Elastography assessment in patients with chronic HCV infection

Introduction: Liver fibrosis (LB) assessment plays an important role in hepatology. A common characteristic of all chronic liver diseases is the occurrence and progression of fibrosis towards cirrhosis. Besides its plain interest for prognosis purposes, determining the fibrosis reveals the natural history of the disease and the risk factors associated with its progression to guide the antifibrotic action of different treatments. Discussion: Today, in clinical practice there are three available methods for the evaluation of LB. Biopsy, which is still considered as the ‘gold standard’ method. Serological markers and their mathematical combination are suggested in the last years in alternative to LB. More recently, transient elastography (TE) was proposed. TE is a simple and noninvasive method for measuring liver stiffness. This technique is based on the progression speed of an elastic shear wave within the liver. Conclusions: Currently, there are just a few studies capable of evaluating the TE effectiveness in chronic liver diseases, mainly in patients infected with hepatitis C virus (HCV). Its application must also be studied in the monitoring of patients suffering from chronic HCV infection and subjected to a treatment that can modify their degree of liver fibrosis. The results of TE must be interpreted according to the clinical background of the specialist.     

Real-Time Elastography in the Assessment of Liver Fibrosis: A Review of Qualitative and Semi-quantitative Methods for Elastogram Analysis

Despite its invasiveness, liver biopsy is still considered the gold standard for the assessment of hepatic fibrosis. Non-invasive ultrasound-based techniques are increasingly employed to assess parenchymal stiffness and the progression of chronic diffuse liver diseases. Real-time elastography is a rapidly evolving technique that can reveal the elastic properties of tissues. This review examines qualitative and semi-quantitative methods developed for analysis of real-time liver elastograms, to estimate parenchymal stiffness and, indirectly, the stage of fibrosis. Qualitative analysis is the most immediate approach for elastogram analysis, but this method increases intra- and inter-observer variability, which is seen as a major limitation of real-time elastography. Semi-quantitative methods include analysis of the histogram derived from color-coded maps, as well as calculation of the elastic ratio and fibrosis index.     

Current and Emerging Biomarkers and Imaging Modalities for Nonalcoholic Fatty Liver Disease: Clinical and Research Applications

PurposeNonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that frequently coexists with obesity, metabolic syndrome, and type 2 diabetes. The NAFLD spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, can be associated with long-term hepatic (hepatic decompensation and hepatocellular carcinoma) and extrahepatic complications. Diagnosis of NAFLD requires detection of liver steatosis with exclusion of other causes of chronic liver disease. Screening for NAFLD and identification of individuals at risk of end-stage liver disease represent substantial challenges that have yet to be met. NAFLD affects up to 25% of adults, yet only a small proportion will progress beyond steatosis to develop advanced disease (steatohepatitis and fibrosis) associated with increased morbidity and mortality. Identification of this cohort has required the gold standard liver biopsy, which is both invasive and expensive. The use of serum biomarkers and noninvasive imaging techniques is an area of significant clinical relevance. This narrative review outlines current and emerging technologies for the diagnosis of NAFLD, nonalcoholic steatohepatitis, and hepatic fibrosis.MethodsWe reviewed the literature using PubMed and reviewed national and international guidelines and conference proceedings to provide a comprehensive overview of the evidence.FindingsSignificant advances have been made during the past 2 decades that have enhanced noninvasive assessment of NAFLD without the need for liver biopsy. For the detection of steatosis, abdominal ultrasonography remains the first-line investigation, although a controlled attenuation parameter using transient elastography is more sensitive. For detecting fibrosis, noninvasive serum markers of fibrosis and algorithms based on routine biochemistry are available, in addition to transient elastography. These techniques are well validated and have been incorporated into national and international screening guidelines. These approaches have facilitated more judicious use of liver biopsy but are yet to entirely replace it. Although serum biomarkers present a pragmatic and widely available screening approach for NAFLD in large population-based studies, magnetic resonance imaging techniques offer the benefit of achieving high degrees of accuracy in disease grading, tumor staging, and assessing therapeutic response.ImplicationsThis diagnostic clinical and research field is rapidly evolving; increasingly combined applications of biomarkers and transient elastography or imaging of selective (intermediate or high risk) cases are being used for clinical and research purposes. Liver biopsy remains the gold standard investigation, particularly in the context of clinical trials, but noninvasive options are emerging, using multimodality assessment, that are quicker, more tolerable, more widely available and have greater patient acceptability.     

