Haoming Lin

Optimal linear combination of ARFI, transient elastography and APRI for the assessment of fibrosis in chronic hepatitis B

Accurate assessment of liver fibrosis in patients with chronic hepatitis B (CHB) is necessary not only to predict the long‐term clinical course but also to determine an appropriate antiviral therapy scheme. Several noninvasive approaches – serum markers and elastography – have been proposed as alternatives for the histopathological analysis of liver biopsies. The aim of this study was to evaluate two ultrasound elastography methods (ARFI and TE) and one biochemical test (APRI), as well as their optimal linear combination, in the assessment of liver fibrosis in CHB.

Quantitative analysis of liver fibrosis in rats with shearwave dispersion ultrasound vibrometry: Comparison with dynamic mechanical analysis

Ultrasonic elastography, a non-invasive technique for assessing the elasticity properties of tissues, has shown promising results for disease diagnosis. However, biological soft tissues are viscoelastic in nature. Shearwave dispersion ultrasound vibrometry (SDUV) can simultaneously measure the elasticity and viscosity of tissue using shear wave propagation speeds at different frequencies. In this paper, the viscoelasticity of rat livers was measured quantitatively by SDUV for normal (stage F0) and fibrotic livers (stage F2). Meanwhile, an independent validation study was presented in which SDUV results were compared with those derived from dynamic mechanical analysis (DMA), which is the only mechanical test that simultaneously assesses the viscoelastic properties of tissue. Shear wave speeds were measured at frequencies of 100, 200, 300 and 400 Hz with SDUV and the storage moduli and loss moduli were measured at the frequency range of 1-40 Hz with DMA. The Voigt viscoelastic model was used in the two methods. The mean elasticity and viscosity obtained by SDUV ranged from 0.84±0.13 kPa (F0) to 1.85±0.30 kPa (F2) and from 1.12±0.11 Pa s (F0) to 1.70±0.31 Pa s (F2), respectively. The mean elasticity and viscosity derived from DMA ranged from 0.62±0.09 kPa (F0) to 1.70±0.84 kPa (F2) and from 3.38±0.32 Pa s (F0) to 4.63±1.30 Pa s (F2), respectively. Both SDUV and DMA demonstrated that the elasticity of rat livers increased from stage F0 to F2, a finding which was consistent with previous literature. However, the elasticity measurements obtained by SDUV had smaller differences than those obtained by DMA, whereas the viscosities obtained by the two methods were obviously different. We suggest that the difference could be related to factors such as tissue microstructure, the frequency range, sample size and the rheological model employed. For future work we propose some improvements in the comparative tests between SDUV and DMA, such as enlarging the harmonic frequency range of the shear wave to highlight the role of viscosity, finding an appropriate rheological model to improve the accuracy of tissue viscoelasticity estimations.

Measurement of Quantitative Viscoelasticity of Bovine Corneas Based on Lamb Wave Dispersion Properties

The viscoelastic properties of the human cornea can provide valuable information for clinical applications such as the early detection of corneal diseases, better management of corneal surgery and treatment and more accurate measurement of intra-ocular pressure. However, few techniques are capable of quantitatively and non-destructively assessing corneal biomechanics in vivo. The cornea can be regarded as a thin plate in which the vibration induced by an external vibrator propagates as a Lamb wave, the properties of which depend on the thickness and biomechanics of the tissue. In this study, pulses of ultrasound radiation force with a repetition frequency of 100 or 200 Hz were applied to the apex of corneas, and the linear-array transducer of a SonixRP system was used to track the tissue motion in the radial direction. Shear elasticity and viscosity were estimated from the phase velocities of the A0 Lamb waves. To assess the effectiveness of the method, some of the corneas were subjected to collagen cross-linking treatment, and the changes in mechanical properties were validated with a tensile test. The results indicated that the shear modulus was 137 ± 37 kPa and the shear viscosity was 3.01 ± 2.45 mPa · s for the group of untreated corneas and 1145 ± 267 kPa and was 0.16 ± 0.11 mPa · s for the treated group, respectively, implying a significant increase in elasticity and a significant decrease in viscosity after collagen cross-linking treatment. This result is in agreement with the results of the mechanical tensile test and with reports in the literature. This initial investigation illustrated the ability of this ultrasound-based method, which uses the velocity dispersion of low-frequency A0 Lamb waves, to quantitatively assess both the elasticity and viscosity of corneas. Future studies could discover ways to optimize this system and to determine the feasibility of using this method in clinical situations.

