Endotoxin biomarkers, hepatic fat fraction, liver volume and liver stiffness among adolescents at high-risk for non-alcoholic fatty liver disease: The HEROES study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is on the rise among youth. Identifying biomarkers of NAFLD progression/risk can aid in prevention efforts. AIMS: This pilot study investigated associations of two endotoxin biomarkers-lipopolysaccharide-binding protein (LBP) and anti-endotoxin core immunoglobulin G (EndoCab)-with markers of NAFLD among 99 Latino/Latina adolescents (11-19 years) with obesity. MATERIALS & METHODS: We used linear regression to examine associations of each endotoxin biomarker (per 1-SD) with hepatic fat fraction (HFF), liver volume, and liver stiffness. RESULTS: We found positive associations of LBP with HFF and liver volume. Each 1-SD increment in LBP corresponded with 2.35% (95% CI: 0.46%, 4.23%) higher HFF and 0.14 (0.06, 0.23) L greater liver volume after adjusting for age, sex, and maternal education. Accounting for abdominal adiposity and Tanner stage did not change results. Excluding 72 participants with NAFLD attenuated associations of LBP with HFF but associations with liver volume persisted (0.11 [0.01, 0.21] L). EndoCab was not associated with any liver outcomes. Neither endotoxin biomarker predicted liver stiffness. DISCUSSION/CONCLUSION: While additional research is warranted, our results support LBP as a biomarker of NAFLD risk/progression in high-risk youth.

MRI-based quantification of adipose tissue distribution in healthy adult cats during body weight gain.

The incidence of obesity in pet population increased over the last decades. Cats have been suggested as model for human obesity because of similar co-morbidities as diabetes and dyslipidaemia. Aim of this study were to quantify the distribution of visceral and subcutaneous adipose tissue (VAT, SAT respectively) in healthy adult cats during feeding-induced body weight (BW) gain by MRI, and to correlate it to the increased hepatic fat fraction (HFF). Cats received a commercial dry food ad libitum for 40 weeks and were longitudinally scanned three times. VAT and SAT were determined from Dixon MRI data by a dedicated software solution (ATLAS, established in human and rodents). HFF was quantified from a commercially available sequence. At both individual and group level, normalized adipose tissue volumes significantly increased longitudinally, with median VAT/SAT ratio always < 1. With increased BW, more than proportional increased total adipose tissue was observed together with more than proportional increased HFF. HFF is disproportionately high in overweight cats compared to SAT and VAT accumulation in the 40 weeks observation period. Quantitative unbiased MRI examination of different body fat components is useful in longitudinal monitoring of obesity in cats.

Relative Enhancement in Gadoxetate Disodium-Enhanced Liver MRI as an Imaging Biomarker in the Diagnosis of Non-Alcoholic Fatty Liver Disease in Pediatric Obesity.

Relative enhancement (RE) in gadoxetate disodium (Gd-EOB-DTPA)-enhanced MRI is a reliable, non-invasive method for the evaluation and differentiation between simple steatosis and non-alcoholic steatohepatitis in adults. This study evaluated the diagnostic accuracy of RE in Gd-EOB-DTPA-enhanced liver MRI and hepatic fat fraction (HFF) in unenhanced liver MRI and ultrasound (US) for non-alcoholic fatty liver disease (NAFLD) screening in pediatric obesity. Seventy-four liver US and MRIs from 68 pediatric patients (13.07 ± 2.95 years) with obesity (BMI > BMI-for-age + 2SD) were reviewed with regard to imaging biomarkers (liver size, volume, echogenicity, HFF, and RE in Gd-EOB-DTPA-enhanced MRIs, and spleen size), blood biomarkers, and BMI. The agreement between the steatosis grade, according to HFF in MRI and the echogenicity in US, was moderate. Alanine aminotransferase correlated better with the imaging biomarkers in MRI than with those in US. BMI correlated better with liver size and volume on MRI than in US. In patients with RE < 1, blood biomarkers correlated better with RE than those in the whole sample, with a significant association between gamma-glutamyltransferase and RE (p = 0.033). In conclusion, the relative enhancement and hepatic fat fraction can be considered as non-invasive tools for the screening and follow-up of NAFLD in pediatric obesity, superior to echogenicity on ultrasound.

Evaluation of a Whole-Liver Dixon-Based MRI Approach for Quantification of Liver Fat in Patients with Type 2 Diabetes Treated with Two Isocaloric Different Diets.

