Reply.

The diagnostic performance of supersonic shear imaging (SSI) in comparison with those of transient elastography (TE) and acoustic radiation force impulse imaging (ARFI) for staging fibrosis in nonalcoholic fatty liver disease (NAFLD) patients has not been fully assessed, especially in Asian populations with relatively lean NAFLD compared to white populations. Thus, we focused on comparing the diagnostic performances of TE, ARFI, and SSI for staging fibrosis in a head-to-head manner, and identifying the clinical, anthropometric, biochemical, and histological features which might affect liver stiffness measurement (LSM) in our prospective biopsy-proven NAFLD cohort. In this study, ninety-four patients with biopsy-proven NAFLD were included prospectively. Liver stiffness was measured using TE, SSI, and ARFI within 1 month of liver biopsy. The diagnostic performance for staging fibrosis was assessed using receiver operating characteristic (ROC) analysis. Anthropometric data were evaluated as covariates influencing LSM by regression analyses. Liver stiffness correlated with fibrosis stage (p < 0.05); the area under the ROC curve of TE (kPa), SSI (kPa), and ARFI (m/s) were as follows: 0.757, 0.759, and 0.657 for significant fibrosis and 0.870, 0.809, and 0.873 for advanced fibrosis. Anthropometric traits were significant confounders affecting SSI, while serum liver injury markers significantly confounded TE and ARFI. In conclusion, the LSM methods had similar diagnostic performance for staging fibrosis in patients with NAFLD. Pre-LSM anthropometric evaluation may help predict the reliability of SSI.

Assessment of liver fibrosis and steatosis is crucial in chronic liver diseases in order to determine the prognosis, the need of treatment, as well as monitor disease progression and response to treatment. Liver biopsy is limited by its invasiveness and patient acceptability. Transient elastography (TE, Fibroscan(®)) is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis and steatosis. TE has been well validated in major liver diseases including chronic hepatitis B and C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis. As alanine aminotransferase (ALT) is one of the major confounding factors of liver stiffness in chronic hepatitis B, an ALT-based algorithm has been developed and higher liver stiffness measurements (LSM) cutoff values for different stages of liver fibrosis should be used in patients with elevated ALT levels up to 5 times of the upper limit of normal. Otherwise falsely-high LSM results up to cirrhotic range may occur during ALT flare. TE is also useful in predicting patient prognosis such as development of hepatocellular carcinoma (HCC), portal hypertension, post-operative complications in HCC patients, and also survival. Unfortunately, failed acquisition of TE is common in obese patients. Furthermore, obese patients may have higher LSM results even in the same stage of liver fibrosis. The new XL probe, a larger probe with lower ultrasound frequency and deeper penetration, increases the success rate of TE in obese patients. The median LSM value with XL probe was found to be lower than that by the conventional M probe, hence cutoff values approximately 1.2 to 1.3 kPa lower than those of M probe should be adopted. Recent studies revealed a novel ultrasonic controlled attenuation parameter (CAP) of the machine is a useful parameter to detect even low-grade steatosis noninvasively. CAP may also be used to quantify liver steatosis by applying different cutoff values. As both LSM and CAP results are instantly available at same measurement, this makes TE a very convenient tool to assess any patients who are suspected or confirmed to suffer from chronic liver diseases.

Bridging the Gap: Screening for Nonalcoholic Fatty Liver Disease in the Primary Care Population

To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 ± 7.23 kPa) compared to Wilson disease (8.30 ± 0.84 kPa) and HCV groups (7.43 ± 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable associated with higher LSM (P < 0.0001). TE appears reliable in distinguishing different stages of liver fibrosis in children. However, its values vary according to the disease type. For that, a disease-specific estimation of cut-off values for fibrosis staging is worthy.

Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

To compare liver stiffness measurement (LSM) provided by Canon 2D-shear wave elastography (2D-SWE) and transient elastography (TE), the latter being the reference method. Prospective study conducted in four European centres from 2015 to 2016 including patients with various chronic liver diseases who had LSMs with both 2D-SWE and TE on the same day. Median of 10 valid measurements (in kPa) was used for comparison using paired t test, Pearson correlation, intraclass correlation coefficient (ICC) and Bland-Altman plot. The ability of 2D-SWE to stratify patient according to recognised LSM-TE thresholds was assessed by ROC curve analysis. Six hundred forty patients were scanned, where 593 (92.7%), 572 (89.4%) and 537 (83.9%) had reliable LSMs by TE, 2D-SWE and both combined, respectively. In the latter (n = 537, 310 [57.7%] male, mean 55.3 ± 14.8 years), median LSM-TE and LSM-2D-SWE had a mean of 10.1 ± 9.4 kPa (range 2.4-75) and 9.1 ± 6.1 kPa (range 3.6-55.7) (paired t test: p < 0.001), respectively. These were significantly correlated (Pearson r = 0.932, p < 0.001, ICC 0.850 (0.825-0.872), bias 0.99 ± 4.33 kPa [95% limits of agreement - 9.48 to + 7.49] with proportional error towards higher LSM values). LSM-2D-SWE values significantly increased with TE categories (ANOVA: p < 0.001). AUROCs ranged from 0.935 ± 0.010 (95% CI 0.910-0.954) to 0.973 ± 0.009 (95% CI 0.955-0.985), resulting in correct classification of 390/537 (73%) patients. Three 2D-SWE measurements were sufficient for reliable LSMs. LSM using 2D-SWE correlates well with TE. It tends to underestimate higher stages of liver fibrosis but correctly classifies the majority of patients. It may be used in TE-derived algorithms to manage patients. • Liver stiffness measurement (LSM) by 2D-shear wave elastography (2D-SWE) and transient elastography (TE) are strongly correlated. • 2D-SWE shows proportionately lower LSM values compared to TE, particularly with the higher LSM range. • Three individual measurements by 2D-SWE are sufficient to assess LSM reliably.

We thank Drs. Sharma and Arora for their comments regarding our study describing the utility of the FibroScan XL probe for liver stiffness measurement (LSM) in overweight and obese patients with various liver disorders.1 The findings of their single-center, Indian study suggest that LSM using the FibroScan M probe may be unnecessary in light of the high success rate of the XL probe. In our multicenter study of a heavier cohort (median body mass index [BMI] 30 kg/m2 versus 25 to 26 kg/m2 in their study), FibroScan failure occurred in only 1% of patients with the XL probe versus 16% with the M probe. Corresponding rates of reliability (valid shots ≥10, success rate ≥60%, and IQR/M ≤30%) were 73% and 50% with the XL and M probes, respectively. Had we taken the approach of Sharma and Arora and first measured patients with the XL probe, reserving the M probe for those with unreliable XL probe results, an additional 27% (20/74) of patients (7% of the total) would be reliably measured with the M probe (Fig. 1). Depending on the outcome of interest (i.e., transient elastography [TE] failure versus reliability), the latter data suggest that the M probe still has a role for LSM, even among overweight and obese patients. If one examines the characteristics of patients with unreliable XL probe measurements, those who were reliably measured with the M probe were lighter (median BMI 32 versus 36 kg/m2; P = 0.008) and were less likely to have a skin-capsular distance exceeding 25 mm (the measurement depth of the M probe; 30% versus 55%; P = 0.07) than those in whom the M probe was unreliable. Reliability of liver stiffness measurement (≥10 valid measurements, IQR/M ≤30%, and success rate ≥60%) using the XL and M probes (*). Before discarding the FibroScan M probe as a useful tool for measuring liver stiffness, additional considerations warrant discussion. Importantly, the larger diameter of the tip of the XL probe (12 mm versus 9 mm with the M probe) may lead to a higher rate of LSM failure or LSM overestimation in smaller adults with narrow intercostal spaces due to interference from the ribs with shear wave propagation and measurement. Due to the limited data describing use of the XL probe in nonobese individuals, the magnitude of this potential problem is unclear. Second, as confirmed by our study and others,1-3 LSMs obtained using the M and XL probes differ systematically due to their different regions of interest (25-65 mm from the skin for the M probe and 35-75 mm with the XL probe). In patients who can be successfully measured with both probes, liver stiffness measured using the XL probe is 1 to 2 kPa lower than that of the M probe.1 Because liver stiffness thresholds will therefore differ by probe (and disease etiology), additional research would be necessary to define the optimal thresholds for use with the XL probe in nonobese individuals. In light of the hundreds of publications that have documented the performance of the M probe for LSM in these patients, it is far too early to recommend use of the XL probe in all patients. Robert P. Myers M.D., M.Sc.*, * Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.

