Search

Nonalcoholic fatty liver disease (NAFLD) affects 30% of adults in the United States and is characterized by accumulation of excess triglycerides in the liver (Younossi et al. 2016). NAFLD is also a common problem worldwide, affecting an estimated 1 billion or more people (Loomba et al, 2018). NAFLD can present as simple hepatic steatosis (i.e., nonalcoholic fatty liver (NAFL)), or as nonalcoholic steatohepatitis (NASH); the more advanced subtype, where inflammation, fibrosis, and histologic evidence of hepatocyte injury [e.g., ballooning] can be present. NASH, especially in those who have developed stage 2 or 3 fibrosis, can progress to cirrhosis, end-stage liver disease, liver transplantation, hepatocellular carcinoma, and death (Tong et al, 2022). The identification of patients with NASH and who are at risk for progression to cirrhosis and clinically meaningful adverse outcomes, and the development of effective therapies for these patients are public health priorities. NAFL is asymptomatic, and NASH is asymptomatic until advanced disease is present; these conditions cannot be readily diagnosed, or distinguished from each other clinically, or by routine laboratory testing. Diagnosis and staging of NASH therefore currently rely on liver biopsy with histologic assessment. However, liver biopsy is invasive and painful, and it carries a non-zero risk of catastrophic complication, including death. Further, histologic evaluation of liver biopsy is limited by moderate accuracy, sampling variability due to the small amount of material gathered for examination relative to the size of, and histologic diversity within the liver, and interpretation variability. Although biopsy is being used as the reference standard for diagnosis and staging of NASH in drug development clinical trials, and clinically, it has imperfect accuracy and precision. There is widely-recognized need to aid, improve, or augment liver biopsy acquisition and interpretation, or to develop non-invasive biomarkers to replace liver biopsy, or both. Ultrasound shear wave elastography (SWE) is an imaging based method to assess liver stiffness, a known surrogate marker for liver fibrosis. This imaging technology has emerged recently, but is now widely available clinically. However, there is a critical lack of consensus on diagnostic thresholds which vary widely based on hardware, context of use, and fibrosis level. The primary goal of this review is to synthesize the existing literature on ultrasound shear wave elastography and provide optimal thresholds for the diagnosis of clinically significant liver fibrosis (stage ≥ F2) and at-risk NASH via meta-analysis. SWE is a subset of ultrasound elastography imaging techniques, of which there are four. Strain elastography is a semi-quantitative elastographic technique that generates a relative tissue stiffness map. As this is non-quantitative, it will not be considered for this review. Vibration controlled transient elastography (VCTE), also known as Fibroscan, uses a vibrating probe tip to generate shear waves and ultrasound to measure tissue stiffness. This device does not generate traditional B-mode ultrasound images, is primarily used in gastroenterology clinics, and will not be included in this review. 2D-SWE and point-SWE are the two SWE techniques; they utilize an acoustic radiation force impulse (ARFI), a focused ultrasound pulse, to generate shear waves and high resolution B-mode imaging to estimate liver stiffness. This technology is deployed within radiology imaging centers and is often performed in conjunction with diagnostic ultrasound imaging. The test output is an estimate of liver stiffness reported in kPa (representing Young’s modulus) or m/s (representing shear wave speed). These values are interconvertible algebraically. Determining the diagnostic threshold for these two SWE techniques will be the focus of this review.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and prevalence of NAFLD is increasing owing to upward trends of obesity and diabetes (24042449). Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD with a higher risk of progression to complications related to cirrhosis, is currently the second most common indication for liver transplantation in the United States, and is expected to become the leading cause in the near future (24768810, 25461851, 25920090). Despite the large societal burden of NASH, there is no safe, effective medication approved by the United States Food and Drug Administration (FDA) (27646933). Most clinical trials for NASH require as an eligibility criterion the presence of ‘at-risk NASH’, defined as diagnosed NASH, NAFLD activity score (NAS) ≥ 4 and significant fibrosis (F≥2). The rationale is that these patients are at substantial risk for progression to complications of cirrhosis, and so might benefit from participating in NASH drug development clinical trials. By comparison, patients without NASH, with NAS ≤ 3, or with F

Elastography has emerged as a preferred non-invasive imaging technique for the clinical assessment of liver fibrosis. Elastography methods provide liver stiffness measurement (LSM) as a surrogate quantitative biomarker for fibrosis burden in chronic liver disease (CLD). Elastography can be performed either with ultrasound or MRI. Currently available ultrasound-based methods include strain elastography, two-dimensional shear wave elastography (2D-SWE), point shear wave elastography (pSWE), and vibration-controlled transient elastography (VCTE). MR Elastography (MRE) is widely available as two-dimensional gradient echo MRE (2D-GRE-MRE) technique. US-based methods provide estimated Young's modulus (eYM) and MRE provides magnitude of the complex shear modulus. MRE and ultrasound methods have proven to be accurate methods for detection of advanced liver fibrosis and cirrhosis. Other clinical applications of elastography include liver decompensation prediction, and differentiation of non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). In this review, we briefly describe the different elastography methods, discuss current clinical applications, and provide an overview of advances in the field of liver elastography.

Tissue stiffness has long been known to be a biomarker of tissue pathology. Ultrasound elastography measures tissue mechanical properties by monitoring the response of tissue to acoustic energy. Different elastographic techniques have been applied to many different tissues and diseases. Depending on the pathology, patient-based factors, and ultrasound operator-based factors, these techniques vary in accuracy and reliability. In this review, we discuss the physical principles of ultrasound elastography, discuss differences between different ultrasound elastographic techniques, and review the advantages and disadvantages of these techniques in clinical practice.

In this study, we evaluated the diagnostic accuracy of shear wave elastography (SWE) for differentiating high-risk non-alcoholic steatohepatitis (hrNASH) from non-alcoholic fatty liver and low-risk non-alcoholic steatohepatitis (NASH). Patients with non-alcoholic fatty liver disease scheduled for liver biopsy underwent pre-biopsy SWE. Ten SWE measurements were obtained. Biopsy samples were reviewed using the NASH Clinical Research Network Scoring System and patients with hrNASH were identified. Receiver operating characteristic curves for SWE-based hrNASH diagnosis were charted. One hundred sixteen adult patients underwent liver biopsy at our institution for the evaluation of non-alcoholic fatty liver disease. The area under the receiver operating characteristic curve of SWE for hrNASH diagnosis was 0.73 (95% confidence interval: 0.61-0.84, p < 0.001). The Youden index-based optimal stiffness cutoff value for hrNASH diagnosis was calculated as 8.4 kPa (1.67 m/s), with a sensitivity of 77% and specificity of 66%. SWE may be useful for the detection of NASH patients at risk of long-term liver-specific morbidity and mortality.