Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores.

BACKGROUND & AIMS: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. METHODS: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. RESULTS: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. CONCLUSIONS: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. IMPACT AND IMPLICATIONS: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved.

Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort.

BACKGROUND & AIMS: Large prospective studies to establish the prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are lacking. We prospectively assessed the prevalence and severity of NAFLD/NASH in a cohort of asymptomatic middle-aged Americans attending a colonoscopy class at a gastroenterology clinic. METHODS: Screening for NAFLD was performed using magnetic resonance (MR)-based LiverMultiScan® proton density fat fraction (LMS-PDFF). MR exams also included corrected T1 and elastography for liver stiffness measurement (LSM). FibroScan® was also used to measure LSM. Participants with predetermined abnormal imaging parameters were offered a liver biopsy. Biopsies were read in a blinded fashion with results based on the consensus by 2 expert pathologists. The prevalence of NAFLD was determined by PDFF ≥5% or by histological diagnosis of NAFLD (if biopsy data were available). The prevalence of NASH was defined by biopsy. RESULTS: Of 835 participants, 664 met the inclusion and exclusion criteria. The mean age was 56 ± 6.4 years, 50% were male, the mean BMI was 30.48 ± 5.46 kg/m2, and 52% were obese. The prevalence of NAFLD was 38% (95% CI 34-41%) and the prevalence of NASH was 14% (95% CI 12-17%). While no patient had cirrhosis on biopsy, significant fibrosis (F ≥2) was present in 5.9% (95% CI 4-8%) and bridging fibrosis in 1.6% (95% CI 1-3%). In a multivariable analysis, factors associated with the presence of NASH were race, obesity, and diabetes. CONCLUSION: Using state-of-the-art liver imaging modalities and reference biopsy, this study establishes an overall prevalence of NAFLD of 38% and NASH by biopsy of 14% in this cohort of asymptomatic middle-aged US adults. LAY SUMMARY: There are no prospective studies to determine how common is nonalcoholic steatohepatitis (NASH), the severe form of non-alcoholic fatty liver disease (NAFLD). In a large number of asymptomatic middle-aged Americans, we used a combination of state-of-the-art liver imaging methods and liver biopsy to prospectively determine the prevalence of NAFLD and NASH. NAFLD was diagnosed in 38%, NASH in 14%, and significant liver fibrosis in 6% of asymptomatic middle-aged Americans.

Improved Ultrasound Attenuation Measurement Method for the Non-invasive Evaluation of Hepatic Steatosis Using FibroScan.

Controlled attenuation parameter (CAP) is a measurement of ultrasound attenuation used to assess liver steatosis non-invasively. However, the standard method has some limitations. This study assessed the performance of a new CAP method by ex vivo and in vivo assessments. The major difference with the new method is that it uses ultrasound data continuously acquired during the imaging phase of the FibroScan examination. Seven reference tissue-mimicking phantoms were used to test the performance. In vivo performance was assessed in two cohorts (in total 195 patients) of patients using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as a reference. The precision of CAP was improved by more than 50% on tissue-mimicking phantoms and 22%-41% in the in vivo cohort studies. The agreement between both methods was excellent, and the correlation between CAP and MRI-PDFF improved in both studies (0.71 to 0.74; 0.70 to 0.76). Using MRI-PDFF as a reference, the diagnostic performance of the new method was at least equal or superior (area under the receiver operating curve 0.889-0.900, 0.835-0.873). This study suggests that the new continuous CAP method can significantly improve the precision of CAP measurements ex vivo and in vivo.

BioMercator: integrating genetic maps and QTL towards discovery of candidate genes.

SUMMARY: Breeding programs face the challenge of integrating information from genomics and from quantitative trait loci (QTL) analysis in order to identify genomic sequences controlling the variation of important traits. Despite the development of integrative databases, building a consensus map of genes, QTL and other loci gathered from multiple maps remains a manual and tedious task. Nevertheless, this is a critical step to reveal co-locations between genes and QTL. Another important matter is to determine whether QTL linked to same traits or related ones is detected in independent experiments and located in the same region, and represents a single locus or not. Statistical tools such as meta-analysis can be used to answer this question. BioMercator has been developed to automate map compilation and QTL meta-analysis, and to visualize co-locations between genes and QTL through a graphical interface. AVAILABILITY: Available upon request (http://moulon/~bioinfo/BioMercator/). Free of charge for academic use.