Use of second generation contrast-enhanced ultrasound in the assessment of focal liver lesions

Ultrasound （US） is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of specific contrast media and the development of specialized imaging techniques. Ultrasound now can fully characterise the enhancement pattern of hepatic lesions, similar to that achieved with contrast enhanced multiphasic computed tomography （CT） and magnetic resonance imaging （MRI）. US contrast agents are safe, well-tolerated and have very few contraindications. Furthermore, real-time evaluation of the vascularity of focal liver lesions has become possible with the use of the newer microbubble contrast agents. This article reviews the enhancement pattern of the most frequent liver lesions seen, using the second generation US contrast media. The common pitfalls for each type of lesion are discussed. The recent developments in US contrast media and specific imaging techniques have been a major advance and this technique, in view of the intrinsic advantages of US, will undoubtedly gain popularity in the years to come.     

Accuracy and reliability of microbubble ultrasound measurements for the non-invasive assessment of hepatic fibrosis in chronic hepatitis C

Aim: Contrast‐enhanced ultrasound can be used to assess liver disease severity non‐invasively by observing intra‐ and extrahepatic hemodynamic changes. Transit times are calculated to include intra‐ and extrahepatic components (hepatic vein transit time, HVTT) or the intrahepatic component (hepatic transit time, HTT), but these have not been compared directly. We aimed to compare diagnostic accuracy of HVTT and HTT in gauging the severity of chronic hepatitis C (CHC) and to assess inter‐ and intra‐observer reliability. Methods: Recorded ultrasound scans performed on 75 patients with biopsy‐staged CHC, using the microbubble contrast agent Sonovue were analyzed. Results: Diagnostic accuracy of HTT and HVTT for diagnosis of cirrhosis was 0.78 and 0.71 (P = 0.24). Diagnostic accuracy of HTT and HVTT for diagnosis of fibrosis stage >2 was 0.76 and 0.72 (P = 0.23). Negative predictive value for cirrhosis using this cut‐off was high for both techniques (HVTT, 88%; HTT, 92%), suggesting utility for exclusion of cirrhosis. Inter‐observer reliability for HTT and HVTT were 0.92 and 0.94, respectively. Intra‐observer reliability for HTT and HVTT were 0.98 and 0.99. Conclusion: In this cohort, reliability exceeded 90% while diagnostic accuracy was in keeping with previous studies of microbubble transit time analysis. Despite higher numerical diagnostic accuracy for HTT, no significant difference was demonstrated between the techniques, suggesting that both methods can be used reliably.     

Adverse reactions to ultrasound contrast agents: is the risk worth the benefit?

The introduction of ultrasound contrast agents has led to a marked improvement in diagnostic capabilities in echocardiography. As no serious adverse events were seen during the preclinical development phase, ultrasound contrast agents were thought to be safe. Recently, three fatal and 19 severe, non-fatal adverse reactions were reported in a post marketing analysis of more than 150,000 studies of Sonovue, which has led to the addition of several contra-indications for the use of this ultrasound contrast agent. Although a strong relationship was established between the non-fatal cases and administration of Sonovue, a causal relationship between the fatal cases and the use of Sonovue is debatable. Therefore, the risk associated with the use of this ultrasound contrast agent should be judged carefully, taking into consideration the prevalence of adverse effects of other contrast media and diagnostic procedures used in cardiology.     

丙型肝炎抗病毒治疗研究进展

丙型肝炎由于进展隐匿、慢性率高及预后不良而倍受关注。研究发现，约20％慢性丙型肝炎患者将进展为肝硬化，约2．5％最终罹患肝癌。据估计，全球有1．7亿丙型肝炎病毒（HCV）携带者，我国人群HCV感染率约在3％左右。以干扰素为基础的治疗在临床上一直居于主导地位，特别是聚乙二醇化干扰素（Peg—IFN）联合利巴韦林的应用使病毒学应答率明显提高。但是，疗程长、有效率低、不良反应大等问题仍未得到根本解决。     

Assessment of liver disease in patients with chronic hepatitis C and unhealthy alcohol use

Hepatitis C virus (HCV) infection and unhealthy alcohol use are major drivers of the burden of liver disease worldwide and commonly co-occur. Assessment of underlying liver damage is a cornerstone of the clinical care of patients with chronic HCV infection and/or unhealthy alcohol use because many of them are diagnosed at advanced stages of disease. Early diagnosis of liver disease before decompensated liver cirrhosis becomes established is essential for treatment with direct acting antivirals and/or abstinence from alcohol consumption, which are the main therapeutic approaches for clinical management. In this review, we discuss current knowledge around the use of non-invasive methods to assess liver disease, such as abdominal ultrasound, controlled attenuation parameter, transient elastography, magnetic resonance imaging, and indices based on serum markers of liver injury.     

