Assessment of a high-SNR chemical-shift-encoded MRI with complex reconstruction for proton density fat fraction (PDFF) estimation overall and in the low-fat range.

BACKGROUND: Improving the signal-to-noise ratio (SNR) of chemical-shift-encoded MRI acquisition with complex reconstruction (MRI-C) may improve the accuracy and precision of noninvasive proton density fat fraction (PDFF) quantification in patients with hepatic steatosis. PURPOSE: To assess the accuracy of high SNR (Hi-SNR) MRI-C versus standard MRI-C acquisition to estimate hepatic PDFF in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using an MR spectroscopy (MRS) sequence as the reference standard. STUDY TYPE: Prospective. POPULATION/SUBJECTS: In all, 231 adult and pediatric patients with known or suspected NAFLD. FIELD STRENGTH/SEQUENCE: PDFF estimated at 3T by three MR techniques: standard MRI-C; a Hi-SNR MRI-C variant with increased slice thickness, decreased matrix size, and no parallel imaging; and MRS (reference standard). ASSESSMENT: MRI-PDFF was measured by image analysts using a region of interest coregistered with the MRS-PDFF voxel. STATISTICAL TESTS: Linear regression analyses were used to assess accuracy and precision of MRI-estimated PDFF for MRS-PDFF as a function of MRI-PDFF using the standard and Hi-SNR MRI-C for all patients and for patients with MRS-PDFF <10%. RESULTS: In all, 271 exams from 231 patients were included (mean MRS-PDFF: 12.6% [SD: 10.4]; range: 0.9-41.9). High agreement between MRI-PDFF and MRS-PDFF was demonstrated across the overall range of PDFF, with a regression slope of 1.035 for the standard MRI-C and 1.008 for Hi-SNR MRI-C. Hi-SNR MRI-C, compared to standard MRI-C, provided small but statistically significant improvements in the slope (respectively, 1.008 vs. 1.035, P = 0.004) and mean bias (0.412 vs. 0.673, P < 0.0001) overall. In the low-fat patients only, Hi-SNR MRI-C provided improvements in the slope (1.058 vs. 1.190, P = 0.002), mean bias (0.168 vs. 0.368, P = 0.007), intercept (-0.153 vs. -0.796, P < 0.0001), and borderline improvement in the R2 (0.888 vs. 0.813, P = 0.01). DATA CONCLUSION: Compared to standard MRI-C, Hi-SNR MRI-C provides slightly higher MRI-PDFF estimation accuracy across the overall range of PDFF and improves both accuracy and precision in the low PDFF range. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:229-238.

Magnetic resonance elastography measured shear stiffness as a biomarker of fibrosis in pediatric nonalcoholic fatty liver disease.

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two-dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross-validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross-validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%-81.1%). Overall cross-validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%-94.5%) for center 1, 90.0% (95% CI, 81.9%-95.3%) for center 2, and 86.7% (95% CI, 77.9%-92.9%) for automated analysis. CONCLUSION: 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (Hepatology 2017;66:1474-1485).

Accuracy of PDFF estimation by magnitude-based and complex-based MRI in children with MR spectroscopy as a reference.

PURPOSE: To assess and compare the accuracy of magnitude-based magnetic resonance imaging (MRI-M) and complex-based MRI (MRI-C) for estimating hepatic proton density fat fraction (PDFF) in children, using MR spectroscopy (MRS) as the reference standard. A secondary aim was to assess the agreement between MRI-M and MRI-C. MATERIALS AND METHODS: This was a HIPAA-compliant, retrospective analysis of data collected in children enrolled in prospective, Institutional Review Board (IRB)-approved studies between 2012 and 2014. Informed consent was obtained from 200 children (ages 8-19 years) who subsequently underwent 3T MR exams that included MRI-M, MRI-C, and T1 -independent, T2 -corrected, single-voxel stimulated echo acquisition mode (STEAM) MRS. Both MRI methods acquired six echoes at low flip angles. T2*-corrected PDFF parametric maps were generated. PDFF values were recorded from regions of interest (ROIs) drawn on the maps in each of the nine Couinaud segments and three ROIs colocalized to the MRS voxel location. Regression analyses assessing agreement with MRS were performed to evaluate the accuracy of each MRI method, and Bland-Altman and intraclass correlation coefficient (ICC) analyses were performed to assess agreement between the MRI methods. RESULTS: MRI-M and MRI-C PDFF were accurate relative to the colocalized MRS reference standard, with regression intercepts of 0.63% and -0.07%, slopes of 0.998 and 0.975, and proportion-of-explained-variance values (R2 ) of 0.982 and 0.979, respectively. For individual Couinaud segments and for the whole liver averages, Bland-Altman biases between MRI-M and MRI-C were small (ranging from 0.04 to 1.11%) and ICCs were high (≥0.978). CONCLUSION: Both MRI-M and MRI-C accurately estimated hepatic PDFF in children, and high intermethod agreement was observed. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1641-1647.

Quantifying Abdominal Adipose Tissue and Thigh Muscle Volume and Hepatic Proton Density Fat Fraction: Repeatability and Accuracy of an MR Imaging-based, Semiautomated Analysis Method.

Purpose To determine the repeatability and accuracy of a commercially available magnetic resonance (MR) imaging-based, semiautomated method to quantify abdominal adipose tissue and thigh muscle volume and hepatic proton density fat fraction (PDFF). Materials and Methods This prospective study was institutional review board- approved and HIPAA compliant. All subjects provided written informed consent. Inclusion criteria were age of 18 years or older and willingness to participate. The exclusion criterion was contraindication to MR imaging. Three-dimensional T1-weighted dual-echo body-coil images were acquired three times. Source images were reconstructed to generate water and calibrated fat images. Abdominal adipose tissue and thigh muscle were segmented, and their volumes were estimated by using a semiautomated method and, as a reference standard, a manual method. Hepatic PDFF was estimated by using a confounder-corrected chemical shift-encoded MR imaging method with hybrid complex-magnitude reconstruction and, as a reference standard, MR spectroscopy. Tissue volume and hepatic PDFF intra- and interexamination repeatability were assessed by using intraclass correlation and coefficient of variation analysis. Tissue volume and hepatic PDFF accuracy were assessed by means of linear regression with the respective reference standards. Results Adipose and thigh muscle tissue volumes of 20 subjects (18 women; age range, 25-76 years; body mass index range, 19.3-43.9 kg/m2) were estimated by using the semiautomated method. Intra- and interexamination intraclass correlation coefficients were 0.996-0.998 and coefficients of variation were 1.5%-3.6%. For hepatic MR imaging PDFF, intra- and interexamination intraclass correlation coefficients were greater than or equal to 0.994 and coefficients of variation were less than or equal to 7.3%. In the regression analyses of manual versus semiautomated volume and spectroscopy versus MR imaging, PDFF slopes and intercepts were close to the identity line, and correlations of determination at multivariate analysis (R2) ranged from 0.744 to 0.994. Conclusion This MR imaging-based, semiautomated method provides high repeatability and accuracy for estimating abdominal adipose tissue and thigh muscle volumes and hepatic PDFF. © RSNA, 2017.

Agreement between region-of-interest- and parametric map-based hepatic proton density fat fraction estimation in adults with chronic liver disease.

PURPOSE: To compare agreement between region-of-interest (ROI)- and parametric map-based methods of hepatic proton density fat fraction (PDFF) estimation in adults with known or suspected hepatic steatosis secondary to chronic liver disease over a range of imaging and analysis conditions. MATERIALS AND METHODS: In this IRB approved HIPAA compliant prospective single-site study, 31 adults with chronic liver disease undergoing clinical gadoxetic acid-enhanced liver magnetic resonance imaging at 3 T were recruited. Multi-echo gradient-echo imaging at flip angles of 10° and 50° was performed before and after administration of gadoxetic acid. Six echoes were acquired at successive nominally out-of-phase and in-phase echo times. PDFF was estimated with a nonlinear fitting algorithm using the first two, three, four, five, and (all) six echoes. Hence, 20 different imaging and analysis conditions were used (pre/post contrast x low/high flip angle x 2/3/4/5/6 echoes). For each condition, PDFF estimation was done in corresponding liver locations using two methods: a region-of-interest (ROI)-based method in which mean signal intensity values within ROIs were run through the fitting algorithm, and a parametric map-based method in which individual signal intensities were run through the fitting algorithm pixel by pixel. Agreement between ROI- and map-based PDFF estimation was assessed by Bland-Altman and intraclass correlation (ICC) analysis. RESULTS: Depending on the condition and method, PDFF ranged from -2.52% to 45.57%. Over all conditions, mean differences between ROI- and map-based PDFF estimates ranged from 0.04% to 0.24%, with all ICCs ≥0.999. CONCLUSION: Agreement between ROI- and parametric map-based PDFF estimation is excellent over a wide range of imaging and analysis conditions.

Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis.

BACKGROUND: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. METHODS: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. RESULTS: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of -4.1% ± 4.9 versus -0.6 ± 4.1 (p < 0.04) with a mean relative percent change of -29.3% ± 33.0 versus +2.0% ± 24.0 (p < 0.004), respectively. CONCLUSIONS: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.

Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial.

BACKGROUND & AIMS: Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF). METHODS: This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and magnetic resonance elastography (MRE) and FIBROSpect® II to assess liver fibrosis. RESULTS: Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: -1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 (p<0.0001), demonstrating the strong internal validity of the findings. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03). CONCLUSIONS: Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD. LAY SUMMARY: In a randomized, double-blind, placebo-controlled study, the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease. This study demonstrates that non-invasive magnetic resonance imaging techniques, including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography, can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials.

Novel 3D Magnetic Resonance Elastography for the Noninvasive Diagnosis of Advanced Fibrosis in NAFLD: A Prospective Study.

OBJECTIVES: Recent studies show two-dimensional (2D)-magnetic resonance elastography (MRE) is accurate in diagnosing advanced fibrosis (stages 3 and 4) in nonalcoholic fatty liver disease (NAFLD) patients. Three-dimensional (3D)-MRE is a more advanced version of the technology that can image shear-wave fields in 3D of the entire liver. The aim of this study was to prospectively compare the diagnostic accuracy of 3D-MRE and 2D-MRE for diagnosing advanced fibrosis in patients with biopsy-proven NAFLD. METHODS: This cross-sectional analysis of a prospective study included 100 consecutive patients (56% women) with biopsy-proven NAFLD who also underwent MRE. Area under the receiver operating characteristic (AUROC) analysis was performed to assess the accuracy of 2D- and 3D-MRE in diagnosing advanced fibrosis. RESULTS: The mean (±s.d.) of age and body mass index were 50.2 (±13.6) years and 32.1 (±5.0) kg/m(2), respectively. The AUROC for diagnosing advanced fibrosis was 0.981 for 3D-MRE at 40 Hz, 0.927 for 3D-MRE at 60 Hz (standard shear-wave frequency), and 0.921 for 2D-MRE at 60 Hz (standard shear-wave frequency). At a threshold of 2.43 kPa, 3D-MRE at 40 Hz had sensitivity 1.0, specificity 0.94, positive predictive value 0.72, and negative predictive value 1.0 for diagnosing advanced fibrosis. 3D-MRE at 40 Hz had significantly higher AUROC (P<0.05) than 2D-MRE at 60 Hz for diagnosing advanced fibrosis. CONCLUSIONS: Utilizing a prospective study design, we demonstrate that 3D MRE at 40 Hz has the highest diagnostic accuracy in diagnosing NAFLD advanced fibrosis. Both 2D- and 3D-MRE at 60 Hz, the standard shear-wave frequency, are also highly accurate in diagnosing NAFLD advanced fibrosis.

Magnetic resonance elastography is superior to acoustic radiation force impulse for the Diagnosis of fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease: A prospective study.

UNLABELLED: Magnetic resonance elastography (MRE), an advanced magnetic resonance-based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound-based imaging technique, are accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head-to-head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We compared MRE versus ARFI head-to-head for diagnosing fibrosis in well-characterized patients with biopsy-proven NAFLD. This cross-sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. The performances of MRE versus ARFI for diagnosing fibrosis were evaluated using area under the receiver operating characteristic curves (AUROCs). The mean (± standard deviation) age and body mass index were 48.9 (±15.4) years and 31.8 (±7.0) kg/m(2) , respectively. For diagnosing any fibrosis (≥ stage 1), the MRE AUROC was 0.799 (95% confidence interval [CI] 0.723-0.875), significantly (P = 0.012) higher than the ARFI AUROC of 0.664 (95% CI 0.568-0.760). In stratified analysis by presence or absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (P < 0.001) but not in nonobese patients (P = 0.722). The MRE AUROCs for diagnosing ≥stages 2, 3, and 4 fibrosis were 0.885 (95% CI 0.816-0.953), 0.934 (95% CI 0.863-1.000), and 0.882 (95% CI 0.729-1.000); and the ARFI AUROCs were 0.848 (95% CI 0.776-0.921), 0.896 (95% CI 0.824-0.968), and 0.862 (95% CI 0.721-1.000). MRE had higher AUROCs than ARFI for discriminating dichotomized fibrosis stages at all dichotomization cutoff points, but the AUROC differences decreased as the cutoff points (fibrosis stages) increased. CONCLUSION: MRE is more accurate than ARFI for diagnosing any fibrosis in NAFLD patients, especially those who are obese.

