To improve liver proton density fat fraction (PDFF) andR 2 * $$ {R}_2^{\ast } $$ quantification at 0.55 T by systematically validating the acquisition parameter choices and investigating the performance of locally low-rank denoising methods.

A Monte Carlo simulation was conducted to design a protocol for PDFF andR 2 * $$ {R}_2^{\ast } $$ mapping at 0.55 T. Using this proposed protocol, we investigated the performance of robust locally low-rank (RLLR) and random matrix theory (RMT) denoising. In a reference phantom, we assessed quantification accuracy (concordance correlation coefficient [ρ c $$ {\rho}_c $$ ] vs. reference values) and precision (using SD) across scan repetitions. We performed in vivo liver scans (11 subjects) and used regions of interest to compare means and SDs of PDFF andR 2 * $$ {R}_2^{\ast } $$ measurements. Kruskal-Wallis and Wilcoxon signed-rank tests were performed (p < 0.05 considered significant).

In the phantom, RLLR and RMT denoising improved accuracy in PDFF andR 2 * $$ {R}_2^{\ast } $$ withρ c $$ {\rho}_c $$ >0.992 and improved precision with >67% decrease in SD across 50 scan repetitions versus conventional reconstruction (i.e., no denoising). For in vivo liver scans, the mean PDFF and meanR 2 * $$ {R}_2^{\ast } $$ were not significantly different between the three methods (conventional reconstruction; RLLR and RMT denoising). Without denoising, the SDs of PDFF andR 2 * $$ {R}_2^{\ast } $$ were 8.80% and 14.17 s-1. RLLR denoising significantly reduced the values to 1.79% and 5.31 s-1 (p < 0.001); RMT denoising significantly reduced the values to 2.00% and 4.81 s-1 (p < 0.001).

We validated an acquisition protocol for improved PDFF andR 2 * $$ {R}_2^{\ast } $$ quantification at 0.55 T. Both RLLR and RMT denoising improved the accuracy and precision of PDFF andR 2 * $$ {R}_2^{\ast } $$ measurements.

This study aimed to evaluate the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, assessing its effectiveness as a biomarker for osteoporosis. A systematic review was conducted by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a mean difference of 11.04 (95% CI: 9.17 to 12.92, Z=11.52, P < 0.00001). Measuring PDFF via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care.

This study aims to assess the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, evaluating its effectiveness as a biomarker for osteoporosis.

This systematic review was carried out by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist.

Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a (MD = 11.04, 95% CI: 9.17 to 12.92, Z = 11.52, P < 0.00001). Subgroup analyses indicated that diagnostic methods, gender, and echo length did not significantly impact the PDFF-osteoporosis association.

PDFF measurement via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care.

To develop Monte Carlo simulations to predict the relationship ofR 2 * $$ {\mathrm{R}}_2^{\ast } $$ with liver fat content at 1.5 T and 3.0 T. For various fat fractions (FFs) from 1% to 25%, four types of virtual liver models were developed by incorporating the size and spatial distribution of fat droplets. Magnetic fields were then generated under different fat susceptibilities at 1.5 T and 3.0 T, and proton movement was simulated for phase accrual and MRI signal synthesis. The synthesized signal was fit to single-peak and multi-peak fat signal models forR 2 * $$ {\mathrm{R}}_2^{\ast } $$ and proton density fat fraction (PDFF) predictions. In addition, the relationships betweenR 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF predictions were compared with in vivo calibrations and Bland-Altman analysis was performed to quantitatively evaluate the effects of these components (type of virtual liver model, fat susceptibility, and fat signal model) onR 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions. A virtual liver model with realistic morphology of fat droplets was demonstrated, andR 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF values were predicted by Monte Carlo simulations at 1.5 T and 3.0 T.R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions were linearly correlated with PDFF, while the slope was unaffected by the type of virtual liver model and increased as fat susceptibility increased. Compared with in vivo calibrations, the multi-peak fat signal model showed superior performance to the single-peak fat signal model, which yielded an underestimation of liver fat. TheR 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF relationships by simulations with fat susceptibility of 0.6 ppm and the multi-peak fat signal model wereR 2 * = 0.490 × PDFF + 28.0 $$ {\mathrm{R}}_2^{\ast }=0.490\times \mathrm{PDFF}+28.0 $$ (R 2 = 0.967 $$ {R}^2=0.967 $$ ,p < 0.01 $$ p<0.01 $$ ) at 1.5 T andR 2 * = 0.928 × PDFF + 39.4 $$ {\mathrm{R}}_2^{\ast }=0.928\times \mathrm{PDFF}+39.4 $$ (R 2 = 0.972 $$ {R}^2=0.972 $$ ,p < 0.01 $$ p<0.01 $$ ) at 3.0 T. Monte Carlo simulations provide a new means forR 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF prediction, which is primarily determined by fat susceptibility, fat signal model, and magnetic field strength. AccurateR 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF calibration has the potential to correct the effect of fat onR 2 * $$ {\mathrm{R}}_2^{\ast } $$ quantification, and may be helpful for accurateR 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements in liver iron overload. In this study, a Monte Carlo simulation of hepatic steatosis was developed to predict the relationship betweenR 2 * $$ {\mathrm{R}}_2^{\ast } $$ and PDFF. Furthermore, the effects of fat droplet morphology, fat susceptibility, fat signal model, and magnetic field strength were evaluated for theR 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF calibration. Our results suggest that Monte Carlo simulations provide a new means forR 2 * $$ {\mathrm{R}}_2^{\ast } $$ -PDFF prediction and this means can be easily generated for various regimes, such as simulations with higher fields and different echo times, as well as correction of magnetic susceptibility measurements for liver iron quantification.

BACKGROUND. Metabolic dysfunction-associated steatotic liver disease is a growing global public health concern. Quantitative ultrasound measurements, such as ultrasound-derived fat fraction (UDFF), could provide noninvasive, cost-effective, and portable steatosis evaluation. OBJECTIVE. The purpose of this article was to evaluate utility of UDFF for steatosis assessment using proton density fat fraction (PDFF) as reference in patients undergoing liver MRI for heterogeneous indications and to assess UDFF variability. METHODS. This prospective study included a primary analysis of 187 patients (mean age, 53.8 years; 112 men, 75 women) who underwent 3-T liver MRI for any clinical indication from December 2020 to July 2021. Patients underwent investigational PDFF measurement, including determination of PDFFwhole-liver (mean PDFF of entire liver), and PDFFvoxel (PDFF in single voxel within right lobe, measured by MR spectroscopy), as well as investigational ultrasound with UDFF calculation (mean of five inter-costal measurements) within 1 hour after MRI. In a subanalysis, 21 of these patients underwent additional UDFF measurements 1, 3, and 5 hours after meal consumption. The study also included repeatability and reproducibility analysis of 30 patients (mean age, 26.3 years; 10 men, 20 women) who underwent clinical abdominal ultrasound between November 2022 and January 2023; in these patients, three operators sequentially performed UDFF measurements. RESULTS. In primary analysis, UDFF and PDFFwhole-liver measurements showed intra-class correlation coefficient (ICC) of 0.79. In Bland-Altman analysis, UDFF and PDFFvoxel measurements showed mean difference of 1.5% (95% CI, 0.6-2.4%), with 95% limits of agreement from -11.0% to 14.0%. UDFF measurements exhibited AUC for detecting PDFFvoxel at historic thresholds of 6.5% and greater, 17.4% and greater, and 22.1% and greater of 0.90, 0.95, and 0.95, respectively. In subanalysis, mean UDFF was not significantly different across time points with respect to meal consumption (p = .21). In repeatability and reproducibility analysis, ICC for intraoperator repeatability ranged from 0.98 to 0.99 and for interoperator reproducibility from 0.90 to 0.96. Visual assessment of patient-level data plots indicated increasing variability of mean UDFF measurements across operators and of intercostal measurements within individual patients with increasing steatosis. CONCLUSION. UDFF showed robust agreement with PDFF, diagnostic performance for steatosis grades, and intraoperator repeatability and interoperator reproducibility. Nonetheless, UDFF exhibited bias toward slightly larger values versus PDFF; intraoperator and interoperator variation increased with increasing steatosis. CLINICAL IMPACT. UDFF shows promise for steatosis assessment across diverse populations, although continued optimization remains warranted.

This retrospective study aimed to evaluate the validity of an automated screening Dixon (e-DIXON) technique for quantifying hepatic steatosis in living liver-donor patients by comparison with magnetic resonance spectroscopy (MRS) as a reference standard.

A total of 285 living liver-donor candidates were examined with the e-DIXON technique and single-voxel MRS to assess hepatic steatosis and iron deposition between January 2014 and February 2019. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of the e-DIXON technique for hepatic steatosis were calculated. The mean fat signal fractions obtained in MRS were compared between the donors diagnosed with hepatic steatosis and the normal group. The mean R2 values of donors with or without hepatic siderosis also were compared.

The e-DIXON technique diagnosed normal in 133 (47%), fat in 124 (44%), iron in one (0.4%), and a combination of both fat and iron in 27 (10%) donors. The sensitivity, specificity, PPV, and NPV ​​for diagnosing hepatic steatosis were 94%, 70%, 64%, and 96%, respectively. There was a significant difference in the mean fat signal fraction obtained in MRS between the steatosis and normal groups (p < 0.001), but R2 values were not significantly different between siderosis and normal groups (p = 0.11). The e-DIXON technique showed a strong correlation with MRS in fat measurement (r2 = 0.92, p < 0.001).

The e-DIXON technique reliably screens for hepatic steatosis but may not accurate for detecting hepatic iron deposition.

To evaluate the diagnostic accuracy of multi-echo Dixon magnetic resonance imaging (MRI) in hepatic fat quantification, in comparison with that of magnetic resonance spectroscopy (MRS), on 3.0-T MRI.

Fifty-five adults with no known liver disease underwent MRI in a 3.0-T scanner for determination of the hepatic fat fraction, with two techniques: multi-echo Dixon, in a manually drawn region of interest (ROI) and in the entire liver parenchyma (automated segmentation); and MRS. The diagnostic accuracy and cutoff value for multi-echo Dixon were determined, with MRS being used as the reference standard.

The mean fat fraction obtained by multi-echo Dixon in the manually drawn ROI and in the entire liver was 5.2 ± 5.8% and 6.6 ± 5.2%, respectively, whereas the mean hepatic fat fraction obtained by MRS was 5.7 ± 6.4%. A very strong positive correlation and good agreement were observed between MRS and multi-echo Dixon, for the ROI (r = 0.988, r2 = 0.978, p < 0.001) and for the entire liver parenchyma (r = 0.960, r2 = 0.922, p < 0.001). A moderate positive correlation was observed between the hepatic fat fraction and body mass index of the participants, regardless of the fat estimation technique employed.

For hepatic fat quantification, multi-echo Dixon MRI demonstrated a very strong positive correlation and good agreement with MRS (often considered the gold-standard noninvasive technique). Because multi-echo Dixon MRI is more readily available than is MRS, it can be used as a rapid tool for hepatic fat quantification, especially when the hepatic fat distribution is not homogeneous.

The bone marrow (BM) evaluation of acute leukemia (AL) mainly depends on invasive BM puncture biopsy. Noninvasive and accurate MR examination technology has potential clinical application value in the BM evaluation of AL patients. Multi-gradient-echo (MGRE) has been found useful to evaluate changes in BM fat and iron content, but has not yet been applied in AL.

To explore the diagnostic capability of BM infiltration of quantitative BM fat fraction (FF) and R2* values obtained from a 3D MGRE sequence in children with primary AL.

Prospective.

Sixty-two pediatric patients with untreated AL and 68 healthy volunteers. AL patients were divided into acute lymphoblastic leukemia (ALL) (n = 39) and acute myeloid leukemia (AML) (n = 23) groups.

3T, 3D chemical-shift-encoded multi-gradient-echo, T1WI, T2WI, T2_STIR.

BM FF and R2* values were assessed by manually drawing regions of interest at the L3, L4, ilium, and 1 cm below the bilateral trochanter of the femur (upper femur).

Independent sample t-tests, variance analysis, Spearman correlation.

BM FF and R2* at L3, L4, ilium, and upper femur, FFtotal and R2*total were significantly lower in the AL than control group. BM FF did not significantly differ between ALL and AML groups (PL3  = 0.060, PL4  = 0.086, Pilium  = 0.179, Pupper femur  = 0.149, and Ptotle  = 0.097, respectively). The R2* was significantly lower in ALL group than AML group for L3, L4, and R2*total . BM FF was moderately positively correlated with R2* in ALL group, and strongly positively correlated in AML group. Area under the receiver operating characteristic curves showed that BM FF had higher AUC in AL, ALL, and AML (all AUC = 1.000) than R2* (0.976, 0.996, and 0.941, respectively).

MGRE-MRI mapping can be applied to measure BM FF and R2* values, and help evaluate BM infiltration and iron storage in children with AL.

1 Technical Efficacy: 2.

Viral hepatitis was previously the most common cause of chronic liver disease. However, in recent years, nonalcoholic fatty liver disease (NAFLD) cases have been increasing, especially in developed countries. NAFLD is histologically characterized by fat, fibrosis, and inflammation in the liver, eventually leading to cirrhosis and hepatocellular carcinoma. Although biopsy is the gold standard for the assessment of the liver parenchyma, quantitative evaluation methods, such as ultrasound, CT, and MRI, have been reported to have good diagnostic performances. The quantification of liver fat, fibrosis, and inflammation is expected to be clinically useful in terms of the prognosis, early intervention, and treatment response for the management of NAFLD. The aim of this review was to discuss the basics and prospects of MRI-based tissue quantifications of the liver, mainly focusing on proton density fat fraction for the quantification of fat deposition, MR elastography for the quantification of fibrosis, and multifrequency MR elastography for the evaluation of inflammation.

This study associated the liver proton density fat fraction (PDFF), measured by multi-echo Dixon (ME-Dixon) and breath-hold single-voxel high-speed T2-corrected multi-echo 1H magnetic resonance spectroscopy (HISTO) at 1.5 T, with serum biomarkers and liver fibrosis stages. This prospective study enrolled 75 patients suspected of liver fibrosis and scheduled for liver biopsy and 23 healthy participants with normal liver function. The participant underwent ME-Dixon and HISTO scanning. The agreement of PDFF measured by ME-Dixon (PDFF-D) and HISTO (PDFF-H) were compared. Correlations between PDFF and serum fat biomarkers (total cholesterol, triglyceride, and high- and low-density lipoproteins) and the liver fibrosis stages were assessed. PDFF were compared among the liver fibrosis stages (F0-F4) based on clinical liver biopsies. The Bland-Altman plot showed agreement between PDFF-D and PDFF-H(LoA, - 4.44 to 6.75), which have high consistency (ICC 0.752, P < 0.001). The correlations with the blood serum markers were mild to moderate (PDFF-H: r = 0.261-0.410, P < 0.01; PDFF-D: r = 0.265-0.367, P < 0.01). PDFF-D, PDFF-H, and steatosis were distributed similarly among the liver fibrosis stages. PDFF-H showed a slight negative correlation with the liver fibrosis stages (r = - 0.220, P = 0.04). Both ME-Dixon and HISTO sequences measured liver fat content noninvasively. Liver fat content was not directly associated with liver fibrosis stages.

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.

To propose standardized MRI-proton density fat fraction (PDFF) cutoff values for diagnosing hepatic steatosis, evaluated using contemporary PDFF measuring methods in a large population of healthy adults, using histologic fat fraction (HFF) as the reference standard.

A retrospective search of electronic medical records between 2015 and 2018 identified 1063 adult donor candidates for liver transplantation who had undergone liver MRI and liver biopsy within a 7-day interval. Patients with a history of liver disease or significant alcohol consumption were excluded. Chemical shift imaging-based MRI (CS-MRI) PDFF and high-speed T2-corrected multi-echo MR spectroscopy (HISTO-MRS) PDFF data were obtained. By temporal splitting, the total population was divided into development and validation sets. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of the MRI-PDFF method. Two cutoff values with sensitivity > 90% and specificity > 90% were selected to rule-out and rule-in, respectively, hepatic steatosis with reference to HFF ≥ 5% in the development set. The diagnostic performance was assessed using the validation set.

Of 921 final participants (624 male; mean age ± standard deviation, 31.5 ± 9.0 years), the development and validation sets comprised 497 and 424 patients, respectively. In the development set, the areas under the ROC curve for diagnosing hepatic steatosis were 0.920 for CS-MRI-PDFF and 0.915 for HISTO-MRS-PDFF. For ruling-out hepatic steatosis, the CS-MRI-PDFF cutoff was 2.3% (sensitivity, 92.4%; specificity, 63.0%) and the HISTO-MRI-PDFF cutoff was 2.6% (sensitivity, 88.8%; specificity, 70.1%). For ruling-in hepatic steatosis, the CS-MRI-PDFF cutoff was 3.5% (sensitivity, 73.5%; specificity, 88.6%) and the HISTO-MRI-PDFF cutoff was 4.0% (sensitivity, 74.7%; specificity, 90.6%).

In a large population of healthy adults, our study suggests diagnostic thresholds for ruling-out and ruling-in hepatic steatosis defined as HFF ≥ 5% by contemporary PDFF measurement methods.

The 2-point DIXON method is widely used to assess fat fractions (FFs) in magnetic resonance images (MRIs) of the tongue, pharyngeal wall, and surrounding tissues in patients with obstructive sleep apnea (OSA). However, the method is semiquantitative and is susceptible to B0 field inhomogeneities and R2* confounding factors. Using the method, although several studies have shown that patients with OSA have increased fat deposition around the pharyngeal cavity, conflicting findings was also reported in 1 study. This discrepancy necessitates that we examine the FF estimation method used in the earlier studies and seek a more accurate method to measure FFs.

We examined the advantages of using the GOOSE (globally optimal surface estimation) method to replace the 2-point DIXON method for quantifying fat in the tongue and surrounding tissues on MRIs. We first used phantoms with known FFs (true FFs) to validate the GOOSE method and examine the errors in the DIXON method. Then, we compared the 2 methods in the tongue, soft palate, pharyngeal wall, and parapharyngeal fat pad of 63 healthy participants to further assess the errors caused by the DIXON method. Six participants were excluded from the comparison of the tongue FFs because of technical failures. Paired Student t tests were performed on FFs to detect significant differences between the 2 methods. All measures were obtained using 3 T Siemens MRI scanners.

In the phantoms, the FFs measured by GOOSE agreed with the true FF, with only a 1.2% mean absolute error. However, the same measure by DIXON had a 10.5% mean absolute error. The FFs obtained by DIXON were significantly lower than those obtained by GOOSE (P < 0.0001) in the human participants. We found strong correlations between GOOSE and DIXON in the tongue (R2 = 0.90), soft palate (R2 = 0.66), and parapharyngeal fat pad (R2 = 0.88), but the correlation was weaker in the posterior pharyngeal walls (R2 = 0.32) in participants.

The widely used 2-point DIXON underestimated FFs, relative to GOOSE, in phantom measurements and tissues studied in vivo. Thus, an advanced method, such as GOOSE, that uses multiecho complex data is preferred for estimating FF.

Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90    mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7-12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3-13.4%) and MRE was 2.5 kPa (range, 1.5-3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR<5%). The top two CpGs, cg25474373 and cg07264203, mapped to or near RFTN2 and PRICKLE2 genes. These two CpG sites were also significantly associated with a NAFLD diagnosis. As higher LFC associates with an adverse cardiometabolic profile already in childhood, altered DNAm may identify these children early in disease course for targeted intervention. Larger, longitudinal studies are needed to validate these findings and determine mechanistic relevance.

Early quantitative assessment of liver fat content is essential for patients with fatty liver disease. Mounting evidence has shown that magnetic resonance (MR) technique has high accuracy in the quantitative analysis of fatty liver, and is suitable for monitoring the therapeutic effect on fatty liver. However, many packaging methods and postprocessing functions have puzzled radiologists in clinical applications. Therefore, selecting a quantitative MR imaging technique for patients with fatty liver disease remains challenging.

To provide information for the proper selection of commonly used quantitative MR techniques to quantify fatty liver.

We completed a systematic literature review of quantitative MR techniques for detecting fatty liver, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Studies were retrieved from PubMed, Embase, and Cochrane Library databases, and their quality was assessed using the Quality Assessment of Diagnostic Studies criteria. The Reference Citation Analysis database (https:// www.referencecitationanalysis.com) was used to analyze citation of articles which were included in this review.

Forty studies were included for spectroscopy, two-point Dixon imaging, and multiple-point Dixon imaging comparing liver biopsy to other imaging methods. The advantages and disadvantages of each of the three techniques and their clinical diagnostic performances were analyzed.

The proton density fat fraction derived from multiple-point Dixon imaging is a noninvasive method for accurate quantitative measurement of hepatic fat content in the diagnosis and monitoring of fatty liver progression.

To develop a 3D multitasking multi-echo (MT-ME) technique for the comprehensive characterization of liver tissues with 5-min free-breathing acquisition; whole-liver coverage; a spatial resolution of 1.5 × 1.5 × 6 mm³ ; and simultaneous quantification of T₁ , water-specific T₁ (T_1w ), proton density fat fraction (PDFF), and R2∗ .

Six-echo bipolar spoiled gradient echo readouts following inversion recovery preparation was performed to generate T₁ , water/fat, and R2∗ contrast. MR multitasking was used to reconstruct the MT-ME images with 3 spatial dimensions: 1 T₁ recovery dimension, 1 multi-echo dimension, and 1 respiratory dimension. A basis function-based approach was developed for T_1w quantification, followed by the estimation of R2∗ and T₁ -corrected PDFF. The intrasession repeatability and agreement against references of MT-ME measurements were tested on a phantom and 15 clinically healthy subjects. In addition, 4 patients with confirmed liver diseases were recruited, and the agreement between MT-ME measurements and references was assessed.

MT-ME produced high-quality, coregistered T₁ , T_1w , PDFF, and R2∗ maps with good intrasession repeatability and substantial agreement with references on phantom and human studies. The intra-class coefficients of T₁ , T_1w , PDFF, and R2∗ from the repeat MT-ME measurements on clinically healthy subjects were 0.989, 0.990, 0.999, and 0.988, respectively. The intra-class coefficients of T₁ , PDFF, and R2∗ between the MT-ME and reference measurements were 0.924, 0.987, and 0.975 in healthy subjects and 0.980, 0.999, and 0.998 in patients. The T_1w was independent to PDFF (R = -0.029, P = .904).

The proposed MT-ME technique quantifies T₁ , T_1w , PDFF, and R2∗ simultaneously and is clinically promising for the comprehensive characterization of liver tissue properties.

To evaluate the precision profile (repeatability and reproducibility) of quantitative STEAM-MRS and to determine the relationships between multiple MR biomarkers of chronic liver disease in subjects with iron overload at both 1.5 Tesla (T) and 3T.

MRS data were acquired in patients with known or suspected liver iron overload. Two STEAM-MRS sequences (multi-TE and multi-TE-TR) were acquired at both 1.5T and 3T (same day), including test-retest acquisition. Each acquisition enabled estimation of R1, R2, and FWHM (each separately for water and fat); and proton density fat fraction. The test-retest repeatability and reproducibility across acquisition modes (multi-TE vs. multi-TE-TR) of the estimates were evaluated using intraclass correlation coefficients, linear regression, and Bland-Altman analyses. Multi-parametric relationships between parameters at each field strength, across field strengths, and with liver iron concentration were also evaluated using linear and nonlinear regression.

Fifty-six (n = 56) subjects (10 to 73 years, 37 males/19 females) were successfully recruited. Both STEAM-MRS sequences demonstrated good-to-excellent precision (intraclass correlation coefficient ≥ 0.81) for the quantification of R1_water , R2_water , FWHM_water , and proton density fat fraction at both 1.5T and 3T. Additionally, several moderate (R² = 0.50 to 0.69) to high (R² ≥ 0.70) correlations were observed between biomarkers, across field strengths, and with liver iron concentration.

Over a broad range of liver iron concentration, STEAM-MRS enables rapid and precise measurement of multiple biomarkers of chronic liver disease. By evaluating the multi-parametric relationships between biomarkers, this work may advance the comprehensive MRS-based assessment of chronic liver disease and may help establish biomarkers of chronic liver disease.

The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH.

In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19).

At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients.

MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization.

Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Background Pharmacologic treatment of nonalcoholic steatohepatitis (NASH) is long term in nature; thus, early noninvasive treatment response assessment is important for therapeutic decision making. Purpose To investigate potential early predictors of the 12-week treatment response estimated by using the MRI-based proton-density fat fraction (PDFF). Materials and Methods In this secondary analysis of a prospective phase Ib clinical trial evaluating a candidate treatment (MET409, a farnesoid X receptor agonist) for NASH, participants were analyzed at baseline and at 4 and 12 weeks after either active treatment with MET409 or placebo treatment between June 2019 and January 2020. Correlation and multiple linear regression analyses were used to identify clinical, laboratory, and imaging predictors of the relative PDFF change at week 12 (W12). Multivariate logistic regression analysis was used to develop predictive models for an at least 30% relative PDFF reduction at W12, a well-validated indicator of histologic improvement. Model performance was characterized by using area under the receiver operating characteristic curve (AUC) analysis, sensitivity, and specificity. Results A total of 48 participants were analyzed (median age, 57 years; age range, 40-62 years; 32 women), among whom 30 received MET409 and 18 received a placebo. The week 4 (W4) relative changes in PDFF (regression coefficient = 1.24, P < .001) and the serum alkaline phosphatase (ALP) level (regression coefficient = -0.29, P = .03) were predictors of the W12 relative PDFF change. An at least 19.3% relative PDFF reduction at W4 yielded an AUC of 0.98 (sensitivity, 89%; specificity, 95%) for predicting an at least 30% relative PDFF reduction at W12. The addition of ALP to the predictive model did not improve model performance. Conclusion In participants with nonalcoholic steatohepatitis enrolled in a phase Ib treatment trial, the relative change in the MRI-based proton-density fat fraction (PDFF) at week 4 was highly predictive of the treatment response estimated by using the week 12 MRI-based PDFF. © RSNA, 2021 Online supplemental material is available for this article.

Chemical-shift-based fat-water MRI signal models with single- or dual-R2 * correction have been proposed for quantification of fat fraction (FF) and assessment of hepatic steatosis. However, there is a void in our understanding of which model truly mimics the underlying biophysical mechanism of steatosis on MRI signal relaxation. The purpose of this study is to morphologically characterize and build realistic steatosis models from histology and synthesize MRI signal using Monte Carlo simulations to investigate the accuracy of single- and dual-R2 * models in quantifying FF and R2 *. Fat morphology was characterized by performing automatic segmentation on 16 mouse liver histology images and extracting the radius, nearest neighbor (NN) distance, and regional anisotropy of fat droplets. A gamma distribution function (GDF) was used to generalize extracted features, and regression analysis was performed to derive relationships between FF and GDF parameters. Virtual steatosis models were created based on derived morphological and statistical descriptors, and the MRI signal was synthesized at 1.5 T and 3 T. R2 * and FF values were calculated using single- and dual-R2 * models and compared with in vivo R2 *-FF calibrations and simulated FFs. The steatosis models generated with regional anisotropy and NN distribution closely mimicked the true in vivo fat morphology. For both R2 * models, predicted R2 * values showed positive correlation with FFs, with slopes similar to those of the in vivo calibrations (P > 0.05), and predicted FFs showed excellent agreement with true FFs (R2  > 0.99), with slopes close to unity. Our study, hence, demonstrates the proof of concept for generating steatosis models from histologic data and synthesizing MRI signal to show the expected signal relaxation under conditions of steatosis. Our results suggest that a single R2 * is sufficient to accurately estimate R2 * and FF values for lower FFs, which agrees with in vivo studies. Future work involves characterizing and building steatosis models at higher FFs and testing single- and dual-R2 * models for accurate assessment of steatosis.

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.

The purpose of this study was to demonstrate the clinical feasibility of an integrated reference phantom method for quantitative ultrasound by creating an ultrasound-derived fat fraction (UDFF) tool. This tool was evaluated with respect to its diagnostic performance as a biomarker for assessing histologic hepatic steatosis and its agreement with the magnetic resonance imaging (MRI) proton density fat fraction (PDFF).

Adults (n = 101) with known or suspected nonalcoholic fatty liver disease consented to participate in this prospective cross-sectional study. All patients underwent MRI-PDFF and ultrasound scans, whereas 90 underwent liver biopsy. A linear least-squares analysis used the attenuation coefficient and backscatter coefficient to create the UDFF model for predicting MRI-PDFF.

The area under the receiver operating characteristic curve values were 0.94 (95% confidence interval [CI], 0.85-0.98) for histologic steatosis grade 0 (n = 6) versus 1 or higher (n = 84), 0.88 (95% CI, 0.8-0.94) for grade 1 or lower (n = 45) versus 2 or higher (n = 45), and 0.83 (95% CI, 0.73-0.9) for grade 2 or lower (n = 78) versus 3 (n = 12). The Pearson correlation coefficient between UDFF and PDFF was ρ = 0.87 with 95% limits of agreement of ±8.5%. Additionally, the diagnosis of steatosis, defined as MRI-PDFF higher than 5% and 10%, had area under the receiver operating characteristic curve values of 0.97 (95% CI, 0.93-0.99) and 0.95 (95% CI, 0.9-0.98), respectively. The body mass index was not correlated with either UDFF or PDFF.

An on-system, integrated UDFF tool provides a simple, noninvasive, accessible, low-cost, and commercially viable clinical tool for quantifying the hepatic fat fraction with a high degree of agreement with histologic biopsy or the MRI-PDFF biomarker.

Excessive intracellular accumulation of triglycerides in the liver, or hepatic steatosis, is a highly prevalent condition affecting approximately one billion people worldwide. In the absence of secondary cause, the term nonalcoholic fatty liver disease (NAFLD) is used. Hepatic steatosis may progress into nonalcoholic steatohepatitis, the more aggressive form of NAFLD, associated with hepatic complications such as fibrosis, liver failure and hepatocellular carcinoma. Hepatic steatosis is associated with metabolic syndrome, cardiovascular disease and represents an independent risk factor for type 2 diabetes, cardiovascular disease and malignancy. Percutaneous liver biopsy is the current reference standard for NAFLD assessment; however, it is an invasive procedure associated with complications and suffers from high sampling variability, impractical for clinical routine and drug efficiency studies. Therefore, noninvasive imaging methods are increasingly used for the diagnosis and monitoring of NAFLD. Among the methods quantifying liver fat, chemical-shift-encoded MRI (CSE-MRI)-based proton density fat-fraction (PDFF) has shown the most promise. MRI-PDFF is increasingly accepted as quantitative imaging biomarker of liver fat that is transforming daily clinical practice and influencing the development of new treatments for NAFLD. Furthermore, CT is an important imaging method for detection of incidental steatosis, and the practical advantages of quantitative ultrasound hold great promise for the future. Understanding the disease burden of NAFLD and the role of imaging may initiate important interventions aimed at avoiding the hepatic and extrahepatic complications of NAFLD. This article reviews clinical burden of NAFLD, and the role of noninvasive imaging techniques for quantification of liver fat.

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).

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).

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).

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.

• 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.

To explore the utility of two different fat quantification methods in the liver and pancreas and to test the accuracy of multi-echo Dixon as a single sequence in detecting early stage of fat deposition.

58 healthy potential liver donors underwent abdominal 3T MRI, prospectively. Single-voxel MR Spectroscopy (MRS), dual-echo Dixon, and multi-echo Dixon were performed. Two independent readers obtained proton density fat fraction (PDFF) of the liver and pancreas by placing ROIs on the 2 Dixon sequences. Correlation between the two PDFF measurements was assessed in the liver and pancreas. Values in the liver were also compared to those obtained by MRS.

PDFF in the liver was 6.3 ± 4.2%, 5.5 ± 3.9%, and 5.1 ± 4.1% by MRS, dual-echo Dixon, and multi-echo Dixon, respectively. Dual-echo Dixon and multi-echo Dixon showed good correlation in PDFF quantification of the liver (r = 0.82, p < 0.0005). Multi-echo Dixon showed a good correlation (r = 0.72, p = 0.0005) between the fat measured in the liver and in the pancreas. To differentiate between normal (PDFF ≤ 6%) and mild fat deposition (PDFF: 6-33%) in the liver, analysis showed sensitivity, specificity, and accuracy of 74%, 81%, and 80% for dual-echo Dixon and 85%, 96%, and 89% for multi-echo Dixon, respectively. Mean PDFF in the pancreas was 7.2 ± 2.8% and 6.7 ± 3.3%, by dual-echo and multi-echo Dixon, respectively. Dual-echo Dixon and multi-echo Dixon showed good correlation in PDFF quantification of the pancreas (r = 0.58, p < 0.0005).

Multi-echo Dixon in liver has high accuracy in distinguishing between subjects with normal liver fat and those with mildly elevated liver fat. Multi-echo Dixon can be used to screen for early fat deposition in the liver and pancreas.

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH.

MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260.

348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom.

Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging.

Madrigal Pharmaceuticals.

Type 1 diabetes mellitus (T1DM) is characterized by hyperglycemia, owing to the loss of pancreatic β cells in response to an autoimmune reaction leading to a state of absolute insulin deficiency. T1DM treatment is shifting from exogenous insulin replacement therapy toward pancreatic β-cell replacement, to restore physiologically responsive insulin secretion to variations in blood glucose levels. β-cell replacement strategies include human whole pancreas transplantation, islet transplantation with cell encapsulation and bioengineered pancreas. Interventional radiology and imaging modalities including positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging, ultrasonography, and molecular imaging are imperative to enable successful β-cell replacement. Herein, the role of radiological modalities in the treatment of T1DM and its prospective use for noninvasive post-transplantation graft monitoring is discussed.

Patients with chronic liver diseases (CLDs) often suffer from lipidosis or siderosis. Proton density fat fraction (PDFF) and R2* can be used as quantitative parameters to assess the fat/iron content of the liver. The aim of this study was to evaluate the influence of liver fibrosis and inflammation on the 3D Multi-echo Dixon (3D ME Dixon) parameters (MRI-PDFF and R2*) in patients with CLDs and to determine the feasibility of 3D ME Dixon technique for the simultaneous assessment of liver steatosis and iron overload using histopathologic findings as the reference standard.

Ninety-nine consecutive patients with CLDs underwent T1-independent, T2*-corrected 3D ME Dixon sequence with reconstruction using multipeak spectral modeling on a 3T MR scanner. Liver specimen was reviewed in all cases, grading liver steatosis, siderosis, fibrosis, and inflammation. Spearman correlation analysis was performed to determine the relationship between 3D ME Dixon parameters (MRI-PDFF and R2*) and histopathological and biochemical features [liver steatosis, iron overload, liver fibrosis, inflammation, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL)]. Multiple regression analysis was applied to identify variables associated with 3D ME Dixon parameters. Receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of these parameters to differentiate liver steatosis or iron overload.

In multivariate analysis, only liver steatosis independently influenced PDFF values (R2=0.803, P<0.001), liver iron overload and fibrosis influenced R2* values (R2=0.647, P<0.001). The Spearman analyses showed that R2* values were moderately correlated with fibrosis stages (r=0.542, P<0.001) in the subgroup with the absence of iron overload. The area under the ROC curve of PDFF was 0.989 for the diagnosis of steatosis grade 1 or greater, and 0.986 for steatosis grade 2 or greater. The area under the ROC curve of R2* was 0.815 for identifying iron overload grade 1 or greater, and 0.876 for iron overload grade 2 or greater.

3D Multi-Echo Dixon can be used to simultaneously evaluate liver steatosis and iron overload in patients with CLDs, especially for quantification of liver steatosis. However, liver R2* value may be affected by the liver fibrosis in the setting of CLDs with absence of iron overload.

Liver iron content (LIC) in chronic liver disease (CLD) is currently determined by performing an invasive liver biopsy. MRI using R2* relaxometry is a noninvasive alternative for estimating LIC. Fat accumulation in the liver, or proton density fat fraction (PDFF), may be a possible confounder of R2* measurements. Previous studies of the effect of PDFF on R2* have not used quantitative LIC measurement.

To assess the associations between R2*, LIC, PDFF, and liver histology in patients with suspected CLD.

Prospective.

Eighty-one patients with suspected CLD.

1.5 T. Multiecho turbo field echo to quantify R2*. PRESS MRS to quantify PDFF.

Each patient underwent an MR examination, followed by two needle biopsies immediately following the MR examination. The first biopsy was used for conventional histological assessment of LIC, whereas the second biopsy was used to quantitatively measure LIC using mass spectrometry. R2* was correlated with both LIC and PDFF. A correction for the influence of fat on R2* was calculated.

Pearson correlation, linear regression, and area under the receiver operating curve.

There was a positive linear correlation between R2* and PDFF (R = 0.69), after removing data from patients with elevated iron levels, as defined by LIC. R2*, corrected for PDFF, was the best method for identifying patients with elevated iron levels, with a correlation of R = 0.87 and a sensitivity and specificity of 87.5% and 98.6%, respectively.

PDFF increases R2*.

2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:325-333.

Complex-based chemical shift imaging-based magnetic resonance imaging (CSE-MRI) is emerging as a preferred method for noninvasively quantifying proton density fat fraction (PDFF), a promising quantitative imaging biomarker (QIB) for longitudinal hepatic steatosis measurement.

To determine linearity, bias, repeatability, and reproducibility of the PDFF measurement using CSE-MRI (CSE-PDFF) across scan intervals, MR field strengths, and readers in phantom and nonalcoholic fatty liver disease (NAFLD) patients.

Institutional Review Board (IRB)-approved prospective.

Fat-water phantom and 20 adult patients.

1.5 T and 3.0 T MR systems and a commercially available CSE-MRI sequence (IDEAL-IQ).

Two independent readers measured CSE-PDFF of fat-water phantom and NAFLD patients across two field strengths and scan intervals (same-day and 2-week) each and in a combination of both. MR spectroscopy-based PDFF (MRS-PDFF) was used as the reference standard for phantom PDFF.

Linearity and bias of measurement were evaluated by linear regression analysis and Bland-Altman plots, respectively. Repeatability and reproducibility were assessed by coefficient of variance and repeatability / reproducibility coefficients (RC). The intraclass correlation coefficient was used to validate intra- and interobserver agreements.

CSE-PDFF showed high linearity and small bias (-0.6-0.4 PDFF%) with 95% limits of agreement within ±2.9 PDFF% across field strengths, 2-week interscan period, and readers in the clinical scans. CSE-PDFF was highly repeatable and reproducible both in phantom and clinical scans, with the largest observed RC across field strengths and 2-week interscan period being 3 PDFF%.

CSE-PDFF is a robust QIB with high linearity, small bias, and excellent repeatability/reproducibility. A change of more than 3 PDFF% across field strengths within 2 weeks of scan interval likely reflects a true change, which is well within the clinically acceptable range.

3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:305-314.

To examine the influence of non-alcoholic fatty liver disease (NAFLD) and hepatic fat content on bone mineral density (BMD), and to investigate whether the relationship between NAFLD and BMD is independent of lifestyle factors related to BMD.

Hepatic fat content (magnetic resonance imaging), BMD, lean mass index, total and abdominal fat mass (dual-energy-X-ray absorptiometry), moderate to vigorous physical activity (MVPA) (accelerometry), and calcium and vitamin D intake (two 24 h recalls) were measured in 115 children with overweight/obesity aged 10.6 ± 1.1 years old.

Children with NAFLD had lower BMD than children without NAFLD regardless of sex, puberty stage, lean mass index, fat mass, MVPA, and calcium and vitamin D intake (0.89 ± 0.01 vs. 0.93 ± 0.01 g/cm² for NAFLD and non-NAFLD, respectively, P < 0.01). Higher hepatic fat content was significantly associated with lower BMD regardless of confounders (adjusted P < 0.05).

