Imaging Proton Density Fat Fraction Research Articles

Elevated serum growth differentiation factor 15 and decorin predict the fibrotic progression of metabolic dysfunction-associated steatotic liver disease.

Mitochondrial dysfunction with oxidative stress contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. We aimed to evaluate the fibrosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. From a population-based general cohort, 144 subjects with MASLD were recruited in the development group and underwent magnetic resonance imaging-based liver examinations, anthropometric and laboratory tests. As an external validation group, 41 patients enrolled in a biopsy-evaluated MASLD cohort participated in this study. Liver fat content and stiffness were measured by magnetic resonance (MR) imaging-proton density fat fraction and MR elastography (MRE), respectively. Serologic stress biomarkers were quantitated by ELISA. Multivariate regression showed that waist-to-height ratio, growth differentiation factor-15 (GDF15), γ-glutamyltransferase, decorin, and alkaline-phosphatase were independent predictors of hepatic fibrosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95% CI)) of the metabolic stress index for fibrosis (MSI-F) was 0.912 (0.85‒0.98) and 0.977 (0.92‒1.00) in development and validation groups, respectively. MSI-F also had better diagnostic accuracy (82.6‒92.4%) than other fibrosis indices in the both study cohorts. MSI-F consistently differentiated fibrosis severities across cohorts of MRE-evaluated general population and biopsy-proven patients with MASLD, while other indices showed no or less discrimination. MSI-F, as a novel non-invasive index based on a stress-stimulated protective hormone GDF15 and decorin, effectively predicted hepatic fibrosis. Furthermore, MSI-F may serve as pre-screening tool to increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.

Development of a Deep Learning Model for Classification of Hepatic Steatosis from Clinical Standard Ultrasound

Early detection and monitoring of hepatic steatosis can help establish appropriate preventative measures against progression to more advanced disease. We aimed to develop a deep learning (DL) program for classification of hepatic steatosis from standard-of-care grayscale ultrasound (US) images. In this single-center retrospective study, we utilized grayscale US images from January 1, 2010, to October 23, 2022, labeled with magnetic resonance imaging (MRI) proton density fat fraction (MRI-PDFF) to develop a DL multi-instance program for differentiating normal (S0) from steatotic liver (S1/2/3) and normal/mild steatosis (S0/1) from moderate/severe steatosis (S2/3). Diagnostic performances were assessed with area under the receiver operating characteristic curves (AUC), sensitivity, specificity and balanced accuracy with 95% confidence interval (CI). A total of 403 patients with 403 US exams were included: 171 (42%) were normal (S0: MRI-PDFF <5%), 154 (38%) had mild steatosis (S1: MRI-PDFF 5-17.4%), 29 (7%) had moderate steatosis (S2: MRI-PDFF >17.4%-22.1%) and 49 (12%) had severe steatosis (S3: MRI-PDFF >22.1%). The dataset was split to include 322 patients in train/validation and 81 patients in a holdout test set (kept blind). The S0 versus S1/2/3 model achieved 81.3% (95% CI 72.1-90.5) AUC, 81.1% (70.6-91.6) sensitivity, 71.4% (54.7-88.2) specificity and 76.3% (66.4-86.2) balanced accuracy. The S0/1 versus S2/3 model achieved 95.9% (89-100) AUC, 87.5% (71.3-100) sensitivity, 96.9% (92.7-100) specificity and 92.2% (83.8-100) balanced accuracy. A multi-class model achieved a sensitivity of 71.4% (54.7-88.2) for S0, 67.6% (52.5-82.7) for S1 and 87.5% (71.3-100) for S2/3; specificity for the same model was 81.1% (70.6-91.6) for S0, 77.3% (64.9-89.7) for S1 and 96.9% (92.7-100) for S2/3. Our DL program offered high sensitivity and accuracy in detecting and categorizing hepatic steatosis from standard-of-care ultrasound.

Association Between Ultraprocessed Food Consumption and Metabolic Disorders in Children and Adolescents with Obesity.

