Jean-Baptiste Hiriart

Non-invasive assessment of liver fibrosis with impulse elastography: Comparison of Supersonic Shear Imaging with ARFI and FibroScan®

BACKGROUND & AIMS Non-invasive assessment of liver fibrosis by elastography is a rapidly developing field with frequent technological innovations. The aim of this study was to assess the diagnostic performances of Supersonic Shear Imaging (SSI) for the diagnosis of liver fibrosis in chronic liver disease. METHODS A total of 349 consecutive patients with chronic liver diseases who underwent liver biopsy from November 2011 to October 2013 were prospectively enrolled. For each patient, liver stiffness was assessed by SSI, ARFI, FibroScan® (M probe for patients with BMI <30 kg/m(2), and XL probe for patients with BMI ⩾30 kg/m(2)), performed within two weeks of liver biopsy. Areas under the receiver operating curves (AUROCs) were performed and compared for each degree of liver fibrosis. RESULTS SSI, FibroScan®, and ARFI correlated significantly with histological fibrosis score (r=0.79, p<0.00001; r=0.70, p<0.00001; r=0.64, p<0.00001, respectively). AUROCs of SSI, FibroScan®, and ARFI were 0.89, 0.86, and 0.84 for the diagnosis of mild fibrosis; 0.88, 0.84, and 0.81 for the diagnosis of significant fibrosis; 0.93, 0.87, and 0.89, for the diagnosis of severe fibrosis; 0.93, 0.90, and 0.90 for the diagnosis of cirrhosis, respectively. SSI had a higher accuracy than FibroScan® for the diagnosis of severe fibrosis (⩾F3) (p=0.0016), and a higher accuracy than ARFI for the diagnosis of significant fibrosis (⩾F2) (p=0.0003). No significant difference was observed for the diagnosis of mild fibrosis and cirrhosis. CONCLUSIONS SSI is an efficient method for the assessment of liver fibrosis in chronic liver diseases, comparing favourably to FibroScan® and ARFI.

Controlled attenuation parameter (CAP) for the diagnosis of steatosis: A prospective study of 5323 examinations

BACKGROUND & AIMS Controlled attenuation parameter (CAP) evaluated with transient elastography (FibroScan®) is a recent method for non-invasive assessment of steatosis. Its usefulness in clinical practice is unknown. We prospectively investigated the determinants of CAP failure and the relationships between CAP and clinical or biological parameters in a large cohort of consecutive patients. METHODS All CAP examinations performed in adult patients with suspected chronic liver disease were included. CAP failure was defined as zero valid shot. The following factors were analyzed for their influence on CAP value and the relationships between CAP and clinico-biological parameters: age, gender, body mass index, waist circumference, hypertension, diabetes, metabolic syndrome, alcohol use, liver stiffness measurement, indication, and different biological parameters. RESULTS CAP failure occurred in 7.7% of 5323 examinations. By multivariate analysis, factors independently associated with CAP measurement failure were female gender, BMI, and metabolic syndrome. By multivariate analysis, factors significantly associated with elevated CAP were BMI [25-30]kg/m(2), BMI >30kg/m(2), metabolic syndrome, alcohol >14 drink/week and liver stiffness >6kPa. CAP increased with the number of parameters of metabolic syndrome, BMI, waist circumference, the presence of diabetes or hypertension, and the cause of the disease. In the 440 patients with liver biopsy, for the diagnosis of steatosis >10%, steatosis >33%, and steatosis >66%, AUROCs of CAP were 0.79 (95% CI 0.74-0.84, p<0.001), 0.84 (95% CI 0.80-0.88, p<0.001), 0.84 (95% CI 0.80-0.88, p<0.001), respectively. CONCLUSIONS CAP provides an immediate assessment of steatosis simultaneously with liver stiffness measurement. The strong association of CAP with the metabolic syndrome and alcohol use could be of interest for the follow-up of NAFLD or alcoholic patients.

Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy

Nonalcoholic fatty liver disease (NAFLD) has become a major public health issue. The goal of this study was to assess the clinical use of liver stiffness measurement (LSM) evaluated by supersonic shear imaging (SSI), FibroScan, and acoustic radiation force impulse (ARFI) in a cohort of NAFLD patients who underwent liver biopsy. A total of 291 NAFLD patients were prospectively enrolled from November 2011 to February 2015 at 2 French university hospitals. LSM was assessed by SSI, FibroScan (M probe), and ARFI within two weeks prior to liver biopsy. Calculations of the area under the receiver operating curve (AUROC) were performed and compared for the staging of liver fibrosis. AUROC for SSI, FibroScan, and ARFI were 0.86, 0.82, and 0.77 for diagnoses of ≥F2; 0.89, 0.86, and 0.84 for ≥F3; and 0.88, 0.87, and 0.84 for F4, respectively. SSI had a higher accuracy than ARFI for diagnoses of significant fibrosis (≥F2) (P = 0.004). Clinical factors related to obesity such as body mass index ≥ 30 kg/m2, waist circumference ≥102 cm or increased parietal wall thickness were associated with LSM failures when using SSI or FibroScan and with unreliable results when using ARFI. In univariate analysis, FibroScan values were slightly correlated with NAFLD activity score and steatosis (R = 0.28 and 0.22, respectively), whereas SSI and ARFI were not; however, these components of NAFLD did not affect LSM results in multivariate analysis. The cutoff values for SSI and FibroScan for staging fibrosis with a sensitivity ≥90% were very close: 6.3/6.2 kPa for ≥F2, 8.3/8.2 kPa for ≥F3, and 10.5/9.5 kPa for F4. Conclusion: Although obesity is associated with an increase in LSM failure, the studied techniques and especially SSI provide high value for the diagnosis of liver fibrosis in NAFLD patients. (Hepatology 2016;63:1817‐1827)

Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease

BACKGROUND & AIMS NAFLD is highly prevalent but only a small subset of patients develop advanced liver fibrosis with impaired liver-related prognosis. We aimed to compare blood fibrosis tests and liver stiffness measurement (LSM) by FibroScan for the diagnosis of liver fibrosis and the evaluation of prognosis in NAFLD. METHODS Diagnostic accuracy was evaluated in a cross-sectional study including 452 NAFLD patients with liver biopsy (NASH-CRN fibrosis stage), LSM, and eight blood fibrosis tests (BARD, NAFLD fibrosis score, FibroMeter(NAFLD), aspartate aminotransferase to platelet ratio index (APRI), FIB4, FibroTest, Hepascore, FibroMeter(V2G)). Prognostic accuracy was evaluated in a longitudinal study including 360 NAFLD patients. RESULTS LSM and FibroMeter(V2G) were the two best-performing tests in the cross-sectional study: AUROCs for advanced fibrosis (F3/4) were, respectively, 0.831±0.019 and 0.817±0.020 (p⩽0.041 vs. other tests); rates of patients with ⩾90% negative/positive predictive values for F3/4 were 56.4% and 46.7% (p<0.001 vs. other tests); Obuchowski indexes were 0.834±0.014 and 0.798±0.016 (p⩽0.036 vs. other tests). Two fibrosis classifications were developed to precisely estimate the histological fibrosis stage from LSM or FibroMeter(V2G) results without liver biopsy (diagnostic accuracy, respectively: 80.8% vs. 77.4%, p=0.190). Kaplan-Meier curves in the longitudinal study showed that both classifications categorised NAFLD patients into subgroups with significantly different prognoses (p<0.001): the higher was the class of the fibrosis classification, the worse was the prognosis. CONCLUSIONS LSM and FibroMeter(V2G) were the most accurate of nine evaluated tests for the non-invasive diagnosis of liver fibrosis in NAFLD. LSM and FibroMeter(V2G) fibrosis classifications help physicians estimate both fibrosis stage and patient prognosis in clinical practice. LAY SUMMARY The amount of liver fibrosis is the main determinant of the liver-related prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated eight blood tests and FibroScan in a cross-sectional diagnostic study and found that FibroScan and the blood test FibroMeter(V2G) were the two most accurate tests for the non-invasive evaluation of liver fibrosis in NAFLD. A longitudinal prognostic study showed these two tests initially developed for the diagnosis are also prognostic markers as they allow for the stratification of NAFLD patients in several subgroups with significantly different prognosis.

Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values

Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132‐298, middle 299‐338, higher 339‐400 dB/m). Among patients with F0‐F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3‐F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848‐0.982; 0.830, 0.753‐0.908; 0.806, 0.723‐0.890). As a consequence, in subjects with F0‐F2 fibrosis, the rates of false‐positive LSM results for F3‐F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. Conclusions: In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145‐1155).

Rnd3/RhoE Is down‐regulated in hepatocellular carcinoma and controls cellular invasion

We performed a review of public microarray data that revealed a significant down‐regulation of Rnd3 expression in hepatocellular carcinoma (HCC), as compared to nontumor liver. Rnd3/RhoE is an atypical RhoGTPase family member because it is always under its active GTP‐bound conformation and not sensitive to classical regulators. Rnd3 down‐regulation was validated by quantitative real‐time polymerase chain reaction in 120 independent tumors. Moreover, Rnd3 down‐expression was confirmed using immunohistochemistry on tumor sections and western blotting on human tumor and cell‐line extracts. Rnd3 expression was significantly lower in invasive tumors with satellite nodules. Overexpression and silencing of Rnd3 in Hep3B cells led to decreased and increased three‐dimensional cell motility, respectively. The short interfering RNA‐mediated down‐regulation of Rnd3 expression induced a loss of E‐cadherin at cell‐cell junctions that was linked to epithelial‐mesenchymal transition through the up‐regulation of the zinc finger E‐box binding homeobox protein, ZEB2, and the down‐regulation of miR‐200b and miR‐200c. Rnd3 knockdown mediated tumor hepatocyte invasion in a matrix‐metalloproteinase–independent, and Rac1‐dependent manner. Conclusion: Rnd3 down‐regulation provides an invasive advantage to tumor hepatocytes, suggesting that RND3 might represent a metastasis suppressor gene in HCC. (HEPATOLOGY 2012;55:1766–1775)

Liver and spleen elastography using supersonic shear imaging for the non-invasive diagnosis of cirrhosis severity and oesophageal varices

BACKGROUND Elastography is a promising non-invasive approach for assessing liver fibrosis. We assessed diagnostic performances of liver and spleen stiffness using supersonic shear imaging for diagnosing cirrhosis severity and oesophageal varices. METHODS 401 consecutive cirrhotic patients were prospectively enrolled from November 2012 to March 2014. All patients underwent liver and spleen stiffness measurement with supersonic shear imaging and Fibroscan. RESULTS Failures of measurement were 6.2% and 29.2% for liver and spleen stiffness (supersonic shear imaging), and 18.4% for liver stiffness (Fibroscan). Liver and spleen stiffness were correlated with severity of cirrhosis, with values increasing according to Child-Pugh subclasses and presence of complications. With a negative predictive value ≥90%, liver stiffness cut-offs for high-risk oesophageal varices, history of ascites, Child-Pugh B/C, variceal bleeding and clinical decompensation were 12.8, 19, 21.4, 30.5, and 39.4 kPa, respectively. Areas under the curve of spleen and liver stiffness (supersonic shear imaging), and liver stiffness (Fibroscan) were 0.80, 0.77 and 0.73 respectively for detection of oesophageal varices. CONCLUSION Liver stiffness using supersonic shear imaging is a relevant diagnostic tool for assessing cirrhosis severity and its complications. Spleen stiffness shows promising results for the detection of oesophageal varices but is not yet sufficiently robust for clinical practice owing to high failure rates.