Findings of the current study suggest that hepatic fat accumulation is associated with decreased BMD independently of adiposity, and regardless of those lifestyle factors closely related to bone mineral accrual in children. These results may have implication in the clinical management of children with overweight/obesity given the high prevalence of pediatric NAFLD.

Patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) often require histologic assessment via liver biopsy. Magnetic resonance imaging (MRI)-based methods for measuring liver triglycerides based on proton density fat fraction (PDFF) are increasingly used as a noninvasive tool to identify patients with hepatic steatosis and to assess for change in liver fat over time. We aimed to determine whether MRI-PDFF accurately reflects a variety of liver histology features in patients with NAFLD or NASH.

We performed a retrospective analysis of pooled data from 3 phase 2a trials of pharmacotherapies for NAFLD or NASH. We collected baseline clinical, laboratory, and histopathology data on all subjects who had undergone MRI analysis in 1 of the trials. We assessed the relationship between liver PDFF values and liver histologic findings using correlation and area under the receiver operating characteristic (AUROC) analyses. As an ancillary analysis, we also simulated a clinical trial selection process and calculated subject exclusion rates and differences in population characteristics caused by PDFF inclusion thresholds of 6% to 15%.

In 370 subjects, the mean baseline PDFF was 17.4% ± 8.6%. Baseline PDFF values correlated with several histopathology parameters, including steatosis grade (r = 0.78; P < .001), NAFLD activity score (NAS, r = 0.54; P < .001), and fibrosis stage (r = -0.59; P < .001). However, PDFF did not accurately identify patients with NAS ≥ 4 (AUROC = 0.72) or fibrosis stage ≥3 (AUROC = 0.66). In a theoretical trial of these subjects, exclusion rates increased as PDFF minimum threshold level increased. There were no significant differences in cohort demographics when PDFF thresholds ranging from 6% to 15% were used, and differences in laboratory and histopathology data were small.

In an analysis of patients with NAFLD or NASH, we determined that although The MRI-PDFF correlated with steatosis grade and NAS, and inversely with fibrosis stage, it was suboptimal in identification of patients with NAS >4 or advanced fibrosis. Although MRI-PDFF is an important imaging biomarker for continued evaluation of this patient population, liver biopsy analysis is still necessary.

The liver R2* value is widely used as a measure of liver iron but may be confounded by the presence of hepatic steatosis and other covariates.

To identify the most influential covariates for liver R2* values in patients with nonalcoholic fatty liver disease (NAFLD).

Retrospective analysis of prospectively acquired data.

Baseline data from 204 subjects enrolled in NAFLD/NASH (nonalcoholic steatohepatitis) treatment trials.

1.5T and 3T; chemical-shift encoded multiecho gradient echo.

Correlation between liver proton density fat fraction and R2*; assessment for demographic, metabolic, laboratory, MRI-derived, and histological covariates of liver R2*.

Pearson's and Spearman's correlations; univariate analysis; gradient boosting machines (GBM) multivariable machine-learning method.

Hepatic proton density fat fraction (PDFF) was the most strongly correlated covariate for R2* at both 1.5T (r = 0.652, P < 0.0001) and at 3T (r = 0.586, P < 0.0001). In the GBM analysis, hepatic PDFF was the most influential covariate for hepatic R2*, with relative influences (RIs) of 61.3% at 1.5T and 47.5% at 3T; less influential covariates had RIs of up to 11.5% at 1.5T and 16.7% at 3T. Nonhepatocellular iron was weakly associated with R2* at 3T only (RI 6.7%), and hepatocellular iron was not associated with R2* at either field strength.

Hepatic PDFF is the most influential covariate for R2* at both 1.5T and 3T; nonhepatocellular iron deposition is weakly associated with liver R2* at 3T only.

4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1456-1466.

The ability to assess skeletal muscle adipose tissue is important given the negative clinical implications associated with greater fat infiltration of the muscle. Computed tomography and magnetic resonance imaging (MRI) are highly accurate for measuring appendicular soft tissue and muscle composition, but have limitations. Peripheral quantitative computed tomography (pQCT) is an alternative that investigators find valuable because of its low radiation, fast scan time, and comparatively lower costs. The present investigation sought to assess the accuracy of pQCT-derived estimates of total, subcutaneous, skeletal muscle, intermuscular, and calculated intramuscular adipose tissue areas, and muscle density in the midthigh of young girls using the gold standard, 3 T MRI, as the criterion. Cross-sectional data were analyzed for 26 healthy girls aged 9-12 years. Midthigh soft tissue composition was assessed by both pQCT and 3 T MRI. Mean tissue area for corresponding adipose compartments by pQCT and MRI was compared using t tests, regression analysis, and Bland-Altman plots. Muscle density was regressed on MRI skeletal muscle adipose tissue, intermuscular adipose tissue, and intramuscular adipose tissue, each expressed as a percentage of total muscle area. Correlations were high between MRI and pQCT for total adipose tissue (r² = 0.98), subcutaneous adipose tissue (r² = 0.95), skeletal muscle adipose tissue (r² = 0.83), and intermuscular adipose tissue (r² = 0.82), and pQCT muscle density correlated well with both MRI skeletal muscle adipose tissue (r² = 0.70) and MRI intermuscular adipose tissue (r² = 0.70). There was a slight, but statistically significant underestimation by pQCT for total and subcutaneous adipose tissue, whereas no significant difference was observed for skeletal muscle adipose tissue. Both pQCT-estimated intramuscular adipose tissue and muscle density were weakly correlated with MRI-intramuscular adipose tissue. We conclude that pQCT is a valid measurement technique for estimating all adipose subcompartments, except for intramuscular adipose tissue, for the midthigh region in young/adolescent girls.