Interpretation, Reporting, and Clinical Applications of Liver MR Elastography.

Chronic liver disease is highly prevalent and often leads to fibrosis or cirrhosis and complications such as liver failure and hepatocellular carcinoma. The diagnosis and staging of liver fibrosis is crucial to determine management and mitigate complications. Liver biopsy for histologic assessment has limitations such as sampling bias and high interreader variability that reduce precision, which is particularly challenging in longitudinal monitoring. MR elastography (MRE) is considered the most accurate noninvasive technique for diagnosing and staging liver fibrosis. In MRE, low-frequency vibrations are applied to the abdomen, and the propagation of shear waves through the liver is analyzed to measure liver stiffness, a biomarker for the detection and staging of liver fibrosis. As MRE has become more widely used in clinical care and research, different contexts of use have emerged. This review focuses on the latest developments in the use of MRE for the assessment of liver fibrosis; provides guidance for image acquisition and interpretation; summarizes diagnostic performance, along with thresholds for diagnosis and staging of liver fibrosis; discusses current and emerging clinical applications; and describes the latest technical developments.

Precision and Test-Retest Repeatability of Stiffness Measurement with MR Elastography: A Multicenter Phantom Study.

Background MR elastography (MRE) has been shown to have excellent performance for noninvasive liver fibrosis staging. However, there is limited knowledge regarding the precision and test-retest repeatability of stiffness measurement with MRE in the multicenter setting. Purpose To determine the precision and test-retest repeatability of stiffness measurement with MRE across multiple centers using the same phantoms. Materials and Methods In this study, three cylindrical phantoms made of polyvinyl chloride gel mimicking different degrees of liver stiffness in humans (phantoms 1-3: soft, medium, and hard stiffness, respectively) were evaluated. Between January 2021 and January 2022, phantoms were circulated between five different centers and scanned with 10 MRE-equipped clinical 1.5-T and 3-T systems from three major vendors, using two-dimensional (2D) gradient-recalled echo (GRE) imaging and/or 2D spin-echo (SE) echo-planar imaging (EPI). Similar MRE acquisition parameters, hardware, and reconstruction algorithms were used at each center. Mean stiffness was measured by a single observer for each phantom and acquisition on a single section. Stiffness measurement precision and same-session test-retest repeatability were assessed using the coefficient of variation (CV) and the repeatability coefficient (RC), respectively. Results The mean precision represented by the CV was 5.8% (95% CI: 3.8, 7.7) for all phantoms and both sequences combined. For all phantoms, 2D GRE achieved a CV of 4.5% (95% CI: 3.3, 5.7) whereas 2D SE EPI achieved a CV of 7.8% (95% CI: 3.1, 12.6). The mean RC of stiffness measurement was 5.8% (95% CI: 3.7, 7.8) for all phantoms and both sequences combined, 4.9% (95% CI: 2.7, 7.0) for 2D GRE, and 7.0% (95% CI: 2.9, 11.2) for 2D SE EPI (all phantoms). Conclusion MRE had excellent in vitro precision and same-session test-retest repeatability in the multicenter setting when similar imaging protocols, hardware, and reconstruction algorithms were used. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Tang in this issue.

Wavelet MRE: Imaging propagating broadband acoustic waves with wavelet-based motion-encoding gradients.

PURPOSE: To demonstrate a novel MR elastography (MRE) technique, termed here wavelet MRE. With this technique, broadband motion sensitivity is achievable. Moreover, the true tissue displacement can be reconstructed with a simple inverse transform. METHODS: A wavelet MRE sequence was developed with motion-encoding gradients based on Haar wavelets. From the phase images' displacement was estimated using an inverse transform. Simulations were performed using a frequency sweep and a transient as ground-truth motions. A PVC phantom was scanned using wavelet MRE and standard MRE with both transient (one and 10 cycles of 90-Hz motion) and steady-state dual-frequency motion (30 and 60 Hz) for comparison. The technique was tested in a human brain, and motion trajectories were estimated for each voxel. RESULTS: In simulation, the displacement information estimated from wavelet MRE closely matched the true motion. In the phantom test, the MRE phase data generated from the displacement information derived from wavelet MRE agreed well with standard MRE data. Testing of wavelet MRE to assess transient motion waveforms in the brain was successful, and the tissue motion observed was consistent with a previous study. CONCLUSION: The uniform and broadband frequency response of wavelet MRE makes it a promising method for imaging transient, multifrequency motion, or motion with unknown frequency content. One potential application is measuring the response of brain tissue undergoing low-amplitude, transient vibrations as a model for the study of traumatic brain injury.

