Liver Fat Content Research Articles

Intermittent compared with continuous calorie restriction for treatment of metabolic dysfunction-associated steatotic liver disease: a randomized clinical trial

BackgroundCalorie restriction has been demonstrated to be effective in treating metabolic dysfunction-associated steatotic liver disease (MASLD). However, it has been limited by poor long-term adherence. ObjectivesThis study aimed to compare intermittent calorie restriction (ICR) with traditional continuous calorie restriction (CCR) for the treatment of MASLD. MethodsWe conducted a 12-wk, parallel-arm, randomized controlled trial that included 60 adults with MASLD and abnormal glucose metabolism. The participants were randomly assigned to either the ICR group (2 successive days of fasting [∼500 kcal/d] and 5 d of recovery per week) or the CCR group. The primary outcome was liver fat content (LFC) measured by 1H-proton magnetic resonance spectroscopy. The secondary and exploratory outcomes included weight, body composition, glucose, insulin, lipids, and liver stiffness. ResultsThe mean reduction in LFC was −20.5% [95% confidence interval (CI): −25.0, −15.9%] in the ICR group and −15.5% (95% CI: −20.3, −10.8%) in the CCR group. Changes in LFC were not significantly different between the 2 groups (P = 0.15), and were homogeneous among different liver segments. The analysis of exploratory endpoints provided clues that the ICR was associated with greater reductions in fat mass and glycosylated hemoglobin. There were no significant differences in changes of weight, lean mass, insulin resistance, triglyceride, and liver stiffness between the 2 groups. Participants showed high adherence to both the ICR and CCR schemes. ConclusionsThe ICR and CCR schemes had similar effects on reducing LFC, suggesting that the ICR 5:2 diet can be an effective alternative for treating MASLD with high adherence. Trial registration numberThis trial was registered at clinicaltrials.gov as NCT04283942.

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. Cross-sectional study in men and women across a range of adiposity. Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.

S1805 Regional Variability in Liver Fat Content in Pediatric NAFLD and Adult NASH Assessed by Proton Density Fat Fraction Imaging

S1805 Regional Variability in Liver Fat Content in Pediatric NAFLD and Adult NASH Assessed by Proton Density Fat Fraction Imaging

Unveiling Resmetirom: A systematic review and meta-analysis on its impact on liver function and safety in non-alcoholic steatohepatitis treatment.

The role of Resmetirom in non-alcoholic steatohepatitis (NASH) represents a promising therapeutic approach in addressing the growing global burden of liver disease. With NASH emerging as a leading cause of liver-related morbidity and mortality worldwide, there is an urgent need for effective treatments. Resmetirom, a selective thyroid hormone receptor-β agonist, offers potential benefits in improving liver histology and metabolic parameters in patients with NASH. This review examines the current evidence surrounding Resmetirom's role in NASH management. A systematic review and meta-analysis was done by searching in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess) (OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tool was used for assessing risk of bias in randomized controlled trials (RCTs). In the analysis, we used RevMan Cochrane software. The study showed that patients who were treated with Resmetirom had significantly lower low-density lipoprotein-cholesterol (LDL-C) levels (mean difference [MD] -10.45; 95% confidence interval [CI] -15.86 to -5.83; P < 0.001) and alanine aminotransferase (ALT) levels (MD -7.18; 95% CI -12.67 to -1.68; P = 0.01) as compared with those in the placebo group. The risk of adverse events including diarrhea [risk ratio (RR)1.81; 95% CI 1.40 to 2.35; P < 0.001] and nausea (RR 1.72; 95% CI 1.31 to 2.27; P < 0.001) was significantly increased for the Resmetirom group as compared with the placebo group. Resmetirom presents a promising therapeutic option for NASH, offering potential benefits in reducing liver fat content and improving histological outcomes. The encouraging results from clinical trials suggest that Resmetirom may address an unmet need in NASH management, providing hope for patients with this progressive liver disease. Further research and long-term studies are warranted to validate its efficacy and safety profile in larger patient populations.