The outcomes of glucose abnormalities in chronic hepatitis C patients receiving interferon-free direct antiviral agents

Direct-acting antiviral agents (DAAs) have been widely used for chronic hepatitis C (CHC) treatment recently. The characteristics of glucose abnormalities after DAAs therapy however, remain elusive. We aimed to elucidate the mutual impact between treatment response and parameters of glucose abnormalities after DAAs therapy in CHC patients. CHC patients who received DAAs therapy were recruited. The primary outcome measurements were their insulin resistance (IR) and beta-cell function assessed by the homeostasis model assessment (HOMA) method before treatment and at end-of-follow-up (EOF). Sixty-five CHC patients (19 males, mean age = 59.8 ± 10.3 years) were consecutively enrolled. They included 47 (72.3%) patients of genotype-1 infection. The treatment regimens among patients were sofosbuvir in 30 patients, paritaprevir-ritonavir/ombitasvir/dasabuvir in 23 patients, and asunaprevir/daclatasvir in 12 patients respectively. The overall sustained virological response rate was 98.5%. The mean IR at EOF was 2.6 ± 1.8, which was not significantly different from baseline level (2.7 ± 2.9, P = 0.75). There was a significant improvement of beta-cell function at EOF compared to baseline (107.7 ± 86.8 to 86.7 ± 44.5, P = 0.05). The amelioration of beta-cell function at EOF was significantly observed among 23 patients of high baseline IR (166.7 ± 111.3 of baseline vs 105.7 ± 48.2 of EOF, P = 0.04). Six (60%) of the 10 pre-diabetic patients at baseline achieved a normoglycemic state at EOF. Successful eradication of HCV by DAAs might improve glucose abnormalities in CHC patients, particularly among those who had high IR.     

Role of contrast enhanced ultrasonography in the assessment of hepatic metastases: A review

Contrast enhanced ultrasonography (CEUS) has improved both the detection and characterization of focal liver lesions. It is now possible to evaluate in real time the perfusion of focal liver lesions in the arterial, portal and late contrast phases, and thus to characterize focal liver lesions with high diagnostic accuracy. As a result, CEUS has taken a central diagnostic role in the evaluation of focal liver lesions that are indeterminate upon computed tomography (CT) and magnetic resonance imaging. The combined use of second generation contrast agents and low mechanical index techniques is essential for the detection of liver metastases, and it now allows the examination of the entire liver in both the portal and late phases. Several studies have shown that using CEUS instead of conventional ultrasonography without contrast agents significantly improves sensitivity in detection of liver metastases. Furthermore, the detection rate with CEUS seems to be similar to that of CT. This review describes the clinical role of CEUS in detecting liver metastases, including details about examination techniques, features of metastases observed with CEUS, and clinical results and guidelines.     

How to characterize non-hypervascular hepatic nodules on contrast-enhanced computed tomography in chronic liver disease: feasibility of contrast-enhanced ultrasound with a microbubble contrast agent

Background and Aim: Although hypervascular appearance is characteristic in hepatocellular carcinoma (HCC), hepatic nodules without hypervascular appearance are sometimes found in patients with chronic liver disease (CLD). The aim of the present study was to clarify the efficacy of contrast‐enhanced ultrasound (CEUS) with Levovist to characterize small, non‐hypervascular hepatic nodules on contrast‐enhanced computed tomography (CECT) in patients with CLD. Methods: The subject was 41 hepatic nodules (<30 mm, 18.5 ± 5.6 mm) which showed non‐hypervascular appearance on CECT in 35 patients with CLD; their histological results were 31 HCC (15 well, 14 moderate, and two poor) and 10 regenerative nodules (RN). CEUS with Levovist was performed under intermittent scanning (1‐s interval) using APLIO at the early phase and the liver‐specific phase, and the contrast enhancement of the nodule was assessed in comparison to that of the surrounding liver parenchyma. The contrast‐enhanced findings with the time‐intensity analysis were compared with the histological results. Results: Twelve nodules with weak enhancement in the liver‐specific phase were HCC, regardless of their early‐phase appearances. The other 29 nodules with equivalent or weak enhancement in the early phase and equivalent enhancement in the liver‐specific phase were 19 HCC and 10 RN. Among them, the maximum‐intensity ratio of tumor to non‐tumor in the early phase was significantly higher in HCC than in RN (P < 0.01, n = 16), and the receiver‐operating characteristic analysis showed a sensitivity of 1.0 and a specificity of 0.83 for their characterization. Conclusion: CEUS with Levovist may be an alternative to biopsy to characterize small, non‐hypervascular hepatic nodules on CECT in patients with CLD.     

