Liver Fibrosis Assessment in Chronic Liver Diseases Using Elastography: A Comprehensive Review of Vibration-Controlled Transient Elastography and Shear Wave Elastography

Lee, Han Ah; Han Ah Lee

doi:10.18525/cu.2024.9.2.70

Clin Ultrasound > Volume 9(2); 2024 > Article

만성 간질환에서 탄성측정법을 이용한 간섬유화 평가: 순간 탄성 측정법과 횡파 탄성초음파에 대한 검토

Review

Clinical Ultrasound 2024; 9(2): 70-84.

Published online: November 30, 2024

DOI: https://doi.org/10.18525/cu.2024.9.2.70

만성 간질환에서 탄성측정법을 이용한 간섬유화 평가: 순간 탄성 측정법과 횡파 탄성초음파에 대한 검토

이한아

중앙대학교 의과대학 내과학교실

Liver Fibrosis Assessment in Chronic Liver Diseases Using Elastography: A Comprehensive Review of Vibration-Controlled Transient Elastography and Shear Wave Elastography

Han Ah Lee

Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea

Address for Correspondence: Han Ah Lee, M.D., Ph.D. Department of Internal Medicine, Chung-Ang University College of Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea Tel: +82-2-6299-1408, Fax: +82-2-6299-2469 E-mail: amelia86@naver.com

Received November 6, 2024 Revised November 17, 2024 Accepted November 22, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Chronic liver diseases (CLD) are a major global health issue, with liver fibrosis progression and cirrhosis as critical determinants of prognosis and treatment strategy. Historically, liver biopsy has been the gold standard for assessing fibrosis, but limitations such as invasiveness, variability in results, and cost have spurred the development of non-invasive tests. Elastography techniques measure liver stiffness, providing important insights into fibrosis severity across various CLDs, including hepatitis B and C and metabolic dysfunction-associated steatotic liver disease (MASLD). Ultrasound-based elastography techniques include vibration-controlled transient elastography (VCTE), point shear wave elastography, and 2D shear wave elastography. Most studies report high accuracy for diagnosing significant fibrosis and cirrhosis. While VCTE is the most widely used elastography method, each technique has strengths and limitations in different patient populations, affected by factors like alanine aminotransaminase levels, obesity, and presence of hepatic inflammation. Elastography proves valuable informations in treatment decisions for hepatitis B patients in the "gray zone" and helps identify high-risk groups requiring post-hepatitis C eradication surveillance. Recent studies emphasize the potential of elastography-based scores, such as the FibroScan-AST and AGILE scores, in improving diagnostic accuracy for patients with MASLD. However, diagnostic performance may vary by setting, requiring validation in primary care. Emerging precision medicine approaches, integrating genomics and novel biomarkers, promise to further enhance risk stratification in CLD management. Despite substantial advances, broader clinical application of elastography and related biomarkers necessitates further validation, particularly in diverse care settings, to ensure their optimal utility in routine clinical practice.

Keywords: Elastography; Chronic liver disease; Liver fibrosis; Non-invasive test

INTRODUCTION

Chronic liver diseases (CLD) are a significant public health concern, contributing substantially to global morbidity and mortality [1]. The prognosis and treatment strategies for these conditions largely depend on the degree and progression of liver fibrosis, as well as the risk of advancing to cirrhosis. Advanced fibrosis is the most clinically significant marker, while cirrhosis in CLD patients triggers surveillance for hepatocellular carcinoma (HCC) and gastroesophageal varices and serves as a key prognostic factor [2,3].

Since the late 1950s, liver biopsy has been regarded as the gold standard for assessing liver fibrosis severity, however, liver biopsy has several notable limitations [4]. Its accuracy in assessing fibrosis is often questioned due to issues like sampling errors and variability between and within observers, which can result in over- or under-staging [5,6]. Additionally, liver biopsy is a costly procedure that requires medical expertise and a facility equipped with periprocedural monitoring [7]. Importantly, it is an invasive procedure with associated risks, ranging from common, mild complications (such as transient pain in 30% to 50% of cases) to rare but potentially life-threatening ones (including serious hemorrhage in 0.6% of cases and a mortality rate of up to 0.1%) [8]. These limitations, along with the availability of effective antiviral therapies and the global increase in metabolic dysfunction-associated steatotic liver disease (MASLD) cases, have driven the development of non-invasive methods to improve diagnosis and prognosis in CLD.

Non-invasive strategies utilize two distinct but complementary approaches of serum biomarkers and elastography techniques based on ultrasound or magnetic resonance imaging [9]. The introduction of vibration-controlled transient elastography (VCTE) in 2003, using the FibroScan device (Echosens, Paris, France), marked the start of a new era in liver stiffness measurement [10]. Since then, numerous other elastography techniques have emerged, including ultrasound-based methods integrated into ultrasound devices, such as point-shear wave elastography (pSWE) and 2D-shear wave elastography (2D-SWE), as well as more recently, magnetic resonance elastography (MRE) [11].

In this review, we explore the role of ultrasound-based elastography in CLD, evaluating its accuracy and clinical implication in assessing the severity of liver fibrosis.

TYPES OF ELASTOGRAPHY

Elastography techniques assess liver stiffness by measuring the speed of an induced shear wave as an indicator of hepatic fibrosis [12]. These methods include ultrasound-based VCTE (FibroScan), pSWE (also called acoustic radiation force impulse), 2D-SWE, and MRI-based MRE.

Vibration-Controlled Transient Elastography

The most commonly used and well-validated technique, VCTE, uses pulse-echo ultrasound to measure the velocity of low-frequency vibrations transmitted into the liver [10,13]. The speed at which these ultrasound waves propagate and return through the transducer is recorded. This speed is then converted into LS values based on Hooke’s law, expressed in kilopascals (kPa). Since tissue stiffness is directly related to the square of the shear wave’s propagation speed, faster wave speeds indicate a stiffer liver, which correlates with more advanced liver fibrosis. LS values on VCTE range from 1.5 to 75 kPa, with a normal upper limit of approximately 5 to 5.5 kPa [14].

The liver stiffness measurement (LSM) obtained through VCTE correlates with the stage of hepatic fibrosis and has been validated across various liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), primary biliary cholangitis, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) [9]. However, the effectiveness of VCTE can depend on the operator and may be affected by factors that elevate liver stiffness or complicate accurate measurement, such as congestive heart failure, cholestasis, acute hepatitis, recent alcohol or food intake, and obesity [15]. To aid in interpreting results, reliability criteria for VCTE have been established (IQR/M <0.30, or IQR/M >0.30 if the median reading is below 7.1 kPa) [15].

The advantages of VCTE include being painless and noninvasive, allowing for quick and simple assessments in an outpatient setting, and providing immediate results. The method also has high reproducibility, directly measures LS, and assesses a liver parenchyma volume over 100 times greater than that in a traditional liver biopsy [16]. Additionally, VCTE is user-friendly, requiring minimal training for clinicians, and offers excellent diagnostic accuracy for detecting liver fibrosis in chronic liver diseases of various etiologies [17,18].