We investigated the effects of ultraprocessed food (UPF) consumption on metabolic disorders (e.g., adiposity, metabolic associated steatotic liver disease [MASLD], and insulin resistance) in children and adolescents with obesity to improve dietary guidelines and public health strategies. The dietary intake of 149 participants (aged 8-17 years) was assessed with food diaries. The NOVA classification system was used to classify food according to the degree of processing. Metabolic outcomes, including the fat mass index (FMI), hepatic fat percentage, and insulin resistance, were measured via dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging proton density fat fraction (MRI-PDFF), and biochemical analysis, respectively. Greater UPF consumption from baseline to the 6-month follow-up was significantly associated with increased insulin and decreased total cholesterol and LDL-cholesterol. UPF consumption was positively associated with the prevalence of MASLD (liver MRI-PDFF ≥ 5%; odds ratio T3 vs. T1 = 1.75; 95% confidence interval [CI] 1.03, 3.00), moderate-to-severe MASLD (liver MRI-PDFF ≥ 10%; OR T3 vs. T1 = 4.19; 95% CI 1.72, 10.22), and insulin resistance (OR T3 vs. T1 = 2.44; 95% CI 1.33, 4.48), after adjusting for covariates. A linear dose-response relationship was observed between UPF consumption and the odds of moderate-to-severe MASLD and insulin resistance. Greater UPF consumption was strongly associated with MASLD and insulin resistance in children and adolescents with obesity, underscoring the importance of reducing UPF consumption through dietary guidelines and public health interventions to mitigate the risk of obesity-related metabolic conditions in young populations.

Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis

AimsTo compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsA database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. ResultsTwenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] −51.47; 95 % confidence interval [CI]: −68.25 to −34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD −47.08; 95 % CI: −58.83 to −35.34; SUCRA 75.5), GLP-1R agonists (MD −37.36; 95 % CI: −69.52 to −5.21; SUCRA 52.3) and THR-β agonists (MD −33.20; 95 % CI: −43.90 to −22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD −9.65; 95 % CI: −19.28 to −0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD −5.79; 95 % CI: −9.50 to −2.09; SUCRA 58.2), and GLP-1RAs (MD −5.58; 95 % CI: −15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. ConclusionThese results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

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%.

Novel Quantitative Liver Steatosis Assessment Method With Ultrasound Harmonic Imaging.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disorder in Western countries, with approximately 20%-30% of the MASLD patients progressing to severe stages. There is an urgent need for noninvasive, cost-effective, widely accessible, and precise biomarkers to evaluate liver steatosis. This study aims to assess and compare the diagnostic performance of a novel reference frequency method-based ultrasound attenuation coefficient estimation (ACE) in both fundamental (RFM-ACE-FI) and harmonic (RFM-ACE-HI) imaging for detecting and grading liver steatosis. An Institutional Review Board-approved prospective study was carried out between December 2018 and October 2022. A total number of 130 subjects were enrolled in the study. The correlation between RFM-ACE-HI values and magnetic resonance imaging proton density fat fraction (MRI-PDFF), as well as between RFM-ACE-FI values and MRI-PDFF were calculated. The diagnostic performance of RFM-ACE-FI and RFM-ACE-HI was evaluated using receiver operating characteristic (ROC) curve analysis, as compared to MRI-PDFF. The reproducibility of RFM-ACE-HI was assessed by interobserver agreement between two sonographers. A strong correlation was observed between RFM-ACE-HI and MRI-PDFF, with R = 0.88 (95% confidence interval [CI]: 0.83-0.92; P < .001), while the correlation between RFM-ACE-FI and MRI-PDFF was R = 0.65 (95% CI: 0.50-0.76; P < .001). The area under the ROC (AUROC) curve for RFM-ACE-HI in staging liver steatosis grades of S ≥ 1 and S ≥ 2 was 0.97 (95% CI: 0.91-0.99; P < .001) and 0.98 (95% CI: 0.93-1.00; P < .001), respectively, and 0.76 (95% CI: 0.65-0.85) and 0.80 (95% CI: 0.70-0.88) for RFM-ACE-FI, respectively. Great reproducibility was achieved for RFM-ACE-HI, with an interobserver agreement of R = 0.97 (95% CI: 0.94-0.99; P < .001). The novel RFM-ACE-HI method offered high liver steatosis diagnostic accuracy and reproducibility, which has important clinical implications for early disease intervention and treatment evaluation.