Contemporary use of elastography in liver fibrosis and portal hypertension

The risk and speed of progression from fibrosis to compensated and decompensated cirrhosis define the prognosis in liver diseases. Therefore, early detection and preventive strategies affect outcomes. Patients with liver disease have traditionally been diagnosed at an advanced stage of disease, in part due to lack of non-invasive markers. Ultrasound elastography to measure liver stiffness can potentially change this paradigm. The purpose of this review was therefore to summarize advances in the field of ultrasound elastography with focus on diagnosis of liver fibrosis, cirrhosis and clinically significant portal hypertension, techniques and limitations. Four types of ultrasound elastography exist, but there is scarce evidence comparing the different techniques. The majority of experience concern transient elastography for diagnosing fibrosis and cirrhosis in patients with chronic viral hepatitis C. That said, the role of elastography in other aetiologies such as alcoholic- and non-alcoholic liver fibrosis still needs clarification. Although elastography can be used to diagnose liver fibrosis and cirrhosis, its true potential lies in the possibility of multiple, repeated measurements that allow for treatment surveillance, continuous risk stratification and monitoring of complications. As such, elastography may be a powerful tool for personalized medicine. While elastography is an exciting technique, the nature of ultrasound imaging limits its applicability, due to the risk of failures and unreliable results. Key factors that limit the applicability of liver stiffness measurements are as follows: liver vein congestion, cholestasis, a recent meal, inflammation, obesity, observer experience and ascites. The coming years will show whether elastography will be widely adapted in general care.     

Diagnostic Accuracy of 2-D Shear Wave Elastography for the Non-Invasive Staging of Liver Fibrosis in Patients with Elevated Alanine Aminotransferase Levels

This study assessed the diagnostic accuracy of 2-D shear wave elastography (2-D-SWE) for the non-invasive staging of liver fibrosis and compared the findings with those for biochemical markers (the aspartate aminotransferase-to-platelet index and fibrosis-4 index) of liver fibrosis in patients with elevated alanine aminotransferase (ALT) levels (>5?×?the upper limit of normal). Patients with chronic liver diseases and elevated ALT levels who underwent liver biopsy were consecutively included. Receiver operating characteristic (ROC) curves were constructed to assess overall accuracy and to identify optimal cutoff values. After exclusions, data from 105 patients were analyzed. The areas under the ROC curves (AUROCs) for significant fibrosis, severe fibrosis and cirrhosis were 0.83, 0.86 and 0.91, respectively. The optimal cutoff values for predicting significant fibrosis, severe fibrosis and cirrhosis were 10.6, 13.2 and 17.6?kPa, respectively. The AUROCs of 2-D-SWE were significantly higher than those of biochemical markers for predicting significant fibrosis, severe fibrosis and cirrhosis (all p values?<?0.05). Therefore, the diagnostic performance of 2-D-SWE in assessing liver fibrosis stages in patients with elevated ALT levels was promising. The optimal cutoff values were increased but appropriate for this cohort because the baseline levels of liver stiffness measurements were increased in these patients, even in the absence of fibrosis.     

Transient elastography: a new noninvasive method for assessment of hepatic fibrosis

Chronic hepatitis is accompanied by progressive deposit of hepatic fibrosis, which may lead to cirrhosis. Evaluation of liver fibrosis is, thus, of great clinical interest and, up to now, has been assessed with liver biopsy. This work aims to evaluate a new noninvasive device to quantify liver fibrosis: the shear elasticity probe or fibroscan®. This device is based on one-dimensional (1-D) transient elastography, a technique that uses both ultrasound (US) (5 MHz) and low-frequency (50 Hz) elastic waves, whose propagation velocity is directly related to elasticity. The intra- and interoperator reproducibility of the technique, as well as its ability to quantify liver fibrosis, were evaluated in 106 patients with chronic hepatitis C. Liver elasticity measurements were reproducible (standardized coefficient of variation: 3%), operator-independent and well correlated (partial correlation COEFFICIENT = 0.71, p < < 0.0001) to fibrosis grade (METAVIR). The areas under the receiver operating characteristic (ROC) curves were 0.88 and 0.99 for the diagnosis of patients with significant fibrosis (≥ F2) and with cirrhosis ( = F4), respectively. The Fibroscan® is a noninvasive, painless, rapid and objective method to quantify liver fibrosis. (E-mail: laurent.sandrin@echosens.com)     

