EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Short Version)

Abstract

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography with a focus on the assessment of diffuse liver disease. The short version provides clinical information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.

Zusammenfassung

Dies ist die erste Überarbeitung der 2013 publizierten EFSUMB-Leitlinien zur klinischen Anwendung der Elastografie und konzentriert sich auf die diffusen Lebererkrankungen. Der klinische Teil dieser Leitlinien erläutert die praktische Anwendung der Elastografie bei der Beurteilung diffuser Lebererkrankungen unter Berücksichtigung der Geräteausstattung und Interpretation der Ergebnisse. Die aktuelle Literatur wurde analysiert unter besonderer Beachtung von Metaanalysen. Die klinische Anwendung der Elastografie wird unter Reflexion unterschiedlicher klinischer Szenarien und der unterschiedlichen Ätiologien diffuser Lebererkrankungen erläutert. Alle Empfehlungen erfolgten gemäß der Evidenz basierten Methodik der Oxford-Klassifikation. Das hier vorgestellte Update soll dem Anfänger und fortgeschrittenen Nutzer eine praktische Hilfe darstellen.

Key words

guidelines - liver - fibrosis - chronic liver disease - hepatitis - chronic viral hepatitis - shear wave elastography - strain elastography - alcoholic hepatitis - NAFLD

Introduction

The short version of this update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of shear wave elastography provides information about the practical use of elastography equipment and interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing evidence from meta-analyses.

The long version also includes an update of the section on the basic principles of elastography, which now includes transient elastography (TE) as a shear wave elastography (SWE) method, and there are additional discussions of issues such as depth of penetration, whether to perform measurements in units of kilopascal (kPa) or ms^–1, and the comparability of data from different systems.

Investigator education

EFSUMB is working to promote high quality in ultrasound education and sustain excellent professional standards in elastography training and practice [1]. To ensure the lowest possible intraoperator variability, EFSUMB recommends that ultrasound elastography be performed by operators that have passed competence Level 1. However, it may also be possible to train dedicated personnel to perform elastographic measurements only [2].

The basic principles and technology for elastography were developed by the academic research community before commercial translation, and it remains a heavily researched and rapidly developing field. EFSUMB recommends that users maintain an awareness of this field.

Shear wave elastography (TE, pSWE and 2D-SWE), general technical comments

Introduction

The liver is an important target organ for the use of elastography; stiffness correlates with the degree of fibrosis and indirectly with portal hypertension (see liver application).

Examination procedure

Subjects should be examined in a supine position with the right arm in maximal extension. The transducer is positioned in a right intercostal space to visualize the right liver lobe in A or B mode. Artefacts and large vessels on the A-mode (TE) or B-mode image (pSWE and 2D-SWE) should be avoided. Optimal measurement quality of pSWE and 2D-SWE occurs with the ROI placed a minimum of 1 – 2 cm and a maximum of 6 cm beneath the liver capsule [3] [4] [5] [6]. A transient breath hold in a neutral position is optimal.

Fasting and resting

Food ingestion increases measurement readings (independent of fibrosis) for an estimated 120 – 180 minutes after the meal [12] [13] [14]. The examination should ideally be performed after an overnight fast, while abstaining from food/drinks (especially caffeine) and smoking. In addition, since exercise increases liver stiffness, subjects should be examined after a minimum of 10 – 20 minutes of rest [15].

Factors influencing liver stiffness independent of liver fibrosis (confounders)

Liver stiffness does not solely reflect liver fibrosis, but can reflect many other physiological or pathological conditions. Liver stiffness is increased with hepatic inflammation (often but not exclusively shown by an elevated transaminase level) [16] [17] [18] [19], obstructive cholestasis [20] and hepatic congestion [21] [22]. For patients with falsely elevated liver stiffness measurements (LSMs) due to alcoholic hepatitis, liver stiffness decreases following 1 – 4 weeks of abstinence [23] [24] [25]. Other diseases, which cause increased liver stiffness, independent of liver fibrosis include amyloidosis, lymphomas and extramedullary hemopoiesis. Presently, it is uncertain whether hepatic steatosis modulates liver stiffness [26] [27] or does not [28] [29].

Normal values

TE measurements of Young’s modulus in healthy people vary between 4.4 and 5.5 kPa (95^th percentile 6.7 kPa) [34] [35] [36] [37]. LSMs are generally higher in men than in women [34] [35] and may be affected by steatosis [34] but are not influenced by age [36] [37].

pSWE measurements using Virtual Touch Quantification (VTQ^®) in healthy populations range between 1.01 and 1.59 m/s, but in most studies the range is 1.07 – 1.16 m/s [9] [10] [38] [39] [40] [41] [42] [43]. Age has no apparent influence on the shear wave speed (SWS) assessed by VTQ^® [38] [39] [43]. All but one study [9] similarly found no correlation between gender or body mass index (BMI) and SWS values. Depth as assessed by the skin-to-liver capsule distance may influence the SWS values assessed by VTQ^® [38]. In healthy children, the mean SWS obtained in the right liver lobe was 1.07 ± 0.10 m/s in one study [44] and 1.12 m/s (range: 0.73 to 1.45 m/s) in another [45].

Values obtained with Elastography point quantification (ElastPQ^®) in healthy people are comparable to those obtained with VTQ^® [46] [47] [48], although in contrast to VTQ^® findings, measurements using ElastPQ^® were 8 % higher in healthy men than in healthy women [48].

2D-SWE measurements of Young’s modulus using supersonic shear imaging (SSI) in healthy subjects cover the range 4.5 – 5.5 kPa (95^th percentile 6.2 kPa) [49] [50]. Healthy men may have higher LSMs than healthy women, while BMI and age do not seem to influence LSM in subjects without liver disease [50].

For all equipment, a SWE measurement within the normal range, in a subject without other clinical or laboratory evidence of liver disease, may exclude significant liver fibrosis with a high degree of certainty.

The current literature has been recently summarized [51].

Transient elastography (TE)

Procedure

Transient elastography uses an ultrasound displacement M-mode and A-mode image produced by the system. The operator locates a portion of the liver at least 6 cm thick and free of large vascular structures. By pressing the acquisition button, the machine displays the median of the measured Young’s modulus in kPa, the interquartile range (IQR) (the difference between the 75th and the 25th percentile), IQR/median (IQR/M), the value of the current measurement and, only in the old version of the system, the success rate (the ratio between valid and total number of acquisitions). The system displays a result only if the acquisition is valid, since the software automatically rejects acquisitions without correct vibration shape or a correct follow-up of the vibration propagation [7] [8] [52].

For children as well as in adults with a thoracic circumference ≤ 75 cm, the S probe is recommended, either S1 for a thoracic circumference < 45 cm or S2 for 45 – 75 cm [53].

How to measure?

Following the manufacturer’s recommendation, assessment is reliable when 10 valid readings and an IQR ≤ 30 % of the median (IQR/M ≤ 30 %) are obtained. The majority of studies have used these reliability criteria as well as a success rate ≥ 60 %. However, these criteria have not been externally validated. A reliable TE assessment can be achieved in over 90 % of adults, when both the M and XL probes are used as required [54] [55] [56] [57]. Because the M probe takes measurements between 25 and 65 mm from the probe, to increase viability, those patients with a skin-to-liver capsule distance (SCD) of > 25 mm should be assessed with the XL probe.

The diagnostic accuracy of the XL probe appears similar to that of the M probe but the Young’s modulus values are lower than those obtained with the M probe by a mean of 1.5 kPa (range of 0.8 – 2.3 kPa) [54] [55] [56] [57] [58].

Reproducibility

The intra- and interobserver agreements are excellent, with reported intraclass correlation coefficients (ICC) above 0.90 [62] [63] [64]. The agreement decreases in overweight patients or in early stages of fibrosis [62] [63]. Although the LSM seems to be reproducible at different examination sites, the best examination site is the median axillary line on the first intercostal space under the liver percussion dullness upper limit, with the patient lying in dorsal decubitus [63].

Point shear wave elastography (pSWE)

Experience with point shear wave elastography (pSWE) has been mainly acquired with the VTQ^® product, because it was the first method available, subsequently followed by ElastPQ^® and, more recently, by pSWE methods from many companies.

Procedure (how to measure?)

The operator can select the depth at which liver elasticity is evaluated by placing a “measuring box” (size depending on the manufacturer) in the right liver lobe (segment V, VIII or VII), via an intercostal approach and with the transducer at 90° in relation to the liver capsule, in an area free of large vessels. In a pSWE study using VTQ^® to measure SWS [3], the best correlation with histological fibrosis was observed for measurements performed 1 – 2 cm and 2 – 3 cm beneath the liver capsule (0.675 and 0.714, respectively), but in up to 15 % of cases, measurements could not be obtained if performed 2 – 3 cm under the liver capsule.

How many measurements?

Most studies perform 10 valid measurements by pSWE and report the median of these values. A few studies have used only 5 [65] [66] or 6 [67] valid measurements. Another study [68] calculated the mean and standard deviation (SD) of 10 valid measurements. A high SD correlated with misclassification of fibrosis. Additionally, higher stages of fibrosis were associated with a higher SD, indirectly indicating that "more" measurements should be obtained in patients with suspected fibrosis.

Reproducibility

pSWE has excellent intra- and interoperator reproducibility for liver elastography assessment in both healthy subjects and patients with chronic liver disease [42] [46] [48] [69] [70] [71].

Quality criteria

One study [72] evaluated factors that influenced the correlation of SWS assessed by VTQ^® with histological fibrosis in a cohort of 106 chronic hepatitis C (CHC) patients. In univariate and multivariate analysis, an IQR/M ≥ 30 % was associated with a discordance of at least 2 stages of fibrosis between SWS and histological fibrosis. Using ElastPQ^®, a recent study has suggested that an IQR/M ≤ 30 % is the most important quality criterion, whereas the number of measurements seems not to affect the performance, provided that they are at least five [73]. Thus, the compliance with quality criteria may increase the diagnostic accuracy of pSWE [68] [72]. Quality parameters have been described for other manufacturers as well [74].

