Transient elastography: Kill two birds with one stone?

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...

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.

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

Reply to: Correspondence on “EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update”

BACKGROUNDHepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIMTo investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs).METHODSPatients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTSAmong 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSIONCAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. This study aimed to evaluate the performance of four ultrasound-based techniques for the non-invasive multiparametric (MPUS) assessment of liver fibrosis (LF), steatosis (HS), and inflammation in patients with NAFLD. We included 215 consecutive adult patients with NAFLD (mean age: 54.9 ± 11.7; 54.5% were male), in whom LF, HS, and viscosity were evaluated in the same session using four new ultrasound-based techniques embedded on the Aixplorer MACH 30 system: ShearWave Elastography (2D-SWE.PLUS), Sound Speed Plane-wave UltraSound (SSp.PLUS), Attenuation Plane-wave UltraSound (Att.PLUS), and Viscosity Plane-wave UltraSound (Vi.PLUS). Transient Elastography (TE) with Controlled Attenuation Parameter (CAP) (FibroScan) were considered as control. All elastographic measurements were performed according to guidelines. Valid liver stiffness measurements (LSM) were obtained in 98.6% of patients by TE, in 95.8% of patients by 2D-SWE.PLUS/Vi.PLUS, and in 98.1% of patients by Att.PLUS/SSp.PLUS, respectively. Therefore, 204 subjects were included in the final analysis. A strong correlation between LSMs by 2D-SWE.PLUS and TE (r = 0.89) was found. The best 2D-SWE.PLUS cut-off value for the presence of significant fibrosis (F ≥ 2) was 7 kPa. Regarding steatosis, SSp.PLUS correlated better than Att.PLUS with CAP values: (r = −0.74) vs. (r = 0.45). The best SSp.PLUS cut-off value for predicting the presence of significant steatosis was 1524 m/s. The multivariate regression analysis showed that Vi.PLUS values were associated with BMI and LSM by 2D-SWE.PLUS. In conclusion, MPUS was useful for assessing fibrosis, steatosis, and inflammation in a single examination in patients with NAFLD.

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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.

Reply.

Chronic liver diseases (CLD) present important clinical problem in children with various age-dependent causes. Nonalcoholic fatty liver disease (NAFLD) with its increasing prevalence is a major problem with regard to its timely recognition and the need for long-term disease monitoring. At present, a perfect non-invasive method for the evaluation of liver fibrosis is not available. A non-systematic literature search was performed to summarize the current knowledge about transient elastography (TE) with controlled attenuation parameter (CAP) in children with CLD. Ovid MEDLINE, Ovid EMBASE, Google scholar, and The Cochrane Library databases were searched for relevant articles evaluating TE in the pediatric population. Normal values of liver stiffness measurements (LSM) according to the age are given, as well as the advantages and disadvantages of the method. The utility of TE in specific liver disease in pediatric population is summarized. TE with CAP is a valuable non-invasive method for the liver-damage assessment. Clinical interpretation of TE results should be made in parallel with the assessment of the patient's demographics, disease etiology, and essential laboratory parameters.

