Preface

Elastography, the science of creating noninvasive images of mechanical characteristics of tissues, has been rapidly evolving in recent years. The advantage of this technique is its ability to rapidly detect and quantify the changes in soft tissue stiffness resulting from specific pathological or physiological processes. Ultrasound elastography is nowadays applied especially on the liver and breast, but the technique has been increasingly used for other tissues including the thyroid, lymph nodes, spleen, pancreas, gastrointestinal tract, kidney, prostate, and the musculoskeletal and vascular systems.

This book presents some of the applications of strain and shear-wave ultrasound elastography in hepatic, pancreatic, breast and musculoskeletal conditions.

Most of the book is focused on diffuse liver conditions, since the evaluation of diffuse liver disease is the best validated application of ultrasound elastography and has been widely adopted for non-invasive detection and staging of liver fibrosis and steatosis, for the diagnosis of cirrhosis and its complications, as well as for monitoring disease progression. The main elastographic techniques in these conditions are reviewed, namely Vibration Controlled Transient Elastography (VCTE), point-Shear Waves Elastography, and 2D Share Wave Elastography.

The use of elastography in breast conditions is also discussed; specifically, the technique is used for differentiating benign focal lesions from suspicious focal lesions (in general, benign lesions have low stiffness, while malignant lesions have high stiffness). Both strain and shear-wave methods have been evaluated for improving the generally high sensitivity and specificity of the Breast Imaging Reporting and Data System (BIRADS) and it is recommended that they are used to enhance the usual ultrasound examination.

Another chapter reviews pancreatic elastography, a challenging new procedure used for inflammatory and tumoral conditions. Certain technical difficulties, such as the deep location of the organ, impede the accurate assessment of pancreatic stiffness, but the new software for both conventional and endoscopic ultrasound offer promise for the differential diagnosis between malignant tumors and different forms of chronic pancreatitis.

The last chapter includes some preliminary data on the strain-based elastography assessment of patients with De Quervain tenosynovitis.

Evidently, further research with unbiased large-scale studies is still required, but ultrasound elastography holds immense potential for various clinical applications, and its continued development will warrant its widespread clinical use in the upcoming years.

**II**

**Chapter 8 95**

Other Application of Ultrasound Elastography **111**

**Chapter 9 113**

**Chapter 10 125**

Assessment of De Quervain Tenosynovitis Patients with Strain-Based

Shearwave Elastography in Differentiating Benign and Malignant

*by Binafsha Manzoor Syed, Jawaid Naeem Qureshi and Bikha Ram Devrajani*

Breast Lesions

Pancreatic Elastography *by Lidia Ciobanu*

*by Ahmad Mohammad Ghandour*

**Section 3**

Elastography

#### **Monica Lupşor-Platon**

**1**

Section 1

Liver Elastography

Associate Professor, Department of Medical Imaging, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania

Section 1 Liver Elastography

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

**2. Principle**

elastography (Fibroscan).

Noninvasive Assessment of

Elastography (VCTE)

*Monica Lupsor-Platon*

Diffuse Liver Diseases Using

Vibration-Controlled Transient

Because of the limitations and invasive nature of liver biopsy, other noninvasive means are being tested for the evaluation of diffuse liver diseases. One of these methods is vibration-controlled transient elastography (VCTE). This chapter reviews the principle of VCTE, the examination technique, the normal range for liver stiffness values, the pathological changes that may influence liver stiffness, as well as the diagnostic performance in several diffuse liver diseases, especially chronic hepatitis C, chronic hepatitis B, nonalcoholic steatohepatitis, and alcoholic liver disease. Apart from the assessment of fibrosis stages, we will also discuss the diagnosis of cirrhosis and its complications as

Chronic liver diseases are an important public health issue. Extensive research has been made lately on the development of noninvasive diagnostic methods, able to accurately assess fibrosis and steatosis. Among these, an important place is reserved for elastographic techniques and especially vibration-controlled transient

Vibration-controlled transient elastography is performed with the Fibroscan® equipment (Echosens, Paris) [1]. The transducer of the device is placed in an intercostal space above the right liver lobe, in a point of maximal hepatic dullness. A mechanical vibrator is mounted on the axis of the device; the vibrator generates a painless vibration, inducing a train of elastic waves, which propagate through the skin and subcutaneous tissue to the liver. In parallel to the vibration, the transducer performs ultrasound acquisitions, at a frequency of 4 kHz [1–3] By comparing the ultrasonographic signals thus obtained, tissue deformation records, induced by the propagation of the elastic wave, can be drawn. The time necessary for the train of waves to propagate along the interest

well as other applications of VCTE, reviewing its advantages and limitations.

**Keywords:** diffuse liver disease, fibrosis, noninvasive, vibration-controlled transient elastography, Fibroscan

#### **Chapter 1**

## Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient Elastography (VCTE)

*Monica Lupsor-Platon*

### **Abstract**

Because of the limitations and invasive nature of liver biopsy, other noninvasive means are being tested for the evaluation of diffuse liver diseases. One of these methods is vibration-controlled transient elastography (VCTE). This chapter reviews the principle of VCTE, the examination technique, the normal range for liver stiffness values, the pathological changes that may influence liver stiffness, as well as the diagnostic performance in several diffuse liver diseases, especially chronic hepatitis C, chronic hepatitis B, nonalcoholic steatohepatitis, and alcoholic liver disease. Apart from the assessment of fibrosis stages, we will also discuss the diagnosis of cirrhosis and its complications as well as other applications of VCTE, reviewing its advantages and limitations.

**Keywords:** diffuse liver disease, fibrosis, noninvasive, vibration-controlled transient elastography, Fibroscan

#### **1. Introduction**

Chronic liver diseases are an important public health issue. Extensive research has been made lately on the development of noninvasive diagnostic methods, able to accurately assess fibrosis and steatosis. Among these, an important place is reserved for elastographic techniques and especially vibration-controlled transient elastography (Fibroscan).

#### **2. Principle**

Vibration-controlled transient elastography is performed with the Fibroscan® equipment (Echosens, Paris) [1]. The transducer of the device is placed in an intercostal space above the right liver lobe, in a point of maximal hepatic dullness. A mechanical vibrator is mounted on the axis of the device; the vibrator generates a painless vibration, inducing a train of elastic waves, which propagate through the skin and subcutaneous tissue to the liver. In parallel to the vibration, the transducer performs ultrasound acquisitions, at a frequency of 4 kHz [1–3] By comparing the ultrasonographic signals thus obtained, tissue deformation records, induced by the propagation of the elastic wave, can be drawn. The time necessary for the train of waves to propagate along the interest

area, as well as the velocity of propagation, is recorded. The liver stiffness can afterwards be calculated using the formula: E = 3ρVs2 (E, the elasticity module; ρ, density; Vs, the elastic wave velocity in the liver parenchyma). The stiffer the tissue, the higher the velocity of the wave train [1–3].

On the other hand, knowing that fat impairs ultrasound propagation and induces attenuation, the producers of the Fibroscan equipment have developed a software able to precisely quantify the ultrasound attenuation. This controlled attenuation parameter (CAP) is expressed in dB/m and is calculated using the same radio-frequency data, and the same region of interest, as the region used to assess the liver stiffness [4, 5].

#### **3. Examination technique**

The patient is placed in a dorsal decubitus position, with the right arm in maximum abduction above the head, in order to best expose the right abdominal quadrant, perpendicularly to the intercostal space, in an area of maximal dullness, free of any large vascular structure [1, 3]. When pressing the transducer button, the vibration is generated and transmitted to the liver. The software of the equipment analyzes the tissue deformation records and measures the stiffness of the parenchyma. The results are expressed in kilopascals (kPa) and represent the median value of 10 valid measurements. The equipment can measure values ranging between 2.5 and 75 kPa [1, 3]. At the same time, the software can measure both the liver stiffness (for the assessment of fibrosis) and the controlled attenuation parameter, CAP (for the assessment of steatosis).

It is important to choose the correct transducer for the examinations (S, M, or XL). The choice is made according to the circumference of the thorax: if below 75 cm, the S probe is chosen (either S1 < 45 cm or S2 for 45–75 cm and the M probe for a thoracic circumference above 75 cm). The XL transducer will be chosen if the distance between the skin and the liver capsule exceeds 25 mm. It is worth mentioning that, when measured with the XL probe, the median liver stiffness is significantly lower than that measured with the M probe [6].

The examination should be performed after an overnight fast, or at least 2 hours after a meal, because a postprandial examination would raise the stiffness value due to increased hepatic blood flow [7, 8]. In addition, the patient should remain at rest for 10 minutes before the examination [9] and hold his or her breath during the examination [10].

A proper measurement can be performed even by a technician after a training period (approximately 100 cases) [6, 10], but the clinical interpretation of results must always be issued by an expert taking into account the demographic data, disease etiology, and biochemical profile at the moment of the examination [3, 11].

Following the manufacturer's recommendation, the assessment is reliable only when 10 valid readings and an IQR ≤ 30% of the median (IQR/M ≤ 30%) are obtained [9].

#### **4. Normal range of liver stiffness**

The mean value of liver stiffness in healthy subjects, without any known liver disease and with normal biochemistry and hematology tests, is 5.5 ± 1.6 kPa according to some authors [12] and 4.8 ± 1.3 kPa according to others [13]. Age does not appear to influence this value, but stiffness is higher in men than in women (5.8 ± 1.6 kPa vs. 5.2 ± 1.6 kPa) as well as in subjects with a BMI > 30 kg/m2

**5**

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient…*

value of 90% for the prediction of a fibrosis stage of at least F1.

**5. Pathological changes influencing liver stiffness**

consideration when interpreting the liver stiffness values.

stage which should be specified in the written report [15].

Further studies are however required to clarify this issue [28].

**6. Diagnostic performance of VCTE**

**6.1 Chronic hepatitis C (CHC)**

(6.3 ± 1.9 kPa vs. 5.4 ± 1.5 kPa) [14]. It is very difficult to establish the normal range of liver stiffness without biopsy, but the reverse is not feasible. In a group of HCV patients, without pathological changes on the biopsy sample, the liver stiffness was 4.84 ± 1.49 kPa [15]. In our unit, values of or above 5.3 kPa have a positive predictive

Although liver stiffness correlates very well with fibrosis, just a single physical parameter (stiffness) cannot be used to completely describe a complex biological system, in which fibrosis is just a part [2]. Liver stiffness is increased by hepatic inflammation (often but not exclusively revealed by an elevated transaminase level) [16–18], obstructive cholestasis [19], hepatic congestion [20], amyloidosis, lymphomas, and extramedullary hematopoiesis [9]. These error factors must be taken into

*Necroinflammatory activity* leads to an increase in liver stiffness alongside the degree of histologic activity [21–23]. For instance, the tissue changes occurring during an acute hepatitis can associate a rise in liver stiffness reaching sometimes cirrhotic values, due to cellular intumescence and sometimes to severe cholestasis [24]. The contribution of these non-fibrotic alterations on stiffness has been demonstrated by recording the progressive decrease in stiffness alongside the decrease in transaminase levels [17, 18]. On the other hand, in patients with relapsed chronic hepatitis, the higher stiffness values are caused not only by pre-existing fibrosis but also to the superimposed cellular intumescence [16]. Therefore, caution is advised when interpreting the liver stiffness values in patients with increased ALT: if the ALT values exceed a 2.5-fold increase, there is a risk of overestimating the fibrosis

*Extrahepatic cholestasis* can increase the stiffness independently from fibrosis [19], and after biliary drainage, the liver stiffness values decrease at a mean rate of 1.2 ± 0.56 kPa for every 1 g/dL decrease in bilirubin levels. It would therefore be prudent to exclude a possible cholestasis through imaging and lab tests before interpreting liver stiffness values in order to avoid overestimating the fibrosis stage. *Congestive heart failure* may lead to increased liver stiffness reaching even cirrhotic levels, due to a higher liver blood volume, in up to 60% of patients [25–27]. *Liver steatosis* influence on liver stiffness values remains controversial. In some studies, steatosis did not significantly affect stiffness values, even after adjusting for fibrosis stage, but the proportion of patients with severe steatosis was too low to allow accurate quantification of a potential influence [1, 21, 28]. Other studies, however, have proven that, for the same fibrosis stage and the same

necroinflammation grade, the presence of steatosis leads to a significant increase in liver stiffness [29]; furthermore, the morphometric analysis of biopsy samples has proven that steatosis does change liver stiffness independently from fibrosis. This influence is negligible in cirrhotic patients, but significant in non-cirrhotic patients.

The first patients to have benefited from vibration-controlled transient elastography were those diagnosed with chronic C viral hepatitis (HCV). Studies performed

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient… DOI: http://dx.doi.org/10.5772/intechopen.89970*

(6.3 ± 1.9 kPa vs. 5.4 ± 1.5 kPa) [14]. It is very difficult to establish the normal range of liver stiffness without biopsy, but the reverse is not feasible. In a group of HCV patients, without pathological changes on the biopsy sample, the liver stiffness was 4.84 ± 1.49 kPa [15]. In our unit, values of or above 5.3 kPa have a positive predictive value of 90% for the prediction of a fibrosis stage of at least F1.

#### **5. Pathological changes influencing liver stiffness**

Although liver stiffness correlates very well with fibrosis, just a single physical parameter (stiffness) cannot be used to completely describe a complex biological system, in which fibrosis is just a part [2]. Liver stiffness is increased by hepatic inflammation (often but not exclusively revealed by an elevated transaminase level) [16–18], obstructive cholestasis [19], hepatic congestion [20], amyloidosis, lymphomas, and extramedullary hematopoiesis [9]. These error factors must be taken into consideration when interpreting the liver stiffness values.

*Necroinflammatory activity* leads to an increase in liver stiffness alongside the degree of histologic activity [21–23]. For instance, the tissue changes occurring during an acute hepatitis can associate a rise in liver stiffness reaching sometimes cirrhotic values, due to cellular intumescence and sometimes to severe cholestasis [24]. The contribution of these non-fibrotic alterations on stiffness has been demonstrated by recording the progressive decrease in stiffness alongside the decrease in transaminase levels [17, 18]. On the other hand, in patients with relapsed chronic hepatitis, the higher stiffness values are caused not only by pre-existing fibrosis but also to the superimposed cellular intumescence [16]. Therefore, caution is advised when interpreting the liver stiffness values in patients with increased ALT: if the ALT values exceed a 2.5-fold increase, there is a risk of overestimating the fibrosis stage which should be specified in the written report [15].

*Extrahepatic cholestasis* can increase the stiffness independently from fibrosis [19], and after biliary drainage, the liver stiffness values decrease at a mean rate of 1.2 ± 0.56 kPa for every 1 g/dL decrease in bilirubin levels. It would therefore be prudent to exclude a possible cholestasis through imaging and lab tests before interpreting liver stiffness values in order to avoid overestimating the fibrosis stage.

*Congestive heart failure* may lead to increased liver stiffness reaching even cirrhotic levels, due to a higher liver blood volume, in up to 60% of patients [25–27].

*Liver steatosis* influence on liver stiffness values remains controversial. In some studies, steatosis did not significantly affect stiffness values, even after adjusting for fibrosis stage, but the proportion of patients with severe steatosis was too low to allow accurate quantification of a potential influence [1, 21, 28]. Other studies, however, have proven that, for the same fibrosis stage and the same necroinflammation grade, the presence of steatosis leads to a significant increase in liver stiffness [29]; furthermore, the morphometric analysis of biopsy samples has proven that steatosis does change liver stiffness independently from fibrosis. This influence is negligible in cirrhotic patients, but significant in non-cirrhotic patients. Further studies are however required to clarify this issue [28].

#### **6. Diagnostic performance of VCTE**

#### **6.1 Chronic hepatitis C (CHC)**

The first patients to have benefited from vibration-controlled transient elastography were those diagnosed with chronic C viral hepatitis (HCV). Studies performed

*Ultrasound Elastography*

the liver stiffness [4, 5].

examination [10].

obtained [9].

**4. Normal range of liver stiffness**

**3. Examination technique**

area, as well as the velocity of propagation, is recorded. The liver stiffness can afterwards be calculated using the formula: E = 3ρVs2 (E, the elasticity module; ρ, density; Vs, the elastic wave velocity in the liver parenchyma). The stiffer the

On the other hand, knowing that fat impairs ultrasound propagation and induces attenuation, the producers of the Fibroscan equipment have developed a software able to precisely quantify the ultrasound attenuation. This controlled attenuation parameter (CAP) is expressed in dB/m and is calculated using the same radio-frequency data, and the same region of interest, as the region used to assess

The patient is placed in a dorsal decubitus position, with the right arm in maximum abduction above the head, in order to best expose the right abdominal quadrant, perpendicularly to the intercostal space, in an area of maximal dullness, free of any large vascular structure [1, 3]. When pressing the transducer button, the vibration is generated and transmitted to the liver. The software of the equipment analyzes the tissue deformation records and measures the stiffness of the parenchyma. The results are expressed in kilopascals (kPa) and represent the median value of 10 valid measurements. The equipment can measure values ranging between 2.5 and 75 kPa [1, 3]. At the same time, the software can measure both the liver stiffness (for the assessment of fibrosis) and the controlled attenuation

It is important to choose the correct transducer for the examinations (S, M, or XL). The choice is made according to the circumference of the thorax: if below 75 cm, the S probe is chosen (either S1 < 45 cm or S2 for 45–75 cm and the M probe for a thoracic circumference above 75 cm). The XL transducer will be chosen if the distance between the skin and the liver capsule exceeds 25 mm. It is worth mentioning that, when measured with the XL probe, the median liver stiffness is signifi-

The examination should be performed after an overnight fast, or at least 2 hours after a meal, because a postprandial examination would raise the stiffness value due to increased hepatic blood flow [7, 8]. In addition, the patient should remain at rest for 10 minutes before the examination [9] and hold his or her breath during the

A proper measurement can be performed even by a technician after a training period (approximately 100 cases) [6, 10], but the clinical interpretation of results must always be issued by an expert taking into account the demographic data, disease etiology, and biochemical profile at the moment of the examination [3, 11]. Following the manufacturer's recommendation, the assessment is reliable only

when 10 valid readings and an IQR ≤ 30% of the median (IQR/M ≤ 30%) are

The mean value of liver stiffness in healthy subjects, without any known liver disease and with normal biochemistry and hematology tests, is 5.5 ± 1.6 kPa according to some authors [12] and 4.8 ± 1.3 kPa according to others [13]. Age does not appear to influence this value, but stiffness is higher in men than in women (5.8 ± 1.6 kPa vs. 5.2 ± 1.6 kPa) as well as in subjects with a BMI > 30 kg/m2

tissue, the higher the velocity of the wave train [1–3].

parameter, CAP (for the assessment of steatosis).

cantly lower than that measured with the M probe [6].

**4**

on large groups of HCV patients indicate that the liver stiffness values are strongly correlated with fibrosis stage, but there is some degree of overlap between adjacent stages. The practical utility of the method is based on establishing certain threshold stiffness values for each fibrosis stage. The diagnosis of stages F ≥ 2, F ≥ 3, and cirrhosis is based on the following stiffness values: 5.2–9.5 kPa, 9.5–9.6 kPa, and 11–15 kPa, respectively, as proposed by certain studies [15, 21, 30–34]. As suggested by studies assessing other noninvasive methods [35], the difference between these values can be explained by the varying prevalence of each fibrosis stage in the analyzed groups as well as by the different aims of the investigation (screening strategy vs. exclusion strategy). Therefore, although the already-defined cutoffs may be relevant to a certain population, they may not be applicable in another population with different prevalence of fibrosis stage and with another diagnostic aim for performing VCTE. In any case, according to the EFSUMB guidelines, "TE can be used as the first-line assessment for the severity of liver fibrosis in patients with chronic viral hepatitis C. It performs best with regard to the ruling out of cirrhosis" [9].

#### **6.2 Chronic hepatitis B (CHB)**

In patients with CHB, VCTE has a similar performance as in CHC patients [9]. For this type of patients, Marcellin and collaborators [36], considering the METAVIR scoring system, have suggested as early as 2009 the 7.2 kPa stiffness value as the cutoff for the prediction of F ≥ 2 (Se 70%, Sp 83%, PPV 80%, NPV 73%, AUROC 0.81), 8.1 kPa for F ≥ 3 (Se 86%, Sp 85%, PPV 65%, NPV 95%, AUROC 0.93), and 11 kPa for the prediction of cirrhosis (Se 93%, Sp 87%, PPV 38%, NPV 99%, AUROC 0.93).

Other articles [37–42] have confirmed the performance of the method, yielding AUROC values raging between 0.80 and 0.90 (for the prediction of significant fibrosis) and liver stiffness cutoffs varying between 6.6 and 8.8 kPa [9, 43–47]. With regard to the prediction of cirrhosis, AUROCs vary between 0.81 and 0.97 and the cutoffs between 9.4 and 13.4 kPa [44, 45]. The meta-analyses have suggested that a liver stiffness above 11.7 kPa should raise the suspicion of cirrhosis in patients with CHB [9, 45].

Generally, the cutoff value used for the cirrhosis prediction is lower in CHB than in CHC patients. One explanation could be the fact that HBV infection is one of the causes of macronodular cirrhosis, so that the predominant macronodular regeneration and the fine fibrous septa surrounding the nodules mean a smaller quantity of fibrosis than in micronodular cirrhosis with thick fibrous septa. It follows that, generally, liver stiffness is lower in macronodular than in micronodular cirrhosis.

On the other hand, liver stiffness values below 5 kPa in patients with normal ALT and low serum HBV DNA levels (<2000 IU/ml) are characteristic for inactive HBV carriers [9, 48, 49]. VCTE can be used to rule out significant fibrosis and cirrhosis in HBV inactive carriers, which is the best indication for VCTE in HBV.

According to the EFSUMB guidelines, "TE is useful in patients with CHB to identify those with cirrhosis, but concomitant assessment of transaminases is required to exclude flare-ups (elevation > 5 times upper limit of normal)". In addition, TE is useful in inactive HBV carriers to rule out fibrosis, in case the liver stiffness is below 5 kPa [9].

#### **6.3 Nonalcoholic steatohepatitis (NASH)**

In NASH patients, the correlation between stiffness and fibrosis is weaker than in patients with chronic viral hepatitis, because of a different fibrosis distribution

**7**

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient…*

pattern (in chronic viral hepatitis, fibrosis appears early in the periportal areas and gives rise to a dense, stellate, and regularly distributed portal fibrosis; in steatohepatitis, however, the fibrosis is located in the perisinusoidal space of the centrilobular area and in the walls of the centrilobular vein) [28, 50]. There is a direct proportion between the amount of dense, stellate portal fibrosis and liver stiffness, whereas perisinusoidal fibrosis distributed preferentially in the centrilobular areas does not proportionally increase the liver stiffness values, as was proven by morphometric

A meta-analysis including 854 NASH patients examined with the M probe [51] has proven the very good performance of VCTE in diagnosing stages F ≥ 3 (Se 82%, Sp 82%) and F4 (Se 92%, Sp 92%) and its moderate performance in diagnosing significant fibrosis F ≥ 2 (Se 79%, Sp 75%). The cutoff yielded by various studies varies between 6.6 and 7.7 kPa (for F ≥ 2), 8–10.4 kPa (for F ≥ 3), and 10.3–17.5 kPa

The available data indicate that, in patients with NAFLD, VCTE is a highly accurate, noninvasive method for the exclusion of advanced fibrosis and a moderately accurate method for the exclusion of significant fibrosis. According to the EFSUMB and EASL Guidelines and Recommendations on the clinical use of liver ultrasound elastography, "TE can be used in NAFLD patients to confidently exclude severe fibrosis and especially cirrhosis," with a high negative predictive value (around

There is no consensus regarding the optimal cutoffs for the prediction of fibrosis stages in ALD patients [9, 58]. In various studies, the cutoffs range between 7.8 and 9.6 kPa for significant fibrosis, 8.0–17.0 kPa for severe fibrosis, and 7.15–34.9 kPa for cirrhosis prediction; the explanation for this variation lies in the difference in prevalence of fibrosis stages in the analyzed groups, as well as in the different patient selection methods (with or without exclusion of acute alcoholic hepatitis or

In a meta-analysis by Pavlov, the cutoffs used for the prediction of fibrosis stages were the following: 5.9 kPa for ≥F1 (Se 83%, Sp 86%, PPV 97.6%, NPV 35.3%, and AUROC 0.84), 7.5 kPa for ≥F2 (Se 94%, Sp 89%, positive likelihood ratio 8.2, negative likelihood ratio 0.07), and 9.5 kPa for ≥F3 (Se 92%, Sp 68%, positive likelihood ratio 2.9, negative likelihood ratio 0.11) [63]. For the prediction of cirrhosis, the proposed 12.5 kPa cutoff had a 95% sensitivity and 71% specificity, a 3.3 positive

The proposed cutoff values for the different stages of hepatic fibrosis may be used in clinical practice, but with caution, since those reported values were simply the most common cutoff values used by the study authors and are insufficiently validated while, additionally, there is always the risk of overestimation of LS values

It is also important to consider the AST levels when using VCTE to assess fibrosis

in ALD patients. For AST levels above 100 U/L, the liver stiffness may increase independently from fibrosis, as a result of steatohepatitis, leading to interpretation errors [59]. On the other hand, liver stiffness decreased significantly after alcohol cessation over a long period of follow-up. It follows that liver stiffness measurements in alcoholic liver disease should be interpreted with caution and assessed in regard to the current alcohol consumption. Large-scale prospective studies should be performed to determine the different optimal cutoff values according to alcohol consumption, and more data are required to determine the best delay after alcohol

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

(for the prediction of cirrhosis) [50, 52–57].

**6.4 Alcoholic liver disease (ALD)**

cessation prior to VCTE evaluation.

of patients with decompensated disease) [59–62].

likelihood ratio, and a 0.07 negative likelihood ratio [63].

in patients who are not abstinent from alcohol consumption.

studies [28].

90%) [9, 34].

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient… DOI: http://dx.doi.org/10.5772/intechopen.89970*

pattern (in chronic viral hepatitis, fibrosis appears early in the periportal areas and gives rise to a dense, stellate, and regularly distributed portal fibrosis; in steatohepatitis, however, the fibrosis is located in the perisinusoidal space of the centrilobular area and in the walls of the centrilobular vein) [28, 50]. There is a direct proportion between the amount of dense, stellate portal fibrosis and liver stiffness, whereas perisinusoidal fibrosis distributed preferentially in the centrilobular areas does not proportionally increase the liver stiffness values, as was proven by morphometric studies [28].

A meta-analysis including 854 NASH patients examined with the M probe [51] has proven the very good performance of VCTE in diagnosing stages F ≥ 3 (Se 82%, Sp 82%) and F4 (Se 92%, Sp 92%) and its moderate performance in diagnosing significant fibrosis F ≥ 2 (Se 79%, Sp 75%). The cutoff yielded by various studies varies between 6.6 and 7.7 kPa (for F ≥ 2), 8–10.4 kPa (for F ≥ 3), and 10.3–17.5 kPa (for the prediction of cirrhosis) [50, 52–57].

The available data indicate that, in patients with NAFLD, VCTE is a highly accurate, noninvasive method for the exclusion of advanced fibrosis and a moderately accurate method for the exclusion of significant fibrosis. According to the EFSUMB and EASL Guidelines and Recommendations on the clinical use of liver ultrasound elastography, "TE can be used in NAFLD patients to confidently exclude severe fibrosis and especially cirrhosis," with a high negative predictive value (around 90%) [9, 34].

#### **6.4 Alcoholic liver disease (ALD)**

*Ultrasound Elastography*

**6.2 Chronic hepatitis B (CHB)**

99%, AUROC 0.93).

CHB [9, 45].

cirrhosis.

stiffness is below 5 kPa [9].

**6.3 Nonalcoholic steatohepatitis (NASH)**

on large groups of HCV patients indicate that the liver stiffness values are strongly correlated with fibrosis stage, but there is some degree of overlap between adjacent stages. The practical utility of the method is based on establishing certain threshold stiffness values for each fibrosis stage. The diagnosis of stages F ≥ 2, F ≥ 3, and cirrhosis is based on the following stiffness values: 5.2–9.5 kPa, 9.5–9.6 kPa, and 11–15 kPa, respectively, as proposed by certain studies [15, 21, 30–34]. As suggested by studies assessing other noninvasive methods [35], the difference between these values can be explained by the varying prevalence of each fibrosis stage in the analyzed groups as well as by the different aims of the investigation (screening strategy vs. exclusion strategy). Therefore, although the already-defined cutoffs may be relevant to a certain population, they may not be applicable in another population with different prevalence of fibrosis stage and with another diagnostic aim for performing VCTE. In any case, according to the EFSUMB guidelines, "TE can be used as the first-line assessment for the severity of liver fibrosis in patients with chronic viral

hepatitis C. It performs best with regard to the ruling out of cirrhosis" [9].

In patients with CHB, VCTE has a similar performance as in CHC patients [9]. For this type of patients, Marcellin and collaborators [36], considering the METAVIR scoring system, have suggested as early as 2009 the 7.2 kPa stiffness value as the cutoff for the prediction of F ≥ 2 (Se 70%, Sp 83%, PPV 80%, NPV 73%, AUROC 0.81), 8.1 kPa for F ≥ 3 (Se 86%, Sp 85%, PPV 65%, NPV 95%, AUROC 0.93), and 11 kPa for the prediction of cirrhosis (Se 93%, Sp 87%, PPV 38%, NPV

Other articles [37–42] have confirmed the performance of the method, yielding AUROC values raging between 0.80 and 0.90 (for the prediction of significant fibrosis) and liver stiffness cutoffs varying between 6.6 and 8.8 kPa [9, 43–47]. With regard to the prediction of cirrhosis, AUROCs vary between 0.81 and 0.97 and the cutoffs between 9.4 and 13.4 kPa [44, 45]. The meta-analyses have suggested that a liver stiffness above 11.7 kPa should raise the suspicion of cirrhosis in patients with

Generally, the cutoff value used for the cirrhosis prediction is lower in CHB than in CHC patients. One explanation could be the fact that HBV infection is one of the causes of macronodular cirrhosis, so that the predominant macronodular regeneration and the fine fibrous septa surrounding the nodules mean a smaller quantity of fibrosis than in micronodular cirrhosis with thick fibrous septa. It follows that, generally, liver stiffness is lower in macronodular than in micronodular

On the other hand, liver stiffness values below 5 kPa in patients with normal ALT and low serum HBV DNA levels (<2000 IU/ml) are characteristic for inactive HBV carriers [9, 48, 49]. VCTE can be used to rule out significant fibrosis and cirrhosis in HBV inactive carriers, which is the best indication for VCTE in HBV. According to the EFSUMB guidelines, "TE is useful in patients with CHB to identify those with cirrhosis, but concomitant assessment of transaminases is required to exclude flare-ups (elevation > 5 times upper limit of normal)". In addition, TE is useful in inactive HBV carriers to rule out fibrosis, in case the liver

In NASH patients, the correlation between stiffness and fibrosis is weaker than in patients with chronic viral hepatitis, because of a different fibrosis distribution

**6**

There is no consensus regarding the optimal cutoffs for the prediction of fibrosis stages in ALD patients [9, 58]. In various studies, the cutoffs range between 7.8 and 9.6 kPa for significant fibrosis, 8.0–17.0 kPa for severe fibrosis, and 7.15–34.9 kPa for cirrhosis prediction; the explanation for this variation lies in the difference in prevalence of fibrosis stages in the analyzed groups, as well as in the different patient selection methods (with or without exclusion of acute alcoholic hepatitis or of patients with decompensated disease) [59–62].

In a meta-analysis by Pavlov, the cutoffs used for the prediction of fibrosis stages were the following: 5.9 kPa for ≥F1 (Se 83%, Sp 86%, PPV 97.6%, NPV 35.3%, and AUROC 0.84), 7.5 kPa for ≥F2 (Se 94%, Sp 89%, positive likelihood ratio 8.2, negative likelihood ratio 0.07), and 9.5 kPa for ≥F3 (Se 92%, Sp 68%, positive likelihood ratio 2.9, negative likelihood ratio 0.11) [63]. For the prediction of cirrhosis, the proposed 12.5 kPa cutoff had a 95% sensitivity and 71% specificity, a 3.3 positive likelihood ratio, and a 0.07 negative likelihood ratio [63].

The proposed cutoff values for the different stages of hepatic fibrosis may be used in clinical practice, but with caution, since those reported values were simply the most common cutoff values used by the study authors and are insufficiently validated while, additionally, there is always the risk of overestimation of LS values in patients who are not abstinent from alcohol consumption.

It is also important to consider the AST levels when using VCTE to assess fibrosis in ALD patients. For AST levels above 100 U/L, the liver stiffness may increase independently from fibrosis, as a result of steatohepatitis, leading to interpretation errors [59]. On the other hand, liver stiffness decreased significantly after alcohol cessation over a long period of follow-up. It follows that liver stiffness measurements in alcoholic liver disease should be interpreted with caution and assessed in regard to the current alcohol consumption. Large-scale prospective studies should be performed to determine the different optimal cutoff values according to alcohol consumption, and more data are required to determine the best delay after alcohol cessation prior to VCTE evaluation.

VCTE is more suited to rule out than to rule in cirrhosis. At a Young's modulus of 12.5 kPa, VCTE may rule out cirrhosis with a negative likelihood ratio of 0.07 if the disease prevalence is 50% or lower.

In conclusion, according to the EFSUMB guidelines, "TE can be used to exclude cirrhosis in patients with alcoholic liver disease, provided that acute alcoholic hepatitis is not present" [9]. The current alcohol drinking status is also relevant.

#### **6.5 Other chronic liver diseases**

The performance of VCTE in identifying significant fibrosis was also assessed in other chronic liver diseases, such as HCV-HIV coinfection [64, 65], post liver transplantation status [66–69], cholestatic liver diseases (primitive biliary cirrhosis or primary sclerosing cholangitis) [70], and hemochromatosis [71]: the results yielded AUROC values between 0.74 and 0.93 for the prediction of significant fibrosis, at cutoffs ranging between 4 and 10.1 kPa.

#### **6.6 The diagnosis of cirrhosis and its complications**

One of the most important applications of VCTE is the noninvasive diagnosis of liver cirrhosis. The diagnostic accuracy of VCTE is far better in the prediction of cirrhosis than that of other stages of fibrosis, with areas under the ROC curve (AUROCs) ranging between 0.90 and 0.99 at cutoffs between 9 and 26.6 kPa. In a meta-analysis performed by Friedrich-Rust [72], the mean AUROC for the diagnosis of cirrhosis was 0.94, and the optimal cutoff for cirrhosis prediction proved to be 13.01 kPa. In Stebbing's meta-analysis [73], the 15.08 kPa cutoff had 84.45% sensitivity and 94.69% specificity for the prediction of cirrhosis. Tsochatzis [74] assessed the diagnostic accuracy of VCTE in the prediction of cirrhosis in a meta-analysis of 30 studies, which yielded a LS optimal cutoff of 15 ± 4.1 kPa (median, 14.5 kPa, ranging between 9 and 26.5 kPa in the various studies analyzed), with 83% sensitivity and 89% specificity. It is however important to keep in mind that the cutoffs proposed by the various studies were chosen based on the AUROCs providing the maximal sum between sensitivity and specificity. As was suggested in certain studies performed for the assessment of other noninvasive methods, the difference between these values can, however, be explained by the difference in prevalence of cirrhosis in the analyzed groups [35].

On the other hand, interpreting the LS value as compatible with the diagnosis of cirrhosis can only be made after excluding some other conditions: significant cytolysis, significant cholestasis, right heart failure, or performing the examination after a meal. Nevertheless, even if the liver stiffness values are not typical for cirrhosis, cirrhosis may however be present in 3% of cases. This is the case of macronodular cirrhosis (more frequent in HBV infection, but also in other liver diseases) where the nodules are surrounded by fine fibrous septa, which do not increase the liver stiffness to "cirrhotic" levels.

#### *6.6.1 Portal hypertension screening*

Various studies have reported on the correlation between the LS value and portal hypertension (PHT), identified either through the presence of esophageal varices (EV) during upper digestive endoscopy [75–77] or by measuring the hepatic venous pressure gradient (HVPG), considered the gold standard in the assessment of portal hypertension [66, 77–79].

**9**

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient…*

prediction of other complications, such as variceal effraction or ascites).

the HVPG threshold for the prediction of varices) or > 12 mm Hg (threshold for the

When analyzing the relationship between liver stiffness and the presence of esophageal varices, the area under the ROC curve for the prediction of varices varied between 0.74 and 0.85. When using the 13.9 kPa, 17.6 kPa, and 21.3 kPa cutoff values, the authors found high sensitivity for the prediction of varices (95%, 90%, and 79%, respectively) but relatively low specificity (43, 43, and

Some authors claim that there is a correlation between liver stiffness values and variceal size [75, 76, 78], while others could find no proof of this correlation [77]. For the prediction of grade 2 and 3 varices, TE had a high sensitivity

(91% and 76%) at the 19 kPa and 30.5 kPa cutoffs, respectively, but with low specificity (60% and 80%, respectively) and positive predictive value (48% and 54%,

According to the Baveno VI criteria [80], in patients with compensated chronic liver diseases of viral etiology, the noninvasive methods may predict the clinically significant portal hypertension, identifying the proportion of patients at risk of having endoscopic markers of PHT. For that purpose, liver stiffness measurements above 20–25 kPa can be used alone or in combination with platelet levels and spleen size. Liver stiffness below 20 kPa and platelet levels above 150,000 indicate a very low risk of esophageal varices requiring treatment, and therefore endoscopic screening can be avoided. These patients must be followed-up annually (VCTE and platelet levels), and an endoscopy must be performed in case of increasing stiffness

The assessment of spleen stiffness has emerged as a new technique in hepatology, which may provide useful information on the presence and degree of portal

Some studies suggested that VCTE could be used as a risk marker for the development of a hepatocarcinoma in patients with hepatitis C [81, 82], who have a fivefold increase in risk at liver stiffness values above 25 kPa. On the other hand, in our experience, in patients with hepatitis C-related cirrhosis, a liver stiffness value > 38 kPa and an IQR > 30% of the median value (after previous exclusion of gross technical errors) are important markers which suggest the need for further imaging investigations in search of a possible hepatocarcinoma (HCC) [83]. Some authors have found that an increase in LS of more than 1 kPa at 3 years is correlated with a worse prognosis and with an increase in mortality rate in the next 2 years; for every 1 kPa increase over the median LS found in any given patient, the relative risk for a severe clinical event in that particular patient increases: 1.07 for hepatic decompensation, 1.11 for HCC, and 1.22 for death [84]. Nevertheless, these results require confirmation through prospective studies performed on large groups of patients, in order to confirm whether liver stiffness can indeed predict complications in decompensated cirrhosis [11]. In case it does, elastography may serve as a method of fast noninvasive screening, in order to classify each patient

The assessment of liver stiffness using VCTE is useful in the monitoring of adverse effects of hepatotoxic medication [86] as well as that of the effect of

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

70%, respectively) [3, 75–77].

respectively) [75, 76].

or decreasing platelets.

in a risk category [85].