MR elastography-based slip interface imaging (SII) for functional assessment of myofascial interfaces: A feasibility study.

PURPOSE: Abnormal adherence at functional myofascial interfaces is hypothesized as an important phenomenon in myofascial pain syndrome. This study aimed to investigate the feasibility of MR elastography (MRE)-based slip interface imaging (SII) to visualize and assess myofascial mobility in healthy volunteers. METHODS: SII was used to assess local shear strain at functional myofascial interfaces in the flexor digitorum profundus (FDP) and thighs. In the FDP, MRE was performed at 90 Hz vibration to each index, middle, ring, and little finger. Two thigh MRE scans were performed at 40 Hz with knees flexed and extended. The normalized octahedral shear strain (NOSS) maps were calculated to visualize myofascial slip interfaces. The entropy of the probability distribution of the gradient NOSS was computed for the two knee positions at the intermuscular interface between vastus lateralis and vastus intermedius, around rectus femoris, and between vastus intermedius and vastus medialis. RESULTS: NOSS map depicted distinct functional slip interfaces in the FDP for each finger. Compared to knee flexion, clearer slip interfaces and larger gradient NOSS entropy at the vastus lateralis-vastus intermedius interface were observed during knee extension, where the quadriceps are not passively stretched. This suggests the optimal position for using SII to visualize myofascial slip interface in skeletal muscles is when muscles are not subjected to any additional force. CONCLUSION: The study demonstrated that MRE-based SII can visualize and assess myofascial interface mobility in extremities. The results provide a foundation for investigating the hypothesis that myofascial pain syndrome is characterized by changes in the mobility of myofascial interfaces.

Change in serial liver stiffness measurement by magnetic resonance elastography and outcomes in NAFLD.

BACKGROUND AND AIMS: The impact of disease progression in NAFLD on liver outcomes remains poorly understood. We aimed to investigate NAFLD progression using longitudinal liver stiffness measurements (LSM) by serial magnetic resonance elastography (MRE) and the association with liver outcomes. APPROACH AND RESULTS: All adult patients with NAFLD who underwent at least two serial MREs for clinical evaluation at Mayo Clinic, Rochester, between 2007 and 2019 were identified from the institutional database. Progression and regression were defined based on LSM change of 19% above or below 19% of initial LSM, respectively, based on Quantitative Imaging Biomarker Alliance consensus. The association between change in LSM and liver-related outcomes occurring after the last MRE was examined using time-to-event analysis. A total of 128 participants underwent serial MREs (53% female, median age 59 years). The median time between paired MREs was 3.4 (range 1-10.7) years. NAFLD progression (LSM = +0.61 kPa/year) was identified in 17 patients (13.3%). NAFLD regression (-0.40 kPa/year) occurred in 35 patients (27.3%). Stable LSM was noted in 76 participants (59.4%). In NAFLD without cirrhosis at baseline ( n = 75), cirrhosis development occurred in 14% of LSM progressors and 2.9% of non-progressors ( p = 0.059) over a median 2.7 years of follow-up from the last MRE. Among those with compensated cirrhosis at baseline MRE ( n = 29), decompensation or death occurred in 100% of LSM progressors and 19% of non-progressors ( p < 0.001) over a median 2.5 years of follow-up after the last MRE. CONCLUSIONS: Noninvasive monitoring of LSM by conventional MRE is a promising method of longitudinal NAFLD monitoring and risk estimation of liver-related outcomes in NAFLD.

Head-to-head comparison of magnetic resonance elastography-based liver stiffness, fat fraction, and T1 relaxation time in identifying at-risk NASH.

BACKGROUND AND AIMS: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. APPROACH AND RESULTS: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUC LS : 0.89 (0.82, 0.95), AUC PDFF : 0.70 (0.58, 0.81), AUC T1 : 0.72 (0.61, 0.82), z -score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUC PDFF : 0.82 (0.72, 0.91), AUC LS : 0.73 (0.63, 0.84), AUC T1 : 0.72 (0.61, 0.83), |z| <1.96 for all]. CONCLUSION: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.

Postprandial splenic stiffness changes on magnetic resonance elastography in a young healthy population.