On the downside, obtaining VCTE results may be challenging in patients with ascites or a narrow intercostal space [10]. Ascites can obstruct the elastic waves from reaching the liver parenchyma, and a narrow intercostal space complicates proper probe positioning. Results may also be less reliable in individuals with a high body mass index (BMI) (>28 kg/m²), though studies report a lower risk of unreliable readings in Asian populations (1.1–3.5%) than in Western populations (4.3–7.0%), possibly due to lower BMI levels among Asians [19].

Shear Wave Elastography

SWE evaluates liver fibrosis severity by measuring the speed of shear waves and capturing imaging data during an abdominal ultrasound exam [20]. This technique includes both pSWE and 2D-SWE. pSWE calculates the speed of shear waves created by focal tissue displacement through acoustic radiation force impulse (ARFI) technology [14,20]. A shear wave is produced from the probe by emitting a longitudinal wave at a frequency of 2.67 MHz within the region of interest (ROI). Ultrasound detection pulses from multiple channels then measure the shear wave speed at a specific location, providing an elasticity measurement in meters per second (m/s) within a range of 0.5– 4.4 m/s [14]. The test is repeated approximately 10 times, and the median elastic modulus value, expressed in m/s or kPa, is recorded [21,22].

2D-SWE uses ARFI and produces a focused wave through a B-mode ultrasound transducer. Unlike pSWE, which focuses on a single area and generates shear waves at one frequency, 2D-SWE continuously sends sound waves aimed at multiple focal zones in the direction of the ultrasound beam. This process produces a high-frequency (60–600 Hz) shear wave that is concentrated into a cone shape. Because of these differences, 2D-SWE has demonstrated greater diagnostic accuracy than pSWE [22-24]. The progress of the shear wave is captured in real time via ultrafast imaging, which can achieve frame rates of up to 20,000 per second. The quantitative elasticity value is displayed in m/s or kPa on the ultrasound monitor. Additionally, 2D-SWE allows for a larger SWETM box range than pSWE and can assess elasticity using one or more adjustable circular ROIs [14,20]. Results are acquired after repeating the measurement 5 to 10 times, with the median of all valid readings being recorded [22].

SWE is an objective and reproducible test, offering the advantage of obtaining quantitative measurements without applying manual pressure and directly assessing tissue elasticity. It allows for real-time elastography with quantified values indicating liver fibrosis severity, and unlike VCTE, it can be conducted while visualizing the liver’s anatomical structure. However, SWE values differ by disease across various studies, and optimal cutoff values for staging liver fibrosis have yet to be established [25]. Additionally, the range of shear wave elasticity values for each fibrosis stage is relatively broad, and the difference between cutoff values for successive stages is minimal [26]. For SWE to be a reliable criterion for staging, the interquartile range to median ratio (IQR/M) should be less than 30% for values reported in kPa and less than 15% for those in m/s [27]. As with VCTE, results may be overestimated in cases of intrahepatic inflammation, cholestasis, liver congestion due to right heart failure, amyloidosis, or after food intake, so careful interpretation is necessary [27,28].

Etiology-Specific Fibrosis Cutoffs in Elastography

In liver diseases, the cutoff values for fibrosis stages determined by elastography vary depending on the etiology. Chronic hepatitis B (CHB) generally has the lowest cutoff values, followed by chronic hepatitis C (CHC), MASLD, and alcohol-related liver disease [29]. Results in meta-analyses of ultrasound-based elastography for the assessment of liver fibrosis by each etiology are recorded in Table 1. The reason for this difference lies in the pathophysiological characteristics of each liver disease. HBV-induced fibrosis often presents with minimal structural stiffness in the early stages, resulting in lower elastography values for significant fibrosis. HCV tends to cause more inflammation and fibrotic progression, requiring slightly higher cutoffs. MASLD and ALD, on the other hand, are associated with a combination of fibrosis and fatty infiltration, leading to even higher baseline stiffness values, which increase the thresholds for identifying fibrosis stages through elastography. The advantages and disadvantages of elastography for each etiology are summarized in Figure 1.

CHRONIC HEPATITIS B

Assessing liver fibrosis in patients with CHB is essential for determining the appropriate timing of treatment and predicting prognosis. Liver biopsy provides insight into the degree of inflammation and fibrosis, which can guide treatment decisions, however, because liver biopsy is invasive, alternative non-invasive tests are used as substitutes [30].

Vibration-Controlled Transient Elastography

The effectiveness of VCTE in evaluating liver fibrosis in CHB patients has been extensively validated through liver histology. For significant fibrosis diagnosis, VCTE’s area under the curve (AUC), cutoff values, sensitivity, and specificity range between 0.66–0.97, 5.2–8.8 kPa, 59–93%, and 38–92%, respectively, while for cirrhosis, these parameters are 0.85–0.98, 9.4–14.1 kPa, 52–100%, and 83–99% [18,31-34]. Diagnostic accuracy for cirrhosis is generally higher than for significant fibrosis in CHB patients.

One meta-analysis, including 4,540 CHB patients, showed an AUC of 0.84, with cutoff values between 6.0–8.8 kPa for significant fibrosis and 8.0–14.1 kPa for cirrhosis [34]. Another meta-analysis, including eight studies (2,003 patients) showed that sensitivity and specificity for diagnosis of significant liver fibrosis were 0.78 and 0.72 respectively [35]. The HSROC for the diagnosis of significant liver fibrosis was 0.81. However, it remains unclear whether patients with conditions like acute liver disease, congestive hepatopathy, infiltrative liver disease, or obstructive cholestasis were excluded from these meta-analyses. Additionally, the reliability of the VCTE results (fasting status and IQR/M ≤0.3) and the probe type used for liver stiffness (LS) measurement were not consistently reported.

A meta-analysis comparing VCTE performance for significant fibrosis and cirrhosis in European and Asian CHB patients found notable ethnic differences [36]. For diagnosing significant fibrosis, AUC, sensitivity, and specificity were 0.80, 73%, and 66% in Europe, compared to 0.87, 73%, and 82% in Asia, showing higher diagnostic accuracy in Asia. For cirrhosis, studies in Europe reported an AUC of 0.91 with 67% sensitivity and 92% specificity, while Asian studies showed a sensitivity of 81% and specificity of 86% with the same AUC. These differences may stem from regional variations or disparities in BMI and obesity rates, suggesting a need for further investigation.

Diagnostic performance across studies varies with patient characteristics and cutoff values, though most studies report a high AUC (>0.80). An algorithm in Europe using cutoffs of 9.4 and 13.1 kPa for cirrhosis diagnosis improved sensitivity and specificity to over 90% [33]. A meta-analysis showed the optimal cutoff value of VCTE for diagnosis of significant liver fibrosis was 7.7 kPa with a sensitivity of 0.64 and specificity of 0.83 [35]. Another meta-analysis of 27 studies involving 4,386 patients found that for diagnosing significant fibrosis, the AUC was 0.81, with a cutoff value of 7.2 kPa, sensitivity of 81%, and specificity of 82%. For diagnosing cirrhosis, the AUC was 0.93, with a cutoff value of 12.2 kPa, sensitivity of 86%, and specificity of 88% [37].