JSUM ultrasound elastography practice guidelines: liver

In diffuse liver disease, it is extremely important to make an accurate diagnosis of liver fibrosis prior to determining indications for therapy or predicting treatment outcome and malignant potential. Although liver biopsy has long been the gold standard in the diagnosis of liver fibrosis, it is still an invasive method. In addition, the sampling error is an intrinsic problem of liver biopsy. Non-invasive serological methods for the diagnosis of liver fibrosis can be affected by factors unrelated to the liver. Recently, after the introduction of FibroScan, it became possible to measure liver fibrosis directly and non-invasively by elastography, which has attracted attention as a non-invasive imaging diagnostic tool for liver fibrosis. In addition, real-time tissue elastography is currently being used to conduct clinical trials at many institutions. Moreover, virtual touch quantification enables the observation of liver stiffness at any location by simply observing B-mode images. Furthermore, the recently developed ShearWave elastography visualizes liver stiffness on a color map. Elastography is thought to be useful for all types of diffuse liver diseases. Because of its association with portal hypertension and liver carcinogenesis, elastography is expected to function as a novel prognostic tool for liver disease. Although various elastographic devices have been developed by multiple companies, each device has its own measurement principle, method, and outcome, creating confusion in clinical settings. Therefore, it is extremely important to understand the characteristics of each device in advance. The objective of this guideline, which describes the characteristics of each device based on the latest knowledge, is for all users to be able to make the correct diagnosis of hepatic fibrosis by ultrasound elastography.     

Noninvasive tests for liver fibrosis

There is little doubt that we need fibrosis markers or scoring systems that have proven utility in assessing common hepatic diseases, such as hepatitis C and NASH. Despite multiple research studies, none has yet proved to be of clinical value. The most likely benefit of these tests will be to distinguish between minimal and advanced fibrosis or cirrhosis. Several panels of markers have shown utility in this regard but are not yet established as useful for all hepatic diseases. Until they have been validated and clinically accepted, liver biopsy will continue to be the "gold standard" for assessing liver fibrosis.     

IRM dans l'évaluation de la cirrhose hépatique

Liver cirrhosis is a chronic and progressive process characterized by fibrosis and anatomically abnormal nodules. Cirrhosis results in liver cell dysfunction, necrosis and regeneration. Although the definitive diagnosis is usually made by biopsy, diagnostic imaging can serve as a noninvasive diagnostic modality. In this review, the value of MR in the diagnosis and management of liver cirrhosis will be evaluated. Specifically, t morphologic changes (gross liver appearance, portal hypertension, splenomegaly, ascites, hilar lymphadenopathy, confluent hepatic fibrosis), signal intensity changes (inhomogeneous hepatic texture, fibrous septa) and contrast enhancement patterns (intravascular and interstitial gadolinium chelates, MnDPDP, iron oxide particles) that allow a diagnosis and grading of cirrhosis will be described. Also, the steps in carcinogenesis leading to the development of hepatocellular carcinomas will be briefly discussed.     

超声定量评估肝纤维化程度研究进展

肝纤维化程度的判断对于监测肝脏疾病的进展和监控药物疗效具有重要意义。作为肝纤维化分期金标准的肝活检因为有创操作,临床上不能广泛开展。而超声作为一种无创性的影像学技术,越来越多地被用于评价肝纤维化程度。本文对瞬时弹性成像技术、实时组织弹性成像技术、声脉冲辐射力弹性成像技术、实时剪切波弹性成像、组织结构声学定量技术,用于无创定量评估肝纤维化程度的研究进展进行综述。     

细胞外基质因子检测对肝纤维化早期诊断的预测价值

目的 :通过对多种细胞外基质因子的检测 ,创建出一套无创、简便易行的诊断肝纤维化的方法。方法 :以肝活检为肝纤维化诊断的金标准 ,同时检测肝纤维化和正常对照者血清中的透明质酸、层黏连蛋白、纤黏连蛋白、血清IV型胶原、血清III型前胶原氨基端肽和血清脯氨酸肽酶 ,并采用多元Logistic回归分析建立诊断方程。结果 :肝硬化组和慢性乙型肝炎 (重度 )以上各指标均无显著差别 ,慢性乙型肝炎 (重度 ) >慢性乙型肝炎 (中度、轻度 ) >正常对照。透明质酸、层黏连蛋白、血清IV型胶原、血清III型前胶原氨基端肽和血清脯氨酸肽酶各因素均进入回归方程。以回归方程预测的肝纤维化T值大于 0 .95者做判断肝纤维化的标准 ,结果该法诊断的灵敏度和特异度分别为 86 .7%和 80 .0 % ,符合率为 85 %。结论 :肝细胞基质透明质酸、层黏连蛋白、纤黏连蛋白、血清IV型胶原、血清III型前胶原氨基端肽和血清脯氨酸肽酶是诊断肝纤维化的敏感指标 ,联合检测可以对肝纤维化进行定量预测诊断     

Increased liver stiffness denotes hepatic dysfunction and mortality risk in critically ill non-cirrhotic patients at a medical ICU

Introduction  

Hepatic dysfunction is a common finding in critically ill patients on the ICU and directly influences survival. Liver stiffness can be measured by the novel method of transient elastography (fibroscan) and is closely associated with hepatic fibrosis in patients with chronic liver disease, but also is increased in patients with acute hepatitis, acute liver failure and cholestasis. We investigated liver stiffness as a potentially useful tool for early detection of patients with hepatic deterioration and risk stratification with respect to short- and long-term mortality.     

