Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis.

BACKGROUND: Diagnostic tools for liver disease can now include estimation of the grade of hepatic steatosis (S0 to S3). Controlled attenuation parameter (CAP) is a non-invasive method for assessing hepatic steatosis that has become available for patients who are obese (FibroScan XL probe), but a consensus has not yet been reached regarding cutoffs and its diagnostic performance. We aimed to assess diagnostic properties and identify relevant covariates with use of an individual patient data meta-analysis. METHODS: We did an individual patient data meta-analysis, in which we searched PubMed and Web of Science for studies published from database inception until April 30, 2019. Studies reporting original biopsy-controlled data of CAP for non-invasive grading of steatosis were eligible. Probe recommendation was based on automated selection, manual assessment of skin-to-liver-capsule distance, and a body-mass index (BMI) criterion. Receiver operating characteristic methods and mixed models were used to assess diagnostic properties and covariates. Patients with non-alcoholic fatty liver disease (NAFLD) were analysed separately because they are the predominant patient group when using the XL probe. This study is registered with PROSPERO, CRD42018099284. FINDINGS: 16 studies reported histology-controlled CAP including the XL probe, and individual data from 13 papers and 2346 patients were included. Patients with a mean age of 46·5 years (SD 14·5) were recruited from 20 centres in nine countries. 2283 patients had data for BMI; 673 (29%) were normal weight (BMI <25 kg/m2), 530 (23%) were overweight (BMI ≥25 to <30 kg/m2), and 1080 (47%) were obese (BMI ≥30 kg/m2). 1277 (54%) patients had NAFLD, 474 (20%) had viral hepatitis, 285 (12%) had alcohol-associated liver disease, and 310 (13%) had other liver disease aetiologies. The XL probe was recommended in 1050 patients, 930 (89%) of whom had NAFLD; among the patients with NAFLD, the areas under the curve were 0·819 (95% CI 0·769-0·869) for S0 versus S1 to S3 and 0·754 (0·720-0·787) for S0 to S1 versus S2 to S3. CAP values were independently affected by aetiology, diabetes, BMI, aspartate aminotransferase, and sex. Optimal cutoffs differed substantially across aetiologies. Risk of bias according to QUADAS-2 was low. INTERPRETATION: CAP cutoffs varied according to cause, and can effectively recognise significant steatosis in patients with viral hepatitis. CAP cannot grade steatosis in patients with NAFLD adequately, but its value in a NAFLD screening setting needs to be studied, ideally with methods beyond the traditional histological reference standard. FUNDING: The German Federal Ministry of Education and Research and Echosens.

FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.

BACKGROUND: The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]). METHODS: This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009. FINDINGS: Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76-0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74-0·95, 0·85; 95% CI 0·83-0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0. INTERPRETATION: The FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease. FUNDING: Echosens and UK National Institute for Health Research.

Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: We estimated the accuracy of FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD). METHODS: We collected data from 450 consecutive adults who underwent liver biopsy analysis for suspected NAFLD at 7 centers in the United Kingdom from March 2014 through January 2017. FibroScan examinations with M or XL probe were completed within the 2 weeks of the biopsy analysis (404 had a valid examination). The biopsies were scored by 2 blinded expert pathologists according to nonalcoholic steatohepatitis clinical research network criteria. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis and fibrosis. We assessed effects of disease prevalence on positive and negative predictive values. For LSM, the effects of histological parameters and probe type were appraised using multivariable analysis. RESULTS: Using biopsy analysis as the reference standard, we found that CAP identified patients with steatosis with an AUROC of 0.87 (95% confidence interval [CI] 0.82-0.92) for S≥S1, 0.77 (95% CI 0.71-0.82) for S≥S2, and 0.70 (95% CI 0.64-0.75) for S=S3. Youden cutoff values for S≥S1, S≥S2, and S≥S3 were 302 dB/m, 331 dB/m, and 337 dB/m, respectively. LSM identified patients with fibrosis with AUROCs of 0.77 (95% CI 0.72-0.82) for F≥F2, 0.80 (95% CI 0.75-0.84) for F≥F3, and 0.89 (95% CI 0.84-0.93) for F=F4. Youden cutoff values for F≥F2, F≥F3, and F=F4 were 8.2 kPa, 9.7 kPa, and 13.6 kPa, respectively. Applying the optimal cutoff values, determined from this cohort, to populations of lower fibrosis prevalence increased negative predictive values and reduced positive predictive values. Multivariable analysis found that the only parameter that significantly affected LSMs was fibrosis stage (P<10-16); we found no association with steatosis or probe type. CONCLUSIONS: In a prospective analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89. Probe type and steatosis did not affect LSM. STUDY REGISTRATION: ClinicalTrials.gov Identifier: NCT01985009.