BackgroundFibroScan® Expert 630 is a novel fibroscan device equipped with SmartExam software, which allows continuous measurement of controlled attenuation parameter (CAP) during the entire examination and automatic measurement depths adaption...

Transient elastography (TE) can reliably stage liver fibrosis via liver stiffness measurement (LSM) in chronic liver disease. However, the accuracy of TE for assessment of liver fibrosis in patients with autoimmune hepatitis (AIH) is still limited. We evaluate TE in staging liver fibrosis in AIH patients and compare with other noninvasive diagnostic tools. A total of 100 patients with biopsy-proven AIH were included. The correlation between LSM and fibrosis stage was analyzed using Spearman correlation test. The optimal cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. The diagnostic accuracy of LSM for severe fibrosis was compared with those of serum biochemical scores. Median LSM in AIH patients was higher than that of healthy controls (11.2 ± 8.2 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM had significant correlation with fibrosis (r = 0.752, P < 0.01) and increased progressively with increasing fibrosis stages in AIH patients. AUROC values of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.878 (95%CI: 0.789-0.967), 0.883 (0.820-0.946), and 0.914 (0.852-0.976), respectively. The optimal cut-off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.45, 8.75, and 12.50 kPa, respectively. LSM was superior to APRI score and FIB-4 score in detecting severe fibrosis (F ≥ 3). Serum ALT levels had minor effect on LSM values. Transient elastography is an accurate and reliable noninvasive tool in assessing liver fibrosis in AIH. Hepatic inflammatory activity had no significant effect on LSM determination.

Reply

Combined alcoholic and non-alcoholic steatohepatitis.

To perform head-to-head comparisons of the feasibility and diagnostic performance of transient elastography (TE), point shear-wave elastography (pSWE), and magnetic resonance elastography (MRE). This prospective, cross-sectional, dual-center imaging study included 100 patients with known or suspected chronic liver disease caused by hepatitis B or C virus, nonalcoholic fatty liver disease, or autoimmune hepatitis identified between 2014 and 2018. Liver stiffness measured with the three elastographic techniques was obtained within 6weeks of a liver biopsy. Confounding effects of inflammation and steatosis on association between fibrosis and liver stiffness were assessed. Obuchowski scores and AUCs for staging fibrosis were evaluated and the latter were compared using the DeLong method. TE, pSWE, and MRE were technically feasible and reliable in 92%, 79%, and 91% subjects, respectively. At univariate analysis, liver stiffness measured by all techniques increased with fibrosis stages and inflammation and decreased with steatosis. For classification of dichotomized fibrosis stages, the AUCs were significantly higher for distinguishing stages F0 vs. ≥ F1 with MRE than with TE (0.88 vs. 0.71; p < 0.05) or pSWE (0.88 vs. 0.73; p < 0.05), and for distinguishing stages ≤ F1 vs. ≥ F2 with MRE than with TE (0.85 vs. 0.75; p < 0.05). TE, pSWE, and MRE Obuchowski scores for staging fibrosis stages were respectively 0.89 (95% CI 0.85-0.93), 0.90 (95% CI 0.85-0.94), and 0.94 (95% CI 0.91-0.96). MRE provided a higher diagnostic performance than TE and pSWE for staging early stages of liver fibrosis. NCT02044523 KEY POINTS: • The technical failure rate was similar between MRE and US-based elastography techniques. • Liver stiffness measured by MRE and US-based elastography techniques increased with fibrosis stages and inflammation and decreased with steatosis. • MRE provided a diagnostic accuracy higher than US-based elastography techniques for staging of early stages of histology-determined liver fibrosis.

