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There has been great interest in the development of non-invasive techniques for the diagnosis of liver fibrosis in chronic liver diseases, including ultrasound elastographic methods. Some of these methods have already been adequately studied for the non-invasive assessment of diffuse liver diseases. Others, however, such as two-dimensional Shear Wave Elastography (SWE), of more recent appearance, have yet to be validated and some aspects are for the moment incompletely elucidated. This review discusses some of the aspects related to two-dimensional SWE: the examination technique, the examination performance indicators, intra and interobserver agreement and clinical applications. Recommendations for a high-quality examination technique are formulated. Key words: – – – Two-dimensional Shear Wave Elastography. Abbreviations: 2D- SWE: Two-dimensional Shear Wave Elastography; 3D- SWE: Three-dimensional Shear Wave Elastography; AUROC: area under the receiver operating characteristic curves; ARFI Acoustic Radiation Force Impulse Elastography; EFSUMB: European Federation of Societies for Ultrasound in Medicine and Biology; HVPG: hepatic venous pressure gradient; LS: liver stiffness; LR: likelihood ratio; NPV: negative predictive value; PPV: positive predictive value; ROI: region of interest; RT-E: Real Time-Elastography; Se: sensitivity; Sp: specificity; TE: Transient Elastography; US: ultrasound; VM: valid measurement; E: Young’s modulus

Background and Aim: Splenomegaly in a common finding in liver cirrhosis that should determine changes in the spleen's density because of portal and splenic congestion and/or because of tissue hyperplasia and fibrosis. These changes might be quantified by elastography, so the aim of the study was to investigate whether spleen stiffness measured by transient elastography varies as liver disease progresses and whether this would be a suitable method for the noninvasive evaluation of the presence of esophageal varices. Patients and Methods: One hundred and ninety-one patients (135 liver cirrhosis, 39 chronic hepatitis and 17 healthy controls) were evaluated by transient elastography for measurements of spleen and liver stiffness. Cirrhotic patients also underwent upper endoscopy for the diagnosis of esophageal varices. Results: Spleen stiffness showed higher values in liver cirrhosis patients as compared with chronic hepatitis and with controls: 60.96 vs 34.49 vs 22.01 KPa (P

The current study aimed to establish the liver stiffness (LS) cut-off values and their performance in the prediction of the fibrosis stage in chronic hepatitis C (CHC) patients, to find the anthropometric and biochemical factors leading to overestimation of the fibrosis stage and to analyze the factors leading to the technique failure.1,202 consecutive CHC patients were prospectively included in the study. All of them underwent percutaneous liver biopsy for grading and staging the disease (METAVIR) and were referred to LS measurement 1 day prior to biopsy.LS values varied between 2.8-75 kPa. Transient elastography success rate (SR) ranged between 0-100% (84.82 +/- 24.46%). In 27 patients (2.2%), no valid measurement was obtained; high BMI influenced independently the measurement failure. In 11.2% of cases, the SR was60%, but 10 valid measurements were nevertheless recorded; the female sex and high BMI were the only factors independently leading to a SR60%. AUROCs for the diagnosis of fibrosis F≥1, F≥2, F≥3, and F=4 were 0.879, 0.889, 0.941 and 0.970, for the cut-off values of 5.3 kPa, 7.4 kPa, 9.1 kPa and 13.2 kPa respectively, and they did not significantly differ from the adjusted AUROC values. The patients with false positive results were younger and had significantly higher serum aminotransferase (ALT, AST) and gamma glutamyl-transpeptidase levels than the patients with concordant results. The multivariate analysis showed that only high ALT levels influenced independently the occurrence of false positive results.Transient elastography is a useful non-invasive method for the assessment of fibrosis in CHC patients. However, it must be interpreted in the clinical and biochemical context, in order to insure high-quality results.

Noninvasive serum liver fibrosis markers and liver stiffness could be used as predictors of esophageal varices in cirrhotic patients because portal hypertension is related to liver fibrosis. The aim of this study was to compare the performance of common serum fibrosis scores and transient elastography in diagnosing esophageal varices and to propose a new algorithm for predicting large varices.231 consecutive cirrhotic patients (58.4% males, mean age 55.9 years) were enrolled. Routine biological tests were performed, so that APRI, FIB-4, Forns Index and Lok Score could be calculated. All patients underwent transient elastography and eso-gastroscopy. The diagnostic performance of the methods was assessed using sensitivity, specificity, positive predictive value, negative predictive value, accuracy, likelihood ratios and receiver operating characteristic curves.The Lok Score was the best among all the serum scores for diagnosing the varices. For a value higher than 0.8, it had a 45.5% positive predictive value, 86.4% negative predictive value and 67.72% diagnostic accuracy for prediction of large varices. For liver stiffness higher than 30.8KPa, the positive predictive value was 47.3%, negative predictive value 81% and diagnostic accuracy 68.32%. Using both tests simultaneously, the presence of large varices was predicted with a diagnostic accuracy of 78.12%, obtaining an increment in NPV and -LR up to 93.67% and 0.21, respectively.The Lok Score is a good predictor for excluding the presence of large varices in cirrhotic patients, similarly with liver stiffness. The two methods can be successfully combined into a noninvasive algorithm for the assessment of esophageal varices in cirrhotic patients.