2D-SWE

Almost all 2D-SWE studies for liver applications have been carried out using SSI, because other companies have only recently introduced 2D-SWE products. This description is therefore limited to the SSI system, but the principles may be applied to other 2D-SWE products.

Procedure

Obtaining an elastogram

2D-SWE evaluation should be performed in a well-visualized area of the right liver lobe, free of large vessels, liver capsule, ligaments and the gallbladder [75]. Since movement greatly influences results, the subject is asked to suspend breathing.

With 2D-SWE working in continuous and not with single shot emissions, the SWE acquisition is continued for 4 – 5 seconds (can be longer for other scanning systems) once a stable SWE image is obtained. The operator should aim to achieve homogeneous color filling of the SWE ROI. Usually a Young’s modulus scale of up to 30 kPa is sufficient, but a higher scale of up to 150 kPa can be adopted on a case-by-case basis. The operator freezes the image (and optionally saves the clip for further post-processing) and an analysis box (Q Box, for SSI) is placed on the most homogeneous, stable elastogram for a few seconds to measure Young’s modulus (SWS, if the scanner is set to that mode).

How to measure?

Analysis box size and shape

For 2D-SWE measurements, the analysis box should be set to at least 10 mm, preferably 15 mm or more. A round shape is usually chosen [31] [32]. The ROI should be placed over an isoechoic area of liver parenchyma, as seen on the grayscale image (no vessel, no nodule, no other structure), in priority in the middle line of the elastogram (avoiding positioning the Q Box on the edges of the elastogram), while also avoiding SWS artefactual areas (reverberation, noisy areas from rib shadowing).

Valid and invalid measurements

There is no agreement on objective quality criteria. Some authors suggest that a minimal Young’s modulus value of ≤ 0.2 kPa in the analyzed region is useful to identify invalid measurements as indicated by a lack of concordance with TE [76], while others use a minimal Young’s modulus value of < 1 kPa. Furthermore, among valid measurements an IQR/M ≤ 30 % is recommended by other studies mimicking TE reliability criteria. For 2D-SWE with Logiq E9 (GE), the manufacturer recommends an IQR/M below 30 % as a quality criterion. Temporal stability of the elastogram for three seconds or more during breath hold in combination with placement of the analysis box in a homogeneous area with complete filling results in high accuracy, high reliability and low variance of measurements with SSI [77] [78] [79]. The new software version of the Aixplorer^® system also shows the stability index (SI) and according to the manufacturer a reliable LSM should exclude measurements with an SI < 90 %. Aplio 500 (Toshiba) provides a display of shear waves travelling within the box, allowing selection of areas not affected by artefacts for analysis. For 2D-SWE with the Philips system, a confidence map guides the operator to perform measurements in areas where the signal-to-noise ratio of the SWS assessment is high.

How many measurements?

From 3 to 15 measurements are used in published studies, but data from several studies suggest that 3 measurements suffice to obtain consistent results for the assessment of liver fibrosis and portal hypertension, and for optimal correlation with TE [6] [32] [33] [79] [80] [81]. There is no convincing evidence to suggest superiority of the mean versus median of the SSI measurements. However, since the median and IQR are robust against non-normal distributed data, they should be preferred for reporting.

Reproducibility

Reproducibility in healthy subjects

In three studies, the intraobserver reproducibility of SSI during the same session was excellent (ICC ranged from 0.92 to 0.95) [49] [83] [84]. The interobserver agreement on different days was affected by operator experience and ranged from 0.63 to 0.84 [83] [84].

Reproducibility in patients

The intraobserver reproducibility of 2D-SWE for liver stiffness assessment in liver fibrosis patients is excellent, with the ICC ranging from 0.90 to 0.95 in published studies [30] [31] [82]. The intra-subject reproducibility (evaluated over periods of 2 days to 4 weeks) ranges between 0.83 and 0.90 [85]. Interobserver reproducibility on the same day ranges from 0.83 [85] to 0.94 [77]. Intra- and interobserver variance may be inferior to pSWE using VTQ^® [85].

Limitations

Failures

Common causes of failure are: depth below 4 – 5 cm [5], poor ultrasound window, reverberations, pulsatile movement, poor breath hold, large amounts of ascites [82], intercostal wall thickness ≥ 25 mm [86], BMI ≥ 30 kg/m², histological steatosis and waist circumference ≥ 102 cm [31] [33].

Unreliable assessments

The main factors limiting the applicability of 2D-SWE include obesity, poor acoustic window or presence of artefacts and inability of the subjects to hold their breath [5] [30] [31] [33] [82].

Comparison of results between systems

Introduction

Different US-based SWS technologies are available for the noninvasive assessment of liver fibrosis and the measurements produced can be slightly to moderately different between systems from different manufacturers. Even systems that use the same technique but were developed by different manufacturers can yield different values due to different and proprietary methods to measure the SWS.

Studies on phantoms

The Ultrasound Shear Wave Speed technical committee of the Radiological Society of North America, Quantitative Imaging Biomarker Alliance (QIBA) has quantified the differences between commercially available systems. Working on elastic phantoms, a statistically significant difference in the SWS estimates among systems and depth of measurement in the phantom was shown, whereas no statistically significant differences were found among operators using the same or equivalent systems under the same conditions [87]. Similar results were obtained using phantoms with viscoelastic properties similar to those observed in normal and fibrotic liver [88]. The measurements were performed at multiple focal depths (3.0, 4.5 and 7.0 cm). The deepest focal depth (7.0 cm) produced the greatest inter-system variability for each phantom (up to 17.7 %) as evaluated by the interquartile range. Inter-system variability was consistent across all phantoms and was not related to stiffness.

Sources of variability

Several sources of variability are detailed in published studies, including technical and patient-dependent factors that could affect comparability between systems.

Technical factors

Measurement depth

As shown by the studies on phantoms [87], the influence of depth on the estimation of elastic properties is not negligible. Furthermore, with curved transducers used in liver imaging, the angle affects the readings, with the best results being achieved when the ROI is straight ahead. Using VTQ^®, it has been shown that the results with the lowest variability are obtained at a depth of 4 – 5 cm with a convex transducer (1 – 4 MHz; mean push pulse: 2.67 MHz) and at a depth of 2 – 3 cm with a linear transducer (4 – 9 MHz; mean push pulse: 4 MHz) [89]. The acoustic push pulse is progressively attenuated as it traverses the tissue. Attenuation is higher in a stiffer liver. Thus, measurements are more variable in cirrhotic patients [4].

Frequency of the transducer

In a prospective study on 89 patients with CHC, pSWE (based on VTQ^®) was performed using both available transducers (4C1 and 9L4) [90]. The linear transducer gave higher values (1.91 ± 0.87 m/s vs. 1.70 ± 0.67 m/s). However, the results were correlated to each other (r = 0.70). Using the same method in a phantom and a series of eight volunteers, it was found that the convex transducer showed values that were significantly higher than those obtained with the linear transducer [89].

Position of the transducer

The highest intra- and interobserver agreement was obtained for the measurements performed through the intercostal space rather than the subcostal approach [48] [69] [91].

Operator experience

Methods using pSWE have shown excellent interobserver agreement, with concordance ranging from 0.80 to 0.97 for measurements performed via an intercostal approach, and independent of operator experience, suggesting that operators require only a short period of training to perform reliably LSMs [42] [46] [69] [92]. Using 2D-SWE (SSI) an expert operator had higher reproducibility of measurements over time than a novice operator [84]. It is suggested that at least 50 supervised 2D-SWE measurements should be performed by a novice operator in order to obtain consistent measurements. Echosens, the manufacturer of the FibroScan device, recommends that TE be performed by an experienced operator (> 100 examinations). Using liver biopsy as the reference standard, a recent study has shown that ElastPQ^® matched TE for accuracy after the operator had performed at least 130 examinations [93].

Equipment

Proprietary elastographic technologies generally give different estimates of the SWS within the same liver. This translates into the need to define threshold values for fibrotic stages for each specific equipment model.

Clinical studies

Diagnostic accuracy

Some comparative studies show similar accuracy for different elastographic systems. Larger prospective studies are necessary to find if there are differences in accuracy between each different system for liver stiffness evaluation.

Liver diseases

Introduction

The assessment of fibrosis in chronic liver diseases is pivotal for prognosis and guiding management, including whether to commence antiviral treatment. Liver biopsy is considered the “gold standard” for fibrosis assessment and stage classification and can also grade necro-inflammatory activity. However, liver biopsy is limited by its invasiveness, sampling error and the inter- and intraobserver variability in microscopic evaluation. Therefore, noninvasive methods for liver fibrosis assessment including ultrasound elastographic methods have been an intense field of research [7].

Due to the differences among elastography methods outlined in previous sections, cut-off values for fibrosis are system-specific and cannot be equated across machines.

It is becoming increasingly clear that the best cut-off values of the different elastography techniques used to evaluate the presence and severity of liver fibrosis depend upon the etiology of the underlying liver disease, and upon the prevalence of the condition under study in the target population. Differences between cut-offs may be simply related to differences in cirrhosis prevalence and severity in the studied populations, known as the spectrum bias. Therefore, elastography values should be interpreted by a liver specialist aware of the clinical aspects of the liver disease to be assessed and aware of the peculiarities of elastography in general and each elastography technique in particular.

Besides increasing evidence regarding liver stiffness measured by different techniques to detect liver fibrosis and cirrhosis (described in detail in the following paragraphs), other new applications of elastography are being tested in the field of liver diseases. They include spleen stiffness assessment for portal hypertension and the evaluation of the stiffness of focal liver lesions to differentiate between benign and malignant nodules. These applications appear promising, but remain under development and cannot yet be recommended in clinical practice.