Optimization of ultrasound-mediated gene transfer: comparison of contrast agents and ultrasound modalities.

AIMS: Ultrasound (US)-enhanced gene transfer for cardiovascular disease is an emerging technique with translational relevance. Prior to pre-clinical applications, optimization of gene transfer using various US contrast agents and parameters is required. In order to do so, two clinically relevant contrast agents (Optison and PESDA), and two US modalities (dedicated continuous wave system and diagnostic scanner) were tested in vitro and in vivo. METHODS AND RESULTS: In vitro, luciferase activity was measured after exposure of primary vascular cells to combinations of luciferase plasmid, contrast agents, and US exposures. US gene transfer was consistently superior to controls. PESDA was better than Optison; there was no significant difference between US modalities. In vivo, luciferase activity in skeletal muscle of rats was measured after injection of plasmid or adenovirus, expressing luciferase with or without US exposure. Diagnostic US was superior to continuous wave. US plasmid gene transfer was highly localized, and was superior to all controls except adenovirus which lacked spatial specificity. To deliver a secreted transgene product, US gene transfer of a plasmid expressing tissue factor pathway inhibitor (TFPI) to skeletal muscle resulted in a dose-related increase in plasma activity for up to 5 days after delivery. CONCLUSION: US-enhanced plasmid gene transfer is capable of transducing skeletal muscle in vivo either directly or via an intravascular route. This enhanced nonviral method is an alternative to plasmid DNA alone or viral vectors.     

Ultrasound-guided intertumoral injection of contrast agents combined with human p53 gene for the treatment of breast cancer

The objective of this study was to investigate the effects of ultrasound-guided injection of ultrasound contrast agents (UCAs) and the p53 gene on the treatment of rats with breast cancer (BC). Assembly of the p53 expression vector as well as that of a rat model with BC consisted of 200 successfully modeled rats randomly divided into 5 groups: p53 gene introduction, p53 gene introduction + ultrasound irradiation, p53 gene introduction + UCAs, p53 gene introduction + UCA + ultrasound irradiation, and UCA + ultrasound irradiation groups. Expression of p53 was detected via quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining. In the p53 gene introduction + ultrasound irradiation group, we observed increased tumor volume with blood flow signals around and necrotic tumor tissues with an inhibition rate of 36.30%, as well as higher expression of p53 than that in the p53 gene introduction group and p53 gene introduction + UCA group. In the p53 gene introduction + UCA + ultrasound irradiation group, tumor volume increased slightly with reduced blood flow signals and massive degenerative necrosis of tumor cells was identified with inhibition rate of 62.62%, and expression of p53 was higher than that in the rest groups. Taken together, the key findings obtained from the present study elucidate that injection of p53 gene and UCA microbubbles guided by ultrasound could increase the expression of p53, thus inhibiting the tumor growth in rats with BC.     

小分子化合物抗病毒治疗丙型肝炎肝硬化

正直接抗病毒药物(direct-acting antiviral agents,DAAs)对丙型肝炎的治疗效果已取得突破性进展,持续病毒学应答(sustained virologic response,SVR)高达90%~95%~([1])。目前,DAAs主要包括NS3/4A蛋白酶抑制剂、核苷类NS5B聚合酶抑制剂、非核苷类NS5B聚合酶抑制剂、NS5A抑制剂。自     