**6.7 Other applications of VCTE**

hypertension and the prediction of its complications.

*6.6.2 Prognostic significance of LS in patients with liver cirrhosis*

Despite an excellent correlation at HVPG values below 10 or 12 mm Hg, the comparison did not yield valuable results at HVPG values > 10 mm Hg (which is

#### *Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient… DOI: http://dx.doi.org/10.5772/intechopen.89970*

the HVPG threshold for the prediction of varices) or > 12 mm Hg (threshold for the prediction of other complications, such as variceal effraction or ascites).

When analyzing the relationship between liver stiffness and the presence of esophageal varices, the area under the ROC curve for the prediction of varices varied between 0.74 and 0.85. When using the 13.9 kPa, 17.6 kPa, and 21.3 kPa cutoff values, the authors found high sensitivity for the prediction of varices (95%, 90%, and 79%, respectively) but relatively low specificity (43, 43, and 70%, respectively) [3, 75–77].

Some authors claim that there is a correlation between liver stiffness values and variceal size [75, 76, 78], while others could find no proof of this correlation [77]. For the prediction of grade 2 and 3 varices, TE had a high sensitivity (91% and 76%) at the 19 kPa and 30.5 kPa cutoffs, respectively, but with low specificity (60% and 80%, respectively) and positive predictive value (48% and 54%, respectively) [75, 76].

According to the Baveno VI criteria [80], in patients with compensated chronic liver diseases of viral etiology, the noninvasive methods may predict the clinically significant portal hypertension, identifying the proportion of patients at risk of having endoscopic markers of PHT. For that purpose, liver stiffness measurements above 20–25 kPa can be used alone or in combination with platelet levels and spleen size. Liver stiffness below 20 kPa and platelet levels above 150,000 indicate a very low risk of esophageal varices requiring treatment, and therefore endoscopic screening can be avoided. These patients must be followed-up annually (VCTE and platelet levels), and an endoscopy must be performed in case of increasing stiffness or decreasing platelets.

The assessment of spleen stiffness has emerged as a new technique in hepatology, which may provide useful information on the presence and degree of portal hypertension and the prediction of its complications.

#### *6.6.2 Prognostic significance of LS in patients with liver cirrhosis*

Some studies suggested that VCTE could be used as a risk marker for the development of a hepatocarcinoma in patients with hepatitis C [81, 82], who have a fivefold increase in risk at liver stiffness values above 25 kPa. On the other hand, in our experience, in patients with hepatitis C-related cirrhosis, a liver stiffness value > 38 kPa and an IQR > 30% of the median value (after previous exclusion of gross technical errors) are important markers which suggest the need for further imaging investigations in search of a possible hepatocarcinoma (HCC) [83]. Some authors have found that an increase in LS of more than 1 kPa at 3 years is correlated with a worse prognosis and with an increase in mortality rate in the next 2 years; for every 1 kPa increase over the median LS found in any given patient, the relative risk for a severe clinical event in that particular patient increases: 1.07 for hepatic decompensation, 1.11 for HCC, and 1.22 for death [84]. Nevertheless, these results require confirmation through prospective studies performed on large groups of patients, in order to confirm whether liver stiffness can indeed predict complications in decompensated cirrhosis [11]. In case it does, elastography may serve as a method of fast noninvasive screening, in order to classify each patient in a risk category [85].

#### **6.7 Other applications of VCTE**

The assessment of liver stiffness using VCTE is useful in the monitoring of adverse effects of hepatotoxic medication [86] as well as that of the effect of

*Ultrasound Elastography*

disease prevalence is 50% or lower.

**6.5 Other chronic liver diseases**

cutoffs ranging between 4 and 10.1 kPa.

**6.6 The diagnosis of cirrhosis and its complications**

increase the liver stiffness to "cirrhotic" levels.

*6.6.1 Portal hypertension screening*

hypertension [66, 77–79].

VCTE is more suited to rule out than to rule in cirrhosis. At a Young's modulus of 12.5 kPa, VCTE may rule out cirrhosis with a negative likelihood ratio of 0.07 if the

In conclusion, according to the EFSUMB guidelines, "TE can be used to exclude

The performance of VCTE in identifying significant fibrosis was also assessed in other chronic liver diseases, such as HCV-HIV coinfection [64, 65], post liver transplantation status [66–69], cholestatic liver diseases (primitive biliary cirrhosis or primary sclerosing cholangitis) [70], and hemochromatosis [71]: the results yielded AUROC values between 0.74 and 0.93 for the prediction of significant fibrosis, at

One of the most important applications of VCTE is the noninvasive diagnosis of liver cirrhosis. The diagnostic accuracy of VCTE is far better in the prediction of cirrhosis than that of other stages of fibrosis, with areas under the ROC curve (AUROCs) ranging between 0.90 and 0.99 at cutoffs between 9 and 26.6 kPa. In a meta-analysis performed by Friedrich-Rust [72], the mean AUROC for the diagnosis of cirrhosis was 0.94, and the optimal cutoff for cirrhosis prediction proved to be 13.01 kPa. In Stebbing's meta-analysis [73], the 15.08 kPa cutoff had 84.45% sensitivity and 94.69% specificity for the prediction of cirrhosis. Tsochatzis [74] assessed the diagnostic accuracy of VCTE in the prediction of cirrhosis in a meta-analysis of 30 studies, which yielded a LS optimal cutoff of 15 ± 4.1 kPa (median, 14.5 kPa, ranging between 9 and 26.5 kPa in the various studies analyzed), with 83% sensitivity and 89% specificity. It is however important to keep in mind that the cutoffs proposed by the various studies were chosen based on the AUROCs providing the maximal sum between sensitivity and specificity. As was suggested in certain studies performed for the assessment of other noninvasive methods, the difference between these values can, however, be explained by the difference in prevalence of cirrhosis in the analyzed groups [35]. On the other hand, interpreting the LS value as compatible with the diagnosis of cirrhosis can only be made after excluding some other conditions: significant cytolysis, significant cholestasis, right heart failure, or performing the examination after a meal. Nevertheless, even if the liver stiffness values are not typical for cirrhosis, cirrhosis may however be present in 3% of cases. This is the case of macronodular cirrhosis (more frequent in HBV infection, but also in other liver diseases) where the nodules are surrounded by fine fibrous septa, which do not

Various studies have reported on the correlation between the LS value and portal hypertension (PHT), identified either through the presence of esophageal varices (EV) during upper digestive endoscopy [75–77] or by measuring the hepatic venous pressure gradient (HVPG), considered the gold standard in the assessment of portal

Despite an excellent correlation at HVPG values below 10 or 12 mm Hg, the comparison did not yield valuable results at HVPG values > 10 mm Hg (which is

cirrhosis in patients with alcoholic liver disease, provided that acute alcoholic hepatitis is not present" [9]. The current alcohol drinking status is also relevant.

**8**

antiviral therapy. Of course, in the latter situation, it is difficult to establish with certainty to what extent the decrease in liver stiffness is caused by a regression in fibrosis, a stabilization of necroinflammation, or both: however, a decrease in LS values in parallel with antiviral treatment exhibited favorable short- and long-term outcomes in patients with chronic viral hepatitis.

### **7. Advantages of VCTE**

The technique is easy to use, painless, noninvasive and does not require hospitalization. It can measure at the same time liver stiffness (for the prediction of fibrosis) and the controlled attenuation parameter (CAP) for the prediction of steatosis, in a volume 100 times larger than that examined during a liver biopsy.

### **8. Limitations of VCTE**

Liver fibrosis cannot be evaluated by VCTE in 5–8% of the cases [3], especially in the case of obesity, ascites, or narrow intercostal spaces. In the case of obesity, using the XL probe helps to lower the measurement failure. The measurement failure is significantly less frequent when using the XL probe than the standard M probe [54]. The XL probe can still yield unreliable results, but only in 25%, as opposed to 50% of cases with the M probe [87]. The main limiting factors for the XL probe are a skin-to-liver capsule distance > 3.4 cm and extreme obesity (BMI > 40 kg/m2 ) [54].

#### **9. Conclusions**

In conclusion, vibration-controlled transient elastography (VCTE) is a useful method in the assessment and monitoring of diffuse liver diseases. It is important to perform the technique correctly and to interpret the results considering the clinical context, disease etiology, and laboratory results.

**11**

**Author details**

Monica Lupsor-Platon1,2

Pharmacy, Cluj-Napoca, Romania

Fodor", Cluj-Napoca, Romania

provided the original work is properly cited.

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient…*

1 Department of Medical Imaging, Iuliu Hatieganu University of Medicine and

2 Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: monica.lupsor@umfcluj.ro

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

### **Conflict of interest**

Nothing to declare.

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient… DOI: http://dx.doi.org/10.5772/intechopen.89970*

#### **Author details**

*Ultrasound Elastography*

**7. Advantages of VCTE**

**8. Limitations of VCTE**

**9. Conclusions**

**Conflict of interest**

Nothing to declare.

outcomes in patients with chronic viral hepatitis.

context, disease etiology, and laboratory results.

antiviral therapy. Of course, in the latter situation, it is difficult to establish with certainty to what extent the decrease in liver stiffness is caused by a regression in fibrosis, a stabilization of necroinflammation, or both: however, a decrease in LS values in parallel with antiviral treatment exhibited favorable short- and long-term

The technique is easy to use, painless, noninvasive and does not require hospitalization. It can measure at the same time liver stiffness (for the prediction of fibrosis) and the controlled attenuation parameter (CAP) for the prediction of steatosis, in a volume 100 times larger than that examined during a liver biopsy.

Liver fibrosis cannot be evaluated by VCTE in 5–8% of the cases [3], especially in the case of obesity, ascites, or narrow intercostal spaces. In the case of obesity, using the XL probe helps to lower the measurement failure. The measurement failure is significantly less frequent when using the XL probe than the standard M probe [54]. The XL probe can still yield unreliable results, but only in 25%, as opposed to 50% of cases with the M probe [87]. The main limiting factors for the XL probe are a skin-to-liver capsule distance > 3.4 cm and extreme obesity (BMI > 40 kg/m2

In conclusion, vibration-controlled transient elastography (VCTE) is a useful method in the assessment and monitoring of diffuse liver diseases. It is important to perform the technique correctly and to interpret the results considering the clinical

) [54].

**10**

Monica Lupsor-Platon1,2

1 Department of Medical Imaging, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

2 Regional Institute of Gastroenterology and Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania

\*Address all correspondence to: monica.lupsor@umfcluj.ro

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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gut.2008.149708

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hep.22577

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

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Beaugrand M. Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndrome. Journal of Hepatology. 2008;**48**(4):606-613

[13] Sirli R, Sporea I, Tudora A, Deleanu A, Popescu A. Transient elastographic evaluation of subjects without known hepatic pathology: Does age change the liver stiffness? Journal of Gastrointestinal and Liver Diseases. 2009;**18**(1):57-60

[14] Corpechot C, El Naggar A, Poupon R. Gender and liver: Is the liver stiffness weaker in weaker sex? Hepatology. 2006;**44**(2):513-514

[15] Lupsor Platon M, Stefanescu H, Feier D, Maniu A, Badea R. Performance of unidimensional transient elastography in staging chronic hepatitis C. Results from a cohort of 1,202 biopsied patients from one single center. Journal of Gastrointestinal and Liver Diseases. 2013;**22**(2):157-166

[16] Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient elastography: A new surrogate marker of liver fibrosis influenced by major changes of transaminases. Journal of Viral Hepatitis. 2007;**14**(5):360-369. DOI: 10.1111/j.1365-2893.2006.00811.x

[17] Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology. 2008;**47**(2):592-595. DOI: 10.1002/hep.22056

[18] Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology. 2008;**47**(2):380-384. DOI: 10.1002/ hep.22007

[19] Millonig G, Reimann FM, Friedrich S, Fonouni H, Mehrabi A, Büchler MW,

et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology. 2008;**48**(5):1718-1723. DOI: 10.1002/ hep.22577

[20] Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, et al. Liver stiffness is directly influenced by central venous pressure. Journal of Hepatology. 2010;**52**(2):206-210. DOI: 10.1016/j.jhep.2009.11.018

[21] Arena U, Vizzutti F, Abraldes JG, Corti G, Stasi C, Moscarella S, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut. 2008;**57**(9):1288-1293. DOI: 10.1136/ gut.2008.149708

[22] Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut. 2007;**56**(7):968-973

[23] Chan HL, Wong GL, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. Journal of Viral Hepatitis. 2009;**16**(1):36-44. DOI: 10.1111/j.1365-2893.2008.01037.x

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hepatitis B: A cohort study with internal validation. Alimentary Pharmacology and Therapeutics. 2011;**34**(3):353-362. DOI: 10.1111/j.1365-2036.2011.04722.x

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*Ultrasound Elastography*

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measurement by transient elastography

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clinical practice guidelines: Noninvasive tests for evaluation of liver disease severity and prognosis. Journal of Hepatology. 2015;**63**(1):237-264. DOI:

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10.1016/j.jhep.2010.05.035

[38] Cardoso AC, Carvalho-Filho RJ, Stern C, Dipumpo A, Giuily N, Ripault MP, et al. Direct comparison of diagnostic performance of transient

10.1016/j.jhep.2015.04.006

2007;**53**(9):1615-1622

with the liver biopsy. World Journal of Gastroenterology. 2008;**14**(42):6513-6517

[27] Bioulac-Sage P, Couffinhal T, Foucher J, Balabaud CP. Interpreting liver stiffness in the cirrhotic range. Journal of Hepatology. 2009;**50**(2):423- 424. DOI: 10.1016/j.jhep.2008.11.003

[28] Ziol M, Kettaneh A, Ganne-Carrié N, Barget N, Tengher-Barna I, Beaugrand M. Relationships between

fibrosis amounts assessed by morphometry and liver stiffness measurements in chronic hepatitis or steatohepatitis. European Journal of Gastroenterology and Hepatology. 2009;**21**(11):1261-1268. DOI: 10.1097/

MEG.0b013e32832a20f5

2008;**17**(2):155-163

2005;**41**(1):48-54

2005;**128**(2):343-350

[32] Sporea I, Sirli R, Deleanu A, Tudora A, Curescu M, Cornianu M, et al. Comparison of the liver stiffness

[30] Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F,

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Kazemi F, et al. Noninvasive assessment

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**14**

[39] Viganò M, Paggi S, Lampertico P, Fraquelli M, Massironi S, Ronchi G, et al. Dual cut-off transient elastography to assess liver fibrosis in chronic hepatitis B: A cohort study with internal validation. Alimentary Pharmacology and Therapeutics. 2011;**34**(3):353-362. DOI: 10.1111/j.1365-2036.2011.04722.x

[40] Oliveri F, Coco B, Ciccorossi P, Colombatto P, Romagnoli V, Cherubini B, et al. Liver stiffness in the hepatitis B virus carrier: A non-invasive marker of liver disease influenced by the pattern of transaminases. World Journal of Gastroenterology. 2008;**14**(40):6154-6162

[41] Lesmana CR, Salim S, Hasan I, Sulaiman AS, Gani RA, Pakasi LS, et al. Diagnostic accuracy of transient elastography (FibroScan) versus the aspartate transaminase to platelet ratio index in assessing liver fibrosis in chronic hepatitis B: The role in primary care setting. Journal of Clinical Pathology. 2011;**64**(10):916-920. DOI: 10.1136/jclinpath-2011-200044

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[44] Meng F, Zheng Y, Zhang Q, Mu X, Xu X, Zhang H, et al. Noninvasive

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Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Digestive and Liver Disease. 2008;**40**(5):371-378. DOI: 10.1016/j.

Fujita K, Endo H, Iida H, et al.

[58] Lupsor-Platon M, Badea R. Noninvasive assessment of alcoholic liver disease using unidimensional transient elastography (Fibroscan(®)). World Journal of Gastroenterology. 2015;**21**(42):11914-11923. DOI: 10.3748/

[59] Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, et al. Increased liver stiffness in alcoholic liver disease: Differentiating

fibrosis from steatohepatitis. World Journal of Gastroenterology. 2010;**16**:966-972. DOI: 10.3748/wjg.v16.

[61] Janssens F, de Suray N,

of advanced fibrosis in alcoholic patients: A real-life study. Journal of Clinical Gastroenterology.

Piessevaux H, Horsmans Y, de Timary P, Stärkel P. Can transient elastography replace liver histology for determination

[60] Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Lédinghen V, Douvin C, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. Journal of Hepatology. 2008;**49**:1062- 1068. DOI: 10.1016/j.jhep.2008.08.011

liv.12584

10.1002/hep.23312

dld.2007.10.019

wjg.v21.i42.11914

i8.966

[51] Kwok R, Tse YK, Wong GL, Ha Y, Lee AU, Ngu MC, et al. Systematic review with metaanalysis: Non-invasive assessment of non-alcoholic fatty liver disease—The role of transient elastography and plasma cytokeratin-18 fragments. Alimentary Pharmacology and Therapeutics. 2014;**39**(3):254-269.

[52] Kumar R, Rastogi A, Sharma MK, Bhatia V, Tyagi P, Sharma P, et al. Liver stiffness measurements in patients with different stages of nonalcoholic fatty liver disease: Diagnostic performance and clinicopathological correlation. Digestive Diseases and Sciences. 2013;**58**(1):265-274. DOI: 10.1007/

**16**

[62] Thiele M, Detlefsen S, Sevelsted Møller L, Madsen BS, Fuglsang Hansen J, Fialla AD, et al. Transient and 2-dimensional shear-wave elastography provide comparable assessment of alcoholic liver fibrosis and cirrhosis. Gastroenterology. 2016;**150**:123-133. DOI: 10.1053/j.gastro.2015.09.040

[63] Pavlov CS, Casazza G, Nikolova D, Tsochatzis E, Burroughs AK, Ivashkin VT, et al. Transient elastography for diagnosis of stages of hepatic fibrosis and cirrhosis in people with alcoholic liver disease. Cochrane Database of Systematic Reviews. 2015;**1**:CD010542. DOI: 10.1002/14651858.CD010542.pub2

[64] de Lédinghen V, Douvin C, Kettaneh A, Ziol M, Roulot D, Marcellin P, et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C viruscoinfected patients. Journal of Acquired Immune Deficiency Syndromes. 2006;**41**(2):175-179

[65] Vergara S, Macías J, Rivero A, et al. The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C virus coinfection. Clinical Infectious Diseases. 2007;**45**(8):969-974. DOI: 10.1086/521857

[66] Carrion JA, Navasa M, Bosch J, Bruguera M, Gilabert R, Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transplantation. 2006;**12**(12):1791- 1798. DOI: 10.1002/lt.20857

[67] Rigamonti C, Donato MF, Fraquelli M, Agnelli F, Ronchi G, Casazza G, et al. Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation. Gut.

2008;**57**(6):821-827. DOI: 10.1136/ gut.2007.135046

[68] Corradi F, Piscaglia F, Flori S, D'Errico-Grigioni A, Vasuri F, Tamé MR, et al. Assessment of liver fibrosis in transplant recipients with recurrent HCV infection: Usefulness of transient elastography. Digestive and Liver Disease. 2009;**41**(3):217-225. DOI: 10.1016/j.dld.2008.06.009

[69] Harada N, Soejima Y, Taketomi A, Yoshizumi T, Ikegami T, Yamashita Y, et al. Assessment of graft fibrosis by transient elastography in patients with recurrent hepatitis C after living donor liver transplantation. Transplantation. 2008;**85**(1):69-74. DOI: 10.1097/01. tp.0000297248.18483.16

[70] Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouillères O, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology. 2006;**43**(5):1118-1124. DOI: 10.1002/hep.21151

[71] Adhoute X, Foucher J, Laharie D, Terrebonne E, Vergniol J, Castéra L, et al. Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: A prospective study. Gastroentérologie Clinique et Biologique. 2008;**32**(2):180-187

[72] Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: A metaanalysis. Gastroenterology. 2008;**134**(4):960-974

[73] Stebbing J, Farouk L, Panos G, Anderson M, Jiao LR, Mandalia S, et al. A meta-analysis of transient elastography for the detection of hepatic fibrosis. Journal of Clinical Gastroenterology. 2010;**44**(3):214-219. DOI: 10.1097/MCG.0b013e3181b4af1f

[74] Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy. Journal of Hepatology. 2011;**54**(4):650-659. DOI: 10.1016/j.jhep.2010.07.033

[75] Castéra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. Journal of Hepatology. 2009;**50**(1):59-68. DOI: 10.1016/j.jhep.2008.08.018

[76] Kazemi F, Kettaneh A, N'kontchou G, Pinto E, Ganne-Carrie N, Trinchet JC, et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. Journal of Hepatology. 2006;**45**(2):230-235. DOI: 10.1016/j.jhep.2006.04.006

[77] Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology. 2007;**45**(5):1290-1297. DOI: 10.1002/ hep.21665

[78] Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Alimentary Pharmacology and Therapeutics. 2008;**27**(12):1261-1268. DOI: 10.1111/j.1365-2036.2008.03701.x

[79] Lemoine M, Katsahian S, Ziol M, Nahon P, Ganne-Carrie N, Kazemi F, et al. Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or

alcohol-related cirrhosis. Alimentary Pharmacology and Therapeutics. 2008;**28**(9):1102-1110. DOI: 10.1111/j.1365-2036.2008.03825.x

[80] de Franchis R, editor. Portal hypertension VI. In: Proceedings of the Sixth Baveno Consensus Workshop: Stratifying Risk and Individualizing Care. Switzerland: Springer International Publishing; 2016. DOI: 10.1007/978-3-319-23018-4

[81] Masuzaki R, Tateishi R, Yoshida H, Yoshida H, Sato S, Kato N, et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. Journal of Clinical Gastroenterology. 2008;**42**(7):839-843

[82] Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T, Ohki T, et al. Prospective risk assessment for hepatocellular carcinoma development in chronic hepatitis C patients by transient elastography. Hepatology. 2009;**49**(6):1954-1961. DOI: 10.1002/ hep.22870

[83] Feier D, Lupsor Platon M, Stefanescu H, Badea R. Transient elastography for the detection of hepatocellular carcinoma in viral C liver cirrhosis. Is there something else than increased liver stiffness? Journal of Gastrointestinal and Liver Diseases. 2013;**22**(3):283-289

[84] Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): Where does it stand in the United States practice. Clinical Gastroenterology and Hepatology. 2015;**13**(1):27-36. DOI: 10.1016/j.cgh.2014.04.039

[85] Pinzani M. Non-invasive evaluation of hepatic fibrosis: Don't count your chickens before they're hatched. Gut. 2006;**55**(3):310-312. DOI: 0.1136/ gut.2005.068585

**19**

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient…*

*DOI: http://dx.doi.org/10.5772/intechopen.89970*

[86] Laharie D, Zerbib F, Adhoute X, Boué-Lahorgue X, Foucher J, Castéra L, et al. Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate. Alimentary Pharmacology and Therapeutics. 2006;**23**(11):1621-1628. DOI: 10.1111/j.1365-2036.2006.02929.x

[87] Castera L, Vilgrain V, Angulo P.

Gastroenterology and Hepatology. 2013;**10**(11):666-675. DOI: 10.1038/

Noninvasive evaluation of NAFLD. Nature Reviews.

nrgastro.2013

*Noninvasive Assessment of Diffuse Liver Diseases Using Vibration-Controlled Transient… DOI: http://dx.doi.org/10.5772/intechopen.89970*

[86] Laharie D, Zerbib F, Adhoute X, Boué-Lahorgue X, Foucher J, Castéra L, et al. Diagnosis of liver fibrosis by transient elastography (FibroScan) and non-invasive methods in Crohn's disease patients treated with methotrexate. Alimentary Pharmacology and Therapeutics. 2006;**23**(11):1621-1628. DOI: 10.1111/j.1365-2036.2006.02929.x

*Ultrasound Elastography*

10.1016/j.jhep.2010.07.033

10.1016/j.jhep.2008.08.018

G, Pinto E, Ganne-Carrie N, Trinchet JC, et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. Journal of

10.1016/j.jhep.2006.04.006

hep.21665

[76] Kazemi F, Kettaneh A, N'kontchou

Hepatology. 2006;**45**(2):230-235. DOI:

[77] Vizzutti F, Arena U, Romanelli RG, Rega L, Foschi M, Colagrande S, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology. 2007;**45**(5):1290-1297. DOI: 10.1002/

[78] Bureau C, Metivier S, Peron JM, Selves J, Robic MA, Gourraud PA, et al. Transient elastography accurately

[79] Lemoine M, Katsahian S, Ziol M, Nahon P, Ganne-Carrie N, Kazemi F, et al. Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or

predicts presence of significant portal hypertension in patients with chronic liver disease. Alimentary Pharmacology and Therapeutics. 2008;**27**(12):1261-1268. DOI: 10.1111/j.1365-2036.2008.03701.x

[75] Castéra L, Le Bail B, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. Journal of Hepatology. 2009;**50**(1):59-68. DOI:

[74] Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy. Journal of Hepatology. 2011;**54**(4):650-659. DOI:

alcohol-related cirrhosis. Alimentary Pharmacology and Therapeutics. 2008;**28**(9):1102-1110. DOI: 10.1111/j.1365-2036.2008.03825.x

[80] de Franchis R, editor. Portal hypertension VI. In: Proceedings of the Sixth Baveno Consensus Workshop: Stratifying Risk and Individualizing

International Publishing; 2016. DOI:

Yoshida H, Yoshida H, Sato S, Kato N, et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. Journal of Clinical Gastroenterology.

Care. Switzerland: Springer

10.1007/978-3-319-23018-4

[81] Masuzaki R, Tateishi R,

[82] Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T, Ohki T, et al. Prospective risk assessment for hepatocellular carcinoma development in chronic hepatitis C patients by transient elastography. Hepatology. 2009;**49**(6):1954-1961. DOI: 10.1002/

[83] Feier D, Lupsor Platon M, Stefanescu H, Badea R. Transient elastography for the detection of hepatocellular carcinoma in viral C liver cirrhosis. Is there something else than increased liver stiffness? Journal of Gastrointestinal and Liver Diseases.

[84] Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): Where does it stand in the United States practice. Clinical Gastroenterology and Hepatology. 2015;**13**(1):27-36. DOI:

[85] Pinzani M. Non-invasive evaluation of hepatic fibrosis: Don't count your chickens before they're hatched. Gut. 2006;**55**(3):310-312. DOI: 0.1136/

2013;**22**(3):283-289

10.1016/j.cgh.2014.04.039

gut.2005.068585

2008;**42**(7):839-843

hep.22870

**18**

[87] Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nature Reviews. Gastroenterology and Hepatology. 2013;**10**(11):666-675. DOI: 10.1038/ nrgastro.2013

**21**

**Chapter 2**

**Abstract**

promising results.

**1. Introduction**

Touch Quantification, ElastPQ

methods can be either biological or elastographic [1].

Techniques

Liver Fibrosis Assessment by

*Roxana Șirli, Alina Popescu and Ioan Sporea*

Point Shear-Wave Elastography

Point shear-wave elastographic (pSWE) techniques use acoustic radiation force impulse (ARFI) to stimulate the liver tissue and to generate shear waves that propagate into the liver. The shear-wave velocity (SWV) increases with the severity of fibrosis. The first type of pSWE was Virtual Touch Quantification (VTQ ) developed by Siemens, followed by ElastPQ by Philips, and nowadays pSWE is available on other systems (Hitachi, Esaote, Samsung). To evaluate liver fibrosis by pSWE, ten valid measurements are performed in the right liver lobe; a median value is calculated, with the results expressed in meters/second or in kilopascals (kPa) (if the operator chooses). VTQ is a reproducible method, the intraclass correlation coefficient (ICC) for inter- and intraobserver measurements ranging from 0.81 to 0.87. Confounding factors for VTQ are non-fasting conditions, elevated aminotransferases, congestive heart failure, and extrahepatic cholestasis. In patients with chronic hepatopathies, the AUROCs for predicting significant fibrosis range between 0.75 and 0.85 and for predicting cirrhosis between 0.85 and 0.95. There were promising results regarding the value of VTQ to predict liver cirrhosis complications, especially portal hypertension. ElastPQ is a newly developed point shearwave elastographic method (from Philips). Only few data were published but with

**Keywords:** liver fibrosis, liver elastography, point shear-wave elastography, Virtual

Evaluation of liver fibrosis severity is essential in chronic hepatopathies, especially for prognosis, but also for decision regarding treatment in some cases or for follow-up [1]. For a long time, liver biopsy was considered to be the reference method for fibrosis assessment. Not only mainly due to its invasiveness [2] but also due to issues regarding inter-observer variability and sampling errors [3], noninvasive methods have been developed to assess the severity of liver fibrosis. These

Elastographic techniques are based on an intrinsic property of tissue elasticity. When an extrinsic force is applied to a tissue, it deforms more or less according to its elasticity. Less elastic, stiffer tissue deforms less when subjected to an external force. Elastographic techniques measure tissue displacement when subjected to

#### **Chapter 2**

## Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques

*Roxana Șirli, Alina Popescu and Ioan Sporea*

#### **Abstract**

Point shear-wave elastographic (pSWE) techniques use acoustic radiation force impulse (ARFI) to stimulate the liver tissue and to generate shear waves that propagate into the liver. The shear-wave velocity (SWV) increases with the severity of fibrosis. The first type of pSWE was Virtual Touch Quantification (VTQ ) developed by Siemens, followed by ElastPQ by Philips, and nowadays pSWE is available on other systems (Hitachi, Esaote, Samsung). To evaluate liver fibrosis by pSWE, ten valid measurements are performed in the right liver lobe; a median value is calculated, with the results expressed in meters/second or in kilopascals (kPa) (if the operator chooses). VTQ is a reproducible method, the intraclass correlation coefficient (ICC) for inter- and intraobserver measurements ranging from 0.81 to 0.87. Confounding factors for VTQ are non-fasting conditions, elevated aminotransferases, congestive heart failure, and extrahepatic cholestasis. In patients with chronic hepatopathies, the AUROCs for predicting significant fibrosis range between 0.75 and 0.85 and for predicting cirrhosis between 0.85 and 0.95. There were promising results regarding the value of VTQ to predict liver cirrhosis complications, especially portal hypertension. ElastPQ is a newly developed point shearwave elastographic method (from Philips). Only few data were published but with promising results.

**Keywords:** liver fibrosis, liver elastography, point shear-wave elastography, Virtual Touch Quantification, ElastPQ

#### **1. Introduction**

Evaluation of liver fibrosis severity is essential in chronic hepatopathies, especially for prognosis, but also for decision regarding treatment in some cases or for follow-up [1]. For a long time, liver biopsy was considered to be the reference method for fibrosis assessment. Not only mainly due to its invasiveness [2] but also due to issues regarding inter-observer variability and sampling errors [3], noninvasive methods have been developed to assess the severity of liver fibrosis. These methods can be either biological or elastographic [1].

Elastographic techniques are based on an intrinsic property of tissue elasticity. When an extrinsic force is applied to a tissue, it deforms more or less according to its elasticity. Less elastic, stiffer tissue deforms less when subjected to an external force. Elastographic techniques measure tissue displacement when subjected to

an external force. In chronic hepatopathies, as fibrosis progresses, the liver tissue becomes stiffer, less elastic; thus, liver stiffness (LS) is considered to be an indicator of liver fibrosis severity [1, 4, 5]. Elastographic techniques can be ultrasound-based or based on magnetic resonance imaging.

According to the latest guidelines [4–9], ultrasound-based elastographic techniques are divided into strain elastography (which measures longitudinal displacement) and shear-wave elastography (SWE—which measures the speed of the shear waves generated into the tissue when an external force is applied). Based on the type of impulse that generates the shear waves, SWE is subdivided into transient elastography (TE—where a mechanical stimulus is applied to the tissue) and acoustic radiation force impulse (ARFI) techniques (where the stimulus deforming the tissue is an acoustic "push pulse" generated by the transducer). Subsequently, ARFI elastography is subdivided into point SWE (in which LS is measured in a region of interest (ROI)) and multidimensional SWE (2D-SWE and 3D-SWE—in which a color-coded elastogram is obtained and shear-wave speed is also measured in a region of interest).

In the following pages, we will present point shear-wave elastography techniques.

#### **2. Point shear-wave elastography: basic principles**

pSWE is a type of SWE in which tissue stimulation is performed at a certain depth by an acoustic radiation force impulse generated by the transducer (ARFI technology), which generates shear waves that propagate into the tissue, perpendicularly on the axis of the initial pulse. Shear-wave velocity (SWV), expressed in meters/second (m/s), is measured in a predefined ROI chosen by the operator while performing B-mode ultrasonography. The average propagation speed of the shear waves, from a point placed on the lateral margin of the ROI to an opposite point on the ROI, can be measured by detecting its time of arrival at that point, relative to the acoustic "push" pulse [5]. The stiffer the tissue, the higher the shearwave velocity [4–9].

Most systems performing pSWE allow the choice to express measurement results either in m/s or in kilopascals (kPa). Kilopascal is the unit of the elastic modulus, obtained by converting the SWV to an elastic modulus, using an equation that assumes that the tissue density is always the same and also that the elastic modulus is not influenced by the magnitude, frequency, and direction of the applied force [5]. Thus, even if kPa is the unit to which users are the most familiar (since it was used for Transient Elastography), the most correct one is m/s [5–7].

Two types of pSWE have been more thoroughly evaluated, the ones developed by Siemens (Virtual Touch Quantification) and by Philips (ElastPQ ). Currently other manufacturers also offer pSWE on their systems: Esaote, Hitachi, and Samsung [5].

#### **3. Point shear-wave elastography (pSWE): examination technique**

First of all, before performing SWE the *operator should be trained* [5, 6, 8, 9]. If for TE training means performing more than 100 examinations under supervision [10], what training means is less precise for pSWE. A study published by Boursier concluded that there is no training effect on the accuracy of LS measurements by VTQ (ARFI) [11]. Concerning ElastPQ, a published study concluded that after a 1-year learning curve, or 130 examinations, the accuracy of ElastPQ matches that

**23**

**Figure 1.** *VTQ measurement.*

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

measurements but also in ultrasonography is needed.

at 4–5 cm from the transducer [5, 6, 8, 9] (**Figures 1** and **2**).

were significantly higher than that at the end-inspiration [17].

of TE [12]. Considering that adequate B-mode image is a must for reliable pSWE measurements [5, 9], it is sensible to consider that training not only in elastographic

According to the guidelines, the *recommended technique* of pSWE measurements is with the patient in supine position with the right arm in maximal extension, through an intercostal approach, during breath hold, avoiding deep inspiration or expiration [5, 6, 8]. The transducer should be perpendicular on the liver capsule, and the ROI should be placed in the right liver lobe, as to avoid large blood vessels and masses, at a depth of minimum 1 cm below the liver capsule, best

A study published by our group demonstrated that the best correlation of VTQ measurements with histology was obtained for SWV measurements made 1–2 and 2–3 cm beneath the liver capsule but with a lower feasibility for deeper measurements [13]. Several studies observed higher SWV by VTQ in the left liver lobe vs. the right liver lobe [14–16]. Regarding ElastPQ, measurements made in liver segment V had the lowest coefficient of variation, and SWVs at the end-expiration

For an appropriate estimation of fibrosis, the guidelines recommend to perform ten pSWE measurements and to calculate the median (M) value [5, 6, 8, 9]. When VTQ was launched, the manufacturer did not recommend *quality criteria*, but several studies demonstrated that there is a better correlation between histologic fibrosis and pSWE measurements if quality criteria such as interquartile range (IQR) and success rate (SR) are met. Regarding VTQ, an IQR/M ≥ 30% was associated with a discordance of at least two stages of fibrosis between SWV and histologic fibrosis [18]. In another study from our group, a very strong correlation of VTQ measurements with histologic fibrosis was observed when quality parameters (IQR < 30% and SR ≥ 60%) were met (r = 0.722, p < 0.0001); if not, there was no significant correlation (r = 0.268, p = 0.07) [19]. Also, standard deviation (SD) of the mean of ten valid SWV measurements by VTQ was evaluated as a quality criterion. Exclusion of patients in whom the SD was higher than 30% lead to an improved accuracy of VTQ [20]. Regarding ElastPQ®, IQR/M ≤ 30% is also the most important quality criterion [21, 22]. European guidelines recommend as quality criterion for pSWE an IQR/M ≤ 30% [5, 8], while the WFUMB guidelines

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

#### *Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

*Ultrasound Elastography*

in a region of interest).

wave velocity [4–9].