Clinical needs

The ranges for intermediate fibrosis stages (F2-F3) are quite narrow, in the order of a Young’s modulus of 2 – 3 kPa (over a total range spanning 2 to 75 kPa with the TE), so that small differences in outputs could shift the assessment of patients from one stage to another [94]. However, in “the real life” situation, attention should be focused on the patient and what is appropriate from a clinical point of view. Following the availability of novel antiviral agents, the European Association for the Study of the Liver (EASL) together with the Asociación Latinoamericana para el Estudio del Hígado (ALEH) have produced guidelines for the clinical use of noninvasive tests for the evaluation of liver disease severity and prognosis [52]. These guidelines have outlined that the two clinically relevant endpoints in patients with viral hepatitis are the detection of significant fibrosis (F≥ 2) and the detection of cirrhosis (F = 4), and the most important endpoint is the detection of cirrhosis, because it guides treatment (A1 recommendation). In patients with NAFLD and with chronic liver diseases of other etiologies, the detection of cirrhosis is also the most important clinical endpoint (A1 recommendation).

Chronic hepatitis C (CHC)

Fibrosis staging

Transient elastography

In patients with CHC, TE can differentiate absent and mild fibrosis from significant fibrosis and cirrhosis, but is not accurate enough to distinguish between separate stages of fibrosis (F1-F4) [95] [96] [97]. A Young’s modulus greater than 6.8 – 7.6 kPa indicates a high probability of significant fibrosis (F ≥ 2) on biopsy. However, optimal cut-off values vary considerably depending on fibrosis prevalence and may range between 5.2 – 9.5 kPa as indicated in the clinical practice guidelines of the EASL [52]. Accordingly, the optimal cut-off values for predicting cirrhosis (F = 4) range between 11 and 15 kPa [52]. Therefore, the local fibrosis prevalence and the diagnostic aim (sensitive screening vs. secure exclusion strategies) must be considered when adapting cut-off values for clinical use. It should be emphasized that TE gives the best diagnostic performance in the context of cirrhosis diagnosis, and for this purpose it is better at ruling out than at ruling in cirrhosis.

In CHC patients with HIV co-infection, TE can be used with similar diagnostic accuracy as compared to HCV infection alone for fibrosis and cirrhosis detection [98]. TE can also be helpful in liver transplant recipients for the staging of recurrent fibrosis and cirrhosis [99].

The use of TE for the diagnosis of cirrhosis and the estimation of fibrosis severity in CHC has been endorsed in the recommendations for the management of viral hepatitis by the EASL and the ALEH, ideally in combination with an alternative and unrelated noninvasive approach such as laboratory tests/serum markers of fibrosis [100]. In the case of TE failure or inconclusive noninvasive test results, biopsy is still recommended when fibrosis staging is relevant for clinical decisions, although a preliminary attempt with an alternative SWE method could be considered.

Point shear wave elastography (pSWE)

As with TE, VTQ^® SWS quantification has been studied extensively in patients with CHC. Cut-offs of 1.21 – 1.34 m/s predict significant fibrosis (F ≥ 2) (AUROC 0.85 – 0.89), while VTQ^® cut-offs between 1.55 and 2 m/s (AUROC 0.89 – 0.93) predict cirrhosis [70] [101]. The diagnostic performance of VTQ^® is comparable to TE [102] with high accuracy for predicting significant (F ≥ 2, AUROC 0.87) and severe fibrosis (F ≥ 3, AUROC 0.91) as well as cirrhosis (AUROC 0.93) [103]. However, discordance (>one fibrosis stage) between VTQ^® and histology occurred in > 30 % in a study including 106 patients infected with HCV. The discordance was associated with female gender and a high interquartile range (IQR/M ≥ 30 %) of Young’s modulus [72]. Therefore, pSWE results require cautious interpretation. Evidence regarding ElastPQ^® is limited [46] [104]. The results in the pilot study [46] for fibrosis staging are similar to those reported for VTQ^®, but more data are needed. Fibrosis biomarkers may help to clarify indistinct cases [105].

2 D shear wave elastography (2D-SWE)

2D-SWE using SSI was reported in several studies in patients with CHC [106] [107]. Diagnostic accuracy was high for the detection of significant and advanced fibrosis and cirrhosis (AUC> 0.90). In these studies the diagnostic performance for 2D-SWE was better than for TE [106] [108] and serum fibrosis markers (FIB-4 index, APRI and Forns' index) [108]. In one study including 102 obese CHC patients, 2D-SWE had excellent diagnostic accuracy for the detection of severe fibrosis and cirrhosis (AUROC > 0.90 for both) [109].

Prediction of hepatic complications

Growing evidence supports the use of TE for risk stratification and the prediction of clinical endpoints. Liver stiffness predicts 5-year mortality with better accuracy than histological fibrosis staging (METAVIR) for HCV mono-infected (TE > 9.5 kPa) [110] and HIV co-infected patients (TE > 9.0 kPa) [111]. Furthermore, an elevated Young’s modulus indicates an increased risk of hepatocellular carcinoma (HCC) development (TE > 10 kPa) [112], hepatic decompensation and variceal bleeding [113]. Especially for patients with an established diagnosis of cirrhosis, TE can be used for grouping patients into different risk classes [112]. The combination of liver stiffness (Young’s modulus of > 14 kPa) with platelet count (< 141 × 10³/μL) and response to antiviral treatment may increase the predictive value of TE for HCC development [114]. In patients with compensated liver cirrhosis, liver stiffness helps to identify patients with portal hypertension (see section recommendations on portal hypertension). Data regarding firm endpoint prediction using pSWE and 2D-SWE are lacking and no evidence-based recommendation can be specified. Two groups evaluated the predictive value of TE in transplant patients with a recurrence of HCV infection [115] [116]. A Young’s modulus > 8.7 kPa at 12 months after liver transplantation was associated with a significantly reduced five-year graft and cumulative patient survival [115].

Role of elastography in the setting of anti-HCV treatments

Role of SWE to identify patients to be treated

In the absence of universal access to direct-acting antiviral agents (DAA) as a consequence of high cost, different countries have implemented strategies to prioritize patients for treatment. TE is used as the first-line investigation for the prioritization of HCV patients for DAA (e. g., Young’s modulus values ≥ 7.1 kPa are considered equivalent to fibrosis ≥F2, and values ≥ 9.5 kPa are considered equivalent to fibrosis ≥F3). In countries using interferon-based strategies, TE can help to identify patients with cirrhosis who have a lower likelihood of achieving a sustained virological response (SVR: undetectable HCV-RNA, 24 weeks after completion of antiviral therapy).

Role of SWE during treatment (monitoring)

Limited evidence in the setting of interferon-based therapy postulated that increasing liver stiffness as measured by TE during the treatment period might indicate a reduced possibility of achieving a sustained virological response [117] [118]. Data in patients undergoing IFN-free antiviral therapies suggest that liver stiffness rapidly declines during treatment, even in patients with advanced fibrosis and cirrhosis. This decline appears to reflect the reduction in liver inflammation, restoration of liver function and the decrease in portal pressure, like an effect of HCV eradication [119] [120].

Role of SWE after treatment (monitoring in follow-up)

Data regarding the usefulness of liver stiffness monitoring during antiviral therapy are scant. In the largest prospective study published (n = 91), a significant liver stiffness decrease was observed during therapy with peg-interferon and ribavirin; the decrease in liver stiffness continued after treatment only in patients who achieved SVR [121]. In the era of DAAs, it is important to remark that after successful HCV eradication, the use of pre-treatment cut-off values can impair the accuracy of TE [122] [123], and it might lead to erroneous conclusions if the SVR status is not carefully taken into account [120]. Several studies have evaluated the use of VTQ^® for monitoring IFN-based antiviral therapy in HCV patients: SWE decrease or increase reflects response or no response to treatment, respectively [124] [125] [126]. For IFN-free antiviral therapies, no data are available.

The monitoring of cirrhotic patients after SVR will become the new standard in the era of DAAs. Although it is tempting to use SWE in this setting to observe the dynamics of liver stiffness over time, no recommendation can be made at this stage on cut-offs and the time interval to identify cirrhosis regression.

Chronic hepatitis B (CHB)

Introduction

A large amount of evidence regarding elastography in CHB is available. There are > 50 published studies. The majority of them use TE but also validate the elastographic methods of pSWE and 2D-SWE.

Fibrosis staging

The most important goal of noninvasive diagnostic tools is diagnosis of compensated cirrhosis that would benefit from treatment regardless of the transaminase level [127].

Transient elastography

Transient elastography is the most validated elastographic method for staging CHB and has similar accuracy in this clinical scenario compared to CHC [52]. Three meta-analyses confirmed the good performance of TE in CHB staging [128] [129] [130]. Despite LSMs showing a substantial overlap among adjacent stages of fibrosis (particularly at lower fibrosis stages), LSM may effectively identify patients with ≥F2 and F4. Recent publications confirmed previous evidence, suggesting that the AUROCs for ≥F2 vary between 0.80 and 0.90 [131] [132] with Young’s modulus cut-off values between 6.6 kPa and 8.8 kPa [132] [133]. Regarding the identification of cirrhosis (F4), recent data confirm previous evidence, with AUROCs ranging between 0.81 and 0.97 [132] and cut-off values between 9.4 and 13.4 kPa [134] [135]. A recent meta-analysis suggested that a value > 11.7 kPa should raise suspicion of cirrhosis [128]. It has been suggested that LSM cut-offs should be adapted to transaminase levels [135] since transaminase levels tend to influence LSM in CHB, and hepatitis flares are often observed in CHB. However, recent studies showed that ALT-adapted cut-offs do not influence TE diagnostic performance [136] and that the only variable associated with overestimation of F4 stage in CHB is moderate/severe necro-inflammatory activity without any direct correlation with transaminase levels [137]. Interestingly, a Young’s modulus of < 5 kPa in patients with normal ALT and low serum HBV DNA levels (< 2000 IU/ml) characterize inactive HBV carriers [138] [139]. TE can be used to rule out significant fibrosis and cirrhosis in HBV inactive carriers, which is the best indication for TE in HBV.

