the RFA zones matched those obtained by using CEUS in all cases.

In another study performed by Leen *et al.*, whose aim was to assess the value of 2D-SWE in monitoring the effects of systemic treatment in liver tumors, 22 healthy volunteers, 30 colorectal cancer subjects with liver metastases (mCRC) (16 pre treatment and 14 post 6 cycles of systemic chemotherapy) were evaluated with 2D-SWE, using an Aixplorer® ultrasound scanner [36]. In all cases the elasticity (kPa) of the liver parenchyma was quantified using the on-board quantification software, following placement of fixed size regions of interest (ROI) over the right lobe of the liver. The metastases' elasticity was also quantified following placement of ROI over the whole lesion. Using B-mode scanning, the liver parenchyma was classified into normal, fatty change or cirrhotic, using a scoring system. Eleven of the 14 subjects who had been treated had B-mode evidence of liver steatosis. The elasticity of those with mCRC and fatty changes was significantly elevated as compared to that of the normal liver parenchyma for the volunteers (12.6±3.7 *vs.* 7.7±3.6; p=0.0025). The elasticity values of tumors which had been treated were also significantly higher as compared with those of untreated metastases (50.7±21.6 *vs.* 4.7±2.8; p=0.0001). This data suggest that 2D-SWE can be used to assess the effects of systemic chemotherapy on liver parenchyma and on treated metastases.

2D-SWE permits the real-time detection of coagulation necrosis produced by radiofrequency and could potentially be used to monitor US-guided thermal ablation [37].

Selective internal radiation therapy (SIRT) is a loco regional radio-embolism technique that is used for the treatment of unresectable liver metastases and as a treatment option for extensive liver metastases that are refractory to first and second line chemotherapies [38].

Recent papers evaluated the tissue stiffness changes measured by 2D-SWE in patients receiving SIRT for hepatic malignancy. In this study tumor stiffness increased throughout the study period and this increase is assumed to be due to

**150** *Hepatic Elastography Using Ultrasound Waves Dănilă and Jurchiş*

fibrosis as a part of tissue healing process [39].

2D-SWE can also be useful in the evaluation of anti-angiogenic therapy for hepatic malignancy [40].

Despite the fact that FLL elastography is at the beginning of its clinical use, these preliminary results seem to show some usefulness for the differential diagnosis of these kinds of lesions. Regarding which elastographic method is better, we shall find out in the future. Ultrasound based elastographic methods have the advantage of being incorporated into an ultrasound machine and thus, that they can be performed immediately after basic liver evaluation with ultrasound waves. Concerning the clinical use of ultrasound based elastography for FLL, this method seems not to be ready yet for daily medical activity, but only for research.

# **CONFLICT OF INTEREST**

The authors confirm that they have no conflict of interest to declare for this publication.

# **ACKNOWLEDGEMENTS**

Declared none.

# **REFERENCES**

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[17] Kato K, Sugimoto H, Kanazumi N, Nomoto S, Takeda S, Nakao A. Intra-operative application of realtime tissue elastography for the diagnosis of liver tumours. Liver Int 2008; 28(9): 1264-71.

#### **152** *Hepatic Elastography Using Ultrasound Waves Dănilă and Jurchiş*

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© 2016 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Guidelines on Liver Elastography**

**Ioan Sporea\*** and **Roxana Şirli**

*Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv., 300736, Timişoara, Romania*

**Abstract:** Scientific papers regarding ultrasound based elastographic techniques have been published in great numbers since new elastographic methods are constantly appearing in the market. Thus it is mandatory that professional societies and experts in the field should try to organize the available data in order to assess the clinical usefulness of elastography. In this regard, guidelines were issued by national and international ultrasound societies, as well as by other professional societies. These guidelines are presented in this chapter.

**Keywords:** EASL guidelines, EFSUMB guidelines, Liver elastography, WFUMB guidelines.

Liver elastography became more and more a clinical procedure. Transient Elastography (TE) was the first method recommended by national or international guidelines (EASL) as an alternative to LB, but the development of other elastographic methods (point or 2D SWE) made guidelines mandatory in order to clarify the value and limits of any elastographic method.

The European Federation of Societies of Ultrasound in Medicine and Biology (EFSUMB) prepared the first guidelines on ultrasound based elastography, as a proof of this technique's development in Europe. They were elaborated by a group of experts from European countries, based on the most relevant scientific papers

**Ioan Sporea & Roxana Șirli (Eds.) © 2016 The Author(s). Published by Bentham Science Publishers**