In vivo breath-hold (1) H MRS simultaneous estimation of liver proton density fat fraction, and T1 and T2 of water and fat, with a multi-TR, multi-TE sequence.

PURPOSE: To examine the intra-examination repeatability of proton density fat fraction (PDFF) and T1 and T2 of liver water and fat as estimated by a novel multi-repetition time (TR)-echo time (TE) (1) H magnetic resonance spectroscopy (MRS)-stimulated echo acquisition mode (STEAM) sequence that acquires 32 spectra for a range of TRs and TEs in single breath-hold. MATERIALS AND METHODS: Sixty-seven subjects undergoing liver MRI examinations at 3T had three multi-TR-TE sequences acquired consecutively in a single session. This sequence was designed to allow accurate estimation of T1 and T2 of both water and fat, as well as PDFF, in a single breath-hold. A standard long-TR, multi-TE sequence was also acquired to allow comparison of estimated PDFF. Regression and interclass correlation (ICC) analyses were performed. RESULTS: There was strong agreement between PDFF estimated by the multi-TR-TE and long-TR, multi-TE sequences (slope 0.997; intercept -0.03; R = 0.997). The multi-TR-TE sequence had high repeatability for estimating PDFF (ICC = 0.999), water T2 (ICC = 0.920), water T1 (ICC = 0.845), and fat T2 (ICC = 0.760), and moderate repeatability for estimating fat T1 (ICC = 0.556). CONCLUSION: A novel multi-TR-TE sequence can estimate PDFF and water and fat T1 and T2 in a single breath-hold. Refinement may be needed to improve repeatability for fat T1 estimation.

Reproducibility of MR-based liver fat quantification across field strength: Same-day comparison between 1.5T and 3T in obese subjects.

PURPOSE: To examine the reproducibility of quantitative magnetic resonance (MR) methods to estimate hepatic proton density fat-fraction (PDFF) at different magnetic field strengths. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the Institutional Review Board. Following informed consent, 25 severely obese subjects (mean body mass index [BMI]: 45 ± 4, range: 38-53 kg/m(2) ) were scanned at 1.5T and 3T on the same day. Two confounder-corrected multiecho chemical shift-encoded gradient-echo-based imaging methods were acquired to estimate PDFF over the entire liver: 3D complex-based (MRI-C) and 2D magnitude-based (MRI-M) MRI. Single-voxel MR spectroscopy (MRS) was performed in the right liver lobe. Using linear regression, pairwise comparisons of estimated PDFF were made between methods (MRI-C, MRI-M, MRS) at each field strength and for each method across field strengths. RESULTS: 1.5T vs. 3T regression analyses for MRI-C, MRI-M, and MRS PDFF measurements yielded R(2) values of 0.99, 0.97, and 0.90, respectively. The best-fit line was near unity (slope(m) = 1, intercept(b) = 0), indicating excellent agreement for each case: MRI-C (m = 0.92 [0.87, 0.99], b = 1.4 [0.7, 1.8]); MRI-M (m = 1.0 [0.90, 1.08], b = -1.4 [-2.4, -0.5]); MRS (m = 0.98 [0.82, 1.15], b = 1.2 [-0.2, 3.0]). Comparing MRI-C and MRI-M yielded an R(2) = 0.98 (m = 1.1 [1.02, 1.16], b = -1.8 [-2.8, -1.1]) at 1.5T, and R(2) = 0.99 (m = 0.98 [0.93, 1.03], b = 1.2 [0.7, 1.7]) at 3T. CONCLUSION: This study demonstrates that PDFF estimation is reproducible across field strengths and across two confounder-corrected MR-based methods.

Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).

UNLABELLED: Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). CONCLUSIONS: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.