Assessing Doppler-Derived Pressure Gradients and Liver Echogenicity to Predict Liver Disease

Liver disease causes an estimated 36,000 deaths in the United States each year. Currently, to detect liver disease, an invasive biopsy is required. Other, less invasive diagnostic alternatives are needed. The purpose of this study was to assess the efficacy of a modified form of sonographic screening, including portal, hepatic, and splenic venous pressure, hepatic venous waveform analysis, portal vein diameter, and echogenicity of liver parenchyma in predicting liver disease. The study was based on conversion of a velocity measurement to a pressure gradient, allowing a fluid comparison between known catheterization venous pressures and sonographic Doppler-derived pressure gradients. This study was a secondary data analysis of a data set from 546 patients who received abdominal sonograms at a medical facility in the western United States between March 2010 and December 2010. The dependent variable was liver disease and the independent variables were ECHOGRADE, hepatic venous waveform (HVW), splenic vein pressure gradient (SVPG), modified portal vein pressure gradient (MPVPG), and hepatic vein pressure gradient (HVPG). Logistic regression was used to analyze the data. ECHOGRADE, HVW, and MPVPG in males were found to be statistically significant in detecting liver disease, supporting the theoretical framework and thus documenting a novel use of Doppler for the detection of liver disease. The social change significance of these results is to provide clinicians with an alternative, noninvasive method of diagnosing early liver disease before it progresses into chronic liver disease. With earlier detection, severe adverse health outcomes leading to irreversible liver cirrhosis may be avoided

Advances in liver US, CT, and MRI: moving toward the future

Over the past two decades, the epidemiology of chronic liver disease has changed with an increase in the prevalence of nonalcoholic fatty liver disease in parallel to the advent of curative treatments for hepatitis C. Recent developments provided new tools for diagnosis and monitoring of liver diseases based on ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), as applied for assessing steatosis, fibrosis, and focal lesions. This narrative review aims to discuss the emerging approaches for qualitative and quantitative liver imaging, focusing on those expected to become adopted in clinical practice in the next 5 to 10 years. While radiomics is an emerging tool for many of these applications, dedicated techniques have been investigated for US (controlled attenuation parameter, backscatter coefficient, elastography methods such as point shear wave elastography [pSWE] and transient elastography [TE], novel Doppler techniques, and three-dimensional contrast-enhanced ultrasound [3D-CEUS]), CT (dual-energy, spectral photon counting, extracellular volume fraction, perfusion, and surface nodularity), and MRI (proton density fat fraction [PDFF], elastography [MRE], contrast enhancement index, relative enhancement, T1 mapping on the hepatobiliary phase, perfusion). Concurrently, the advent of abbreviated MRI protocols will help fulfill an increasing number of examination requests in an era of healthcare resource constraints

Liver Biopsy

Liver biopsy is recommended as the gold standard method to determine diagnosis, fibrosis staging, prognosis and therapeutic indications in patients with chronic liver disease. However, liver biopsy is an invasive procedure with a risk of complications which can be serious. This book provides the management of the complications in liver biopsy. Additionally, this book provides also the references for the new technology of liver biopsy including the non-invasive elastography, imaging methods and blood panels which could be the alternatives to liver biopsy. The non-invasive methods, especially the elastography, which is the new procedure in hot topics, which were frequently reported in these years. In this book, the professionals of elastography show the mechanism, availability and how to use this technology in a clinical field of elastography. The comprehension of elastography could be a great help for better dealing and for understanding of liver biopsy

Ultrasound Elastography

Elastography, the science of creating noninvasive images of mechanical characteristics of tissues, has been rapidly evolving in recent years. The advantage of this technique resides in the ability to rapidly detect and quantify the changes in the stiffness of soft tissues resulting from specific pathological or physiological processes. Ultrasound elastography is nowadays applied especially on the liver and breast, but the technique has been increasingly used for other tissues including the thyroid, lymph nodes, spleen, pancreas, gastrointestinal tract, kidney, prostate, and the musculoskeletal and vascular systems. This book presents some of the applications of strain and shear-wave ultrasound elastography in hepatic, pancreatic, breast, and musculoskeletal conditions