PBMC transcriptome reveals an early metabolic risk profile in young rats with metabolically obese, normal-weight phenotype

Metabolically obese, normal-weight (MONW) phenotype is characterized by visceral adiposity and obesity-related complications despite the absence of excess body weight. Early identification of this phenotype is crucial to establish preventive strategies. We aim to validate the utility of peripheral blood mononuclear cells (PBMC) transcriptome to detect metabolic risk related to the MONW phenotype at early life stages (young adulthood). Male Wistar rats were pair-fed either standard (NW group) or a high-fat diet (MONW group) after weaning, until 3.5 months. Global gene expression was examined by microarray in PBMC, and specific genes of interest by RT-qPCR in PBMC and liver. Results were validated in adult 6-month-old MONW rats. Young MONW rats had similar weight to controls but greater adiposity, including liver fat content, and insulin resistance signs. PBMC transcriptome distinguished clearly MONW from NW animals. Neurological pathways were affected in line with impaired cognition in these animals. Most top-regulated genes were related to inflammation, including the top-up and down-regulated genes, Hpgds and Slfn4. Expression of fatty liver-related genes like Mkrn1 and Nampt was also affected in PBMC of the young MONW group mirroring liver alteration. Slfn4 and Mkrn1 appeared as especially relevant biomarkers with altered expression also in PBMC of adult 6-month-old MONW rats. In conclusion, PBMC transcriptomic analysis emerges as a tool for identifying early biomarkers of obesity-related metabolic risk in young and apparently healthy (lean) subjects, pointing towards increased inflammation, liver fat deposition, and cognitive alterations.

Ex Vivo Demonstration of a Novel Dual-Frequency Ultrasound Method for Quantitative Measurements of Liver Fat Content

ObjectiveThe rise in metabolic dysfunction–associated steatotic liver disease prevalence, closely linked with metabolic syndromes and obesity, demands accurate, cost-effective diagnostic methods for early-stage fat quantification in the liver. Here we demonstrate a novel dual-frequency ultrasound method that enables the quantitative measurement of liver fat fraction ex vivo and its correlation with actual fat content. MethodsA total of 24 Wistar rats were divided into four different groups, where three groups were given a high-fat diet for 2, 4, and 6 wk, and the last group was given a control diet for 6 wk. Livers were imaged with ultrasound ex vivo in a water bath with a dual-frequency ultrasound transducer and experimental imaging protocol implemented on the Verasonics Vantage research ultrasound scanner. Ultrasound data were post-processed to estimate the non-linear bulk elasticity parameter and the liver samples were analyzed with respect to fat fraction and triglycerides. ResultsRats given a high-fat diet had increased mean levels of liver fat compared with the control group. More importantly, correlation between the ultrasound-based estimation of the non-linear bulk elasticity parameter and fat fraction and triglycerides on an individual level was found to be strong (R2 = 0.81, p = 5.8 × 10-9 and R2 = 0.72, p = 3.6 × 10-7, respectively). ConclusionThis study demonstrates the potential of the novel dual-frequency ultrasound method for the quantitative measurement of liver fat fraction in excised rat livers, showing great promise for this method to become clinically relevant in the diagnosis and follow-up of patients with fatty liver disease.