VCTE results may be influenced by intrahepatic inflammation in CHB patients, leading to potential overestimation of fibrosis [38]. Elevated ALT levels can independently raise LS values, so results should be carefully interpreted [9]. Additionally, antiviral therapy (AVT) may lower LS values due to reduced intrahepatic inflammation, meaning cutoff values established in untreated patients may not be applicable for those on AVT. VCTE can be difficult to perform in patients with right hepatectomy, ascites, severe obesity, or during pregnancy, and results may be affected by recent food intake, liver masses, congestion, cholestasis, or infiltrative liver disease [31].

Point Shear Wave Elastography

For diagnosing significant fibrosis, pSWE’s AUC, cutoff values, sensitivity, and specificity ranged from 0.76 to 0.86, 1.23–1.59 m/s, 59–90%, and 63–88%, respectively. For cirrhosis diagnosis, the AUC, cutoff values, sensitivity, and specificity were 0.72–0.97, 1.75–1.98 m/s, 67–85%, and 73–92%, respectively [39-44]. A meta-analysis of eight studies involving 518 CHB patients found AUCs of 0.79 for significant fibrosis and 0.90 for cirrhosis, with cutoff values of 1.34 and 1.80 m/s, respectively [40]. Among 126 CHB patients who underwent liver resection, pSWE yielded AUCs of 0.86 for significant fibrosis and 0.95 for cirrhosis, surpassing AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), which had AUCs of 0.75–0.77 and 0.75–0.78, respectively [44].

In a study with 180 CHB patients, pSWE and VCTE showed comparable diagnostic accuracy, with AUCs of 0.76 and 0.83 for pSWE, and 0.81 and 0.80 for VCTE in diagnosing significant fibrosis and cirrhosis, respectively. Like VCTE, pSWE’s cutoff values for fibrosis and cirrhosis were higher in patients with elevated ALT levels [41]. In a Chinese study of 81 CHB patients undergoing liver biopsy, pSWE and VCTE had AUCs of 0.76 and 0.72 for significant fibrosis and 0.75 and 0.87 for cirrhosis, indicating similar diagnostic capabilities between the two methods [44].

2D-Shear Wave Elastography

Numerous studies have demonstrated the high diagnostic accuracy of 2D-SWE in evaluating liver fibrosis in CHB patients [45-54]. Using 2D-SWE, the AUC, cutoff values, sensitivity, and specificity for diagnosing significant fibrosis ranged from 0.88 to 0.97, 6.9–8.2 kPa, 77–94%, and 74–92%, respectively. For diagnosing cirrhosis, these values were 0.83–0.98, 8.0–21.4 kPa, 80–97%, and 73–95%, respectively.

A meta-analysis of 13 studies involving 400 CHB patients found that the AUC, cutoff, sensitivity, and specificity were 0.91, 7.1 kPa, 88%, and 74% for significant fibrosis, and 0.91, 11.5 kPa, 80%, and 93% for cirrhosis [55]. Another meta-analysis of 11 studies including 2,623 patients reported an AUC of 0.92 with a 7.9 kPa cutoff for significant fibrosis [56]. Studies excluding patients on AVT showed a lower average cutoff of 7.2 kPa for significant fibrosis compared to 8.9 kPa in studies with patients receiving AVT, indicating the need for AVT-specific cutoffs [53].

Another meta-analysis found that 2D-SWE outperformed VCTE by 11.2% for significant fibrosis and 6.5% for cirrhosis [55]. However, a Greek study involving 106 CHB patients showed that VCTE had a slightly higher success rate in measurements for obese patients compared to 2D-SWE (92% vs. 86%) [57]. ALT levels also influence SWE results. In a study of 515 CHB patients, using two ALT-based cutoffs enhanced 2D-SWE’s diagnostic performance [58]. Cutoffs of 5.4 and 9.0 kPa were applied for ALT levels ≤2 times the upper limit of normal (ULN), while 7.1 and 11.2 kPa were used for ALT levels >2 times the ULN for diagnosing significant fibrosis. For cirrhosis, cutoff values were 8.1 and 12.3 kPa for ALT levels ≤ 2 times the ULN, and 11.9 and 24.7 kPa for ALT levels >2 times the ULN [56].

Treatment Decisions Using Elastography in CHB

CHB patients with ALT levels consistently one to two times the ULN are typically classified in the gray zone. Approximately 30% of CHB patients fall into a “gray zone,” where serum HBV DNA and ALT levels do not clearly correspond to any specific phase in the virus's natural progression [59,60]. Studies have shown that CHB patients in the gray zone have a higher HCC risk compared to those in the immune-tolerant and immune-inactive phases. However, AVT is often withheld in these cases because ALT levels, a marker of liver injury, are not significantly elevated [61].

A recent multinational study indicates that AVT in gray zone CHB patients may reduce HCC risk by up to 70% compared to untreated patients, with a notable reduction in cumulative HCC incidence within five years after AVT initiation [62]. Consequently, strategies are being developed to identify high-risk gray zone patients who may benefit from AVT. AVT can be started if moderate or greater inflammation or significant fibrosis is confirmed [30]. Patients aged 30–40 years or older with ALT at the ULN, or those with normal ALT but persistently high HBV DNA levels, also face elevated HCC risk and should be evaluated for liver fibrosis, with AVT considered as needed [30]. Liver fibrosis can be assessed using non-invasive tests like VCTE and MRE, and AVT may be initiated if significant fibrosis is detected [63]. Considering the results of previously reported two meta-analyses, if VCTE results are above 7.2–7.7 kPa, there is a possibility of significant fibrosis, and antiviral therapy could be actively considered [35,37].

CHRONIC HEPATITIS C

Assessing fibrotic burden in CHC patients is essential, as it significantly impacts prognosis, including risks of HCC, liver-related complications, and mortality [64]. Imaging techniques such as VCTE and SWE have been used to diagnose liver fibrosis in CHC patients.

Vibration-Controlled Transient Elastography

The effectiveness of VCTE for assessing liver fibrosis in CHC patients has been supported by numerous studies. Sensitivity for diagnosing significant fibrosis ranges from 48% to 96%, with specificity between 32% and 93%, depending on study-specific characteristics and cutoff values. For cirrhosis diagnosis, sensitivity varies from 65% to 100%, while specificity is between 85% and 96% [32,38,65-70].