Shear Wave Propagation in Soft Tissue and Ultrasound Vibrometry

Studies have found that shear moduli, having the dynamic range of several orders of magnitude for various biological tissues [1], are highly correlated with the pathological statues of human tissue such as livers [2, 3]. The shear moduli can be investigated by measuring the attenuation and velocity of the shear wave propagation in a tissue region. Many efforts have been made to measure shear wave propagations induced by different types of force, which include the motion force of human organs, external applied force [4], and ultrasound radiation force [5].

Ex vivo study of acoustic radiation force impulse imaging elastography for evaluation of rat liver with steatosis

HighlightsThe research by ARFI technology is focused on steatosis without fibrosis.ARFI elastography offers good diagnostic accuracy in evaluating the normal rat liver and rat liver with steatosis.The SWV measurements have no significant difference between the grades of steatosis.The early grade of inflammation activity does not significantly affect the SWV measurements. &NA; Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in developed countries. Accurate, noninvasive tests for diagnosing NAFLD are urgently needed. The goals of this study were to evaluate the utility of acoustic radiation force impulse (ARFI) elastography for determining the severity grade of steatosis in rat livers, and to investigate the changes in various histologic and biochemical characteristics. Steatosis was induced in the livers of 57 rats by gavage feeding of a high fat emulsion; 12 rats received a standard diet only and served as controls. Liver mechanics were measured ex vivo using shear wave velocity (SWV) induced by acoustic radiation force. The measured mean values of liver SWV ranged from 1.33 to 3.85 m/s for different grades of steatosis. The area under the receiver operative characteristic curve (≥S1) was equal to 0.82 (95% CI = 0.69, 0.96) between the steatosis group and the normal group, and the optimal cutoff value was 2.59 with sensitivity of 88% and specificity of 76%. However, there are no significant differences in SWV measurements between the steatosis grades. SWV values did not correlate with the early grade of inflammation. In conclusion, ARFI elastography is a promising method for differentiating normal rat liver from rat liver with steatosis, but it cannot reliably predict the grade of steatosis in rat livers. The early grade of inflammation activity did not significantly affect the SWV measurements.

Analyzing and modeling rheological behavior of liver fibrosis in rats using shear viscoelastic moduli.

The process of liver fibrosis changes the rheological properties of liver tissue. This study characterizes and compares liver fibrosis stages from F0 to F4 in rats in terms of shear viscoelastic moduli. Here two viscoelastic models, the Zener model and Voigt model, were applied to experimental data of rheometer tests and then values of elasticity and viscosity were estimated for each fibrosis stage. The results demonstrate that moderate fibrosis (≤F2) has a good correlation with liver viscoelasticity. The mean Zener elasticity E1 increases from (0.452±0.094) kPa (F0) to (1.311±0.717) kPa (F2), while the mean Voigt elasticity E increases from (0.618±0.089) kPa (F0) to (1.701±0.844) kPa (F2). The mean Zener viscosity increases from (3.499±0.186) Pa·s (F0) to (4.947±1.811) Pa·s (F2) and the mean Voigt viscosity increases from (3.379±0.316) Pa·s (F0) to (4.625±1.296) Pa·s (F2). Compared with viscosity, the elasticity shows smaller variations at stages F1 and F2 no matter what viscoelastic model is used. Therefore, the estimated elasticity is more effective than viscosity for differentiating the fibrosis stages from F0 to F2.概要研究目的肝脏的纤维化进程改变肝脏组织的流变属性。创新要点本文利用剪切黏弹性模量描绘并比较了大鼠肝脏F0 期到F4 期的纤维化过程。研究方法两个黏弹性模型, 即Zener 模型和Voigt 模型用于解释流变力学测试得到的实验数据, 由此得到每个纤维化分期的肝脏弹性和黏性值。重要结论肝脏中度纤维化(≤F2 期)与黏弹性值密切相关。 Zener 模型的弹性均值E1 从F0 期的 (0.452±0.094) kPa 增加到F2 期的(1.311±0.717) kPa, 而Voigt 模型的弹性均值E 从F0 期的 (0.618±0.089) kPa 增加到 F2 期的(1.701±0.844) kPa。 Zener 模型的黏性均值从F0 期的 (3.499±0.186) Pa·s 增加到F2 期的(4.947±1.811) Pa·s, 而Voigt 模型的黏性均值从F0 期的 (3.379±0.316) Pa·s 增加到F2 期的(4.625±1.296) Pa·s。 无论选用哪个黏弹性模型, 在F1 期和 F2 期, 肝脏弹性值的标准差比黏性值的标准差变化要小。 因此, 测得的弹性比黏性更有效地区分肝纤维化F0 期到F2 期。

Development of a Simple Noninvasive Model to Predict Significant Fibrosis in Patients with Chronic Hepatitis B: Combination of Ultrasound Elastography, Serum Biomarkers, and Individual Characteristics