Samsung [5].

techniques.

or based on magnetic resonance imaging.

an external force. In chronic hepatopathies, as fibrosis progresses, the liver tissue becomes stiffer, less elastic; thus, liver stiffness (LS) is considered to be an indicator of liver fibrosis severity [1, 4, 5]. Elastographic techniques can be ultrasound-based

According to the latest guidelines [4–9], ultrasound-based elastographic techniques are divided into strain elastography (which measures longitudinal displacement) and shear-wave elastography (SWE—which measures the speed of the shear waves generated into the tissue when an external force is applied). Based on the type of impulse that generates the shear waves, SWE is subdivided into transient elastography (TE—where a mechanical stimulus is applied to the tissue) and acoustic radiation force impulse (ARFI) techniques (where the stimulus deforming the tissue is an acoustic "push pulse" generated by the transducer). Subsequently, ARFI elastography is subdivided into point SWE (in which LS is measured in a region of interest (ROI)) and multidimensional SWE (2D-SWE and 3D-SWE—in which a color-coded elastogram is obtained and shear-wave speed is also measured

In the following pages, we will present point shear-wave elastography

pSWE is a type of SWE in which tissue stimulation is performed at a certain depth by an acoustic radiation force impulse generated by the transducer (ARFI technology), which generates shear waves that propagate into the tissue, perpendicularly on the axis of the initial pulse. Shear-wave velocity (SWV), expressed in meters/second (m/s), is measured in a predefined ROI chosen by the operator while performing B-mode ultrasonography. The average propagation speed of the shear waves, from a point placed on the lateral margin of the ROI to an opposite point on the ROI, can be measured by detecting its time of arrival at that point, relative to the acoustic "push" pulse [5]. The stiffer the tissue, the higher the shear-

Most systems performing pSWE allow the choice to express measurement results either in m/s or in kilopascals (kPa). Kilopascal is the unit of the elastic modulus, obtained by converting the SWV to an elastic modulus, using an equation that assumes that the tissue density is always the same and also that the elastic modulus is not influenced by the magnitude, frequency, and direction of the applied force [5]. Thus, even if kPa is the unit to which users are the most familiar (since it was used for Transient Elastography), the most correct one is m/s [5–7]. Two types of pSWE have been more thoroughly evaluated, the ones developed by Siemens (Virtual Touch Quantification) and by Philips (ElastPQ ). Currently other manufacturers also offer pSWE on their systems: Esaote, Hitachi, and

**3. Point shear-wave elastography (pSWE): examination technique**

First of all, before performing SWE the *operator should be trained* [5, 6, 8, 9]. If for TE training means performing more than 100 examinations under supervision [10], what training means is less precise for pSWE. A study published by Boursier concluded that there is no training effect on the accuracy of LS measurements by VTQ (ARFI) [11]. Concerning ElastPQ, a published study concluded that after a 1-year learning curve, or 130 examinations, the accuracy of ElastPQ matches that

**2. Point shear-wave elastography: basic principles**

**22**

of TE [12]. Considering that adequate B-mode image is a must for reliable pSWE measurements [5, 9], it is sensible to consider that training not only in elastographic measurements but also in ultrasonography is needed.

According to the guidelines, the *recommended technique* of pSWE measurements is with the patient in supine position with the right arm in maximal extension, through an intercostal approach, during breath hold, avoiding deep inspiration or expiration [5, 6, 8]. The transducer should be perpendicular on the liver capsule, and the ROI should be placed in the right liver lobe, as to avoid large blood vessels and masses, at a depth of minimum 1 cm below the liver capsule, best at 4–5 cm from the transducer [5, 6, 8, 9] (**Figures 1** and **2**).

A study published by our group demonstrated that the best correlation of VTQ measurements with histology was obtained for SWV measurements made 1–2 and 2–3 cm beneath the liver capsule but with a lower feasibility for deeper measurements [13]. Several studies observed higher SWV by VTQ in the left liver lobe vs. the right liver lobe [14–16]. Regarding ElastPQ, measurements made in liver segment V had the lowest coefficient of variation, and SWVs at the end-expiration were significantly higher than that at the end-inspiration [17].

For an appropriate estimation of fibrosis, the guidelines recommend to perform ten pSWE measurements and to calculate the median (M) value [5, 6, 8, 9]. When VTQ was launched, the manufacturer did not recommend *quality criteria*, but several studies demonstrated that there is a better correlation between histologic fibrosis and pSWE measurements if quality criteria such as interquartile range (IQR) and success rate (SR) are met. Regarding VTQ, an IQR/M ≥ 30% was associated with a discordance of at least two stages of fibrosis between SWV and histologic fibrosis [18]. In another study from our group, a very strong correlation of VTQ measurements with histologic fibrosis was observed when quality parameters (IQR < 30% and SR ≥ 60%) were met (r = 0.722, p < 0.0001); if not, there was no significant correlation (r = 0.268, p = 0.07) [19]. Also, standard deviation (SD) of the mean of ten valid SWV measurements by VTQ was evaluated as a quality criterion. Exclusion of patients in whom the SD was higher than 30% lead to an improved accuracy of VTQ [20]. Regarding ElastPQ®, IQR/M ≤ 30% is also the most important quality criterion [21, 22]. European guidelines recommend as quality criterion for pSWE an IQR/M ≤ 30% [5, 8], while the WFUMB guidelines

**Figure 1.** *VTQ measurement.*

**Figure 2.** *ElastPQ measurement.*

recommend an even smaller IQR/M, of less than 15%, if results are expressed in m/s [9]. A new multicenter study with ElastPQ® showed that the median value of five measurements with an IQR/M ≤ 30% is accurate enough for daily practice [22].

#### **4. Point shear-wave elastography (pSWE): feasibility and reproducibility**

As opposed to TE, pSWE is *feasible* in patients with ascites [5, 6, 8, 9]. Furthermore, in published studies, the feasibility is better as compared to TE, being higher than 92%, both in VTQ [11, 23–25] and in ElastPQ [26, 27]. In a multicenter study on VTQ, older age, higher BMI, and male gender were associated with failed and unreliable measurements [25].

Regarding *reproducibility* of VTQ, several studies demonstrated very good inter- and intraobserver reproducibility, with intraclass correlation coefficients (ICC) higher than 0.81 [10, 28, 29]. A study that evaluated factors that influenced reproducibility found out that intraoperator reproducibility was better than the inter-operator one (ICC of 0.90 vs. 0.81) [28]. Both intra- and inter-operator reproducibilities were better in men than in women, in patients with lower BMI, and in patients with no ascites and in cirrhotic than in non-cirrhotic patients [28].

ElastPQ was also proved to be a reproducible method, reported ICC ranging from 0.798 [30] to 0.96 [31]. In a study published by Fraquelli, the reproducibility was influenced by training, but not by age, gender, BMI, liver enzymes, and liver etiology [12].

#### **5. Point shear-wave elastography (pSWE): confounding factors**

One of the first confounding factors that should be taken into consideration is examination in *non-fasting* conditions. In a study published by our group, it was demonstrated that food intake can lead to a significant increase in SWVs measured by VTQ in healthy volunteers 1 hour post meal, the values decreasing to baseline 3 hours after the meal [32]. Even if no data was published regarding ElastPQ, the

**25**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

ments should be performed in fasting patients [5, 6, 8, 9].

be performed after a minimum 10 minutes of rest [5].

observation in VTQ was similar to what happens with TE measurements in nonfasting patients, and thus the guidelines recommendation that pSWE measure-

Another factor that can lead to a falsely increased SWV measured by VTQ is *physical exercise* [33]. Thus, the EFSUMB guidelines recommend that SWE should

An important confounding factor for SWE is liver necroinflammation, objectified by *elevated aminotransferase levels*. Several studies demonstrated that elevated aminotransferase levels are associated with higher SWVs by VTQ for the same severity of liver fibrosis, as compared to those observed in patients with normal or only slightly elevated aminotransferases [34, 35]. Also, a significant decrease in SWVs was observed in a case report of acute liver failure, in parallel to the normal-

The influence of necroinflammation on SWVs measured by ElastPQ is controversial. In a study by Ma et al., the grade of necroinflammatory activity was independently associated with higher ElastPQ values [30], while in the study of

are *right heart failure* [37] and the *presence of extrahepatic cholestasis* [38].

**6. Point shear-wave elastography (pSWE): normal values** 

The SWV by pSWE in healthy livers were evaluated by several authors. Regarding VTQ, normal SWV values ranged between 1.07 and 1.19 m/s [15, 39–42], and they were not influenced by gender and age, but higher values were observed in

Regarding ElastPQ**,** normal values are in the same range as for VTQ [17, 31, 43],

Current guidelines state that SWE measurements in the liver in normal range can rule out significant fibrosis if they are in accordance with clinical and biologic

Multiple studies have been published regarding the value of VTQ elastography in patients with chronic liver diseases, considering biopsy as the reference. We sum-

Four meta-analyses were published regarding the value of VTQ for liver fibrosis

assessment. The first one, by Friedrich-Rust et al., included 518 patients with hepatopathies of various etiologies. The summary AUROCs of VTQ for predicting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3), and cirrhosis were 0.87, 0.91,

**7. Point shear-wave elastography (pSWE) in patients with chronic** 

Similar to TE, other confounding factors, which falsely increase SWVs by pSWE

Considering all the studies mentioned above, EFSUMB and WFUMB guidelines caution about the confounding factors for pSWE and state that liver inflammation (indicated by AST and/or ALT elevation >5 times the normal limits), obstructive cholestasis, liver congestion, acute hepatitis, and infiltrative liver diseases should be excluded before pSWE to avoid overestimation of fibrosis and/or should be consid-

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

ization of liver function tests [36].

Ferraioli et al., it had no influence [31].

ered when interpreting the results [5, 9].

the left liver lobe than in the right liver lobe [15].

but a study found higher values in men than in women [17].

**in a healthy liver**

data [5, 9].

**hepatopathies**

marized some of them in **Table 1**.

**7.1 Mixed cohorts**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

*Ultrasound Elastography*

**reproducibility**

**Figure 2.**

*ElastPQ measurement.*

and unreliable measurements [25].

recommend an even smaller IQR/M, of less than 15%, if results are expressed in m/s [9]. A new multicenter study with ElastPQ® showed that the median value of five measurements with an IQR/M ≤ 30% is accurate enough for daily practice [22].

**4. Point shear-wave elastography (pSWE): feasibility and** 

As opposed to TE, pSWE is *feasible* in patients with ascites [5, 6, 8, 9].

Furthermore, in published studies, the feasibility is better as compared to TE, being higher than 92%, both in VTQ [11, 23–25] and in ElastPQ [26, 27]. In a multicenter study on VTQ, older age, higher BMI, and male gender were associated with failed

Regarding *reproducibility* of VTQ, several studies demonstrated very good inter- and intraobserver reproducibility, with intraclass correlation coefficients (ICC) higher than 0.81 [10, 28, 29]. A study that evaluated factors that influenced reproducibility found out that intraoperator reproducibility was better than the inter-operator one (ICC of 0.90 vs. 0.81) [28]. Both intra- and inter-operator reproducibilities were better in men than in women, in patients with lower BMI, and in patients with no ascites and in cirrhotic than in non-cirrhotic patients [28].

ElastPQ was also proved to be a reproducible method, reported ICC ranging from 0.798 [30] to 0.96 [31]. In a study published by Fraquelli, the reproducibility was influenced by training, but not by age, gender, BMI, liver enzymes, and liver

One of the first confounding factors that should be taken into consideration is examination in *non-fasting* conditions. In a study published by our group, it was demonstrated that food intake can lead to a significant increase in SWVs measured by VTQ in healthy volunteers 1 hour post meal, the values decreasing to baseline 3 hours after the meal [32]. Even if no data was published regarding ElastPQ, the

**5. Point shear-wave elastography (pSWE): confounding factors**

**24**

etiology [12].

observation in VTQ was similar to what happens with TE measurements in nonfasting patients, and thus the guidelines recommendation that pSWE measurements should be performed in fasting patients [5, 6, 8, 9].

Another factor that can lead to a falsely increased SWV measured by VTQ is *physical exercise* [33]. Thus, the EFSUMB guidelines recommend that SWE should be performed after a minimum 10 minutes of rest [5].

An important confounding factor for SWE is liver necroinflammation, objectified by *elevated aminotransferase levels*. Several studies demonstrated that elevated aminotransferase levels are associated with higher SWVs by VTQ for the same severity of liver fibrosis, as compared to those observed in patients with normal or only slightly elevated aminotransferases [34, 35]. Also, a significant decrease in SWVs was observed in a case report of acute liver failure, in parallel to the normalization of liver function tests [36].

The influence of necroinflammation on SWVs measured by ElastPQ is controversial. In a study by Ma et al., the grade of necroinflammatory activity was independently associated with higher ElastPQ values [30], while in the study of Ferraioli et al., it had no influence [31].

Similar to TE, other confounding factors, which falsely increase SWVs by pSWE are *right heart failure* [37] and the *presence of extrahepatic cholestasis* [38].

Considering all the studies mentioned above, EFSUMB and WFUMB guidelines caution about the confounding factors for pSWE and state that liver inflammation (indicated by AST and/or ALT elevation >5 times the normal limits), obstructive cholestasis, liver congestion, acute hepatitis, and infiltrative liver diseases should be excluded before pSWE to avoid overestimation of fibrosis and/or should be considered when interpreting the results [5, 9].

#### **6. Point shear-wave elastography (pSWE): normal values in a healthy liver**

The SWV by pSWE in healthy livers were evaluated by several authors. Regarding VTQ, normal SWV values ranged between 1.07 and 1.19 m/s [15, 39–42], and they were not influenced by gender and age, but higher values were observed in the left liver lobe than in the right liver lobe [15].

Regarding ElastPQ**,** normal values are in the same range as for VTQ [17, 31, 43], but a study found higher values in men than in women [17].

Current guidelines state that SWE measurements in the liver in normal range can rule out significant fibrosis if they are in accordance with clinical and biologic data [5, 9].

#### **7. Point shear-wave elastography (pSWE) in patients with chronic hepatopathies**

#### **7.1 Mixed cohorts**

Multiple studies have been published regarding the value of VTQ elastography in patients with chronic liver diseases, considering biopsy as the reference. We summarized some of them in **Table 1**.

Four meta-analyses were published regarding the value of VTQ for liver fibrosis assessment. The first one, by Friedrich-Rust et al., included 518 patients with hepatopathies of various etiologies. The summary AUROCs of VTQ for predicting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3), and cirrhosis were 0.87, 0.91,


#### **Table 1.**

*Performance of VTQ in the assessment of liver fibrosis in cohorts of patients with mixed etiologies of chronic hepatopathies, considering LB as the reference method.*

and 0.93, respectively. TE performed significantly better than VTQ for F2 and cirrhosis, while for F3 the performances evaluated by AUROC were similar [51].

The second one included 1163 patients with chronic hepatopathies evaluated by LB, TE, and VTQ [52]. The first conclusion was that VTQ had a better feasibility than TE (unreliable measurements in 2.1 vs. 6.6% cases, respectively, p < 0.001). The diagnostic odds ratios were similar for VTQ and TE for detection of significant fibrosis and cirrhosis. The mean optimal cutoff value of VTQ for the detection of F2 was 1.30 ± 0.07 m/s, and for cirrhosis, it was 1.80 ± 0.16 m/s.

The third meta-analysis included 3951 patients with liver biopsy as reference method. The AUROCs of VTQ for predicting the presence of F2, F3, and cirrhosis were 0.84, 0.89, and 0.91, respectively [53].

Finally, the fourth meta-analysis including 2691 patients calculated global sensitivity and specificity of VTQ to predict any stage of fibrosis to be 79 and 86%, respectively. The performance of VTQ was higher for more advanced fibrosis: for F ≥ 3 84% Se and 90% Sp (AUROC—0.94), while for F4 86% Se and 84% Sp (AUROC—0.91) [54].

Regarding *ElastPQ*, few data are available. In a study that compared ElastPQ to TE considered as reference, ElastPQ had a better feasibility than TE: 98.7% vs. 90.7%. The AUROCs calculated for significant fibrosis, severe fibrosis, and cirrhosis were 0.94, 0.97, and 0.97, respectively [27].

#### **7.2 Chronic hepatitis C**

There is a lot of published data regarding the performance of VTQ elastography for the assessment of liver fibrosis in patients with chronic hepatitis C, as shown in **Table 2**.

To summarize, according to EFSUMB guidelines, VTQ® cutoffs of 1.21–1.34 m/s predict significant fibrosis (F ≥ 2) (AUROC 0.85–0.89), while VTQ® cutoffs between 1.55 and 2 m/s (AUROC 0.89–0.93) predict cirrhosis [5]. Furthermore,

**27**

out of cirrhosis."

**7.3 Chronic hepatitis B**

with cirrhosis" [5].

obtained in a more recent study [60].

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

**Cutoff (m/s)**

**F ≥ 2 F ≥ 3 F = 4**

**AUROC Cutoff** 

**(m/s)**

**AUROC**

**AUROC Cutoff** 

**(m/s)**

LB—64 p 1.35 0.86 1.55 0.93 1.75 0.95

LB—112 p 1.34 0.851 1.61 0.869 2 0.945

LB—274 p 1.21 0.893 1.58 0.908 1.82 0.937

LB—914 p 1.33 0.792 1.43 0.829 1.55 0.842

LB—139 p 1.3 0.86 1.7 0.94 2 0.89

LB—127 p 1.55 0.847 1.81 0.902 1.98 0.831

according to recommendation 17 of the same guidelines, "pSWE as demonstrated with VTQ® can be used as the first-line assessment for the severity of liver fibrosis in patients with chronic viral hepatitis C. It performs best with regard to the ruling

*Performance of VTQ in the assessment of liver fibrosis in patients with chronic hepatitis C.*

Li et al. [59] LB—128 p 1.53 0.775 1.79 0.901 1.79 0.792

Data regarding the value of ElastPQ for the assessment of liver fibrosis severity in chronic hepatitis C is scarce. In a pilot study, the AUROCs of VTQ for predicting F2, F3, and F4 were 0.80, 0.88, and 0.95, respectively [31]. Similar results have been

*Following successful antiviral HCV treatment*, a significant decrease of VTQ

Several studies have been published regarding the value of VTQ for liver fibrosis

Sub-analysis of data regarding patients with HBV chronic hepatitis from the Nierhoff meta-analysis on VTQ calculated AUROCs of 0.88 for F2 and 0.93 for F4,

Data regarding ElastPQ and chronic HBV hepatitis is scarce, and validation is needed. In a study that compared ElastPQ to liver biopsy in chronic hepatitis B, the authors calculated an AUROC of 0.94 with a cutoff of 6.99 kPa for F2 and an

Regarding HBV chronic hepatitis and pSWE, EFSUMB guidelines state that "pSWE as demonstrated with VTQ is useful in patients with CHB to identify those

Several studies have been published regarding VTQ in the evaluation of liver

values was observed in a study performed by Goertz et al. [61].

assessment in chronic hepatitis B, as shown in **Table 3**.

AUROC of 0.89 with a cutoff of 9.00 kPa for cirrhosis [30].

fibrosis in NAFLD patients. Data is presented in **Table 4**.

with cutoffs of 1.35 and 1.87 m/s, respectively [53].

**7.4 Nonalcoholic fatty liver disease (NAFLD)**

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

**method**

**Study Reference** 

Friedrich-Rust et al. [44]

Lupșor et al. [23]

Sporea et al. [55]

Sporea et al. [56]

Rizzo et al. [57]

Chen et al. [58]

**Table 2.**


*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

#### **Table 2.**

*Ultrasound Elastography*

Friedrich-Rust et al. [44]

Sporea et al. [45]

Takahashi et al. [46]

Goertz et al. [47]

Ebinuma et al. [48]

Colombo et al. [49]

Cassinotto et al. [50]

**Table 1.**

and 0.93, respectively. TE performed significantly better than VTQ for F2 and cirrhosis, while for F3 the performances evaluated by AUROC were similar [51].

*Performance of VTQ in the assessment of liver fibrosis in cohorts of patients with mixed etiologies of chronic* 

**Study Etiology F2 F4**

86 patients HBV + HCV

223 patients Healthy + HBV + HCV

80 patients Healthy + HBV + HCV

> 57 patients HBV + HCV

131 patients Mixed

68 Healthy + mixed

> 349 Mixed

**AUROC TE**

**Cutoff AUROC VTQ**

0.86

0.890

0.94

0.891

— 0.85 — 0.87

0.897 0.922 0.815 0.934

0.84 0.81 0.90 0.90

0.86 1.37 m/s

0.953 1.27 m/s

— 1.34 m/s

0.871 1.3 m/s

**AUROC TE**

**Cutoff AUROC VTQ**

0.91

0.931

0.96

0.888

0.91 1.75 m/s

0.985 1.7 m/s

— 1.8 m/s

0.817 1.88 m/s

was 1.30 ± 0.07 m/s, and for cirrhosis, it was 1.80 ± 0.16 m/s.

were 0.84, 0.89, and 0.91, respectively [53].

*hepatopathies, considering LB as the reference method.*

were 0.94, 0.97, and 0.97, respectively [27].

(AUROC—0.91) [54].

**7.2 Chronic hepatitis C**

The second one included 1163 patients with chronic hepatopathies evaluated by LB, TE, and VTQ [52]. The first conclusion was that VTQ had a better feasibility than TE (unreliable measurements in 2.1 vs. 6.6% cases, respectively, p < 0.001). The diagnostic odds ratios were similar for VTQ and TE for detection of significant fibrosis and cirrhosis. The mean optimal cutoff value of VTQ for the detection of F2

The third meta-analysis included 3951 patients with liver biopsy as reference method. The AUROCs of VTQ for predicting the presence of F2, F3, and cirrhosis

Finally, the fourth meta-analysis including 2691 patients calculated global sensitivity and specificity of VTQ to predict any stage of fibrosis to be 79 and 86%, respectively. The performance of VTQ was higher for more advanced fibrosis: for F ≥ 3 84% Se and 90% Sp (AUROC—0.94), while for F4 86% Se and 84% Sp

Regarding *ElastPQ*, few data are available. In a study that compared ElastPQ to TE considered as reference, ElastPQ had a better feasibility than TE: 98.7% vs. 90.7%. The AUROCs calculated for significant fibrosis, severe fibrosis, and cirrhosis

There is a lot of published data regarding the performance of VTQ elastography for the assessment of liver fibrosis in patients with chronic hepatitis C, as shown in

To summarize, according to EFSUMB guidelines, VTQ® cutoffs of 1.21–1.34 m/s

predict significant fibrosis (F ≥ 2) (AUROC 0.85–0.89), while VTQ® cutoffs between 1.55 and 2 m/s (AUROC 0.89–0.93) predict cirrhosis [5]. Furthermore,

**26**

**Table 2**.

*Performance of VTQ in the assessment of liver fibrosis in patients with chronic hepatitis C.*

according to recommendation 17 of the same guidelines, "pSWE as demonstrated with VTQ® can be used as the first-line assessment for the severity of liver fibrosis in patients with chronic viral hepatitis C. It performs best with regard to the ruling out of cirrhosis."

Data regarding the value of ElastPQ for the assessment of liver fibrosis severity in chronic hepatitis C is scarce. In a pilot study, the AUROCs of VTQ for predicting F2, F3, and F4 were 0.80, 0.88, and 0.95, respectively [31]. Similar results have been obtained in a more recent study [60].

*Following successful antiviral HCV treatment*, a significant decrease of VTQ values was observed in a study performed by Goertz et al. [61].

#### **7.3 Chronic hepatitis B**

Several studies have been published regarding the value of VTQ for liver fibrosis assessment in chronic hepatitis B, as shown in **Table 3**.

Sub-analysis of data regarding patients with HBV chronic hepatitis from the Nierhoff meta-analysis on VTQ calculated AUROCs of 0.88 for F2 and 0.93 for F4, with cutoffs of 1.35 and 1.87 m/s, respectively [53].

Data regarding ElastPQ and chronic HBV hepatitis is scarce, and validation is needed. In a study that compared ElastPQ to liver biopsy in chronic hepatitis B, the authors calculated an AUROC of 0.94 with a cutoff of 6.99 kPa for F2 and an AUROC of 0.89 with a cutoff of 9.00 kPa for cirrhosis [30].

Regarding HBV chronic hepatitis and pSWE, EFSUMB guidelines state that "pSWE as demonstrated with VTQ is useful in patients with CHB to identify those with cirrhosis" [5].

#### **7.4 Nonalcoholic fatty liver disease (NAFLD)**

Several studies have been published regarding VTQ in the evaluation of liver fibrosis in NAFLD patients. Data is presented in **Table 4**.


#### **Table 3.**

*Performance of VTQ in the assessment of liver fibrosis in patients with chronic hepatitis B.*


#### **Table 4.**

*Performance of VTQ in the assessment of liver fibrosis in patients with nonalcoholic fatty liver disease.*

A recently published meta-analysis including 723 patients who evaluated VTQ as a predictor of liver fibrosis in NAFLD patients calculated a summary sensitivity and specificity of VTQ in detecting significant fibrosis of 80.2 and 85.2%, respectively, with a pooled diagnostic odds ratio of 30.13 and with an AUROC of 0.898 [68].

Considering all these data, EFSUMB guidelines conclude that VTQ can be used to exclude cirrhosis in NAFLD patients [5].

#### **8. Point shear-wave elastography (pSWE) for the prediction of liver cirrhosis complications**

Cirrhosis is the final stage of chronic hepatopathies and can have severe complications such as portal hypertension, hepatocellular carcinoma, decompensation, etc. The measurement of hepatic vein pressure gradient (HVPG) is the most accurate method for portal hypertension assessment, but it is an invasive method. HVPG >10 mm Hg means clinically significant portal hypertension (CSPH), while HVPG >12 mm Hg is predictive for variceal bleeding [69].

#### **8.1 Portal hypertension**

An initial study found a good correlation (r = 0.709) of VTQ measurements to HVPG measurements in 48 patients, with the AUROC for predicting CSPH being 0.874 [70]. In a Romanian study in 145 patients, the mean value of VTQ measurements in patients with grades 2 and 3 esophageal varices (EV) was significantly higher than the one in patients with no or small EV (3.06 ± 0.67 vs. 2.81 ± 0.80, p = 0.03) [71].

**29**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

Several studies have evaluated SWVs in the spleen for the prediction of portal hypertension, with conflicting results. In the study by Rifai et al., spleen SWVs performed better than liver SWVs for predicting CSPH [72]. In the study by Vermehren et al., spleen SWV and liver SWV had similar AUROCs for predicting the presence of at least grade 2 EV, but multiple regression analysis showed that spleen measurements performed better [73]. In the study of Takuma et al., spleen VTQ measurements also performed better than in the liver to predict the presence of varices in a

However, according to the EFSUMB guidelines "reliable cut-offs are not available yet and no strong recommendation regarding the cut-offs to be used can be

Published data showed only poor value of VTQ to predict the occurrence of

Even if pSWE is currently implemented in other systems than from Siemens and

pSWE technique implemented on the Hitachi Ascendus system was evaluated

A very interesting idea is to combine several techniques in order to assess not only fibrosis severity but also steatosis and inflammation using the same ultrasound machine. pSWE was combined with strain elastography on a Hitachi system. A study evaluated 388 patients with this combined technique, considering liver biopsy as reference method [76]. The AUROCs to predict fibrosis stage were 0.87, 0.80, 0.83, and 0.80 for F1, F2, F3, and F4, respectively, while the AUROCs for activity

pSWE is an easy to perform elastographic technique, integrated into a standard ultrasound machine, with similar performance to TE to predict fibrosis severity in patients with hepatopathies of various etiologies, the performance increasing with

by a study published in 2017 [75]. Reliable SWV measurements (SWM) were obtained in 87.2% of the 445 patients included. Considering TE as the reference method, cutoff values for pSWE from Hitachi had been calculated to rule in and rule out patients with significant fibrosis (F ≥ 2) and cirrhosis, respectively. SWV were converted to elastic modulus and expressed in kPa. To rule in F ≥ 2, the SWM cutoff was 6.78 kPa, while to rule it out, it was 5.55 kPa (AUROC—0.92). To rule in cirrhosis, the SWM cutoff was 9.15 kPa, and to rule it out, it was 8.41 kPa

**9. Point shear-wave elastography (pSWE): perspectives**

grade were 0.94, 0.74, and 0.76 for A1, A2, and A3, respectively.

Philips, published studies are small or missing altogether.

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

cohort of 340 cirrhotic patients [74].

made due to the limited evidence" [5].

**8.2 Hepatocellular carcinoma (HCC)**

HCC, with an AUROC of 0.54 [73]. There is no data regarding ElastPQ.

(AUROC—0.94).

**10. Conclusion**

the fibrosis severity.

No data is available regarding ElastPQ.

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

Several studies have evaluated SWVs in the spleen for the prediction of portal hypertension, with conflicting results. In the study by Rifai et al., spleen SWVs performed better than liver SWVs for predicting CSPH [72]. In the study by Vermehren et al., spleen SWV and liver SWV had similar AUROCs for predicting the presence of at least grade 2 EV, but multiple regression analysis showed that spleen measurements performed better [73]. In the study of Takuma et al., spleen VTQ measurements also performed better than in the liver to predict the presence of varices in a cohort of 340 cirrhotic patients [74].

No data is available regarding ElastPQ.

However, according to the EFSUMB guidelines "reliable cut-offs are not available yet and no strong recommendation regarding the cut-offs to be used can be made due to the limited evidence" [5].

#### **8.2 Hepatocellular carcinoma (HCC)**

*Ultrasound Elastography*

Friedrich Rust et al. [62]

Zhang et al. [63]

Dong et al. [64]

**Table 3.**

**Study Reference** 

**method**

AUROC of 0.898 [68].

**Table 4.**

to exclude cirrhosis in NAFLD patients [5].

**Study Reference** 

HVPG >12 mm Hg is predictive for variceal bleeding [69].

**cirrhosis complications**

**8.1 Portal hypertension**

A recently published meta-analysis including 723 patients who evaluated VTQ as a predictor of liver fibrosis in NAFLD patients calculated a summary sensitivity and specificity of VTQ in detecting significant fibrosis of 80.2 and 85.2%, respectively, with a pooled diagnostic odds ratio of 30.13 and with an

*Performance of VTQ in the assessment of liver fibrosis in patients with nonalcoholic fatty liver disease.*

**Cutoff (m/s)**

**AUROC Cutoff** 

**(m/s)**

LB—133 p — 0.69 — 0.83 — 0.96

LB—180 p 1.63 0.764 1.74 0.852 2 0.825

LB—81 p 1.29 0.762 1.54 0.882 1.83 0.732

Yoneda et al. [65] LB—54 p 1.77 0.973 1.9 0.976 Friedrich-Rust et al. [66] LB—61 p — 0.71 — 0.74 Fierbinteanu et al. [67] LB—64 p — 0.944 — 0.984

**F ≥ 3 F = 4**

**AUROC Cutoff** 

**(m/s)**

**F ≥ 2 F ≥ 3 F = 4**

**AUROC Cutoff** 

**(m/s)**

**AUROC**

**AUROC**

**method**

*Performance of VTQ in the assessment of liver fibrosis in patients with chronic hepatitis B.*

**Cutoff (m/s)**

Considering all these data, EFSUMB guidelines conclude that VTQ can be used

**8. Point shear-wave elastography (pSWE) for the prediction of liver** 

Cirrhosis is the final stage of chronic hepatopathies and can have severe complications such as portal hypertension, hepatocellular carcinoma, decompensation, etc. The measurement of hepatic vein pressure gradient (HVPG) is the most accurate method for portal hypertension assessment, but it is an invasive method. HVPG >10 mm Hg means clinically significant portal hypertension (CSPH), while

An initial study found a good correlation (r = 0.709) of VTQ measurements to HVPG measurements in 48 patients, with the AUROC for predicting CSPH being 0.874 [70]. In a Romanian study in 145 patients, the mean value of VTQ measurements in patients with grades 2 and 3 esophageal varices (EV) was significantly higher than the one in patients with no or small EV (3.06 ± 0.67 vs. 2.81 ± 0.80,

**28**

p = 0.03) [71].

Published data showed only poor value of VTQ to predict the occurrence of HCC, with an AUROC of 0.54 [73].

There is no data regarding ElastPQ.

#### **9. Point shear-wave elastography (pSWE): perspectives**

Even if pSWE is currently implemented in other systems than from Siemens and Philips, published studies are small or missing altogether.

pSWE technique implemented on the Hitachi Ascendus system was evaluated by a study published in 2017 [75]. Reliable SWV measurements (SWM) were obtained in 87.2% of the 445 patients included. Considering TE as the reference method, cutoff values for pSWE from Hitachi had been calculated to rule in and rule out patients with significant fibrosis (F ≥ 2) and cirrhosis, respectively. SWV were converted to elastic modulus and expressed in kPa. To rule in F ≥ 2, the SWM cutoff was 6.78 kPa, while to rule it out, it was 5.55 kPa (AUROC—0.92). To rule in cirrhosis, the SWM cutoff was 9.15 kPa, and to rule it out, it was 8.41 kPa (AUROC—0.94).

A very interesting idea is to combine several techniques in order to assess not only fibrosis severity but also steatosis and inflammation using the same ultrasound machine. pSWE was combined with strain elastography on a Hitachi system. A study evaluated 388 patients with this combined technique, considering liver biopsy as reference method [76]. The AUROCs to predict fibrosis stage were 0.87, 0.80, 0.83, and 0.80 for F1, F2, F3, and F4, respectively, while the AUROCs for activity grade were 0.94, 0.74, and 0.76 for A1, A2, and A3, respectively.

#### **10. Conclusion**

pSWE is an easy to perform elastographic technique, integrated into a standard ultrasound machine, with similar performance to TE to predict fibrosis severity in patients with hepatopathies of various etiologies, the performance increasing with the fibrosis severity.

*Ultrasound Elastography*

#### **Author details**

Roxana Șirli\*, Alina Popescu and Ioan Sporea Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, Timișoara, Romania

\*Address all correspondence to: roxanasirli@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**31**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

of ultrasound elastography: Part 1: Basic principles and terminology. Ultrasound in Medicine & Biology.

[8] Sporea I, Bota S, Saftoiu A, Sirli R, Gradinaru-Tascau O, Popescu A, et al. Romanian national guidelines and practical recommendations on liver elastography. Medical Ultrasonography.

[9] Ferraioli G, Wong VW, Castera L, Berzigotti A, Sporea I, Dietrich CF, et al. Liver ultrasound Elastography: An update to the world Federation for Ultrasound in medicine and biology guidelines and recommendations. Ultrasound in Medicine & Biology.

[10] Boursier J, Konate A, Gorea G, Reaud S, Quemener E, Oberti F, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clinical Gastroenterology and Hepatology. 2008;**6**(11):1263-1269

[11] Boursier J, Isselin G, Fouchard-Hubert I, Oberti F, Dib N, Lebigot J, et al. Acoustic radiation force impulse: A new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis. European Journal of Gastroenterology & Hepatology.

[12] Fraquelli M, Baccarin A, Casazza G, Conti CB, Giunta M, Massironi S, et al. Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics.

2015;**41**(5):1126-1147

2014;**16**(2):123-138

2018;**44**(12):2419-2440

2010;**22**(9):1074-1084

2016;**44**(4):356-365

[13] Sporea I, Sirli RL, Deleanu A, Popescu A, Focsa M, Danila M, et al. Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

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[2] Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following

percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. Journal of Hepatology.

[3] Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. The American Journal of Gastroenterology. 2002;**97**(10):2614-2618

[4] Bamber J, Cosgrove D, Dietrich CF, Fromageau J, Bojunga J, Calliada F, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology. Ultraschall in

der Medizin. 2013;**34**(2):169-184

Bota S, Cantisani V, Castera L, et al. EFSUMB guidelines and

Medizin. 2017;**38**(4):e48

Biology. 2015;**41**(5):1161-1179

[7] Shiina T, Nightingale KR, Palmeri ML, Hall TJ, Bamber JC, Barr RG, et al. WFUMB guidelines and recommendations for clinical use

[5] Dietrich CF, Bamber J, Berzigotti A,

recommendations on the clinical use of liver ultrasound Elastography, update 2017 (long version). Ultraschall in der

[6] Ferraioli G, Filice C, Castera L, Choi BI, Sporea I, Wilson SR, et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: Liver. Ultrasound in Medicine &

1986;**2**(2):165-173

**References**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

#### **References**

*Ultrasound Elastography*

**30**

**Author details**

Roxana Șirli\*, Alina Popescu and Ioan Sporea

Medicine and Pharmacy, Timișoara, Romania

provided the original work is properly cited.