Magnetic resonance elastography (MRE) is an accurate noninvasive diagnostic tool for assessing the stiffness of parenchymal organs, including the spleen. However, this measurement may be biased due to postprandial changes in splenic stiffness. The aim of the current study was to evaluate postprandial changes in spleen stiffness assessed by MRE in a large sample of healthy volunteers. This was a prospective institutional research ethics board-approved study. Healthy volunteers with no history of liver disease were recruited for an MRE test and blood draw from December 2018 to July 2019. Each participant underwent spleen MRE after at least 4 h of fasting and again 30 min after a 1000 kcal meal. Also, 14 randomly selected volunteers underwent additional MRE examinations at 1.5 and 2.5 h after food intake. The MRE data were acquired at 60 Hz using a 1.5-T MRI scanner. The spleen stiffness was assessed using a weighted mean of stiffness values from regions of interest manually drawn on three to five spleen slices. Spearman's rank correlation, Wilcoxon signed-rank, Friedman, and Mann-Whitney tests were used for statistical analysis. A total of 100 volunteers met the inclusion criteria and were eventually enrolled in this study (age 23 ± 2 years; 65 women). The mean spleen stiffness for the whole group increased by 7.9% (p < 0.001) from the mean ± SD value of 5.09 ± 0.63 (95% CI: 4.96-5.21) kPa in the fasting state to 5.47 ± 0.66 (95% CI 5.34-5.60) kPa 30 min after the meal and then gradually decreased. However, even 2 h 30 min after the meal, the spleen stiffness was higher than in the fasting state. This difference was statistically significant at p less than 0.001. It was concluded that meal intake results in a statistically significant elevation of spleen stiffness that persists for 2.5 h. This finding supports the recommendation for routine fasting for more than 2.5 h prior to assessing MRE-based spleen stiffness.

Acquisition Efficiency and Technical Repeatability of Dual-Frequency 3D Vector MR Elastography of the Liver.

BACKGROUND: MR elastography (MRE) at 60 Hz is widely used for staging liver fibrosis. MRE with lower frequencies may provide inflammation biomarkers. PURPOSE: To establish a practical simultaneous dual-frequency liver MRE protocol at both 30 Hz and 60 Hz during a single examination and validate the occurrence of second harmonic waves at 30 Hz. STUDY TYPE: Retrospective. SUBJECTS: One hundred six patients (48 females, age: 50.0 ± 13.4 years) were divided as follows: Cohort One (15 patients with chronic liver disease [CLD] and 25 healthy volunteers) with simultaneous dual-frequency MRE. Cohort Two (66 patients with CLD) with second harmonic MRE. FIELD STRENGTH/SEQUENCE: 3-T, single- or dual-frequency MRE at 30 Hz and 60 Hz. ASSESSMENT: Liver stiffness (LS) in both cohorts was evaluated with manually placed volumetric ROIs by two independent analyzers. Image quality was assessed by three independent readers on a 4-point scale (0-3: none/failed, fair, moderate, excellent) based on the depth of wave propagation with 1/3 incremental penetration. The success rate was derived from the percentage of nonzero quality scores. STATISTICAL TESTS: Measurement agreement, bias, and repeatability of LS were assessed using intraclass correlation coefficients (ICCs), Bland-Altman plots, and repeatability coefficient (RC). Mann-Whitney U tests were used to evaluate the differences in image quality between different methods. A P-value <0.05 was considered statistically significant. RESULTS: Success rate was 97.5% in Cohort One and 91% success rate for the second harmonic MRE in Cohort Two. The second harmonic and conventional MRE showed excellent agreement in LS (all ICCs >0.90). The quality scores for the second harmonic wave images were lower than those from the conventional MRE (Z = -4.523). DATA CONCLUSION: Compared with conventional and second harmonic methods, simultaneous dual-frequency had better image quality, high success rate and the advantage of intrinsic co-registration, while the second harmonic method can be an alternative if custom waveform is not available. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

Apparent diffusion coefficient and tissue stiffness are associated with different tumor microenvironment features of hepatocellular carcinoma.