Transient elastography (TE) is a noninvasive method for predicting liver fibrosis, mainly validated in patients with viral hepatitis. Information is still limited concerning its performance in non-alcoholic steatohepatitis (NASH) patients. We aimed to assess the value of TE in the prediction of fibrosis stage in NASH as well as the factors determining the discordance between the TE-predicted and the biopsy-proven fibrosis stage in these patients.Liver biopsy and TE were performed on 72 consecutive NASH patients. Fibrosis, lobular inflammation, ballooning and steatosis were evaluated (Brunt system).Liver stiffness (LS) values ranged from 2.80 to 16.90 kPa. In the univariate analysis, LS was correlated with fibrosis (r=0.661; p0.0001), steatosis (r=0.435, p0.0001), ballooning (r=0.385; p=0.001) and lobular inflammation (r=0.364; p=0.002). In multivariate analysis, only fibrosis significantly correlated with LS (p0.0001). The median (and range) LS values (kPa) according to the fibrosis stages were: 4.90 (2.80-7.30) for F0; 6.15 (4.80-12.50) for F1; 6.90 (3.30-16.90) for F2 and 14.00 (10.70-14.10) for F3, with significant difference between stages, except for F1-F2 (p=0.249). Cut off values were calculated for predicting each fibrosis stage: 5.3 kPa (AUROC=0.879) for F1; 6.8 kPa (AUROC=0.789) for F2; and 10.4 kPa (AUROC=0.978) for F3. Patients with false-positive results had a significantly higher ALT level than those with concordant results (p=0.039).In NASH patients, TE allows a reliable assessment and prediction of liver fibrosis, especially in advanced stages. Steatosis, ballooning and inflammation do not influence liver stiffness.

The current study aims to evaluate the performance of a new elastographic method (ARFI) in noninvasive fibrosis assessment and to compare it to another validated technology (transient elastography, TE).112 consecutive chronic hepatitis C patients (histologically proven according to the Metavir scoring system: 12.5% F0, 26.6% F1, 16.1% F2, 7.1% F3, 37.5% F4) were prospectively included in this study. They were examined on the same day, using both ARFI (with shear wave velocity--SWV-quantification) and TE (with liver stiffness quantification).SWV is correlated only with fibrosis (r=0.717, p less than 0.0001) and necroinflammatory activity (r=0.328, p=0.014), but not with steatosis (r=0.122, p=0.321). There is a significant increase of SWV in parallel with the increase in the fibrosis stage: 1.079+/-0.150 (F0-F1), 1.504+/-0.895 (F2), 1.520+/-0.575 (F3), 2.552+/-0.782 (F4), p0.0001, but there is a certain degree of overlap between the consecutive stages F1-F2 (p=0.072), F2-F3 (p=0.965). SWV cut-off values (m/s) that were predictive for each fibrosis stage were: 1.19 (F more or equal to 1), 1.34 (For=2), 1.61 (F more or equal to 3) and 2.00 (F4). AUROC for ARFI vs TE were: 0.709 vs 0.902, p=0.006 (For=1), 0.851 vs 0.941, p=0.022 (For=2), 0.869 vs 0.926, p=0.153 (For=3) and 0.911 vs 0.945, p=0.331 (F4).ARFI allows SWV quantification, in strong correlation with the fibrosis stage. Steatosis does not influence SWV. The maximal performance of the method consists of the prediction in severe fibrosis and cirrhosis. The diagnostic accuracy is strongly comparable to TE only for the prediction of severe fibrosis and cirrhosis, whereas for earlier stages, TE performs better.