THE EFFECTS OF EXERCISE INTENSITY ON METABOLIC HEALTH IN PATIENTS WITH NAFLD AND TYPE 2 DIABETES: A COMPARATIVE STUDY

Introduction: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are chronic metabolic disorders that are increasingly prevalent globally, posing significant health challenges. Both conditions are linked to obesity, insulin resistance, and sedentary lifestyles, leading to severe complications such as cardiovascular diseases and liver cirrhosis. Exercise is a crucial lifestyle modification that improves metabolic health in these conditions, but the optimal exercise intensity remains debated. This study investigates the effects of different exercise intensities on metabolic health in patients with NAFLD and T2DM to provide insights for tailored exercise prescriptions. Materials and Methods: This randomized controlled trial involved 100 participants with NAFLD and T2DM, divided into two groups: MICT and HIIT, over 12 weeks. Participants were adults aged 30-65 years with confirmed NAFLD and T2DM, and a sedentary lifestyle. Exclusion criteria included other liver diseases, uncontrolled hypertension, severe diabetic complications, recent participation in a structured exercise program, and contraindications to exercise. Participants were randomly assigned to MICT or HIIT, with exercise sessions supervised by certified physiologists. Primary outcomes were liver fat content and insulin sensitivity, while secondary outcomes included lipid profiles, inflammatory markers, feasibility, and safety. Results: A total of 100 participants (50 per group) completed the study with comparable baseline characteristics. Both groups showed significant reductions in liver fat content and improvements in insulin sensitivity, with HIIT showing greater reductions (p=0.01 for liver fat, p=0.02 for insulin sensitivity). HIIT also led to more significant improvements in triglycerides, LDL, HDL, and inflammatory markers compared to MICT. Adherence rates were high in both groups, although slightly lower in the HIIT group, and dropout rates were comparable. Conclusion: Both MICT and HIIT significantly improve metabolic health in patients with NAFLD and T2DM, with HIIT yielding superior outcomes in reducing liver fat, improving insulin sensitivity, enhancing lipid profiles, and decreasing inflammatory markers. These findings support incorporating HIIT into exercise regimens for this population, highlighting its potential for greater metabolic health benefits. Future research should explore the long-term sustainability and broader applicability of HIIT and strategies to enhance adherence and safety.

Assessing Quality of Ultrasound Attenuation Coefficient Results for Liver Fat Quantification.

Algorithms for quantifying liver fat content based on the ultrasound attenuation coefficient (AC) are currently available; however, little is known about whether their accuracy increases by applying quality criteria such as the interquartile range-to-median ratio (IQR/M) or whether the median or average AC value should be used. AC measurements were performed with the Aplio i800 ultrasound system using the attenuation imaging (ATI) algorithm (Canon Medical Systems, Otawara, Tochigi, Japan). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) was the reference standard. The diagnostic performance of the AC median value of 5 measurements (AC-M) was compared to that of AC average value (AC-A) of 5 or 3 acquisitions and different levels of IQR/M for median values or standard deviation/average (SD/A) for average values were also analyzed. Concordance between AC-5M, AC-5A, and AC3A was evaluated with concordance correlation coefficient (CCC). A total of 182 individuals (94 females; mean age, 51.2y [SD: 15]) were evaluated. A total of 77 (42.3%) individuals had S0 steatosis (MRI-PDFF < 6%), 75 (41.2%) S1 (MRI-PDFF 6-17%), 10 (5.5%) S2 (MRI-PDFF 17.1-22%), and 20 (11%) S3 (MRI-PDFF ≥ 22.1%). Concordance of AC-5A and AC-3A with AC-5M was excellent (CCC: 0.99 and 0.96, respectively). The correlation with MRI-PDFF was almost perfect. Diagnostic accuracy of AC-5M, AC-5A, and AC3A was not significantly affected by different levels of IQR/M or SD/A. The accuracy of AC in quantifying liver fat content was not affected by reducing the number of acquisitions (from five to three), by using the mean instead of the median, or by reducing the IQR/M or SD/A to ≤5%.