Point shear wave elastography (pSWE)

VTQ^® has the advantage of a lower failure rate and has a similar diagnostic performance as TE. The discriminative ability for staging fibrosis in CHB is good, with AUROCs for ≥F2 and F4 of 0.76 – 0.91 [134] [140] and 0.72 – 0.97 [103] [134], respectively. These findings were confirmed in a meta-analysis that included patients with several etiologies of liver disease. The analysis of data of patients with CHB showed an AUROC for ≥F2 of 0.88 and the best cut-off was 1.35 m/s and the AUROC for F4 was 0.93 and the best cut-off was 1.87 m/s [141] [142]. There is limited data about other pSWE methods. ElastPQ^® has been used for staging CHB patients in four studies, with good performance for staging liver fibrosis. Further validation is required [92] [142] [143] [144].

2 D shear wave elastography (2D-SWE)

Recently, 2D-SWE (SSI) was tested in patients with CHB and proved to have a lower failure rate than TE and at least similar performance for fibrosis staging [145]. The AUROC for ≥F2 varies between 0.85 and 0.91 [32] [146], with Young’s modulus cut-offs between 7.1 and 8.0 kPa [145] [146], while the AUROC for F4 varies between 0.92 and 0.98 [145] [147], with optimal cut-offs between 10.1 and 11.7 kPa [32] [145]. The best indications of 2D-SWE in HBV are inactive carriers to rule out significant fibrosis and cirrhosis diagnosis.

Monitoring (evaluation of) response to treatment

Under nucleoside/nucleotide analogs, liver stiffness measured by TE significantly decreases regardless of the baseline values of ALT [148] [149]. The only factors associated with decline of LSM are higher baseline LSM and HBV DNA levels [148]. The diagnostic accuracy and thresholds of liver stiffness using TE may differ in untreated and treated patients with chronic hepatitis B and C. This aspect should be taken into account when interpreting the results of elastography. Moreover, even if liver stiffness declines with antiviral treatment, it is unknown if this reflects disease regression and LSM changes should not affect management.

Prognostic relevance

Baseline LSM by TE has modest prognostic relevance with an AUROC between 0.70 and 0.73 for liver-related events [150] [151], which may be increased by adding spleen diameter and platelet count as a prediction model called LSPS (= LSM × spleen diameter/platelet count) up to a level of 0.83 [152]. TE is a good prognostic marker for HCC development that may occur without cirrhosis. A Young’s modulus of > 8 kPa might be a value indicating the need to start screening for HCC, even if a complete virological response was achieved [153] [154]. The risk of HCC is even higher if the Young’s modulus by TE is > 12 – 13 kPa, which also implies an increased risk of decompensation [131] [153] [154] [155].

Non-alcoholic fatty liver disease (NAFLD)

In NAFLD patients, noninvasive markers should aim at the following: a) identify the risk of NAFLD/NASH among individuals with metabolic syndrome; b) identify those with a worse prognosis; c) monitor disease progression; d) predict response to treatment.

Fibrosis staging (NAFLD)

Transient elastography

TE performance is better for cirrhosis than for significant fibrosis [156] [157]. TE has a higher rate of false-positive than false-negative results and a higher negative predictive value (NPV) than positive predictive value (PPV). Therefore, the ability to diagnose bridging fibrosis or cirrhosis is insufficient for clinical decision-making [158] [159]. A systematic review of TE in patients with NAFLD involved 9 studies and 1047 patients [160]. TE was excellent in diagnosing F3 fibrosis (85 % sensitivity, 82 % specificity) and cirrhosis (92 % sensitivity, 92 % specificity), but had only moderate accuracy for F2 fibrosis (79 % sensitivity, 75 % specificity).

With the M probe, patients with steatosis > 66 % at liver biopsy had higher LSM values, which led to higher false-positive LSM results [26]. Thus, in obese patients with a high degree of steatosis, TE (using the M probe) may be less accurate in diagnosing severe fibrosis in NAFLD, and additional evaluation may be warranted to avoid overestimation of fibrosis. However, additional studies on the effects of steatosis on LSM measured with an XL probe are needed. The XL probe produces lower stiffness values than the M probe. Different cut-offs should be used [57]. With the M probe, at a Young’s modulus cut-off value of 7.9 kPa, the sensitivity, specificity, PPV and NPV for F3 or greater disease are 91 %, 75 %, 52 %, and 97 %, respectively [29].

In NAFLD patients, the best cut-off for F3 or greater disease is 7.2 kPa. With this cut-off, the NPV to exclude F3 or greater disease is 89 % (95 % CI 84 – 95 %). Cut-off values of 5.7 kPa and 9.3 kPa have 90 % sensitivity and specificity to rule out and rule in F3 disease, respectively [29].

Point shear wave elastography (pSWE)

A systematic review of 7 studies for a total of 723 patients who underwent SWS measurements with VTQ^® technique to evaluate the diagnostic efficacy of pSWE in patients with NAFLD was recently published [161]. The summary sensitivity was 80.2 % for detecting significant fibrosis, which is not an appropriate endpoint.

2 D shear wave elastography (2D-SWE)

There are only two studies that evaluate the performance of 2D-SWE (SSI) [31] [162]. The results are too limited to make recommendations.

Comparison of different elastographic methods for NAFLD

One study recently compared TE (using the M probe), pSWE (VTQ^®) and 2D-SWE (SSI) in 291 patients with NAFLD enrolled in two different hospitals [31]. All methods showed AUROCs ≥ 0.84 for severe fibrosis and cirrhosis and had a similar performance for the diagnosis of these endpoints. The diagnostic performance of 2D-SWE was superior to that of VTQ^® for the diagnosis of significant fibrosis.

Follow-up of patients

Monitoring of the progression of fibrosis is also necessary in the follow-up of these patients. Patients who achieved a ≥ 5 % weight loss at the 6-month follow-up showed a decrease in LSM by TE, independent of the changes in aminotransferase levels [158]. No data are available for pSWE and 2D-SWE.

Prediction of liver-related complications

A recent study supports the use of TE for risk stratification and prediction of clinical endpoints [163]. For pSWE and 2D-SWE data on this aspect are lacking and no evidence-based recommendation can be given.

Alcoholic liver disease (ALD)

Fibrosis staging

Transient elastography in patients with prior or current chronic alcohol overuse can distinguish absent and mild fibrosis (F0 – 1) from severe fibrosis and cirrhosis, but similar to other etiologies, there is no evidence to suggest that it can differentiate absent and mild fibrosis from significant fibrosis. [164] Additionally, in the eight published single etiology studies on TE for staging liver fibrosis, there is no consensus regarding optimal Young’s modulus cut-off values for significant fibrosis (≥F2), severe fibrosis (≥F3) or cirrhosis (= F4) [23] [30] [165] [166] [167] [168] [169] [170]. The optimal cut-off values range from 7.8 [166] to 9.6 [30] kPa for significant fibrosis, from 8.0 [23] to 17.0 [168] kPa for severe fibrosis and from 12.5 [23] to 22.7 [165] kPa for cirrhosis. The considerable discrepancy between cut-off values in individual studies is likely a consequence of differences in fibrosis stage prevalence with overrepresentation of cirrhotic patients, place of recruitment, and whether patients with alcoholic hepatitis or decompensated disease were excluded.

TE is more suited to rule out than rule in cirrhosis. At a Young’s modulus of 12.5 kPa, TE may rule out cirrhosis with a negative likelihood ratio of 0.07 if the disease prevalence is 50 % or lower [164].

Prognostication of alcoholic liver cirrhosis

There is scant evidence to suggest a role for ultrasound elastography for determining the prognosis and for the monitoring of patients with alcoholic liver disease [171], or for TE to predict esophageal varices [172] and the hepatic venous pressure gradient in patients with alcoholic cirrhosis [171].

Timing of liver stiffness measurements with regard to alcohol abstinence

In patients undergoing alcohol detoxification, 0.5 to 4 weeks of abstinence causes a clinically significant decrease in TE [23] [24] [25] [173]. However, the decrease is associated with a normalization of transaminases, bilirubin, alkaline phosphatase and/or gamma-glutamyltransferase. It is, therefore, unclear whether alcohol alone or alcohol-induced hepatitis and cholangiocyte damage cause the increase in liver stiffness. [170]. One study suggests that TE is accurate for staging in patients with ongoing alcohol abuse but normal gamma-glutamyltransferase [30], while another study suggests that AUROC for the diagnosis of cirrhosis in alcoholic patients diminishes when AST is above 100 – 150 U/L [170].

Screening the general population or high-risk groups in primary care

Ultrasound elastography for systematic screening of high-risk populations in primary care for alcoholic liver disease was performed in one study. TE was offered to primary care patients with an AST:ALT ratio ≥ 0.8 [174]. However, this study did not include biopsy confirmation in patients with elevated TE. In a diagnostic study, TE had excellent diagnostic accuracy for significant fibrosis and cirrhosis in a subgroup of 71 patients recruited from primary alcohol rehabilitation centers [30].

With a prevalence of cirrhosis of 2 – 4 % in a background population of at-risk individuals [175], the positive predictive value of TE should be considered low regardless of cut-off values.

Point shear wave elastography (pSWE) and 2D-SWE

There is only one study to support the use of 2D-SWE (SSI) for assessing alcoholic liver fibrosis [30]. There are three small studies on the use of pSWE [176] [177] [178], two of which report diagnostic accuracies and test probabilities. The results are consistent regarding diagnostic accuracy, which suggests that VTQ^® may be used to rule out severe fibrosis and cirrhosis. The results regarding cut-off values are, however, inconsistent. Therefore, there is insufficient evidence to make recommendations for using VTQ^® to distinguish absent and mild fibrosis (F0 – 1) from significant or severe fibrosis and cirrhosis. Thus, there is still insufficient evidence to evaluate the role of pSWE or 2D-SWE in alcoholic liver disease.

Cholestatic liver disease and autoimmune hepatitis (AIH)

Risk stratification is a major need in patients with chronic cholestatic diseases in order to allow personalized management and the selection of candidates for clinical trials of new drugs. Studies of liver stiffness as a surrogate of liver fibrosis and prognosis focusing on cholestatic liver disease (primary biliary cholangitis-PBC, primary sclerosing cholangitis-PSC) or AIH are scarce. Most available data focus on TE [179] [180] [181].