\*Address all correspondence to: roxanasirli@gmail.com

Department of Gastroenterology and Hepatology, "Victor Babeș" University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] European Association for Study of Liver, Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH clinical practice guidelines: Noninvasive tests for evaluation of liver disease severity and prognosis. Journal of Hepatology. 2015;**63**(1):237-264

[2] Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. Journal of Hepatology. 1986;**2**(2):165-173

[3] Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. The American Journal of Gastroenterology. 2002;**97**(10):2614-2618

[4] Bamber J, Cosgrove D, Dietrich CF, Fromageau J, Bojunga J, Calliada F, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology. Ultraschall in der Medizin. 2013;**34**(2):169-184

[5] Dietrich CF, Bamber J, Berzigotti A, Bota S, Cantisani V, Castera L, et al. EFSUMB guidelines and recommendations on the clinical use of liver ultrasound Elastography, update 2017 (long version). Ultraschall in der Medizin. 2017;**38**(4):e48

[6] Ferraioli G, Filice C, Castera L, Choi BI, Sporea I, Wilson SR, et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: Liver. Ultrasound in Medicine & Biology. 2015;**41**(5):1161-1179

[7] Shiina T, Nightingale KR, Palmeri ML, Hall TJ, Bamber JC, Barr RG, et al. WFUMB guidelines and recommendations for clinical use

of ultrasound elastography: Part 1: Basic principles and terminology. Ultrasound in Medicine & Biology. 2015;**41**(5):1126-1147

[8] Sporea I, Bota S, Saftoiu A, Sirli R, Gradinaru-Tascau O, Popescu A, et al. Romanian national guidelines and practical recommendations on liver elastography. Medical Ultrasonography. 2014;**16**(2):123-138

[9] Ferraioli G, Wong VW, Castera L, Berzigotti A, Sporea I, Dietrich CF, et al. Liver ultrasound Elastography: An update to the world Federation for Ultrasound in medicine and biology guidelines and recommendations. Ultrasound in Medicine & Biology. 2018;**44**(12):2419-2440

[10] Boursier J, Konate A, Gorea G, Reaud S, Quemener E, Oberti F, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clinical Gastroenterology and Hepatology. 2008;**6**(11):1263-1269

[11] Boursier J, Isselin G, Fouchard-Hubert I, Oberti F, Dib N, Lebigot J, et al. Acoustic radiation force impulse: A new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis. European Journal of Gastroenterology & Hepatology. 2010;**22**(9):1074-1084

[12] Fraquelli M, Baccarin A, Casazza G, Conti CB, Giunta M, Massironi S, et al. Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease. Alimentary Pharmacology & Therapeutics. 2016;**44**(4):356-365

[13] Sporea I, Sirli RL, Deleanu A, Popescu A, Focsa M, Danila M, et al. Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies. Ultraschall in der Medizin. 2011;**32**(Suppl 1):S46-S52

[14] Piscaglia F, Salvatore V, Di Donato R, D'Onofrio M, Gualandi S, Gallotti A, et al. Accuracy of VirtualTouch acoustic radiation force impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall in der Medizin. 2011;**32**(2):167-175

[15] Karlas T, Pfrepper C, Wiegand J, Wittekind C, Neuschulz M, Mossner J, et al. Acoustic radiation force impulse imaging (ARFI) for non-invasive detection of liver fibrosis: Examination standards and evaluation of interlobe differences in healthy subjects and chronic liver disease. Scandinavian Journal of Gastroenterology. 2011;**46**(12):1458-1467

[16] Toshima T, Shirabe K, Takeishi K, Motomura T, Mano Y, Uchiyama H, et al. New method for assessing liver fibrosis based on acoustic radiation force impulse: A special reference to the difference between right and left liver. Journal of Gastroenterology. 2011;**46**(5):705-711

[17] Ling W, Lu Q, Quan J, Ma L, Luo Y. Assessment of impact factors on shear wave based liver stiffness measurement. European Journal of Radiology. 2013;**82**(2):335-341

[18] Bota S, Sporea I, Sirli R, Popescu A, Jurchis A. Factors which influence the accuracy of acoustic radiation force impulse (ARFI) elastography for the diagnosis of liver fibrosis in patients with chronic hepatitis C. Ultrasound in Medicine & Biology. 2013;**39**(3):407-412

[19] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Sendroiu M. Factors that influence the correlation of acoustic radiation force impulse (ARFI), elastography with liver fibrosis. Medical Ultrasonography. 2011;**13**(2):135-140

[20] Goertz RS, Sturm J, Pfeifer L, Wildner D, Wachter DL, Neurath

MF, et al. ARFI cut-off values and significance of standard deviation for liver fibrosis staging in patients with chronic liver disease. Annals of Hepatology. 2013;**12**(6):935-941

[21] Ferraioli G, Maiocchi L, Lissandrin R, Tinelli C, De Silvestri A, Filice C, et al. Accuracy of the ElastPQ technique for the assessment of liver fibrosis in patients with chronic hepatitis C: A "real life" single center study. Journal of Gastrointestinal and Liver Diseases. 2016;**25**(3):331-335

[22] Ferraioli G, De Silvestri A, Reiberger T, Taylor-Robinson SD, de Knegt RJ, Maiocchi L, et al. Adherence to quality criteria improves concordance between transient elastography and ElastPQ for liver stiffness assessment—A multicenter retrospective study. Digestive and Liver Disease. 2018;**50**(10):1056-1061

[23] Lupsor M, Badea R, Stefanescu H, Sparchez Z, Branda H, Serban A, et al. Performance of a new elastographic method (ARFI technology) compared to unidimensional transient elastography in the noninvasive assessment of chronic hepatitis C. preliminary results. Journal of Gastrointestinal and Liver Diseases. 2009;**18**(3):303-310

[24] Fierbinteanu-Braticevici C, Andronescu D, Usvat R, Cretoiu D, Baicus C, Marinoschi G. Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis. World Journal of Gastroenterology. 2009;**15**(44):5525-5532

[25] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Jurchis A, et al. Factors associated with the impossibility to obtain reliable liver stiffness measurements by means of acoustic radiation force impulse (ARFI) elastography—analysis of a cohort of 1,031 subjects. European Journal of Radiology. 2014;**83**(2):268-272

**33**

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques*

results. Ultrasound in Medicine & Biology. 2013;**39**(4):579-584

Windhaber J, Dudea SM, Riccabona M. The influence of acute physical effort on liver stiffness estimation using virtual touch quantification (VTQ ). Preliminary results. Medical Ultrasonography. 2016;**18**(2):151-156

[33] Gersak MM, Sorantin E,

[34] Bota S, Sporea I, Peck-Radosavljevic M, Sirli R, Tanaka H, Iijima H, et al. The influence of aminotransferase levels on liver stiffness assessed by acoustic radiation force impulse Elastography: A retrospective multicentre study. Digestive and Liver Disease.

2013;**45**(9):762-768

2012;**57**(6):1682-1691

2012;**33**(4):380-385

2014;**46**(7):625-631

[35] Yoon KT, Lim SM, Park JY, Kim DY, Ahn SH, Han KH, et al. Liver stiffness measurement using acoustic radiation force impulse (ARFI) elastography and effect of necroinflammation. Digestive Diseases and Sciences.

[36] Kuroda H, Takikawa Y, Onodera M, Kakisaka K, Yoshida Y, Kataoka K, et al. Serial changes of liver stiffness measured by acoustic radiation force impulse imaging in acute liver failure: A case report. Journal of Clinical Ultrasound. 2012;**40**(2):99-104

[37] Goertz RS, Egger C, Neurath MF, Strobel D. Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver. Ultraschall in der Medizin.

[38] Attia D, Pischke S, Negm AA, Rifai K, Manns MP, Gebel MJ, et al. Changes in liver stiffness using acoustic radiation force impulse imaging in patients with obstructive cholestasis and cholangitis. Digestive and Liver Disease.

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

Elastographic methods for liver fibrosis assessment. Medical Ultrasonography.

[27] Mare R, Sporea I, Lupusoru R, Sirli R, Popescu A, Danila M, et al. The value of ElastPQ for the evaluation of liver stiffness in patients with B and C chronic hepatopathies. Ultrasonics.

[28] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Costachescu D. Intraand interoperator reproducibility of acoustic radiation force impulse (ARFI) elastography—Preliminary results. Ultrasound in Medicine & Biology.

[29] Guzman-Aroca F, Reus M, Berna-Serna JD, Serrano L, Serrano C, Gilabert A, et al. Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: A study in healthy volunteers. Journal of Ultrasound in Medicine.

[30] Ma JJ, Ding H, Mao F, Sun HC, Xu C, Wang WP. Assessment of liver fibrosis with elastography point quantification technique in chronic hepatitis B virus patients: A comparison with liver pathological results. Journal of Gastroenterology and Hepatology.

[31] Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Dal Bello B, Filice G, et al. Point shear wave elastography method for assessing liver stiffness. World Journal of Gastroenterology.

[32] Popescu A, Bota S, Sporea I, Sirli R, Danila M, Racean S, et al. The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary

[26] Sporea I, Mare R, Lupusoru R, Popescu A, Danila M, Bende F, et al. Comparative study between four ultrasound shear waves

2018;**20**(3):265-271

2017;**77**:144-151

2012;**38**(7):1103-1108

2011;**30**(7):975-979

2014;**29**(4):814-819

2014;**20**(16):4787-4796

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

[26] Sporea I, Mare R, Lupusoru R, Popescu A, Danila M, Bende F, et al. Comparative study between four ultrasound shear waves Elastographic methods for liver fibrosis assessment. Medical Ultrasonography. 2018;**20**(3):265-271

*Ultrasound Elastography*

with chronic hepatopathies. Ultraschall in der Medizin. 2011;**32**(Suppl 1):S46-S52 MF, et al. ARFI cut-off values and significance of standard deviation for liver fibrosis staging in patients with chronic liver disease. Annals of Hepatology. 2013;**12**(6):935-941

[21] Ferraioli G, Maiocchi L, Lissandrin R, Tinelli C, De Silvestri A, Filice C, et al. Accuracy of the ElastPQ technique for the assessment of liver fibrosis in patients with chronic hepatitis C: A "real life" single center study. Journal of Gastrointestinal and Liver Diseases.

2016;**25**(3):331-335

[22] Ferraioli G, De Silvestri A, Reiberger T, Taylor-Robinson SD, de Knegt RJ, Maiocchi L, et al.

Disease. 2018;**50**(10):1056-1061

Diseases. 2009;**18**(3):303-310

Baicus C, Marinoschi G.

[24] Fierbinteanu-Braticevici C, Andronescu D, Usvat R, Cretoiu D,

Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis. World Journal of Gastroenterology. 2009;**15**(44):5525-5532

[25] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Jurchis A, et al. Factors associated with the impossibility to obtain reliable liver stiffness measurements by means of acoustic radiation force impulse (ARFI) elastography—analysis of a cohort of 1,031 subjects. European Journal of Radiology. 2014;**83**(2):268-272

Adherence to quality criteria improves concordance between transient elastography and ElastPQ for liver stiffness assessment—A multicenter retrospective study. Digestive and Liver

[23] Lupsor M, Badea R, Stefanescu H, Sparchez Z, Branda H, Serban A, et al. Performance of a new elastographic method (ARFI technology) compared to unidimensional transient elastography in the noninvasive assessment of chronic hepatitis C. preliminary results. Journal of Gastrointestinal and Liver

[14] Piscaglia F, Salvatore V, Di Donato R, D'Onofrio M, Gualandi S, Gallotti A, et al. Accuracy of VirtualTouch acoustic radiation force impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall in der

Medizin. 2011;**32**(2):167-175

[15] Karlas T, Pfrepper C, Wiegand J, Wittekind C, Neuschulz M, Mossner J, et al. Acoustic radiation force impulse imaging (ARFI) for non-invasive detection of liver fibrosis: Examination standards and evaluation of interlobe differences in healthy subjects and chronic liver disease. Scandinavian Journal of Gastroenterology. 2011;**46**(12):1458-1467

[16] Toshima T, Shirabe K, Takeishi K, Motomura T, Mano Y, Uchiyama H, et al. New method for assessing liver fibrosis based on acoustic radiation force impulse: A special reference to the difference between right and left liver. Journal of Gastroenterology.

[17] Ling W, Lu Q, Quan J, Ma L, Luo Y. Assessment of impact factors on shear wave based liver stiffness measurement.

European Journal of Radiology.

[18] Bota S, Sporea I, Sirli R, Popescu A, Jurchis A. Factors which influence the accuracy of acoustic radiation force impulse (ARFI) elastography for the diagnosis of liver fibrosis in patients with chronic hepatitis C. Ultrasound in Medicine & Biology. 2013;**39**(3):407-412

[19] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Sendroiu M. Factors that influence the correlation of acoustic radiation force impulse (ARFI),

elastography with liver fibrosis. Medical Ultrasonography. 2011;**13**(2):135-140

[20] Goertz RS, Sturm J, Pfeifer L, Wildner D, Wachter DL, Neurath

2011;**46**(5):705-711

2013;**82**(2):335-341

**32**

[27] Mare R, Sporea I, Lupusoru R, Sirli R, Popescu A, Danila M, et al. The value of ElastPQ for the evaluation of liver stiffness in patients with B and C chronic hepatopathies. Ultrasonics. 2017;**77**:144-151

[28] Bota S, Sporea I, Sirli R, Popescu A, Danila M, Costachescu D. Intraand interoperator reproducibility of acoustic radiation force impulse (ARFI) elastography—Preliminary results. Ultrasound in Medicine & Biology. 2012;**38**(7):1103-1108

[29] Guzman-Aroca F, Reus M, Berna-Serna JD, Serrano L, Serrano C, Gilabert A, et al. Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: A study in healthy volunteers. Journal of Ultrasound in Medicine. 2011;**30**(7):975-979

[30] Ma JJ, Ding H, Mao F, Sun HC, Xu C, Wang WP. Assessment of liver fibrosis with elastography point quantification technique in chronic hepatitis B virus patients: A comparison with liver pathological results. Journal of Gastroenterology and Hepatology. 2014;**29**(4):814-819

[31] Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Dal Bello B, Filice G, et al. Point shear wave elastography method for assessing liver stiffness. World Journal of Gastroenterology. 2014;**20**(16):4787-4796

[32] Popescu A, Bota S, Sporea I, Sirli R, Danila M, Racean S, et al. The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary

results. Ultrasound in Medicine & Biology. 2013;**39**(4):579-584

[33] Gersak MM, Sorantin E, Windhaber J, Dudea SM, Riccabona M. The influence of acute physical effort on liver stiffness estimation using virtual touch quantification (VTQ ). Preliminary results. Medical Ultrasonography. 2016;**18**(2):151-156

[34] Bota S, Sporea I, Peck-Radosavljevic M, Sirli R, Tanaka H, Iijima H, et al. The influence of aminotransferase levels on liver stiffness assessed by acoustic radiation force impulse Elastography: A retrospective multicentre study. Digestive and Liver Disease. 2013;**45**(9):762-768

[35] Yoon KT, Lim SM, Park JY, Kim DY, Ahn SH, Han KH, et al. Liver stiffness measurement using acoustic radiation force impulse (ARFI) elastography and effect of necroinflammation. Digestive Diseases and Sciences. 2012;**57**(6):1682-1691

[36] Kuroda H, Takikawa Y, Onodera M, Kakisaka K, Yoshida Y, Kataoka K, et al. Serial changes of liver stiffness measured by acoustic radiation force impulse imaging in acute liver failure: A case report. Journal of Clinical Ultrasound. 2012;**40**(2):99-104

[37] Goertz RS, Egger C, Neurath MF, Strobel D. Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver. Ultraschall in der Medizin. 2012;**33**(4):380-385

[38] Attia D, Pischke S, Negm AA, Rifai K, Manns MP, Gebel MJ, et al. Changes in liver stiffness using acoustic radiation force impulse imaging in patients with obstructive cholestasis and cholangitis. Digestive and Liver Disease. 2014;**46**(7):625-631

[39] Popescu A, Sporea I, Sirli R, Bota S, Focsa M, Danila M, et al. The mean values of liver stiffness assessed by acoustic radiation force impulse elastography in normal subjects. Medical Ultrasonography. 2011;**13**(1):33-37

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**35**

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patient factors on noninvasive liver stiffness measurement using acoustic radiation force impulse elastography in patients with chronic hepatitis C. BMC

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[62] Friedrich-Rust M, Buggisch P, de Knegt RJ, Dries V, Shi Y, Matschenz K, et al. Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B. Journal of Viral Hepatitis.

[63] Zhang D, Chen M, Wang R, Liu Y, Zhang D, Liu L, et al. Comparison of acoustic radiation force impulse imaging and transient elastography for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B. Ultrasound in Medicine & Biology.

[64] Dong DR, Hao MN, Li C, Peng Z, Liu X, Wang GP, et al. Acoustic radiation force impulse elastography, FibroScan(R), Forns' index and their combination in the assessment of liver fibrosis in patients with chronic hepatitis B, and the impact of inflammatory activity and steatosis on

Gastroenterology. 2012;**12**:105

2014;**20**(28):9528-9533

2017;**37**(2):187-195

2013;**20**(4):240-247

2015;**41**(1):7-14

*DOI: http://dx.doi.org/10.5772/intechopen.87212*

meta-analysis. Journal of Viral Hepatitis.

[52] Bota S, Herkner H, Sporea I, Salzl P, Sirli R, Neghina AM, et al. Metaanalysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver International.

[53] Nierhoff J, Chavez Ortiz AA, Herrmann E, Zeuzem S, Friedrich-Rust M. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: A meta-analysis. European Radiology.

[54] Hu X, Qiu L, Liu D, Qian L. Acoustic radiation force impulse (ARFI) Elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: A systematic review and meta-analysis. Medical Ultrasonography. 2017;**19**(1):23-31

[55] Sporea I, Sirli R, Bota S,

Fierbinteanu-Braticevici C, Petrisor A, Badea R, et al. Is ARFI elastography reliable for predicting fibrosis severity in chronic HCV hepatitis? World Journal

[56] Sporea I, Bota S, Peck-Radosavljevic M, Sirli R, Tanaka H, Iijima H, et al. Acoustic radiation force impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: An international multicenter study. European Journal of Radiology.

[57] Rizzo L, Calvaruso V, Cacopardo B, Alessi N, Attanasio M, Petta S, et al. Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. The American Journal of Gastroenterology.

[58] Chen SH, Li YF, Lai HC, Kao JT, Peng CY, Chuang PH, et al. Effects of

of Radiology. 2011;**3**(7):188-193

2012;**81**(12):4112-4118

2011;**106**(12):2112-2120

2012;**19**(2):e212-e219

2013;**33**(8):1138-1147

2013;**23**(11):3040-3053

*Liver Fibrosis Assessment by Point Shear-Wave Elastography Techniques DOI: http://dx.doi.org/10.5772/intechopen.87212*

meta-analysis. Journal of Viral Hepatitis. 2012;**19**(2):e212-e219

*Ultrasound Elastography*

2011;**13**(1):33-37

[39] Popescu A, Sporea I, Sirli R, Bota S, Focsa M, Danila M, et al. The mean values of liver stiffness assessed by acoustic radiation force impulse elastography in normal subjects. Medical Ultrasonography. impulse elastography for the evaluation of liver stiffness? Hepatitis Monthly.

[46] Takahashi H, Ono N, Eguchi Y, Eguchi T, Kitajima Y, Kawaguchi Y, et al. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: A pilot study. Liver International.

[47] Goertz RS, Zopf Y, Jugl V, Heide R, Janson C, Strobel D, et al. Measurement of liver elasticity with acoustic radiation force impulse (ARFI) technology: An alternative noninvasive method for staging liver fibrosis in viral hepatitis. Ultraschall in der Medizin.

[48] Ebinuma H, Saito H, Komuta M, Ojiro K, Wakabayashi K, Usui S, et al. Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse: Comparison with Fibroscan ((R)). Journal of Gastroenterology. 2011;**46**(10):1238-1248

[49] Colombo S, Buonocore M, Del Poggio A, Jamoletti C, Elia S, Mattiello M, et al. Head-to-head comparison of transient elastography (TE), real-time tissue elastography (RTE), and acoustic radiation force impulse (ARFI) imaging in the diagnosis of liver fibrosis. Journal of Gastroenterology.

[50] Cassinotto C, Lapuyade B, Mouries A, Hiriart JB, Vergniol J, Gaye D, et al. Non-invasive assessment of liver fibrosis with impulse elastography: Comparison of supersonic shear imaging with ARFI and FibroScan(R). Journal of Hepatology. 2014;**61**(3):550-557

[51] Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, Fierbinteanu-Braticevici C, Strobel D, et al. Performance of acoustic radiation force impulse imaging for the staging of liver fibrosis: A pooled

2011;**11**(7):532-538

2010;**30**(4):538-545

2010;**31**(2):151-155

2012;**47**(4):461-469

[40] Son CY, Kim SU, Han WK, Choi GH, Park H, Yang SC, et al. Normal liver elasticity values using acoustic radiation force impulse imaging: A prospective study in healthy living liver and kidney donors. Journal of Gastroenterology and

Hepatology. 2012;**27**(1):130-136

2011;**80**(3):e226-e230

[41] Goertz RS, Amann K, Heide R, Bernatik T, Neurath MF, Strobel D. An abdominal and thyroid status with acoustic radiation force impulse Elastometry—A feasibility study: Acoustic Radiation Force Impulse Elastometry of human organs. European Journal of Radiology.

[42] Madhok R, Tapasvi C, Prasad U, Gupta AK, Aggarwal A. Acoustic radiation force impulse imaging of the liver: Measurement of the normal mean values of the shearing wave velocity in a healthy liver. Journal of Clinical and Diagnostic Research. 2013;**7**(1):39-42

[43] Sporea I, Bota S, Gradinaru-Tascau O, Sirli R, Popescu A. Comparative study between two point shear wave Elastographic techniques: Acoustic radiation force impulse (ARFI) elastography and ElastPQ. Medical Ultrasonography. 2014;**16**(4):309-314

[44] Friedrich-Rust M, Wunder K, Kriener S, Sotoudeh F, Richter S, Bojunga J, et al. Liver fibrosis in viral hepatitis: Noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology. 2009;**252**(2):595-604

[45] Sporea I, Badea R, Sirli R, Lupsor M, Popescu A, Danila M, et al. How efficient is acoustic radiation force

**34**

[52] Bota S, Herkner H, Sporea I, Salzl P, Sirli R, Neghina AM, et al. Metaanalysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver International. 2013;**33**(8):1138-1147

[53] Nierhoff J, Chavez Ortiz AA, Herrmann E, Zeuzem S, Friedrich-Rust M. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: A meta-analysis. European Radiology. 2013;**23**(11):3040-3053

[54] Hu X, Qiu L, Liu D, Qian L. Acoustic radiation force impulse (ARFI) Elastography for noninvasive evaluation of hepatic fibrosis in chronic hepatitis B and C patients: A systematic review and meta-analysis. Medical Ultrasonography. 2017;**19**(1):23-31

[55] Sporea I, Sirli R, Bota S, Fierbinteanu-Braticevici C, Petrisor A, Badea R, et al. Is ARFI elastography reliable for predicting fibrosis severity in chronic HCV hepatitis? World Journal of Radiology. 2011;**3**(7):188-193

[56] Sporea I, Bota S, Peck-Radosavljevic M, Sirli R, Tanaka H, Iijima H, et al. Acoustic radiation force impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: An international multicenter study. European Journal of Radiology. 2012;**81**(12):4112-4118

[57] Rizzo L, Calvaruso V, Cacopardo B, Alessi N, Attanasio M, Petta S, et al. Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. The American Journal of Gastroenterology. 2011;**106**(12):2112-2120

[58] Chen SH, Li YF, Lai HC, Kao JT, Peng CY, Chuang PH, et al. Effects of patient factors on noninvasive liver stiffness measurement using acoustic radiation force impulse elastography in patients with chronic hepatitis C. BMC Gastroenterology. 2012;**12**:105

[59] Li SM, Li GX, Fu DM, Wang Y, Dang LQ. Liver fibrosis evaluation by ARFI and APRI in chronic hepatitis C. World Journal of Gastroenterology. 2014;**20**(28):9528-9533

[60] Conti F, Serra C, Vukotic R, Fiorini E, Felicani C, Mazzotta E, et al. Accuracy of elastography point quantification and steatosis influence on assessing liver fibrosis in patients with chronic hepatitis C. Liver International. 2017;**37**(2):187-195

[61] Goertz RS, Sturm J, Zopf S, Wildner D, Neurath MF, Strobel D. Outcome analysis of liver stiffness by ARFI (acoustic radiation force impulse) elastometry in patients with chronic viral hepatitis B and C. Clinical Radiology. 2014;**69**(3):275-279

[62] Friedrich-Rust M, Buggisch P, de Knegt RJ, Dries V, Shi Y, Matschenz K, et al. Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B. Journal of Viral Hepatitis. 2013;**20**(4):240-247

[63] Zhang D, Chen M, Wang R, Liu Y, Zhang D, Liu L, et al. Comparison of acoustic radiation force impulse imaging and transient elastography for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B. Ultrasound in Medicine & Biology. 2015;**41**(1):7-14

[64] Dong DR, Hao MN, Li C, Peng Z, Liu X, Wang GP, et al. Acoustic radiation force impulse elastography, FibroScan(R), Forns' index and their combination in the assessment of liver fibrosis in patients with chronic hepatitis B, and the impact of inflammatory activity and steatosis on these diagnostic methods. Molecular Medicine Reports. 2015;**11**(6):4174-4182

[65] Yoneda M, Suzuki K, Kato S, Fujita K, Nozaki Y, Hosono K, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology. 2010;**256**(2):640-647

[66] Friedrich-Rust M, Romen D, Vermehren J, Kriener S, Sadet D, Herrmann E, et al. Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD. European Journal of Radiology. 2012;**81**(3):e325-e331

[67] Fierbinteanu Braticevici C, Sporea I, Panaitescu E, Tribus L. Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease. Ultrasound in Medicine & Biology. 2013;**39**(11):1942-1950

[68] Liu H, Fu J, Hong R, Liu L, Li F. Acoustic radiation force impulse Elastography for the non-invasive evaluation of hepatic fibrosis in nonalcoholic fatty liver disease patients: A Systematic Review & Meta-Analysis. PLoS One. 2015;**10**(7):e0127782

[69] Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes JG. Measurement of portal pressure and its role in the management of chronic liver disease. Seminars in Liver Disease. 2006;**26**(4):348-362

[70] Salzl P, Reiberger T, Ferlitsch M, Payer BA, Schwengerer B, Trauner M, et al. Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index. Ultraschall in der Medizin. 2014;**35**(6):528-533

[71] Bota S, Sporea I, Sirli R, Focsa M, Popescu A, Danila M, et al. Can ARFI elastography predict the presence of significant esophageal varices in newly diagnosed cirrhotic patients? Annals of Hepatology. 2012;**11**(4):519-525

[72] Rifai K, Cornberg J, Bahr M, Mederacke I, Potthoff A, Wedemeyer H, et al. ARFI elastography of the spleen is inferior to liver elastography for the detection of portal hypertension. Ultraschall in der Medizin. 2011;**32**(Suppl 2):E24-E30

[73] Vermehren J, Polta A, Zimmermann O, Herrmann E, Poynard T, Hofmann WP, et al. Comparison of acoustic radiation force impulse imaging with transient elastography for the detection of complications in patients with cirrhosis. Liver International. 2012;**32**(5):852-858

[74] Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Toshikuni N, et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. Gastroenterology. 2013;**144**(1):92-101 e2

[75] Ferraioli G, Maiocchi L, Lissandrin R, Tinelli C, De Silvestri A, Filice C. Ruling-in and ruling-out significant fibrosis and cirrhosis in patients with chronic hepatitis C using a shear wave measurement method. Journal of Gastrointestinal and Liver Diseases. 2017;**26**(2):139-143

[76] Yada N, Tamaki N, Koizumi Y, Hirooka M, Nakashima O, Hiasa Y, et al. Diagnosis of fibrosis and activity by a combined use of strain and shear wave imaging in patients with liver disease. Digestive Diseases. 2017;**35**(6):515-520

**37**

**Chapter 3**

**Abstract**

2D Shear Wave Elastography for

2D shear wave elastography is a technique embedded in ultrasound machines which allows the interrogation of the tissue by acoustic radiation force impulses induced into the tissues by focused ultrasonic beams and captures the propagation of resulting shear waves in real time. Elasticity is displayed using a color-coded image superimposed on a B-mode image, and at the same time, a quantitative estimation of liver stiffness (LS) can be performed in a certain region of interest (ROI). The published data showed a real value of this method for liver stiffness estimation in patients with chronic hepatitis. It has the following advantages: it is integrated into standard ultrasound systems; it is a real-time elastographic method; and it is also feasible in patients with ascites and

Chronic liver diseases of different etiologies are still an important health problem, staging fibrosis being one of the issues that relate to prognosis and treatment decision. Liver biopsy, the gold standard method for liver fibrosis assessment, is an invasive procedure, with possible complications and lower compliance as compared

Ultrasound-based liver elastography was developed as a noninvasive, easy to perform, and well-accepted tool for liver fibrosis assessment and proved to be a very dynamic research field in the last years, this being demonstrated also by the large

2D shear wave elastography is one of the new developed ultrasound-based techniques [1], embedded in ultrasound machines, that allow the interrogation of the tissue by dynamic acoustic radiation force impulses induced into the tissues by focused ultrasonic beams and capture the propagation of resulting shear waves in real time. The technique has the advantage that the elasticity is displayed using a color-coded image superimposed on a B-mode image, and at the same time, a quantitative estimation of liver stiffness (LS) can be performed in a certain region

The measurements are performed, similar to other elastography techniques, with the patient lying in supine position with the right arm in maximal abduction, in the right liver lobe, by placing the probe in between the ribs, in the seventh to ninth intercostal space, perpendicular on the liver surface [1]. The examiner should apply sufficient pressure on the probe to make good contact with the tissue,

Liver Fibrosis Evaluation

*Alina Popescu, Roxana Şirli and Ioan Sporea*

with large and adjustable size of the ROI that will be evaluated.

chronic liver diseases, liver cirrhosis

**1. Introduction**

to noninvasive techniques.

**Keywords:** 2D shear wave elastography, liver stiffness, liver fibrosis,

number of publications and guidelines published in this field [1–3].

of interest (ROI), the results being expressed in kPa or m/s.

#### **Chapter 3**

*Ultrasound Elastography*

2010;**256**(2):640-647

these diagnostic methods. Molecular Medicine Reports. 2015;**11**(6):4174-4182 elastography predict the presence of significant esophageal varices in newly diagnosed cirrhotic patients? Annals of

Hepatology. 2012;**11**(4):519-525

[72] Rifai K, Cornberg J, Bahr M, Mederacke I, Potthoff A, Wedemeyer H, et al. ARFI elastography of the spleen is inferior to liver elastography for the detection of portal hypertension.

Ultraschall in der Medizin. 2011;**32**(Suppl 2):E24-E30

2012;**32**(5):852-858

2013;**144**(1):92-101 e2

2017;**26**(2):139-143

[73] Vermehren J, Polta A, Zimmermann O, Herrmann E, Poynard T, Hofmann WP, et al. Comparison of acoustic radiation force impulse imaging with transient elastography for the detection of complications in patients with cirrhosis. Liver International.

[74] Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Toshikuni N, et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging

[75] Ferraioli G, Maiocchi L, Lissandrin R, Tinelli C, De Silvestri A, Filice C. Ruling-in and ruling-out significant fibrosis and cirrhosis in patients with chronic hepatitis C using a shear wave measurement method. Journal of Gastrointestinal and Liver Diseases.

[76] Yada N, Tamaki N, Koizumi Y, Hirooka M, Nakashima O, Hiasa Y, et al. Diagnosis of fibrosis and activity by a combined use of strain and shear wave imaging in patients with liver disease. Digestive Diseases. 2017;**35**(6):515-520

identifies cirrhotic patients with esophageal varices. Gastroenterology.

[65] Yoneda M, Suzuki K, Kato S, Fujita K, Nozaki Y, Hosono K, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology.

[66] Friedrich-Rust M, Romen D, Vermehren J, Kriener S, Sadet D, Herrmann E, et al. Acoustic radiation force impulse-imaging and transient elastography for non-invasive

in NAFLD. European Journal of Radiology. 2012;**81**(3):e325-e331

[67] Fierbinteanu Braticevici C, Sporea I, Panaitescu E, Tribus L. Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease. Ultrasound in Medicine & Biology.

[68] Liu H, Fu J, Hong R, Liu L, Li F. Acoustic radiation force impulse Elastography for the non-invasive evaluation of hepatic fibrosis in nonalcoholic fatty liver disease patients: A Systematic Review & Meta-Analysis. PLoS One. 2015;**10**(7):e0127782

[69] Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes JG. Measurement of portal pressure and its role in the management of chronic liver disease. Seminars in Liver Disease. 2006;**26**(4):348-362

[70] Salzl P, Reiberger T, Ferlitsch M, Payer BA, Schwengerer B, Trauner M, et al. Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index. Ultraschall in der

[71] Bota S, Sporea I, Sirli R, Focsa M, Popescu A, Danila M, et al. Can ARFI

Medizin. 2014;**35**(6):528-533

2013;**39**(11):1942-1950

assessment of liver fibrosis and steatosis

**36**

## 2D Shear Wave Elastography for Liver Fibrosis Evaluation

*Alina Popescu, Roxana Şirli and Ioan Sporea*

#### **Abstract**

2D shear wave elastography is a technique embedded in ultrasound machines which allows the interrogation of the tissue by acoustic radiation force impulses induced into the tissues by focused ultrasonic beams and captures the propagation of resulting shear waves in real time. Elasticity is displayed using a color-coded image superimposed on a B-mode image, and at the same time, a quantitative estimation of liver stiffness (LS) can be performed in a certain region of interest (ROI). The published data showed a real value of this method for liver stiffness estimation in patients with chronic hepatitis. It has the following advantages: it is integrated into standard ultrasound systems; it is a real-time elastographic method; and it is also feasible in patients with ascites and with large and adjustable size of the ROI that will be evaluated.

**Keywords:** 2D shear wave elastography, liver stiffness, liver fibrosis, chronic liver diseases, liver cirrhosis

#### **1. Introduction**

Chronic liver diseases of different etiologies are still an important health problem, staging fibrosis being one of the issues that relate to prognosis and treatment decision. Liver biopsy, the gold standard method for liver fibrosis assessment, is an invasive procedure, with possible complications and lower compliance as compared to noninvasive techniques.

Ultrasound-based liver elastography was developed as a noninvasive, easy to perform, and well-accepted tool for liver fibrosis assessment and proved to be a very dynamic research field in the last years, this being demonstrated also by the large number of publications and guidelines published in this field [1–3].

2D shear wave elastography is one of the new developed ultrasound-based techniques [1], embedded in ultrasound machines, that allow the interrogation of the tissue by dynamic acoustic radiation force impulses induced into the tissues by focused ultrasonic beams and capture the propagation of resulting shear waves in real time. The technique has the advantage that the elasticity is displayed using a color-coded image superimposed on a B-mode image, and at the same time, a quantitative estimation of liver stiffness (LS) can be performed in a certain region of interest (ROI), the results being expressed in kPa or m/s.

The measurements are performed, similar to other elastography techniques, with the patient lying in supine position with the right arm in maximal abduction, in the right liver lobe, by placing the probe in between the ribs, in the seventh to ninth intercostal space, perpendicular on the liver surface [1]. The examiner should apply sufficient pressure on the probe to make good contact with the tissue,

#### *Ultrasound Elastography*

**Figure 1.** *2D SWE.SSI.*

**39**

*2D Shear Wave Elastography for Liver Fibrosis Evaluation*

should stabilize the hand and the probe while performing the measurement, and should ask the patient to stop breathing and avoid deep inspiration. The ROI should be placed in an area free of vessels, at least 1–2 cm and at maximum of 6 cm

The technique has the advantage that can be performed also in patients with ascites, but an adequate B-mode ultrasound live image is necessary for reliable results. On the other hand, published data showed that for a high feasibility of the method, ultrasound experience is needed, especially in difficult cases, for example,

First 2D SWE technique was developed by Supersonic Imagine (France) (2D SWE.SSI) and embedded in Aixplorer® system (**Figure 1**)*.* Other companies followed with similar techniques, for example, General Electric (2D SWE.GE) (**Figure 2**), 2D SWE technique with a propagation map Canon-Toshiba (**Figure 3**),

Published data showed that 2D SWE.SSI is a feasible and reproducible method [6]. The manufacturer recommends a minimum of three valid measurements to be obtained and rejects any measurement that achieves less than 90% stability index (SI), as a reliability criterion. Other authors [7] used standard deviation/median liver stiffness of ≤0.10 and measurement depth of <5.6 cm as quality parameters for reliable measurements. Most published data showed that reliable LS measurements can be obtained in 90–98.9% of cases [5–10] with a good intra- and interobserver

*DOI: http://dx.doi.org/10.5772/intechopen.88183*

under the liver capsule [1].

*2D SWE with a propagation map (Canon).*

**Figure 3.**

Philips (ElastQ ), Samsung, etc.

reproducibility [9, 11, 12].

**2. 2D SWE.SSI**

obese patients or narrow intercostal spaces [1, 4, 5].

**Figure 2.** *2D SWE.GE.*

*Ultrasound Elastography*

**38**

**Figure 2.** *2D SWE.GE.*

**Figure 1.** *2D SWE.SSI.*

**Figure 3.** *2D SWE with a propagation map (Canon).*

should stabilize the hand and the probe while performing the measurement, and should ask the patient to stop breathing and avoid deep inspiration. The ROI should be placed in an area free of vessels, at least 1–2 cm and at maximum of 6 cm under the liver capsule [1].

The technique has the advantage that can be performed also in patients with ascites, but an adequate B-mode ultrasound live image is necessary for reliable results. On the other hand, published data showed that for a high feasibility of the method, ultrasound experience is needed, especially in difficult cases, for example, obese patients or narrow intercostal spaces [1, 4, 5].

First 2D SWE technique was developed by Supersonic Imagine (France) (2D SWE.SSI) and embedded in Aixplorer® system (**Figure 1**)*.* Other companies followed with similar techniques, for example, General Electric (2D SWE.GE) (**Figure 2**), 2D SWE technique with a propagation map Canon-Toshiba (**Figure 3**), Philips (ElastQ ), Samsung, etc.

#### **2. 2D SWE.SSI**

Published data showed that 2D SWE.SSI is a feasible and reproducible method [6]. The manufacturer recommends a minimum of three valid measurements to be obtained and rejects any measurement that achieves less than 90% stability index (SI), as a reliability criterion. Other authors [7] used standard deviation/median liver stiffness of ≤0.10 and measurement depth of <5.6 cm as quality parameters for reliable measurements. Most published data showed that reliable LS measurements can be obtained in 90–98.9% of cases [5–10] with a good intra- and interobserver reproducibility [9, 11, 12].

#### **2.1 Healthy volunteers**

The values of LS evaluated by 2D SWE.SSI in healthy volunteers varied from 2.6 to 6.2 kPa [13–15], with higher values in male vs. female patients (6.6 ± 1.5 vs. 5.7 ± 1.3 kPa, p = 0.01.) [14].

#### **2.2 Confounding factors**

Similar to other ultrasound-based elastographic methods, the liver stiffness results obtained by 2D SWE.SSI may be influenced by food intake; some authors suggest that the values increase significantly in the first hour after food intake and decrease after 60 min after meal [16, 17], while in other studies, these results were not reproduced [18], suggesting that maybe this method is less influenced by food intake. Nevertheless, while more studies are necessary to clarify this issue, the measurements should be performed in fasting condition to avoid any errors.

Other studies are also needed to evaluate the effect of cytolysis, cholestasis, or congestive heart failure on the liver stiffness values obtained through 2D SWE.

#### **2.3 2D SWE.SSI for predicting liver fibrosis in chronic liver diseases of various etiologies**

Several studies showed good accuracy for 2D SWE.SSI for predicting significant fibrosis and liver cirrhosis in chronic liver diseases of different etiologies (**Table 1**). Overall, the method has good accuracy for evaluating both significant and severe fibrosis, slightly better for liver cirrhosis, but with very different cutoff values between etiologies and between different studies.


**41**

10.5/9.5 kPa for F4.

diagnosis of mild fibrosis and cirrhosis.