Hepatocellular nodules in liver cirrhosis: MR evaluation

Liver cirrhosis is a major public health problem worldwide. Common causes of cirrhosis include hepatitis C virus, hepatitis B virus, alcohol consumption, and nonalcoholic steatohepatitis. Cirrhotic livers are characterized by advanced hepatic fibrosis and the development of hepatocellular nodules such as regenerative nodules, dysplastic or neoplastic nodules. Cirrhosis is the strongest predisposing factor for hepatocellular carcinoma (HCC). For example, viral hepatitis is the main risk factor for cirrhosis and is associated with the increased incidence (1%–4% per year) of HCC after development of cirrhosis. Currently, a variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) are used in noninvasive evaluation of patients with chronic liver disease and suspected HCC. With technological development of MR scanners, MR imaging has emerged as an important imaging modality for assessing cirrhosis and its complications such as HCC. The recent advance in MR is the introduction of faster sequences which have allowed high-quality imaging of the entire liver with high intrinsic soft-tissue contrast, and also multiphasic dynamic MRI that is essential for the detection and characterization of HCC. In addition, functional MRI including diffusion-weighted MRI, MR elastography, and new MR contrast agent with dual function have been investigated for the clinical utility of detection and characterization of HCCs. In this article, we provide an overview of the state-of-the-art MR imaging techniques being used for noninvasive assessment of hepatocellular nodules including conventional dynamic imaging, liver-specific contrast-enhanced MR imaging, diffusion-weighted imaging, MR spectroscopy, and MR elastography.     

The diagnostic value of ultrasound elastography in patients with hepatitis B virus infection: a prospective study

The aim of this prospective study was to investigate the diagnostic value of ultrasound elastography for evaluating liver stiffness measurement (LSM) in 74 patients with hepatitis B virus (HBV) infection, treated with telbivudine (22 with chronic HBV infection, 32 with compensated cirrhosis and 20 with decompensated cirrhosis). Each patient underwent ultrasound elastography measurements and serum liver marker assays before and after 6 months' treatment with 600 mg telbivudine, orally, once daily. In the 22 patients with chronic HBV infection, LSM values measured by ultrasound elastography decreased significantly following the treatment period compared with baseline. The LSM values were significantly higher in the 20 patients with decompensated cirrhosis than in the 32 patients with compensated cirrhosis after treatment. Significant decreases in serum hepatic fibrosis indices occurred in all patients following treatment. The correlation between fibrosis index, hyaluronic acid level and LSM was statistically significant in all patients, whereas the correlation between alanine aminotransferase and LSM was not. The findings suggest that liver stiffness in patients with HBV can be measured simply with ultrasound elastography and that it is reduced within 6 months by treatment with telbivudine. The main adverse events noted during the study period were that creatine kinase levels were increased in seven patients and that seven patients had influenza-like symptoms.     

超声弹性成像评价肝纤维化程度的研究现状

肝脏活检是评估肝纤维化的金标准,但其有创且有出血等并发症的发生,限制其广泛应用。而超声弹性成像技术能检测肝脏的物理弹性数据,以此分析纤维化程度。本文介绍目前临床上常用的3种超声弹性成像技术,即实时弹性成像、瞬间弹性成像、声脉冲辐射力成像在肝纤维化诊断中的研究现状及新进展。     

Novel serum biomarker candidates for liver fibrosis in hepatitis C patients

BACKGROUND: Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. METHODS: We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. RESULTS: We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) fragments, alpha1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-alpha2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and beta2 glycoprotein I (beta2GPI) were increased. In general, alpha2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, beta2GPI, and thioester-cleaved products of a2M. CONCLUSIONS: Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis of fibrosis during early stages will allow early treatment, thereby preventing fibrosis progression.     

Discordance between conventional ultrasonography and ElastPQ for assessing hepatic fibrosis in chronic hepatitis B: frequency and independent factors

Purpose

To investigate the frequency of discordance and to identify factors associated with discordance between ultrasonographic and elastographic grades for assessing hepatic fibrosis in Asian patients with chronic hepatitis B.