The largest study to date, involving 1,289 CHC patients across three cohorts, reported an AUC of 0.76 for significant fibrosis with an 8.8 kPa cutoff, 48% sensitivity, and 93% specificity. For cirrhosis, the AUC was 0.90, with a 14.5 kPa cutoff, 65% sensitivity, and 95% specificity, showing comparable results [66]. However, in a multicenter study conducted in Korea with 349 CHC patients, the AUC for diagnosing significant fibrosis using VCTE was 0.82, with a cutoff of 6.8 kPa, sensitivity of 67.0%, and specificity of 86.4% [70]. The cutoff values for significant or advanced fibrosis in this study were slightly lower than in previous research, as it only included patients with ALT levels below five times the upper limit of normal to adjust for the higher LS values seen with elevated ALT. The AUC for cirrhosis diagnosis was 0.91, with a cutoff of 14.5 kPa, sensitivity of 81.8%, and specificity of 89.0%, aligning with results from studies in Western populations.

A meta-analysis of 37 studies on CHC patients found that VCTE cutoff values for significant fibrosis ranged from 5.2 to 10.1 kPa, with a sensitivity of 79% and specificity of 83%, while for cirrhosis, cutoffs ranged from 9.2 to 17.3 kPa, with 89% sensitivity and 91% specificity [71]. Another meta-analysis, presented by the American Gastroenterological Association and including 17 studies with 5,812 CHC patients, reported a VCTE cutoff of 12.5 kPa, with a sensitivity of 86% and specificity of 90% [72]. For groups with a cirrhosis prevalence below 5%, a cutoff of 12.5 kPa yielded a 0.7% false-negative rate and an 8.6% false-positive rate. In high-risk groups with a 30% cirrhosis prevalence, the false-negative rate was 4.2% and the false-positive rate was 6.3%.

Research on VCTE’s diagnostic accuracy for liver fibrosis in CHC patients after antiviral therapy and achieving sustained virologic response (SVR) is limited. In a study involving patients with an initial LS value of 10 kPa or higher who achieved SVR after AVT, LS values decreased post-SVR, yet over half showed histological evidence of cirrhosis three years later [73]. The AUC of VCTE for diagnosing cirrhosis post-SVR was 0.75, with pre-treatment LS values being the strongest predictor of cirrhosis. Serum markers, such as APRI and FIB-4, provided similar findings.

While VCTE generally shows high diagnostic accuracy with AUC values above 0.8 for fibrosis in CHC studies, limitations remain. Previous studies often lacked clear exclusion criteria for coexisting conditions that could affect VCTE results and included patients with substantial intrahepatic inflammation, potentially leading to overestimation of test values [38,74].

Point Shear Wave Elastography

Several studies have evaluated pSWE for diagnosing liver fibrosis in CHC patients. In a study of 61 CHC patients, the AUC of pSWE for significant fibrosis was 0.79 with a cutoff of 1.33 m/s. For advanced fibrosis, the AUC was 0.83 with a 1.43 m/s cutoff, and for cirrhosis, the AUC was 0.84 with a 1.55 m/s cutoff [75]. In another study involving 101 CHC patients in Korea, pSWE showed an AUC of 0.85 for significant fibrosis with a 1.335 m/s cutoff, yielding 84% sensitivity and 76% specificity. For advanced fibrosis, the AUC was 0.84 with a 1.645 m/s cutoff, providing 80% sensitivity and 76% specificity. For cirrhosis, the AUC was 0.83 with a 1.665 m/s cutoff, along with 85% sensitivity and 69% specificity [76]. A meta-analysis of three studies identified pSWE cutoff values of 1.21–1.34 m/s for significant fibrosis, with 79% sensitivity and 89% specificity. For cirrhosis, based on four studies, the cutoff ranged from 1.6 to 2.3 m/s, with sensitivity of 84% and specificity of 77% [71].

A multicenter prospective study in Europe with 241 CHC patients compared the diagnostic accuracy of pSWE and VCTE [77]. The AUCs for pSWE and VCTE were 0.81 and 0.85 for diagnosing significant fibrosis, 0.88 and 0.92 for advanced fibrosis, and 0.89 and 0.94 for cirrhosis, demonstrating similar diagnostic effectiveness. However, VCTE had a higher measurement failure rate at 10%, compared to 5.3% for pSWE.

2D-Shear Wave Elastography

In a study of 211 CHC patients, 2D-SWE showed an AUC of 0.83 for diagnosing significant fibrosis with a cutoff of 6.16 kPa [78]. For advanced fibrosis, the AUC was 0.95 with a cutoff of 6.8 kPa, providing 97% sensitivity and 90% specificity. Diagnostic accuracy decreased in patients with a BMI over 30 kg/m². For another group, the AUC for significant fibrosis was 0.92 with a cutoff of 1.56 m/s, yielding 85% sensitivity and 86% specificity. For advanced fibrosis, the AUC was 0.94 with a cutoff of 1.72 m/s, achieving 89% sensitivity and 84% specificity. For cirrhosis, the AUC was 0.949 with a cutoff of 1.93 m/s, with 91.4% sensitivity and 90.8% specificity [78].

In a study assessing non-invasive tests among 79 CHC patients, the AUCs for diagnosing significant fibrosis were: 2D-SWE at 0.75, VCTE at 0.95, FIB-4 at 0.81, and APRI at 0.77, with 2D-SWE having the lowest AUC [76]. For cirrhosis diagnosis, the AUCs were 0.83 for 2D-SWE, 0.99 for VCTE, 0.81 for FIB-4, and 0.77 for APRI, with 2D-SWE showing lower diagnostic performance than VCTE.

The diagnostic accuracy of SWE in CHC patients has not been as extensively validated as other non-invasive tests, and caution is advised when interpreting results due to the variety of equipment used. Although SWE may achieve a higher measurement success rate, including in obese patients, there is a risk of overestimation in cases of severe intrahepatic inflammation. Comparative studies with other non-invasive tests (NITs) are limited, and findings have sometimes been inconsistent. Nonetheless, most studies report high diagnostic accuracy for SWE, comparable to VCTE, indicating its potential usefulness in assessing liver fibrosis in CHC patients.

Identifying High-Risk Groups Requiring Post-HCV Eradication Surveillance Using Elastography

Recommendations for HCC surveillance differ across guidelines for HCV patients in the post-SVR period who have advanced fibrosis (METAVIR F3) or cirrhosis (METAVIR F4) [79,80]. In addition to the limited research on the accuracy of VCTE for diagnosing liver fibrosis in CHC patients post-SVR with antiviral therapy, the potential for antiviral therapy to improve liver health and reduce the risk of HCV-related HCC highlights the importance of tracking changes in non-invasive measurements during the post-SVR period as a crucial component of HCC risk assessment [81,82].