*chronic liver diseases—adapted after Jeong JY et al. [19].*

*2D Shear Wave Elastography for Liver Fibrosis Evaluation*

**(***n***)**

**Fibrosis stage**

**AUROC Cutoffs (kPa)**

2014 HBV 206 F ≥ 2 0.917 7.200 86.36 86.96 88.8 84.2

2016 HBV 437 F ≥ 2 0.903 8.200 78.16 85.28 82.6 81.4

2017 HBV 304 F ≥ 2 0.970 7.600 92.00 90.00 98.4 64.3

2017 HBV 257 F ≥ 2 0.882 7.100 88.89 76.38 76.2 89.0

2016 Alcohol 199 F ≥ 2 0.940 10.20 82.0 93.0 90.0 88.0

2017 Autoimmune 114 F ≥ 2 0.850 9.70 81.7 81.3 91.8 63.4

2016 NAFLD 291 F ≥ 2 0.860 8.90 68.0 94.0

2018 NAFLD 71 F ≥ 2 0.750 11.57 52.0 44.0

**Se (%)**

F = 4 0.980 10.100 97.40 93.00 60.1 99.6

F = 4 0.945 11.700 91.89 89.70 66.7 98.0

F = 4 0.926 11.256 91.80 84.31 48.7 98.4

F = 4 0.980 10.400 94.60 94.90 95.7 93.5

F = 4 0.926 11.300 93.55 87.25 52.7 98.9

F = 4 0.950 16.40 94.0 91.0 71.0 99.0

F = 4 0.860 16.30 87.0 80.2 52.6 96.1

F = 4 0.880 10.00 95.0 69.0

F = 4 0.900 15.73 100.0 82.0

**Sp (%)** **PPV (%)**

**NPV (%)**

Two comparative studies between transient elastography, point SWE (VTQ ) and 2D SWE.SSI, were proposed by Cassinotto et al. in chronic liver diseases [35] and NAFLD patients [30]. The first study enrolled 349 consecutive patients with chronic liver diseases who underwent liver biopsy. For each patient, LS was assessed by 2D SWE.SSI, pSWE (VTQ ), and transient elastography (FibroScan, M and XL probes). 2D SWE.SSI, transient elastography and VTQ, correlated significantly with histological fibrosis score (r = 0.79, p < .00001; r = 0.70, p < .00001; r = 0.64, p < .00001, respectively) with no significant differences between methods for the

2018 Autoimmune 51 F ≥ 2 0.781 9.15 83.3 72.7

*Diagnostic performance of 2D SWE.SSI for significant fibrosis (F* ≥ *2) and cirrhosis (F = 4) in different* 

The second study [30] included 291 NAFLD patients in whom liver stiffness was assessed by 2D SWE.SSI, transient elastography (M probe), and VTQ within 2 weeks prior to liver biopsy. The AUROC for 2D SWE.SSI, transient elastography, and 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. The cutoff values for 2D SWE.SSI and transient elastography for predicting fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and

*DOI: http://dx.doi.org/10.5772/intechopen.88183*

**Ref. Year Etiology Patients** 

Zeng et al. [26]

Wu et al. [27]

Zhuang et al. [28]

Zeng et al. [29]

Cassinotto et al. [30]

Takeuchi et al. [31]

Thiele et al. [32]

Zeng et al. [33]

Li et al. [34]

**Table 1.**


#### *2D Shear Wave Elastography for Liver Fibrosis Evaluation DOI: http://dx.doi.org/10.5772/intechopen.88183*

#### **Table 1.**

*Ultrasound Elastography*

**2.1 Healthy volunteers**

5.7 ± 1.3 kPa, p = 0.01.) [14].

**2.2 Confounding factors**

**various etiologies**

Jeong et al. [20]

Deffieux et al. [21]

Sporea et al. [22]

Sporea et al. [23]

Bavu et al. [24]

Ferraioli et al. [5]

Tada et al. [25]

Leung et al. [8]

between etiologies and between different studies.

**(***n***)**

**Ref. Year Etiology Patients** 

The values of LS evaluated by 2D SWE.SSI in healthy volunteers varied from 2.6 to 6.2 kPa [13–15], with higher values in male vs. female patients (6.6 ± 1.5 vs.

Similar to other ultrasound-based elastographic methods, the liver stiffness results obtained by 2D SWE.SSI may be influenced by food intake; some authors suggest that the values increase significantly in the first hour after food intake and decrease after 60 min after meal [16, 17], while in other studies, these results were not reproduced [18], suggesting that maybe this method is less influenced by food intake. Nevertheless, while more studies are necessary to clarify this issue, the measurements should be performed in fasting condition to avoid any errors.

Other studies are also needed to evaluate the effect of cytolysis, cholestasis, or congestive heart failure on the liver stiffness values obtained through 2D SWE.

Several studies showed good accuracy for 2D SWE.SSI for predicting significant fibrosis and liver cirrhosis in chronic liver diseases of different etiologies (**Table 1**). Overall, the method has good accuracy for evaluating both significant and severe fibrosis, slightly better for liver cirrhosis, but with very different cutoff values

> **Fibrosis stage**

**AUROC Cutoffs (kPa)**

2014 Mixt 70 F ≥ 2 0.915 8.60 78.2 93.3 97.7 53.8

2015 Mixt 120 F ≥ 2 0.890 8.90 77.0 79.0 77.0 79.0

2014 Mixt 383 F ≥ 2 0.859 7.8 76.8 82.6 77.9 81.5

2018 Mixt 82 F ≥ 2 0.853 7.1 96.8 78 73.8 97.5

2012 HCV 121 F ≥ 2 0.920 7.10 90.0 87.5 91.3 85.7

2013 HCV 55 F ≥ 2 0.940 8.80 88.9 91.9 84.2 94.4

2013 HBV 226 F ≥ 2 0.880 7.100 84.70 92.10 85.3 91.7

2011 HCV 113 F ≥ 2 0.950 9.12 81.0 72.0

**Se (%)**

F = 4 0.878 14.00 77.3 85.4 70.8 89.2

F = 4 0.890 10.20 83.0 76.0 38.0 96.0

F = 4 0.914 11.5 80.6 92.7 60.9 97.1

F = 4 0.94 13 78.9 97.7 88.2 95.5

F = 4 0.980 10.40 87.5 96.8 87.5 96.8

F = 4 0.970 13.30 80.0 87.0

**Sp (%)** **PPV (%)**

**NPV (%)**

**2.3 2D SWE.SSI for predicting liver fibrosis in chronic liver diseases of** 

**40**

*Diagnostic performance of 2D SWE.SSI for significant fibrosis (F* ≥ *2) and cirrhosis (F = 4) in different chronic liver diseases—adapted after Jeong JY et al. [19].*

Two comparative studies between transient elastography, point SWE (VTQ ) and 2D SWE.SSI, were proposed by Cassinotto et al. in chronic liver diseases [35] and NAFLD patients [30]. The first study enrolled 349 consecutive patients with chronic liver diseases who underwent liver biopsy. For each patient, LS was assessed by 2D SWE.SSI, pSWE (VTQ ), and transient elastography (FibroScan, M and XL probes). 2D SWE.SSI, transient elastography and VTQ, correlated significantly with histological fibrosis score (r = 0.79, p < .00001; r = 0.70, p < .00001; r = 0.64, p < .00001, respectively) with no significant differences between methods for the diagnosis of mild fibrosis and cirrhosis.

The second study [30] included 291 NAFLD patients in whom liver stiffness was assessed by 2D SWE.SSI, transient elastography (M probe), and VTQ within 2 weeks prior to liver biopsy. The AUROC for 2D SWE.SSI, transient elastography, and 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. The cutoff values for 2D SWE.SSI and transient elastography for predicting 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.

In an individual patient data based on meta-analysis [36] that included 1340 patients and compared 2D SWE.SSI with liver biopsy as reference method, 2D SWE.SSI showed a good to excellent performance in LS assessment in patients with HCV, HBV, and NAFLD, with AUROCs of 86.3, 91.6, and 85.9% for diagnosing significant fibrosis (F ≥ 2) and 96.1, 97.1, and 95.5% for diagnosing cirrhosis (F = 4), respectively. The optimal cutoff for diagnosing significant fibrosis in all patients was 7.1 kPa, while for diagnosing liver cirrhosis was 13.5 kPa in HCV and NAFLD and 11.5 kPa in HBV patients.

Other three meta-analyses published that included more than 900 patients each [37–39] confirmed these results, with pooled sensitivities between 0.84 and 0.85, pooled specificities between 0.81 and 0.83 and AUROC between 0.85 and 0.87 for significant fibrosis and with pooled sensitivities between 0.87 and 0.89, and pooled specificities between 0.86 and 0.88 and AUROC between 0.93 and 0.94 for liver cirrhosis.

#### **2.4 2D SWE.SSI for predicting liver cirrhosis complications**

The method was studied also as a predictor for the presence of clinically significant portal hypertension. Thus, while Kim et al. showed that for a cutoff value of 15.2 kPa, the sensitivity and specificity of 2D SWE.SSI for predicting clinically significant portal hypertension were 85.7 and 80%, respectively, (AUROC 0.819) (HVPG >10 mmHg) [40], Procopet et al. [7], by using standard deviation/median liver stiffness ≤0.10 and measurement depth < 5.6 cm as quality criteria, had better results for the optimal cutoff value of 15.4 kPa (AUROC =0.948, with sensitivity and specificity both higher than 90%).

Another study that included 79 patients with liver cirrhosis [41] evaluated LS and spleen stiffness (SS) by 2D SWE.SSI, TE, and HVPG measurements; 2D SWE. SSI LS of more than 24.6 kPa had a sensitivity, specificity, and accuracy for clinically significant portal hypertension of 81, 88, and 82%, respectively, with better performance than SS (AUROC of 0.87 vs. 0.64, P = 0.003).

In a larger study that enrolled 401 consecutive cirrhotic patients [42], the LS cutoff values for a NPV ≥90% for 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, with AUROC of 0.77 for detection of esophageal varices.

Jeong et al. [43] looked on the role of 2D SWE in predicting the development of hepatocellular carcinoma, showing that patients with LS ≥10 kPa by 2D SWE had a fourfold higher risk of presenting hepatocellular carcinoma than those with LS <10 kPa.

More studies are needed to address these issues and conclude for the clinical practice.

#### **2.5 2D SWE.SSI in pediatric population**

The field of elastography, as noninvasive evaluation tool, became of interest also in pediatric population [44]. Thus a study that enrolled 54 consecutive children and adolescents with different chronic liver diseases that were examined by means of TE, ARFI, and 2D SWE.SSI showed a sensitivity of 2D SWE.SSI for detecting F1, F2, F3, and liver cirrhosis of 92.85, 83.33, 87.5, and 85.71%, respectively [45], better than a point SWE technique.

#### **3. 2D SWE.GE**

Another system that implemented the 2D SWE technique comes from General Electrics, embedded first in **LOGIQ E9/LOGIQ E10** ultrasound systems.

**43**

**5. Conclusion**

*2D Shear Wave Elastography for Liver Fibrosis Evaluation*

This new technique showed also good intra- and interobserver reproducibility. In a study that included 60 patients evaluated by 2D SWE.GE by three examiners with different levels of experience in ultrasound-based elastography and ultrasound, the overall agreement between examiners was excellent: 0.915 (95% confidence interval [CI]: 0.870-0.946). The intra-observer reproducibility for each of the examiners was excellent; however, the inter-class correlation coefficients were higher for the examiners more experienced in elastography: 0.936 (95% CI: 0.896- 0.963) vs. 0.966 (95% CI: 0.943-0.980) vs. 0.984 (95% CI: 0. 973-0.991) [46]. The method showed also very good feasibility and reproducibility also in pediatric population. In a study that enrolled 243 healthy participants aged 4–17 years, valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D SWE. GE, with an intraclass correlation coefficients between observers of 0.84 [47]. The mean LS measurement by 2D SWE.GE in healthy subjects was 5.1 ± 1.3kPa, significantly higher than the LS measurement assessed by transient elastography (4.3 ± 0.9kPa, p < 0.0001) and significantly higher for male vs. female, 5.9 ± 1.2vs.

There are few data available in the literature regarding the performance of this method in evaluating liver fibrosis in chronic liver diseases, but the results are

Thus in a study that enrolled 331 consecutive subjects with or without chronic hepatopathies [49] in whom LS was evaluated in the same session by means of two elastographic techniques, transient elastography and 2D SWE.GE, reliable LS measurements were obtained in 95.8% subjects by 2D SWE.GE and 94.2% by TE (p = 0.44), with a strong correlation between the LS values obtained by the two methods: r = 0.83, p < 0.0001. The best cutoff value for F ≥ 2, F ≥ 3, and for F = 4

Similar results were obtained in an Italian study [50] that enrolled 54 healthy subjects and 174 patients with chronic liver diseases and compared 2D SWE.GE with liver biopsy as reference method and obtained reliable LS measurements in all subjects, with a strong correlation the LS measurements and liver fibrosis (r = 0.628). The AUROC values were better also for severe fibrosis: for F ≥ 2: 0.857,

**2D SWE with propagation map** (**Figure 3**), technique developed by Canon-Toshiba, is a more recent technology that appeared on the market but also with good perspectives in the field of liver elastography. Thus, in a study [51] on 115 consecutive patients that underwent 2D SWE by two different operators and transient elastography by sonographers during the same day, the correlation coefficient of the intraclass correlation test between an experienced radiologist and a third-year radiology resident was 0.878, and there was a moderate correlation between 2D SWE and transient elastography (r = 0.511) in the diagnosis of liver fibrosis. The best cutoff values for predicting significant fibrosis and liver cirrhosis by 2D SWE were > 1.78 (AUROC = 0.777) and > 2.24 m/s

Even if 2D SWE techniques are quite newer on the market, they proved to be reliable methods for liver fibrosis evaluation, and several advantages can be

*DOI: http://dx.doi.org/10.5772/intechopen.88183*

4.7 ± 1.2kPa (p = 0.0005) [48].

were 6.7, 8.2, and 9.3 kPa.

for F ≥ 3: 0.946, and for F = 4: 0.935.

**4. 2D SWE with propagation map**

(AUROC = 0.935), respectively.

promising.

*2D Shear Wave Elastography for Liver Fibrosis Evaluation DOI: http://dx.doi.org/10.5772/intechopen.88183*

*Ultrasound Elastography*

and 11.5 kPa in HBV patients.

and specificity both higher than 90%).

**2.5 2D SWE.SSI in pediatric population**

than a point SWE technique.

**3. 2D SWE.GE**

In an individual patient data based on meta-analysis [36] that included 1340 patients and compared 2D SWE.SSI with liver biopsy as reference method, 2D SWE.SSI showed a good to excellent performance in LS assessment in patients with HCV, HBV, and NAFLD, with AUROCs of 86.3, 91.6, and 85.9% for diagnosing significant fibrosis (F ≥ 2) and 96.1, 97.1, and 95.5% for diagnosing cirrhosis (F = 4), respectively. The optimal cutoff for diagnosing significant fibrosis in all patients was 7.1 kPa, while for diagnosing liver cirrhosis was 13.5 kPa in HCV and NAFLD

Other three meta-analyses published that included more than 900 patients each [37–39] confirmed these results, with pooled sensitivities between 0.84 and 0.85, pooled specificities between 0.81 and 0.83 and AUROC between 0.85 and 0.87 for significant fibrosis and with pooled sensitivities between 0.87 and 0.89, and pooled specificities between 0.86 and 0.88 and AUROC between 0.93 and 0.94 for liver cirrhosis.

The method was studied also as a predictor for the presence of clinically significant portal hypertension. Thus, while Kim et al. showed that for a cutoff value of 15.2 kPa, the sensitivity and specificity of 2D SWE.SSI for predicting clinically significant portal hypertension were 85.7 and 80%, respectively, (AUROC 0.819) (HVPG >10 mmHg) [40], Procopet et al. [7], by using standard deviation/median liver stiffness ≤0.10 and measurement depth < 5.6 cm as quality criteria, had better results for the optimal cutoff value of 15.4 kPa (AUROC =0.948, with sensitivity

Another study that included 79 patients with liver cirrhosis [41] evaluated LS and spleen stiffness (SS) by 2D SWE.SSI, TE, and HVPG measurements; 2D SWE. SSI LS of more than 24.6 kPa had a sensitivity, specificity, and accuracy for clinically significant portal hypertension of 81, 88, and 82%, respectively, with better

In a larger study that enrolled 401 consecutive cirrhotic patients [42], the LS cutoff

The field of elastography, as noninvasive evaluation tool, became of interest also in pediatric population [44]. Thus a study that enrolled 54 consecutive children and adolescents with different chronic liver diseases that were examined by means of TE, ARFI, and 2D SWE.SSI showed a sensitivity of 2D SWE.SSI for detecting F1, F2, F3, and liver cirrhosis of 92.85, 83.33, 87.5, and 85.71%, respectively [45], better

Another system that implemented the 2D SWE technique comes from General

Electrics, embedded first in **LOGIQ E9/LOGIQ E10** ultrasound systems.

values for a NPV ≥90% for 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, with AUROC of 0.77 for detection of esophageal varices. Jeong et al. [43] looked on the role of 2D SWE in predicting the development of hepatocellular carcinoma, showing that patients with LS ≥10 kPa by 2D SWE had a fourfold higher risk of presenting hepatocellular carcinoma than those with LS <10 kPa. More studies are needed to address these issues and conclude for the clinical

**2.4 2D SWE.SSI for predicting liver cirrhosis complications**

performance than SS (AUROC of 0.87 vs. 0.64, P = 0.003).

**42**

practice.

This new technique showed also good intra- and interobserver reproducibility. In a study that included 60 patients evaluated by 2D SWE.GE by three examiners with different levels of experience in ultrasound-based elastography and ultrasound, the overall agreement between examiners was excellent: 0.915 (95% confidence interval [CI]: 0.870-0.946). The intra-observer reproducibility for each of the examiners was excellent; however, the inter-class correlation coefficients were higher for the examiners more experienced in elastography: 0.936 (95% CI: 0.896- 0.963) vs. 0.966 (95% CI: 0.943-0.980) vs. 0.984 (95% CI: 0. 973-0.991) [46].

The method showed also very good feasibility and reproducibility also in pediatric population. In a study that enrolled 243 healthy participants aged 4–17 years, valid measurements were obtained in 242 of 243 (99.6%) subjects for 2D SWE. GE, with an intraclass correlation coefficients between observers of 0.84 [47].

The mean LS measurement by 2D SWE.GE in healthy subjects was 5.1 ± 1.3kPa, significantly higher than the LS measurement assessed by transient elastography (4.3 ± 0.9kPa, p < 0.0001) and significantly higher for male vs. female, 5.9 ± 1.2vs. 4.7 ± 1.2kPa (p = 0.0005) [48].

There are few data available in the literature regarding the performance of this method in evaluating liver fibrosis in chronic liver diseases, but the results are promising.

Thus in a study that enrolled 331 consecutive subjects with or without chronic hepatopathies [49] in whom LS was evaluated in the same session by means of two elastographic techniques, transient elastography and 2D SWE.GE, reliable LS measurements were obtained in 95.8% subjects by 2D SWE.GE and 94.2% by TE (p = 0.44), with a strong correlation between the LS values obtained by the two methods: r = 0.83, p < 0.0001. The best cutoff value for F ≥ 2, F ≥ 3, and for F = 4 were 6.7, 8.2, and 9.3 kPa.

Similar results were obtained in an Italian study [50] that enrolled 54 healthy subjects and 174 patients with chronic liver diseases and compared 2D SWE.GE with liver biopsy as reference method and obtained reliable LS measurements in all subjects, with a strong correlation the LS measurements and liver fibrosis (r = 0.628). The AUROC values were better also for severe fibrosis: for F ≥ 2: 0.857, for F ≥ 3: 0.946, and for F = 4: 0.935.

#### **4. 2D SWE with propagation map**

**2D SWE with propagation map** (**Figure 3**), technique developed by Canon-Toshiba, is a more recent technology that appeared on the market but also with good perspectives in the field of liver elastography. Thus, in a study [51] on 115 consecutive patients that underwent 2D SWE by two different operators and transient elastography by sonographers during the same day, the correlation coefficient of the intraclass correlation test between an experienced radiologist and a third-year radiology resident was 0.878, and there was a moderate correlation between 2D SWE and transient elastography (r = 0.511) in the diagnosis of liver fibrosis. The best cutoff values for predicting significant fibrosis and liver cirrhosis by 2D SWE were > 1.78 (AUROC = 0.777) and > 2.24 m/s (AUROC = 0.935), respectively.

#### **5. Conclusion**

Even if 2D SWE techniques are quite newer on the market, they proved to be reliable methods for liver fibrosis evaluation, and several advantages can be

#### *Ultrasound Elastography*

highlighted: they are integrated into standard ultrasound systems, are real-time elastographic methods, and are feasible also in patients with ascites and with large and adjustable size of the ROI that will be evaluated. These techniques have better accuracy for predicting liver cirrhosis, with accuracy more than 95%, and they also have good accuracy (more than 85%) for predicting significant fibrosis (F2).

### **Author details**

Alina Popescu\*, Roxana Şirli and Ioan Sporea Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania

\*Address all correspondence to: alinamircea.popescu@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**45**

*2D Shear Wave Elastography for Liver Fibrosis Evaluation*

fibrosis and spleen stiffness in chronic hepatitis B carriers: Comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology.

[9] Hudson JM, Milot L, Parry C, et al. Inter- and intra-operator reliability and repeatability of shear wave elastography

volunteers. Ultrasound in Medicine &

[10] Poynard T, Munteanu M, Luckina E, et al. Liver fibrosis evaluation using real-time shear wave elastography: Applicability and diagnostic

performance using methods without a gold standard. Journal of Hepatology.

[11] Ferraioli G, Tinelli C, Zicchetti M, et al. Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity. European Journal of

Radiology. 2012;**81**:3102-3106

[12] Zoumpoulis PS, Theotokas I, Mastorakou E, et al. Technical and software adjustments for a reliable shear wave Elastography estimation of fibrosis in chronic liver disease. Ultrasound in Medicine & Biology. 2011;**8S**:S58

[13] Zoumpoulis PS, Mastorakou E, Theotokas I, et al. Shear wave

Medicine & Biology. 2011;**8S**:S58

2013;**39**:1362-1367

Elastography for the evaluation of diffuse liver disease: Determining Normal and pathological values in kPa. Ultrasound in

[14] Șirli R, Bota S, Sporea I, et al. Liver stiffness measurements by means of supersonic shear imaging in patients without known liver pathology. Ultrasound in Medicine & Biology.

[15] Suh CH, Kim SY, Kim KW, et al. Determination of normal hepatic

in the liver: A study in healthy

Biology. 2013;**39**:950-955

2013;**58**:928-935

2013;**269**:910-918

*DOI: http://dx.doi.org/10.5772/intechopen.88183*

[1] Dietrich CF, Bamber J, Berzigotti A,

recommendations on the clinical use of liver ultrasound Elastography, update 2017 (short version). Ultraschall in der

et al. EFSUMB guidelines and

Medizin. 2017;**38**(4):377-394

2015;**41**(5):1161-1179

2014;**16**(2):123-138

[2] Ferraioli G, Filice C, Castera L, et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: Liver. Ultrasound in Medicine & Biology.

[3] Sporea I, Bota S, Săftoiu A, et al. Romanian Society of Ultrasound in medicine and biology. Romanian national guidelines and practical recommendations on liver

elastography. Medical Ultrasonography.

[4] Grădinaru-Taşcău O, Sporea I, Bota S, et al. Does experience play a role in the ability to perform liver stiffness measurements by means of supersonic

[5] Ferraioli G, Tinelli C, Dal Bello B, et al. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: A pilot study. Hepatology. 2012;**56**:2125-2133

[6] Lupșor-Platon M, Badea R, Gersak M,

[7] Procopet B, Berzigotti A, Abraldes JG,

elastography: Applicability, reliability and accuracy for clinically significant portal hypertension. Journal of Hepatology. 2015;**62**:1068-1075

[8] Leung VY, Shen J, Wong VW, et al. Quantitative elastography of liver

shear imaging (SSI)? Medical Ultrasonography. 2013;**15**:180-183

et al. Noninvasive assessment of liver diseases using 2D shear wave Elastography. Journal of Gastrointestinal and Liver Diseases.

et al. Real-time shear-wave

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*2D Shear Wave Elastography for Liver Fibrosis Evaluation DOI: http://dx.doi.org/10.5772/intechopen.88183*

#### **References**

*Ultrasound Elastography*

**44**

**Author details**

Alina Popescu\*, Roxana Şirli and Ioan Sporea

Medicine and Pharmacy Timișoara, Romania

provided the original work is properly cited.

Department of Gastroenterology and Hepatology, "Victor Babeș" University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

highlighted: they are integrated into standard ultrasound systems, are real-time elastographic methods, and are feasible also in patients with ascites and with large and adjustable size of the ROI that will be evaluated. These techniques have better accuracy for predicting liver cirrhosis, with accuracy more than 95%, and they also have good accuracy (more than 85%) for predicting significant fibrosis (F2).

\*Address all correspondence to: alinamircea.popescu@gmail.com

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[26] Zeng J, Liu GJ, Huang ZP, et al. Diagnostic accuracy of two-dimensional shear wave elastography for the noninvasive staging of hepatic fibrosis in chronic hepatitis B: A cohort study with internal validation. European Radiology. 2014;**24**:2572-2581

[27] Wu T, Wang P, Zhang T, et al. Comparison of two-dimensional shear wave Elastography and real-time tissue Elastography for assessing liver fibrosis in chronic hepatitis B. Digestive Diseases. 2016;**34**:640-649

[28] Zhuang Y, Ding H, Zhang Y, et al. Two-dimensional shear-wave Elastography performance in the noninvasive evaluation of liver fibrosis in patients with chronic hepatitis B: Comparison with serum fibrosis indexes. Radiology. 2017;**283**:873-882

[29] Zeng J, Zheng J, Huang Z, et al. Comparison of 2-D shear wave Elastography and transient Elastography

**47**

*2D Shear Wave Elastography for Liver Fibrosis Evaluation*

data-based meta-analysis. Hepatology.

[37] Li C, Zhang C, Li J, et al. Diagnostic accuracy of real-time shear wave

Elastography for staging of liver fibrosis: A meta-analysis. Medical Science Monitor. 2016;**22**:1349-1359

[38] Jiang T, Tian G, Zhao Q, et al. Diagnostic accuracy of 2D-shear wave Elastography for liver fibrosis severity: A meta-analysis. PLoS One.

[39] Feng JC, Li J, Wu XW, et al.

Medicine. 2016;**35**(2):329-339

Diagnostic accuracy of SuperSonic shear imaging for staging of liver fibrosis: A meta-analysis. Journal of Ultrasound in

[40] Kim TY, Jeong WK, Sohn JH, et al. Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients. Liver International.

[41] Elkrief L, Rautou PE, Ronot M, et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient Elastography for detection of portal hypertension in cirrhosis. Radiology. 2015;**275**(2):589-598

[42] Cassinotto C, Charrie A, Mouries A, et al. Liver and spleen elastography using supersonic shear imaging for the noninvasive diagnosis of cirrhosis severity and oesophageal varices. Digestive and Liver Disease. 2015;**47**(8):695-701

[43] Jeong JY, Sohn JH, Sohn W, Park CH, Kim TY, Jun DW, et al. Role of shear wave Elastography in evaluating the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Gut and Liver.

[44] Dietrich CF, Sirli R, Ferraioli G,

ultrasound-based liver Elastography of Pediatric patients. Applied Sciences.

et al. Current knowledge in

2018;**67**:260-272

2016;**11**(6):e0157219

2015;**35**:2416-2424

2017;**11**:852-859

2018;**8**(6):944

*DOI: http://dx.doi.org/10.5772/intechopen.88183*

[31] Takeuchi H, Sugimoto K, Oshiro H, et al. Liver fibrosis: Noninvasive assessment using supersonic shear imaging and FIB4 index in patients with non-alcoholic fatty liver disease. Journal of Medical Ultrasonics. 2018;**45**:243-249

[32] Thiele M, Detlefsen S, Sevelsted Møller L, et al. Transient and

[33] Zeng J, Huang ZP, Zheng J, et al. Non-invasive assessment of liver fibrosis using two-dimensional shear wave elastography in patients with autoimmune liver diseases. World Journal of Gastroenterology.

[34] Li C, Dhyani M, Bhan AK, et al. Diagnostic performance of shear wave Elastography in patients with autoimmune liver disease. Journal of Ultrasound in Medicine. 2019

[35] Cassinotto C, Lapuyade B, Mouries A, et al. Noninvasive assessment of liver fibrosis with impulse elastography: Comparison of supersonic shear imaging with ARFI and Fibroscan. Journal of Hepatology. 2014;**61**(3):550-557

[36] Herrmann E, de Lédinghen V, Cassinotto C, et al. Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient

2017;**23**:4839-4846

Jan;**38**(1):103-111

2-dimensional shear-wave Elastography provide comparable assessment of alcoholic liver fibrosis and cirrhosis. Gastroenterology. 2016;**150**:123-133

for assessing liver fibrosis in chronic hepatitis B. Ultrasound in Medicine &

Biology. 2017;**43**:1563-1570

2016;**63**:1817-1827

[30] Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology.

*2D Shear Wave Elastography for Liver Fibrosis Evaluation DOI: http://dx.doi.org/10.5772/intechopen.88183*

for assessing liver fibrosis in chronic hepatitis B. Ultrasound in Medicine & Biology. 2017;**43**:1563-1570

*Ultrasound Elastography*

2014;**271**(3):895-900

elasticity by using real-time shearwave elastography. Radiology.

different stages of liver fibrosis,

[23] Sporea I, Mare R, Lupusoru R, et al. Comparative study between four ultrasound shear waves

2018;**20**(3):265-271

Elastographic methods for liver fibrosis assessment. Medical Ultrasonography.

[24] Bavu E, Gennisson JL, Couade M, et al. Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: A clinical study on 113

hepatitis C virus patients. Ultrasound in Medicine & Biology. 2011;**37**:1361-1373

[25] Tada T, Kumada T, Toyoda H, et al. Utility of real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C infection without cirrhosis: Comparison of liver fibrosis indices. Hepatology Research. 2015;**45**:E122-E129

[26] Zeng J, Liu GJ, Huang ZP, et al. Diagnostic accuracy of two-dimensional shear wave elastography for the noninvasive staging of hepatic fibrosis in chronic hepatitis B: A cohort study with internal validation. European Radiology.

[27] Wu T, Wang P, Zhang T, et al. Comparison of two-dimensional shear wave Elastography and real-time tissue Elastography for assessing liver fibrosis in chronic hepatitis B. Digestive

[28] Zhuang Y, Ding H, Zhang Y, et al.

[29] Zeng J, Zheng J, Huang Z, et al. Comparison of 2-D shear wave

Elastography and transient Elastography

Diseases. 2016;**34**:640-649

Two-dimensional shear-wave Elastography performance in the noninvasive evaluation of liver fibrosis in patients with chronic hepatitis B: Comparison with serum fibrosis indexes. Radiology. 2017;**283**:873-882

2014;**24**:2572-2581

considering transient Elastography (TE) as the reference method? European Journal of Radiology. 2014;**83**:e118-e122

Pelckmans P, Michielsen P, Francque S.

[17] Gersak MM, Badea R, Lenghel LM, Vasilescu D, Botar-Jid C, Dudea SM. Influence of food intake on 2-D shear wave Elastography assessment of liver stiffness in healthy subjects. Ultrasound in Medicine & Biology.

[18] Popescu A, Lupusoru R, Bende F, et al. The influence of food intake on liver stiffness measurements obtained by two 2D-SWE methods. Ultraschall in der Medizin. 2016;**37**:S1-S78. DOI:

[19] Jeong JY, Cho YS, Sohn JH. Role of two-dimensional shear wave elastography in chronic liver diseases: A narrative review. World Journal of Gastroenterology. 2018;**24**(34):3849-3860

[20] Jeong JY, Kim TY, Sohn JH, et al. Real time shear wave elastography in chronic liver diseases: Accuracy for predicting liver fibrosis, in comparison with serum markers. World Journal of Gastroenterology. 2014;**20**:13920-13929

[21] Deffieux T, Gennisson JL, Bousquet L, et al. Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography. Journal of Hepatology. 2015;**62**:317-324

[22] Sporea I, Bota S, Grădinaru-Taşcău O, et al. Which are the cut-off values of 2D-shear wave Elastography (2D-SWE) liver stiffness measurements predicting

[16] Vonghia L, Werlinden W,

Liver stiffness by shear wave elastography is influenced by meal and meal related haemodynamic modifications. Ultraschall in der Medizin. 2013;**34**:WS\_SL24\_09. DOI:

10.1055/s-0033-1354961

2016;**42**:1295-1302

10.1055/s-0036-1587862

**46**

[30] Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology. 2016;**63**:1817-1827

[31] Takeuchi H, Sugimoto K, Oshiro H, et al. Liver fibrosis: Noninvasive assessment using supersonic shear imaging and FIB4 index in patients with non-alcoholic fatty liver disease. Journal of Medical Ultrasonics. 2018;**45**:243-249

[32] Thiele M, Detlefsen S, Sevelsted Møller L, et al. Transient and 2-dimensional shear-wave Elastography provide comparable assessment of alcoholic liver fibrosis and cirrhosis. Gastroenterology. 2016;**150**:123-133

[33] Zeng J, Huang ZP, Zheng J, et al. Non-invasive assessment of liver fibrosis using two-dimensional shear wave elastography in patients with autoimmune liver diseases. World Journal of Gastroenterology. 2017;**23**:4839-4846

[34] Li C, Dhyani M, Bhan AK, et al. Diagnostic performance of shear wave Elastography in patients with autoimmune liver disease. Journal of Ultrasound in Medicine. 2019 Jan;**38**(1):103-111

[35] Cassinotto C, Lapuyade B, Mouries A, et al. Noninvasive assessment of liver fibrosis with impulse elastography: Comparison of supersonic shear imaging with ARFI and Fibroscan. Journal of Hepatology. 2014;**61**(3):550-557

[36] Herrmann E, de Lédinghen V, Cassinotto C, et al. Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis. Hepatology. 2018;**67**:260-272

[37] Li C, Zhang C, Li J, et al. Diagnostic accuracy of real-time shear wave Elastography for staging of liver fibrosis: A meta-analysis. Medical Science Monitor. 2016;**22**:1349-1359

[38] Jiang T, Tian G, Zhao Q, et al. Diagnostic accuracy of 2D-shear wave Elastography for liver fibrosis severity: A meta-analysis. PLoS One. 2016;**11**(6):e0157219

[39] Feng JC, Li J, Wu XW, et al. Diagnostic accuracy of SuperSonic shear imaging for staging of liver fibrosis: A meta-analysis. Journal of Ultrasound in Medicine. 2016;**35**(2):329-339

[40] Kim TY, Jeong WK, Sohn JH, et al. Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients. Liver International. 2015;**35**:2416-2424

[41] Elkrief L, Rautou PE, Ronot M, et al. Prospective comparison of spleen and liver stiffness by using shear-wave and transient Elastography for detection of portal hypertension in cirrhosis. Radiology. 2015;**275**(2):589-598

[42] Cassinotto C, Charrie A, Mouries A, et al. Liver and spleen elastography using supersonic shear imaging for the noninvasive diagnosis of cirrhosis severity and oesophageal varices. Digestive and Liver Disease. 2015;**47**(8):695-701

[43] Jeong JY, Sohn JH, Sohn W, Park CH, Kim TY, Jun DW, et al. Role of shear wave Elastography in evaluating the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Gut and Liver. 2017;**11**:852-859

[44] Dietrich CF, Sirli R, Ferraioli G, et al. Current knowledge in ultrasound-based liver Elastography of Pediatric patients. Applied Sciences. 2018;**8**(6):944

[45] Belei O, Sporea I, Gradinaru-Tascau O, et al. Comparison of three ultrasound based elastographic techniques in children and adolescents with chronic diffuse liver diseases. Medical Ultrasonography. 2016;**18**(2):145-150

Chapter 4

Abstract

1. Introduction

49

Quantification of Liver Steatosis

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing in the modern world. Fatty infiltration of the liver can be assessed by standard ultrasound, by controlled attenuation parameter (CAP) using the FibroScan device or, more recently, by ultrasound systems that evaluate the attenuation in the liver. Standard ultrasound (US) for steatosis evaluation was used for a long time as a semi-quantitative method for steatosis assessment in the liver. A "bright liver" with "posterior attenuation" is the typical US sign of liver steatosis. Considering the attenuation severity, steatosis is subjectively graded as mild, moderate or severe. Using the kidney/liver ratio, a more accurate evaluation can be made. Controlled attenuation parameter (CAP) was developed by EchoSens, France, and implemented into the FibroScan device. CAP manages an objective assessment of steatosis severity with rather good accuracy. More recently, ultrasound companies such as Hitachi, General Electric and Canon, implemented in their system algorithms which allow an objective assessment of liver steatosis, using the attenuation of the ultrasound beams.

Keywords: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver steatosis, standard ultrasound, controlled attenuation parameter

In the last years, the field of hepatology changed regarding the etiology of predominant liver diseases. New treatments with direct acting agents (DAA) for HCV chronic infection, or modern analogues for HBV infection, decreased the importance of the very precise evaluation of liver fibrosis severity in these two diseases. Furthermore, the increasing number of patients with obesity, type 2 diabetes or hypertriglyceridemia in the developed world, increased the prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis

Speaking about the risk factors for NAFLD, overweight and obesity play a central role. Worldwide estimations show that approximately 1.9 billion people are overweight and approximately 650 million are obese [1]. In such patients, fatty infiltration of the liver is quite common, going from simple steatosis to NASH. On the other hand, in adult population (and especially in aging population), the prevalence of type 2 diabetes mellitus can be as high as 1/11 individuals [2]. Thus, in this huge cohort of patients, it became essential to make a confident and non-invasive evaluation of liver disease severity. This assessment must reveal the severity of

In this chapter, we will cover only the quantification of liver steatosis using ultrasound methods. They are quite simple, inexpensive, and can be performed as

(NASH), changing the focus of hepatologists on these diseases.

steatosis, the severity of fibrosis and inflammation.

point of care methods, by clinicians or by radiologists.

Ioan Sporea, Roxana Șirli and Alina Popescu

[46] Moga TV, Stepan AM, Pienar C, et al. Intra- and inter-observer reproducibility of a 2-D shear wave Elastography technique and the impact of ultrasound experience in achieving reliable data. Ultrasound in Medicine & Biology. 2018;**44**(8):1627-1637

[47] Mjelle AB, Mulabecirovic A, Havre RF, et al. Normal liver stiffness values in children: A comparison of three different Elastography methods. Journal of Pediatric Gastroenterology and Nutrition. 2019;**68**(5):706-712

[48] Bende F, Mulabecirovic A, Sporea I, et al. Assessing liver stiffness by 2-D shear wave Elastography in a healthy cohort. Ultrasound in Medicine & Biology. 2018;**44**(2):332-341

[49] Bende F, Sporea I, Șirli R, et al. Performance of 2D-SWE.GE for predicting different stages of liver fibrosis, using transient Elastography as the reference method. Medical Ultrasound. 2017;**19**(2):143-149

[50] Serra C, Grasso V, Conti F, et al. A new two-dimensional shear wave Elastography for noninvasive assessment of liver fibrosis in healthy subjects and in patients with chronic liver disease. Ultraschall in der Medizin. 2018;**39**:432-439

[51] Lee ES, Lee JB, Park HR, et al. Shear wave liver Elastography with a propagation map: Diagnostic performance and inter-observer correlation for hepatic fibrosis in chronic hepatitis. Ultrasound in Medicine & Biology. 2017;**43**(7):1355-1363

#### Chapter 4

*Ultrasound Elastography*

2016;**18**(2):145-150

2018;**44**(8):1627-1637

[47] Mjelle AB, Mulabecirovic A, Havre RF, et al. Normal liver stiffness values in children: A comparison of three different Elastography methods. Journal of Pediatric Gastroenterology and Nutrition. 2019;**68**(5):706-712

[45] Belei O, Sporea I, Gradinaru-Tascau O, et al. Comparison of three ultrasound based elastographic techniques in children and

adolescents with chronic diffuse liver diseases. Medical Ultrasonography.