Longitudinal association of peripheral blood DNA methylation with liver fat content: distinguishing between predictors and biomarkers

BackgroundAlterations in DNA methylation (DNAm) have been observed in patients with fatty liver, but whether they are cause or consequence remains unknown. The study aimed to investigate longitudinal association of epigenome-wide DNAm with liver fat content (LFC) in Chinese participants, and explore their temporal relationships.MethodsData were obtained from 2 waves over a four-year time period of the Shanghai Changfeng Study (discovery, n = 407 and replication, n = 126). LFC and peripheral blood DNAm were repeatedly measured using quantitative hepatic ultrasonography and the 850 K Illumina EPIC BeadChip, respectively. Longitudinal and cross-sectional epigenome-wide association studies (EWASs) were conducted with linear mixed model and linear regression model, respectively. Meta-analysis was performed using METAL. Cross-lagged panel analysis (CLPA) was carried out to infer temporal relationships between the significant CpGs and LFC.ResultsLongitudinal EWAS identified cg11024682 (SREBF1), cg06500161 (ABCG1), cg16740586 (ABCG1), cg15659943 (ABCA1) and cg00163198 (SNX19) significantly associated with LFC with P < 1e-7. Another 6 of the 22 previously reported CpGs were replicated in the present longitudinal EWAS. CLPA showed longitudinal effects of cg11024682 (SREBF1) (β = 0.14 [0.06, 0.23]), cg16740586 (ABCG1) (β = 0.17 [0.08, 0.25]), cg06500161 (ABCG1) (β = 0.12 [0.03, 0.20]), cg17901584 (DHCR24) (β = -0.10 [-0.18, -0.02]), cg00574958 (CPT1A) (β = -0.09 [-0.17, -0.01]), cg08309687 (LINC00649) (β = -0.11 [-0.19, -0.03]), and cg27243685 (ABCG1) (β = 0.09 [0.01, 0.18]) on subsequent LFC. The effects were attenuated when further adjusting for body mass index. High levels of LFC led to alterations in DNAm of cg15659943 (ABCA1) (β = 0.13 [0.04, 0.21]), cg07162647 (β = -0.11 [-0.19, -0.03]), cg06500161 (ABCG1) (β = 0.10 [0.02, 0.18]), and cg27243685 (ABCG1) (β = 0.10 [0.02, 0.18]).ConclusionsBlood DNAm at SREBF1, ABCG1, DHCR24, CPT1A, and LINC00649 may be predictors of subsequent LFC change. The effects of DNAm at SREBF1 and ABCG1 on LFC were partially influenced by obesity. The findings have potential implications in understanding disease pathogenesis and highlight the potential of DNAm for early detection or intervention of fatty liver.

Impact of cortisol on liver fat and metabolic health in adrenal incidentalomas and Cushing's syndrome.

To evaluate liver fat content in patients with non-functional adrenal incidentalomas (NFAI), mild autonomous cortisol secretion (MACS), and Cushing's syndrome (CS), and assess its relationship with cortisol levels. This cross-sectional study used retrospective data from 103 NFAI patients, 100 MACS (serum cortisol after a 1-mg dexamethasone test >50 nmol/L), and 59 with CS. Abdominal CT scans measured hepatic and splenic CT values to calculate the liver-to-spleen (L/S) ratio. Metabolic indicators including fasting plasma glucose (FPG), LDL-c, HDL-c, HbA1c, etc were measured. Mediation analysis was used to explore the indirect effects of metabolic traits on the cortisol-liver fat relationship. Patients included 103 NFAI, 100 MACS, and 59 CS. MACS patients had higher NAFLD prevalence (57%) than NFAI (26.2%, p < 0.001) but lower than CS (66.1%, p < 0.001). MACS and CS were associated with NAFLD (OR 3.83 and OR 5.73, p < 0.01), adjusted for age, body mass index (BMI), and covariates. Midnight serum cortisol correlated with L/S ratio (p < 0.001). HbA1c and Triglyceride-glucose index (TyG) mediated 24.5% and 49.5% of the cortisol and L/S ratio association, respectively. FPG, HbA1c, HDL-c, and TyG mediated the association between MACS or CS and the L/S ratio. Homeostasis model assessment of insulin resistance (HOMA-IR), fructosamine, and triglycerides mediated for MACS, while alkaline phosphatase did so for CS. Total cholesterol, LDL-c, ALT, AST, γ-GT, insulin, and uric acid did not mediate the association. MACS and CS are linked to significant metabolic disturbances, including increased liver fat and impaired glucose and lipid metabolism, contributing to fatty liver.