Supersonic shear imaging (SSI) is a new ultrasound-based technique for real-time visualization of soft tissue viscoelastic properties. Using ultrasonic focused beams, it is possible to remotely generate mechanical vibration sources radiating low-frequency, shear waves inside tissues. Relying on this concept, SSI proposes to create such a source and make it move at a supersonic speed. In analogy with the "sonic boom" created by a supersonic aircraft, the resulting shear waves will interfere constructively along a Mach cone, creating two intense plane shear waves. These waves propagate through the medium and are progressively distorted by tissue heterogeneities. An ultrafast scanner prototype is able to both generate this supersonic source and image (5000 frames/s) the propagation of the resulting shear waves. Using inversion algorithms, the shear elasticity of medium can be mapped quantitatively from this propagation movie. The SSI enables tissue elasticity mapping in less than 20 ms, even in strongly viscous medium like breast. Modalities such as shear compounding are implementable by tilting shear waves in different directions and improving the elasticity estimation. Results validating SSI in heterogeneous phantoms are presented. The first in vivo investigations made on healthy volunteers emphasize the potential clinical applicability of SSI for breast cancer detection.

Supersonic shear imaging (SSI) is a new ultrasound based technique for real time visualization of soft tissue viscoelastic properties. Using ultrasound focused beams, it is possible to remotely generate inside the body mechanical sources radiating low frequency shear waves. SSI is based on the ultrasonic generation of a shear source moving at a supersonic speed inside the body. In a complete analogy with the "sonic boom" created by a supersonic aircraft, the resulting shear waves will constructively interfere along a Mach cone, creating two intense plane waves. These plane shear waves propagate through the medium and are progressively distorted by tissue mechanical inhomogeneities. The ultrafast scanner developed in our laboratory (5000 images/s) is able to generate this supersonic source and image, in real time, the propagation of the resulting shear waves. Using inversion algorithms, viscosity and elasticity maps of the medium can be deduced from this shear wave propagation movie. Creating such a supersonic regime enables quantitative tissue elasticity mapping in less than 20 ms, even in strongly viscous medium like breast or liver. Results validating SSI for quantitative shear elasticity mapping in heterogeneous tissue mimicking phantoms are presented. Detection of in vitro thermally-induced lesions on fresh tissue samples is shown. In vivo tests made on healthy volunteers show the potential clinical applicability of SSI for breast cancer detection. Finally, viscosity mapping using SSI has been studied theoretically and experimentally. Based on a Voigt model, simulations in different viscous and elastic media were compared and fitted to in vitro experiments. Using this theoretical background, viscosity maps using SSI were for the first time derived in viscoelastic phantoms.

To compare point shear wave elastography (pSWE, ElastPQ®) and transient elastography (TE) with Liver Biopsy in order to evaluate fibrosis stage in non-alcoholic fatty liver disease (NAFLD). Our prospective study from September 2017 to October 2020 included 50 consecutively enrolled patients with NAFLD (52.2 ± 13.0years, 32 male). All patients underwent clinical evaluation, B-mode ultrasound, pSWE, TE and liver biopsy in a single evaluation. The clinical, laboratory and liver biopsy data were compared with liver stiffness (LS) measurement obtained with pSWE and TE. TE and pSWE diagnostic accuracy for the diagnosis of the different fibrosis stages were evaluated using the area under receiver operating characteristic curve (AUROC). Only fibrosis stage was independently associated with TE and pSWE. The median liver stiffness measurement for fibrosis stages F0, F1, F2, F3, and F4 using TE was 4.8 (4.7-6.1) kPa, 5.5 (4.4-7.3) kPa, 7.7 (6.1-9.1) kPa, 9.9 (8.8-13.8) kPa, and 20.2kPa, respectively. The corresponding median liver stiffness measurement using pSWE was 4.2 (4.0-4.8) kPa, 4.7 (4.2-5.8) kPa, 5.1 (4.1-6.9) kPa, 8.5 (5.2-13.3), and 15.1kPa, respectively. The AUROC of TE for diagnosis of fibrosis stage F1, ≥ F2, ≥ F3, and F4 were 0.795, 0.867, 0.927, and 0.990, respectively. The corresponding AUROC of pSWE was 0.717, 0.733, 0.908, and 1.000, respectively. No association was observed with other histological parameters. TE was significantly better than pSWE for the diagnosis of fibrosis stage ≥ F2. No statistically significant differences were found between TE and pSWE AUROC of fibrosis stage ≥ F1, ≥ F3, and F4.