[46] Moga TV, Stepan AM, Pienar C, et al. Intra- and inter-observer reproducibility of a 2-D shear wave Elastography technique and the impact of ultrasound

experience in achieving reliable data. Ultrasound in Medicine & Biology.

[48] Bende F, Mulabecirovic A, Sporea I, et al. Assessing liver stiffness by 2-D shear wave Elastography in a healthy cohort. Ultrasound in Medicine & Biology. 2018;**44**(2):332-341

[49] Bende F, Sporea I, Șirli R, et al. Performance of 2D-SWE.GE for predicting different stages of liver fibrosis, using transient Elastography as the reference method. Medical Ultrasound. 2017;**19**(2):143-149

[50] Serra C, Grasso V, Conti F, et al. A new two-dimensional shear wave Elastography for noninvasive assessment of liver fibrosis in healthy subjects and in patients with chronic liver disease. Ultraschall in der Medizin.

[51] Lee ES, Lee JB, Park HR, et al. Shear wave liver Elastography with a propagation map: Diagnostic performance and inter-observer correlation for hepatic fibrosis in chronic hepatitis. Ultrasound

2018;**39**:432-439

in Medicine & Biology. 2017;**43**(7):1355-1363

**48**

## Quantification of Liver Steatosis

Ioan Sporea, Roxana Șirli and Alina Popescu

#### Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing in the modern world. Fatty infiltration of the liver can be assessed by standard ultrasound, by controlled attenuation parameter (CAP) using the FibroScan device or, more recently, by ultrasound systems that evaluate the attenuation in the liver. Standard ultrasound (US) for steatosis evaluation was used for a long time as a semi-quantitative method for steatosis assessment in the liver. A "bright liver" with "posterior attenuation" is the typical US sign of liver steatosis. Considering the attenuation severity, steatosis is subjectively graded as mild, moderate or severe. Using the kidney/liver ratio, a more accurate evaluation can be made. Controlled attenuation parameter (CAP) was developed by EchoSens, France, and implemented into the FibroScan device. CAP manages an objective assessment of steatosis severity with rather good accuracy. More recently, ultrasound companies such as Hitachi, General Electric and Canon, implemented in their system algorithms which allow an objective assessment of liver steatosis, using the attenuation of the ultrasound beams.

Keywords: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver steatosis, standard ultrasound, controlled attenuation parameter

#### 1. Introduction

In the last years, the field of hepatology changed regarding the etiology of predominant liver diseases. New treatments with direct acting agents (DAA) for HCV chronic infection, or modern analogues for HBV infection, decreased the importance of the very precise evaluation of liver fibrosis severity in these two diseases. Furthermore, the increasing number of patients with obesity, type 2 diabetes or hypertriglyceridemia in the developed world, increased the prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), changing the focus of hepatologists on these diseases.

Speaking about the risk factors for NAFLD, overweight and obesity play a central role. Worldwide estimations show that approximately 1.9 billion people are overweight and approximately 650 million are obese [1]. In such patients, fatty infiltration of the liver is quite common, going from simple steatosis to NASH. On the other hand, in adult population (and especially in aging population), the prevalence of type 2 diabetes mellitus can be as high as 1/11 individuals [2]. Thus, in this huge cohort of patients, it became essential to make a confident and non-invasive evaluation of liver disease severity. This assessment must reveal the severity of steatosis, the severity of fibrosis and inflammation.

In this chapter, we will cover only the quantification of liver steatosis using ultrasound methods. They are quite simple, inexpensive, and can be performed as point of care methods, by clinicians or by radiologists.

Fatty infiltration of the liver can be assessed by standard ultrasound, by controlled attenuation parameter (CAP) using the FibroScan device (EchoSens, Paris), or, more recently, by ultrasound systems that evaluate the attenuation in the liver.

respectively. However, when only severe steatosis was taken into consideration (a subgroup of patients who had steatosis of ≥30%) the Se, Sp, PPV and NPV were

was graded as none, mild, moderate or severe. In patients with increased

In another study performed by Mathiesen et al. [4] liver ultrasound was compared with hepatic histology for steatosis assessment in a series of 165 patients. The steatosis

echogenicity, 86.7% had liver steatosis at least moderate. This study revealed that for the detection of steatosis, standard US had 90% Se, 82% Sp, 87% PPV and 87% NPV. Some studies tried to use Computer Assisted Diagnosis (CAD) to increase the accuracy of US for the detection and evaluation of steatosis severity [5]. In a study performed in 120 subjects, CAD was able to make a correct classification of steatosis

Similar results were obtained by the group of Xia [7] in a study on 127 subjects. In this study, CAD was used to compare liver attenuation and liver/kidney index by US to magnetic resonance spectroscopy considered as the "gold standard". A very good correlation of US findings with MRI steatosis quantification (r = 0.884) was observed. Ultrasound hepatic/renal ratio in connection with hepatic attenuation can increase the accuracy of liver fat quantification [8]. In a study performed by Zhang, in a cohort of 170 subjects, where ultrasound was compared with magnetic resonance spectroscopy, an equation of quantitative model for fatty liver prediction was assessed, using ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate. In this quantitative ultrasound model, sensitivity and specificity for fatty

In review paper by Castera et al. [9] it was concluded that liver US has 60–94% sensitivity and 84–95% specificity for detecting hepatic steatosis and that the sensi-

Probably the most relevant study concerning the performance of US in diagnosing liver steatosis is a large meta-analysis that included 49 studies and 4720 subjects [10]. In this study, the sensitivity of US for moderate and severe steatosis was 84.8%, with 93.6% specificity as compared to liver biopsy, with the area under the summary receiving operating characteristics curve of 0.93. Considering this study as reference, we can say that standard transabdominal US can be used in clinical practice to perform a semi-quantitative evaluation of steatosis, with quite good accuracy. However, if we intend to follow-up these kind of patients, maybe a more objective method is needed, with results expressed as numeric values. On the other hand, the operator's experience in ultrasound is important for steatosis quantification, and, maybe, the quality of the ultrasound machine should be taken into

Controlled attenuation parameter (CAP) was developed by EchoSens, France, and implemented into the FibroScan device. Initially the CAP algorithm was available only on the M probe (for non-obese patients), but more recently it is also

Many studies were published showing the value of CAP for liver steatosis assessment, most of them using liver biopsy as the reference method. CAP measures the total ultrasound attenuation, using vibration controlled Transient Elastography (TE). The measurement results are expressed in dB/m, with values ranging between 100 and 400 dB/m. The first evaluation of CAP was performed in a cohort of 115 patients with liver histology [11]. CAP was very well correlated with steatosis (Spearman ρ = 0.81, p < 0.00001) and the AUROCs for the detection of >10

91, 93, 89 and 94%, respectively.

DOI: http://dx.doi.org/10.5772/intechopen.87938

Quantification of Liver Steatosis

severity with 82.2% accuracy [6].

liver were 94.7 and 100%.

consideration.

51

tivity increases with the severity of fatty infiltration.

3. Controlled attenuation parameter (CAP)

available on the XL probe (for obese) (Figure 3).

#### 2. Standard ultrasound (US) for steatosis evaluation

Standard ultrasound (US) for steatosis evaluation was used for a long time as a semi-quantitative method for steatosis assessment in the liver. A "bright liver" with "posterior attenuation" is the typical US sign of liver steatosis (Figure 1). Considering the attenuation severity, steatosis is subjectively graded as mild, moderate or severe. Using the kidney/liver ratio, a more accurate evaluation can be made (knowing that in normal conditions, the liver and right kidney have similar ultrasound appearance) (Figure 2).

Some studies were published regarding the value of transabdominal ultrasound for the quantification of steatosis, considering liver biopsy as the "gold standard". In a study performed by Palmentieri et al. [3] the ultrasound "bright liver" echo pattern was compared to liver biopsy in a cohort of 235 patients. "Bright liver" was found in 67% of patients with steatosis of any degree and in 89% of patients with histologic steatosis ≥30%. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of "bright liver" echo pattern and "posterior attenuation" for the presence of any steatosis were 64, 97, 96 and 65%,

Figure 1. Moderate steatosis-posterior attenuation.

Figure 2. Increased hepato-renal index.

#### Quantification of Liver Steatosis DOI: http://dx.doi.org/10.5772/intechopen.87938

Fatty infiltration of the liver can be assessed by standard ultrasound, by controlled attenuation parameter (CAP) using the FibroScan device (EchoSens, Paris), or, more recently, by ultrasound systems that evaluate the attenuation in the liver.

Standard ultrasound (US) for steatosis evaluation was used for a long time as a semi-quantitative method for steatosis assessment in the liver. A "bright liver" with "posterior attenuation" is the typical US sign of liver steatosis (Figure 1). Considering the attenuation severity, steatosis is subjectively graded as mild, moderate or severe. Using the kidney/liver ratio, a more accurate evaluation can be made (knowing that in normal conditions, the liver and right kidney have similar ultra-

Some studies were published regarding the value of transabdominal ultrasound for the quantification of steatosis, considering liver biopsy as the "gold standard". In a study performed by Palmentieri et al. [3] the ultrasound "bright liver" echo pattern was compared to liver biopsy in a cohort of 235 patients. "Bright liver" was found in 67% of patients with steatosis of any degree and in 89% of patients with histologic steatosis ≥30%. The sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of "bright liver" echo pattern and "posterior attenuation" for the presence of any steatosis were 64, 97, 96 and 65%,

2. Standard ultrasound (US) for steatosis evaluation

sound appearance) (Figure 2).

Ultrasound Elastography

Figure 1.

Figure 2.

50

Increased hepato-renal index.

Moderate steatosis-posterior attenuation.

respectively. However, when only severe steatosis was taken into consideration (a subgroup of patients who had steatosis of ≥30%) the Se, Sp, PPV and NPV were 91, 93, 89 and 94%, respectively.

In another study performed by Mathiesen et al. [4] liver ultrasound was compared with hepatic histology for steatosis assessment in a series of 165 patients. The steatosis was graded as none, mild, moderate or severe. In patients with increased echogenicity, 86.7% had liver steatosis at least moderate. This study revealed that for the detection of steatosis, standard US had 90% Se, 82% Sp, 87% PPV and 87% NPV.

Some studies tried to use Computer Assisted Diagnosis (CAD) to increase the accuracy of US for the detection and evaluation of steatosis severity [5]. In a study performed in 120 subjects, CAD was able to make a correct classification of steatosis severity with 82.2% accuracy [6].

Similar results were obtained by the group of Xia [7] in a study on 127 subjects. In this study, CAD was used to compare liver attenuation and liver/kidney index by US to magnetic resonance spectroscopy considered as the "gold standard". A very good correlation of US findings with MRI steatosis quantification (r = 0.884) was observed.

Ultrasound hepatic/renal ratio in connection with hepatic attenuation can increase the accuracy of liver fat quantification [8]. In a study performed by Zhang, in a cohort of 170 subjects, where ultrasound was compared with magnetic resonance spectroscopy, an equation of quantitative model for fatty liver prediction was assessed, using ultrasound hepatic/renal ratio and hepatic echo-intensity attenuation rate. In this quantitative ultrasound model, sensitivity and specificity for fatty liver were 94.7 and 100%.

In review paper by Castera et al. [9] it was concluded that liver US has 60–94% sensitivity and 84–95% specificity for detecting hepatic steatosis and that the sensitivity increases with the severity of fatty infiltration.

Probably the most relevant study concerning the performance of US in diagnosing liver steatosis is a large meta-analysis that included 49 studies and 4720 subjects [10]. In this study, the sensitivity of US for moderate and severe steatosis was 84.8%, with 93.6% specificity as compared to liver biopsy, with the area under the summary receiving operating characteristics curve of 0.93. Considering this study as reference, we can say that standard transabdominal US can be used in clinical practice to perform a semi-quantitative evaluation of steatosis, with quite good accuracy. However, if we intend to follow-up these kind of patients, maybe a more objective method is needed, with results expressed as numeric values. On the other hand, the operator's experience in ultrasound is important for steatosis quantification, and, maybe, the quality of the ultrasound machine should be taken into consideration.

#### 3. Controlled attenuation parameter (CAP)

Controlled attenuation parameter (CAP) was developed by EchoSens, France, and implemented into the FibroScan device. Initially the CAP algorithm was available only on the M probe (for non-obese patients), but more recently it is also available on the XL probe (for obese) (Figure 3).

Many studies were published showing the value of CAP for liver steatosis assessment, most of them using liver biopsy as the reference method. CAP measures the total ultrasound attenuation, using vibration controlled Transient Elastography (TE). The measurement results are expressed in dB/m, with values ranging between 100 and 400 dB/m. The first evaluation of CAP was performed in a cohort of 115 patients with liver histology [11]. CAP was very well correlated with steatosis (Spearman ρ = 0.81, p < 0.00001) and the AUROCs for the detection of >10

#### Ultrasound Elastography

respectively. Two important information came from this study: the AUROCs of CAP are decreasing with the severity of steatosis, and the cut-off values of CAP are

of steatosis, the first being proposed by the manufacturer: 230 dB/m for mild steatosis, 275 dB/m for moderate steatosis and 300 dB/m for severe steatosis. Other studies obtained different values, but they were correlated with the cohort of patients, with the severity of steatosis, the presence of diabetes and others.

In different studies, different cut-off values were proposed for different degrees

The first meta-analysis evaluating the accuracy of CAP for steatosis quantification showed that the optimal CAP cut-off values for mild, moderate and severe steatosis were 232.5, 255 and 290 dB/m respectively [17]. In this study, the summarized sensitivity and specificity values were 78 and 79% for mild, 85 and 79% for moderate, and 83 and 79% for severe steatosis. However, this meta-analysis calcu-

Another meta-analysis, comparing CAP with liver biopsy, was performed by Karlas in a cohort of 2735 patients: 37% with chronic hepatitis B, 36% with chronic hepatitis C, 20% with NAFLD/NASH, 7% with other chronic hepatitis. Histologic steatosis distribution was as follows: 51/27/16/6% for S0/S1/S2/S3. In this metaanalysis, the calculated optimal cut-offs were 248 dB/m for S0 vs. S1–S3, 268 dB/m for S0–S1 vs. S2–S3 and 280 dB/m for S0–S2 vs. S3, with AUROCs of 0.82, 0.86 and

Other studies compared CAP to MRI quantification of steatosis. Proton density fat fraction (PDFF) by MRI was lately proposed as a sensitive modality of liver fat evaluation. In a cohort of 104 consecutive patients, all with liver biopsy, MRI-PDFF was compared with CAP for diagnosis of steatosis (grades 1–3 vs. 0) [19]. In this study, MRI-PDFF detected any steatosis with an AUROC of 0.99, significantly higher than that of CAP (AUROC 0.85). In the same time, MRI-PDFF identified S2 or S3 with AUROC values of 0.90 and 0.92, while CAP identified S2 or S3 with

In another comparative study between CAP and PDFF, performed in Japan in a cohort of 142 patients with NAFLD and liver biopsy, CAP measurements identified patients with S ≥ 2 with an AUROC of 0.73 and PDFF methods identified them with

A comparative study between CAP and PDFF was performed in 119 adults with liver biopsy, evaluating the performance to diagnose 5 and 10% fatty infiltration in PDFF [21]. In this study, using CAP with M or XL probes, AUROC of CAP for the detection of MRI-PDFF ≥ 5% was 0.80 (at the cut-point of 288 dB/m) and of MRI-PDFF ≥ 10% was 0.87 (at the cut-point of 306 dB/m). When the authors considered the IQR (interquartile range) as a qualitative parameter, it was shown that CAP measurements with an IQR (inter quartile range) below 30 dB/m had a more robust AUROC as compared to those with an IQR higher than this (0.92 versus 0.70,

In the study performed by Wong et al. [22] in a prospective multicenter study, including 754 patients, they found that the IQR of CAP was associated with the accuracy of this method and that the AUROC of CAP was 0.90 in patients with IQR <40 (and 0.77 if ≥40 dB/m, respectively, p = 0.004). Finally they proposed like a

These comparative studies clearly showed a better performance of MRI-PDFF vs. CAP to diagnose steatosis, but we must have in mind that CAP can be a point of care method and that the price of such investigation is much lower than the price of MRI-PDFF. Most published papers concerning the accuracy of CAP for fat quantification calculated accuracies ranging from 0.75 to 0.85, increasing with the severity

higher than in other published studies, for all degrees of steatosis.

lated a rather low specificity for CAP, being approx. 80%.

0.88 respectively [18].

Quantification of Liver Steatosis

DOI: http://dx.doi.org/10.5772/intechopen.87938

AUROC values of 0.70 and 0.73.

qualitative criteria for CAP to use IQR < 40 dB/m.

an AUROC of 0.90 [20].

p = 0.0117).

of steatosis.

53

#### Figure 3.

FibroScan with CAP, with M and XL probes. Steatosis values are displayed in light blue and liver stiffness values in yellow.

and >33% steatosis were 91 and 95% respectively. CAP was evaluated also with the XL probe by the same author in a cohort of 59 patients [12]. In this study, the AUROCs for the detection of >2 and >16% liver fat were 83/84% and 92/91% for the M/XL probes, respectively.

Another study performed on 440 patients who had liver biopsy as reference method showed that the AUROCs of CAP for the diagnosis of steatosis >10, >33 and >66% were 79, 84, and 84%, respectively [13]. On multivariate analysis, factors significantly associated with elevated CAP were BMI 25–30 kg/m2 , BMI > 30 kg/m2 , metabolic syndrome, alcohol intake more than 14 drinks/week and liver stiffness >6 kPa.

In a study on 201 patients who also had undergone liver biopsy, histologic steatosis was the only factor that independently influenced CAP values [14]. For moderate and severe steatosis, CAP cut-off values of 285 and 294 dB/m had 82.0 and 81.5% accuracy, respectively. However, for mild steatosis, the accuracy was only 76.1% at a cut-off 260 dB/m. These last two studies showed maybe a more realistic value of CAP for liver steatosis assessment, the accuracy being around 80–85% (less for mild steatosis).

In another study in a cohort of 101 NAFLD patients with liver biopsy, CAP was associated in a multivariate analysis with steatosis grade (odds ratio [OR] = 29.16, p < 0.001), serum triglycerides (OR = 13.59, p = 0.037) and body mass index (BMI; OR = 4.34, p < 0.001) [15]. In this study, the optimal CAP cut-offs for estimation of steatosis grades S1 (5–33% of hepatocytes), S2 (>33–66% of hepatocytes), and S3 (>66% of the hepatocytes) were 263dB/m, 281dB/m, and 283dB/m, respectively, and the AUROC's for S1, S2, and S3 were 0.97, 0.86, and 0.75, respectively.

In a very recent multicenter study [16], where FibroScan was compared to liver biopsy in patients with NAFLD, from 450 consecutive patients, 404 patients had valid measurements using M and XL probes. AUROC of CAP for steatosis evaluation was 0.87 for S ≥ S1, 0.77 for S ≥ S2, and 0.70 for S3. In the same study, the cutoff values for S ≥ S1, S ≥ S2, and S = S3 were 302 dB/m, 331 dB/m, and 337 dB/m,

#### Quantification of Liver Steatosis DOI: http://dx.doi.org/10.5772/intechopen.87938

respectively. Two important information came from this study: the AUROCs of CAP are decreasing with the severity of steatosis, and the cut-off values of CAP are higher than in other published studies, for all degrees of steatosis.

In different studies, different cut-off values were proposed for different degrees of steatosis, the first being proposed by the manufacturer: 230 dB/m for mild steatosis, 275 dB/m for moderate steatosis and 300 dB/m for severe steatosis. Other studies obtained different values, but they were correlated with the cohort of patients, with the severity of steatosis, the presence of diabetes and others.

The first meta-analysis evaluating the accuracy of CAP for steatosis quantification showed that the optimal CAP cut-off values for mild, moderate and severe steatosis were 232.5, 255 and 290 dB/m respectively [17]. In this study, the summarized sensitivity and specificity values were 78 and 79% for mild, 85 and 79% for moderate, and 83 and 79% for severe steatosis. However, this meta-analysis calculated a rather low specificity for CAP, being approx. 80%.

Another meta-analysis, comparing CAP with liver biopsy, was performed by Karlas in a cohort of 2735 patients: 37% with chronic hepatitis B, 36% with chronic hepatitis C, 20% with NAFLD/NASH, 7% with other chronic hepatitis. Histologic steatosis distribution was as follows: 51/27/16/6% for S0/S1/S2/S3. In this metaanalysis, the calculated optimal cut-offs were 248 dB/m for S0 vs. S1–S3, 268 dB/m for S0–S1 vs. S2–S3 and 280 dB/m for S0–S2 vs. S3, with AUROCs of 0.82, 0.86 and 0.88 respectively [18].

Other studies compared CAP to MRI quantification of steatosis. Proton density fat fraction (PDFF) by MRI was lately proposed as a sensitive modality of liver fat evaluation. In a cohort of 104 consecutive patients, all with liver biopsy, MRI-PDFF was compared with CAP for diagnosis of steatosis (grades 1–3 vs. 0) [19]. In this study, MRI-PDFF detected any steatosis with an AUROC of 0.99, significantly higher than that of CAP (AUROC 0.85). In the same time, MRI-PDFF identified S2 or S3 with AUROC values of 0.90 and 0.92, while CAP identified S2 or S3 with AUROC values of 0.70 and 0.73.

In another comparative study between CAP and PDFF, performed in Japan in a cohort of 142 patients with NAFLD and liver biopsy, CAP measurements identified patients with S ≥ 2 with an AUROC of 0.73 and PDFF methods identified them with an AUROC of 0.90 [20].

A comparative study between CAP and PDFF was performed in 119 adults with liver biopsy, evaluating the performance to diagnose 5 and 10% fatty infiltration in PDFF [21]. In this study, using CAP with M or XL probes, AUROC of CAP for the detection of MRI-PDFF ≥ 5% was 0.80 (at the cut-point of 288 dB/m) and of MRI-PDFF ≥ 10% was 0.87 (at the cut-point of 306 dB/m). When the authors considered the IQR (interquartile range) as a qualitative parameter, it was shown that CAP measurements with an IQR (inter quartile range) below 30 dB/m had a more robust AUROC as compared to those with an IQR higher than this (0.92 versus 0.70, p = 0.0117).

In the study performed by Wong et al. [22] in a prospective multicenter study, including 754 patients, they found that the IQR of CAP was associated with the accuracy of this method and that the AUROC of CAP was 0.90 in patients with IQR <40 (and 0.77 if ≥40 dB/m, respectively, p = 0.004). Finally they proposed like a qualitative criteria for CAP to use IQR < 40 dB/m.

These comparative studies clearly showed a better performance of MRI-PDFF vs. CAP to diagnose steatosis, but we must have in mind that CAP can be a point of care method and that the price of such investigation is much lower than the price of MRI-PDFF. Most published papers concerning the accuracy of CAP for fat quantification calculated accuracies ranging from 0.75 to 0.85, increasing with the severity of steatosis.

and >33% steatosis were 91 and 95% respectively. CAP was evaluated also with the XL probe by the same author in a cohort of 59 patients [12]. In this study, the AUROCs for the detection of >2 and >16% liver fat were 83/84% and 92/91% for the

FibroScan with CAP, with M and XL probes. Steatosis values are displayed in light blue and liver stiffness

Another study performed on 440 patients who had liver biopsy as reference method showed that the AUROCs of CAP for the diagnosis of steatosis >10, >33 and >66% were 79, 84, and 84%, respectively [13]. On multivariate analysis, factors significantly asso-

In a study on 201 patients who also had undergone liver biopsy, histologic steatosis was the only factor that independently influenced CAP values [14]. For moderate and severe steatosis, CAP cut-off values of 285 and 294 dB/m had 82.0 and 81.5% accuracy, respectively. However, for mild steatosis, the accuracy was only 76.1% at a cut-off 260 dB/m. These last two studies showed maybe a more realistic value of CAP for liver steatosis assessment, the accuracy being around

In another study in a cohort of 101 NAFLD patients with liver biopsy, CAP was associated in a multivariate analysis with steatosis grade (odds ratio [OR] = 29.16, p < 0.001), serum triglycerides (OR = 13.59, p = 0.037) and body mass index (BMI; OR = 4.34, p < 0.001) [15]. In this study, the optimal CAP cut-offs for estimation of steatosis grades S1 (5–33% of hepatocytes), S2 (>33–66% of hepatocytes), and S3 (>66% of the hepatocytes) were 263dB/m, 281dB/m, and 283dB/m, respectively, and the AUROC's for S1, S2, and S3 were 0.97, 0.86, and 0.75, respectively.

In a very recent multicenter study [16], where FibroScan was compared to liver biopsy in patients with NAFLD, from 450 consecutive patients, 404 patients had valid measurements using M and XL probes. AUROC of CAP for steatosis evaluation was 0.87 for S ≥ S1, 0.77 for S ≥ S2, and 0.70 for S3. In the same study, the cutoff values for S ≥ S1, S ≥ S2, and S = S3 were 302 dB/m, 331 dB/m, and 337 dB/m,

, BMI > 30 kg/m2

, metabolic syndrome,

M/XL probes, respectively.

Figure 3.

52

values in yellow.

Ultrasound Elastography

80–85% (less for mild steatosis).

ciated with elevated CAP were BMI 25–30 kg/m2

alcohol intake more than 14 drinks/week and liver stiffness >6 kPa.

### 4. Ultrasound systems evaluating the attenuation

For a long time the posterior attenuation of ultrasound beams in standard liver evaluation was used as a subjective parameter for steatosis assessment. More recently, ultrasound companies such as Hitachi, General Electric and Canon, implemented in their system algorithms which allows an objective assessment of liver steatosis, using the attenuation of the ultrasound beams.

4.2 Ultrasound-guided attenuation parameter (UGAP)

the results obtained with CAP.

Quantification of Liver Steatosis

DOI: http://dx.doi.org/10.5772/intechopen.87938

4.3 Attenuation image (ATI)

Figure 6.

55

(a) Attenuation image from Canon and (b) evaluation of dispersion with Canon system.

Ultrasound-guided attenuation parameter (UGAP) from General Electric was recently proposed for steatosis quantification. In a paper published by a Japanese group, UGAP was compared with liver biopsy and CAP in a cohort of 163 patients [24]. In this study, the median value of UGAP in patients with S0, S1, S2 and S3 grade steatosis were 0.485, 0.560, 0.660 and 0.720 respectively (increasing with the severity of steatosis), and in the same time, the AUROCs of UGAP for identifying >S1, >S2 and S3 were 0.900, 0.953 and 0.959, respectively, significantly better than

Attenuation image (ATI) from Canon was introduced for liver steatosis quantification. This method permit a simple quantification of liver steatosis, by using a region of interest applied on the standard ultrasound image, where the attenuation is evaluated. Values of this parameter are expressed in dB/cm/MHz and it also has a parameter of the quality of acquisition, that must be higher than R2 > 0.90 (Figure 6a).

#### 4.1 Attenuation coefficient (ATT)

Attenuation coefficient (ATT) from Hitachi was evaluated in a prospective multicenter cohort of 351 patients [23], where liver biopsy and ATT measurement were performed in the same day. In this study, the median values of ATT for steatosis grades S0, S1, S2, and S3 were 0.55, 0.63, 0.69 and 0.85 dB/cm/MHz, respectively, increasing with the severity of steatosis (p < 0.001). In the same time, the AUROCs for S ≥ 1, S ≥ 2, and S ≥ 3 were 0.79, 0.87, and 0.96, respectively.

The Combi-Elasto algorithm from Hitachi quantifies steatosis (ATT), but in the same time the shear-waves speed is used for estimation of the stiffness or elasticity (E) of the liver expressed in kPa and also to produce some indexes, such as Liver Fibrosis Index (LFI) and Activity Index (AI) (Figures 4–5).

Figure 4. Attenuation coefficient (ATT).

Figure 5. ATT coefficient with ten measurement values.

#### 4.2 Ultrasound-guided attenuation parameter (UGAP)

Ultrasound-guided attenuation parameter (UGAP) from General Electric was recently proposed for steatosis quantification. In a paper published by a Japanese group, UGAP was compared with liver biopsy and CAP in a cohort of 163 patients [24]. In this study, the median value of UGAP in patients with S0, S1, S2 and S3 grade steatosis were 0.485, 0.560, 0.660 and 0.720 respectively (increasing with the severity of steatosis), and in the same time, the AUROCs of UGAP for identifying >S1, >S2 and S3 were 0.900, 0.953 and 0.959, respectively, significantly better than the results obtained with CAP.

#### 4.3 Attenuation image (ATI)

4. Ultrasound systems evaluating the attenuation

liver steatosis, using the attenuation of the ultrasound beams.

for S ≥ 1, S ≥ 2, and S ≥ 3 were 0.79, 0.87, and 0.96, respectively.

Fibrosis Index (LFI) and Activity Index (AI) (Figures 4–5).

4.1 Attenuation coefficient (ATT)

Ultrasound Elastography

Figure 4.

Figure 5.

54

ATT coefficient with ten measurement values.

Attenuation coefficient (ATT).

For a long time the posterior attenuation of ultrasound beams in standard liver

Attenuation coefficient (ATT) from Hitachi was evaluated in a prospective multicenter cohort of 351 patients [23], where liver biopsy and ATT measurement were performed in the same day. In this study, the median values of ATT for steatosis grades S0, S1, S2, and S3 were 0.55, 0.63, 0.69 and 0.85 dB/cm/MHz, respectively, increasing with the severity of steatosis (p < 0.001). In the same time, the AUROCs

The Combi-Elasto algorithm from Hitachi quantifies steatosis (ATT), but in the same time the shear-waves speed is used for estimation of the stiffness or elasticity (E) of the liver expressed in kPa and also to produce some indexes, such as Liver

evaluation was used as a subjective parameter for steatosis assessment. More recently, ultrasound companies such as Hitachi, General Electric and Canon, implemented in their system algorithms which allows an objective assessment of

> Attenuation image (ATI) from Canon was introduced for liver steatosis quantification. This method permit a simple quantification of liver steatosis, by using a region of interest applied on the standard ultrasound image, where the attenuation is evaluated. Values of this parameter are expressed in dB/cm/MHz and it also has a parameter of the quality of acquisition, that must be higher than R2 > 0.90 (Figure 6a).

#### Ultrasound Elastography

In a preliminary study in which ATI was compared with CAP (FibroScan, EchoSens), in a cohort of 113 consecutive subjects [25], a strong positive correlation was found between the attenuation coefficients of steatosis obtained by the 2 methods, r = 0.81, p < 0.001. Using CAP as reference, the AUROCs of ATI for ≥S1, ≥S2 and ≥S3 were excellent (0.89, 0.88, respectively 0.95, p < 0.001) and the proposed cut-off values for were: S1 = 0.64 dB/cm/mHz, S2 = 0.79 dB/cm/mHz and S3 = 0.86 dB/cm/mHz.

Many of the new ultrasound systems are able to estimate with the same machine steatosis severity, liver stiffness and, more recently, inflammation. This is the next step toward a multiparametric approach of liver diseases, using ultrasound machines. In conclusion, quantification of liver steatosis using ultrasound is a good method

for daily practice. The low cost, easy feasibility and accessibility make these methods useful for the large number of potential patients with fatty liver.

Quantification of Liver Steatosis

DOI: http://dx.doi.org/10.5772/intechopen.87938

Author details

57

Ioan Sporea, Roxana Șirli\* and Alina Popescu

Medicine and Pharmacy, Timișoara, Romania

provided the original work is properly cited.

\*Address all correspondence to: roxanasirli@gmail.com

Department of Gastroenterology and Hepatology, "Victor Babeș" University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The Canon system can also evaluate dispersion, considering the viscoelastic properties of liver tissue (Figure 6b).

#### 4.4 Attenuation parameter

Attenuation parameter from Aixplorer evaluates attenuation of ultrasound, concomitantly with the display of speed of sound (SoS), used for fatty infiltration estimation. Similar to other modern ultrasound machines, the new system is able to quantify the tissue viscosity, expressed in Pa s (Figure 7a and b).

Figure 7 (a) Attenuation quantification and (b) viscosity imaging.

#### Quantification of Liver Steatosis DOI: http://dx.doi.org/10.5772/intechopen.87938

In a preliminary study in which ATI was compared with CAP (FibroScan, EchoSens), in a cohort of 113 consecutive subjects [25], a strong positive correlation

The Canon system can also evaluate dispersion, considering the viscoelastic

Attenuation parameter from Aixplorer evaluates attenuation of ultrasound, concomitantly with the display of speed of sound (SoS), used for fatty infiltration estimation. Similar to other modern ultrasound machines, the new system is able to

quantify the tissue viscosity, expressed in Pa s (Figure 7a and b).

was found between the attenuation coefficients of steatosis obtained by the 2 methods, r = 0.81, p < 0.001. Using CAP as reference, the AUROCs of ATI for ≥S1, ≥S2 and ≥S3 were excellent (0.89, 0.88, respectively 0.95, p < 0.001) and the proposed cut-off values for were: S1 = 0.64 dB/cm/mHz, S2 = 0.79 dB/cm/mHz and

S3 = 0.86 dB/cm/mHz.

Ultrasound Elastography

Figure 7

56

(a) Attenuation quantification and (b) viscosity imaging.

4.4 Attenuation parameter

properties of liver tissue (Figure 6b).

Many of the new ultrasound systems are able to estimate with the same machine steatosis severity, liver stiffness and, more recently, inflammation. This is the next step toward a multiparametric approach of liver diseases, using ultrasound machines.

In conclusion, quantification of liver steatosis using ultrasound is a good method for daily practice. The low cost, easy feasibility and accessibility make these methods useful for the large number of potential patients with fatty liver.

#### Author details

Ioan Sporea, Roxana Șirli\* and Alina Popescu Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, Timișoara, Romania

\*Address all correspondence to: roxanasirli@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### References

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[2] International Diabetes Federation. Diabetes: Facts and Figures. 2019. Available online: http://www.idf.org/ [Accessed: 30 June 2019]

[3] Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Digestive and Liver Disease. 2006;38:485-489

[4] Mathiesen UL, Franzen LE, Aselius H, et al. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/ moderate abnormalities of liver transaminases. Digestive and Liver Disease. 2002;34:516-522

[5] Gaitini D, Baruch Y, Ghersin E, et al. Feasibility study of ultrasonic fatty liver biopsy: Texture vs. attenuation and backscatter. Ultrasound in Medicine & Biology. 2004;30:1321-1327

[6] Mihăilescu DM, Gui V, Toma CI, et al. Computer aided diagnosis method for steatosis rating in ultrasound images using random forests. Medical Ultrasonography. 2013;15:184-190

[7] Xia MF, Yan HM, He WY, et al. Standardized ultrasound hepatic/renal ratio and hepatic attenuation rate to quantify liver fat content: An improvement method. Obesity. 2012;20: 444-452

[8] Zhang B, Ding F, Chen T, et al. Ultrasound hepatic/renal ratio and hepatic attenuation rate for quantifying liver fat content. World Journal of Gastroenterology. 2014;20:17985-17992

[9] Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nature Reviews. Gastroenterology & Hepatology. 2013;10:666-675

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[17] Shi KQ, Tang JZ, Zhu XL, et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: A meta-analysis of

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[18] Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. Journal of Hepatology. 2017;66:

[19] Park CC, Nguyen P, Hernandez C. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsyproven nonalcoholic fatty liver disease. Gastroenterology. 2017;152:598-607

[20] Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;

[21] Caussy C, Alquiraish MH, Nguyen P, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018;67:

[22] Wong VWS, Petta S, Hiriart JB, et al. Validity criteria for the diagnosis

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[10] Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis. Hepatology. 2011;54:1082-1090

[11] Sasso M, Beaugrand M, de Ledinghen V, et al. Controlled attenuation parameter (CAP): A novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: Preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound in Medicine & Biology. 2010;36:1825-1835

[12] Sasso M, Audière S, Kemgang A, et al. Liver steatosis assessed by controlled attenuation parameter (CAP) measured with the XL probe of the FibroScan: A pilot study assessing diagnostic accuracy. Ultrasound in Medicine & Biology. 2016;42:92-103

[13] de Lédinghen V, Vergniol J, Capdepont M, et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinations. Journal of Hepatology. 2014;60:1026-1031

[14] Lupșor-Platon M, Feier D, Stefănescu H, et al. Diagnostic accuracy of controlled attenuation parameter measured by transient elastography for the non-invasive assessment of liver steatosis: A prospective study. Journal of Gastrointestinal and Liver Diseases. 2015;24:35-42

[15] Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in Quantification of Liver Steatosis DOI: http://dx.doi.org/10.5772/intechopen.87938

nonalcoholic fatty liver disease. Journal of Gastroenterology and Hepatology. 2014;29:1470-1476

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Ultrasound Elastography

10:686-690

[1] Loomba R, Sanyal AJ. The global NAFLD epidemic. Nature Reviews. Gastroenterology & Hepatology. 2013; [9] Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nature Reviews. Gastroenterology &

[10] Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: A meta-analysis. Hepatology.

attenuation parameter (CAP): A novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: Preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound in Medicine & Biology. 2010;36:1825-1835

[12] Sasso M, Audière S, Kemgang A, et al. Liver steatosis assessed by

[13] de Lédinghen V, Vergniol J, Capdepont M, et al. Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinations. Journal of Hepatology. 2014;60:1026-1031

[14] Lupșor-Platon M, Feier D,

[15] Chan WK, Nik Mustapha NR, Mahadeva S. Controlled attenuation parameter for the detection and quantification of hepatic steatosis in

2015;24:35-42

Stefănescu H, et al. Diagnostic accuracy of controlled attenuation parameter measured by transient elastography for the non-invasive assessment of liver steatosis: A prospective study. Journal of Gastrointestinal and Liver Diseases.

controlled attenuation parameter (CAP) measured with the XL probe of the FibroScan: A pilot study assessing diagnostic accuracy. Ultrasound in Medicine & Biology. 2016;42:92-103

Hepatology. 2013;10:666-675

[11] Sasso M, Beaugrand M, de Ledinghen V, et al. Controlled

2011;54:1082-1090

[2] International Diabetes Federation. Diabetes: Facts and Figures. 2019. Available online: http://www.idf.org/

[3] Palmentieri B, de Sio I, La Mura V, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Digestive and Liver Disease.