Dixon-based methods for the detection of fatty liver have the advantage of being non-invasive, easy to perform and analyze, and to provide a whole-liver coverage during the acquisition. The aim of the study was to assess the feasibility of a whole-liver Dixon-based approach for liver fat quantification in type 2 diabetes (T2D) patients who underwent two different isocaloric dietary treatments: a diet rich in monosaturated fatty acids (MUFA) and a multifactorial diet. Thirty-nine T2D patients were randomly assigned to MUFA diet (n = 21) and multifactorial diet (n = 18). The mean values of the proton density fat fraction (PDFF) over the whole liver and over the ROI corresponding to that chosen for MRS were compared to MRS-PDFF using Spearman's correlation (ρ). Before-after changes in percentage of liver volume corresponding to MRI-PDFF above thresholds associated with hepatic steatosis (LV%TH, with TH = 5.56%, 7.97% and 8.8%) were considered to assess the proposed approach and compared between diets using Wilcoxon rank-sum test. Statistical significance set at p < 0.05. A strong linear relationship was found between MRS-PDFF and MRI-PDFFs (ρ = 0.85, p < 0.0001). Changes in LV%TH% were significantly higher (p < 0.05) in the multifactorial diet than in MUFA diet (25% vs. 9%, 35% vs. 12%, and 38% vs. 13% decrease, respectively, for TH = 5.56%, 7.97%, and 8.8%) and this was reproducible compared to results obtained using the standard liver fat analysis. A volumetric approach based on Dixon method could be an effective, non-invasive technique that could be used for the quantitative analysis of hepatic steatosis in T2D patients.

Pegbelfermin selectively reduces secondary bile acid concentrations in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms. METHODS: Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses. RESULTS: Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed. CONCLUSIONS: PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation. LAY SUMMARY: Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.

A Prudent dietary pattern is inversely associated with liver fat content among multi-ethnic youth.

OBJECTIVES: To identify dietary patterns associated with hepatic fat fraction (HFF), a measure of liver fat content and risk factor for non-alcoholic fatty liver disease, in a prospective study of 397 multi-ethnic youth. METHODS: We obtained information on habitual dietary intake via the Block Kids Food Frequency Questionnaire at age 6 to 15 years ('T1') and 12 to 19 years ('T2'), and measured HFF using magnetic resonance imaging at T2. We derived dietary patterns via principal components analysis and examined associations with ln-transformed HFF using linear regression models that accounted for maternal education, gestational diabetes exposure and smoking habits; and child pubertal status, BMI and physical activity. RESULTS: At T1, none of the dietary patterns identified were associated with HFF measured at T2. At T2, a Prudent dietary pattern characterized by high fruit and vegetable intake was inversely associated with HFF (-0.08 [95% CI: -0.16, -0.00]). Similarly, increased adherence to the Prudent pattern across T1 and T2 corresponded with lower ln-HFF (-0.11 [-0.18, -0.04] units). On the other hand, adherence to a Western pattern comprising fried foods and refined carbohydrates at T2 correlated with higher HFF among non-Hispanic White participants (0.16 [0.06, 0.26]). These findings persisted after accounting for child BMI. CONCLUSIONS: Even in healthy youth, a diet high in fruits and vegetables is associated with lower HFF, whereas a diet high in fried foods and refined carbohydrates is related to higher HFF. Dietary changes may serve as an early preventive measure to mitigate liver fat accrual.

Comparison of the Effects of Hepatic Steatosis on Monoexponential DWI, Intravoxel Incoherent Motion Diffusion-weighted Imaging and Diffusion Kurtosis Imaging.

RATIONALE AND OBJECTIVES: Diffusion-weighted imaging (DWI) techniques have drawn attention for their capability of staging hepatic fibrosis. However, the diagnostic performance of DWI for hepatic fibrosis might be affected by hepatic steatosis because hepatic steatosis and fibrosis may have a similar effect on diffusion/perfusion parameters. Therefore, the purpose of our study is to investigate the effect of hepatic steatosis on DWI parameters. MATERIALS AND METHODS: 51 patients with MR elastography liver stiffness values below 3.45kPa underwent DWI with multiple b-values and a multi-echo Dixon sequence for fat quantification. Correlation analysis was conducted between fat fraction and DWI parameters, and DWI parameters were compared between steatosis and non-steatosis groups. RESULTS: Significant negative correlation was observed between fat fraction and apparent diffusion coefficient (ADC) (r = -0.62, p <0.001), pure molecular diffusion (D) (r = -0.62, p <0.001), corrected ADC (Dapp) (r = -0.36, p = 0.01) and a positive correlation with mean kurtosis (Kapp) (r = 0.53, p <0.001). The results of the comparison of DWI parameters were that ADC, D and Dapp were statistically lower in the steatosis group (p < 0.001, p < 0.001 and p = 0.026, respectively) and Kapp was significantly higher in the steatosis group (p <0.001) compared to the non-steatosis group. However, perfusion-related parameters (D* and f) did not show any statistical significance. CONCLUSION: DWI parameters except for perfusion-related parameters (D* and f) are affected by changes in hepatic steatosis. Thus, hepatic steatosis may be considered as a possible confounding factor in DWI-based assessment of liver fibrosis.

Sex-Specific Metabolite Biomarkers of NAFLD in Youth: A Prospective Study in the EPOCH Cohort.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed nations. There are currently no accurate biomarkers of NAFLD risk in youth. OBJECTIVE: Identify sex-specific metabolomics biomarkers of NAFLD in a healthy cohort of youth. DESIGN/SETTING: This prospective study included 395 participants of the EPOCH cohort in Colorado, who were recruited 2006-2009 ("T1 visit") and followed for 5 years ("T2 visit"). We entered 767 metabolites measured at T1 into a reduced rank regression model to identify the strongest determinants of hepatic fat fraction (HFF) at T2, separately for boys and girls. We compared the capacity of metabolites versus conventional risk factors (overweight/obesity, insulin, alanine transaminase, aspartate transaminase) to predict NAFLD (HFF ≥5%) and high HFF (fourth vs first quartile) using area under the receiver operating characteristic curve (AUC). RESULTS: Prevalence of NAFLD was 7.9% (8.5% of boys, 7.1% of girls). Mean ± SD HFF was 2.5 ± 3.1%. We identified 13 metabolites in girls and 10 metabolites in boys. Metabolites were in lipid, amino acid, and carbohydrate metabolism pathways. At T1, the metabolites outperformed conventional risk factors in prediction of high HFF but not NAFLD. At T2, the metabolites were superior to conventional risk factors as predictors of high HFF (AUC for metabolites vs conventional risk factors for boys: 0.9565 vs 0.8851, P = 0.02; for girls: 0.9450 vs 0.8469, P = 0.02) with similar trends for NAFLD, although the differences were not significant. CONCLUSIONS: The metabolite profiles identified herein are superior predictors of high HFF when assessed 5 years prior and concurrently in a general-risk setting.

Noninvasive assessment of abdominal adipose tissues and quantification of hepatic and pancreatic fat fractions in type 2 diabetes mellitus.

The purpose of this study was to evaluate adipose tissue distributions and hepatic and pancreatic fat contents using a 6-point Dixon MRI technique in type 2 diabetes mellitus (T2DM), and to assess associations between fat distributions and biochemical markers of insulin resistance. Intra-abdominal MRI was investigated in 14 T2DM patients, 13 age- and sex-matched healthy controls (HC) and 11 young HC using a 3 T Prisma MRI scanner. All T2DM subjects completed a fasting comprehensive metabolic panel, and demographic measurements were taken according to standardized methodologies. We observed excellent correlation (R2 = 0.94) between hepatic fat fraction quantified using 6-point Dixon MRI and gold standard MRS, establishing the accuracy and reliability of the Dixon technique. Significantly increased visceral adipose tissue (VAT) volumes were found in T2DM patients compared to age-matched HC (1569.81 ± 670.62 cm3 vs. 1106.60 ± 566.85 cm3, p = .04). We also observed a trend of increasing subcutaneous adipose tissues (SAT), and total abdominal fat (TAT) volumes in T2DM compared to age-matched HC. Hepatic fat fraction percentage (HFF%) was 44.6% higher in T2DM compared to age-matched HC and 64.4% higher compared to young HC. Pancreatic fat fractions in the head and body/tail were higher in T2DM patients compared to both healthy cohorts. We also observed correlations between fat contents of the liver and pancreas in T2DM patients, and association between biochemical markers of T2DM with HFF, indicating a risk for non-alcoholic fatty liver disease among T2DM. In summary, this study provides evidence of T2DM patients having increased liver and pancreatic fat, as well as increased adipose tissues.

Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.