A large meta-analysis of 24 studies with 2,934 HCV patients reported a significant decrease in LSM using VCTE after SVR [83]. Without paired liver biopsies, it is unclear whether this LSM reduction reflects hepatic inflammation resolution or actual fibrosis regression. A recent meta-analysis including 27 studies (169,911 patients) showed that pre-treatment VCTE values of >9.2–13 kPa showed pooled AUCs of 0.79 for predicting HCC development after SVR [84]. While post-SVR VCTE values of >8.4–11 kPa retained strong predictive performance, though slightly lower, with pooled AUCs of 0.77. The optimal cut-off for HCC development after SVR was identified as 12.6 kPa for pre-treatment VCTE and 11.2 kPa for VCTE measured post-SVR.

METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE

The prognosis of MASLD depends significantly on histological features, particularly liver fibrosis, which is the primary predictor of long-term outcomes, including risks of HCC and liver-related mortality [85]. In clinical practice, NITs such as VCTE, SWE, and MRE are commonly used to assess liver steatosis and fibrosis; however, in MASLD patients with obesity or elevated ALT, increased liver steatosis can decrease the diagnostic accuracy of VCTE, requiring cautious interpretation of results [86-88].

Vibration-Controlled Transient Elastography

Many studies have evaluated the diagnostic utility of VCTE in MASLD patients, showing high sensitivity and specificity in meta-analyses [88-93]. VCTE demonstrates an AUC of 0.65–0.98 for advanced fibrosis with cutoff values between 6.6–10.4 kPa, and an AUC of 0.94–0.97 for cirrhosis with cutoffs from 10.3–17 kPa, indicating strong diagnostic value in both cases. This meta-analysis included data from 63 studies with 19,199 patients. However, accuracy decreases in patients with abdominal obesity, and around 5–20% cannot complete the test with a standard M probe [94,95]. Using an XL probe in these cases significantly reduces failure rates [96].

In a study of severely obese individuals undergoing bariatric surgery (mean BMI 42.3 kg/m²), VCTE showed an AUC of 0.85 and a cutoff of 7.6 kPa for advanced fibrosis, with the XL probe used in 96% of patients due to a skin-to-liver capsule distance of ≥2.5 cm [97]. A multicenter study in Hong Kong and France demonstrated similar median LS values and diagnostic performance with both M and XL probes for patients with BMI above or below 30 kg/m² [98]. Conversely, a study in Japan suggested different cutoffs for advanced fibrosis when using XL versus M probes (8.2 kPa for XL and 10.8 kPa for M), indicating further validation is needed [99].

In obese patients (BMI ≥30 kg/m²) or those with ALT ≥100 IU/L, VCTE accuracy decreased, with higher controlled attenuation parameter (CAP) scores linked to an increased false positive rate [88,100,101]. Researchers recommend combining NAFLD fibrosis score or liver biopsy for fibrosis assessment in patients with CAP scores over 300 dB/m and VCTE values between 10.1–12.5 kPa. VCTE results require cautious interpretation as they can be influenced by fasting status, abdominal obesity, cholestasis, elevated aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) levels, and liver steatosis [102].

A recent international, multicenter cohort study introduced the FibroScan-AST (FAST) score, integrating VCTE results, CAP score, and AST to assess patients with metabolic dysfunction-associated steatohepatitis and significant fibrosis [103]. With a cutoff of 0.35, the FAST score achieved a PPV of 83% and an NPV of 85%, and demonstrated a c-index of 0.85 in external validation, confirming high diagnostic accuracy.

Another international study across seven centers proposed the AGILE score, which leverages VCTE and outperformed FIB-4 and VCTE alone in diagnosing advanced fibrosis and cirrhosis [104]. AGILE 3+, which incorporates age, sex, AST/ALT ratio, platelet count, type 2 diabetes mellitus status, and VCTE, had a lower cutoff of 0.451 and upper cutoff of 0.679, achieving an AUC of 0.76 and a PPV of 0.72 for advanced fibrosis. For cirrhosis, AGILE 4, with cutoffs of 0.251 and 0.565, showed an AUC of 0.93 and a PPV of 0.73.

Point Shear Wave Elastography

When used to detect significant fibrosis in MASLD patients, pSWE achieves an AUC of ≥0.8 [105,106]. pSWE is particularly effective for diagnosing advanced fibrosis, with reported sensitivity and specificity of 100% and 91%, respectively [107]. In a single-center study in Korea, pSWE demonstrated an AUC of 0.861 and a cutoff of 1.395 for advanced fibrosis; however, in patients with liver steatosis, diagnostic accuracy decreased as steatosis severity increased, with AUCs of 0.911, 0.847, and 0.686 for mild, moderate, and severe steatosis, respectively [26]. Several meta-analyses have shown pSWE’s diagnostic performance to be comparable to that of VCTE [108,109].

2D-Shear Wave Elastography

In a prospective study, 2D-SWE achieved an AUC of 0.920 for diagnosing advanced fibrosis, comparable to VCTE (AUC 0.915) [110]. However, a recent meta-analysis of 82 studies involving 47,609 MASLD patients reported an AUC of 0.72 for 2D-SWE in diagnosing advanced fibrosis, slightly lower than pSWE (AUC 0.89) and VCTE (AUC 0.92), indicating the need for further investigation [109]. Interpretation of SWE results should be approached with caution, as they can be influenced by factors such as fasting, abdominal obesity, cholestasis, AST, ALT, and liver steatosis. Notably, 2D-SWE may be more user-friendly for obese patients, as its measurement location can be adjusted in real-time [111].

Referral Pathways and Strategies for Managing MASLD

Despite MASLD’s high prevalence in primary care, it is largely unrecognized outside of Hepatology and Gastroenterology, with many physicians overlooking it [112]. Consequently, fewer than 10% of NAFLD patients are referred to specialists, missing opportunities for early intervention [113].

There is extensive evidence on the diagnostic accuracy of non-invasive tests for detecting advanced fibrosis in MASLD patients. However, these methods are limited in general population application [114]. Test performance is heavily influenced by the prevalence of the condition being assessed, meaning that tests developed and validated in referral centers should only be applied in primary care if specifically validated for that context. Evaluations for MASLD and advanced fibrosis are recommended for individuals with (A) T2D, (B) abdominal obesity plus one or more additional metabolic risk factors, or (C) persistently elevated liver enzymes.

A multi-step process is recommended to identify individuals at risk for advanced fibrosis. First, the FIB-4 test should be administered. If the FIB-4 score is above 1.3 (or above 2.0 for individuals over 65), the likelihood of advanced fibrosis increases. However, due to a high false positive rate, this may lead to excessive additional testing. Therefore, in individuals with FIB-4 scores between 1.3 and 2.67, liver elastography could be performed as a second step to confirm fibrosis stage [114].

If VCTE fails or further assessment of liver fibrosis is required, MRE and liver biopsy are possible options [9,115]. Patients at moderate or high risk should be referred to a hepatologist for precise evaluation and appropriate management of liver fibrosis. The hepatologist will perform a thorough review of the patient’s history and liver fibrosis risk, with additional non-invasive tests such as MRE, ELF, and the AGILE score, available for further fibrosis assessment. In cases where cirrhosis is diagnosed, careful monitoring and follow-up are essential due to the significantly elevated risk of liver-related complications and HCC. A liver biopsy may be conducted in patients with inconclusive NIT results or when the level of fibrosis is challenging to determine, with follow-up and treatment tailored according to fibrosis progression.

