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Background and aimsPatients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD.MethodsAdult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort.Results147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89).ConclusionsThis cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and

Purpose of reviewNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are strongly associated. Both also associate with an increased risk of cardiovascular disease (CVD).Recent findingsSeveral studies have provided evidence that NAFLD could be an independent CVD risk factor. Given the strong association between NAFLD and T2DM, assessing the independent CV effect of these two conditions remains challenging. However, patients with T2DM and NAFLD exhibit higher risk of CVD compared with T2DM without NAFLD suggesting a potential synergistic increase of CV risk in patients with both T2DM and NAFLD supported by several shared pathophysiological pathways. Several anti-diabetic therapies have shown beneficial effect on both NAFLD and CVD. Patients with T2DM and NAFLD should be considered at high risk of CVD and could benefit from more intensive CV prevention. Additional long-term follow-up is needed to demonstrate that the treatment of NAFLD effectively reduces the risk of CVD.

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.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

Background & aimsControlled 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.MethodsWe 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 ≥ 5%, and detection of hepatic fat content ≥ 10%, defined as MRI-PDFF ≥ 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 ≥ 5%) and of hepatic fat content ≥ 10%.ResultsOf 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

Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (DM2).1 Accurately assessing CVD risk in NAFLD patients is critical to improving clinical outcomes.1 Use of liver stiffness measurements to noninvasively assess for liver fibrosis is broadening, and magnetic resonance elastography (MRE) is the most accurate modality in NAFLD.2 However, the association between fibrosis severity on MRE and the degree of CVD risk is unknown. The aim of this study was to determine whether MRE-assessed liver fibrosis stage is associated with CVD risk determined by Framingham risk score (FRS) and coronary artery calcium (CAC).

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in developed countries.1 Patients with nonalcoholic steatohepatitis (NASH) are considered to be at a higher risk of fibrosis progression and development to cirrhosis and hepatocellular carcinoma.

BackgroundEicosanoid and related docosanoid polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives have been proposed as noninvasive lipidomic biomarkers of nonalcoholic steatohepatitis (NASH). Therefore, we investigated associations between plasma eicosanoids and liver fibrosis to evaluate their utility in diagnosing and monitoring NASH-related fibrosis.MethodsOur analysis used baseline eicosanoid data from 427 patients with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), and longitudinal measurements along with liver fibrosis staging from 63 patients with NASH and stage 2/3 fibrosis followed for 24 weeks in a phase II trial.ResultsAt baseline, four eicosanoids were significantly associated with liver fibrosis stage: 11,12-DIHETE, tetranor 12-HETE, adrenic acid, and 14, 15-DIHETE. Over 24 weeks of follow up, a combination of changes in seven eicosanoids [5-HETE, 7,17-DHDPA, adrenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), 16-HDOHE, and 9-HODE) had good diagnostic accuracy for the prediction of ⩾1 stage improvement in fibrosis (AUROC: 0.74; 95% CI: 0.62-0.87), and a combination of four eicosanoids (7,17-DHDPA, 14,15-DIHETRE, 9-HOTRE, and free adrenic acid) accurately predicted improvement in hepatic collagen content (AUROC: 0.72; 95% CI: 0.50-0.77).ConclusionThis study provides preliminary evidence that plasma eicosanoids may serve as noninvasive biomarkers of liver fibrosis and may predict liver fibrosis improvement in NASH.

ObjectiveNon-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis.DesignThis is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling.ResultsIn the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively.ConclusionA combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.

N-terminal propeptide of type 3 procollagen (PRO-C3) is a biomarker of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants, including 44 probands with NAFLD-cirrhosis and their 72 first-degree relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree relatives, and 72 controls without NAFLD and their 72 first-degree relatives. Liver steatosis was assessed by magnetic resonance imaging proton density fat fraction, and liver fibrosis was assessed by MRE-stiffness. Serum PRO-C3 was assessed by competitive, enzyme-linked immunosorbent assay. We assessed the familial correlation of PRO-C3 concentration, the shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and the association between PRO-C3 concentration and genetic variants in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing (MBOAT), and glucokinase regulator (CGKR) genes. In multivariable-adjusted models including age, sex, body mass index, and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r2  = 0.50, P

The presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis.