The current study aims to assess the role of the histological parameters in liver biopsy for explaining the variance of liver stiffness, as well as the performance of transient elastography in quantifying liver fibrosis in patients with chronic hepatitis C.324 consecutive CHC patients were prospectively included in this study. All of them had positive HCV-RNA in serum and had underwent percutaneous liver biopsy for grading and staging the diseases (METAVIR scoring system). All were referred to liver stiffness measurement 1 day prior to biopsy.Liver stiffness values were strongly correlated with fibrosis (r=0.759, p0.0005). They also correlated with steatosis (r=0.255, p0.0005), necroinflammatory activity (r=0.378, p0.0005) and hepatic iron deposition (r=0.143, p=0.03). The univariate regression analysis demonstrated that fibrosis (sq.R=0.610, p0.0005), activity (sq.R=0.145, p0.0005) and steatosis (sq.R=0.037, p=0.002) were correlated with liver stiffness. In multiple regression analysis, all three variables independently influenced liver stiffness: fibrosis (p0.0005), activity (p=0.039) and steatosis (p=0.025). Together they explained 62.4% of the variance of the liver stiffness. The areas under ROC curve for the diagnosis of fibrosis For =1, For =2, For =3, and F=4 were 0.936, 0.862, 0.910 and 0.938, for the cut-off values of 4.9 kPa, 7.4 kPa, 9.1 kPa and 11.85 kPa respectively.Transient elastography is a useful method for chronic hepatitis C assessment. Fibrosis is the main predictor of liver stiffness, but activity and steatosis also influence liver stiffness.

Conclusions: The common PNPLA3 polymorphism confers an increased risk of liver fibrosis in patients with chronic liver diseases. This observation can be attributed to the additive harmful effects of hepatic fat accumulation and inflammation in response to chronic liver injury. Our findings point to a novel non-invasive genetic screening strategy to identify patients with chronic liver diseases at risk for cirrhosis.

Poster: "ECR 2010 / C-0101 / The diagnosis performance of ultrasonic transient elastography for noninvasive assessment of liver fibrosis in chronic hepatitis B patients" by: "M. Lupsor-Platon, R. Badea, H. Stefanescu, Z. Sparchez, H. Branda, A. Serban, A. Maniu; Cluj-Napoca/RO"

cellular mechanisms and utilization of high-throughput functional genomics analysis. We investigated the genomic and functional characteristics of liver tissues in chronic hepatitis B (CHB) patients. Methods: Liver biopsies were utilized in 139 CHB patients and pathological Scheuer stages were defined among the specimens. The Affymetrix GeneChipTM Human Genome U133A microarray, used to establish the gene expression signature. Genomic profiles and data analysis were obtained through GeneSpring 10 software. Gene Ontology annotations were used to assess functional characterization. Results: 1. Samples were clustered according to Scheuer’s stage groups (S0–S4: n =48; 23; 37; 17; 14). 2. Cluster analysis led to result supporting the conclusion that the gene expression profiles robustly reflected the Scheuer’s classification. 3. An Welch t-test, in order to find the significant differentially expressed genes between S1–4 groups and S0 group, generated a list of 1,451 genes (P-value = 5×10−6). Group-based comparisons for S4 versus S0, it showed over 2 times up-regulated genes (n =174) and down-regulated genes (n =45). Among up-regulated 174 genes, genes with function in the structural molecular activity were most frequently up-regulated (n =58, 26.7%), and genes involved in signal transduction (n =26, 12.0%) or cell adhesion (n =24, 11.1%) were less commonly upregulated respectively. (4) A detailed analysis of the pathways related to differentially expressed genes was characterized involved in activation of 164 signaling pathways (P ≤ 0.05) and 15 signaling pathways (P ≤ 0.001). Conclusions: Through analysis of gene expression profiles of liver tissues in CHB patients, we have identified a set of genes and signaling pathways defining a molecular portrait of fibrogenesis. The present study described differentially expressed genes throughout all stages of HBV-related fibrosis and nearly 50% genes of twice up-regulated with functions in structural molecular activity, signal transduction, and cell adhesion. Furthermore, many signaling pathways are activated during the transition to cirrhosis, including inflammatory/immune responses, cell proliferation, and apoptosis pathways.

Hepatic steatosis is a condition frequently encountered in clinical practice, with potential progression towards chirrhosis and hepatocellular carcinoma. Ultrasonography (US) is one of the noninvasive imaging techniques used in the diagnosis of steatosis. We will review the US diagnostic criteria, the US performance in the diagnosis and grading of hepatic steatosis, the US steatosis models, but also its limitations in the diagnosis of steatosis. In addition, we will discuss 2 modern methods of assessing hepatic steatosis using ultrasounds, namely the computerized processing of data forming the US image and the controlled attenuation parameter measured with unidimensional transient elastography.