原发性肝癌超声造影诊断的特征性声像图表现

目的探讨超声造影诊断原发性肝癌的特征性声像图表现。方法对经病理检查或穿刺活组织检查确诊的25例(30个病灶)原发性肝癌患者实施超声造影检查,观察患者病灶特征和声像图表现,并将诊断结果与常规超声诊断结果进行比较,判断两种诊断方式的敏感性。结果原发性肝癌的内部结节数目不多,多为单发,病灶与正常组织间界限清楚,边缘处较为整齐,回声除小部分不均匀外,其余皆比较均匀,其形状表现为圆形或类圆形。有19例患者诊断为肝细胞癌,声像图表现为"快进快出","快进快出"表现越为明显患者,其肿瘤分化程度也越低。有6例患者诊断为肝内胆管细胞癌,声像图主要表现为"快进快出",病灶图像在动脉期呈现为网格状增强,部分显示无增强;在门静脉期时,病灶周边环状不规则增高,病灶内部则表现为网格状增强或无增强;当处于门静脉期时,病灶周边环状不规则增强明显消退。超声造影诊断敏感度为96%,与常规超声的72%比较,存在明显差异(P0.05)。结论超声造影诊断原发性肝癌可以清楚的显示病灶图像特征,较常规超声诊断敏感性高。     

Changes in hepatitis C-related liver disease in a large clinic population

Background: Hepatitis C virus (HCV) infection is a significant problem in the Australian community. Over the past few years, the number of patients with diagnosed hepatitis C has increased greatly. The aims of the present study were to define the clinical features of a large group of patients with chronic HCV infection and to examine changes occurring in the referral base and epidemiological characteristics of this group since analysis of the first 342 patients in 1994. Methods: The study included 1546 consecutive anti‐HCV‐positive patients who had been referred to St Vincent's Hospital from January 1990 to June 1998. Clinical and laboratory data were collected on all patients. Results: Referrals from general practitioners increased from 31% to 70% of all patients between 1990–1993 and 1994–1998. A history of injecting drug use (IDU) was present in 64% of the patients. While 89% of the IDU group was Australasian born, 49% of those in the sporadic group were born overseas. Cirrhosis was found in 18% of biopsied patients. Age, infection duration, age at infection, Mediterranean or Asian origin and a history of transfusion or lack of HCV risk factors were associated with cirrhosis on univariate analysis. Patient age was the only independent predictor of cirrhosis. Conclusion: The majority of patients with HCV are diagnosed in general practice. A risk factor for infection is identified in 82% of patients. While our reported prevalence of cirrhosis may be an overestimate of that in the overall HCV community, the ultimate disease burden is likely to be significant. (Intern Med J 2001; 31: 90–96)     

丙型肝炎直接抗病毒治疗研究进展

正目前,我国针对慢性丙型肝炎(chronic hepatitis C,CHC)的标准治疗方案(standard of care,SOC)仍然是聚乙二醇干扰素(pegylated interferon,PEGIFN)-α联合利巴韦林(ribavirin,RBV),简称PR治疗。但是近年来,针对HCV生活周期中病毒蛋白靶向特异性治疗的许多小分子化合物研究进展非常迅速,这些药物被统一命名为直接作用抗病毒药物     

Value of duplex Doppler ultrasonography in non-invasive assessment of children with chronic liver disease

AIM:To investigate the value of duplex Doppler ultrasonography (US) in the assessment of the hemodynamics of the portal and hepatic veins in a cohort of children with chronic liver disease (CLD) and to detect any relationship between the US changes,etiology and severity (or stage) of CLD. METHODS:We prospectively enrolled 25 children with biopsy-proven CLD. Thirteen had cirrhosis (aged 8.9 ± 2.0 years) and 12 had chronic hepatitis (aged 9.3 ± 2.3 years). Gray scale and color-coded duplex Doppler US were performed for all,as well as 30 healthy age and sex-matched controls. Findings were correlated with clinical,laboratory and histopathological characteristics. RESULTS:Prominent caudate lobe was detected in 100% of cirrhotics,but none of the chronic hepatitis or controls. Thickened lesser omentum and loss of the triphasic waveform of the hepatic vein were present in 69.2% and 53.8% of cirrhotics vs 33.3% and 8.3% of chronic hepatitis respectively. Portal vein flow velocity was significantly lower (P < 0.0001) and the congestion index was significantly higher (P < 0.005) in both patient groups compared to controls. Child-Pugh’s staging showed a positive correlation with both abnormal hepatic vein waveform and direction of portal blood flow; and a negative correlation with both hepatic and portal vein flow velocities. No correlation with the etiology of CLD could be detected. CONCLUSION:Duplex Doppler added to grayscale US can detect significant morphologic and portal hemodynamic changes that correlate with the severity (stage) of CLD,but not with etiology.     