Background & aimsMagnetic 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.MethodsWe 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.ResultsOur 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).ConclusionIn 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.

BackgroundThe fasting-state serum bile acid profile in nonalcoholic fatty liver disease (NAFLD) has been reported to differ when nonalcoholic steatohepatitis is compared to nonalcoholic fatty liver. However, there are few data comparing changes in NAFLD vs non-NAFLD, or whether the bile acid profile differs according to the degree of fibrosis.AimTo examine the serum bile acid profile across the entire spectrum of NAFLD.MethodsWe performed a cross-sectional analysis of two complementary cohorts: a Twin and Family cohort of 156 participants, and a biopsy-proven-NAFLD cohort of 156 participants with fasting bile acid profiling using liquid chromatography/mass spectrometry.ResultsIn the Twin and Family cohort (mean age 46.3 years and body mass index (BMI) 26.6 kg/m2 ), 36 (23%) participants had NAFLD (magnetic resonance imaging proton density fat fraction ≥ 5%). Higher chenodeoxycholyl conjugates (9.0% vs 6.5%, P = 0.019) and lower glycohyocholate (1.2% vs 3.6%, P

Background & aimsMagnetic 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.MethodsWe 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).ResultsIn 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.ConclusionsWe 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.

The aim of the current study is to demonstrate the feasibility of radiofrequency (RF) pulses generated via an optimal control (OC) algorithm to perform magnetic resonance elastography (MRE) and quantify the mechanical properties of materials with very short transverse relaxation times (T2 < 5 ms) for the first time. OC theory applied to MRE provides RF pulses that bring isochromats from the equilibrium state to a fixed target state, which corresponds to the phase pattern of a conventional MRE acquisition. Such RF pulses applied with a constant gradient allow to simultaneously perform slice selection and motion encoding in the slice direction. Unlike conventional MRE, no additional motion‐encoding gradients (MEGs) are needed, enabling shorter echo times. OC pulses were implemented both in turbo spin echo (OC rapid acquisition with refocused echoes [RARE]) and ultrashort echo time (OC UTE) sequences to compare their motion‐encoding efficiency with the conventional MEG encoding (classical MEG MRE). MRE experiments were carried out on agar phantoms with very short T2 values and on an ex vivo bovine tendon. Magnitude images, wave field images, phase‐to‐noise ratio (PNR), and shear storage modulus maps were compared between OC RARE, OC UTE, and classical MEG MRE in samples with different T2 values. Shear storage modulus values of the agar phantoms were in agreement with values found in the literature, and that of the bovine tendon was corroborated with rheometry measurements. Only the OC sequences could encode motion in very short T2 samples, and only OC UTE sequences yielded magnitude images enabling proper visualization of short T2 samples and tissues. The OC UTE sequence produced the best PNRs, demonstrating its ability to perform anatomical and mechanical characterization. Its success warrants in vivo confirmation in further studies. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic flexibility (MetF), defined as the ability to switch between fat and glucose oxidation, is increasingly recognised as a critical marker for assessing responses to dietary interventions. Previously, we showed that the consumption of multifibre bread improved insulin sensitivity and reduced low‐density lipoprotein cholesterol (LDLc) levels in overweight and obese individuals. As a secondary objective, we aimed to explore whether our intervention could also improve MetF. Methods: In this study, 39 subjects at cardiometabolic risk participated in a double‐blind, randomised, crossover trial lasting 8 weeks, repeated twice. During each phase, participants consumed either 150 g of standard bread daily or bread enriched with a mixture of seven dietary fibres. MetF response was assessed using a mixed‐meal tolerance test (MMTT), analysing changes in respiratory quotient (∆RQ) measured using indirect calorimetry. Results: Although there were no significant differences in ∆RQ changes induced by dietary fibre between the two diets, these changes were positively correlated with postprandial triglyceride excursion (∆TG) at baseline. Subgroup analysis of baseline fasting and postprandial plasma metabolites was conducted to characterise MetF responders. These responders exhibited higher baseline fasting LDLc levels and greater post‐MMTT ∆TG. Conclusion: In conclusion, although dietary fibres did not directly impact MetF in this study, our findings highlight potential determinants of MetF response, warranting further investigation in dedicated future interventions. Highlights: The term 'metabolic flexibility' (MetF) was initially used to describe the ability of helminths to generate energy through either aerobic respiration or anaerobic respiration, enabling them to adapt to environmental changes. This concept was later applied to human metabolism, emphasising the body's capacity to switch between different energy sources, such as carbohydrates and fats, based on energy requirements.MetF has been studied in the context of transitions between fasting and fed states, or in response to insulin stimulation. It refers to the body's ability to adapt its energy utilisation in response to changing metabolic demands.Research has shown that insulin resistance, often linked to type 2 diabetes and obesity, may be associated with reduced MetF, characterised by altered patterns of carbohydrate and fat oxidation. [ABSTRACT FROM AUTHOR]