Comparing Three Ultrasound-Based Techniques for Diagnosing and Grading Hepatic Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease

ObjectiveTo compare the diagnostic accuracy and grading ability of ultrasound-derived fat fraction (UDFF), controlled attenuation parameters (CAP), and hepatic/renal ratio (HRR) for hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) using magnetic resonance imaging proton density fat fraction (PDFF) as the gold standard. MethodsPatients suspected of having MASLD in our hospital between October 2023 and May 2024 were divided into the MASLD group and the control group. All patients underwent UDFF, CAP and PDFF examinations. HRR was measured during routine ultrasound examination. In statistical analysis, we initially assessed the correlation between UDFF, CAP, HRR, and general characteristics of subjects with PDFF. Subsequently, receiver operating characteristic curve were employed to evaluate and compare the diagnostic performance of UDFF, CAP, and HRR for different grades of hepatic steatosis in MASLD. Their area under the curve, optimal cut-off value, sensitivity, and specificity were also determined. Finally, predictive factors determined hepatic steatosis in MASLD (PDFF≥6%) were identified through binary logistic regression analysis. Results115 individuals were ultimately included in the MASLD group, while 102 were included in the control group. UDFF, CAP, and HRR were all positively correlated with PDFF. Among them, UDFF exhibited the strongest correlation with PDFF (ρ=0.91). Furthermore, in the comparison of diagnostic efficacy among different grades of hepatic steatosis, UDFF outperformed CAP and HRR (p<0.05). However, there were no statistically significant differences in AUCs between CAP and HRR across all three grades. The AUCs for UDFF in ≥S1, ≥S2, and ≥S3 were 0.99 (95% CI 0.97 to 1.00), 0.96 (95% CI 0.93 to 0.98), and 0.97 (95% CI 0.94 to 0.99) respectively. The optimal thresholds for UDFF determined as follows: ≥6% for grade S1; ≥15% for grade S2; and ≥23% for grade S3. Multivariate analysis revealed that only age, UDFF, and CAP were important influencing factors for hepatic steatosis in MASLD. ConclusionThe diagnostic accuracy of UDFF surpassed that of CAP and HRR in the detection and grading of hepatic steatosis in MASLD.

Two-week continuous glucose monitoring-derived metrics and degree of hepatic steatosis: a cross-sectional study among Chinese middle-aged and elderly participants

BackgroundContinuous glucose monitoring (CGM) devices provide detailed information on daily glucose control and glycemic variability. Yet limited population-based studies have explored the association between CGM metrics and fatty liver. We aimed to investigate the associations of CGM metrics with the degree of hepatic steatosis.MethodsThis cross-sectional study included 1180 participants from the Guangzhou Nutrition and Health Study. CGM metrics, covering mean glucose level, glycemic variability, and in-range measures, were separately processed for all-day, nighttime, and daytime periods. Hepatic steatosis degree (healthy: n = 698; mild steatosis: n = 242; moderate/severe steatosis: n = 240) was determined by magnetic resonance imaging proton density fat fraction. Multivariate ordinal logistic regression models were conducted to estimate the associations between CGM metrics and steatosis degree. Machine learning models were employed to evaluate the predictive performance of CGM metrics for steatosis degree.ResultsMean blood glucose, coefficient of variation (CV) of glucose, mean amplitude of glucose excursions (MAGE), and mean of daily differences (MODD) were positively associated with steatosis degree, with corresponding odds ratios (ORs) and 95% confidence intervals (CIs) of 1.35 (1.17, 1.56), 1.21 (1.06, 1.39), 1.37 (1.19, 1.57), and 1.35 (1.17, 1.56) during all-day period. Notably, lower daytime time in range (TIR) and higher nighttime TIR were associated with higher steatosis degree, with ORs (95% CIs) of 0.83 (0.73, 0.95) and 1.16 (1.00, 1.33), respectively. For moderate/severe steatosis (vs. healthy) prediction, the average area under the receiver operating characteristic curves were higher for the nighttime (0.69) and daytime (0.66) metrics than that of all-day metrics (0.63, P < 0.001 for all comparisons). The model combining both nighttime and daytime metrics achieved the highest predictive capacity (0.73), with nighttime MODD emerging as the most important predictor.ConclusionsHigher CGM-derived mean glucose and glycemic variability were linked with higher steatosis degree. CGM-derived metrics during nighttime and daytime provided distinct and complementary insights into hepatic steatosis.

Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content.

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.

Efficacy of Ayurveda interventions and lifestyle versus lifestyle interventions alone in grade I and II non-alcoholic fatty liver disease: Protocol for a multicenter exploratory pilot randomized controlled trial

Abstract INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a worldwide public health issue affecting 20%–30% of adults, with dominance in men, particularly in the obese population. Current interventions focus on lifestyle modifications, highlighting the need for effective pharmacological options. This study explores the clinical efficacy of Arogyavardhini Vati and Pippalyadyasava, traditional Ayurvedic formulations, in the management of NAFLD. BACKGROUND AND RATIONALE: With Ayurvedic medicine emphasizing holistic well-being, this study is aimed to assess the efficacy of Ayurveda interventions viz., Arogyavardhini Vati and Pippalyadyasava combined with lifestyle modifications in grade I and II NAFLD. MATERIALS AND METHODS: The study includes individuals aged 18–60 years and diagnosed with NAFLD of grade I or II. The intervention arm receives Arogyavardhini Vati and Pippalyadyasava along with lifestyle modifications, while the control group adopts lifestyle modifications for 90 days. Both groups are then followed up for more than 30 days with lifestyle modifications ongoing. Primary outcomes include the change in the fibroscan score and controlled attenuation parameter value or magnetic resonance imaging proton density fat fraction. Secondary outcomes are changes in liver function markers, lipid profile, HbA1C, Body Mass Index, and Fatty Liver Index. CONCLUSION: This study may inform about the efficacy of the Ayurvedic interventions adjuvant to lifestyle modification in the management of NAFLD. TRIAL REGISTRATION: CTRI/2022/02/040321 dated February 15, 2022.

Application of Quantitative Ultrasonography and Artificial Intelligence for Assessing Severity of Fatty Liver: A Pilot Study.

Non-alcoholic fatty liver disease (NAFLD), prevalent among conditions like obesity and diabetes, is globally significant. Existing ultrasound diagnosis methods, despite their use, often lack accuracy and precision, necessitating innovative solutions like AI. This study aims to validate an AI-enhanced quantitative ultrasound (QUS) algorithm for NAFLD severity assessment and compare its performance with Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF), a conventional diagnostic tool. A single-center cross-sectional pilot study was conducted. Liver fat content was estimated using an AI-enhanced quantitative ultrasound attenuation coefficient (QUS-AC) of Barreleye Inc. with an AI-based QUS algorithm and two conventional ultrasound techniques, FibroTouch Ultrasound Attenuation Parameter (UAP) and Canon Attenuation Imaging (ATI). The results were compared with MRI-PDFF values. The intraclass correlation coefficient (ICC) was also assessed. Significant correlation was found between the QUS-AC and the MRI-PDFF, reflected by an R value of 0.95. On other hand, ATI and UAP displayed lower correlations with MRI-PDFF, yielding R values of 0.73 and 0.51, respectively. In addition, ICC for QUS-AC was 0.983 for individual observations. On the other hand, the ICCs for ATI and UAP were 0.76 and 0.39, respectively. Our findings suggest that AC with AI-enhanced QUS could serve as a valuable tool for the non-invasive diagnosis of NAFLD.

Diagnosis and non-invasive assessment of MASLD in type 2 diabetes and obesity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease and an important cause of cirrhosis and hepatocellular carcinoma. It is strongly associated with type 2 diabetes and obesity. Because of the huge number of patients at risk of MASLD, it is imperative to use non-invasive tests appropriately. To provide a narrative review on the performance and limitations of non-invasive tests, with a special emphasis on the impact of diabetes and obesity. We searched PubMed and Cochrane databases for articles published from 1990 to August 2023. Abdominal ultrasonography remains the primary method to diagnose hepatic steatosis, while magnetic resonance imaging proton density fat fraction is currently the gold standard to quantify steatosis. Simple fibrosis scores such as the Fibrosis-4 index are well suited as initial assessment in primary care and non-hepatology settings to rule out advanced fibrosis and future risk of liver-related complications. However, because of its low positive predictive value, an abnormal test should be followed by specific blood (e.g. Enhanced Liver Fibrosis score) or imaging biomarkers (e.g. vibration-controlled transient elastography and magnetic resonance elastography) of fibrosis. Some non-invasive tests of fibrosis appear to be less accurate in patients with diabetes. Obesity also affects the performance of abdominal ultrasonography and transient elastography, whereas magnetic resonance imaging may not be feasible in some patients with severe obesity. This article highlights issues surrounding the clinical application of non-invasive tests for MASLD in patients with type 2 diabetes and obesity.