[4] Mathiesen UL, Franzen LE, Aselius H, et al. Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/ moderate abnormalities of liver transaminases. Digestive and Liver

[5] Gaitini D, Baruch Y, Ghersin E, et al. Feasibility study of ultrasonic fatty liver biopsy: Texture vs. attenuation and backscatter. Ultrasound in Medicine &

[6] Mihăilescu DM, Gui V, Toma CI, et al. Computer aided diagnosis method for steatosis rating in ultrasound images

[7] Xia MF, Yan HM, He WY, et al. Standardized ultrasound hepatic/renal ratio and hepatic attenuation rate to quantify liver fat content: An

[8] Zhang B, Ding F, Chen T, et al. Ultrasound hepatic/renal ratio and hepatic attenuation rate for quantifying liver fat content. World Journal of Gastroenterology. 2014;20:17985-17992

improvement method. Obesity. 2012;20:

[Accessed: 30 June 2019]

Disease. 2002;34:516-522

Biology. 2004;30:1321-1327

using random forests. Medical Ultrasonography. 2013;15:184-190

444-452

58

2006;38:485-489

[16] Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156:1717-1730

[17] Shi KQ, Tang JZ, Zhu XL, et al. Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: A meta-analysis of diagnostic accuracy. Journal of Gastroenterology and Hepatology. 2014; 29:1149-1158

[18] Karlas T, Petroff D, Sasso M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. Journal of Hepatology. 2017;66: 1022-1030

[19] Park CC, Nguyen P, Hernandez C. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsyproven nonalcoholic fatty liver disease. Gastroenterology. 2017;152:598-607

[20] Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016; 150:626-637

[21] Caussy C, Alquiraish MH, Nguyen P, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis. Hepatology. 2018;67: 1348-1359

[22] Wong VWS, Petta S, Hiriart JB, et al. Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter. Journal of Hepatology. 2017;67:577-584

[23] Tamaki N, Koizumi Y, Hirooka M, et al. Novel quantitative assessment system of liver steatosis using a newly developed attenuation measurement method. Hepatology Research. 2018;48: 821-828

[24] Fujiwara Y, Kuroda H, Abe T, et al. The B-mode image-guided US attenuation parameter accurately detect hepatic steatosis in chronic liver disease. Ultrasound in Medicine and Biology. 2018;44(11):2223-2232

[25] Sporea I, Bâldea V, Lupușoru R, et al. Value of Viscosity, Viscoelasticity and Attenuation Measurement Using Shear Wave Ultrasound Elastography. Oral Presentation. Granada, Spain: Euroson; 2019

**61**

**Chapter 5**

**Abstract**

Diseases

*Samuel N. Gitau and Issa K. Menge*

**Keywords:** diffuse liver disease, hepatitis B, hepatitis C,

nonalcoholic fatty liver disease

**1. Introduction**

carcinoma develop.

Elastography in Chronic Liver

Elastography is useful for diagnosing and grading hepatic fibrosis in patients with chronic liver diseases (CLD). In addition, it may be used as a noninvasive tool for surveillance and prognostication of patients with complications related to CLD. Elastography uses real-time ultrasound to assess for tissue elasticity and is a fast, simple, reproducible, and reliable method for noninvasive liver fibrosis evaluation. Management of chronic liver disease is dependent on the grade of liver fibrosis to ascertain the urgency and choice of treatment and advice on further screening for cirrhosis and hepatocellular carcinoma. This chapter will highlight the role of elastography in the evaluation of chronic liver disease including hepatitis B and C and HIV-related liver disease and nonalcoholic fatty liver disease (NAFLD).

Chronic liver diseases are a major cause of morbidity and mortality worldwide with around 800,000 deaths per year attributable to liver cirrhosis [1]. There are a myriad of causes of chronic liver disease including viral infections, alcohol abuse, nonalcoholic fatty liver disease, biliary disease, autoimmune disease, genetic causes, and metabolic disorders [2]. Liver fibrosis results from chronic injury induced by a variety of causes with infection being the leading one. Most patients with chronic liver disease are often asymptomatic with symptoms only setting in when complications of the disease such as portal hypertension, cirrhosis, and hepatocellular

Management of chronic liver disease is dependent on the grade of liver fibrosis to ascertain the urgency and choice of treatment and advice on further screening for cirrhosis and hepatocellular carcinoma. Though liver biopsy has traditionally been the gold standard for diagnosis and staging of liver fibrosis, the procedure has paramount shortfalls as a medical screening test. It lacks the safety profile, accuracy, and accessibility of a standard medical screening test. It is an invasive technique with rates of morbidity of 3 in 100 and mortality of 3 in 10,000 reported [3]. In addition, sampling errors may arise because only 1/50,000 of the liver is sampled during the procedure. Inter- and intra-observer variability of between 10 and 20% in interpretation and staging of hepatic fibrosis have been reported which may lead to under-staging or over-staging of fibrosis [4]. A study by Maharaj et al. [5], where three percutaneous liver biopsies were performed in the same patients using the same entry points, found a concordance rate for cirrhosis in all three

#### **Chapter 5**

## Elastography in Chronic Liver Diseases

*Samuel N. Gitau and Issa K. Menge*

#### **Abstract**

Elastography is useful for diagnosing and grading hepatic fibrosis in patients with chronic liver diseases (CLD). In addition, it may be used as a noninvasive tool for surveillance and prognostication of patients with complications related to CLD. Elastography uses real-time ultrasound to assess for tissue elasticity and is a fast, simple, reproducible, and reliable method for noninvasive liver fibrosis evaluation. Management of chronic liver disease is dependent on the grade of liver fibrosis to ascertain the urgency and choice of treatment and advice on further screening for cirrhosis and hepatocellular carcinoma. This chapter will highlight the role of elastography in the evaluation of chronic liver disease including hepatitis B and C and HIV-related liver disease and nonalcoholic fatty liver disease (NAFLD).

**Keywords:** diffuse liver disease, hepatitis B, hepatitis C, nonalcoholic fatty liver disease

#### **1. Introduction**

Chronic liver diseases are a major cause of morbidity and mortality worldwide with around 800,000 deaths per year attributable to liver cirrhosis [1]. There are a myriad of causes of chronic liver disease including viral infections, alcohol abuse, nonalcoholic fatty liver disease, biliary disease, autoimmune disease, genetic causes, and metabolic disorders [2]. Liver fibrosis results from chronic injury induced by a variety of causes with infection being the leading one. Most patients with chronic liver disease are often asymptomatic with symptoms only setting in when complications of the disease such as portal hypertension, cirrhosis, and hepatocellular carcinoma develop.

Management of chronic liver disease is dependent on the grade of liver fibrosis to ascertain the urgency and choice of treatment and advice on further screening for cirrhosis and hepatocellular carcinoma. Though liver biopsy has traditionally been the gold standard for diagnosis and staging of liver fibrosis, the procedure has paramount shortfalls as a medical screening test. It lacks the safety profile, accuracy, and accessibility of a standard medical screening test. It is an invasive technique with rates of morbidity of 3 in 100 and mortality of 3 in 10,000 reported [3]. In addition, sampling errors may arise because only 1/50,000 of the liver is sampled during the procedure. Inter- and intra-observer variability of between 10 and 20% in interpretation and staging of hepatic fibrosis have been reported which may lead to under-staging or over-staging of fibrosis [4]. A study by Maharaj et al. [5], where three percutaneous liver biopsies were performed in the same patients using the same entry points, found a concordance rate for cirrhosis in all three

#### *Ultrasound Elastography*

biopsy specimens of only 50%. Taking into consideration all these shortfalls, the "gold standard" for the true liver disease status would be the histological analysis of nearly the entire liver which is not feasible. Effectively, liver biopsy is an "imperfect gold standard," and the definitive diagnosis of liver fibrosis in routine clinical practice is practically impossible [6].

Elastography uses real-time ultrasound to assess for tissue elasticity and is a fast, simple, reproducible, and reliable method for noninvasive liver fibrosis evaluation.

Elastography as a tool for evaluation of disease relates to one of the first physical exam skills every physician learns, i.e., palpation. This is based on the premise that diseased organs feel harder than the normal surrounding tissue. Using elastography, tissue stiffness (or hardness) can be measured and converted into an image. Young's modulus is used to quantify the elasticity or stiffness of a tissue and is calculated from the ratio between a uniform compression (stress, s) applied to the tissue and the resulting induced tissue deformation (strain, e) as shown in the equation below [7].

Young"s modulus (elasticity) = Stress/Strain or E = s/e (1)

Using a reference amount of force applied to the tissue, its elasticity can be determined. Elasticity is measured in pressure units, pascal, or kilopascals (kPa).

The stiffness (elasticity) of normal, healthy liver is very low (of the order of 2 kPa, comparable to a soft gelatin gel) [8]. In response to inflammation, liver cells die and are replaced by scar tissue. As fibrosis progresses, the scar tissue becomes progressively rigid, and as a result the stiffness of the tissue increases. The stiffness of fibrotic liver is a reflection of the severity of the disease. Using elastography, an image of the shear stiffness of a tissue can be created [9]. It can therefore be used to monitor the extent of liver damage. Elastography is a painless and rapid procedure and does not require any preparation.

There are two main ways of performing elastography. The maiden method which has been widely used is transient elastography (TE) popularly known as FibroScan. The other relatively new methods are real-time elastography (RTE) using shear waves and acoustic radiation force impulse imaging (ARFI) [10–12].

Transient elastography uses both ultrasound (around 5 MHz) and low-frequency (50 Hz) mechanically generated shear waves to determine tissue elasticity. The propagation velocity of the shear waves is directly related to elasticity with the speed greater in stiff (fibrosed) tissue than in a softer tissue. The shear wave is generated by an external low-frequency vibrator which strikes the patient's skin and produces the shear wave whose propagation in the tissue of interest is measured and provided as an average elasticity [10]. In evaluation of liver elasticity, the measurements are acquired from the right lobe of the liver through the intercostal space. Ten liver stiffness measurements are obtained and the median considered as the representative value.

The limitations of this technique include the low volume of parenchyma explored, absence of real-time ultrasound guidance, measurement difficulties in cases of obesity and presence of ascites, and lack of specificity for the distinction of significant fibrosis level. The learning curve in correctly performing the examination without imaging guidance also serves to limit its reproducibility [10]. These drawbacks have led to the quest for a better elastographic method the birth of which is real-time elastography (RTE).

RTE does not require an external vibrator to generate the shear wave as is the case with transient elastography. The probe of the ultrasound machine produces a localized radiation force deep in the tissue of interest. This radiation force induces a shear wave, which then propagates through the tissue from a focal point. Several

**63**

**Figure 1.**

*Image illustrating propagation of shear waves from a focal point.*

*Elastography in Chronic Liver Diseases*

skin (**Figure 1**).

(**Figure 2**).

and Prevention [16].

performing liver biopsy [17].

*DOI: http://dx.doi.org/10.5772/intechopen.88228*

**2. Elastography in hepatitis B and C**

focal points are then generated in a line perpendicular to the surface of the patient's

The transmission of the shear wave is then detected by the rapid acquisition of ultrasound which takes only a few milliseconds, thus the patient or operator movement does not impact the result. The speed at which the shear wave propagates is then estimated from the measurement of the displacement induced by the shear wave and a real-time two-dimensional color map displayed. This color map is color-coded for the different shear wave speeds representing the degrees of stiffness from soft to hard. This color map is accompanied by an anatomic reference grayscale (or B-mode) image; hence the area of sampling can be identified on the image

Elastographic reference ranges have been developed for distinguishing mild fibrosis from significant fibrosis and cirrhosis following using histology (METAVIR

An estimated 240 and 160 million people in the world have chronic hepatitis B and C virus infections, respectively, according to the Centers for Disease Control

Elastography has been validated as a surrogate marker of liver fibrosis in a great number of studies, mainly in patients with chronic hepatitis B and C infections, and has enabled decision on when to start antiviral treatment without the need of

The recommended velocity cutoffs for degree of liver fibrosis in patients with hepatitis C using the different elastography techniques are summarized in **Table 1**

[18]. These cutoffs have been adapted for all cases of chronic liver disease. In chronic hepatitis C, elastography has been shown to perform better for diagnosis of significant fibrosis (METAVIR score F ≥ 2) and cirrhosis (METAVIR score F4). The area under the ROC curve (AUROC) for the assessment of significant fibrosis ranged from 0.77 to 0.90 (F ≥ 2) and 0.90 to 0.97 for assessment of cirrhosis [17, 19–21]. Similar findings have been observed in patients with chronic viral

score) as the reference standard [13–15] (see details in **Table 1**).

#### *Elastography in Chronic Liver Diseases DOI: http://dx.doi.org/10.5772/intechopen.88228*

*Ultrasound Elastography*

equation below [7].

representative value.

is real-time elastography (RTE).

practice is practically impossible [6].

and does not require any preparation.

biopsy specimens of only 50%. Taking into consideration all these shortfalls, the "gold standard" for the true liver disease status would be the histological analysis of nearly the entire liver which is not feasible. Effectively, liver biopsy is an "imperfect gold standard," and the definitive diagnosis of liver fibrosis in routine clinical

Elastography uses real-time ultrasound to assess for tissue elasticity and is a fast, simple, reproducible, and reliable method for noninvasive liver fibrosis evaluation. Elastography as a tool for evaluation of disease relates to one of the first physical exam skills every physician learns, i.e., palpation. This is based on the premise that diseased organs feel harder than the normal surrounding tissue. Using elastography, tissue stiffness (or hardness) can be measured and converted into an image. Young's modulus is used to quantify the elasticity or stiffness of a tissue and is calculated from the ratio between a uniform compression (stress, s) applied to the tissue and the resulting induced tissue deformation (strain, e) as shown in the

Young"s modulus (elasticity) = Stress/Strain or E = s/e (1)

There are two main ways of performing elastography. The maiden method which has been widely used is transient elastography (TE) popularly known as FibroScan. The other relatively new methods are real-time elastography (RTE) using shear

Transient elastography uses both ultrasound (around 5 MHz) and low-frequency (50 Hz) mechanically generated shear waves to determine tissue elasticity. The propagation velocity of the shear waves is directly related to elasticity with the speed greater in stiff (fibrosed) tissue than in a softer tissue. The shear wave is generated by an external low-frequency vibrator which strikes the patient's skin and produces the shear wave whose propagation in the tissue of interest is measured and provided as an average elasticity [10]. In evaluation of liver elasticity, the measurements are acquired from the right lobe of the liver through the intercostal space. Ten liver stiffness measurements are obtained and the median considered as the

The limitations of this technique include the low volume of parenchyma explored, absence of real-time ultrasound guidance, measurement difficulties in cases of obesity and presence of ascites, and lack of specificity for the distinction of significant fibrosis level. The learning curve in correctly performing the examination without imaging guidance also serves to limit its reproducibility [10]. These drawbacks have led to the quest for a better elastographic method the birth of which

RTE does not require an external vibrator to generate the shear wave as is the case with transient elastography. The probe of the ultrasound machine produces a localized radiation force deep in the tissue of interest. This radiation force induces a shear wave, which then propagates through the tissue from a focal point. Several

waves and acoustic radiation force impulse imaging (ARFI) [10–12].

Using a reference amount of force applied to the tissue, its elasticity can be determined. Elasticity is measured in pressure units, pascal, or kilopascals (kPa). The stiffness (elasticity) of normal, healthy liver is very low (of the order of 2 kPa, comparable to a soft gelatin gel) [8]. In response to inflammation, liver cells die and are replaced by scar tissue. As fibrosis progresses, the scar tissue becomes progressively rigid, and as a result the stiffness of the tissue increases. The stiffness of fibrotic liver is a reflection of the severity of the disease. Using elastography, an image of the shear stiffness of a tissue can be created [9]. It can therefore be used to monitor the extent of liver damage. Elastography is a painless and rapid procedure

**62**

focal points are then generated in a line perpendicular to the surface of the patient's skin (**Figure 1**).

The transmission of the shear wave is then detected by the rapid acquisition of ultrasound which takes only a few milliseconds, thus the patient or operator movement does not impact the result. The speed at which the shear wave propagates is then estimated from the measurement of the displacement induced by the shear wave and a real-time two-dimensional color map displayed. This color map is color-coded for the different shear wave speeds representing the degrees of stiffness from soft to hard. This color map is accompanied by an anatomic reference grayscale (or B-mode) image; hence the area of sampling can be identified on the image (**Figure 2**).

Elastographic reference ranges have been developed for distinguishing mild fibrosis from significant fibrosis and cirrhosis following using histology (METAVIR score) as the reference standard [13–15] (see details in **Table 1**).

#### **2. Elastography in hepatitis B and C**

An estimated 240 and 160 million people in the world have chronic hepatitis B and C virus infections, respectively, according to the Centers for Disease Control and Prevention [16].

Elastography has been validated as a surrogate marker of liver fibrosis in a great number of studies, mainly in patients with chronic hepatitis B and C infections, and has enabled decision on when to start antiviral treatment without the need of performing liver biopsy [17].

The recommended velocity cutoffs for degree of liver fibrosis in patients with hepatitis C using the different elastography techniques are summarized in **Table 1** [18]. These cutoffs have been adapted for all cases of chronic liver disease.

In chronic hepatitis C, elastography has been shown to perform better for diagnosis of significant fibrosis (METAVIR score F ≥ 2) and cirrhosis (METAVIR score F4). The area under the ROC curve (AUROC) for the assessment of significant fibrosis ranged from 0.77 to 0.90 (F ≥ 2) and 0.90 to 0.97 for assessment of cirrhosis [17, 19–21]. Similar findings have been observed in patients with chronic viral

**Figure 1.** *Image illustrating propagation of shear waves from a focal point.*

#### **Figure 2.**

*Gray-scale image showing acquisition of an elastography reading using RTE.*


#### **Table 1.**

*Recommended velocity cutoffs for degree of liver fibrosis in patients with hepatitis C using the different elastography techniques. Source: [18].*

#### **Figure 3.**

*A 39-year-old male with the human immunodeficiency virus and hepatitis B virus coinfection. (a) Grayscale ultrasound image of the liver shows a shear wave elastography acquisition box (arrow) with a high elastography score of 7.4 kPa. (b) a table showing 10 liver stiffness measurements readings for the same patient with a high median elastography score of 6.35 kPa (encircled). Source: [25].*

**65**

*Elastography in Chronic Liver Diseases*

*DOI: http://dx.doi.org/10.5772/intechopen.88228*

fibrosis that would warrant treatment.

**3. Nonalcoholic fatty liver disease**

cause fatty liver infiltration [30].

hepatocellular carcinoma (2.6% per year) [31–36].

this (**Figure 3**).

infection [26].

hepatitis B where AUROC values ranged from 0.81 to 0.95 for significant fibrosis and from 0.80 to 0.98 for patients with cirrhosis [22, 23]. This shows that elastography forms an important screening tool for identifying patients with significant

There has been an increase in the proportion of liver-related deaths due to HCC in patients with HIV (from 15% in 2000 to 25% in 2005) with underlying HIV-HCV coinfection in the majority of the deaths [24]. In a study on liver fibrosis in patients with HIV-HBV coinfection using shear wave elastography, HBV coinfection was associated with 4.5 times increase in the prevalence of significant fibrosis which impacts progress of liver disease with its potential associated morbidity and mortality in patients with HIV [25]. Monitoring of degree of fibrosis in these patients is therefore very important, and elastography provides a noninvasive means of doing

The World Health Organization recommends the use of elastography (where

Due to the increasing rates of sedentary lifestyle and obesity, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of abnormal liver function tests (LFTs) in the Western world [27]. NAFLD is defined as the presence of more than 5% of steatotic hepatocytes in patients who do not consume excessive alcohol (less than 30 g/day for men and less than 20 g/day for women) [28, 29]. It is a spectrum of disease starting from simple steatosis progressing to nonalcoholic steatohepatitis (NASH), through advanced fibrosis and cirrhosis. Up to 80% of patients with central obesity and type 2 diabetes have evidence of NAFLD on imaging [28]. In most patients, NAFLD coexists with other liver pathologies including hepatitis C, hemochromatosis, and alcoholic liver disease. The presence of NAFLD on a background of these diseases causes more rapid disease progression. Treatment with steatogenic drugs including steroids, tamoxifen, and amiodarone can also

Most patients with NAFLD have simple steatosis, which has good clinical outcome and no overall increase in mortality. However, up to a third of these patients have NASH which is the progressive form of NAFLD. Up to 40% of patients with NASH develop progressive liver fibrosis with 20–30% culminating in cirrhosis. Patients with cirrhosis secondary to NASH are at an increased risk of developing

NAFLD can be diagnosed by the demonstration of hepatic steatosis on imaging or histology where other etiologies of liver disease or steatosis have been excluded. Although most clinicians rely on deranged liver function tests to identify patients with NAFLD, this can be inaccurate as majority of the patients will remain within normal-range ALT levels. Furthermore, even for those patients identified to have elevated ALT, the ALT typically falls (and AST may rise) as fibrosis progresses to cirrhosis. Importantly ALT values do not demonstrate positive correlation with histological findings. Therefore, isolated measurement of ALT is of little value in

When fatty liver disease is suspected clinically, this should be confirmed with imaging. Ultrasound is usually the first-line investigation for patients suspected to have hepatic steatosis. It provides a qualitative assessment of fatty infiltration of the liver where gray-scale findings are used. The echogenicity of the liver parenchyma is compared to that of the kidney and other internal liver structures such the vascular

both the diagnosis of NAFLD and determination of its severity [37–39].

available) for screening for liver fibrosis in patients with chronic hepatitis B

#### *Elastography in Chronic Liver Diseases DOI: http://dx.doi.org/10.5772/intechopen.88228*

*Ultrasound Elastography*

**Figure 2.**

**64**

**Figure 3.**

**Table 1.**

*elastography techniques. Source: [18].*

*A 39-year-old male with the human immunodeficiency virus and hepatitis B virus coinfection. (a) Grayscale ultrasound image of the liver shows a shear wave elastography acquisition box (arrow) with a high elastography score of 7.4 kPa. (b) a table showing 10 liver stiffness measurements readings for the same patient* 

*Recommended velocity cutoffs for degree of liver fibrosis in patients with hepatitis C using the different* 

*with a high median elastography score of 6.35 kPa (encircled). Source: [25].*

*Gray-scale image showing acquisition of an elastography reading using RTE.*

hepatitis B where AUROC values ranged from 0.81 to 0.95 for significant fibrosis and from 0.80 to 0.98 for patients with cirrhosis [22, 23]. This shows that elastography forms an important screening tool for identifying patients with significant fibrosis that would warrant treatment.

There has been an increase in the proportion of liver-related deaths due to HCC in patients with HIV (from 15% in 2000 to 25% in 2005) with underlying HIV-HCV coinfection in the majority of the deaths [24]. In a study on liver fibrosis in patients with HIV-HBV coinfection using shear wave elastography, HBV coinfection was associated with 4.5 times increase in the prevalence of significant fibrosis which impacts progress of liver disease with its potential associated morbidity and mortality in patients with HIV [25]. Monitoring of degree of fibrosis in these patients is therefore very important, and elastography provides a noninvasive means of doing this (**Figure 3**).

The World Health Organization recommends the use of elastography (where available) for screening for liver fibrosis in patients with chronic hepatitis B infection [26].

#### **3. Nonalcoholic fatty liver disease**

Due to the increasing rates of sedentary lifestyle and obesity, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of abnormal liver function tests (LFTs) in the Western world [27]. NAFLD is defined as the presence of more than 5% of steatotic hepatocytes in patients who do not consume excessive alcohol (less than 30 g/day for men and less than 20 g/day for women) [28, 29]. It is a spectrum of disease starting from simple steatosis progressing to nonalcoholic steatohepatitis (NASH), through advanced fibrosis and cirrhosis. Up to 80% of patients with central obesity and type 2 diabetes have evidence of NAFLD on imaging [28].

In most patients, NAFLD coexists with other liver pathologies including hepatitis C, hemochromatosis, and alcoholic liver disease. The presence of NAFLD on a background of these diseases causes more rapid disease progression. Treatment with steatogenic drugs including steroids, tamoxifen, and amiodarone can also cause fatty liver infiltration [30].

Most patients with NAFLD have simple steatosis, which has good clinical outcome and no overall increase in mortality. However, up to a third of these patients have NASH which is the progressive form of NAFLD. Up to 40% of patients with NASH develop progressive liver fibrosis with 20–30% culminating in cirrhosis. Patients with cirrhosis secondary to NASH are at an increased risk of developing hepatocellular carcinoma (2.6% per year) [31–36].

NAFLD can be diagnosed by the demonstration of hepatic steatosis on imaging or histology where other etiologies of liver disease or steatosis have been excluded. Although most clinicians rely on deranged liver function tests to identify patients with NAFLD, this can be inaccurate as majority of the patients will remain within normal-range ALT levels. Furthermore, even for those patients identified to have elevated ALT, the ALT typically falls (and AST may rise) as fibrosis progresses to cirrhosis. Importantly ALT values do not demonstrate positive correlation with histological findings. Therefore, isolated measurement of ALT is of little value in both the diagnosis of NAFLD and determination of its severity [37–39].

When fatty liver disease is suspected clinically, this should be confirmed with imaging. Ultrasound is usually the first-line investigation for patients suspected to have hepatic steatosis. It provides a qualitative assessment of fatty infiltration of the liver where gray-scale findings are used. The echogenicity of the liver parenchyma is compared to that of the kidney and other internal liver structures such the vascular

walls to diagnose and grade hepatosteatosis. Normal liver is hypoechoic relative to the renal cortex and becomes relatively hyperechoic with the presence of fatty infiltration. Ultrasound is effective in diagnosing steatosis if the percentage of involved hepatocytes is >33%; its diagnostic performance is however low with lesser degrees of fatty liver infiltration. Consequently, a normal liver ultrasound finding does not invariably rule out the presence of mild liver steatosis. Additionally, conventional ultrasound cannot assess the degree of fibrosis [40].

Liver elastography technique can measure steatosis simultaneously with the assessment of liver stiffness. It is paramount to stage the degree of fibrosis in patients with NAFLD as this will help identify patients with advanced fibrosis and resultant increased risk of liver-related complications such as liver failure and hepatocellular carcinoma [41].

It has been shown that there is a positive correlation between shear wave velocity and increasing hepatic fibrosis. In a study of 246 subjects with NAFLD, the AUROCs for the detection of F ≥ 2 and F ≥ 3 were 0.84 and 0.93, respectively. The sensitivity and specificity for advanced fibrosis (F ≥ 3) were 91% and 75% with an elastography score cutoff of 7.9 kPa [42].

Inflammation is also known to increase shear wave velocity since the presence of edema results in reduced elasticity. It is therefore important to exclude active inflammation as this can confound the staging of liver fibrosis in the setting of NASH [43].

In summary, elastography plays a critical role in the evaluation of patients with NAFLD since early diagnosis of severe liver fibrosis allows for the institution of appropriate therapy as well as prognostication.

#### **Author details**

Samuel N. Gitau\* and Issa K. Menge Department of Radiology, Aga Khan University Hospital, Nairobi, Kenya

\*Address all correspondence to: samuelnguku12@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**67**

*Elastography in Chronic Liver Diseases*

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[2] Sebastiani G, Castera L, Halfon P, et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: An international study of 2411 cases. Alimentary Pharmacology & Therapeutics. 2011;**34**(10):1202-1216

[3] Montalto G, Soresi M, Carroccio A, Bascone F, Tripi S, Aragona F, et al. Percutaneous liver biopsy: A safe outpatient procedure? Digestion.

[4] Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: Results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the liver (AFEF). Hepatology.

[5] Maharaj B, Maharaj RJ, Leary WP, Cooppan RM, Naran AD, Pirie D, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet.

[6] Poynard T, Munteanu M, Imbert-Bismut F, Charlotte F, Thabut D, Le Calvez S, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clinical Chemistry.

[8] Catheline S, Gennisson JL, Delon G, Fink M, Sinkus R, Abouelkaram S, et al. Measuring of viscoelastic properties

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Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound in Medicine & Biology.

[11] Srinivasa Babu A, Wells ML, Teytelboym OM, et al. Elastography in chronic liver disease: Modalities, techniques, limitations, and future directions. Radiographics.

[12] Frulio N, Trillaud H. Ultrasound elastography in liver. Diagnostic and Interventional Imaging.

[13] Ferraioli G, Parekh P, Levitov AB, Filice C. Shear wave elastography for evaluation of liver fibrosis. Journal of Ultrasound in Medicine.

[14] Leung VY, Shen J, Wong VW, Abrigo J, Wong GL, Chim AM, et al. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: Comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology.

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[9] Carstensen EL, Parker KJ, Lerner RM. Elastography in the management of liver disease. Ultrasound in Medicine & Biology.

### **References**

*Ultrasound Elastography*

hepatocellular carcinoma [41].

NASH [43].

**Author details**

Samuel N. Gitau\* and Issa K. Menge

provided the original work is properly cited.

elastography score cutoff of 7.9 kPa [42].

appropriate therapy as well as prognostication.

walls to diagnose and grade hepatosteatosis. Normal liver is hypoechoic relative to the renal cortex and becomes relatively hyperechoic with the presence of fatty infiltration. Ultrasound is effective in diagnosing steatosis if the percentage of involved hepatocytes is >33%; its diagnostic performance is however low with lesser degrees of fatty liver infiltration. Consequently, a normal liver ultrasound finding does not invariably rule out the presence of mild liver steatosis. Additionally, conventional

Liver elastography technique can measure steatosis simultaneously with the assessment of liver stiffness. It is paramount to stage the degree of fibrosis in patients with NAFLD as this will help identify patients with advanced fibrosis and resultant increased risk of liver-related complications such as liver failure and

It has been shown that there is a positive correlation between shear wave velocity and increasing hepatic fibrosis. In a study of 246 subjects with NAFLD, the AUROCs for the detection of F ≥ 2 and F ≥ 3 were 0.84 and 0.93, respectively. The sensitivity and specificity for advanced fibrosis (F ≥ 3) were 91% and 75% with an

Inflammation is also known to increase shear wave velocity since the presence of edema results in reduced elasticity. It is therefore important to exclude active inflammation as this can confound the staging of liver fibrosis in the setting of

In summary, elastography plays a critical role in the evaluation of patients with NAFLD since early diagnosis of severe liver fibrosis allows for the institution of

Department of Radiology, Aga Khan University Hospital, Nairobi, Kenya

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: samuelnguku12@gmail.com

ultrasound cannot assess the degree of fibrosis [40].

**66**

[1] WHO. Mortality database 2006. 2006 (updated 2006; cited 2009 Dec 1). Available from: http://www.who.int/ healthinfo/morttables/en/index.html

[2] Sebastiani G, Castera L, Halfon P, et al. The impact of liver disease aetiology and the stages of hepatic fibrosis on the performance of non-invasive fibrosis biomarkers: An international study of 2411 cases. Alimentary Pharmacology & Therapeutics. 2011;**34**(10):1202-1216

[3] Montalto G, Soresi M, Carroccio A, Bascone F, Tripi S, Aragona F, et al. Percutaneous liver biopsy: A safe outpatient procedure? Digestion. 2001;**63**(1):55-60

[4] Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: Results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the liver (AFEF). Hepatology. 2000;**32**(3):477-481

[5] Maharaj B, Maharaj RJ, Leary WP, Cooppan RM, Naran AD, Pirie D, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;**1**(8480):523-525

[6] Poynard T, Munteanu M, Imbert-Bismut F, Charlotte F, Thabut D, Le Calvez S, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clinical Chemistry. 2004;**50**(8):1344-1355

[7] Garra BS. Imaging and estimation of tissue elasticity by ultrasound. Ultrasound Quarterly. 2007;**23**(4):255-268

[8] Catheline S, Gennisson JL, Delon G, Fink M, Sinkus R, Abouelkaram S, et al. Measuring of viscoelastic properties

of homogeneous soft solid using transient elastography: An inverse problem approach. The Journal of the Acoustical Society of America. 2004;**116**(6):3734-3741

[9] Carstensen EL, Parker KJ, Lerner RM. Elastography in the management of liver disease. Ultrasound in Medicine & Biology. 2008;**34**(10):1535-1546

[10] Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound in Medicine & Biology. 2003;**29**(12):1705-1713

[11] Srinivasa Babu A, Wells ML, Teytelboym OM, et al. Elastography in chronic liver disease: Modalities, techniques, limitations, and future directions. Radiographics. 2016;**36**(7):1987-2006

[12] Frulio N, Trillaud H. Ultrasound elastography in liver. Diagnostic and Interventional Imaging. 2013;**94**(5):515-534

[13] Ferraioli G, Parekh P, Levitov AB, Filice C. Shear wave elastography for evaluation of liver fibrosis. Journal of Ultrasound in Medicine. 2014;**33**(2):197-203

[14] Leung VY, Shen J, Wong VW, Abrigo J, Wong GL, Chim AM, et al. Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: Comparison of shear-wave elastography and transient elastography with liver biopsy correlation. Radiology. 2013;**269**(3):910-918

[15] Kettaneh A, Marcellin P, Douvin C, Poupon R, Ziol M, Beaugrand M, et al. Features associated with success

rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: A prospective study of 935 patients. Journal of Hepatology. 2007;**46**(4):628-634

[16] Centers for Disease Control and Prevention. Viral hepatitis. 2014. Centers for Disease Control and Prevention website: http://www.cdc. gov/hepatitis/index.htm

[17] Castera L, Forns X, Alberti A. Noninvasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology. 2008;**48**(5):835-847

[18] General Electric. LOGIQ E9 shear wave elastography white paper (document ID: JB23292GB). GE website

[19] Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;**41**:48-54

[20] Arena U, Vizzutti F, Abraldes JG, Corti G, Stasi C, Moscarella S, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut. 2008;**57**:1288-1293

[21] Kim SU, Jang HW, Cheong JY, Kim JK, Lee MH, Kim DJ, et al. The usefulness of liver stiffness measurement using FibroScan in chronic hepatitis C in South Korea: A multicenter, prospective study. Journal of Gastroenterology and Hepatology. 2011;**26**:171-178

[22] Ogawa E, Furusyo N, Murata M, Ohnishi H, Toyoda K, Taniai H, et al. Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog. Hepatology Research. 2011;**41**:1178-1188

[23] Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver International. 2009;**29**:242-247

[24] Salmon-Ceron D, Lewden C, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Liver disease as a major cause of death among HIV infected patients: Role of hepatitis C and B viruses and alcohol. Journal of Hepatology. 2005;**42**(6):799-805

[25] Gitau SN, Vinayak S, Silaba M, Adam R, Shah R. High prevalence of liver fibrosis in patients with human immunodeficiency virus monoinfection and human immunodeficiency virus hepatitis-B Co-infection as assessed by shear wave elastography: Study at a teaching hospital in Kenya. Journal of Clinical Imaging Science. 2016;**6**:22. [Published: 07 June 2016]

[26] WHO Guidelines for the prevention, care and treatment of persons with chronic hepatitis b infection. March 2015

[27] Armstrong MJ. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. Journal of Hepatology. 2012;**56**:234-240

[28] Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middleaged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011;**140**:124-131

[29] Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clinics in Liver Disease. 2009;**13**:511-531

[30] Powell EE, Jonsson JR, Clouston AD. Steatosis: Co-factor in other liver diseases. Hepatology. 2005;**42**(1):5-13

**69**

*Elastography in Chronic Liver Diseases*

[31] Matteoni CA, Younossi ZM, Gramlich T, et al. Non alcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology.

[33] Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology.

et al. Disease progression of non-alcoholic fatty liver disease: A prospective study with paired liver biopsies at 3 years. Gut.

[34] Wong VW, Wong GL, Choi PC,

[35] Fassio E, Alvarez E, Dominguez N, et al. Natural history of non alcoholic steatohepatitis: A longitudinal study of repeat liver biopsies. Hepatology.

[36] Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;**51**:1972-1978

[37] Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology.

[38] Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;**37**:1286-1292

[39] McPherson S, Stewart SF,

Henderson E, et al. Simple non-invasive

1999;**116**:1413-1419

2006;**44**:865-873

2010;**59**:969-974

2004;**40**:820-826

2012;**142**:1592-1609

*DOI: http://dx.doi.org/10.5772/intechopen.88228*

fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease.

[40] Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;**123**:745-750

[41] Sasso M, Tengher-Barna I, Ziol M, et al. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): Validation in chronic hepatitis C. Journal of Viral Hepatitis. 2012;**19**:244-253

Anstee QM. Republished: Non-alcoholic

[42] Dyson JK, McPherson S,

2014;**90**:254-266

fatty liver disease: Non-invasive investigation and risk stratification. Postgraduate Medical Journal.

[43] Deffieux T, Gennisson JL, Bousquet L, Corouge M, Cosconea S, Amroun D, et al. Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography. Journal of Hepatology. 2015;**62**:317-324

Gut. 2010;**59**:1265-1269

[32] Dam-Larsen S. Long term prognosis of fatty liver: Risk of chronic liver disease and death. Gut. 2004;**53**:750-755

*Elastography in Chronic Liver Diseases DOI: http://dx.doi.org/10.5772/intechopen.88228*

*Ultrasound Elastography*

rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: A prospective et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver

International. 2009;**29**:242-247

[24] Salmon-Ceron D, Lewden C, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Liver disease as a major cause of death among HIV infected patients: Role of hepatitis C and B viruses and alcohol. Journal of Hepatology. 2005;**42**(6):799-805

[25] Gitau SN, Vinayak S, Silaba M, Adam R, Shah R. High prevalence of liver fibrosis in patients with human immunodeficiency virus monoinfection and human immunodeficiency virus hepatitis-B Co-infection as assessed by shear wave elastography: Study at a teaching hospital in Kenya. Journal of Clinical Imaging Science. 2016;**6**:22.

[Published: 07 June 2016]

infection. March 2015

2012;**56**:234-240

[26] WHO Guidelines for the prevention, care and treatment of persons with chronic hepatitis b

[27] Armstrong MJ. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. Journal of Hepatology.

[28] Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty

steatohepatitis among a largely middleaged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011;**140**:124-131

Epidemiology and natural history of non-alcoholic steatohepatitis. Clinics in

liver disease and nonalcoholic

[29] Argo CK, Caldwell SH.

Liver Disease. 2009;**13**:511-531

[30] Powell EE, Jonsson JR, Clouston AD. Steatosis: Co-factor in other liver diseases. Hepatology.