Methods

Three hundred thirty-four patients with chronic hepatitis B for which both conventional ultrasonography and liver stiffness measurements using elastography were available were included. Patients were graded as ‘normal’, ‘chronic liver disease’, or ‘liver cirrhosis’ by ultrasonography, and as ‘no significant fibrosis’, ‘significant fibrosis’, or ‘liver cirrhosis’ by elastography, and the results of these two modalities were compared. Logistic regression analyses were performed to identify independent factors associated with discordant results.

Results

Of the 334 patients, 153 (45.8 %), 115 (34.4 %), and 66 (19.8 %) patients were ‘normal’, ‘chronic liver disease’, and ‘liver cirrhosis’, respectively, based on the ultrasonographic grades, and 290 (86.8 %), 29 (8.7 %), and 15 (4.5 %) patients were ‘no significant fibrosis,’ ‘significant fibrosis’, and ‘liver cirrhosis’, respectively, based on the elastographic values. Among them, 173 (51.8 %) showed discordance with respect to severity of hepatic fibrosis. In multivariable analysis, discordance was more frequent in patients with ultrasonographic grades of ‘chronic liver disease’ [adjusted odds ratio (AOR), 1924; P < 0.001] and ‘liver cirrhosis’ (AOR, 4498; P < 0.001), whereas patients with an elastographic grade of ‘liver cirrhosis’ showed a negative association with discordance (AOR, 0.002; P = 0.007).

Conclusion

There was a high rate of discordance between hepatic fibrosis grades determined by ultrasonography and elastography. Considering the accuracy of liver stiffness evaluation by elastography, conventional ultrasonography might overestimate hepatic fibrosis in chronic hepatitis B.

     

Shear Wave Elastography for Evaluation of Liver Fibrosis

The prognosis and management of chronic viral hepatitis mainly depend on the extent of liver fibrosis, particularly in chronic hepatitis C. Liver histologic analysis is still considered the reference standard in the assessment of liver fibrosis despite the interobserver and interobserver variability in staging and some morbidity and mortality risks. Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In the last decade, ultrasound‐based techniques to estimate the stage of liver fibrosis have become commercially available. They all have the capability to noninvasively evaluate differences in the elastic properties of soft tissues by measuring tissue behavior when a mechanical stress is applied. Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by an external push. This article reviews the results that have been obtained with shear wave elastography for assessment of liver fibrosis.     

FIBROSpect II: a potential noninvasive test to assess hepatic fibrosis

Many forms of liver disease may ultimately lead to fibrosis of the liver, the most advanced state being cirrhosis. Cirrhosis is a morphologic disease that eventually results in a functional change of the liver. It is generally not accompanied by signs or symptoms early in its course, and is often diagnosed late when signs of liver failure become overt. Imaging studies may suggest cirrhosis, but only if there have been gross changes in the appearance of the liver, and this is often not the case. The only way to diagnose cirrhosis reliably has been through direct histologic examination of liver tissue. The drawback to histologic diagnosis has been the risks and discomfort associated with liver biopsy. Hesitation to perform the procedure also exists due to lack of experience of many practitioners and the low reimbursement rates for a procedure that is viewed as time consuming and potentially dangerous. The search for noninvasive modalities to assess fibrosis through biochemical and other means has begun. Several markers are currently under investigation, many of which are combined with clinical assessment and other biochemical parameters, to establish the presence of liver fibrosis. FIBROSpect II is an example of a commercially available assay that employs a combination of three markers to distinguish between no, minimal and advanced fibrosis.     

慢性肝炎患者乙型肝炎病毒复制与肝纤维化标志物的关系

目的研究慢性乙型肝炎（下称乙肝）患者血清乙肝病毒（HBV）复制水平与肝纤维化血清标志物的关系。方法选择150例临床确诊为慢性乙肝的50例早期肝硬化患者，采用荧光定量聚合酶链反应（FQ-PCR）检测血清HBVDNA水平，放射免疫法和酶免疫法检测肝纤维化血清标志物（透明质酸、层黏连蛋白、Ⅲ型前胶原和Ⅳ型胶原），对血清HBVDNA水平与肝纤维化标志物的关系进行分析，并与100例无肝硬化患者血清HBVDNA及肝纤维化标志物水平进行比较。结果慢性乙肝患者血清HBVDNA水平与肝纤维化标志物的关系无统计学意义（P〉0．05），早期肝硬化患者血清肝纤维化标志物水平显著高于无肝硬化患者，但HBVDNA水平却低于无肝硬化患者（P〈0．05）。结论慢性乙肝患者血清HBVDNA水平与肝纤维化标志物水平无显著相关性。