Assessment of Hepatic Steatosis Using Ultrasound-Based Techniques: Focus on Fat Quantification

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, affecting more than 30% of the global population, and is associated with increased liver-related morbidity and mortality, and extrahepatic complications. With the increasing prevalence of MASLD, there is an urgent need for accessible, non-invasive methods to detect hepatic steatosis. Currently, liver biopsy and magnetic resonance imaging proton density fat fraction are considered reference standards for diagnosing hepatic steatosis; however, their invasiveness and limited accessibility limit their widespread use. Ultrasonography (US) is a promising alternative owing to its cost-effectiveness and widespread accessibility. Recently, quantitative US techniques have been developed and commercialized by several vendors to measure steatosis by detecting changes in various acoustic properties associated with hepatic steatosis, making it readily accessible. Controlled attenuation parameter (CAP), which evaluates hepatic steatosis using the attenuation of the US beam, is the most widely studied algorithm as a non-imaging technique. Several other algorithms are also available on B-mode ultrasound systems, and their diagnostic performance is comparable to or better than that of the CAP. Therefore, we aimed to review current US-based methods for detecting and grading hepatic steatosis, discussing their diagnostic performance and utilization.

Role of Resmetirom, a Liver-Directed, Thyroid Hormone Receptor Beta-Selective Agonist, in Managing Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis

BackgroundResmetirom, a liver-directed, thyroid hormone receptor beta-selective agonist, has recently been approved to treat nonalcoholic steatohepatitis (NASH). This meta-analysis aimed to summarize the efficiency and safety of resmetirom in treating NASH. MethodsElectronic databases were searched for randomized controlled trials (RCTs) of resmetirom vs placebo in patients with NASH. The primary outcomes were the changes from baseline in hepatic fat content, liver histology, including NASH resolution, and noninvasive markers of hepatic fibrosis. ResultsThree randomized controlled trials (n = 2231) met the inclusion criteria. Compared to placebo, resmetirom achieved greater reductions from baseline in hepatic fat content assessed by magnetic resonance imaging proton density fat fraction (for resmetirom 80 mg: MD −27.76% [95%CI: −32.84, −22.69]; for resmetirom 100 mg: MD −36.01% [95%CI: −41.54, −30.48]; P < .00001 for both) and FibroScan controlled attenuation parameter (for resmetirom 80 mg: MD −21.45 dBm [95%CI: −29.37, −13.52]; for resmetirom 100 mg: MD −25.51 dBm [95%CI: −33.53, −17.49]; P < .00001 for both). Resmetirom 80 mg outperformed placebo in NASH resolution and ≥2-point nonalcoholic fatty liver disease activity score reduction. Moreover, resmetirom 80 mg and 100 mg were superior to placebo in cytokeratin-18 (M30) reduction. Greater reductions in liver enzymes, lipids, and reverse triiodothyronine were observed in the resmetirom arms with no impact on triiodothyronine. Nausea and diarrhea were more common with resmetirom than with placebo; other adverse events were comparable. ConclusionResmetirom improves hepatic fat content, liver enzymes, and fibrosis biomarkers in NASH patients. Resmetirom generally does not affect thyroid function and is well-tolerated.

A prospective study on the prevalence of at-risk MASH in patients with type 2 diabetes mellitus in the United States.

There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis.