Longitudinal changes of serum metabolomic profile after laparoscopic sleeve gastrectomy in obesity.

Bariatric surgery induces significant weight loss, increases insulin sensitivity, and improves dyslipidemia. As one of the most widely performed bariatric surgeries, laparoscopic sleeve gastrectomy (LSG) is thought to improve the metabolic profile along with weight loss. The objective of this study was to evaluate longitudinal changes in the serum metabolite levels after LSG and elucidate the underlying mechanisms of metabolic improvement. Clinical metabolic parameters and serum samples were collected preoperatively and at 1, 3, and 6 months postoperatively from nine patients with obesity undergoing LSG. Serum metabolites were measured using a non-targeted metabolic liquid chromatography-mass spectrometry method. During the 1, 3, and 6 months postoperative follow-up, the body mass index, HOMA-IR, and liver fat content showed a gradual descending trend. A total of 328 serum metabolites were detected, and 38 were differentially expressed. The up-regulated metabolites were mainly enriched in ketone body metabolism, alpha-linolenic acid and linoleic acid metabolism, pantothenate and CoA biosynthesis, glycerolipid metabolism, and fructose and mannose degradation, while the down-regulated metabolites were closely related to caffeine metabolism, oxidation of branched-chain fatty acids, glutamate metabolism, and homocysteine degradation. Notably, nine metabolites (oxoglutarate, 2-ketobutyric acid, succinic acid semialdehyde, phthalic acid, pantetheine, eicosapentaenoate, 3-hydroxybutanoate, oxamic acid, and dihydroxyfumarate) showed persistent differential expression at 1, 3, and 6 months follow-up. Some were found to be significantly associated with weight loss, insulin resistance improvement, and liver fat content reduction. This finding may provide a new perspective for revealing novel biomarkers and mechanisms of metabolic improvement in obesity and related comorbidities.

Associations between dietary fatty acid and plasma fatty acid composition in non-alcoholic fatty liver disease: secondary analysis from a randomised trial with a hypoenergetic low-carbohydrate high-fat and intermittent fasting diet.

Dietary fatty acids (FA) affect metabolic risk factors. The aim of this study was to explore if changes in dietary fat intake during energy restriction were associated with plasma FA composition. The study also investigated if these changes were associated with changes in liver fat, liver stiffness and plasma lipids among persons with non-alcoholic fatty liver disease. Dietary and plasma FA were investigated in patients with non-alcoholic fatty liver disease (n 48) previously enrolled in a 12-week-long open-label randomised controlled trial comparing two energy-restricted diets: a low-carbohydrate high-fat diet and intermittent fasting diet (5:2), to a control group. Self-reported 3 d food diaries were used for FA intake, and plasma FA composition was analysed using GC. Liver fat content and stiffness were measured by MRI and transient elastography. Changes in intake of total FA (r 0·41; P = 0·005), SFA (r 0·38; P = 0·011) and MUFA (r 0·42; P = 0·004) were associated with changes in liver stiffness. Changes in plasma SFA (r 0·32; P = 0·032) and C16 : 1n-7 (r 0·33; P = 0·028) were positively associated with changes in liver fat, while total n-6 PUFA (r -0·33; P = 0·028) and C20 : 4n-6 (r -0·42; P = 0·005) were inversely associated. Changes in dietary SFA, MUFA, cholesterol and C20:4 were positively associated with plasma total cholesterol and LDL-cholesterol. Modifying the composition of dietary fats during dietary interventions causes changes in the plasma FA profile in patients with non-alcoholic fatty liver disease. These changes are associated with changes in liver fat, stiffness, plasma cholesterol and TAG. Replacing SFA with PUFA may improve metabolic parameters in non-alcoholic fatty liver disease patients during weight loss treatment.

