Background & Aims Liver biopsy analysis is the standard method used to diagnose nonalcoholic fatty liver disease (NAFLD). Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis, but is expensive. Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity, specificity, and quantitative accuracy, and results vary among operators. A new quantitative ultrasound (QUS) technique can identify steatosis in animal models. We assessed the accuracy of QUS in the diagnosis and quantification hepatic steatosis, comparing findings with those from MRI proton density fat fraction (MRI-PDFF) analysis as a reference. Methods We performed a prospective, cross-sectional analysis of a cohort of adults (n=204) with NAFLD (MRI-PDFF≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California, San Diego, from February 2012 through March 2014. QUS parameters and backscatter coefficient (BSC) values were calculated. Patients were randomly assigned to training (n=102; mean age, 51±17 years; mean body mass index, 31±7 kg/m2) and validation (n=102; mean age, 49±17 years; body mass index, 30±6 kg/m2) groups; 69% of patients in each group had NAFLD. Results BSC (range 0.00005–0.25 1/cm-sr) correlated with MRI-PDFF (Spearman’s ρ=0.80; P<.0001). In the training group, the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 (95% confidence interval, 0.95–1.00; P<.0001). The optimal BSC cutoff value identified patients with NAFLD in the training and validation groups with 93% and 87% sensitivity, 97% and 91% specificity, 86% and 76% negative predictive values, and 99% and 95% positive predictive values, respectively. Conclusions QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis, based on a cross-sectional analysis that used MRI-PDFF as the reference. With further validation, QUS could be an inexpensive, widely available method to screen the general or at-risk population for NAFLD.

OBJECTIVE The purpose of this study is to explore the diagnostic performance of two investigational quantitative ultrasound (QUS) parameters, attenuation coefficient and backscatter coefficient, in comparison with conventional ultrasound (CUS) and MRI-estimated proton density fat fraction (PDFF) for predicting histology-confirmed steatosis grade in adults with nonalcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS In this prospectively designed pilot study, 61 adults with histology-confirmed NAFLD were enrolled from September 2012 to February 2014. Subjects underwent QUS, CUS, and MRI examinations within 100 days of clinical-care liver biopsy. QUS parameters (attenuation coefficient and backscatter coefficient) were estimated using a reference phantom technique by two analysts independently. Three-point ordinal CUS scores intended to predict steatosis grade (1, 2, or 3) were generated independently by two radiologists on the basis of QUS features. PDFF was estimated using an advanced chemical shift–based MRI technique. Using histologic examination as the reference standard, ROC analysis was performed. Optimal attenuation coefficient, backscatter coefficient, and PDFF cutoff thresholds were identified, and the accuracy of attenuation coefficient, backscatter coefficient, PDFF, and CUS to predict steatosis grade was determined. Interobserver agreement for attenuation coefficient, backscatter coefficient, and CUS was analyzed. RESULTS CUS had 51.7% grading accuracy. The raw and cross-validated steatosis grading accuracies were 61.7% and 55.0%, respectively, for attenuation coefficient, 68.3% and 68.3% for backscatter coefficient, and 76.7% and 71.3% for MRI-estimated PDFF. Interobserver agreements were 53.3% for CUS (κ = 0.61), 90.0% for attenuation coefficient (κ = 0.87), and 71.7% for backscatter coefficient (κ = 0.82) (p < 0.0001 for all). CONCLUSION Preliminary observations suggest that QUS parameters may be more accurate and provide higher interobserver agreement than CUS for predicting hepatic steatosis grade in patients with NAFLD.

N onalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, affecting approximately 25% of the human population (1). NAFLD covers a spectrum of liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis. Hepatic steatosis, characterized by the accumulation of fat droplets within hepatocytes, can progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma (1,2). Early detection and treatment may halt or reverse NAFLD progression (2). Liver biopsy remains the reference standard for diagnosing NALFD and grading hepatic steatosis. However, biopsy is costly, invasive, and inappropriate for screening.There is a critical need to develop noninvasive imaging methods to assess hepatic steatosis. Several modalities have been investigated (3-8), among which MRI and conventional (qualitative) US have the advantage of involving no ionizing radiation. Confounder-corrected chemical shiftencoded MRI can measure the proton density fat fraction (PDFF), a leading method for noninvasive quantification of hepatic steatosis (4,5). However, chemical shift-encoded MRI is not routinely accessible. Conventional US is widely