Established and emerging roles for ultrasound enhancing agents (contrast echocardiography)

The ability to opacify the left ventricle and delineate the endocardium after intravenous injection of microbubble ultrasound enhancing agents is of established value to quantify volumes and function in suboptimal unenhanced images, particularly in stress echocardiograms. However, applications other than quantitation of left ventricle structure and function exist for contrast enhanced left ventricular opacification. Contrast agents enable recording of Doppler velocity signals in patients with poor ultrasound transmission, providing estimates of aortic stenosis gradient and pulmonary artery pressures. Contrast echo is of value in detecting apical hypertrophic cardiomyopathy and accompanying apical aneurysms. Most importantly, ultrasound enhancing agents can identify apical and left atrial masses when they cannot be visualized in unenhanced images, and can distinguish thrombi from tumors by visualizing the vascularity inherent in tumors. Contrast agents distinguish trabecular from compacted myocardium in noncompaction syndrome, and hypertrabeculation with other abnormal conditions. A major potential application of ultrasound enhancing agents is myocardial opacification, which can assist in identifying nonviable myocardium. Also, the delayed reappearance of myocardial perfusion after microbubble destruction identifies impaired contrary flow and can diagnose coronary stenosis. Innovative applications of ultrasound contrast agents currently under investigation, include visualizing the vaso vasorum to identify plaques and assess their vulnerability, and theranostic agents to deliver drugs and biologists and to assist in sonothrombolysis. It is anticipated that the role of ultrasound contrast agents will continue to increase in the future.     

慢性肝病者乙型和丙型肝炎病毒重叠感染的研究

对２１３例老年慢性肝病患者的乙型肝炎病毒（ＨＢＶ）和丙型肝炎病毒（ＨＣＶ）血清标志物检测发现：ＨＢＶ感染占７３．２４％、ＨＢＶ和ＨＣＶ重叠感染占重叠感染点１５．４９％、ＨＣＶ感染占７．０４％、其它占４．２６％；ＨＢＶ阴性者ＨＣＶ检出率高于ＨＢＶ阳性者，肝癌和肝硬化患者较慢性肝炎患者高；ＨＢＶ和ＨＣＶ重叠感染患者的血清血蛋白下降显著，γ－球蛋白升高明显，肝硬化并腹水和上消化道出血者了多。结果表明，老     

New perspectives for the use of contrast-enhanced liver ultrasound in clinical practice

The introduction of second-generation microbubble ultrasound contrast agents and the development of contrast specific ultrasound techniques have improved the ability of contrast enhanced ultrasound in detecting and characterising liver lesions, offering new perspectives for its exploitation in clinical hepatology. Indeed, several studies have demonstrated a high diagnostic accuracy in focal lesion characterisation (85-96%) in patients either with or without underlying chronic liver disease. This review article describes the basic principles of contrast enhanced ultrasound, defines the different vascular features of benign and malignant liver lesions, and assesses its clinical impact in different clinical scenarios, according to the guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology, contrast enhanced ultrasound enables the characterisation of focal liver lesions, regardless of the presence or absence of underlying chronic liver disease. Contrast enhanced ultrasound is also useful in staging and follow-up of cancer patients and in monitoring local ablative treatment. Contrast enhanced ultrasound is expected to be considerably increased and replace many computed tomography and magnetic resonance imaging examinations in near future, according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Therefore, it is necessary to take measures in order to meet the demand for an increasing number of these procedures.     

慢性乙型肝炎患者炎症及纤维化程度的超声与病理学诊断的对照分析

肝活组织检查是肝纤维化诊断的金标准,但由于其有创性和受检查条件的限制,不能作为常规诊断和病情观察的方法.超声作为一种可重复非创伤性的检查方法在临床广泛应用.     

Management of hepatitis C patients with decompensated liver disease

Little is known about the tolerance and effectiveness of novel oral direct acting antivirals (DAA) in hepatitis C patients with decompensated cirrhosis. To examine the studies relevant to the treatment of hepatitis C virus(HCV)-related decompensated liver disease, we performed computer–based searches for English articles between 1947 and August 2015. Fourteen articles including HCV patients with decompensated cirrhosis were reviewed. The combinations of ledipasvir(LDV)/sofosbuvir(SOF)/ribavirin(RBV) for 12 weeks, or daclatasvir/SOF/RBV for 12 weeks are safe and effective for HCV genotype 1 or 4 infection, and daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks might be effective and safe for HCV genotype 2 or 3 infection. In conclusion, current evidence supports the use of all oral DAA regimens in HCV patients with decompensated cirrhosis.