Search

Dysregulation of the gut microbiome has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, we compared stool microbiomes across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients, and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles by using the random forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, area under curve [AUC]). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species might offer universal utility as a non-invasive diagnostic test for cirrhosis.

International audience; BACKGROUND & AIMS: Controlled attenuation parameter (CAP) measurements using M probe have been reported to be lower than those of the XL-probe in detection of hepatic steatosis. However, there has been no direct comparison of CAP with the M vs the XL probe in patients with nonalcoholic fatty liver disease (NAFLD). We compared CAP with the M vs the XL probe for quantification of hepatic fat content, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the standard. METHODS: We performed a prospective study of 100 adults (mean body mass index [BMI], 30.6+/-4.7 kg/m2) with and without NAFLD, assessed by CAP with the M probe and XL probe on the same day, at a single research center, from November 2017 through November 2018. We then measured the MRI-PDFF as the reference standard. Outcomes were presence of hepatic steatosis, defined as MRI-PDFF \textgreater/= 5%, and detection of hepatic fat content \textgreater/= 10%, defined as MRI-PDFF \textgreater/= 10%. We performed area under the receiver operating characteristic curve (AUROC) analyses to assess the diagnostic accuracy of CAP for each probe in detection of hepatic steatosis (MRI-PDFF \textgreater/= 5%) and of hepatic fat content \textgreater/= 10%. RESULTS: Of the study participants, 68% had an MRI-PDFF of 5% or more and 48% had an MRI-PDFF of 10% or more. The mean CAP measured by the M probe (310+/-62 db/m) was significantly lower than by the X probe (317+/-63 db/m) (P=.007). When M probe was used in participants with BMIs \textless30 kg/m(2) and XL probe in participants with BMIs \textgreater/=30 kg/m(2), the CAP measured by the M probe (312+/-51.4 db/m) remained significantly lower than that of the XL probe (345+/-47.6 db/m) (P=.0035.), when the MRI-PDFF was above 5%. The optimal threshold of CAP for the detection of MRI-PDFF\textgreater/=5%, was 294 db/m with the M probe and 307 db/m with the XL probe. The optimal threshold of CAP for the detection of MRI-PDFF \textgreater/= 10%, was 311 db/m with the M probe and 322 db/m with the XL probe. For only the XL probe, CAP measurements with an interquartile range below 30 dB/m detected an MRI-PDFF\textgreater/=5% with a lower AUROC (0.97; 95% CI, 0.80-1.00) than CAP measurements with an interquartile range above 30 dB/m (AUROC, 0.82; 95% CI, 0.71-0.90) (P=.0129). CONCLUSIONS: In an analysis of the same patients using CAP with the M probe and XL probe, with MRI-PDFF as the standard, we found that the M probe under-quantifies CAP values compared with the XL probe, independent of BMI. The type of probe should be considered when interpreting CAP data from patients with NAFLD.

© 2018 by the American Association for the Study of Liver Diseases. Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG:0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG:0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).

OBJECTIVES:To assess the repeatability and reproducibility of the ultrasonic attenuation coefficient (AC) and backscatter coefficient (BSC) measured in the livers of adults with known or suspected nonalcoholic fatty liver disease (NAFLD). METHODS:The Institutional Review Board approved this Health Insurance Portability and Accountability Act-compliant prospective study; informed consent was obtained. Forty-one research participants with known or suspected NAFLD were recruited and underwent same-day ultrasound examinations of the right liver lobe with a clinical scanner by a clinical sonographer. Each participant underwent 2 scanning trials, with participant repositioning between trials. Two transducers were used in each trial. For each transducer, machine settings were optimized by the sonographer but then kept constant while 3 data acquisitions were obtained from the liver without participant repositioning and then from an external calibrated phantom. Raw RF echo data were recorded. The AC and BSC were measured within 2.6 to 3.0 MHz from a user-defined hepatic field of interest from each acquisition. The repeatability and reproducibility were analyzed by random-effects models. RESULTS:The mean AC and log-transformed BSC (logBSC) were 0.94 dB/cm-MHz and -27.0 dB, respectively. Intraclass correlation coefficients were 0.88 to 0.94 for the AC and 0.87 to 0.95 for the logBSC acquired without participant repositioning. For between-trial repeated scans with participant repositioning, the intraclass correlation coefficients were 0.80 to 0.84 for the AC and 0.69 to 0.82 for the logBSC after averaging results from 3 within-trial images. The variability introduced by the transducer was less than the repeatability error. CONCLUSIONS:Hepatic AC and BSC measures using a reference phantom technique on a clinical scanner are repeatable and reproducible between transducers in adults with known or suspected NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and the progressive form of this condition, nonalcoholic steatohepatitis (NASH), has become one of the leading indications for liver transplantation. Despite intensive investigations, there are currently no United States Food and Drug Administration-approved therapies for treating NASH. A major barrier for drug development in NASH is that treatment response assessment continues to require liver biopsy, which is invasive and interpreted subjectively. Therefore, there is a major unmet need for developing noninvasive, objective, and quantitative biomarkers for diagnosis and assessment of treatment response. Emerging data support the use of magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as a noninvasive, quantitative, and accurate measure of liver fat content to assess treatment response in early-phase NASH trials. In this review, we discuss the role and utility, including potential sample size reduction, of MRI-PDFF as a quantitative and noninvasive imaging-based biomarker in early-phase NASH trials. Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide.(()) NAFLD can be broadly classified into two categories: nonalcoholic fatty liver, which has a minimal risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), the more progressive form of NAFLD, which has a significantly increased risk of progression to cirrhosis.(()) Over the past two decades, NASH-related cirrhosis has become the second leading indication for liver transplantation in the United States.(()) For these reasons, pharmacological therapy for NASH is needed urgently. Despite intensive investigations, there are currently no therapies for treating NASH that have been approved by the United States Food and Drug Administration.(()\textless/SUP)

International audience; BACKGROUND & AIMS: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort. METHODS: We performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3). RESULTS: In the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex. CONCLUSIONS: We identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI.

International audience; Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P \textless 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was R-G:0.57,95%CI:0.27-0.80, P \textless 0.001 and with fibrosis was R-G:0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).

Background & aimsWe assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference.MethodsWe collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed.ResultsAt baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0-1 vs 2-3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91-0.98), and grade 0-2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93-0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2-3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71-0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63-0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity.ConclusionsBased on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.