Glycogenic hepatopathy associated with hepatic steatosis in type 1 diabetes

AimsGlycogenic hepatopathy is associated with significant psychosocial consequences and health costs. Metabolic Dysfunction-Associated Steatotic Liver Disease and glycogenic hepatopathy are frequently confused as “fatty liver” when seen on ultrasonography. We wished to examine liver fat and glycogen content in groups defined based on metabolic and liver disease phenotypes. MethodsThis case-control study undertaken in a tertiary hospital used nuclear proton magnetic resonance spectroscopy (1H-MRS) to examine liver fat and glycogen content in five clinical groups, each containing five participants: 1. type 1 diabetes with glycogenic hepatopathy, 2. satisfactorily controlled type 1 diabetes with no liver disease, 3. poorly controlled type 1 diabetes without liver disease, 4. a control group of body mass index- and age-matched individuals without diabetes or liver disease, and 5. hepatic steatosis. ResultsFat content was highest in the hepatic steatosis (median 15.4 %, IQR 10.0–19.3) and glycogenic hepatopathy (median 6.5 %, IQR 4.5–9.1) groups and compared to both of these groups was lower in the control group (median 1.0 %, IQR 0.7–1.1, p 0.002 and 0.022), the T1DM group with satisfactory control (median 0.3 %, IQR 0.2–0.6, p < 0.001 and <0.001), and the T1DM group with poor control without liver disease (median 1.1 %, IQR 0.9–1.1, p 0.001 and 0.012).No participants from the type 1 diabetes poor control, type 1 diabetes satisfactory control or the no diabetes groups had 1H-MRS-diagnosed hepatic steatosis.1H-MRS glycogen content could not be interpreted in the majority of those with glycogenic hepatopathy because of interference from the fat signal. ConclusionsIn cases diagnosed with glycogenic hepatopathy there may be significant concomitant fat accumulation, compounding the already elevated cardiovascular risk in this cohort.The technique of 1H-MRS has not been demonstrated to be useful for diagnosing glycogenic hepatopathy.

Investigating the efficacy of acupuncture in treating patients with metabolic-associated fatty liver disease: a protocol for a randomised controlled clinical trial

IntroductionAcupuncture is widely used for metabolic-associated fatty liver disease (MAFLD) treatment; however, the clinical efficacy has not been confirmed due to the lack of high-level evidence-based clinical practice. The purpose...

Sex-specific effects of PNPLA3 I148M.

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction-associated steatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex-specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex-specific role of PNPLA3 I148M in the development of MASLD, several invitro, exvivo and invivo models have been developed.

Evaluation of MRI proton density fat fraction in hepatic steatosis: a systematic review and meta-analysis.

Amidst the global rise of metabolic dysfunction-associated steatotic liver disease (MASLD), driven by increasing obesity rates, there is a pressing need for precise, non-invasive diagnostic tools. Our research aims to validate MRI Proton Density Fat Fraction (MRI-PDFF) utility, compared to liver biopsy, in grading hepatic steatosis in MASLD. A systematic search was conducted across Embase, PubMed/Medline, Scopus, and Web of Science until January 13, 2024, selecting studies that compare MRI-PDFF with liver biopsy for hepatic steatosis grading, defined as grades 0 (< 5% steatosis), 1 (5-33% steatosis), 2 (34-66% steatosis), and 3 (> 66% steatosis). Twenty-two studies with 2844 patients were included. The analysis showed high accuracy of MRI-PDFF with AUCs of 0.97 (95% CI = 0.96-0.98) for grade 0 vs ≥ 1, 0.91 (95% CI = 0.88-0.93) for ≤ 1 vs ≥ 2, and 0.91 (95% CI = 0.88-0.93) for ≤ 2 vs 3, diagnostic odds ratio (DOR) from 98.74 (95% CI = 58.61-166.33) to 23.36 (95% CI = 13.76-39.68), sensitivity and specificity from 0.93 (95% CI = 0.88-0.96) to 0.76 (95% CI = 0.63-0.85) and 0.93 (95% CI = 0.88-0.96) to 0.89 (95% CI = 0.84-0.93), respectively. Likelihood ratio (LR) + ranged from 13.3 (95% CI = 7.4-24.0) to 7.2 (95% CI = 4.9-10.5), and LR - from 0.08 (95% CI = 0.05-0.13) to 0.27 (95% CI = 0.17-0.42). The proposed MRI-PDFF threshold of 5.7% for liver fat content emerges as a potential cut-off for the discrimination between grade 0 vs ≥ 1 (p = 0.075). MRI-PDFF is a precise non-invasive technique for diagnosing and grading hepatic steatosis, warranting further studies to establish its diagnostic thresholds. This study underscores the high diagnostic accuracy of MRI-PDFF for distinguishing between various grades of hepatic steatosis for early detection and management of MASLD, though further research is necessary for broader application. MRI-PDFF offers precision in diagnosing and monitoring hepatic steatosis. The diagnostic accuracy of MRI-PDFF decreases as the grade of hepatic steatosis advances. A 5.7% MRI-PDFF threshold differentiates steatotic from non-steatotic livers.