2005;**42**(1):5-13

study of 935 patients. Journal of Hepatology. 2007;**46**(4):628-634

gov/hepatitis/index.htm

2005;**41**:48-54

2008;**57**:1288-1293

2011;**26**:171-178

2011;**41**:1178-1188

[16] Centers for Disease Control and Prevention. Viral hepatitis. 2014. Centers for Disease Control and Prevention website: http://www.cdc.

[17] Castera L, Forns X, Alberti A. Noninvasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology. 2008;**48**(5):835-847

[19] Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology.

[20] Arena U, Vizzutti F, Abraldes JG, Corti G, Stasi C, Moscarella S, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut.

[21] Kim SU, Jang HW, Cheong JY, Kim JK, Lee MH, Kim DJ, et al. The usefulness of liver stiffness measurement using FibroScan in chronic hepatitis C in South Korea: A multicenter, prospective study. Journal of Gastroenterology and Hepatology.

[22] Ogawa E, Furusyo N, Murata M, Ohnishi H, Toyoda K, Taniai H, et al. Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog. Hepatology Research.

[23] Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V,

[18] General Electric. LOGIQ E9 shear wave elastography white paper (document ID: JB23292GB). GE website

**68**

[31] Matteoni CA, Younossi ZM, Gramlich T, et al. Non alcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology. 1999;**116**:1413-1419

[32] Dam-Larsen S. Long term prognosis of fatty liver: Risk of chronic liver disease and death. Gut. 2004;**53**:750-755

[33] Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;**44**:865-873

[34] Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: A prospective study with paired liver biopsies at 3 years. Gut. 2010;**59**:969-974

[35] Fassio E, Alvarez E, Dominguez N, et al. Natural history of non alcoholic steatohepatitis: A longitudinal study of repeat liver biopsies. Hepatology. 2004;**40**:820-826

[36] Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;**51**:1972-1978

[37] Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;**142**:1592-1609

[38] Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;**37**:1286-1292

[39] McPherson S, Stewart SF, Henderson E, et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;**59**:1265-1269

[40] Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;**123**:745-750

[41] Sasso M, Tengher-Barna I, Ziol M, et al. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): Validation in chronic hepatitis C. Journal of Viral Hepatitis. 2012;**19**:244-253

[42] Dyson JK, McPherson S, Anstee QM. Republished: Non-alcoholic fatty liver disease: Non-invasive investigation and risk stratification. Postgraduate Medical Journal. 2014;**90**:254-266

[43] Deffieux T, Gennisson JL, Bousquet L, Corouge M, Cosconea S, Amroun D, et al. Investigating liver stiffness and viscosity for fibrosis, steatosis and activity staging using shear wave elastography. Journal of Hepatology. 2015;**62**:317-324

**71**

**Chapter 6**

**Abstract**

**1. Relevance**

disease (45.6%) [3].

*and Alexander Kinzersky*

normal ones for pediatric patients.

Elastometry Indices of Unchanged

Two hundred healthy children aged 3–18 years were included in the study to determine liver stiffness indices by means of shear wave elastometry. The difference is significant when we compared shear wave velocity in children aged 3–6 years, on the one hand, and in children aged 7–18 years, on the other (*p* = 0.001). Liver stiffness indices in boys and girls were not different. As a result, liver stiffness indices in children in various age groups have been obtained, which can be recommended as

**Keywords:** ultrasound diagnostics, shear wave elastography, fibrosis, liver, children

Chronic diffuse liver diseases are an urgent issue in present children gastroenterology. Interest to this group of liver diseases is due to their increasing incidence, frequent severe course, tendency to progression, and unfavorable outcomes. This problem requires great attention as chronic liver diseases are often polyetiological and their course is insufficiently symptomatic because of the great compensatory capacities of the organ. Clinical manifestations and patient presentation often take place when severe morphological changes have already occurred and adaptation and compensatory mechanisms have been wasted. [1]. Regardless of the etiology, cirrhosis is the cause of fatal outcome in patients due to the development of complications, i.e., hemorrhage from the esophageal varices, ascites, encephalopathy, hemorrhagic syndrome, and transformation to hepatocellular carcinoma [2]. In children chronic liver diseases develop as a result of influence of various etiologic factors such as viruses, autoantibodies, cholestasis, metabolic disorders, toxic agents, etc. on the liver parenchyma for a long time. Most often the process evolves due to bile duct disorders (75.6%), alpha-1 antitrypsin insufficiency (63.6%), autoimmune hepatitis (56.9%), chronic hepatitis D (57.4%), and Wilson-Konovalov

Diagnostics of early fibrosis changes in the liver is prognostically important in the evaluation of the disease course. Presently, "the gold standard" of diagnostic method in diffuse liver disease is considered transcutaneous puncture biopsy with histologic investigation of tissue sampling, which enables to confirm, specify, and even alter the clinical diagnosis. However, the method is invasive and may cause a number of complications; moreover, in children their number is greater coming up to 4%. There are objective reasons limiting the use of biopsy method, i.e., a small

Liver in Healthy Children

*Mikhail Pykov, Natalia Kuzmina, Nikolay Rostovtsev* 

#### **Chapter 6**

## Elastometry Indices of Unchanged Liver in Healthy Children

*Mikhail Pykov, Natalia Kuzmina, Nikolay Rostovtsev and Alexander Kinzersky*

#### **Abstract**

Two hundred healthy children aged 3–18 years were included in the study to determine liver stiffness indices by means of shear wave elastometry. The difference is significant when we compared shear wave velocity in children aged 3–6 years, on the one hand, and in children aged 7–18 years, on the other (*p* = 0.001). Liver stiffness indices in boys and girls were not different. As a result, liver stiffness indices in children in various age groups have been obtained, which can be recommended as normal ones for pediatric patients.

**Keywords:** ultrasound diagnostics, shear wave elastography, fibrosis, liver, children

#### **1. Relevance**

Chronic diffuse liver diseases are an urgent issue in present children gastroenterology. Interest to this group of liver diseases is due to their increasing incidence, frequent severe course, tendency to progression, and unfavorable outcomes. This problem requires great attention as chronic liver diseases are often polyetiological and their course is insufficiently symptomatic because of the great compensatory capacities of the organ. Clinical manifestations and patient presentation often take place when severe morphological changes have already occurred and adaptation and compensatory mechanisms have been wasted. [1]. Regardless of the etiology, cirrhosis is the cause of fatal outcome in patients due to the development of complications, i.e., hemorrhage from the esophageal varices, ascites, encephalopathy, hemorrhagic syndrome, and transformation to hepatocellular carcinoma [2]. In children chronic liver diseases develop as a result of influence of various etiologic factors such as viruses, autoantibodies, cholestasis, metabolic disorders, toxic agents, etc. on the liver parenchyma for a long time. Most often the process evolves due to bile duct disorders (75.6%), alpha-1 antitrypsin insufficiency (63.6%), autoimmune hepatitis (56.9%), chronic hepatitis D (57.4%), and Wilson-Konovalov disease (45.6%) [3].

Diagnostics of early fibrosis changes in the liver is prognostically important in the evaluation of the disease course. Presently, "the gold standard" of diagnostic method in diffuse liver disease is considered transcutaneous puncture biopsy with histologic investigation of tissue sampling, which enables to confirm, specify, and even alter the clinical diagnosis. However, the method is invasive and may cause a number of complications; moreover, in children their number is greater coming up to 4%. There are objective reasons limiting the use of biopsy method, i.e., a small

size of the tissue sampling. As liver fibrosis may have irregular distribution, different locations may show different stages of liver fibrosis and histologic activity [4, 5]. Thus, in pediatric medical practice, specialists are encouraged to search for noninvasive methods enabling not only to reveal liver changes but also to dynamically follow up the fibrosis process.

Ultrasound elastography is a great breakthrough in the evolution of noninvasive methods of visualization of liver conditions in general and ultrasound diagnostics in particular. There are only a few publications describing indices of liver stiffness in children obtained by one-dimensional and two-dimensional shear wave elastography (SWE). While studying stiffness indices in kPa (kilopascal) and m/s, the scientists pay attention to the data on liver stiffness obtained by different ultrasound and elastography techniques which cannot be compared. Normal indices for various age and gender groups are not clearly defined in the literature. Taking all these into account, the purpose of our study is to determine gender-age indices of liver "stiffness" in healthy children.

#### **2. Material and methods**

Two hundred healthy children aged 3–18 years were included in the study. Written informed consent was obtained from the legal representatives of all children. The study was approved by the ethics committee of FGBOU DPO, Moscow. All patients were allocated to three age groups according to age periodization of Mazurin and Vorantsov [6]. The first group consisted of 103 children, the second one consisted of 52, and the third one consisted of 45. According to this periodization, extrauterine period (besides the neonatal, infancy, and early childhood periods) includes preschool period (from 3 to 6 years), junior school period (from 7 to 11 years), and senior school period (from 12 to 18 years). There were 103 girls and 97 boys among them. The following criteria were considered allocating children to the control group: height and weight of each child within the interval from 5th to 95th percentile of age norm [7]; absence of liver diseases and (or) congestive heart failure in the anamnesis: absence of inflammatory alterations according to general and biochemical blood analysis (signs of cholestasis, cytolysis); absence of pathology of the liver, bile ducts, pancreas, and spleen according to ultrasound study in the grayscale and Doppler study (chromatic Doppler mapping, impulsewave Doppler) modes; and a quiet behavior of a child during examination. The examination was performed on Aixplorer device (SuperSonic Imagine, France) by broadband convex sensor acting within frequency range of 1–6 MHz. The study was done when a patient was fasting after standard ultrasound examination of abdominal organs and retroperitoneal space. Finishing the grayscale mode and Doppler ultrasound, elastography shear wave (SWE ) mode was started. Tissue stiffness was demonstrated on the screen as a chromatic coded map (qualitative characteristics), and quantitative value of stiffness was evaluated in kilopascal (kPa).

After SWE mode activation, there appeared two images on the screen: the first one, displayed in the real-time mode a scanned area in the B-mode, and the second one, the same image with elastogram (**Figure 1**).

The mapping color depended on the chosen type of chromatic map. The chosen type of chromatic map colored stiffer tissues in red, while softer tissues in blue. The tissues of "mean" stiffness were colored in intermediate colors from light blue and green to yellow.

Elastometry was performed in elder children during breath-holding for not more than 10 s or during shallow breathing in. The patients were in a supine or pronation position. To visualize the liver, subcostal, intercostal, longitudinal, and

**73**

**4. Results**

stiffness.

**Figure 1.**

**3. Statistical analysis of data**

*Elastometry Indices of Unchanged Liver in Healthy Children*

transversal epigastric accesses were used. The sensor was placed perpendicularly to the body surface. Measurements were taken in different segments of the right and left hepatic lobes and in the areas free from the vascular structures, fixing the zone of scanning at the depth of 3–5 cm from the capsule. The area of interest (a light window) was chosen with subsequent expectation of image stabilization to get a homogeneous coloring of the light window. The measurement was considered successful when region of interest (ROI) was filled with color by more than 90%. Not <10 measurements were made, which enabled to calculate the mean value of liver

*ESB mode study. Bellow a scanned area in the B-mode, above the same image with elastogram.*

Statistical analysis of data was performed by IBM SPSS Statistics 19. If the parameters were normal, Kolmogorov-Smirnov criterion with Liljefors significance adjustment was used. As the distribution of characteristic in one of the groups deviated from normal, Kruskal-Wallis criterion was used with subsequent pairwise comparison by means of nonparametric Mann-Whitney test. All quantitative values were presented as *M* (mean value), *m* (standard error of the mean value), *σ* (standard deviation), median (50th percentile), and 25th–75th percentiles of both minimal and maximal values. Comparison of quantitative parameters was performed using Mann–Whitney test, and qualitative ones were compared by Fisher

criterion of accuracy. Differences (*p* < 0.05) were considered significant.

blue without areas of local stiffness increase (**Figure 2**).

obtained data are presented in **Table 1**.

Elastography image of the unchanged liver in all patients in the comparison group was characterized by parenchyma coloring of both lobes in homogeneous

Median of Emean value in the comparison group was 5.00 kPa, Emax—6.3 kPa. The

*DOI: http://dx.doi.org/10.5772/intechopen.88004*

*Elastometry Indices of Unchanged Liver in Healthy Children DOI: http://dx.doi.org/10.5772/intechopen.88004*

*Ultrasound Elastography*

cally follow up the fibrosis process.

liver "stiffness" in healthy children.

**2. Material and methods**

size of the tissue sampling. As liver fibrosis may have irregular distribution, different locations may show different stages of liver fibrosis and histologic activity [4, 5]. Thus, in pediatric medical practice, specialists are encouraged to search for noninvasive methods enabling not only to reveal liver changes but also to dynami-

Ultrasound elastography is a great breakthrough in the evolution of noninvasive methods of visualization of liver conditions in general and ultrasound diagnostics in particular. There are only a few publications describing indices of liver stiffness in children obtained by one-dimensional and two-dimensional shear wave elastography (SWE). While studying stiffness indices in kPa (kilopascal) and m/s, the scientists pay attention to the data on liver stiffness obtained by different ultrasound and elastography techniques which cannot be compared. Normal indices for various age and gender groups are not clearly defined in the literature. Taking all these into account, the purpose of our study is to determine gender-age indices of

Two hundred healthy children aged 3–18 years were included in the study. Written informed consent was obtained from the legal representatives of all children. The study was approved by the ethics committee of FGBOU DPO, Moscow. All patients were allocated to three age groups according to age periodization of Mazurin and Vorantsov [6]. The first group consisted of 103 children, the second one consisted of 52, and the third one consisted of 45. According to this periodization, extrauterine period (besides the neonatal, infancy, and early childhood periods) includes preschool period (from 3 to 6 years), junior school period (from 7 to 11 years), and senior school period (from 12 to 18 years). There were 103 girls and 97 boys among them. The following criteria were considered allocating children to the control group: height and weight of each child within the interval from 5th to 95th percentile of age norm [7]; absence of liver diseases and (or) congestive heart failure in the anamnesis: absence of inflammatory alterations according to general and biochemical blood analysis (signs of cholestasis, cytolysis); absence of pathology of the liver, bile ducts, pancreas, and spleen according to ultrasound study in the grayscale and Doppler study (chromatic Doppler mapping, impulsewave Doppler) modes; and a quiet behavior of a child during examination. The examination was performed on Aixplorer device (SuperSonic Imagine, France) by broadband convex sensor acting within frequency range of 1–6 MHz. The study was done when a patient was fasting after standard ultrasound examination of abdominal organs and retroperitoneal space. Finishing the grayscale mode and Doppler ultrasound, elastography shear wave (SWE ) mode was started. Tissue stiffness was demonstrated on the screen as a chromatic coded map (qualitative characteristics),

and quantitative value of stiffness was evaluated in kilopascal (kPa).

one, the same image with elastogram (**Figure 1**).

After SWE mode activation, there appeared two images on the screen: the first one, displayed in the real-time mode a scanned area in the B-mode, and the second

The mapping color depended on the chosen type of chromatic map. The chosen type of chromatic map colored stiffer tissues in red, while softer tissues in blue. The tissues of "mean" stiffness were colored in intermediate colors from light blue and

Elastometry was performed in elder children during breath-holding for not more than 10 s or during shallow breathing in. The patients were in a supine or pronation position. To visualize the liver, subcostal, intercostal, longitudinal, and

**72**

green to yellow.

**Figure 1.** *ESB mode study. Bellow a scanned area in the B-mode, above the same image with elastogram.*

transversal epigastric accesses were used. The sensor was placed perpendicularly to the body surface. Measurements were taken in different segments of the right and left hepatic lobes and in the areas free from the vascular structures, fixing the zone of scanning at the depth of 3–5 cm from the capsule. The area of interest (a light window) was chosen with subsequent expectation of image stabilization to get a homogeneous coloring of the light window. The measurement was considered successful when region of interest (ROI) was filled with color by more than 90%. Not <10 measurements were made, which enabled to calculate the mean value of liver stiffness.

#### **3. Statistical analysis of data**

Statistical analysis of data was performed by IBM SPSS Statistics 19. If the parameters were normal, Kolmogorov-Smirnov criterion with Liljefors significance adjustment was used. As the distribution of characteristic in one of the groups deviated from normal, Kruskal-Wallis criterion was used with subsequent pairwise comparison by means of nonparametric Mann-Whitney test. All quantitative values were presented as *M* (mean value), *m* (standard error of the mean value), *σ* (standard deviation), median (50th percentile), and 25th–75th percentiles of both minimal and maximal values. Comparison of quantitative parameters was performed using Mann–Whitney test, and qualitative ones were compared by Fisher criterion of accuracy. Differences (*p* < 0.05) were considered significant.

#### **4. Results**

Elastography image of the unchanged liver in all patients in the comparison group was characterized by parenchyma coloring of both lobes in homogeneous blue without areas of local stiffness increase (**Figure 2**).

Median of Emean value in the comparison group was 5.00 kPa, Emax—6.3 kPa. The obtained data are presented in **Table 1**.

#### **Figure 2.**

*An example of liver stiffness evaluation in a healthy child aged 5 years: B-mode (below) and two-dimensional shear wave elastography mode (above). These are the results of one of 10 measurements. Emean = 4.0 kPa. Homogeneous coloring without areas of local stiffness increase.*


**Table 1.**

*Young modulus value (Emean, kPa) of the unchanged liver parenchyma in the study group of healthy children.*


**Table 2.**

*Young modulus value (Emean, kPa) of parenchyma of unchanged liver in different age groups.*

Median in the age group 3–6 years (*n* = 103) was 4.90 kPa, Emax—6.18 kPa. Median in the age group 7–11 years (*n* = 52) was 5.03 kPa, Emax—6.00 kPa. Median in the age group 12–18 years (*n* = 45) was 5.24 kPa, Emax——6.20 kPa. The obtained data on unchanged liver parenchyma values in different age groups are presented in **Table 2**.

To adjust gender differences in the values of unchanged liver parenchyma, Young modulus analysis in girls (*n* = 103) and in boys (*n* = 97) was performed. Emean median in boys is 5.08 kPa and in girls is 4.99 kPa (*p* = 0.345). The analysis results are presented in **Table 3**.

**75**

statistical power.

*Elastometry Indices of Unchanged Liver in Healthy Children*

**Group Young modulus, kPa**

Thus, normal elastography picture of the liver is characterized by homogeneous coloring of parenchyma in the color window without areas of local stiffness increase. Mean value of Young modulus is 5.01 ± 0.03 kPa, and median of Emean value in the comparison group was—5.00 kPa (4.70–5.38). Significant increase of liver stiffness in children older than 6 years was established. Significant gender

*Young modulus value (Emean, kPa) of parenchyma of unchanged liver in different gender groups of healthy* 

*M* **±** *m* **Median Maximal-minimal** 

Boys (*n* = 97) 5.07 ± 0.07 5.08 4.06–6.00 4.82–5.50 0.48 Girls (*n* = 103) 5.03 ± 0.05 4.99 4.26–5.70 4.78–5.33 0.36

**values**

**25th–75th percentile**

**σ**

According to the results of other research groups, the values of the shear wave velocity in the liver parenchyma of the right and left lobes do not have statistically significant differences. Point shear wave elastography (ARFI elastography) was performed by Feoktistova et al. [8] in 100 children aged from 6 months up to 16 years. There were no any significant differences of shear wave speed between the right and left lobes [8]. The authors believed it is possible to measure the stiffness of both the right and left lobes of the liver due to the relatively lesser force of the aortic pulsation, as well as the small thickness of the anterior abdominal wall with a small degree of subcutaneous and preperitoneal fat tissue in the epigastrium. To determine the standard shear wave velocity values [9], 103 children aged from 2 weeks to 17 years were examined. The authors indicate that during statistical processing of

Taking into account literature data testifying the absence of significant differences between the right and left lobe stiffness, measurements were made in both of them. The findings were combined to further analyze the quantitative data. Mean liver stiffness value was calculated in 10 measurements in two lobes of each child. Interestingly, the mean value of stiffness in the control group (5.01 ± 0.03) kPa

coincided more with the study of researchers Huang et al. (509 healthy adult volunteers) [10] and Shin et al. (76 healthy children [11], which were 5.10 ± 1.02 and 5.5 ± 1.3 kPa, respectively) (two-dimensional elastometry). The mean value of stiffness in the study of Engelmann et al. (TE) was 4.7 kPa [12]. The results differed from the findings of Franchi-Abella et al. [13] and Tutar et al. [14] where the mean value of stiffness obtained by convex sensor was higher: 6.94 ± 1.42 and 7.41 kPa, respectively. But one should take into consideration that both studies were performed on control groups consisting of 50 healthy children, which may reduce their

To adjust age-specific features of unchanged parenchyma stiffness, all study patients were allocated to three groups according to Mazurin and Vorontsov age periodization. Subgroup 1 consisted of 103 children aged 3–6 years. Subgroup 2 consisted of 52 children aged 7–11 years. Subgroup 3 consisted of 45 children aged 12–18 years. Median in the age group 3–6 years (*n* = 103) was 4.90 kPa, in the age group 7–11 years (*n* = 52) was 5.03 kPa, and in the age group 12–18 years (*n* = 45) was 5.24 kPa (**Table 2**). Significant differences of stiffness were obtained comparing the values in age groups 3–6 and 7–11 years (*p* = 0.001) and 3–6 and 12–18 years (*p* = 0.001). Statistically significant differences between subgroups 2 and 3 were not established (*p* > 0.001). Thus, liver stiffness values in children older than 6 years

data, no significant differences were found in the lobes of the liver [9].

*DOI: http://dx.doi.org/10.5772/intechopen.88004*

differences in stiffness were not found.

**Table 3.**

*children (aged 3–18 years).*

*Elastometry Indices of Unchanged Liver in Healthy Children DOI: http://dx.doi.org/10.5772/intechopen.88004*


**Table 3.**

*Ultrasound Elastography*

**74**

**Table 2**.

**Table 2.**

**Figure 2.**

**Group**  *N* **= 200**

**Table 1.**

are presented in **Table 3**.

Median in the age group 3–6 years (*n* = 103) was 4.90 kPa, Emax—6.18 kPa. Median in the age group 7–11 years (*n* = 52) was 5.03 kPa, Emax—6.00 kPa. Median in the age group 12–18 years (*n* = 45) was 5.24 kPa, Emax——6.20 kPa. The obtained data on unchanged liver parenchyma values in different age groups are presented in

*Young modulus value (Emean, kPa) of parenchyma of unchanged liver in different age groups.*

*M* **±** *m* **Median Maximal-minimal** 

3–6 years (*n* = 103) 4.89 ± 0.04 4.90 3.48–6.18 4.56–5.22 0.45 7–11 years (*n* = 52) 5.09 ± 0.07 5.03 3.00–6.00 4.98–5.41 0.48 12–18 years (*n* = 45) 5.18 ± 0.08 5.24 4.05–6.20 4.77–5.54 0.51

*An example of liver stiffness evaluation in a healthy child aged 5 years: B-mode (below) and two-dimensional shear wave elastography mode (above). These are the results of one of 10 measurements. Emean = 4.0 kPa.* 

*M* **±** *m* **Median Maximal-minimal** 

*Young modulus value (Emean, kPa) of the unchanged liver parenchyma in the study group of healthy children.*

3–18 years 5.01 ± 0.03 5.00 3.00–6.30 4.70–5.38 0.49

**values**

**Young modulus, kPa**

**values**

**25th–75th percentile**

**25th–75th percentile**

**σ**

**σ**

**Age groups** *N* **= 200 Young modulus, kPa**

*Homogeneous coloring without areas of local stiffness increase.*

To adjust gender differences in the values of unchanged liver parenchyma, Young modulus analysis in girls (*n* = 103) and in boys (*n* = 97) was performed. Emean median in boys is 5.08 kPa and in girls is 4.99 kPa (*p* = 0.345). The analysis results

*Young modulus value (Emean, kPa) of parenchyma of unchanged liver in different gender groups of healthy children (aged 3–18 years).*

Thus, normal elastography picture of the liver is characterized by homogeneous coloring of parenchyma in the color window without areas of local stiffness increase. Mean value of Young modulus is 5.01 ± 0.03 kPa, and median of Emean value in the comparison group was—5.00 kPa (4.70–5.38). Significant increase of liver stiffness in children older than 6 years was established. Significant gender differences in stiffness were not found.

According to the results of other research groups, the values of the shear wave velocity in the liver parenchyma of the right and left lobes do not have statistically significant differences. Point shear wave elastography (ARFI elastography) was performed by Feoktistova et al. [8] in 100 children aged from 6 months up to 16 years. There were no any significant differences of shear wave speed between the right and left lobes [8]. The authors believed it is possible to measure the stiffness of both the right and left lobes of the liver due to the relatively lesser force of the aortic pulsation, as well as the small thickness of the anterior abdominal wall with a small degree of subcutaneous and preperitoneal fat tissue in the epigastrium. To determine the standard shear wave velocity values [9], 103 children aged from 2 weeks to 17 years were examined. The authors indicate that during statistical processing of data, no significant differences were found in the lobes of the liver [9].

Taking into account literature data testifying the absence of significant differences between the right and left lobe stiffness, measurements were made in both of them. The findings were combined to further analyze the quantitative data. Mean liver stiffness value was calculated in 10 measurements in two lobes of each child.

Interestingly, the mean value of stiffness in the control group (5.01 ± 0.03) kPa coincided more with the study of researchers Huang et al. (509 healthy adult volunteers) [10] and Shin et al. (76 healthy children [11], which were 5.10 ± 1.02 and 5.5 ± 1.3 kPa, respectively) (two-dimensional elastometry). The mean value of stiffness in the study of Engelmann et al. (TE) was 4.7 kPa [12]. The results differed from the findings of Franchi-Abella et al. [13] and Tutar et al. [14] where the mean value of stiffness obtained by convex sensor was higher: 6.94 ± 1.42 and 7.41 kPa, respectively. But one should take into consideration that both studies were performed on control groups consisting of 50 healthy children, which may reduce their statistical power.

To adjust age-specific features of unchanged parenchyma stiffness, all study patients were allocated to three groups according to Mazurin and Vorontsov age periodization. Subgroup 1 consisted of 103 children aged 3–6 years. Subgroup 2 consisted of 52 children aged 7–11 years. Subgroup 3 consisted of 45 children aged 12–18 years. Median in the age group 3–6 years (*n* = 103) was 4.90 kPa, in the age group 7–11 years (*n* = 52) was 5.03 kPa, and in the age group 12–18 years (*n* = 45) was 5.24 kPa (**Table 2**). Significant differences of stiffness were obtained comparing the values in age groups 3–6 and 7–11 years (*p* = 0.001) and 3–6 and 12–18 years (*p* = 0.001). Statistically significant differences between subgroups 2 and 3 were not established (*p* > 0.001). Thus, liver stiffness values in children older than 6 years

are significantly higher. Probably, in a larger sampling, there will appear a tendency to stiffness increase as patients get older.

The same results of stiffness increase with age were established by Engelmann et al. and Sagir et al. [15] who studied normal indices of stiffness by transient elastography method in groups of 240 and 198 children. Engelmann et al. [12] established the values of stiffness median for age group 0–5 years, 4.40 kPa; for age group 6–11 years, 4.73 kPa; and for age group 11–18 years, 5.10 kPa (*p* = 0.001). Sagir et al. [15] also observed age and stiffness dependence: 4.8 ± 1.4 kPa (0–5 years), 5.6 ± 1.3 kPa (6–11 years), and 5.7 ± 1.7 kPa (12–18 years). Stiffness values in these age groups coincided with the results obtained in our study.

As a result of the study, there were no established statistically significant differences in gender stiffness values: Emean median in boys is 5.08 kPa and in girls is 4.99 kPa (*p* = 0.345). Comparing the two groups, statistically significant differences were considered (*p* > 0.001).

Gender characteristics of parenchyma stiffness were analyzed in the work of Franchi-Abella et al. where any differences in stiffness depending on the gender were also not established [13].

#### **5. Conclusion**

Young modulus values obtained from healthy children may be recommended as a standard investigation. The use of shear wave elastometry within a complex ultrasound evaluation will contribute to better early diagnostics of the changed parenchyma. Prospectively, a widespread use of ultrasound elastography will result in decreasing the number of biopsies.

#### **Author details**

Mikhail Pykov1 \*, Natalia Kuzmina2 , Nikolay Rostovtsev3 and Alexander Kinzersky4

1 Division of Pediatric Radiology, Russian Medical Academy of Postgraduate Education, Moscow, Russia

2 Ultrasound Diagnostics Department, Chelyabinsk Regional Children Clinical Hospital, Chelyabinsk, Russia

3 Department of Pediatric Surgery, Federal State Budgetary Institution of Higher Education "South Ural State Medical University", Chelyabinsk, Russia

4 Professor Kinzersky Clinic, Chelyabinsk, Russia

\*Address all correspondence to: pykov@yandex.ru

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**77**

*Elastometry Indices of Unchanged Liver in Healthy Children*

force impulse imaging—Normal values of liver stiffness in healthy children. Pediatric Radiology. 2013;**43**(5):539-544

[10] Huang Z, Zheng J, Zeng J, Wang X, Wu T, Zheng R. Normal liver stiffness in healthy adults assessed by realtime shear wave elastography and factors that influence this method. Ultrasound in Medicine and Biology.

[11] Shin HJ, Kim M-J, Kim HY, Roh YH, Lee M-J. Optimal acquisition number for hepatic shear wave velocity measurements in children. PLoS One. 2016;**11**(12). DOI: 10.1371/journal.pone.0168758. [Accessed:

[12] Engelmann G, Gebhardt C, Wenning D, Wühl E, Hoffmann GF, Selmi B, et al. Feasibility study and control values of transient elastography in healthy children. European Journal of

Pediatrics. 2012;**171**(2):353-360

[13] Franchi-Abella S, Corno L, Gonzales E, Antoni G, Fabre M,

[14] Tutar O, Beşer ÖF, Adaletli I, Tunc N, Gulcu D, Kantarci F, et al. Shear wave elastography in the

evaluation of liver fibrosis in children. Journal of Pediatric Gastroenterology and Nutrition. 2014;**58**(6):750-755

[15] Sagir A, Ney D, Oh J, Pandey S, Kircheis G, Mayatepek E, et al. Evaluation of acoustic radiation force impulse imaging (ARFI) for the determination of liver stiffness using transient elastography as a reference in children. Ultrasound International

Open. 2015;**1**(1):E2-E7. DOI: 10.1055/s-0035-1554659

2016;**278**(2):554-562

Ducot B, et al. Feasibility and diagnostic accuracy of supersonic shear-wave elastography for the assessment of liver stiffness and liver fibrosis in children: A pilot study of 96 patients. Radiology.

2014;**40**(11):2549-2555

21 December 2016]

*DOI: http://dx.doi.org/10.5772/intechopen.88004*

[1] Orlovsky DV, Oshmyanskaya NY, Nedzvetskaya NV. Place of puncture biopsy in diagnosis of chronic diffuse liver diseases. Gastroenterology.

[2] Gotje SV. Liver transplantation: The current state of the problem. Almanac of the Vishnevsky Institute of surgery.

[3] Gotje SV, Kaganov BS, Zaynutdinov ZM, Tsirulnikova OM. Criteria of diagnostics and clinical course of liver cirrhosis in children. Infectious

Wiseman DA, MacDonald FR, Ding DL. Prospective study of the incidence of ultrasound-detected intrahepatic and subcapsular hematomas in patients randomized to 6 or 24 hours of bed rest after percutaneous liver biopsy. Gastroenterology. 1987;**92**(2):290-293

[5] Dezsőfi A, Baumann U, Dhawan A, Durmaz O, Fischler B, Hadzic N, et al. Liver biopsy in children: Position paper of the ESPGHAN hepatology committee. Journal of Pediatric Gastroenterology and Nutrition. 2015;**60**(3):408-420

[6] Mazurin AV, Vorontsov IM. Propaedeutics of Children Diseases. Moscow: Medicine; 1985. p. 432

[7] Baranov AA, editor. Pediatrics. National Guidelines. GEOTAR-Media:

ARFI—Elastography for liver stiffness evaluation of children of different age groups. Ultrasound and Functional

[8] Feoktistova EV, Pykov MI, Amosova AA, Tarasov MA, Dubrovin MM. Application of

Diagnostics. 2013;**6**:46-55

[9] Hanquinet S, Courvoisier D, Kanavaki A, et al. Acoustic radiation

Moscow; 2009. p. 1024

**References**

2013;**48**(2):47-52

2008;**3**(30):9-17

Diseases. 2008;**6**(3):14-21

[4] Minuk GY, Sutherland LR,

*Elastometry Indices of Unchanged Liver in Healthy Children DOI: http://dx.doi.org/10.5772/intechopen.88004*

#### **References**

*Ultrasound Elastography*

to stiffness increase as patients get older.

were considered (*p* > 0.001).

were also not established [13].

in decreasing the number of biopsies.

**Author details**

**5. Conclusion**

Mikhail Pykov1

Education, Moscow, Russia

Hospital, Chelyabinsk, Russia

\*, Natalia Kuzmina2

4 Professor Kinzersky Clinic, Chelyabinsk, Russia

\*Address all correspondence to: pykov@yandex.ru

provided the original work is properly cited.

, Nikolay Rostovtsev3

are significantly higher. Probably, in a larger sampling, there will appear a tendency

The same results of stiffness increase with age were established by Engelmann et al. and Sagir et al. [15] who studied normal indices of stiffness by transient elastography method in groups of 240 and 198 children. Engelmann et al. [12] established the values of stiffness median for age group 0–5 years, 4.40 kPa; for age group 6–11 years, 4.73 kPa; and for age group 11–18 years, 5.10 kPa (*p* = 0.001). Sagir et al. [15] also observed age and stiffness dependence: 4.8 ± 1.4 kPa (0–5 years), 5.6 ± 1.3 kPa (6–11 years), and 5.7 ± 1.7 kPa (12–18 years). Stiffness values in these age groups coincided with the results obtained in our study.

As a result of the study, there were no established statistically significant differences in gender stiffness values: Emean median in boys is 5.08 kPa and in girls is 4.99 kPa (*p* = 0.345). Comparing the two groups, statistically significant differences

Gender characteristics of parenchyma stiffness were analyzed in the work of Franchi-Abella et al. where any differences in stiffness depending on the gender

Young modulus values obtained from healthy children may be recommended as a standard investigation. The use of shear wave elastometry within a complex ultrasound evaluation will contribute to better early diagnostics of the changed parenchyma. Prospectively, a widespread use of ultrasound elastography will result

1 Division of Pediatric Radiology, Russian Medical Academy of Postgraduate

2 Ultrasound Diagnostics Department, Chelyabinsk Regional Children Clinical

3 Department of Pediatric Surgery, Federal State Budgetary Institution of Higher

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Education "South Ural State Medical University", Chelyabinsk, Russia

and Alexander Kinzersky4

**76**

[1] Orlovsky DV, Oshmyanskaya NY, Nedzvetskaya NV. Place of puncture biopsy in diagnosis of chronic diffuse liver diseases. Gastroenterology. 2013;**48**(2):47-52

[2] Gotje SV. Liver transplantation: The current state of the problem. Almanac of the Vishnevsky Institute of surgery. 2008;**3**(30):9-17

[3] Gotje SV, Kaganov BS, Zaynutdinov ZM, Tsirulnikova OM. Criteria of diagnostics and clinical course of liver cirrhosis in children. Infectious Diseases. 2008;**6**(3):14-21

[4] Minuk GY, Sutherland LR, Wiseman DA, MacDonald FR, Ding DL. Prospective study of the incidence of ultrasound-detected intrahepatic and subcapsular hematomas in patients randomized to 6 or 24 hours of bed rest after percutaneous liver biopsy. Gastroenterology. 1987;**92**(2):290-293

[5] Dezsőfi A, Baumann U, Dhawan A, Durmaz O, Fischler B, Hadzic N, et al. Liver biopsy in children: Position paper of the ESPGHAN hepatology committee. Journal of Pediatric Gastroenterology and Nutrition. 2015;**60**(3):408-420

[6] Mazurin AV, Vorontsov IM. Propaedeutics of Children Diseases. Moscow: Medicine; 1985. p. 432

[7] Baranov AA, editor. Pediatrics. National Guidelines. GEOTAR-Media: Moscow; 2009. p. 1024

[8] Feoktistova EV, Pykov MI, Amosova AA, Tarasov MA, Dubrovin MM. Application of ARFI—Elastography for liver stiffness evaluation of children of different age groups. Ultrasound and Functional Diagnostics. 2013;**6**:46-55

[9] Hanquinet S, Courvoisier D, Kanavaki A, et al. Acoustic radiation force impulse imaging—Normal values of liver stiffness in healthy children. Pediatric Radiology. 2013;**43**(5):539-544

[10] Huang Z, Zheng J, Zeng J, Wang X, Wu T, Zheng R. Normal liver stiffness in healthy adults assessed by realtime shear wave elastography and factors that influence this method. Ultrasound in Medicine and Biology. 2014;**40**(11):2549-2555

[11] Shin HJ, Kim M-J, Kim HY, Roh YH, Lee M-J. Optimal acquisition number for hepatic shear wave velocity measurements in children. PLoS One. 2016;**11**(12). DOI: 10.1371/journal.pone.0168758. [Accessed: 21 December 2016]

[12] Engelmann G, Gebhardt C, Wenning D, Wühl E, Hoffmann GF, Selmi B, et al. Feasibility study and control values of transient elastography in healthy children. European Journal of Pediatrics. 2012;**171**(2):353-360

[13] Franchi-Abella S, Corno L, Gonzales E, Antoni G, Fabre M, Ducot B, et al. Feasibility and diagnostic accuracy of supersonic shear-wave elastography for the assessment of liver stiffness and liver fibrosis in children: A pilot study of 96 patients. Radiology. 2016;**278**(2):554-562

[14] Tutar O, Beşer ÖF, Adaletli I, Tunc N, Gulcu D, Kantarci F, et al. Shear wave elastography in the evaluation of liver fibrosis in children. Journal of Pediatric Gastroenterology and Nutrition. 2014;**58**(6):750-755

[15] Sagir A, Ney D, Oh J, Pandey S, Kircheis G, Mayatepek E, et al. Evaluation of acoustic radiation force impulse imaging (ARFI) for the determination of liver stiffness using transient elastography as a reference in children. Ultrasound International Open. 2015;**1**(1):E2-E7. DOI: 10.1055/s-0035-1554659

**79**

Section 2

Breast Elastography

Section 2