Automated Liver Volumetry and Hepatic Steatosis Quantification with Magnetic Resonance Imaging Proton Density Fat Fraction

BackgroundPreoperative imaging evaluation of liver volume and hepatic steatosis for the donor affects transplantation outcomes. However, computed tomography (CT) for liver volumetry and magnetic resonance spectroscopy (MRS) for hepatic steatosis are time consuming. Therefore, we investigated the correlation of automated 3D-multi-echo-Dixon sequence magnetic resonance imaging (ME-Dixon MRI) and its derived proton density fat fraction (MRI-PDFF) with CT liver volumetry and MRS hepatic steatosis measurements in living liver donors. MethodsThis retrospective cross-sectional study was conducted from December 2017 to November 2022. We enrolled donors who received a dynamic CT scan and an MRI exam within 2 days. First, the CT volumetry was processed semiautomatically using commercial software, and ME-Dixon MRI volumetry was automatically measured using an embedded sequence. Next, the signal intensity of MRI-PDFF volumetric data was correlated with MRS as the gold standard. ResultsWe included the 165 living donors. The total liver volume of ME-Dixon MRI was significantly correlated with CT (r = 0.913, p < 0.001). The fat percentage measured using MRI-PDFF revealed a strong correlation between automatic segmental volume and MRS (r = 0.705, p < 0.001). Furthermore, the hepatic steatosis group (MRS ≥ 5%) had a strong correlation than the non–hepatic steatosis group (MRS < 5%) in both volumetric (r = 0.906 vs. r = 0.887) and fat fraction analysis (r = 0.779 vs. r = 0.338). ConclusionAutomated ME-Dixon MRI liver volumetry and MRI-PDFF were strongly correlated with CT liver volumetry and MRS hepatic steatosis measurements, especially in donors with hepatic steatosis.

Velacur ACE outperforms FibroScan CAP for diagnosis of MASLD.

As the prevalence of metabolic dysfunction-associated steatotic liver disease increases, it is imperative to have noninvasive alternatives to liver biopsy. Velacur offers a non-invasive, point-of-care ultrasound-based method for the assessment of liver stiffness and attenuation. The aim of this study was to perform a head-to-head comparison of liver stiffness and liver fat determined by Velacur and FibroScan using MRI-based measurements as the reference standard. This prospective cross-sectional study included 164 adult participants with well-characterized metabolic dysfunction-associated steatotic liver disease. Patients underwent a research exam including Velacur, FibroScan and contemporaneous magnetic resonance elastography, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) scans. The primary outcome was the presence of advanced fibrosis (>F2) as measured by magnetic resonance elastography and the presence of liver fat (>5%) as measured by MRI-PDFF. The mean age and body mass index were 57±12 years and 30.6±4.8kg/m2, respectively. The mean liver stiffness on magnetic resonance elastography was 3.22±1.39kPa and the mean liver fat on MRI-PDFF was 14.2±8%. The liver stiffness assessments by Velacur and FibroScan were similar for the detection of advanced fibrosis (AUC 0.95 vs. 0.97) and were not statistically different (p=0.43). Velacur was significantly better than FibroScan (AUC 0.94 vs. 0.79, p=0.01), for the detection of MRI-PDFF >5% (diagnosis of metabolic dysfunction-associated liver disease). Velacur was superior to FibroScan for liver fat detection with MRI-PDFF as the reference. Velacur and FibroScan were not statistically different for liver stiffness assessment as defined by magnetic resonance elastography.

Correlation between magnetic resonance imaging proton density fat fraction (MRI-PDFF) and liver biopsy to assess hepatic steatosis in obesity

Obesity is highly associated with Non-alcoholic fatty liver disease (NAFLD) and increased risk of liver cirrhosis and liver cancer-related death. We determined the diagnostic performance of the complex-based chemical shift technique MRI-PDFF for quantifying liver fat and its correlation with histopathologic findings in an obese population within 24 h before bariatric surgery. This was a prospective, cross-sectional, Institutional Review Board-approved study of PDFF-MRI of the liver and MRI-DIXON image volume before bariatric surgery. Liver tissues were obtained during bariatric surgery. The prevalence of NAFLD in the investigated cohort was as high as 94%. Histologic hepatic steatosis grades 0, 1, 2, and 3 were observed in 3 (6%), 25 (50%), 14 (28%), and 8 (16%) of 50 obese patients, respectively. The mean percentages of MRI-PDFF from the anterior and posterior right hepatic lobe and left lobe vs. isolate left hepatic lobe were 15.6% (standard deviation [SD], 9.28%) vs. 16.29% (SD, 9.25%). There was a strong correlation between the percentage of steatotic hepatocytes and MRI-PDFF in the left hepatic lobe (r = 0.82, p < 0.001) and the mean value (r = 0.78, p < 0.001). There was a strong correlation between MRI-derived subcutaneous adipose tissue volume and total body fat mass by dual-energy X-ray absorptiometry, especially at the L2–3 and L4 level (r = 0.85, p < 0.001). MRI-PDFF showed good performance in assessing hepatic steatosis and was an excellent noninvasive technique for monitoring hepatic steatosis in an obese population.