Transient elastography

Transient elastography is currently considered one of the best surrogates of fibrosis in PBC. High baseline or increasing values over time indicate a worse outcome in this population [141] [179]. Liver stiffness was investigated in 73 patients with PSC, regularly undergoing clinical and elastographic follow-up [182]. LSMs were able to differentiate severe vs. non-severe fibrosis with a high discriminative accuracy for cirrhosis (AUROC 0.88). There was high reproducibility between two operators. Higher baseline LSM and an increase of LSM over time were associated with adverse outcome such as death, liver transplantation, ascites, hepatic encephalopathy, gastrointestinal bleeding, or HCC [182]. Dilatation of the intrahepatic biliary system due to a dominant stricture should be excluded in PSC before interpreting the LSMs. Cholestasis increases liver stiffness independent of liver fibrosis.

Data regarding the pediatric population with biliary atresia suggest that liver (and spleen) elastography could be a valuable tool to predict outcomes before surgery, and might be used after the Kasai operation to monitor liver disease and portal hypertension [183].

Due to the limited evidence, no recommendation can be given.

Point shear wave elastography (pSWE)

VTQ^® was initially performed in 9 patients with AIH, PBC and PSC having higher shear wave velocities than healthy volunteers [184]. In total, two studies dealt with VTQ^® in AIH and primary biliary cholangitis. In 15 patients with treated AIH, VTQ^® could differentiate between the absence of fibrosis and significant fibrosis [185]. SWS assessed by VTQ^® showed good diagnostic accuracy for detecting cirrhosis (AUROC 0.91) in 61 patients with primary biliary cholangitis [186].

2 D shear wave elastography (2D-SWE)

Data regarding 2D-SWE in AIH, PBC and PSC are not available. Liver stiffness assessment helped in differentiating between biliary atresia and neonatal hepatitis in one study [187].

Due to the paucity of data, no recommendation can be given.

Portal hypertension

Transient elastography

In patients with compensated advanced chronic liver disease/cirrhosis, LSM correlates with the hepatic venous pressure gradient (HVPG). Even though the correlation between the two does not allow for an accurate estimate of the exact HVPG value (range: 0.59 – 0.70), the discriminative ability of liver stiffness for the presence of clinically significant portal hypertension (CSPH, defined as HVPG ≥ 10 mmHg, threshold for the appearance of complications) is very high, with a summary AUROC of 0.93 in a recent meta-analysis [188]. However, it should be emphasized that most of the patients included in the studies concerning HVPG had viral or alcoholic cirrhosis, and evidence regarding other etiologies is limited. In viral cirrhosis, Young’s modulus values of > 20 – 25 kPa are highly specific for CSPH, and values of > 21 kPa predict the onset of a first clinical decompensation with an accuracy similar to that of HVPG > 10 mmHg [189].

The accuracy of LSM in predicting the presence and size of gastroesophageal varices has been the subject of several studies. Despite the fact that it is currently the best single noninvasive predictor in this field with summary AUROCs of 0.84 for esophageal varices (EV) and 0.78 for large EV in a recent meta-analysis [188], the cut-offs vary widely among the studies, and the accuracy is not sufficient to replace endoscopy. The accuracy of LSM for the diagnosis of CSPH and varices improves if it is combined with platelet count and spleen size [190] [191]. Recent data indicates that if a combination of a Young’s modulus value of < 20 kPa and a platelet count of > 150 G/L is used, varices needing treatment can be ruled out with a high accuracy (< 5 % of patients missed) [192] [193], and endoscopy can be safely avoided [194].

Point shear wave elastography (pSWE)

Point SWE (VTQ^®) has been used in three studies addressing the diagnosis of CSPH [195] [196] [197] and showed excellent applicability and very good diagnostic accuracy (AUROC 0.82 – 0.90). VTQ^® has been used in a few studies addressing the diagnosis and severity of esophageal varices. SWS was higher in patients with esophageal varices of any size, and was even higher in patients with large varices [195] [196]. However, reliable cut-offs are not available yet. No strong recommendation regarding the cut-offs to be used can be made due to the limited evidence.

2 D shear wave elastography (2D-SWE)

2D-SWE (SSI) has been tested for the diagnosis of CSPH in 4 studies and a further small series [6] [198] [199] [200] [201]. The accuracy of the method was reliable in all of the published studies (AUROC 0.80 – 0.92).

Two studies performed a head-to-head comparison between LSM by TE and 2D-SWE [6] [198]. TE was less applicable, and both techniques showed similar accuracy for the diagnosis of CSPH.

LSM by 2D-SWE is higher in patients with esophageal varices of any size and is further increased in patients with large varices. However, reliable cut-offs are not available yet. No strong recommendation regarding the cut-offs for 2D-SWE can be given, and further evidence is needed.

Conflict of interest

Some authors declare conflicts of interest, which are available from the publisher.

Acknowledgement

The authors thank the EFSUMB secretary Lynne Rudd for her never-ending support of the EFSUMB guidelines. We also thank the following companies for funding a consensus meeting of the authors held in London in July 2016, at which we agreed the recommendations made in this paper: bk/Ultrasound, Echosens, Esaote SpA, GE Healthcare, Hitachi Medical Systems, Philips Healthcare, Shenzhen Mindray Bio-medical Electronics Co., Ltd, Siemens Healthineers, SuperSonic and Toshiba Medical. Representatives of these companies were in attendance at this meeting, to assist with product technical information, but did not take part in forming the manuscript or the recommendations.