CONCLUSION

Over the past two decades, significant progress has been made in the non-invasive assessment and risk stratification of CLDs. These advances have largely been driven by high-throughput analytic platforms and data science, leading to a precision medicine approach, which tailors treatment to individual genetic and physiological profiles, potentially improving outcomes in CLDs. Although MRE demonstrates the highest diagnostic performance, particularly excelling in distinguishing fibrosis stage 2, US-based elastography offers notable advantages, including shorter examination time, lower cost, and greater accessibility. Considering the strengths and limitations of each method, the selection of an appropriate diagnostic tool or a sequential testing strategy may provide a more accurate assessment of fibrosis stages and prognosis in patients with chronic liver disease. Further validation and integration of elastography-based methods, along with novel biomarkers, are needed before these tools can be widely implemented in clinical practice.

ACKNOWLEDGMENTS

None.

FUND

None.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Figure 1.

Characteristics and applications of ultrasound-based elastography for assessment of liver fibrosis in various chronic liver diseases. HBV, hepatitis B virus; HCV, hepatitis C virus; MASLD, metabolic dysfunction-associated steatotic liver disease; ALT, alanine aminotransaminase; HCC, hepatocellular carcinoma; SVR, sustained virologic response; VCTE, vibration-controlled transient elastography; ROI, region of interest; pSWE, point-shear wave elastography; 2D-SWE, two-dimensional shear wave elastography.

Table 1.

Meta-analyses of ultrasound-based elastography for assessment of liver fibrosis

Noninvasive test	Significant fibrosis (≥F2)				Advanced fibrosis (≥F3)				Cirrhosis (F4)
Noninvasive test	No. of studies (patients)	AUC (95% CI)	Cutoff value	Sensitivity%/specificity%	No. of studies (patients)	AUC (95% CI)	Cutoff value	Sensitivity%/specificity%	No. of studies (patients)	AUC (95% CI)	Cutoff value	Sensitivity%/specificity%
Chronic hepatitis B
VCTE	10 (1,625)	0.859 (0.857–0.860)	7.9 kPa	74.3/78.3	4 (960)	0.887 (0.886–0.887)	8.8	74.0/63.8	13 (2,051)	0.929 (0.928–0.929)	11.7	84.6/81.5
	19	0.88 (0.85–0.81)	7.2 kPa	81.0/82.0	19	0.91 (0.88–0.93)	9.1	82.0/87.0	24	0.93 (0.91–0.95)	12.2	86.0/88.0
	35 (6,202)	0.86 (0.83–0.89)	7.3 kPa	78.0/81.0	-	-	-	-	41 (7,205)	0.92 (0.90–0.94)	12.4	84.0/87.0
	23 (3,879)	0.84 (0.81–0.87)	6.0–8.8 kPa	76.0/79.0	-	-	-	-	26 (4,441)	0.90 (0.88–0.93)	8.0–14.1	84.0/84.0
pSWE	8 (518)	0.79 (0.63–0.96)	1.34	79.0/85.0	8 (518)	0.83 (0.70–0.96)	1.55	86.0/86.0	8 (518)	0.90 (0.79–1.00)	1.80	92.0/86.0
2D-SWE	4 (400)	0.91	7.1	87.6/73.6	4 (400)	0.93	8.1	94.9/73.1	4 (400)	0.96	11.5	79.9/93.3
	-	0.92 (0.89–0.94)	7.9	88.0/83.0	-	-	-	-	-	-	-	-
	13 (1,716)	0.89 (0.86–0.92)	7.6	80.9/79.3	8 (1,020)	0.95 (0.91–0.95)	9.1	89.1/84.7	12 (782)	0.94 (0.92–0.96)	10.9	87.3/86.1
Chronic hepatitis C
VCTE	37	-	5.2–10.1 kPa	79.0/83.0	19	-	8.6–15.4 kPa	88.0/90.0	36	-	9.2–17.3 kPa	89.0/91.0
pSWE	3	-	1.21–1.34 m/s	79.0/89.0	4	-	1.49-2.11 m/s	85.0/89.0	4	-	1.6–2.3 m/s	84.0/77.0
Metabolic dysfunction-associated steatotic liver disease
VCTE	37 (2,763)	0.83 (0.80–0.87)	3.8–10.2 kPa	80.0/73.0	44 (4,219)	0.85 (0.83–0.87)	6.8–12.9 kPa	80.0/77.0	22 (337)	0.89 (0.84–0.93)	6.9–19.4 kPa	76.0/88.0
pSWE	9 (805)	0.86 (0.78–0.90)	1.18–1.81 m/s	69.0/85.0	11 (1,209)	0.89 (0.83–0.95)	1.34–4.21 m/s	80.0/86.0	8 (759)	0.90 (0.82–0.95)	1.36–2.54 m/s	76.0/88.0
2D-SWE	4 (488)	0.75 (0.58–0.87)	8.3–11.6 kPa	71.0/67.0	4 (488)	0.72 (0.60–0.84)	9.3–13.1 kPa	72.0/72.0	3 (372)	0.88 (0.81–0.91)	14.4–15.7 kPa	78.0/84.0

VCTE, vibration-controlled transient elastography; pSWE, point shear wave elastography; 2D-SWE, two-dimensional shear wave elastography; AUC, area under the curve; CI, confidence interval; kPa, kilopascal.

REFERENCES

1. Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol 2023;79:516–537.

2. Korean Liver Cancer Association (KLCA); National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022;28:583–705.

3. Lee HA, Kim SU, Seo YS, et al. Prediction of the varices needing treatment with non-invasive tests in patients with compensated advanced chronic liver disease. Liver Int 2019;39:1071–1079.

4. Menghini G. One-second needle biopsy of the liver. Gastroenterology 1958;35:190–199.

5. Davison BA, Harrison SA, Cotter G, et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials. J Hepatol 2020;73:1322–1332.

6. Brunt EM, Clouston AD, Goodman Z, et al. Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD. J Hepatol 2022;76:1030–1041.

7. Tapper EB, Lok ASF. Use of liver imaging and biopsy in clinical practice. N Engl J Med 2017;377:2296–2297.

8. Castéra L, Nègre I, Samii K, Buffet C. Patient-administered nitrous oxide/oxygen inhalation provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroenterol 2001;96:1553–1557.

9. Kim MN, Han JW, An J, et al. KASL clinical practice guidelines for noninvasive tests to assess liver fibrosis in chronic liver disease. Clin Mol Hepatol 2024;30(Suppl):S5–S105.

10. Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705–1713.

11. Friedrich-Rust M, Poynard T, Castera L. Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol 2016;13:402–411.

12. Anstee QM, Castera L, Loomba R. Impact of non-invasive biomarkers on hepatology practice: Past, present and future. J Hepatol 2022;76:1362–1378.