Liver stiffness measurements for evaluation of central venous pressure in congenital heart diseases

Objective Transient elastography (TE; Fibroscan, Echosens, France) is a non-invasive and reproducible approach to assess liver stiffness (LS). LS has been reported to be associated with fibrosis but central venous pressure (CVP) can also influence LS values. We sought to evaluate the correlation between LS and CVP in a large cohort of children and adults with congenital heart disease. Methods All patients referred in our institution between 2012 and 2013 for diagnostic or interventional right heart catheterisation (RHC) were prospectively enrolled excluding patients with acute heart failure, chronic alcohol abuse, chronic liver disease, severe obesity and ascites. Patients underwent LS measurement and CVP measurement by RHC under general anaesthesia within the same or subsequent day. Results Sixty children (7.4±5.5 years) and 36 adults (38±16 years) were included. Median CVP was 6 mm Hg (range 3–15), median LS was 5 kPa (range 2.8–47.2). LS significantly correlated with CVP (r=0.75, p<10−4). In the two subgroups (ie, children and adults), correlation was r=0.68 and r=0.84 (p<10−4), respectively. In the overall population, the area under the curve of LS for identification of CVP >10 mm Hg was 0.972 (95% CI 0.855 to 1; p<0.05). Optimal cut-off value of LS for detection of CVP >10 mm Hg was 8.8 kPa (sensitivity=91.67%, specificity=96.25%). Conclusions LS measurement using TE is a rapid and reliable method to evaluate CVP in patients with congenital heart disease.

Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter

BACKGROUND & AIMS Controlled attenuation parameter (CAP) can be performed together with liver stiffness measurement (LSM) by transient elastography (TE) and is often used to diagnose fatty liver. We aimed to define the validity criteria of CAP. METHODS CAP was measured by the M probe prior to liver biopsy in 754 consecutive patients with different liver diseases at three centers in Europe and Hong Kong (derivation cohort, n=340; validation cohort, n=414; 101 chronic hepatitis B, 154 chronic hepatitis C, 349 non-alcoholic fatty liver disease, 37 autoimmune hepatitis, 49 cholestatic liver disease, 64 others; 277 F3-4; age 52±14; body mass index 27.2±5.3kg/m2). The primary outcome was the diagnosis of fatty liver, defined as steatosis involving ≥5% of hepatocytes. RESULTS The area under the receiver-operating characteristics curve (AUROC) for CAP diagnosis of fatty liver was 0.85 (95% CI 0.82-0.88). The interquartile range (IQR) of CAP had a negative correlation with CAP (r=-0.32, p<0.001), suggesting the IQR-to-median ratio of CAP would be an inappropriate validity parameter. In the derivation cohort, the IQR of CAP was associated with the accuracy of CAP (AUROC 0.86, 0.89 and 0.76 in patients with IQR of CAP <20 [15% of patients], 20-39 [51%], and ≥40dB/m [33%], respectively). Likewise, the AUROC of CAP in the validation cohort was 0.90 and 0.77 in patients with IQR of CAP <40 and ≥40dB/m, respectively (p=0.004). The accuracy of CAP in detecting grade 2 and 3 steatosis was lower among patients with body mass index ≥30kg/m2 and F3-4 fibrosis. CONCLUSIONS The validity of CAP for the diagnosis of fatty liver is lower if the IQR of CAP is ≥40dB/m. Lay summary: Controlled attenuation parameter (CAP) is measured by transient elastography (TE) for the detection of fatty liver. In this large study, using liver biopsy as a reference, we show that the variability of CAP measurements based on its interquartile range can reflect the accuracy of fatty liver diagnosis. In contrast, other clinical factors such as adiposity and liver enzyme levels do not affect the performance of CAP.

Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD.

The accuracy of available non‐invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited.