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Background There is a need for reliable noninvasive methods for diagnosing and monitoring nonalcoholic fatty liver disease (NAFLD). Thus, the multidisciplinary Non-invasive Biomarkers of Metabolic Liver disease (NIMBLE) consortium was formed to identify and advance the regulatory qualification of NAFLD imaging biomarkers. Purpose To determine the different-day same-scanner repeatability coefficient of liver MRI biomarkers in patients with NAFLD at risk for steatohepatitis. Materials and Methods NIMBLE 1.2 is a prospective, observational, single-center short-term cross-sectional study (October 2021 to June 2022) in adults with NAFLD across a spectrum of low, intermediate, and high likelihood of advanced fibrosis as determined according to the fibrosis based on four factors (FIB-4) index. Participants underwent up to seven MRI examinations across two visits less than or equal to 7 days apart. Standardized imaging protocols were implemented with six MRI scanners from three vendors at both 1.5 T and 3 T, with central analysis of the data performed by an independent reading center (University of California, San Diego). Trained analysts, who were blinded to clinical data, measured the MRI proton density fat fraction (PDFF), liver stiffness at MR elastography (MRE), and visceral adipose tissue (VAT) for each participant. Point estimates and CIs were calculated using χ2 distribution and statistical modeling for pooled repeatability measures. Results A total of 17 participants (mean age, 58 years ± 8.5 [SD]; 10 female) were included, of which seven (41.2%), six (35.3%), and four (23.5%) participants had a low, intermediate, or high likelihood of advanced fibrosis, respectively. The different-day same-scanner mean measurements were 13%-14% for PDFF, 6.6 L for VAT, and 3.15 kPa for two-dimensional MRE stiffness. The different-day same-scanner repeatability coefficients were 0.22 L (95% CI: 0.17, 0.29) for VAT, 0.75 kPa (95% CI: 0.6, 0.99) for MRE stiffness, 1.19% (95% CI: 0.96, 1.61) for MRI PDFF using magnitude reconstruction, 1.56% (95% CI: 1.26, 2.07) for MRI PDFF using complex reconstruction, and 19.7% (95% CI: 15.8, 26.2) for three-dimensional MRE shear modulus. Conclusion This preliminary study suggests that thresholds of 1.2%-1.6%, 0.22 L, and 0.75 kPa for MRI PDFF, VAT, and MRE, respectively, should be used to discern measurement error from real change in patients with NAFLD. ClinicalTrials.gov registration no. NCT05081427 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kozaka and Matsui in this issue.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Biomarcadores , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Fibrose , Fígado/diagnóstico por imagem , Fígado/patologia , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos ProspectivosRESUMO
BACKGROUND. The confounder-corrected chemical shift-encoded MRI (CSE-MRI) sequence used to determine proton density fat fraction (PDFF) for hepatic fat quantification is not widely available. As an alternative, hepatic fat can be assessed by a two-point Dixon method to calculate signal fat fraction (FF) from conventional T1-weighted in- and opposed-phase (IOP) images, although signal FF is prone to biases, leading to inaccurate quantification. OBJECTIVE. The purpose of this study was to compare hepatic fat quantification by use of PDFF inferred from conventional T1-weighted IOP images and deep-learning convolutional neural networks (CNNs) with quantification by use of two-point Dixon signal FF with CSE-MRI PDFF as the reference standard. METHODS. This study entailed retrospective analysis of data from 292 participants (203 women, 89 men; mean age, 53.7 ± 12.0 [SD] years) enrolled at two sites from September 1, 2017, to December 18, 2019, in the Strong Heart Family Study (a prospective population-based study of American Indian communities). Participants underwent liver MRI (site A, 3 T; site B, 1.5 T) including T1-weighted IOP MRI and CSE-MRI (used to reconstruct CSE PDFF and CSE R2* maps). With CSE PDFF as reference, a CNN was trained in a random sample of 218 (75%) participants to infer voxel-by-voxel PDFF maps from T1-weighted IOP images; testing was performed in the other 74 (25%) participants. Parametric values from the entire liver were automatically extracted. Per-participant median CNN-inferred PDFF and median two-point Dixon signal FF were compared with reference median CSE-MRI PDFF by means of linear regression analysis, intraclass correlation coefficient (ICC), and Bland-Altman analysis. The code is publicly available at github.com/kang927/CNN-inference-of-PDFF-from-T1w-IOP-MR. RESULTS. In the 74 test-set participants, reference CSE PDFF ranged from 1% to 32% (mean, 11.3% ± 8.3% [SD]); reference CSE R2* ranged from 31 to 457 seconds-1 (mean, 62.4 ± 67.3 seconds-1 [SD]). Agreement metrics with reference to CSE PDFF for CNN-inferred PDFF were ICC = 0.99, bias = -0.19%, 95% limits of agreement (LoA) = (-2.80%, 2.71%) and for two-point Dixon signal FF were ICC = 0.93, bias = -1.11%, LoA = (-7.54%, 5.33%). CONCLUSION. Agreement with reference CSE PDFF was better for CNN-inferred PDFF from conventional T1-weighted IOP images than for two-point Dixon signal FF. Further investigation is needed in individuals with moderate-to-severe iron overload. CLINICAL IMPACT. Measurement of CNN-inferred PDFF from widely available T1-weighted IOP images may facilitate adoption of hepatic PDFF as a quantitative bio-marker for liver fat assessment, expanding opportunities to screen for hepatic steatosis and nonalcoholic fatty liver disease.
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Aprendizado Profundo , Hepatopatia Gordurosa não Alcoólica , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Prótons , Estudos Retrospectivos , Estudos Prospectivos , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
Background: Pediatric studies have shown associations between hepatic steatosis and total body fat, visceral fat, and lean mass. However, these associations have not been assessed simultaneously, leaving their relative importance unknown. Objective: To evaluate associations between hepatic steatosis and total-body adiposity, visceral adiposity, and lean mass in children. Method: In children at risk for fatty liver, hepatic steatosis, adipose, and lean mass were estimated with magnetic resonance imaging and dual-energy X-ray absorptiometry. Results: Two hundred twenty-seven children with mean age 12.1 years had mean percent body fat of 38.9% and mean liver fat of 8.4%. Liver fat was positively associated with total-body adiposity, visceral adiposity, and lean mass (P < 0.001), and negatively associated with lean mass percentage (P < 0.001). After weight adjustment, liver fat was only positively associated with measures of central adiposity (P < 0.001). Visceral adiposity also had the strongest association with liver fat (P < 0.001). Conclusions: In children, hepatic steatosis is more strongly associated with visceral adiposity than total adiposity, and the association of lean mass is not independent of weight or fat mass. These relationships may help guide the choice of future interventions to target hepatic steatosis.
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Adiposidade , Fígado Gorduroso , Humanos , Criança , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/epidemiologia , Fígado/metabolismo , Obesidade/metabolismo , Gordura Intra-Abdominal/metabolismo , Imageamento por Ressonância Magnética , Obesidade Abdominal/complicações , Obesidade Abdominal/diagnóstico por imagem , Obesidade Abdominal/metabolismo , Músculos/patologiaRESUMO
Background Several early-phase clinical trials for the treatment of nonalcoholic steatohepatitis (NASH) use liver fat content as measured with the MRI-derived proton density fat fraction (PDFF) for a primary outcome. These trials have shown relative reductions in liver fat content with placebo treatment alone, a phenomenon termed "the placebo effect." This phenomenon confounds the results and limits generalizability to future trials. Purpose To quantify the effect of placebo treatment on change in the absolute PDFF value and to identify variables associated with this observed change. Materials and Methods This is a secondary analysis of prospectively collected data from seven early phase clinical trials that included participants with a diagnosis of NASH based on MRI and/or liver biopsy who received placebo treatment. The primary outcome was a greater than or equal to 30% relative reduction in PDFF after placebo treatment. Normalization of PDFF, relative change in alanine aminotransferase (ALT) level, and normalization of ALT level were also examined. An exploratory linear mixed-effects model was used to estimate an overall change in absolute PDFF and to explore parameters associated with this response. Results A total of 187 participants (median age, 52 years [IQR, 43-60 years]; 114 women) who received placebo treatment were evaluated. A greater than or equal to 30% relative reduction in baseline PDFF was seen in 20% of participants after 12 weeks of placebo treatment (10 of 49), 9% of participants after 16 weeks (two of 22), and 28% of participants after 24 weeks (34 of 122). A repeated-measures linear mixed-effects model estimated a decrease of 2.3 units (median relative reduction of 13%) in absolute PDFF values after 24 weeks of placebo treatment (95% CI: 3.2, 1.4; P < .001). Conclusion In this analysis of 187 participants, a clinically relevant decrease in PDFF was observed with placebo treatment. Based on the study model, assuming an absolute PDFF decrease of approximately 3 units (upper limit of 95% CI) to account for this "placebo effect" in sample size calculations for future clinical trials is suggested. Clinical trial registration nos. NCT01066364, NCT01766713, NCT01963845, NCT02443116, NCT02546609, NCT02316717, and NCT02442687 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Yoon in this issue.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Feminino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fígado/diagnóstico por imagem , Fígado/patologia , Imageamento por Ressonância Magnética/métodos , Prótons , BiópsiaRESUMO
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement. METHODS: Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI. RESULTS: Treatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively). CONCLUSIONS: In adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF. CLINICAL TRIAL NUMBER: NCT01265498. IMPACT AND IMPLICATIONS: Although central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.
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Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Abdominal , Fígado/diagnóstico por imagem , Fígado/patologia , Fibrose , Obesidade/complicações , Obesidade/patologia , Gordura Abdominal/patologia , Imageamento por Ressonância Magnética/métodos , Tecido Adiposo/patologiaRESUMO
BACKGROUND: The three-dimensional (3D) structure of chromatin has a massive effect on its function. Because of this, it is desirable to have an understanding of the 3D structural organization of chromatin. To gain greater insight into the spatial organization of chromosomes and genomes and the functions they perform, chromosome conformation capture (3C) techniques, particularly Hi-C, have been developed. The Hi-C technology is widely used and well-known because of its ability to profile interactions for all read pairs in an entire genome. The advent of Hi-C has greatly expanded our understanding of the 3D genome, genome folding, gene regulation and has enabled the development of many 3D chromosome structure reconstruction methods. RESULTS: Here, we propose a novel approach for 3D chromosome and genome structure reconstruction from Hi-C data using Particle Swarm Optimization (PSO) approach called ParticleChromo3D. This algorithm begins with a grouping of candidate solution locations for each chromosome bin, according to the particle swarm algorithm, and then iterates its position towards a global best candidate solution. While moving towards the optimal global solution, each candidate solution or particle uses its own local best information and a randomizer to choose its path. Using several metrics to validate our results, we show that ParticleChromo3D produces a robust and rigorous representation of the 3D structure for input Hi-C data. We evaluated our algorithm on simulated and real Hi-C data in this work. Our results show that ParticleChromo3D is more accurate than most of the existing algorithms for 3D structure reconstruction. CONCLUSIONS: Our results also show that constructed ParticleChromo3D structures are very consistent, hence indicating that it will always arrive at the global solution at every iteration. The source code for ParticleChromo3D, the simulated and real Hi-C datasets, and the models generated for these datasets are available here: https://github.com/OluwadareLab/ParticleChromo3D.
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BACKGROUND. Histologic fibrosis stage is the most important prognostic factor in chronic liver disease. MR elastography (MRE) is the most accurate noninvasive method for detecting and staging liver fibrosis. Although accurate, manual ROI-based MRE analysis is complex, time-consuming, requires specialized readers, and is prone to methodologic variability and suboptimal interreader agreement. OBJECTIVE. The purpose of this study was to develop an automated convolutional neural network (CNN)-based method for liver MRE analysis, evaluate its agreement with manual ROI-based analysis, and assess its performance for classifying dichotomized fibrosis stages using histology as the reference standard. METHODS. In this retrospective cross-sectional study, 675 participants who underwent MRE using different MRI systems and field strengths at 28 imaging sites from five multicenter international clinical trials of nonalcoholic steatohepatitis were included for algorithm development and internal testing of agreement between automated CNN-based and manual ROI-based analyses. Eighty-one patients (52 women, 29 men; mean age, 54 years) who underwent MRE using a single 3-T system and liver biopsy for clinical purposes at a single institution were included for external testing of agreement between the two analysis methods and assessment of fibrosis stage discriminative performance. Agreement was evaluated using intraclass correlation coefficients (ICCs). Bootstrapping was used to compute 95% CIs. Discriminative performance of each method for dichotomized histologic fibrosis stage was evaluated by AUC and compared using bootstrapping. RESULTS. Mean CNN- and manual ROI-based stiffness measurements ranged from 3.21 to 3.34 kPa in trial participants and from 3.21 to 3.30 kPa in clinical patients. ICC for CNN- and manual ROI-based measurements was 0.98 (95% CI, 0.97-0.98) in trial participants and 0.99 (95% CI, 0.98-0.99) in clinical patients. AUCs for classification of dichotomized fibrosis stage ranged from 0.89 to 0.93 for CNN-based analysis and 0.87 to 0.93 for manual ROI-based analysis (p = .23-.75). CONCLUSION. Stiffness measurements using the automated CNN-based method agreed strongly with manual ROI-based analysis across MRI systems and field strengths, with excellent discriminative performance for histology-determined dichotomized fibrosis stages in external testing. CLINICAL IMPACT. Given the high incidence of chronic liver disease worldwide, it is important that noninvasive tools to assess fibrosis are applied reliably across different settings. CNN-based analysis is feasible and may reduce reliance on expert image analysts.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Feminino , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVES: To assess reproducibility and fibrosis classification accuracy of magnetic resonance elastography (MRE)-determined liver stiffness measured manually at two different centers, and by automated analysis software in adults with nonalcoholic fatty liver disease (NAFLD), using histopathology as a reference standard. METHODS: This retrospective, cross-sectional study included 91 adults with NAFLD who underwent liver MRE and biopsy. MRE-determined liver stiffness was measured independently for this analysis by an image analyst at each of two centers using standardized manual analysis methodology, and separately by an automated analysis. Reproducibility was assessed pairwise by intraclass correlation coefficient (ICC) and Bland-Altman analysis. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analyses. RESULTS: ICC of liver stiffness measurements was 0.95 (95% CI: 0.93, 0.97) between center 1 and center 2 analysts, 0.96 (95% CI: 0.94, 0.97) between the center 1 analyst and automated analysis, and 0.94 (95% CI: 0.91, 0.96) between the center 2 analyst and automated analysis. Mean bias and 95% limits of agreement were 0.06 ± 0.38 kPa between center 1 and center 2 analysts, 0.05 ± 0.32 kPa between the center 1 analyst and automated analysis, and 0.11 ± 0.41 kPa between the center 2 analyst and automated analysis. The area under the ROC curves for the center 1 analyst, center 2 analyst, and automated analysis were 0.834, 0.833, and 0.847 for distinguishing fibrosis stage 0 vs. ≥ 1, and 0.939, 0.947, and 0.940 for distinguishing fibrosis stage ≤ 2 vs. ≥ 3. CONCLUSION: MRE-determined liver stiffness can be measured with high reproducibility and fibrosis classification accuracy at different centers and by an automated analysis. KEY POINTS: ⢠Reproducibility of MRE liver stiffness measurements in adults with nonalcoholic fatty liver disease is high between two experienced centers and between manual and automated analysis methods. ⢠Analysts at two centers had similar high diagnostic accuracy for distinguishing dichotomized fibrosis stages. ⢠Automated analysis provides similar diagnostic accuracy as manual analysis for advanced fibrosis.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Adulto , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Curva ROC , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVES: To investigate associations between histology and hepatic mechanical properties measured using multiparametric magnetic resonance elastography (MRE) in adults with known or suspected nonalcoholic fatty liver disease (NAFLD) without histologic fibrosis. METHODS: This was a retrospective analysis of 88 adults who underwent 3T MR exams including hepatic MRE and MR imaging to estimate proton density fat fraction (MRI-PDFF) within 180 days of liver biopsy. Associations between MRE mechanical properties (mean shear stiffness (|G*|) by 2D and 3D MRE, and storage modulus (G'), loss modulus (Gâ³), wave attenuation (α), and damping ratio (ζ) by 3D MRE) and histologic, demographic and anthropometric data were assessed. RESULTS: In univariate analyses, patients with lobular inflammation grade ≥ 2 had higher 2D |G*| and 3D Gâ³ than those with grade ≤ 1 (p = 0.04). |G*| (both 2D and 3D), G', and Gâ³ increased with age (rho = 0.25 to 0.31; p ≤ 0.03). In multivariable regression analyses, the association between inflammation grade ≥ 2 remained significant for 2D |G*| (p = 0.01) but not for 3D Gâ³ (p = 0.06); age, sex, or BMI did not affect the MRE-inflammation relationship (p > 0.20). CONCLUSIONS: 2D |G*| and 3D Gâ³ were weakly associated with moderate or severe lobular inflammation in patients with known or suspected NAFLD without fibrosis. With further validation and refinement, these properties might become useful biomarkers of inflammation. Age adjustment may help MRE interpretation, at least in patients with early-stage disease. KEY POINTS: ⢠Moderate to severe lobular inflammation was associated with hepatic elevated shear stiffness and elevated loss modulus (p =0.04) in patients with known or suspected NAFLD without liver fibrosis; this suggests that with further technical refinement these MRE-assessed mechanical properties may permit detection of inflammation before the onset of fibrosis in NAFLD. ⢠Increasing age is associated with higher hepatic shear stiffness, and storage and loss moduli (rho = 0.25 to 0.31; p ≤ 0.03); this suggests that age adjustment may help interpret MRE results, at least in patients with early-stage NAFLD.
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Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Biomarcadores , Fibrose , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE: Chemical shift-encoded MRI (CSE-MRI) is well-established to quantify proton density fat fraction (PDFF) as a quantitative biomarker of hepatic steatosis. However, temperature is known to bias PDFF estimation in phantom studies. In this study, strategies were developed and evaluated to correct for the effects of temperature on PDFF estimation through simulations, temperature-controlled experiments, and a multi-center, multi-vendor phantom study. THEORY AND METHODS: A technical solution that assumes and automatically estimates a uniform, global temperature throughout the phantom is proposed. Computer simulations modeled the effect of temperature on PDFF estimation using magnitude-, complex-, and hybrid-based CSE-MRI methods. Phantom experiments were performed to assess the temperature correction on PDFF estimation at controlled phantom temperatures. To assess the temperature correction method on a larger scale, the proposed method was applied to data acquired as part of a nine-site multi-vendor phantom study and compared to temperature-corrected PDFF estimation using an a priori guess for ambient room temperature. RESULTS: Simulations and temperature-controlled experiments show that as temperature deviates further from the assumed temperature, PDFF bias increases. Using the proposed correction method and a reasonable a priori guess for ambient temperature, PDFF bias and variability were reduced using magnitude-based CSE-MRI, across MRI systems, field strengths, protocols, and varying phantom temperature. Complex and hybrid methods showed little PDFF bias and variability both before and after correction. CONCLUSION: Correction for temperature reduces temperature-related PDFF bias and variability in phantoms across MRI vendors, sites, field strengths, and protocols for magnitude-based CSE-MRI, even without a priori information about the temperature.
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Fígado , Prótons , Imageamento por Ressonância Magnética , Reprodutibilidade dos Testes , TemperaturaRESUMO
OBJECTIVE: To evaluate the relationship between hepatic steatosis and bone mineral density (BMD) in children. In addition, to assess 25-hydroxyvitamin D levels in the relationship between hepatic steatosis and BMD. STUDY DESIGN: A community-based sample of 235 children was assessed for hepatic steatosis, BMD, and serum 25-hydroxyvitamin D. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction (MRI-PDFF). BMD was measured by whole-body dual-energy x-ray absorptiometry. RESULTS: The mean age of the study population was 12.5 years (SD 2.5 years). Liver MRI-PDFF ranged from 1.1% to 40.1% with a mean of 9.3% (SD 8.5%). Across this broad spectrum of hepatic fat content, there was a significant negative relationship between liver MRI-PDFF and BMD z score (R = -0.421, P < .001). Across the states of sufficiency, insufficiency, and deficiency, there was a significant negative association between 25-hydroxyvitamin D and liver MRI-PDFF (P < .05); however, there was no significant association between vitamin D status and BMD z score (P = .94). Finally, children with clinically low BMD z scores were found to have higher alanine aminotransferase (P < .05) and gamma-glutamyl transferase (P < .05) levels compared with children with normal BMD z scores. CONCLUSIONS: Across the full range of liver MRI-PDFF, there was a strong negative relationship between hepatic steatosis and BMD z score. Given the prevalence of nonalcoholic fatty liver disease and the critical importance of childhood bone mineralization in protecting against osteoporosis, clinicians should prioritize supporting bone development in children with nonalcoholic fatty liver disease.
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Densidade Óssea/fisiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Absorciometria de Fóton , Adolescente , Alanina Transaminase/sangue , Criança , Feminino , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Estudos de Amostragem , Vitamina D/análogos & derivados , Vitamina D/sangue , gama-Glutamiltransferase/sangueRESUMO
PURPOSE: To evaluate repeatability of ROI-sampling strategies for quantifying hepatic proton density fat fraction (PDFF) and to assess error relative to the 9-ROI PDFF. METHODS: This was a secondary analysis in subjects with known or suspected nonalcoholic fatty liver disease who underwent MRI for magnitude-based hepatic PDFF quantification. Each subject underwent three exams, each including three acquisitions (nine acquisitions total). An ROI was placed in each hepatic segment on the first acquisition of the first exam and propagated to other acquisitions. PDFF was calculated for each of 511 sampling strategies using every combination of 1, 2, , all 9 ROIs. Intra- and inter-exam intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs) were estimated for each sampling strategy. Mean absolute error (MAE) was estimated relative to the 9-ROI PDFF. Strategies that sampled both lobes evenly ("balanced") were compared with those that did not ("unbalanced") using two-sample t tests. RESULTS: The 29 enrolled subjects (23 male, mean age 24 years) had mean 9-ROI PDFF 11.8% (1.1-36.3%). With more ROIs, ICCs increased, RCs decreased, and MAE decreased. Of the 60 balanced strategies with 4 ROIs, all (100%) achieved inter- and intra-exam ICCs > 0.998, 55 (92%) achieved intra-exam RC < 1%, 50 (83%) achieved inter-exam RC < 1%, and all (100%) achieved MAE < 1%. Balanced sampling strategies had higher ICCs and lower RCs, and lower MAEs than unbalanced strategies in aggregate (p < 0.001 for comparisons between balanced vs. unbalanced strategies). CONCLUSION: Repeatability improves and error diminishes with more ROIs. Balanced 4-ROI strategies provide high repeatability and low error.
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Hepatopatia Gordurosa não Alcoólica , Prótons , Adulto , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Background Proton density fat fraction (PDFF) estimated by using chemical shift-encoded (CSE) MRI is an accepted imaging biomarker of hepatic steatosis. This work aims to promote standardized use of CSE MRI to estimate PDFF. Purpose To assess the accuracy of CSE MRI methods for estimating PDFF by determining the linearity and range of bias observed in a phantom. Materials and Methods In this prospective study, a commercial phantom with 12 vials of known PDFF values were shipped across nine U.S. centers. The phantom underwent 160 independent MRI examinations on 27 1.5-T and 3.0-T systems from three vendors. Two three-dimensional CSE MRI protocols with minimal T1 bias were included: vendor and standardized. Each vendor's confounder-corrected complex or hybrid magnitude-complex based reconstruction algorithm was used to generate PDFF maps in both protocols. The Siemens reconstruction required a configuration change to correct for water-fat swaps in the phantom. The MRI PDFF values were compared with the known PDFF values by using linear regression with mixed-effects modeling. The 95% CIs were calculated for the regression slope (ie, proportional bias) and intercept (ie, constant bias) and compared with the null hypothesis (slope = 1, intercept = 0). Results Pooled regression slope for estimated PDFF values versus phantom-derived reference PDFF values was 0.97 (95% CI: 0.96, 0.98) in the biologically relevant 0%-47.5% PDFF range. The corresponding pooled intercept was -0.27% (95% CI: -0.50%, -0.05%). Across vendors, slope ranges were 0.86-1.02 (vendor protocols) and 0.97-1.0 (standardized protocol) at 1.5 T and 0.91-1.01 (vendor protocols) and 0.87-1.01 (standardized protocol) at 3.0 T. The intercept ranges (absolute PDFF percentage) were -0.65% to 0.18% (vendor protocols) and -0.69% to -0.17% (standardized protocol) at 1.5 T and -0.48% to 0.10% (vendor protocols) and -0.78% to -0.21% (standardized protocol) at 3.0 T. Conclusion Proton density fat fraction estimation derived from three-dimensional chemical shift-encoded MRI in a commercial phantom was accurate across vendors, imaging centers, and field strengths, with use of the vendors' product acquisition and reconstruction software. © RSNA, 2021 See also the editorial by Dyke in this issue.
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Fígado Gorduroso/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imagens de Fantasmas , Algoritmos , Biomarcadores , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Estudos Prospectivos , Prótons , Reprodutibilidade dos Testes , Estados UnidosRESUMO
OBJECTIVES: We sought to evaluate the relevance of pediatric dairy fat recommendations for children at risk for nonalcoholic fatty liver disease (NAFLD) by studying the association between dairy fat intake and the amount of liver fat. The effects of dairy fat may be mediated by odd chain fatty acids (OCFA), such as pentadecanoic acid (C15:0), and monomethyl branched chain fatty acids (BCFA), such as iso-heptadecanoic acid (iso-C17:0). Therefore, we also evaluated the association between plasma levels of OCFA and BCFA with the amount of liver fat. METHODS: Observational, cross-sectional, community-based sample of 237 children ages 8 to 17. Dairy fat intake was assessed by 3 24-hour dietary recalls. Plasma fatty acids were measured by gas chromatography-mass spectrometry. Main outcome was hepatic steatosis measured by whole liver magnetic resonance imaging proton density fat fraction (MRI-PDFF). RESULTS: Median dairy fat intake was 10.6âgrams/day (range 0.0--44.5âg/day). Median liver MRI-PDFF was 4.5% (range 0.9%-45.1%). Dairy fat intake was inversely correlated with liver MRI-PDFF (râ=â-0.162; Pâ=â.012). In multivariable log linear regression, plasma C15:0 and iso-C17:0 were inverse predictors of liver MRI-PDFF (Bâ=â-0.247, Pâ=â0.048; and Bâ=â-0.234, Pâ=â0.009). CONCLUSIONS: Dairy fat intake, plasma C15:0, and plasma iso-C17:0 were inversely correlated with hepatic steatosis in children. These hypothesis-generating findings should be tested through clinical trials to better inform dietary guidelines.
Assuntos
Ácidos Graxos , Hepatopatia Gordurosa não Alcoólica , Adolescente , Criança , Estudos Transversais , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagemRESUMO
BACKGROUND: Controlled attenuation parameter (CAP) is an ultrasound-based point-of-care method to quantify liver fat; however, the optimal threshold for CAP to detect pathologic liver fat among persons living with human immunodeficiency virus (HIV; PLWH) is unknown. Therefore, we aimed to identify the diagnostic accuracy and optimal threshold of CAP for the detection of liver-fat among PLWH with magnetic resonance imaging proton-density fat fraction (MRI-PDFF) as the reference standard. METHODS: Patients from a prospective single-center cohort of PLWH at risk for HIV-associated nonalcoholic fatty liver disease (NAFLD) who underwent contemporaneous MRI-PDFF and CAP assessment were included. Subjects with other forms of liver disease including viral hepatitis and excessive alcohol intake were excluded. Receiver operatic characteristic (ROC) curve analysis were performed to identify the optimal threshold for the detection of HIV-associated NAFLD (liver fat ≥ 5%). RESULTS: Seventy PLWH (90% men) at risk for NAFLD were included. The mean (± standard deviation) age and body mass index were 48.6 (±10.2) years and 30 (± 5.3) kg/m2, respectively. The prevalence of HIV-associated NAFLD (MRI-PDFF ≥ 5%) was 80%. The M and XL probes were used for 56% and 44% of patients, respectively. The area under the ROC curve of CAP for the detection of MRI-PDFF ≥ 5% was 0.82 (0.69-0.95) at the cut-point of 285 dB/m. The positive predictive value of CAP ≥ 285 dB/m was 93.2% in this cohort with sensitivity of 73% and specificity of 78.6%. CONCLUSIONS: The optimal cut-point of CAP to correctly identify HIV-associated NAFLD was 285 dB/m, is similar to previously published cut-point for primary NAFLD and may be incorporated into routine care to identify patients at risk of HIV-associated NAFLD.
Assuntos
Técnicas de Imagem por Elasticidade , Infecções por HIV , Hepatopatia Gordurosa não Alcoólica , Biópsia , Feminino , Infecções por HIV/complicações , Humanos , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Estudos Prospectivos , Curva ROC , Padrões de ReferênciaRESUMO
PURPOSE: To compare longitudinal hepatic proton density fat fraction (PDFF) changes estimated by magnitude- vs. complex-based chemical-shift-encoded MRI during a weight loss surgery (WLS) program in severely obese adults with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: This was a secondary analysis of a prospective dual-center longitudinal study of 54 adults (44 women; mean age 52 years; range 27-70 years) with obesity, biopsy-proven NAFLD, and baseline PDFF ≥ 5%, enrolled in a WLS program. PDFF was estimated by confounder-corrected chemical-shift-encoded MRI using magnitude (MRI-M)- and complex (MRI-C)-based techniques at baseline (visit 1), after a 2- to 4-week very low-calorie diet (visit 2), and at 1, 3, and 6 months (visits 3 to 5) after surgery. At each visit, PDFF values estimated by MRI-M and MRI-C were compared by a paired t test. Rates of PDFF change estimated by MRI-M and MRI-C for visits 1 to 3, and for visits 3 to 5 were assessed by Bland-Altman analysis and intraclass correlation coefficients (ICCs). RESULTS: MRI-M PDFF estimates were lower by 0.5-0.7% compared with those of MRI-C at all visits (p < 0.001). There was high agreement and no difference between PDFF change rates estimated by MRI-M vs. MRI-C for visits 1 to 3 (ICC 0.983, 95% CI 0.971, 0.99; bias = - 0.13%, p = 0.22), or visits 3 to 5 (ICC 0.956, 95% CI 0.919-0.977%; bias = 0.03%, p = 0.36). CONCLUSION: Although MRI-M underestimates PDFF compared with MRI-C cross-sectionally, this bias is consistent and MRI-M and MRI-C agree in estimating the rate of hepatic PDFF change longitudinally. KEY POINTS: ⢠MRI-M demonstrates a significant but small and consistent bias (0.5-0.7%; p < 0.001) towards underestimation of PDFF compared with MRI-C at 3 T. ⢠Rates of PDFF change estimated by MRI-M and MRI-C agree closely (ICC 0.96-0.98) in adults with severe obesity and biopsy- proven NAFLD enrolled in a weight loss surgery program. ⢠Our findings support the use of either MRI technique (MRI-M or MRI-C) for clinical care or by individual sites or for multi-center trials that include PDFF change as an endpoint. However, since there is a bias in their measurements, the same technique should be used in any given patient for longitudinal follow-up.
Assuntos
Cirurgia Bariátrica , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Obesidade Mórbida/cirurgia , Adulto , Idoso , Biópsia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade Mórbida/complicações , Estudos Prospectivos , PrótonsRESUMO
The aim of this study was to estimate parameters determining liver triglyceride composition (TC) using 1 H MRS and to assess how TC estimability is affected by proton density fat fraction (PDFF) in adults with nonalcoholic fatty liver disease (NAFLD). In this prospective single-site study, 199 adults with known or suspected NAFLD in whom other causes of liver disease were excluded underwent two 1 H MRS STimulated Echo Acquisition Method (STEAM) sequences at 3 T. A respiratory-gated water-suppressed free breathing sequence (TE 10 ms, 16 signal averages) was used to assess TC in terms of the number of double bonds (ndb) and methylene-interrupted double bonds (nmidb), and a single breath-hold-long TR, multi-TE sequence (TR 3500 ms), which acquired five single average spectra over TE 10-30 ms, was used to estimate liver PDFF. Ndb and nmidb estimability was qualitatively assessed for each case and summarized descriptively. The consistency of ndb and nmidb estimation was examined using ROC analysis. The relationship between ndb and nmidb values and PDFF was presented graphically. Quality-of-fit of ndb and nmidb versus PDFF was evaluated by Pearson-r correlation. A significance level of 0.05 was used. In 263 1 H MRS examinations performed on 199 adult participants, ndb and nmidb were successfully estimated in 7/53 (13.2%) examinations with PDFF < 4%, 13/30 (43.3%) examinations with PDFF between 4% and 7%, 33/41 (80.5%) examinations with PDFF between 7% and 10%, and 124/139 (89.2%) examinations with PDFF > 10% (maximum PDFF 38.1%). Liver TC could be estimated consistently for PDFF > 6.7%. Both ndb and nmidb decreased with increasing PDFF (ndb = 2.83-0.0160·PDFF, r = -0.449, P < 0.0001); nmidb = 0.75-0.0088·PDFF, r = -0.350, P < 0.0001). In a cohort of adults with known or suspected NAFLD, liver TC becomes more saturated as PDFF increases.
Assuntos
Fígado/diagnóstico por imagem , Fígado/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Prótons , Triglicerídeos/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto JovemRESUMO
BACKGROUND AND AIMS: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). APPROACH AND RESULTS: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). CONCLUSIONS: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.
Assuntos
Azetidinas/farmacologia , Ácidos Isonicotínicos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Adolescente , Adulto , Idoso , Azetidinas/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Ácidos Isonicotínicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND AIMS: Emerging data from a single-center study suggests that a 30% relative reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) from baseline may be associated with histologic improvement in nonalcoholic steatohepatitis (NASH). There are limited multicenter data comparing an active drug versus placebo on the association between the quantity of liver fat reduction assessed by MRI-PDFF and histologic response in NASH. This study aims to examine the association between 30% relative reduction in MRI-PDFF and histologic response in obeticholic acid (OCA) versus placebo-treated patients in the FLINT (farnesoid X receptor ligand obeticholic acid in NASH trial). APPROACH AND RESULTS: This is a secondary analysis of the FLINT trial including 78 patients with MRI-PDFF measured before and after treatment along with paired liver histology assessment. Histologic response was defined as a 2-point improvement in nonalcoholic fatty liver disease activity score without worsening of fibrosis. OCA (25 mg orally once daily) was better than placebo in improving MRI-PDFF by an absolute difference of -3.4% (95% confidence interval [CI], -6.5 to -0.2%, P value = 0.04) and relative difference of -17% (95% CI, -34 to 0%, P value = 0.05). The optimal cutoff point for relative decline in MRI-PDFF for histologic response was 30% (using Youden's index). The rate of histologic response in those who achieved less than 30% decline in MRI-PDFF versus those who achieved a 30% or greater decline in MRI-PDFF (MRI-PDFF responders) relative to baseline was 19% versus 50%, respectively. Compared with MRI-PDFF nonresponders, MRI-PDFF responders demonstrated both a statistically and clinically significant higher odds 4.86 (95% CI, 1.4-12.8, P value < 0.009) of histologic response, including significant improvements in both steatosis and ballooning. CONCLUSION: OCA was better than placebo in reducing liver fat. This multicenter trial provides data regarding the association between 30% decline in MRI-PDFF relative to baseline and histologic response in NASH.
Assuntos
Tecido Adiposo/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Fígado/patologia , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tecido Adiposo/diagnóstico por imagem , Adulto , Idoso , Ácido Quenodesoxicólico/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Prótons , Redução de PesoRESUMO
PURPOSE: MRI proton density fat fraction (PDFF) can be calculated using magnitude (MRI-M) or complex (MRI-C) MRI data. The purpose of this study was to identify, assess, and compare the accuracy of common PDFF thresholds for MRI-M and MRI-C for assessing hepatic steatosis in patients with obesity, using histology as reference. METHODS: This two-center prospective study included patients undergoing MRI-C- and MRI-M-PDFF estimations within 3 days before weight loss surgery. Liver biopsy was performed, and histology-determined steatosis grades were used as reference standard. Using receiver operating characteristics (ROC) analysis on data pooled from both methods, single common thresholds for diagnosing and differentiating none or mild (0-1) from moderate to severe steatosis (2-3) were selected as the ones achieving the highest sensitivity while providing at least 90% specificity. Selection methods were cross-validated. Performances were compared using McNemar's tests. RESULTS: Of 81 included patients, 54 (67%) had steatosis. The common PDFF threshold for diagnosing steatosis was 5.4%, which provided a cross-validated 0.88 (95% CI 0.77-0.95) sensitivity and 0.92 (0.75-0.99) specificity for MRI-M and 0.87 sensitivity (0.75-0.94) with 0.81 (0.61-0.93) specificity for MRI-C. The common PDFF threshold to differentiate steatosis grades 0-1 from 2 to 3 was 14.7%, which provided cross-validated 0.86 (95% CI 0.59-0.98) sensitivity and 0.95 (0.87-0.99) specificity for MRI-M and 0.93 sensitivity (0.68-0.99) with 0.97(0.89-0.99) specificity for MRI-C. CONCLUSION: If independently validated, diagnostic thresholds of 5.4% and 14.7% could be adopted for both techniques for detecting and differentiating none to mild from moderate to severe steatosis, respectively, with high diagnostic accuracy.