13. Foucher J, Chanteloup E, Vergniol J, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55:403–408.

14. Shiina T, Nightingale KR, Palmeri ML, et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 1: basic principles and terminology. Ultrasound Med Biol 2015;41:1126–1147.

15. Boursier J, Zarski JP, de Ledinghen V, et al. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology 2013;57:1182–1191.

16. Kim SU, Kim JK, Park JY, et al. Variability in liver stiffness values from different intercostal spaces. Liver Int 2009;29:760–766.

17. Boursier J, Konate A, Guilluy M, et al. Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography. Eur J Gastroenterol Hepatol 2008;20:693–701.

18. Marcellin P, Ziol M, Bedossa P, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int 2009;29:242–247.

19. Kim SU, Han KH, Ahn SH. Transient elastography in chronic hepatitis B: an Asian perspective. World J Gastroenterol 2010;16:5173–5180.

20. Tang A, Cloutier G, Szeverenyi NM, Sirlin CB. Ultrasound elastography and MR elastography for assessing liver fibrosis: Part 1, principles and techniques. AJR Am J Roentgenol 2015;205:22–32.

21. Sigrist RMS, Liau J, Kaffas AE, Chammas MC, Willmann JK. Ultrasound elastography: Review of techniques and clinical applications. Theranostics 2017;7:1303–1329.

22. Barr RG, Wilson SR, Rubens D, Garcia-Tsao G, Ferraioli G. Update to the society of radiologists in ultrasound liver elastography consensus statement. Radiology 2020;296:263–274.

23. Barr RG. Shear wave liver elastography. Abdom Radiol (NY) 2018;43:800–807.

24. Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016;63:1817–1827.

25. European Association for the Study of the Liver; Clinical Practice Guideline Panel; EASL Governing Board representative. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021;75:659–689.

26. Kennedy P, Wagner M, Castéra L, et al. Quantitative elastography methods in liver disease: Current evidence and future directions. Radiology 2018;286:738–763.

27. Fang C, Jaffer OS, Yusuf GT, et al. Reducing the number of measurements in liver point shear-wave elastography: Factors that influence the number and reliability of measurements in assessment of liver fibrosis in clinical practice. Radiology 2018;287:844–852.

28. Ferraioli G, Maiocchi L, Lissandrin R, Tinelli C, De Silvestri A, Filice C. 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.

29. Dhyani M, Anvari A, Samir AE. Ultrasound elastography: liver. Abdom Imaging 2015;40:698–708.

30. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022;28:276–331.

31. Oliveri F, Coco B, Ciccorossi P, et al. Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008;14:6154–6162.

32. Degos F, Perez P, Roche B, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010;53:1013–1021.

33. Viganò M, Paggi S, Lampertico P, et al. Dual cut-off transient elastography to assess liver fibrosis in chronic hepatitis B: a cohort study with internal validation. Aliment Pharmacol Ther 2011;34:353–362.

34. Mingkai L, Sizhe W, Xiaoying W, Ying L, Wu B. Diagnostic performance of elastography on liver fibrosis in antiviral treatment-naive chronic hepatitis B patients: a meta-analysis. Gastroenterol Rep (Oxf ) 2022;10:goac005.

35. Kim MN, An J, Kim EH, et al. Vibration-controlled transient elastography for significant fibrosis in treatment-naïve chronic hepatitis B patients: A systematic review and meta-analysis. Clin Mol Hepatol 2024;30(Suppl):S106–S116.

36. 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.

37. 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.

38. 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.

39. 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:e212–219.

40. Friedrich-Rust M, Buggisch P, de Knegt RJ, et al. Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B. J Viral Hepat 2013;20:240–247.

41. Zhang D, Chen M, Wang R, et al. Comparison of acoustic radiation force impulse imaging and transient elastography for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B. Ultrasound Med Biol 2015;41:7–14.

42. Dong DR, Hao MN, Li C, et al. Acoustic radiation force impulse elastography, FibroScan®, 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.

43. Park MS, Kim SW, Yoon KT, et al. Factors influencing the diagnostic accuracy of acoustic radiation force impulse elastography in patients with chronic hepatitis B. Gut Liver 2016;10:275–282.

44. Li J, Yu J, Peng XY, et al. Acoustic radiation force impulse (ARFI) elastography and serological markers in assessment of liver fibrosis and free portal pressure in patients with hepatitis B. Med Sci Monit 2017;23:3585–3592.

45. 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.

46. 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.

47. 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.

48. Wu T, Wang P, Zhang T, et al. Comparison of two-dimensional shear wave elastography and real-time tissue elastography for assessing liver fibrosis in chronic hepatitis B. Dig Dis 2016;34:640–649.

49. Zhuang Y, Ding H, Zhang Y, Sun H, Xu C, Wang W. Two-dimensional shear-wave elastography performance in the noninvasive evaluation of liver fibrosis in patients with chronic hepatitis B: Comparison with serum fibrosis indexes. Radiology 2017;283:873–882.

50. Zeng J, Zheng J, Huang Z, et al. Comparison of 2-D shear wave elastography and transient elastography for assessing liver fibrosis in chronic hepatitis B. Ultrasound Med Biol 2017;43:1563–1570.

51. Xie X, Feng Y, Lyu Z, et al. Liver stiffness as measured by two-dimensional shear wave elastography overestimates the stage of fibrosis in patients with chronic hepatitis B and hepatic steatosis. Clin Res Hepatol Gastroenterol 2021;45:101421.

52. Song L, Zhao L, Deng J, et al. Staging liver fibrosis in patients with chronic hepatitis B using two-dimensional shear wave elastography based on histopathological findings: a prospective multicenter study. Quant Imaging Med Surg 2023;13:2376–2387.

53. Wei H, Jiang HY, Li M, Zhang T, Song B. Two-dimensional shear wave elastography for significant liver fibrosis in patients with chronic hepatitis B: A systematic review and meta-analysis. Eur J Radiol 2020;124:108839.

54. Dong B, Lyu G, Chen Y, et al. Comparison of two-dimensional shear wave elastography, magnetic resonance elastography, and three serum markers for diagnosing fibrosis in patients with chronic hepatitis B: a meta-analysis. Expert Rev Gastroenterol Hepatol 2021;15:1077–1089.

55. Herrmann E, de Lédinghen V, Cassinotto C, et al. Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis. Hepatology 2018;67:260–272.

56. Zeng J, Zheng J, Jin JY, et al. Shear wave elastography for liver fibrosis in chronic hepatitis B: Adapting the cut-offs to alanine aminotransferase levels improves accuracy. Eur Radiol 2019;29:857–865.

57. Karagiannakis DS, Voulgaris T, Angelopoulos T, et al. Comparative utility of transient and 2D shear wave elastography for the assessment of liver fibrosis in clinical practice. J Digit Imaging 2021;34:1342–1348.