AIMS/INTRODUCTION: Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS: In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS: Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS: Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.

Effect of Electroacupuncture on Visceral and Hepatic Fat in Women with Abdominal Obesity: A Randomized Controlled Study Based on Magnetic Resonance Imaging.

OBJECTIVE: Visceral adipose tissue (VAT) and hepatic fat deposition are the most important risk factors for women's health. Acupuncture, including electroacupuncture (EA), is used to treat obesity throughout the world. The effect of EA is evaluated mainly by body mass index (BMI) and waist circumference (WC). Few studies have assessed its effect in reducing VAT volume and hepatic fat fraction (HFF) based on an exact measurement method such as magnetic resonance imaging (MRI). This study aimed to resolve this issue. METHODS: Thirty subjects were randomly divided into two groups. The control group (n = 15) did not receive any intervention and maintained a normal diet and their usual exercise habits. The treatment group (n = 15) received EA three times a week for 3 months. BMI and WC were measured using different devices. VAT and HFF were measured by MRI and calculated by related software before and after the intervention. RESULTS: A marked difference was evident in group that received EA treatment in the following tests. The differences in BMI (U = 21.00, p < 0.001), WC (U = 40.50, p = 0.002), VAT volume (U = 13.00, p < 0.001), and mean HFF (U = 0.00, p < 0.001) before and after the intervention in the treatment group were distinct and significant compared with those of the control group. Three months later, the treatment group showed a lower BMI (W = 91.00, p = 0.001), WC (t = 4.755, p < 0.001), VAT volume (t = 5.164, p < 0.001), and mean HFF (W = 120.00, p = 0.001) compared with pretreatment levels. Compared with the control group, the treatment group showed a lower VAT volume (t = 60.00, p = 0.029) after 3 months of treatment. After 3 months, the control group showed higher mean HFF (t = -2.900, p = 0.012) and VAT volume (W = 11.50, p = 0.006) compared with their initial levels. CONCLUSION: Based on MRI evaluation, this randomized controlled study proved that EA treatment reduces BMI and WC as well as VAT volume and HFF in women with abdominal obesity.

Atlas-based liver segmentation and hepatic fat-fraction assessment for clinical trials.

Automated assessment of hepatic fat-fraction is clinically important. A robust and precise segmentation would enable accurate, objective and consistent measurement of hepatic fat-fraction for disease quantification, therapy monitoring and drug development. However, segmenting the liver in clinical trials is a challenging task due to the variability of liver anatomy as well as the diverse sources the images were acquired from. In this paper, we propose an automated and robust framework for liver segmentation and assessment. It uses single statistical atlas registration to initialize a robust deformable model to obtain fine segmentation. Fat-fraction map is computed by using chemical shift based method in the delineated region of liver. This proposed method is validated on 14 abdominal magnetic resonance (MR) volumetric scans. The qualitative and quantitative comparisons show that our proposed method can achieve better segmentation accuracy with less variance comparing with two other atlas-based methods. Experimental results demonstrate the promises of our assessment framework.

MRI measurement of liver fat content predicts the metabolic syndrome.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease among cardiometabolic patients is not completely known because liver biopsy cannot be routinely performed. However, as magnetic resonance imaging (MRI) allows accurate and safe measurement of the hepatic fat fraction (HFF), the aim of this study was to quantify liver fat content in a dysmetabolic adult population. METHODS: A total of 156 adults were included in this cross-sectional study. Liver and visceral fat were assessed by MRI in these subjects, who presented with zero to five metabolic components of the metabolic syndrome (MetS). Arterial stiffness was recorded by ultrasonography, and the maximum Youden index was used to set the optimal HFF cutoff value predictive of the presence of the MetS. RESULTS: Overall, 72% of participants displayed three or more MetS components. HFF ranged from 0.3% to 52% (mean 13.4%). Age- and gender-adjusted HFF was positively correlated with BMI (r=0.44), blood pressure (r=0.19), triglyceridaemia (r=0.22) and glycaemia (r=0.31). MRI-measured visceral adipose tissue did not influence the relationship of steatosis with glycaemia, HOMA-IR and carotid stiffness, but there was a dose-response relationship between the number of MetS components and mean HFF. The optimal HFF for predicting the MetS was found to be 5.2% according to the maximum Youden index point. CONCLUSION: This study highlighted the impact of liver steatosis on cardiometabolic abnormalities with an optimal cutoff value of 5.2% for defining increased metabolic risk.