Characteristics of intestinal flora in nonobese nonalcoholic fatty liver disease patients and the impact of ursodeoxycholic acid treatment on these features.

The study aimed to investigate the alterations in gut microbiota among nonobese individuals with nonalcoholic fatty liver disease (NAFLD) and their response to treatment with ursodeoxycholic acid (UDCA). A total of 90 patients diagnosed with NAFLD and 36 healthy subjects were recruited to participate in this study. Among them, a subgroup of 14 nonobese nonalcoholic steatohepatitis (NASH) were treated with UDCA. Demographic and serologic data were collected for all participants, while stool samples were obtained for fecal microbiome analysis using 16S sequencing. In nonobese NAFLD patients, the alpha diversity of intestinal flora decreased (Shannon index, p < 0.05), and the composition of intestinal flora changed (beta diversity, p < 0.05). The abundance of 20 genera, including Fusobacterium, Lachnoclostridium, Klebsiella, etc., exhibited significant changes (p < 0.05). Among them, nine species including Fusobacterium, Lachnoclostridium, Klebsiella, etc. were found to be associated with abnormal liver enzymes and glucolipid metabolic disorders. Among the 14 NASH patients treated with UDCA, improvements were observed in terms of liver enzymes, CAP values, and E values (p < 0.05), however, no improve the glucolipid metabolism. While the alpha diversity of intestinal flora did not show significant changes after UDCA treatment, there was a notable alteration in the composition of intestinal flora (beta diversity, p < 0.05). Furthermore, UCDA treatment led to an improvement in the relative abundance of Alistipes, Holdemanella, Gilisia, etc. among nonobese NASH patients (p < 0.05). Nonobese NAFLD patients exhibit dysbiosis of the intestinal microbiota. UDCA can ameliorate hepatic enzyme abnormalities and reduce liver fat content in nonobese NASH patients, potentially through its ability to restore intestinal microbiota balance.

Potential of Raman-Reflectance Combination in Quantifying Liver Steatosis and Fat Droplet Size: Evidence From Monte Carlo Simulations and Phantom Studies.

This study explores a combined strategy of Raman and reflectance spectroscopy for quantifying liver fat content and fat droplet size, crucial in assessing donor livers. By using Monte Carlo simulations and experimental setups with oil-in-water phantoms, our findings indicate that Raman scattering can solely differentiate between varying fat contents. At the same time, reflectance intensity is influenced by both fat content and oil droplet size, with a more pronounced sensitivity to fat droplet size. This study demonstrates the efficacy of combined Raman and reflectance spectroscopy in assessing liver steatosis and fat droplet size, potentially aiding in assessing donor livers for transplantation.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH

MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. NCT02443116, NCT03976401, NCT03551522.

Causal effects of female reproductive features on nonalcoholic fatty liver disease: A mendelian randomization study.

Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.