• References

• 1 EFSUMB. Education and Professional Standards Committee (EPSC) Minimum Training recommendations for the practice of medical ultrasound. Ultraschall in Med 2006; 27: 79-105
• 2 Fabrellas N. Alemany M. Urquizu M. et al. Using transient elastography to detect chronic liver diseases in a primary care nurse consultancy. Nurs Res 2013; 62: 450-454
• 3 Sporea I. Sirli RL. Deleanu A. et al. Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies. Ultraschall in Med 2011; 32: S46-S52
• 4 Barr RG. Ferraioli G. Palmeri ML. et al. Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement. Radiology 2015; 276: 845-861
• 5 Wang CZ. Zheng J. Huang ZP. et al. Influence of measurement depth on the stiffness assessment of healthy liver with real-time shear wave elastography. Ultrasound Med Biol 2014; 40: 461-469
• 6 Procopet B. Berzigotti A. Abraldes JG. et al. Real-time shear-wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol 2015; 62: 1068-1075
• 7 Bamber J. Cosgrove D. Dietrich CF. et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology. Ultraschall in Med 2013; 34: 169-184
• 8 Ferraioli G. Filice C. Castera L. et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver. Ultrasound Med Biol 2015; 41: 1161-1179
• 9 Liao LY. Kuo KL. Chiang HS. et al. Acoustic radiation force impulse elastography of the liver in healthy patients: test location, reference range and influence of gender and body mass index. Ultrasound Med Biol 2015; 41: 698-704
• 10 Goertz RS. Egger C. Neurath MF. et al. Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver. Ultraschall in Med 2012; 33: 380-385
• 11 Goertz RS. Zopf Y. Jugl V. 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 Med 2010; 31: 151-155
• 12 Mederacke I. Wursthorn K. Kirschner J. et al. Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection. Liver Int 2009; 29: 1500-1506
• 13 Arena U. Lupsor Platon M. Stasi C. et al. Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution. Hepatology 2013; 58: 65-72
• 14 Berzigotti A. De Gottardi A. Vukotic R. et al. Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension. PLoS One 2013; 8: e58742
• 15 Gersak MM. Sorantin E. Windhaber J. et al. The influence of acute physical effort on liver stiffness estimation using Virtual Touch Quantification (VTQ). Preliminary results. Med Ultrason 2016; 18: 151-156
• 16 Coco B. Oliveri F. Maina AM. et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360-369
• 17 Sagir A. Erhardt A. Schmitt M. et al. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008; 47: 592-595
• 18 Arena U. Vizzutti F. Corti G. et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008; 47: 380-384
• 19 Vigano M. Massironi S. Lampertico P. et al. Transient elastography assessment of the liver stiffness dynamics during acute hepatitis B. Eur J Gastroenterol Hepatol 2010; 22: 180-184
• 20 Millonig G. Reimann FM. Friedrich S. et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718-1723
• 21 Millonig G. Friedrich S. Adolf S. et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52: 206-210
• 22 Colli A. Pozzoni P. Berzuini A. et al. Decompensated chronic heart failure: increased liver stiffness measured by means of transient elastography. Radiology 2010; 257: 872-878
• 23 Mueller S. Millonig G. Sarovska L. et al. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010; 16: 966-972
• 24 Trabut JB. Thepot V. Nalpas B. et al. Rapid decline of liver stiffness following alcohol withdrawal in heavy drinkers. Alcohol Clin Exp Res 2012; 36: 1407-1411
• 25 Bardou-Jacquet E. Legros L. Soro D. et al. Effect of alcohol consumption on liver stiffness measured by transient elastography. World J Gastroenterol 2013; 19: 516-522
• 26 Petta S. Maida M. Macaluso FS. et al. The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease. Hepatology 2015; 62: 1101-1110
• 27 Macaluso FS. Maida M. Camma C. et al. Steatosis affects the performance of liver stiffness measurement for fibrosis assessment in patients with genotype 1 chronic hepatitis C. J Hepatol 2014; 61: 523-529
• 28 Yoneda M. Yoneda M. Mawatari H. et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis 2008; 40: 371-378
• 29 Wong VW. Vergniol J. Wong GL. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51: 454-462
• 30 Thiele M. Detlefsen S. Sevelsted Moller L. et al. Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis. Gastroenterology 2016; 150: 123-133
• 31 Cassinotto C. Boursier J. De Ledinghen 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
• 32 Zeng J. Liu GJ. Huang ZP. et al. Diagnostic accuracy of two-dimensional shear wave elastography for the non-invasive staging of hepatic fibrosis in chronic hepatitis B: a cohort study with internal validation. Eur Radiol 2014; 24: 2572-2581
• 33 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. J Hepatol 2014; 61: 550-557
• 34 Colombo S. Belloli L. Zaccanelli M. et al. Normal liver stiffness and its determinants in healthy blood donors. Dig Liver Dis 2011; 43: 231-236
• 35 Roulot D. Costes JL. Buyck JF. et al. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 2011; 60: 977-984
• 36 Corpechot C. El Naggar A. Poupon R. Gender and liver: is the liver stiffness weaker in weaker sex?. Hepatology 2006; 44: 513-514
• 37 Sirli R. Sporea I. Tudora A. et al. Transient elastographic evaluation of subjects without known hepatic pathology: does age change the liver stiffness?. J Gastrointestin Liver Dis 2009; 18: 57-60
• 38 Horster S. Mandel P. Zachoval R. et al. Comparing acoustic radiation force impulse imaging to transient elastography to assess liver stiffness in healthy volunteers with and without valsalva manoeuvre. Clin Hemorheol Microcirc 2010; 46: 159-168
• 39 Karlas T. Pfrepper C. Wiegand 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. Scand J Gastroenterol 2011; 46: 1458-1467
• 40 Popescu A. Bota S. Sporea I. et al. The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary results. Ultrasound Med Biol 2013; 39: 579-584
• 41 Son CY. Kim SU. Han WK. et al. Normal liver elasticity values using acoustic radiation force impulse imaging: a prospective study in healthy living liver and kidney donors. J Gastroenterol Hepatol 2012; 27: 130-136
• 42 Guzmán-Aroca F. Reus M. Berná-Serna JD. et al. Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: a study in healthy volunteers. J Ultrasound Med 2011; 30: 975-979
• 43 Toshima T. Shirabe K. Takeishi K. 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. J Gastroenterol 2011; 46: 705-711
• 44 Matos H. Trindade A. Noruegas MJ. Acoustic radiation force impulse imaging in paediatric patients: normal liver values. J Pediatr Gastroenterol Nutr 2014; 59: 684-688
• 45 Hanquinet S. Courvoisier D. Kanavaki A. et al. Acoustic radiation force impulse imaging-normal values of liver stiffness in healthy children. Pediatr Radiol 2013; 43: 539-544
• 46 Ferraioli G. Tinelli C. Lissandrin R. et al. Point shear wave elastography method for assessing liver stiffness. World J Gastroenterol 2014; 20: 4787-4796
• 47 Sporea I. Bota S. Grădinaru-Taşcău O. et al. Comparative study between two point Shear Wave Elastographic techniques: Acoustic Radiation Force Impulse (ARFI) elastography and ElastPQ. Med Ultrason 2014; 16: 309-314
• 48 Ling W. Lu Q. Quan J. et al. Assessment of impact factors on shear wave based liver stiffness measurement. Eur J Radiol 2013; 82: 335-341
• 49 Suh CH. Kim SY. Kim KW. et al. Determination of normal hepatic elasticity by using real-time shear-wave elastography. Radiology 2014; 271: 895-900
• 50 Huang Z. Zheng J. Zeng J. et al. Normal liver stiffness in healthy adults assessed by real-time shear wave elastography and factors that influence this method. Ultrasound Med Biol 2014; 40: 2549-2555
• 51 Dong Y. Sirli R. Ferraioli G. et al. Shear Wave Elastography of the liver, review on normal values. Z Gastroenterol 2017; 55: 153-166
• 52 European Association for Study of L, Asociacion Latinoamericana para el Estudio del H. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63: 237-264
• 53 Engelmann G. Gebhardt C. Wenning D. et al. Feasibility study and control values of transient elastography in healthy children. Eur J Pediatr 2012; 171: 353-360
• 54 de Ledinghen V. Wong VW. Vergniol J. et al. Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: comparison between M and XL probe of FibroScan(R). J Hepatol 2012; 56: 833-839
• 55 de Ledinghen V. Vergniol J. Foucher J. et al. Feasibility of liver transient elastography with FibroScan using a new probe for obese patients. Liver Int 2010; 30: 1043-1048
• 56 Durango E. Dietrich C. Seitz HK. et al. Direct comparison of the FibroScan XL and M probes for assessment of liver fibrosis in obese and nonobese patients. Hepat Med 2013; 5: 43-52
• 57 Wong VW. Vergniol J. Wong GL. et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012; 107: 1862-1871
• 58 Carrion JA. Puigvehi M. Coll S. et al. Applicability and accuracy improvement of transient elastography using the M and XL probes by experienced operators. J Viral Hepat 2015; 22: 297-306
• 59 Lucidarme D. Foucher J. Le Bail B. et al. Factors of accuracy of transient elastography (fibroscan) for the diagnosis of liver fibrosis in chronic hepatitis C. Hepatology 2009; 49: 1083-1089
• 60 Myers RP. Crotty P. Pomier-Layrargues G. et al. Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy. Liver Int 2010; 30: 1471-1480
• 61 Myers RP. Pomier-Layrargues G. Kirsch R. et al. Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe. J Hepatol 2012; 56: 564-570
• 62 Fraquelli M. Rigamonti C. Casazza G. et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56: 968-973
• 63 Boursier J. Konate A. Gorea G. et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clin Gastroenterol Hepatol 2008; 6: 1263-1269
• 64 Afdhal NH. Bacon BR. Patel K. et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clin Gastroenterol Hepatol 2015; 13: 772-779 e771-e773
• 65 Takahashi H. Ono N. Eguchi Y. et al. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study. Liver Int 2010; 30: 538-545
• 66 Rizzo L. Calvaruso V. Cacopardo B. et al. Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. Am J Gastroenterol 2011; 106: 2112-2120
• 67 Piscaglia F. Salvatore V. Di Donato R. et al. Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall in Med 2011; 32: 167-175
• 68 Goertz RS. Sturm J. Pfeifer L. et al. S. ARFI cut-off values and significance of standard deviation for liver fibrosis staging in patients with chronic liver disease. Ann Hepato 2013; 12: 935-941
• 69 D'Onofrio M. Gallotti A. Mucelli RP. Tissue quantification with acoustic radiation force impulse imaging: Measurement repeatability and normal values in the healthy liver. Am J Roentgenol 2010; 195: 132-136
• 70 Friedrich-Rust M. Wunder K. Kriener S. et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252: 595-604
• 71 Bota S. Sporea I. Sirli R. et al. Intra- and interoperator reproducibility of acoustic radiation force impulse (ARFI) elastography--preliminary results. Ultrasound Med Biol 2012; 38: 1103-1108
• 72 Bota S. Sporea I. Sirli R. et al. 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 Med Biol 2013; 30: 407-412
• 73 Ferraioli G. Maiocchi L. Lissandrin R. 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. J Gastrointestin Liver Dis 2016; 25: 331-335