Ultrasonic backscattering coefficient (BSC) has been used extensively to characterize tissue. In most cases, sparse scatterer concentrations are assumed. However, many types of tissues have dense scattering media. This study addresses the problem of dense media scattering by taking into account the correlation among scatterers using the structure functions. The effect of scatterer polydispersity on the structure functions is investigated. Structure function models based on polydisperse scatterers are theoretically developed and experimentally evaluated against the structure functions obtained from cell pellet biophantoms. The biophantoms were constructed by placing live cells of known concentration in coagulation media to form a clot. The BSCs of the biophantoms were estimated using single-element transducers over the frequency range from 11 to 105 MHz. Experimental structure functions were obtained by comparing the BSCs of two cell concentrations. The structure functions predicted by the models agreed with the experimental structure functions. Fitting the models yielded cell radius estimates that were consistent with direct light microscope measures. The results demonstrate the role of scatterer position correlation on dense media scattering, and the significance of scatterer polydispersity on structure functions. This work may lead to more accurate modeling of ultrasonic scattering in dense medium for improved tissue characterization.

N onalcoholic fatty liver disease (NAFLD) affects approximately 25% of the human population (1,2) and may soon overtake hepatitis C as the leading cause of liver transplantation (3). The earliest and characteristic histologic feature of NAFLD is hepatic steatosis, defined as the accumulation of fat droplets within hepatocytes. Steatosis can lead to nonalcoholic steatohepatitis, a more rapidly progressive variant of NAFLD. Nonalcoholic steatohepatitis occurs in 20% of adults with NAFLD, and can contribute to development of fibrosis, cirrhosis, and even hepatocellular carcinoma (1,2). Liver biopsy is the current reference standard for NAFLD diagnosis (4). Proton density fat fraction (PDFF) measured at confounder-corrected chemical shift-encoded MRI is an accurate, repeatable, and reproducible noninvasive method for hepatic steatosis quantification (5-7). However, chemical shift-encoded MRI is not routinely available.There is a critical need to develop noninvasive, widely available, accurate, and cost-effective methods to assess steatosis. US is a promising modality for this purpose, but conventional US is limited by its qualitative nature, system and operator dependency, and modest accuracy (4). Various methods have been investigated to extract quantitative information from US to improve steatosis assessment (8-16), each with its own strengths and weaknesses. For example, the hepatorenal index is accurate for steatosis assessment ( 8), but it depends on the right kidney being normal and disease-free. The right kidney is not always visible on US images. Controlled attenuation parameter is

The purpose of this study is to evaluate the repeatability and reproducibility (R&R) of quantitative ultrasound (QUS) estimates, specifically attenuation coefficient (AC) and backscattering coefficient (BSC), using the same Siemens 3000 clinical ultrasound scanner. Additionally, the purpose of this work is to detail the measurement and analysis methodology. Repeatability is closeness of agreement between measures obtained with the same method under same conditions (same sonographer and same transducer) and reproducibility is closeness of agreement between measures obtained with the same method under different conditions (different sonographers and/or different transducers). Calibrated phantoms were scanned by two sonographers using two transducers in each session for multiple sessions over a period of four months. The phantom scans occurred as part of a clinical QUS liver study in human research participants spanning a spectrum of obesity and liver disease severity. The scanner was adjusted in each participant to obtain the highest quality liver B-mode images prior to acquiring data from the phantoms for which no scanner adjustments were made. The R&R were analyzed and estimated using the unweighted sums of squares ANOVA approach by applying two random effect models. The measurement variance caused by repeatability and reproducibility is small (AC: 2.4–3.2×10−4 [dB/cm-MHz]2; 10log10BSC: 0.23–0.27 dB2). The reproducibility variance is statistically significantly lower than the repeatability variance. The total R&R was not influenced by phantom properties over a wide range representing those found in liver in vivo.

A cell pellet biophantom technique is introduced, and applied to the ultrasonic backscatter coefficient (BSC) estimate using Chinese hamster ovary (CHO) cells. Also introduced is a concentric sphere scattering model because of its geometrical similarities to cells with a nucleus. BSC comparisons were made between the concentric sphere model and other well-understood models for mathematical verification purposes. BSC estimates from CHO cell pellet biophantoms of known number density were performed with 40 and 80 MHz focused transducers (overall bandwidth: 26-105 MHz). These biophantoms were histologically processed and then evaluated for cell viability. Cell pellet BSC estimates were in agreement with the concentric sphere model. Fitting the model to the BSC data yielded quantitative values for the outer sphere and inner sphere. The radius of the cell model was 6.8 ± 0.7 μm; the impedance of the cytoplasm model was 1.63 ± 0.03 Mrayl and the impedance of the nuclear model was 1.55 ± 0.09 Mrayl. The concentric sphere model appears as a new tool for providing quantitative information on cell structures and will tend to have a fundamental role in the classification of biological tissues.

Hepatic AC and BSC measures using a reference phantom technique on a clinical scanner are repeatable and reproducible between transducers in adults with known or suspected NAFLD.