58. Dietrich CF, Bamber J, Berzigotti A, et al. EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, update 2017 (short version). Ultraschall Med 2017;38:377–394.

59. Di Bisceglie AM, Lombardero M, Teckman J, et al. Determination of hepatitis B phenotype using biochemical and serological markers. J Viral Hepat 2017;24:320–329.

60. Yao K, Liu J, Wang J, et al. Distribution and clinical characteristics of patients with chronic hepatitis B virus infection in the grey zone. J Viral Hepat 2021;28:1025–1033.

61. Teng W, Chang TT, Yang HI, et al. Risk scores to predict HCC and the benefits of antiviral therapy for CHB patients in gray zone of treatment guidelines. Hepatol Int 2021;15:1421–1430.

62. Huang DQ, Tran A, Yeh ML, et al. Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase. Hepatology 2023;78:1558–1568.

63. Liu K, Wong VWS, Liang LY, Lui GCY, Chan HLY, Wong GLH. Clinical outcomes and management of patients with chronic hepatitis B and liver stiffness measurement in the grey zone. Liver Int 2019;39:494–502.

64. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835–847.

65. 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.

66. Poynard T, de Ledinghen V, Zarski JP, et al. Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: a step toward the truth in the absence of a gold standard. J Hepatol 2012;56:541–548.

67. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48–54.

68. Ganne-Carrié N, Ziol M, de Ledinghen V, et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 2006;44:1511–1517.

69. Castéra L, Le Bail B, Roudot-Thoraval F, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009;50:59–68.

70. Seo YS, Kim MY, Kim SU, et al. Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study. Liver Int 2015;35:2246–2255.

71. Crossan C, Tsochatzis EA, Longworth L, et al. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess 2015;19:1–409. v-vi.

72. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American gastroenterological association institute technical review on the role of elastography in chronic liver diseases. Gastroenterology 2017;152:1544–1577.

73. Broquetas T, Herruzo-Pino P, Mariño Z, et al. Elastography is unable to exclude cirrhosis after sustained virological response in HCV-infected patients with advanced chronic liver disease. Liver Int 2021;41:2733–2746.

74. Verveer C, Zondervan PE, ten Kate FJ, Hansen BE, Janssen HL, de Knegt RJ. Evaluation of transient elastography for fibrosis assessment compared with large biopsies in chronic hepatitis B and C. Liver Int 2012;32:622–628.

75. 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.

76. 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.

77. 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 Med 2015;36:239–247.

78. 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.

79. European Association for the Study of the Liver; Clinical Practice Guidelines Panel; EASL Governing Board representative. EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol 2020;73:1170–1218.

80. Bhattacharya D, Aronsohn A, Price J, Lo Re V. Hepatitis C guidance 2023 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Clin Infect Dis 2023;ciad319.

81. Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142:105–114.

82. 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.

83. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and kinetics of decrease in liver stiffness after antiviral therapy in patients with chronic hepatitis C: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018;16:27–38.e4.

84. Lee HA, Kim MN, Lee HA, et al. Non-invasive prediction of post-sustained virological response hepatocellular carcinoma in hepatitis C virus: A systematic review and meta-analysis. Clin Mol Hepatol 2024;30(Suppl):S172–S185.

85. Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547–1554.

86. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–750.

87. Joo SK, Kim W, Kim D, et al. Steatosis severity affects the diagnostic performances of noninvasive fibrosis tests in nonalcoholic fatty liver disease. Liver Int 2018;38:331–341.

88. Petta S, Wai-Sun Wong V, Bugianesi E, et al. Impact of obesity and alanine aminotransferase levels on the diagnostic accuracy for advanced liver fibrosis of noninvasive tools in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2019;114:916–928.

89. 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.

90. Petta S, Di Marco V, Cammà C, Butera G, Cabibi D, Craxì A. Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index. Aliment Pharmacol Ther 2011;33:1350–1360.

91. 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.

92. Park CC, Nguyen P, Hernandez C, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterology 2017;152:598–607.e2.

93. Lee DH, Sung SU, Lee YK, et al. A sequential approach using the age-adjusted fibrosis-4 index and vibration-controlled transient elastography to detect advanced fibrosis in Korean patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2022;55:994–1007.

94. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617–649.

95. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–835.

96. Vuppalanchi R, Siddiqui MS, Van Natta ML, et al. Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. Hepatology 2018;67:134–144.

97. 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.

98. Wong VW, Irles M, Wong GL, et al. Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease. Gut 2019;68:2057–2064.

99. Oeda S, Takahashi H, Imajo K, et al. Accuracy of liver stiffness measurement and controlled attenuation parameter using FibroScan® M/XL probes to diagnose liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease: a multicenter prospective study. J Gastroenterol 2020;55:428–440.

100. 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.

101. Petta S, Wong VW, Cammà C, et al. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values. Hepatology 2017;65:1145–1155.

102. Chen J, Yin M, Talwalkar JA, et al. Diagnostic performance of MR elastography and vibration-controlled transient elastography in the detection of hepatic fibrosis in patients with severe to morbid obesity. Radiology 2017;283:418–428.

103. Newsome PN, Sasso M, Deeks JJ, et al. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol 2020;5:362–373.

104. Sanyal AJ, Foucquier J, Younossi ZM, et al. Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores. J Hepatol 2023;78:247–259.

105. Karlas T, Dietrich A, Peter V, et al. Evaluation of transient elastography, acoustic radiation force impulse imaging (ARFI), and enhanced liver function (ELF) score for detection of fibrosis in morbidly obese patients. PLoS One 2015;10:e0141649.

106. Liu H, Fu J, Hong R, Liu L, Li F. 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.

107. Yoneda M, Suzuki K, Kato S, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010;256:640–647.

108. Bota S, Herkner H, Sporea I, et al. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int 2013;33:1138–1147.

109. Selvaraj EA, Mózes FE, Jayaswal ANA, et al. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis. J Hepatol 2021;75:770–785.

110. Imajo K, Honda Y, Kobayashi T, et al. Direct comparison of US and MR elastography for staging liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterol Hepatol 2022;20:908–917.e11.

111. Chimoriya R, Piya MK, Simmons D, Ahlenstiel G, Ho V. The use of two-dimensional shear wave elastography in people with obesity for the assessment of liver fibrosis in non-alcoholic fatty liver disease. J Clin Med 2020;10:95.

112. Younossi ZM, Ong JP, Takahashi H, et al. A global survey of physicians knowledge about nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2022;20:e1456–e1468.

113. Blais P, Husain N, Kramer JR, Kowalkowski M, El-Serag H, Kanwal F. Nonalcoholic fatty liver disease is underrecognized in the primary care setting. Am J Gastroenterol 2015;110:10–14.

114. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492–542.

115. Yu JH, Lee HA, Kim SU. Noninvasive imaging biomarkers for liver fibrosis in nonalcoholic fatty liver disease: current and future. Clin Mol Hepatol 2023;29(Suppl):S136–S149.