• 74 Dietrich CF. Dong Y. Shear wave elastography with a new reliability indicator. J Ultrason 2016; 16: 281-287
• 75 Samir AE. Dhyani M. Vij A. et al. Shear-wave elastography for the estimation of liver fibrosis in chronic liver disease: determining accuracy and ideal site for measurement. Radiology 2015; 274: 888-896
• 76 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. J Hepatol 2013; 58: 928-935
• 77 Cassinotto C. Charrie A. Mouries A. et al. Liver and spleen elastography using supersonic shear imaging for the non-invasive diagnosis of cirrhosis severity and oesophageal varices. Dig Liver Dis 2015; 47: 695-701
• 78 Cassinotto C. de Lédinghen V. Reply to: “New imaging assisted methods for liver fibrosis quantification: Is it really favorable to classical transient elastography?”. J Hepatol 2015; 63: 767
• 79 Thiele M. Madsen BS. Procopet B. et al. Reliability criteria for liver stiffness measurements with real-time 2D shear wave elastography in different clinical scenarios of chronic liver disease. Ultraschall in Med 2016; DOI: 10.1055/s-0042-108431.
• 80 Sporea I. Gradinaru-Tascau O. Bota S. et al. How many measurements are needed for liver stiffness assessment by 2D-Shear Wave Elastography (2D-SWE) and which value should be used: the mean or median?. Med Ultrason 2013; 15: 268-272
• 81 Sporea I. Bota S. Jurchis A. et al. Acoustic radiation force impulse and supersonic shear imaging versus transient elastography for liver fibrosis assessment. Ultrasound Med Biol 2013; 39: 1933-1941
• 82 Yoon JH. Lee JM. Han JK. et al. Shear wave elastography for liver stiffness measurement in clinical sonographic examinations: evaluation of intraobserver reproducibility, technical failure, and unreliable stiffness measurements. J Ultrasound Med 2014; 33: 437-447
• 83 Hudson JM. Milot L. Parry C. et al. Inter- and intra-operator reliability and repeatability of shear wave elastography in the liver: a study in healthy volunteers. Ultrasound in Med & Biol 2013; 39: 950-955
• 84 Ferraioli G. Tinelli C. Zicchetti M. et al. Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 2012; 81: 3102-3106
• 85 Woo H. Lee JY. Yoon JH. et al. Comparison of the Reliability of Acoustic Radiation Force Impulse Imaging and Supersonic Shear Imaging in Measurement of Liver Stiffness. Radiology 2015; 277: 881-886
• 86 Staugaard B. Christensen PB. Mossner B. et al. Feasibility of transient elastography versus real-time two-dimensional shear wave elastography in difficult-to-scan patients. Scand J Gastroenterol 2016; 51: 1354-1359
• 87 Hall TJ. Milkowski A. Garra B. et al. RSNA/QIBA: shear wave speed as a biomarker for liver fibrosis staging. In: Ultrasonics Symposium (IUS), 2013. I.E. International; 2013: 397-400
• 88 Palmeri M. Nightingale K. Fielding S. et al. RSNA QIBA ultrasound shear wave speed Phase II phantom study in viscoelastic media. Proceedings of the 2015 IEEE Ultrasonics Symposium, 2015. International; 2013: 397-400
• 89 Chang S. Kim MJ. Kim J. et al. Variability of shear wave velocity using different frequencies in acoustic radiation force impulse (ARFI) elastography: a phantom and normal liver study. Ultraschall in Med 2013; 34: 260-265
• 90 Potthoff A. Attia D. Pischke S. et al. Influence of different frequencies and insertion depths on the diagnostic accuracy of liver elastography by acoustic radiation force impulse imaging (ARFI). Eur J Radiol 2013; 82: 1207-1212
• 91 Ferraioli G. Lissandrin R. Zicchetti M. et al. Ultrasound point shear wave elastography assessment of liver and spleen stiffness: effect of training on repeatability of measurements. Eur Radiol 2014; 24: 1283-1289
• 92 Ma JJ. Ding H. Mao F. et al. Assessment of liver fibrosis with elastography point quantification technique in chronic hepatitis B virus patients: a comparison with liver pathological results. J Gastroenterol Hepatol 2014; 29: 814-819
• 93 Fraquelli M. Baccarin A. Casazza G. et al. Liver stiffness measurement reliability and main determinants of point shear-wave elastography in patients with chronic liver disease. Aliment Pharmacol Ther 2016; 44: 356-365
• 94 Piscaglia F. Salvatore V. Mulazzani L. et al. Ultrasound Shear Wave Elastography for Liver Disease. A Critical Appraisal of the Many Actors on the Stage. Ultraschall in Med 2016; 37: 1-5
• 95 Friedrich-Rust M. Ong MF. Martens S. et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960-974
• 96 Chang PE. Goh GB. Ngu JH. et al. Clinical applications, limitations and future role of transient elastography in the management of liver disease. World J Gastrointest Pharmacol Ther 2016; 7: 91-106
• 97 Tsochatzis EA. Gurusamy KS. Ntaoula S. et al. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011; 54: 650-659
• 98 Njei B. McCarty TR. Luk J. et al. Use of Transient Elastography in Patients with HIV-HCV Co-infection: A Systematic Review and Meta-analysis. J Gastroenterol Hepatol 2016; 31: 1684-1693
• 99 Barrault C. Roudot-Thoraval F. Tran Van Nhieu J. et al. Non-invasive assessment of liver graft fibrosis by transient elastography after liver transplantation. Clin Res Hepatol Gastroenterol 2013; 37: 347-352
• 100 European Association for Study of L. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60: 392-420
• 101 Sporea I. Bota S. Peck-Radosavljevic M. et al. Acoustic Radiation Force Impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: an international multicenter study. Eur J Radiol 2012; 81: 4112-4118
• 102 Friedrich-Rust M. Lupsor M. de Knegt R. et al. Point Shear Wave Elastography by Acoustic Radiation Force Impulse Quantification in Comparison to Transient Elastography for the Noninvasive Assessment of Liver Fibrosis in Chronic Hepatitis C: A Prospective International Multicenter Study. Ultraschall in Med 2015; 36: 239-247
• 103 Friedrich-Rust M. Nierhoff J. Lupsor M. et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012; 19: e212-e219
• 104 Conti F. Serra C. Vukotic R. et al. Accuracy of elastography point quantification and steatosis influence on assessing liver fibrosis in patients with chronic hepatitis C. Liver Int 2017; 37: 187-195
• 105 Joo SK. Kim JH. Oh S. et al. Prospective Comparison of Noninvasive Fibrosis Assessment to Predict Advanced Fibrosis or Cirrhosis in Asian Patients With Hepatitis C. J Clin Gastroenterol 2015; 49: 697-704
• 106 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
• 107 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 Med Biol 2011; 37: 1361-1373
• 108 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. Hepatol Res 2015; 45: 122-129
• 109 Yoneda M. Thomas E. Sclair SN. et al. Supersonic shear imaging and transient elastography with the XL probe accurately detect fibrosis in overweight or obese patients with chronic liver disease. Clin Gastroenterol Hepatol 2015; 13: 1502-1509 e1505
• 110 Vergniol J. Foucher J. Terrebonne E. et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011; 140: 1970-1979
• 111 Macias J. Camacho A. Von Wichmann MA. et al. Liver stiffness measurement versus liver biopsy to predict survival and decompensations of cirrhosis among HIV/hepatitis C virus-coinfected patients. AIDS 2013; 27: 2541-2549
• 112 Masuzaki R. Tateishi R. Yoshida H. et al. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 2009; 49: 1954-1961
• 113 Poynard T. Vergniol J. Ngo Y. et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and transient elastography (FibroScan(R)). J Hepatol 2014; 60: 706-714
• 114 Narita Y. Genda T. Tsuzura H. et al. Prediction of liver stiffness hepatocellular carcinoma in chronic hepatitis C patients on interferon-based anti-viral therapy. J Gastroenterol Hepatol 2014; 29: 137-143
• 115 Crespo G. Lens S. Gambato M. et al. Liver stiffness 1 year after transplantation predicts clinical outcomes in patients with recurrent hepatitis C. Am J Transplant 2014; 14: 375-383
• 116 Carrion JA. Navasa M. Bosch J. et al. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl 2006; 12: 1791-1798
• 117 Stasi C. Piluso A. Arena U. et al. Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study. World J Gastroenterol 2015; 21: 3013-3019
• 118 Yada N. Sakurai T. Minami T. et al. Ultrasound elastography correlates treatment response by antiviral therapy in patients with chronic hepatitis C. Oncology 2014; 87 (Suppl. 01) 118-123
• 119 Mandorfer M. Kozbial K. Freissmuth C. et al. Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses. Aliment Pharmacol Ther 2015; 42: 707-718
• 120 Deterding K. Schlevogt B. Port K. et al. Letter: can persisting liver stiffness indicate increased risk of hepatocellular cell carcinoma after successful anti-HCV therapy? – authors' reply. Aliment Pharmacol Ther 2016; 43: 546-547
• 121 Hezode C. Castera L. Roudot-Thoraval F. et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther 2011; 34: 656-663
• 122 Lee HW. Chon YE. Kim SU. et al. Predicting Liver-Related Events Using Transient Elastography in Chronic Hepatitis C Patients with Sustained Virological Response. Gut Liver 2016; 10: 429-436
• 123 D'Ambrosio R. Aghemo A. Fraquelli M. et al. The diagnostic accuracy of Fibroscan for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response. J Hepatol 2013; 59: 251-256
• 124 Osakabe K. Ichino N. Nishikawa T. et al. Changes of shear-wave velocity by interferon-based therapy in chronic hepatitis C. World J Gastroenterol 2015; 21: 10215-10223
• 125 Goertz RS. Sturm J. Zopf S. et al. Outcome analysis of liver stiffness by ARFI (acoustic radiation force impulse) elastometry in patients with chronic viral hepatitis B and C. Clin Radiol 2014; 69: 275-279
• 126 Yamada R. Hiramatsu N. Oze T. et al. Significance of liver stiffness measurement by acoustic radiation force impulse (ARFI) among hepatitis C patients. J Med Virol 2014; 86: 241-247
• 127 Liver EAFTSOT. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167-185
• 128 Chon YE. Choi EH. Song KJ. et al. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis. PLoS One 2012; 7: e44930
• 129 Xu X. Su Y. Song R. et al. Performance of transient elastography assessing fibrosis of single hepatitis B virus infection: a systematic review and meta-analysis of a diagnostic test. Hepatol Int 2015; 9: 558-566
• 130 Li Y. Huang YS. Wang ZZ. et al. Systematic review with meta-analysis: the diagnostic accuracy of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B. Aliment Pharmacol Ther 2016; 43: 458-469
• 131 Seo YS. Kim MN. Kim SU. et al. Risk Assessment of Hepatocellular Carcinoma Using Transient Elastography Vs. Liver Biopsy in Chronic Hepatitis B Patients Receiving Antiviral Therapy. Medicine (Baltimore) 2016; 95: e2985
• 132 Meng F. Zheng Y. Zhang Q. et al. Noninvasive evaluation of liver fibrosis using real-time tissue elastography and transient elastography (FibroScan). J Ultrasound Med 2015; 34: 403-410
• 133 Liu Y. Dong CF. Yang G. et al. Optimal linear combination of ARFI, transient elastography and APRI for the assessment of fibrosis in chronic hepatitis B. Liver Int 2015; 35: 816-825
• 134 Dong DR. Hao MN. Li C. 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. Mol Med Rep 2015; 11: 4174-4182
• 135 Chan HL. Wong GL. Choi PC. et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J Viral Hepat 2009; 16: 36-44