OBJECTIVES: To investigate associations between tissue diffusion, stiffness, and different tumor microenvironment features in resected hepatocellular carcinoma (HCC). METHODS: Seventy-two patients were prospectively included for preoperative magnetic resonance (MR) diffusion-weighted imaging and MR elastography examination. The mean apparent diffusion coefficient (ADC) and stiffness value were measured on the central three slices of the tumor and peri-tumor area. Cell density, tumor-stroma ratio (TSR), lymphocyte-rich HCC (LR-HCC), and CD8 + T cell infiltration were estimated in resected tumors. The interobserver agreement of MRI measurements and subjective pathological evaluation was assessed. Variables influencing ADC and stiffness were screened with univariate analyses, and then identified with multivariable linear regression. The potential relationship between explored imaging biomarkers and histopathological features was assessed with linear regression after adjustment for other influencing factors. RESULTS: Seventy-two patients (male/female: 59/13, mean age: 56 ± 10.2 years) were included for analysis. Inter-reader agreement was good or excellent regarding MRI measurements and histopathological evaluation. No correlation between tumor ADC and tumor stiffness was found. Multivariable linear regression confirmed that cell density was the only factor associated with tumor ADC (Estimate = -0.03, p = 0.006), and tumor-stroma ratio was the only factor associated with tumor stiffness (Estimate = -0.18, p = 0.03). After adjustment for fibrosis stage (Estimate = 0.43, p < 0.001) and age (Estimate = 0.04, p < 0.001) in the multivariate linear regression, intra-tumoral CD8 + T cell infiltration remained a significant factor associated with peri-tumor stiffness (Estimate = 0.63, p = 0.02). CONCLUSIONS: Tumor ADC surpasses tumor stiffness as a biomarker of cellularity. Tumor stiffness is associated with tumor-stroma ratio and peri-tumor stiffness might be an imaging biomarker of intra-tumoral immune microenvironment. CLINICAL RELEVANCE STATEMENT: Tissue stiffness could potentially serve as an imaging biomarker of the intra-tumoral immune microenvironment of hepatocellular carcinoma and aid in patient selection for immunotherapy. KEY POINTS: Apparent diffusion coefficient reflects cellularity of hepatocellular carcinoma. Tumor stiffness reflects tumor-stroma ratio of hepatocellular carcinoma and is associated with tumor-infiltrating lymphocytes. Tumor and peri-tumor stiffness might serve as imaging biomarkers of intra-tumoral immune microenvironment.

MR Elastography: Practical Questions, From the AJR Special Series on Imaging of Fibrosis.

MR elastography (MRE), first described in 1995 and FDA-cleared in 2009, has emerged as an important tool for noninvasively detecting and staging liver fibrosis in patients with known or suspected chronic liver disease. This review focuses on a series of practical questions about the clinical use of MRE. Most head-to-head comparison studies with other laboratory and imaging-based tests have concluded that MRE has the highest diagnostic performance among tests for staging liver fibrosis. Limitations in the accuracy of biopsy as a standard of truth in staging liver fibrosis are increasingly being recognized. MRE-based measurements show promise as quantitative surrogates of disease severity and predictors of important clinical outcomes. The appropriate role of MRE in the management of patients with chronic liver disease is being actively incorporated into recognized clinical guidelines. Growing evidence shows that MRI measurement of elevated liver fat is the most important single biomarker for detecting nonalcoholic steatohepatitis (NASH) and that MRE-based liver stiffness is the most important single biomarker for detecting at-risk NASH (i.e., NASH with stage ≥ F2 fibrosis). Advances in MRE technology are offering higher precision and new biomarkers, which have potential to allow independent assessment of inflammation and other histologic processes in addition to fibrosis.

An individual patient data meta-analysis to determine cut-offs for and confounders of NAFLD-fibrosis staging with magnetic resonance elastography.

BACKGROUND & AIMS: We conducted an individual patient data meta-analysis to establish stiffness cut-off values for magnetic resonance elastography (MRE) in staging liver fibrosis and to assess potential confounding factors. METHODS: A systematic review of the literature identified studies reporting MRE data in patients with NAFLD. Data were obtained from the corresponding authors. The pooled diagnostic cut-off value for the various fibrosis stages was determined in a two-stage meta-analysis. Multilevel modelling methods were used to analyse potential confounding factors influencing the diagnostic accuracy of MRE in staging liver fibrosis. RESULTS: Eight independent cohorts comprising 798 patients were included in the meta-analysis. The area under the receiver operating characteristic curve (AUROC) for MRE in detecting significant fibrosis was 0.92 (sensitivity, 79%; specificity, 89%). For advanced fibrosis, the AUROC was 0.92 (sensitivity, 87%; specificity, 88%). For cirrhosis, the AUROC was 0.94 (sensitivity, 88%, specificity, 89%). Cut-offs were defined to explore concordance between MRE and histopathology: ≥F2, 3.14 kPa (pretest probability, 39.4%); ≥F3, 3.53 kPa (pretest probability, 24.1%); and F4, 4.45 kPa (pretest probability, 8.7%). In generalized linear mixed model analysis, histological steatohepatitis with higher inflammatory activity (odds ratio 2.448, 95% CI 1.180-5.079, p <0.05) and high gamma-glutamyl transferase (GGT) concentration (>120U/L) (odds ratio 3.388, 95% CI 1.577-7.278, p <0.01] were significantly associated with elevated liver stiffness, and thus affecting accuracy in staging early fibrosis (F0-F1). Steatosis, as measured by magnetic resonance imaging proton density fat fraction, and body mass index(BMI) were not confounders. CONCLUSIONS: MRE has excellent diagnostic performance for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Elevated inflammatory activity and GGT level may lead to overestimation of early liver fibrosis, but anthropometric measures such as BMI or the degree of steatosis do not. IMPACT AND IMPLICATIONS: This individual patient data meta-analysis of eight international cohorts, including 798 patients, demonstrated that MRE achieves excellent diagnostic accuracy for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Cut-off values (significant fibrosis, 3.14 kPa; advanced fibrosis, 3.53 kPa; and cirrhosis, 4.45 kPa) were established. Elevated inflammatory activity and gamma-glutamyltransferase level may affect the diagnostic accuracy of MRE, leading to overestimation of liver fibrosis in early stages. We observed no impact of diabetes, obesity, or any other metabolic disorder on the diagnostic accuracy of MRE.

Longitudinal Changes in MR Elastography-based Biomarkers in Obese Patients Treated with Bariatric Surgery.

Obesity-related chronic inflammation contributes to nonalcoholic fatty liver disease (NAFLD) progression in obese patients (body mass index [BMI] >30 kg/m2).1 The early detection of inflammation with noninvasive imaging technology may help identify individuals with a high risk of developing NAFLD.

Magnetic resonance elastography for prediction of long-term progression and outcome in chronic liver disease: A retrospective study.

BACKGROUND AND AIMS: Although magnetic resonance elastography (MRE) has been well-established for detecting and staging liver fibrosis, its prognostic role in determining outcomes of chronic liver disease (CLD) is mostly unknown. APPROACH AND RESULTS: This retrospective study consisted of 1269 subjects who underwent MRE between 2007 and 2009 and followed up until death or last known clinical encounter or end of study period. Charts were reviewed for cirrhosis development, decompensation, and transplant or death. The cohort was split into baseline noncirrhosis (group 1), compensated cirrhosis (group 2), and decompensated cirrhosis (group 3). Cox-regression analysis with age, sex, splenomegaly, CLD etiology, Child-Pugh Score (CPS), Fibrosis-4 Index (FIB-4) score, and Model for End-Stage Liver Disease (MELD)-adjusted HR for every 1-kPa increase in liver stiffness measurement (LSM) were used to assess the predictive performance of MRE on outcomes. Group 1 (n = 821) had baseline median LSM of 2.8 kPa, and cirrhosis developed in 72 (8.8%) subjects with an overall rate of about 1% cirrhosis/year. Baseline LSM predicted the future cirrhosis with multivariable adjusted HR of 2.38 (p < 0.0001) (concordance, 0.84). In group 2 (n = 277) with baseline median LSM of 5.7 kPa, 83 (30%) subjects developed decompensation. Baseline LSM predicted the future decompensation in cirrhosis with FIB-4 and MELD-adjusted HR of 1.22 (p < 0.0001) (concordance, 0.75). In group 3 (n = 171) with median baseline LSM of 6.8 kPa (5.2, 8.4), 113 (66%) subjects had either death or transplant. Baseline LSM predicted the future transplant or death with HR of 1.11 (p = 0.013) (concordance 0.53) but not in CPS and MELD-adjusted models (p = 0.08). CONCLUSION: MRE-based LSM is independently predictive of development of future cirrhosis and decompensation, and has predictive value in future transplant/death in patients with CLD.

Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD. APPROACH AND RESULTS: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort. CONCLUSIONS: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.