OBJECTIVES: The accurate assessment of liver fibrosis is clinically important in patients with chronic hepatitis B (CHB). Blood tests and elastography are now widely used for the noninvasive diagnosis of liver fibrosis in CHB patients. The aim of this study was to develop a new and more accurate predictive model, which combines elastography data, serum biomarkers, and individual characteristics, to discriminate between CHB patients with and without significant liver fibrosis. METHODS: Two noninvasive methods, specifically, an ultrasound elastography technique termed acoustic radiation force impulse imaging (ARFI) and a blood test, were used to assess a cohort of 345 patients (estimation group, 218 patients; validation group, 127 patients) with CHB. Multivariate logistic regression analysis revealed that ARFI, the aspartate aminotransferase (AST) to platelet ratio, and age were significantly associated with fibrosis. Based on these results, we constructed and validated a model for the diagnosis of significant hepatic fibrosis. RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.921 for the estimation group and 0.929 for the validation group, significantly higher than those for ARFI (0.887, 0.893) and for the AST‐to‐platelet ratio index (APRI; 0.811, 0.859). Using an optimal cutoff of 3.05 in the validation group, all the indices of the proposed model, including accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic odds ratio, were better than those for ARFI or APRI. CONCLUSIONS: We developed a simple noninvasive model that used ultrasound elastography, routine serum biomarkers, and individual characteristics to accurately differentiate significant fibrosis in patients with CHB. Compared with elastography or the biomarker index alone, this model was significantly more accurate and robust.

Ultrasound vibrometry using orthogonal- frequency-based vibration pulses

New vibration pulses are developed for shear wave generation in a tissue region with preferred spectral distributions for ultrasound vibrometry applications. The primary objective of this work is to increase the frequency range of detectable harmonics of the shear wave. The secondary objective is to reduce the required peak intensity of transmitted pulses that induce the vibrations and shear waves. Unlike the periodic binary vibration pulses, the new vibration pulses have multiple pulses in one fundamental period of the vibration. The pulses are generated from an orthogonal-frequency wave composed of several sinusoidal signals, the amplitudes of which increase with frequency to compensate for higher loss at higher frequency in tissues. The new method has been evaluated by studying the shear wave propagation in in vitro chicken and swine liver. The experimental results show that the new vibration pulses significantly increase tissue vibration with a reduced peak ultrasound intensity, compared with the binary vibration pulses.

Improved shear wave motion detection using coded excitation for transient elastography

Transient elastography (TE) is well adapted for use in studying liver elasticity. However, because the shear wave motion signal is extracted from the ultrasound signal, the weak ultrasound signal can significantly deteriorate the shear wave motion tracking process and make it challenging to detect the shear wave motion in a severe noise environment, such as within deep tissues and within obese patients. This paper, therefore, investigated the feasibility of implementing coded excitation in TE for shear wave detection, with the hypothesis that coded ultrasound signals can provide robustness to weak ultrasound signals compared with traditional short pulse. The Barker 7, Barker 13, and short pulse were used for detecting the shear wave in the TE application. Two phantom experiments and one in vitro liver experiment were done to explore the performances of the coded excitation in TE measurement. The results show that both coded pulses outperform the short pulse by providing superior shear wave signal-to-noise ratios (SNR), robust shear wave speed measurement, and higher penetration intensity. In conclusion, this study proved the feasibility of applying coded excitation in shear wave detection for TE application. The proposed method has the potential to facilitate robust shear elasticity measurements of tissue.

Model-dependent and model-independent approaches for evaluating hepatic fibrosis in rat liver using shearwave dispersion ultrasound vibrometry

This study assesses gradations of hepatic fibrosis in rat livers using both model-dependent and model-independent approaches. Liver fibrosis was induced in 37 rats using carbon tetrachloride (CCl4); 6 rats served as the controls. Shear wave velocity as a function of frequency, referred to as velocity dispersion, was measured in vitro by an ultrasound elastography method called shearwave dispersion ultrasound vibrometry (SDUV). For the model-dependent approach, the velocity dispersion data were fit to the Voigt model to solve the viscoelastic modulus. For the model-independent approach, the pattern of the velocity dispersion data was analyzed by linear regression to extract the slope and intercept features. The parameters obtained by both approaches were evaluated separately using a receiver operating characteristic (ROC) curve analysis. The results show that, of all the parameters for differentiating between grade F0-F1 and grade F2-F4 fibrosis, the intercept had the greatest value for the area under the ROC curve. This finding suggests that the model-independent approach may provide an alternative method to the model-dependent approach for staging liver fibrosis.