Non-invasive diagnosis of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has become one of the top concerns for the practising hepato-gastroenterologist due to the obesity epidemic and its potential to progress to an advanced liver disease that significantly impacts on overall and liver-related mortality. Due to the rapidly advancing epidemics of obesity and diabetes, a large segment of the population is at risk for NAFLD. Particularly worrisome is the emergence of NAFLD or non-alcoholic steatohepatitis (NASH) with a significant fibrotic disease in developing countries, even in patients of normal or underweight. A critical issue in patients with NAFLD is the differentiation of NASH from simple steatosis (SS). It is then of particular importance to identify NASH patients as they are at greatest risk of developing cardiovascular diseases and complications such as cirrhosis, liver failure or hepatocellular carcinoma. There is a need, in NAFLD management, to develop non-invasive methods to detect NASH and to predict advanced fibrosis stages. Therefore, we evaluated the following items: (i) A tool-based on optical analysis of liver magnetic resonance images as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance protocols using 1.5T General Electric or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardized and validated using the area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95%CI: 0.73-0.93), and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95%CI: 0.77-0.94). These findings were independent of the magnetic resonance system used. We conclude that the optical analysis of magnetic resonance images has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI). (ii) Genetic and epigenetic biomarkers, such as human patatin-like phospholipase domain containing 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2) and fibroblast growth factor 21 (FGF21) variants as well as a panel of most abundant liver microRNAs. After univariate and multivariate analysis, we confirmed that GG genotype of PNPLA3 exerted a clear role in NASH development, and we identified the impact of a novel risk variant located in FGF21 gene in significant fibrosis stages. Besides, we found overexpression of FGF21 levels in both liver and serum, directly related to NASH condition. Finally, two microRNAs (miR-200b-3p and miR-224-5p) were screened and validated in human liver tissue and plasma of biopsy proven NAFLD patients, and were found raised in NASH, conferring them potential as non-invasive biomarkers.Premio Extraordinario de Doctorado U

Ultrasound shear wave imaging for diagnosis of nonalcoholic fatty liver disease

Pour le diagnostic et la stratification de la fibrose hépatique, la rigidité du foie est un biomarqueur quantitatif estimé par des méthodes d'élastographie. L'élastographie par ondes de cisaillement (« shear wave », SW) utilise des ultrasons médicaux non invasifs pour évaluer les propriétés mécaniques du foie sur la base des propriétés de propagation des ondes de cisaillement. La vitesse des ondes de cisaillement (« shear wave speed », SWS) et l'atténuation des ondes de cisaillement (« shear wave attenuation », SWA) peuvent fournir une estimation de la viscoélasticité des tissus. Les tissus biologiques sont intrinsèquement viscoélastiques et un modèle mathématique complexe est généralement nécessaire pour calculer la viscoélasticité en imagerie SW. Le calcul précis de l'atténuation est essentiel, en particulier pour une estimation précise du module de perte et de la viscosité. Des études récentes ont tenté d'augmenter la précision de l'estimation du SWA, mais elles présentent encore certaines limites. Comme premier objectif de cette thèse, une méthode de décalage de fréquence revisitée a été développée pour améliorer les estimations fournies par la méthode originale de décalage en fréquence [Bernard et al 2017]. Dans la nouvelle méthode, l'hypothèse d'un paramètre de forme décrivant les caractéristiques spectrales des ondes de cisaillement, et assumé initialement constant pour tous les emplacements latéraux, a été abandonnée permettant un meilleur ajustement de la fonction gamma du spectre d'amplitude. En second lieu, un algorithme de consensus d'échantillons aléatoires adaptatifs (« adaptive random sample consensus », A-RANSAC) a été mis en œuvre pour estimer la pente du paramètre de taux variable de la distribution gamma afin d’améliorer la précision de la méthode. Pour valider ces changements algorithmiques, la méthode proposée a été comparée à trois méthodes récentes permettant d’estimer également l’atténuation des ondes de cisaillements (méthodes de décalage en fréquence, de décalage en fréquence en deux points et une méthode ayant comme acronyme anglophone AMUSE) à l'aide de données de simulations ou fantômes numériques. Également, des fantômes de gels homogènes in vitro et des données in vivo acquises sur le foie de canards ont été traités. Comme deuxième objectif, cette thèse porte également sur le diagnostic précoce de la stéatose hépatique non alcoolique (NAFLD) qui est nécessaire pour prévenir sa progression et réduire la mortalité globale. À cet effet, la méthode de décalage en fréquence revisitée a été testée sur des foies humains in vivo. La performance diagnostique de la nouvelle méthode a été étudiée sur des foies humains sains et atteints de la maladie du foie gras non alcoolique. Pour minimiser les sources de variabilité, une méthode d'analyse automatisée faisant la moyenne des mesures prises sous plusieurs angles a été mise au point. Les résultats de cette méthode ont été comparés à la fraction de graisse à densité de protons obtenue de l'imagerie par résonance magnétique (« magnetic resonance imaging proton density fat fraction », MRI-PDFF) et à la biopsie du foie. En outre, l’imagerie SWA a été utilisée pour classer la stéatose et des seuils de décision ont été établis pour la dichotomisation des différents grades de stéatose. Finalement, le dernier objectif de la thèse consiste en une étude de reproductibilité de six paramètres basés sur la technologie SW (vitesse, atténuation, dispersion, module de Young, viscosité et module de cisaillement). Cette étude a été réalisée chez des volontaires sains et des patients atteints de NAFLD à partir de données acquises lors de deux visites distinctes. En conclusion, une méthode robuste de calcul du SWA du foie a été développée et validée pour fournir une méthode de diagnostic de la NAFLD.For diagnosis and staging of liver fibrosis, liver stiffness is a quantitative biomarker estimated by elastography methods. Ultrasound shear wave (SW) elastography utilizes noninvasive medical ultrasound to assess the mechanical properties of the liver based on the monitoring of the SW propagation. SW speed (SWS) and SW attenuation (SWA) can provide an estimation of tissue viscoelasticity. Biological tissues are inherently viscoelastic in nature and a complex mathematical model is usually required to compute viscoelasticity in SW imaging. Accurate computation of attenuation is critical, especially for accurate loss modulus and viscosity estimation. Recent studies have made attempts to increase the precision of SWA estimation, but they still face some limitations. As a first objective of this thesis, a revisited frequency-shift method was developed to improve the estimates provided by the original implementation of the frequency-shift method [Bernard et al 2017]. In the new method, the assumption of a constant shape parameter of the gamma function describing the SW magnitude spectrum has been dropped for all lateral locations, allowing a better gamma fitting. Secondly, an adaptive random sample consensus algorithm (A-RANSAC) was implemented to estimate the slope of the varying rate parameter of the gamma distribution to improve the accuracy of the method. For the validation of these algorithmic changes, the proposed method was compared with three recent methods proposed to estimate SWA (frequency-shift, two-point frequency-shift and AMUSE methods) using simulation data or numerical phantoms. In addition, in vitro homogenous gel phantoms and in vivo animal (duck) liver data were processed. As a second objective, this thesis also aimed at improving the early diagnosis of nonalcoholic fatty liver disease (NAFLD), which is necessary to prevent its progression and decrease the overall mortality. For this purpose, the revisited frequency-shift method was tested on in vivo human livers. The new method's diagnosis performance was investigated with healthy and NAFLD human livers. To minimize sources of variability, an automated analysis method averaging measurements from several angles has been developed. The results of this method were compared to the magnetic resonance imaging proton density fat fraction (MRI-PDFF) and to liver biopsy. SWA imaging was used for grading steatosis and cut-off decision thresholds were established for dichotomization of different steatosis grades. As a third objective, this thesis is proposing a reproducibility study of six SW-based parameters (speed, attenuation, dispersion, Young’s modulus, viscosity and shear modulus). The assessment was performed in healthy volunteers and NAFLD patients using data acquired at two separate visits. In conclusion, a robust method for computing the liver’s SWA was developed and validated to provide a diagnostic method for NAFLD