Combined alcoholic and non-alcoholic steatohepatitis.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum that progresses through stages of liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). NAFLD has more than doubled in incidence over the last decade alongside the obesity pandemic, and Latinos are at least twice as likely to be affected. The key clinical challenge is how to efficiently screen high-risk communities to identify individuals with severe steatosis and advanced fibrosis or cirrhosis who would benefit from lifestyle modifications, therapeutics, or cancer surveillance. A high proportion of patients with NAFLD are asymptomatic for long periods of time with normal laboratory tests, thus non-invasive procedures for early identification are needed. Transient elastography (TE) is a validated non-invasive diagnostic tool which can identify patients with liver disease. Methods: From March-June 2019, we recruited 76 Latino participants attending a community health screening event in Los Angeles to determine the prevalence of undiagnosed liver disease. We utilized TE performed with a FibroScan® (Echosens) to produce liver stiffness measurement (LSM, a measure of fibrosis in kPa) and a controlled attenuation parameter (CAP, a measure of steatosis in dB/m) on fasting participants, and we collected a self-administered questionnaire for basic characteristics and past medical history, offered in Spanish or English. Results: A total of 74 participants had a valid test with a minimum of ten LSMs with an interquartile range/median value less than 0.3. The mean age of participants was 50 years, and 65% were female. For metabolic risk factors, 78% were overweight or obese, with a mean BMI of 29.5 kg/m2, and the percentage of participants with diabetes or high blood pressure was 29% and 15%, respectively. A minority of participants (4%) reported drinking alcohol 2-3 times per week or more. As for prior liver disease, 16% of participants reported a prior diagnosis of chronic liver disease: NAFLD (N=11), hepatitis B virus (N=1), or cholestatic disease (N=1). In subsequent analyses, we excluded participants with known liver disease. The TE data generated show that steatosis was present in 66% of participants (4% mild, 13% moderate, 49% severe steatosis), with a mean CAP of 273.9 dB/m. The mean LSM in this population was 5.8 kPa, with 22% of participants having kPa measure equivalent to a moderate fibrosis grade (F2 or greater). In univariate analyses, LSM was positively associated with BMI (P= 0.008) and CAP (P&amp;lt;0.001); CAP was positive associated with age (P=0.004) and BMI (P&amp;lt;0.001). In multiple linear regression, CAP (P=0.015), but not BMI, was significantly associated with LSM; and BMI (P&amp;lt;0.001) and age (P&amp;lt;0.002) were both significantly associated with CAP. Conclusion: This study demonstrates the feasibility of using TE at a community-based health screening in a high-risk population. We detected a high rate of clinically significant fibrosis and steatosis suggesting a high prevalence of undiagnosed NAFLD among Latinos. Citation Format: Shehnaz Hussain, Jihane Benhammou. Community-based screening for nonalcoholic fatty liver disease with transient elastography in Latinos without overt liver disease at high risk of hepatocellular carcinoma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C090.

Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10kPa or <20kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n= 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p= 0.004) and mortality (hazard ratio 3.22, p= 0.01). LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII.

PurposeThis study compared the controlled attenuation parameter (CAP) to attenuation imaging (ATI) in the diagnosis of steatosis and transient elastography (TE) to two-dimensional shear wave elastography (2D-SWE) for the diagnosis of fibrosis in a prospectively constructed nonalcoholic fatty liver disease (NAFLD) patient cohort.MethodsParticipants who underwent TE with CAP were included from a previously constructed NAFLD cohort with multiparametric ultrasound data. The degree of hepatic steatosis and stage of liver fibrosis were assessed. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) for the grades of steatosis (S1-3) and fibrosis (F0-F4).ResultsThere were 105 participants. The distribution of hepatic steatosis grades (S0-S3) and liver fibrosis stages (F0-F4) was as follows: S0, n=34; S1, n=41; S2, n=22; S3, n=8; F0, n=63; F1, n=25; F2, n=5; F3, n=7; and F4, n=5. No significant difference was found between CAP and ATI in detecting ≥S1 (AUROC: 0.93 vs. 0.93, P=0.956) or ≥S2 (0.94 vs. 0.94, P=0.769). However, the AUROC of ATI in detecting ≥S3 was significantly higher than that of CAP (0.94 vs. 0.87, P=0.047). Regarding the detection of liver fibrosis, no significant difference was found between TE and 2D-SWE. The AUROCs of TE and 2D-SWE were as follows: ≥F1, 0.94 vs. 0.89 (P=0.107); ≥F2, 0.89 vs. 0.90 (P=0.644); ≥F3, 0.91 vs. 0.90 (P=0.703); and ≥F4, 0.88 vs. 0.92 (P=0.209).Conclusion2D-SWE and TE showed comparable diagnostic performance in assessing liver fibrosis, and ATI provided significantly better performance in detecting ≥S3 steatosis than CAP.

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.