• 136 Cardoso AC. Carvalho-Filho RJ. Stern C. et al. Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C. Liver Int 2012; 32: 612-621
• 137 Fraquelli M. Rigamonti C. Casazza G. et al. Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol 2011; 54: 621-628
• 138 Invernizzi F. Vigano M. Grossi G. et al. The prognosis and management of inactive HBV carriers. Liver Int 2016; 36 (Suppl. 01) 100-104
• 139 Castera L. Bernard PH. Le Bail B. et al. Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers. Aliment Pharmacol Ther 2011; 33: 455-465
• 140 Dong CF. Xiao J. Shan LB. et al. Combined acoustic radiation force impulse, aminotransferase to platelet ratio index and Forns index assessment for hepatic fibrosis grading in hepatitis B. World J Hepatol 2016; 8: 616-624
• 141 Nierhoff J. Chavez Ortiz AA. Herrmann E. et al. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis. Eur Radiol 2013; 23: 3040-3053
• 142 Ding H. Ma JJ. Wang WP. et al. Assessment of liver fibrosis: the relationship between point shear wave elastography and quantitative histological analysis. J Gastroenterol Hepatol 2015; 30: 553-558
• 143 Lu Q. Lu C. Li J. et al. Stiffness values and serum biomarkers in liver fibrosis staging: study in large surgical specimens in patients with chronic Hepatitis B. Radiology 2016; 280: 290-299
• 144 Yegin EG. Yegin K. Karatay E. et al. Quantitative assessment of liver fibrosis by digital image analysis: Relationship to Ishak staging and elasticity by shear-wave elastography. J Dig Dis 2015; 16: 217-227
• 145 Leung VY. Shen J. Wong VW. 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: 910-918
• 146 Feng JC. Li J. Wu XW. et al. Diagnostic Accuracy of SuperSonic Shear Imaging for Staging of Liver Fibrosis: A Meta-analysis. J Ultrasound Med 2016; 35: 329-339
• 147 Li C. Zhang C. Li J. et al. Diagnostic Accuracy of Real-Time Shear Wave Elastography for Staging of Liver Fibrosis: A Meta-Analysis. Med Sci Monit 2016; 22: 1349-1359
• 148 Kim MN. Kim SU. Kim BK. et al. Long-term changes of liver stiffness values assessed using transient elastography in patients with chronic hepatitis B receiving entecavir. Liver Int 2014; 34: 1216-1223
• 149 Yo IK. Kwon OS. Park JW. et al. The factors associated with longitudinal changes in liver stiffness in patients with chronic hepatitis B. Clin Mol Hepatol 2015; 21: 32-40
• 150 Park MS. Kim SU. Kim BK. et al. Prognostic value of the combined use of transient elastography and fibrotest in patients with chronic hepatitis B. Liver Int 2015; 35: 455-462
• 151 Kim MN. Kim SU. Park JY. et al. Risk assessment of liver-related events using transient elastography in patients with chronic hepatitis B receiving entecavir. J Clin Gastroenterol 2014; 48: 272-278
• 152 Shin SH. Kim SU. Park JY. et al. Liver stiffness-based model for prediction of hepatocellular carcinoma in chronic hepatitis B virus infection: comparison with histological fibrosis. Liver Int 2015; 35: 1054-1062
• 153 Wong GL. Chan HL. Wong CK. et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. J Hepatol 2014; 60: 339-345
• 154 Lee HW. Yoo EJ. Kim BK. et al. Prediction of development of liver-related events by transient elastography in hepatitis B patients with complete virological response on antiviral therapy. Am J Gastroenterol 2014; 109: 1241-1249
• 155 Kim MN. Kim SU. Kim BK. et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology 2015; 61: 1851-1859
• 156 Petta S. Vanni E. Bugianesi E. et al. The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 2015; 35: 1566-1573
• 157 Naveau S. Lamouri K. Pourcher G. et al. The diagnostic accuracy of transient elastography for the diagnosis of liver fibrosis in bariatric surgery candidates with suspected NAFLD. Obes Surg 2014; 24: 1693-1701
• 158 Tapper EB. Challies T. Nasser I. et al. The Performance of Vibration Controlled Transient Elastography in a US Cohort of Patients With Nonalcoholic Fatty Liver Disease. Am J Gastroenterol 2016; 111: 677-684
• 159 Kumar R. Rastogi A. Sharma MK. et al. Liver stiffness measurements in patients with different stages of nonalcoholic fatty liver disease: diagnostic performance and clinicopathological correlation. Dig Dis Sci 2013; 58: 265-274
• 160 Kwok R. Tse YK. Wong GL. et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease--the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther 2014; 39: 254-269
• 161 Liu H. Fu J. Hong R. et al. Acoustic Radiation Force Impulse Elastography for the Non-Invasive Evaluation of Hepatic Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review & Meta-Analysis. PLoS One 2015; 10: e0127782
• 162 Zheng J. Guo H. Zeng J. et al. Two-dimensional shear-wave elastography and conventional US: the optimal evaluation of liver fibrosis and cirrhosis. Radiology 2015; 275: 290-300
• 163 Boursier J. Vergniol J. Guillet A. et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by Fibroscan in non-alcoholic fatty liver disease. J Hepatol 2016; 65: 570-578
• 164 Pavlov CS. Casazza G. Nikolova D. et al. Transient elastography for diagnosis of stages of hepatic fibrosis and cirrhosis in people with alcoholic liver disease. Cochrane Database Syst Rev 2015; 1: CD010542
• 165 Nahon P. Kettaneh A. Tengher-Barna I. et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol 2008; 49: 1062-1068
• 166 Nguyen-Khac E. Chatelain D. Tramier B. et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther 2008; 28: 1188-1198
• 167 Kim SG. Kim YS. Jung SW. et al. The usefulness of transient elastography to diagnose cirrhosis in patients with alcoholic liver disease. Korean J Hepatol 2009; 15: 42-51
• 168 Janssens F. de Suray N. Piessevaux H. et al. Can transient elastography replace liver histology for determination of advanced fibrosis in alcoholic patients: a real-life study. J Clin Gastroenterol 2010; 44: 575-582
• 169 Fernandez M. Trepo E. Degre D. et al. Transient Elastography using Fibroscan is the most reliable noninvasive method for the diagnosis of advanced fibrosis and cirrhosis in alcoholic liver disease. Eur J Gastroenterol Hepatol 2015; 27: 1074-1079
• 170 Mueller S. Englert S. Seitz HK. et al. Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease. Liver International 2015; 35: 2514-2521
• 171 Cho EJ. Kim MY. Lee JH. et al. Diagnostic and Prognostic Values of Noninvasive Predictors of Portal Hypertension in Patients with Alcoholic Cirrhosis. PLoS One 2015; 10: e0133935
• 172 Sporea I. Ratiu I. Bota S. et al. Are different cut-off values of liver stiffness assessed by transient elastography according to the etiology of liver cirrhosis for predicting significant esophageal varices?. Med Ultrason 2013; 15: 111-115
• 173 Gelsi E. Dainese R. Truchi R. et al. Effect of detoxification on liver stiffness assessed by Fibroscan(R) in alcoholic patients. Alcohol Clin Exp Res 2011; 35: 566-570
• 174 Harman DJ. Ryder SD. James MW. et al. Direct targeting of risk factors significantly increases the detection of liver cirrhosis in primary care: a cross-sectional diagnostic study utilising transient elastography. BMJ Open 2015; 5: e007516
• 175 Bellentani S. Saccoccio G. Costa G. et al. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut 1997; 41: 845-850
• 176 Kiani A. Brun V. Laine F. et al. Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease. World J Gastroenterol 2016; 22: 4926-4935
• 177 Zhang D. Li P. Chen M. et al. Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease using acoustic radiation force impulse elastography. Abdom Imaging 2015; 40: 723-729
• 178 Liu F. Wei L. Tang X. et al. Clinical value of virtual touch tissue quantification and PGA index in evaluation of alcoholic liver fibrosis. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2015; 40: 1246-1252
• 179 Corpechot C. Carrat F. Poujol-Robert A. et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 2012; 56: 198-208
• 180 Corpechot C. El Naggar A. Poujol-Robert A. et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006; 43: 1118-1124
• 181 Wang QX. Shen L. Qiu DK. et al. Validation of transient elastography (Fibroscan) in assessment of hepatic fibrosis in autoimmune hepatitis. Zhonghua Gan Zang Bing Za Zhi 2011; 19: 782-784
• 182 Corpechot C. Gaouar F. El Naggar A. et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology 2014; 146: 970-979 quiz e915–976
• 183 Colecchia A. Di Biase AR. Scaioli E. et al. Non-invasive methods can predict oesophageal varices in patients with biliary atresia after a Kasai procedure. Dig Liver Dis 2011; 43: 659-663
• 184 Righi S. Fiorini E. De Molo C. et al. ARFI elastography in patients with chronic autoimmune liver diseases: A preliminary study. J Ultrasound 2012; 15: 226-231
• 185 Efe C. Gungoren MS. Ozaslan E. et al. Acoustic Radiation Force Impulse (ARFI) for Fibrosis Staging in Patients with Autoimmune Hepatitis. Hepatogastroenterology 2015; 62: 670-672
• 186 Zhang DK. Chen M. Liu Y. et al. Acoustic radiation force impulse elastography for non-invasive assessment of disease stage in patients with primary biliary cirrhosis: A preliminary study. Clin Radiol 2014; 69: 836-840
• 187 Wang X. Qian L. Jia L. et al. Utility of Shear Wave Elastography for Differentiating Biliary Atresia From Infantile Hepatitis Syndrome. J Ultrasound Med 2016; 35: 1475-1479
• 188 Shi KQ. Fan YC. Pan ZZ. et al. Transient elastography: a meta-analysis of diagnostic accuracy in evaluation of portal hypertension in chronic liver disease. Liver Int 2013; 33: 62-71
• 189 Robic MA. Procopet B. Metivier S. et al. Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: a prospective study. J Hepatol 2011; 55: 1017-1024
• 190 Berzigotti A. Seijo S. Arena U. et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013; 144: 102-111
• 191 Takuma Y. Nouso K. Morimoto Y. et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. Gastroenterology 2013; 144: 92-101 e102
• 192 Augustin S. Millan L. Gonzalez A. et al. Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: a prospective study. J Hepatol 2014; 60: 561-569
• 193 Ding NS. Nguyen T. Iser DM. et al. Liver stiffness plus platelet count can be used to exclude high-risk oesophageal varices. Liver Int 2016; 36: 240-245
• 194 de Franchis R. Baveno VIF. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-752
• 195 Attia D. Schoenemeier B. Rodt T. et al. Evaluation of Liver and Spleen Stiffness with Acoustic Radiation Force Impulse Quantification Elastography for Diagnosing Clinically Significant Portal Hypertension. Ultraschall in Med 2015; 36: 603-610
• 196 Salzl P. Reiberger T. Ferlitsch 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 Med 2014; 35: 528-533
• 197 Takuma Y. Nouso K. Morimoto Y. et al. Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness. Radiology 2016; 279: 609-619
• 198 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: 589-598
• 199 Kim TY. Jeong WK. Sohn JH. et al. Evaluation of portal hypertension by real-time shear wave elastography in cirrhotic patients. Liver Int 2015; 35: 2416-2424
• 200 Jansen C. Bogs C. Verlinden W. et al. Algorithm to rule out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multicentre study. Gut 2016; 65: 1057-1058
• 201 Choi SY. Jeong WK. Kim Y. et al. Shear-Wave Elastography: A Noninvasive Tool for Monitoring Changing Hepatic Venous Pressure Gradients in Patients with Cirrhosis. Radiology 2014; 273: 917-926