Speed of sound index for liver steatosis estimation: a reliability study in normal subjects

PURPOSENon-alcoholic fatty liver disease (NAFLD) is the most widespread type of chronic liver disease in the Western countries. Ultrasound (US) is widely used for NAFLD staging. The Resona 7 US system (Mindray Bio-Medical Electronics Co., Ltd.) includes an image optimization and speed of ultrasound-related feature, Sound Speed Index (SSI). SSI is applied in a region of interest (ROI) that could potentially aid in tissue characterization. The purpose of this study is to evaluate the reliability of SSI on various examination parameters on normal subjects.METHODSTwenty normal subjects were examined by two radiologists performing SSI measurements in the liver in different ROI depths and sizes. Intraclass correlation coefficient (ICC) was calculated to measure intra- and inter-observer variability and inter-ROI variability.RESULTSFor all ROIs and both radiologists, the mean inter-observer ICC was 0.62 and the mean intraobserver ICC was 0.52 and 0.79. The mean SSI values for all ROIs and examiners were in the range 1528.79-1540.16 m/s.CONCLUSIONThe results indicate that SSI can lead to reliable measurements on normal subjects, independent of ROI size but dependent on ROI placement. More studies processing NAFLD patients, utilizing reference methods of liver fat quantification either for reliability or correlation with SSI, should be performed to further investigate the relevance of the SSI as a potential biomarker in clinical practice for liver steatosis grading

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

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Quantification of liver fibrosis—a comparative study

Liver disease has been targeted as the fifth most common cause of death worldwide and tends to steadily rise. In the last three decades, several publications focused on the quantification of liver fibrosis by means of the estimation of the collagen proportional area (CPA) in liver biopsies obtained from digital image analysis (DIA). In this paper, early and recent studies on this topic have been reviewed according to these research aims: the datasets used for the analysis, the employed image processing techniques, the obtained results, and the derived conclusions. The purpose is to identify the major strengths and “gray-areas” in the landscape of this topic