Impact of material homogeneity assumption on cortical stiffness estimates by MR elastography.

PURPOSE: Inversion algorithms used to convert acquired MR elastography wave data into material property estimates often assume that the underlying materials are locally homogeneous. Here we evaluate the impact of that assumption on stiffness estimates in gray-matter regions of interest in brain MR elastography. METHODS: We describe an updated neural network inversion framework using finite-difference model-derived data to train convolutional neural network inversion algorithms. Neural network inversions trained on homogeneous simulations (homogeneous learned inversions [HLIs]) or inhomogeneous simulations (inhomogeneous learned inversions [ILIs]) are generated with a variety of kernel sizes. These inversions are evaluated in a brain MR elastography simulation experiment and in vivo in a test-retest repeatability experiment including 10 healthy volunteers. RESULTS: In simulation and in vivo, HLI and ILI with small kernels produce similar results. As kernel size increases, the assumption of homogeneity has a larger effect, and HLI and ILI stiffness estimates show larger differences. At each inversion's optimal kernel size in simulation (7 × 7 × 7 for HLI, 11 × 11 × 11 for ILI), ILI is more sensitive to true changes in stiffness in gray-matter regions of interest in simulation. In vivo, there is no difference in the region-level repeatability of stiffness estimates between the inversions, although ILI appears to better maintain the stiffness map structure as kernel size increases, while decreasing the spatial variance in stiffness estimates. CONCLUSIONS: This study suggests that inhomogeneous inversions provide small but significant benefits even when large stiffness gradients are absent.

Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis.

BACKGROUND: Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis. PURPOSE: This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model. STUDY TYPE: Preclinical. ANIMAL MODEL: This study included a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) model and 6-week-old, male C57BL/6J mice (N = 78). FIELD STRENGTH/SEQUENCE: This study was performed using: 3T: gradient-echo two-point Dixon and spin-echo (SE) echo-planar imaging elastography (200 Hz) and 7T: SE two-point Dixon and SE elastography (200 Hz). ASSESSMENT: MRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG-FGF21v dosing (baseline), and after PEG-FGF21v treatment (WK4/8). Regions of interest for MRI-HFF and MRE-SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured. STATISTICAL TESTS: Two-tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE-SS at WK8, posterior means, and 95% credible intervals were presented. RESULTS: CDAHFD significantly increased baseline MRI-HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE-SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG-FGF21v significantly decreased MRI-HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE-SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RDI ) were -68% (-90%, -44%; 3T) and -64% (-78%, -52%; 7T). MRI-HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92). DATA CONCLUSIONS: MRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Liver stiffness measurement by magnetic resonance elastography is not affected by hepatic steatosis.

OBJECTIVES: To evaluate the relationship between biopsy-assessed hepatic steatosis, magnetic resonance imaging (MRI)-assessed proton density fat fraction (PDFF), and magnetic resonance elastography (MRE)-assessed liver stiffness measurement (LSM), in patients with or at risk for nonalcoholic fatty liver disease (NAFLD). METHODS: A retrospective study was performed, encompassing 256 patients who had a liver biopsy and MRI/MRE examination performed within 1 year. Clinical and laboratory data were retrieved from the electronic medical record. Hepatic steatosis and fibrosis were assessed by histopathological grading/staging. First, we analyzed the diagnostic performance of PDFF for distinguishing hepatic steatosis with the receiver operating characteristic analyses. Second, variables influencing LSM were screened with univariant analyses, then identified with multivariable linear regression. Finally, the potential relationship between PDFF and LSM was assessed with linear regression after adjustment for other influencing factors, in patients with diagnosed steatosis (PDFF ≥ 5%). RESULTS: The diagnostic accuracy of PDFF in distinguishing steatosis grades (S0-3) was above 0.82. No significant difference in LSM was found between patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. No statistically significant relationship was found between the LSM and PDFF (estimate = - 0.02, p = 0.065) after adjustment for fibrosis stage and age in patients with diagnosed steatosis (PDFF ≥ 5%). CONCLUSIONS: In patients with NAFLD, the severity of hepatic steatosis has no significant influence on the liver stiffness measurement with magnetic resonance elastography. KEY POINTS: • The MRI-based proton density fat fraction provides a quantitative assessment of hepatic steatosis with high accuracy. • No significant effect of hepatic steatosis on MRE-based liver stiffness measurement was found in patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. • After adjusting for fibrosis stage and age, there was no statistically significant relationship between liver stiffness and proton density fat fraction in patients with hepatic steatosis (p = 0.065).