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).

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.().

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%) (P = .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; P = .049). Our findings associate higher liver fat content, measured by MRI-PDFF, with fibrosis progression.

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-PDFF ≥ 5%. 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 ( ± standard 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-PDFF ≥ 5%) and MRI-PDFF ≥ 10% was 70.6% and 47.1%, respectively. The area under the receiver operating characteristic (AUROC) of CAP for the detection of MRI-PDFF ≥ 5% was 0.80 (95% confidence interval [CI], 0.70-0.90) at the cut-point of 288 dB/m and of MRI-PDFF ≥ 10% 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]; P = 0.0117), and these differences were statistically and clinically significant.ConclusionThe cut-point of CAP for presence of hepatic steatosis (MRI-PDFF ≥ 5%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when the IQR of CAP is

BackgroundThe 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.MethodsThis 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).ResultsThe 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).ConclusionUsing 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 registrationUcsd irb140084.FundingNational Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

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 characterized the 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 or 4 fibrosis). We identified a set of 40 features (p < 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 diagnostic accuracy (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.

Objective: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is closely associated with obesity. We aimed to assess the impact of obesity on the performance of different noninvasive tests, including liver stiffness measurement (LSM) and Agile3+ (A3+), to detect advanced fibrosis (AF) in a population of patients with MASLD encompassing a wide range of BMI values. Methods: A total of 479 patients with MASLD were consecutively included (Lyon Hepatology Institute). Clinical data and noninvasive tests, including FibroTest, LSM, A3+, Fibrosis‐4 (FIB‐4), magnetic resonance elastography, and liver biopsies, were collected. AF was determined by a composite endpoint, i.e., histological stage ≥ F3, overt diagnosis of cirrhosis by magnetic resonance elastography, or concordant LSM ≥ 9.6 kPa and FibroTest ≥ F3. Results: The median BMI was 35.0 kg/m2, and the prevalence of AF was 28.6%. Patients with BMI ≥ 35 versus <35 had a lower proportion of AF, i.e., 19.3% versus 38.1% (p < 0.001), but higher indeterminate status for AF (34.2% vs. 15.4%; p < 0.001). In the case of BMI ≥ 35, LSM had lower specificity to rule in AF (77.9%) versus A3+ (90.4%), but A3+ had decreased sensitivity to rule out AF. A sequential LSM/A3+ strategy achieved high specificity to rule in AF and lowered the proportion of indeterminate cases in patients with BMI ≥ 35. Conclusions: The grade of obesity affects the detection of MASLD‐related AF. A sequential use of LSM/A3+ could improve AF detection in patients with BMI ≥ 35. [ABSTRACT FROM AUTHOR]