AdipoScan: A Novel Transient Elastography-Based Tool Used to Non-Invasively Assess Subcutaneous Adipose Tissue Shear Wave Speed in Obesity.

We describe a novel device called the AdipoScan that was adapted from the FibroScan to specifically assess shear wave speed (SWS) in human abdominal subcutaneous adipose tissue (scAT). Measurement reproducibility was assessed on tissue-mimicking phantoms with and without repositioning, with resultant coefficients of variation of 1% and 0%, respectively, as well as in vivo (14% and 7%, respectively). The applicability of the AdipoScan was tested on 19 non-obese volunteers, and a scAT thickness >2 cm was found to be mandatory to perform a valid measurement. Abdominal scAT SWS was assessed in 73 severely obese subjects, all candidates for bariatric surgery. Subcutaneous AT SWS was positively associated with scAT fibrosis and obesity-related co-morbidities such as hypertension, glycemic status, dyslipidemia and liver dysfunction. These results suggest that the AdipoScan could be a useful non-invasive tool to evaluate scAT fibrosis and metabolic complications in obesity. Further investigation is required to evaluate the relevance of using the AdipoScan to predict patient weight trajectories and metabolic outcomes after bariatric surgery.

Accumulation and Changes in Composition of Collagens in Subcutaneous Adipose Tissue After Bariatric Surgery.

CONTEXT: Extracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored. OBJECTIVE: The objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS. MAIN OUTCOME MEASURES: scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls. RESULTS: Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163(+) cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase [LOX], LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation. CONCLUSIONS: After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss.

Association of adipose tissue and liver fibrosis with tissue stiffness in morbid obesity: links with diabetes and BMI loss after gastric bypass.

CONTEXT: Liver and white adipose tissue (WAT) develop inflammation and fibrosis. OBJECTIVE: The aim of the study was to evaluate the bioclinical relevance of WAT fibrosis in morbid obesity and diabetes and the relationships with tissue stiffness measured using a novel device. DESIGN AND SETTING: Observational and longitudinal studies were conducted in a hospital nutrition department. PATIENTS: Biopsies of liver and subcutaneous WAT (scWAT) and omental adipose tissue were collected from 404 obese bariatric surgery candidates, of whom 243 were clinically characterized before surgery and 3, 6, and 12 months after surgery. In 123 subjects, liver and scWAT stiffness was assessed noninvasively using vibration-controlled transient elastography (VCTE). INTERVENTIONS: Bariatric surgery was performed for some patients. MAIN OUTCOME MEASURE: Adipose tissue fibrosis and stiffness and their link to obesity phenotypes were measured. RESULTS: scWAT fibrosis was positively associated with liver fibrosis (fibrosis score ≥2) (ϱ= 0.14; P = .01). VCTE-evaluated liver and scWAT stiffness was positively correlated with immunohistochemistry-determined liver (ϱ= 0.46; P = .0009) and scWAT fibrosis (ϱ= 0.48; P = .0001). VCTE-evaluated scWAT stiffness measures negatively associated with dual-energy x-ray absorptiometry-evaluated body fat mass (R = -0.25; P = .009) and were correlated with metabolic variables. Diabetic subjects showed increased scWAT stiffness. Participants less responsive to gastric bypass were older and more frequently diabetic, and they had increased body mass index, serum IL-6, and scWAT and liver fibrosis. Subjects with no diabetes and normal liver had higher fat mass and lower tissue fibrosis and stiffness. CONCLUSION: scWAT stiffness was associated with tissue fibrosis, obesity, and diabetes-related traits. Noninvasive evaluation of scWAT stiffness might be useful in clinical practice.