Research ArticleNoninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease
Introduction
Nonalcoholic fatty liver disease (NAFLD), a serious public health concern, is increasing with the rise in obesity and is currently the most common form of chronic liver disease in both children and adults [1], [2]. Estimates suggest that approximately 80 million Americans may have NAFLD [3]. NAFLD is a clinicopathologic condition associated with over-accumulation of fat in the liver; it is characterized by simple steatosis on the benign end of the spectrum with progression to nonalcoholic steatohepatitis (NASH), an intermediate stage of the disease, and increased risk for progression to cirrhosis, need for liver transplant and/or hepatocellular carcinoma in a minority of patients with NAFLD [4], [5], [6]. The clinician has limited ability to characterize disease severity by patient history, physical examination, routine laboratory studies, and/or radiological imaging modalities [6]. Liver biopsy remains the only reliable “gold standard” method for distinguishing benign steatosis from NASH and staging the severity of hepatic fibrosis for patients with obesity-related liver disease [7]. However, due to increased cost, possible risk, and health-care resource utilization, an invasive liver biopsy is poorly suited as a diagnostic test for such a prevalent condition. Furthermore, the histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial stratification and staging inaccuracies [8].
Ultrasound is an ideal technology to non-invasively characterize advanced liver diseases. The majority of the liver can be interrogated using a variety of imaging locations (i.e., both inter- and subcostally). Further, ultrasound equipment and scanners have become much more compact, are portable, can be utilized in a variety of clinical settings (inpatient and outpatient, clinical and radiology suites), and can be performed at the bedside as diagnostic tools or for assessment of anatomy at the time of liver biopsy.
The use of ultrasound to characterize liver stiffness has been explored with transient elastography (FibroScan®, EchoSens, Paris, France), which has been shown to represent a promising non invasive tool for staging hepatic fibrosis [9], [18]. While body mass indices (BMI) >28 kg/m2 have been identified as an independent risk factor for failure to obtain a measure of liver elastography [10], more recent clinical studies using the FibroScan® system have appeared in the literature that have demonstrated increasing liver stiffness with advanced fibrosis in patients with NAFLD [11], [12], [13]. Patients with ascites, however, present challenges for systems such as the FibroScan® since shear waves will not propagate through fluids, making shear stiffness reconstructions in these patients impossible with transient elastography; this is not a limitation for the Acoustic Radiation Force Impulse (ARFI) shear wave imaging technique presented herein [14], [15]. Transient tissue deformations of several microns are induced in liver tissue by acoustic radiation force, generating shear waves that can be used to estimate the tissue stiffness, as detailed in [15].
Given NAFLD’s enormous public health burden, there is a great need for the development and optimization of a non-invasive approach to determine the presence or absence of advanced liver disease. We evaluated ARFI shear wave imaging as a potential non-invasive method to assess the hepatic fibrosis stage in patients with biopsy-proven NAFLD.
Section snippets
Study design and population
We performed a retrospective/prospective study of patients with biopsy-proven NAFLD at the Duke University Medical Center. Patients were enrolled from March 2008 to March 2010. Patients who met the following criteria were used for our analysis (n = 172): (1) age 18 or older; (2) available liver histology data; (3) no significant alcohol consumption (<14 drinks/week in men or <7 drinks/week in women on average within the past 2 years); (4) no other coexisting causes of chronic liver disease as
Results
One hundred thirty five of the 172 total subjects had successful shear stiffness reconstruction using the RANSAC algorithm. Table 1 outlines the distribution of study subjects as a function of gender, BMI, and fibrosis stage. Liver stiffness did not vary significantly as a function of imaging location (p = 0.11); therefore, the stiffness values from all imaging locations were pooled together for each study subject. The IQR/mean shear stiffness over all successfully reconstructed patients was 0.19 ±
Discussion
ARFI shear wave imaging was able to successfully reconstruct liver stiffnesses in patients with fibrosis stages ranging from F0 to F4, with the most significant distinction occurring between patients grouped with little-to-moderate fibrosis (F0–2) versus those with advanced fibrosis/cirrhosis (F3–4). These results are consistent with those presented by Wong et al. [12] with the FibroScan®, though Yonega et al. did show more separation between the little-to-moderate fibrosis stages [11]. Both
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Financial support
This work is supported by NIH Grant R01 EB002132. Dr. Abdelmalek is supported by NIH/NIDDK Mentored Career Development Award K23-DK062116.
Acknowledgments
The authors would like to thank Siemens Medical Solutions, USA for their technical support, and Veronica Rotemberg, Miriam Chitty, Samantha Kwan, Melissa Smith, Pamela Anderson, and Nicole Rothfusz for their assistance in the hepatology clinic and with data collection.
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