Aspirin for Metabolic Dysfunction–Associated Steatotic Liver Disease Without Cirrhosis

ImportanceAspirin may reduce severity of metabolic dysfunction–associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.ObjectiveTo test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.Design, Setting, and ParticipantsThis 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.InterventionsParticipants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.Main Outcomes and MeasuresThe primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.ResultsAmong 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was −6.6% with aspirin vs 3.6% with placebo (difference, −10.2% [95% CI, −27.7% to −2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (−8.8 vs 30.0 percentage points; mean difference, −38.8 percentage points [95% CI, −66.7 to −10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (−2.7% vs 0.9%; mean difference, −3.7% [95% CI, −6.1% to −1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (−11.7 vs 15.7 percentage points; mean difference, −27.3 percentage points [95% CI, −45.2 to −9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.Conclusions and RelevanceIn this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04031729

Protocol of quantitative ultrasound techniques for noninvasive assessing of hepatic steatosis after bariatric surgery.

Roux-en-Y gastric bypass surgery can effectively improve steatosis, necroinflammatory activity, and hepatic fibrosis in individuals diagnosed with morbid obesity or nonalcoholic steatohepatitis (NASH). Common methods such as body mass index (BMI) to evaluate the postoperative effect of clinical bariatric surgery cannot differentiate subcutaneous fats from visceral fats and muscles. Several Quantitative ultrasound (QUS)-based approaches have been developed to quantify hepatic steatosis. QUS techniques (tissue attenuation imaging (TAI), tissue scatter distribution imaging (TSI)) from radio frequency (RF) data analysis as a means for the detection and grading of hepatic steatosis has been posited as an objective and noninvasive approach. The implementation and standardization of QUS techniques (TAI, TSI) in assessing hepatic steatosis quantitatively after bariatric surgery is of high-priority. Our study is aimed to assess hepatic steatosis with QUS techniques (TAI, TSI) in morbidly obese individuals before and after bariatric surgery, and to compare with anthropometric measurements, laboratory assessments and other imaging methods. The present investigation, a self-discipline examination of navigational capacity devoid of visual cues, is designed as a single-site, forward-looking evaluation of efficacy with the imprimatur of the institutional review board. The duration of the study has been provisionally determined to span from 1 January 2023 through 31 December 2025. Our cohort shall encompass one hundred participants, who was scheduled to undergo Roux-en-Y gastric bypass (RYGB) at Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. All patients will undergo anthropometric measurements, blood-based biochemical analyses, ultrasonic examination and magnetic resonance imaging proton density fat fraction (MRI-PDFF). The primary endpoint is the analysis of evaluating the efficacy of QUS techniques assessing hepatic steatosis compared to other methods before and after bariatric surgery. Prior to the fomal study, we recruited 21 obese Chinese participants who received ultrasonic examination (TAI, TSI) and MRI-PDFF. AC-TAI showed moderate correlations with MRI-PDFF (adjusted r = 0.632; P < 0.05). For MRI-PDFF ≥10%, SC-TSI showed moderate correlations with MRI-PDFF (adjusted r = 0.677; P < 0.05). Our pre-experiment results signified that using QUS techniques for postoperative evaluation of bariatric surgery is promising. QUS techniques will be signed a widespread availability, real-time functionality, and low-cost approach for assessing hepatic steatosis before and after bariatric surgery in obese individuals, thus is capable for subsequent scale-up liver fat quantification. The present research endeavor has been bestowed with the imprimatur of the Ethics Committee of the Hospital, as indicated by its Approval Number: 2023-KY-015. In due course, upon completion of the study, we intend to disseminate our findings by publishing them in a suitable academic journal, thereby facilitating their widespread utilization. The trial is duly registered with the Chinese Clinical Trial Registry, and with a unique Trial Registration Number, ChiCTR2300069892, approved on March 28, 2023.