Cyrielle Caussy

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease.

The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterizedxa0the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0-2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 orxa04xa0fibrosis). We identified a set of 40 features (pxa0< 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnosticxa0accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD.

Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis

BACKGROUND. The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS. This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS. The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8–126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1–146.1, P = 0.0438). CONCLUSION. Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION. UCSD IRB: 140084. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

Optimal threshold of controlled attenuation parameter with MRI‐PDFF as the gold standard for the detection of hepatic steatosis

The optimal threshold of controlled attenuation parameter (CAP) for the detection of hepatic steatosis using both M and XL probe is unknown in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance imaging proton density fat fraction (MRI‐PDFF) is an accurate and precise method of detecting the presence of hepatic steatosis that is superior to CAP. Thus, the aim of this study was to evaluate the diagnostic accuracy and optimal threshold of CAP for the detection of hepatic steatosis as defined by MRI‐PDFFu2009≥u20095%. This prospective cross‐sectional study included 119 adults (59% women) with and without NAFLD who underwent MRI‐PDFF and CAP using either M or XL probe when indicated within a 6‐month period at the NAFLD Research Center, University of California, San Diego. The mean (u2009±u2009standard deviation) age and body mass index were 52.4 (±15.2) years and 29.9 (±5.5) kg/m2, respectively. The prevalence of NAFLD (MRI‐PDFFu2009≥u20095%) and MRI‐PDFFu2009≥u200910% was 70.6% and 47.1%, respectively. The area under the receiver operating characteristic (AUROC) of CAP for the detection of MRI‐PDFFu2009≥u20095% was 0.80 (95% confidence interval [CI], 0.70‐0.90) at the cut‐point of 288 dB/m and of MRI‐PDFFu2009≥u200910% was 0.87 (95% CI, 0.80‐0.94) at the cut‐point of 306 dB/m. When stratified by the interquartile range (IQR) of CAP, we observed that an IQR below the median (30 dB/m) had a robust AUROC compared with an IQR above the median (0.92 [95% CI, 0.85‐1.00] versus 0.70 [95% CI, 0.56‐0.85]; Pu2009=u20090.0117), and these differences were statistically and clinically significant. Conclusion: The cut‐point of CAP for presence of hepatic steatosis (MRI‐PDFFu2009≥u20095%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when the IQR of CAP is <30 dB/m. These data have implications for the clinical use of CAP in the assessment of NAFLD. (Hepatology 2018;67:1348‐1359)

Noninvasive, Quantitative Assessment of Liver Fat by MRI‐PDFF as an Endpoint in NASH Trials

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.

Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD.

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).

Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease

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.

Magnetic Resonance Imaging Proton Density Fat Fraction Associates With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

Markers are needed to predict progression of nonalcoholic fatty liver disease (NAFLD). The proton density fat fraction, measured by magnetic resonance imaging (MRI-PDFF), provides an accurate, validated marker of hepatic steatosis; however, it is not clear whether the PDFF identifies patients at risk for NAFLD progression. We performed a follow-up study of 95 well-characterized patients with biopsy-proven NAFLD and examined the association between liver fat content and fibrosis progression. MRI-PDFF measurements were made at study entry (baseline). Biopsies were collected from patients at baseline and after a mean time period of 1.75 years. Among patients with no fibrosis at baseline, a higher proportion of patients in the higher liver fat group (MRI-PDFF ≥15.7%) had fibrosis progression (38.1%) than in the lower liver fat group (11.8%) (Pxa0= .067). In multivariable-adjusted logistic regression models (adjusted for age, sex, ethnicity, and body mass index), patients in the higher liver fat group had a significantly higher risk of fibrosis progression (multivariable-adjusted odds ratio 6.7; 95% confidence interval 1.01-44.1; Pxa0= .049). Our findings associate higher liver fat content, measured by MRI-PDFF, with fibrosis progression.

Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants.

Background & Aims: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques for detection of liver fibrosis. Single‐center studies have compared the diagnostic performance of MRE vs TE in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pooled analysis of individual participant data from published studies to compare the diagnostic performance of MRE vs TE for staging of liver fibrosis in patients with NAFLD, using liver biopsy as reference. Methods: We performed a systematic search of publication databases, from 2005 through 2017. We identified 3 studies of adults with NAFLD who were assessed by MRE, TE, and liver biopsy. In a pooled analysis, we calculated the cluster‐adjusted area under the curve (AUROC) of MRE and TE for the detection of each stage of fibrosis. AUROC comparisons between MRE and TE were performed using the Delong test. Results: Our pooled analysis included 230 participants with biopsy‐proven NAFLD with mean age of 52.2±13.9 years and a body mass index of 31.9±7.5 kg/m2. The proportions of patients with fibrosis of stages 0, 1, 2, 3, and 4 were: 31.7%, 27.8%, 15.7%, 13.9%, and 10.9%, respectively. The AUROC of TE vs MRE for detection of fibrosis stages ≥1 was 0.82 (95% CI, 0.76–0.88) vs 0.87 (95% CI, 0.82–0.91) (P=.04); for stage≥ 2 was 0.87 (95% CI, 0.82–0.91) vs 0.92 (95% CI, 0.88–0.96) (P=.03); for stage ≥3 was 0.84 (95% CI, 0.78–0.90) vs 0.93 (95% CI, 0.89–0.96) (P=.001); for stage ≥ 4 was 0.84 (95% CI, 0.73–0.94) vs 0.94 (95% CI, 0.89–0.99) (P=.005). Conclusion: In a pooled analysis of data from individual participants with biopsy‐proven NAFLD, we found MRE to have a statistically significantly higher diagnostic accuracy than TE in detection of each stage of fibrosis. MRE and TE each have roles in detection of fibrosis in patients with NAFLD, depending upon the level of accuracy desired.

Gut microbiome, microbial metabolites and the development of NAFLD

New findings show that a gut microbiome signature derived from metagenomic and phenomic data can accurately predict nonalcoholic fatty liver disease (NAFLD) in obese women. The data highlight a role for phenylacetic acid, a microbial product of aromatic amino acid metabolism, in the cross-talk between the gut microbiome and the host hepatic phenotype.