MR Elastography-Based Shear Strain Mapping for Assessment of Microvascular Invasion in Hepatocellular Carcinoma.

OBJECTIVES: To evaluate the potential of MR elastography (MRE)-based shear strain mapping to noninvasively predict the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: Fifty-nine histopathology-proven HCC patients with conventional 60-Hz MRE examinations (+/-MVI, n = 34/25) were enrolled retrospectively between December 2016 and October 2019, with one subgroup comprising 29/59 patients (+/-MVI, n = 16/13) who also underwent 40- and 30-Hz MRE examinations. Octahedral shear strain (OSS) maps were calculated, and the percentage of peritumoral interface length with low shear strain (i.e., a low-shear-strain length, pLSL, %) was recorded. For OSS-pLSL, differences between the MVI (+) and MVI (-) groups and diagnostic performance at different MRE frequencies were analyzed using the Mann-Whitney test and area under the receiver operating characteristic curve (AUC), respectively. RESULTS: The peritumor OSS-pLSL was significantly higher in the MVI (+) group than in the MVI (-) group at the three frequencies (all p < 0.01). The AUC of peritumor OSS-pLSL for predicting MVI was good/excellent in all frequency groups (60-Hz: 0.73 (n = 59)/0.80 (n = 29); 40-Hz: 0.84; 30-Hz: 0.90). On further analysis of the 29 cases with all frequencies, the AUCs were not significantly different. As the frequency decreased from 60-Hz, the specificity of OSS increased at 40-Hz (53.8-61.5%) and further increased at 30-Hz (53.8-76.9%), and the sensitivity remained high at lower frequencies (100.0-93.8%) (all p > 0.05). CONCLUSIONS: MRE-based shear strain mapping is a promising technique for noninvasively predicting the presence of MVI in patients with HCC, and the most recommended frequency for OSS is 30-Hz. KEY POINTS: • MR elastography (MRE)-based shear strain mapping has the potential to predict the presence of microvascular invasion (MVI) in hepatocellular carcinoma preoperatively. • The low interface shear strain identified at tumor-liver boundaries was highly correlated with the presence of MVI.

MR elastography in nonalcoholic fatty liver disease: inter-center and inter-analysis-method measurement reproducibility and accuracy at 3T.

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.

Liver Stiffness by Magnetic Resonance Elastography Predicts Future Cirrhosis, Decompensation, and Death in NAFLD.

OBJECTIVES: Magnetic resonance elastography (MRE) is the most accurate method of liver stiffness measurement (LSM) in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the role of MRE in the prediction of hard outcomes in NAFLD. METHODS AND RESULTS: Adults with NAFLD who underwent MRE between 2007 and 2019 at Mayo Clinic, Rochester were identified. Cox regression analyses were used to explore the predictive role of baseline LSM for 1) development of cirrhosis in noncirrhotic NAFLD and 2) development of liver decompensation or death in those with compensated cirrhosis. A total of 829 NAFLD subjects (54% women, median age 58 years) were identified. Of 639 subjects without cirrhosis, 20 developed cirrhosis after a median follow-up of 4 years. Baseline LSM was predictive of future cirrhosis development: age-adjusted HR = 2.93 (95% CI, 1.86-4.62, p <.0001) per 1 kPa increment (C-statistic = 0.86). Baseline LSM by MRE can be used to guide timing of longitudinal noninvasive monitoring: 5, 3 and 1 years for LSM of 2, 3 and 4-5 kPa, respectively. Of 194 subjects with compensated cirrhosis, 81 developed decompensation or death after a median follow-up of 5 years. Baseline LSM was predictive of future decompensation or death: HR = 1.32 (95% CI, 1.13-1.56, p = .0007) per 1 kPa increment after adjusting for age, sex and MELD-Na. The 1-year probability of future decompensation or death in cirrhosis with baseline LSM of 5 kPa vs 8 kPa is 9% vs 20%, respectively. CONCLUSION: In NAFLD, LSM by MRE is a significant predictor of future development of cirrhosis. These data expand the role of MRE in clinical practice beyond the estimation of liver fibrosis and provide important evidence that improves individualized disease monitoring and patient counseling.