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.

Magnetic resonance elastography biomarkers for detection of histologic alterations in nonalcoholic fatty liver disease in the absence of fibrosis.

OBJECTIVES: To investigate associations between histology and hepatic mechanical properties measured using multiparametric magnetic resonance elastography (MRE) in adults with known or suspected nonalcoholic fatty liver disease (NAFLD) without histologic fibrosis. METHODS: This was a retrospective analysis of 88 adults who underwent 3T MR exams including hepatic MRE and MR imaging to estimate proton density fat fraction (MRI-PDFF) within 180 days of liver biopsy. Associations between MRE mechanical properties (mean shear stiffness (|G*|) by 2D and 3D MRE, and storage modulus (G'), loss modulus (G″), wave attenuation (α), and damping ratio (ζ) by 3D MRE) and histologic, demographic and anthropometric data were assessed. RESULTS: In univariate analyses, patients with lobular inflammation grade ≥ 2 had higher 2D |G*| and 3D G″ than those with grade ≤ 1 (p = 0.04). |G*| (both 2D and 3D), G', and G″ increased with age (rho = 0.25 to 0.31; p ≤ 0.03). In multivariable regression analyses, the association between inflammation grade ≥ 2 remained significant for 2D |G*| (p = 0.01) but not for 3D G″ (p = 0.06); age, sex, or BMI did not affect the MRE-inflammation relationship (p > 0.20). CONCLUSIONS: 2D |G*| and 3D G″ were weakly associated with moderate or severe lobular inflammation in patients with known or suspected NAFLD without fibrosis. With further validation and refinement, these properties might become useful biomarkers of inflammation. Age adjustment may help MRE interpretation, at least in patients with early-stage disease. KEY POINTS: • Moderate to severe lobular inflammation was associated with hepatic elevated shear stiffness and elevated loss modulus (p =0.04) in patients with known or suspected NAFLD without liver fibrosis; this suggests that with further technical refinement these MRE-assessed mechanical properties may permit detection of inflammation before the onset of fibrosis in NAFLD. • Increasing age is associated with higher hepatic shear stiffness, and storage and loss moduli (rho = 0.25 to 0.31; p ≤ 0.03); this suggests that age adjustment may help interpret MRE results, at least in patients with early-stage NAFLD.

Normal range for MR elastography measured liver stiffness in children without liver disease.

BACKGROUND: Magnetic resonance elastography (MRE) can determine the presence and stage of liver fibrosis. Data on normative MRE values, while reported in adults, are limited in children. PURPOSE: To determine the distribution of MRE-measured liver stiffness in children without liver disease. STUDY TYPE: Prospective, observational. POPULATION: Eighty-one healthy children (mean 12.6 ± 2.6 years, range 8-17 years). FIELD STRENGTH/SEQUENCE: 3.0T Signa HDxt, General Electric MR Scanner; 2D GRE MRE sequence. ASSESSMENT: History, examination, laboratory evaluation, and (MR) exams (proton density fat fraction, PDFF, and MRE) were performed. MR elastograms were analyzed manually at two reading centers and compared with each other for agreement and with published values in healthy adults and thresholds for fibrosis in adult and pediatric patients. STATISTICAL TESTS: Descriptive statistics, Bland-Altman analysis, t-test to compare hepatic stiffness values with reference standards. RESULTS: Stiffness values obtained at both reading centers were similar, without significant bias (P = 0.362) and with excellent correlation (intraclass correlation coefficient [ICC] = 0.782). Mean hepatic stiffness value for the study population was 2.45 ± 0.35 kPa (95th percentile 3.19 kPa), which was significantly higher than reported values for healthy adult subjects (2.10 ± 0.23 kPa, P < 0.001). In all, 74-85% of subjects had stiffness measurements suggestive of no fibrosis. DATA CONCLUSION: Mean liver stiffness measured with MRE in this cohort was significantly higher than that reported in healthy adults. Despite rigorous screening, some healthy children had stiffness measurements suggestive of liver fibrosis using current published thresholds. Although MRE has the potential to provide noninvasive assessment in patients with suspected hepatic disease, further refinement of this technology will help advance its use as a diagnostic tool for evidence of fibrosis in pediatric populations. LEVEL OF EVIDENCE: 1 Technical Efficacy: 5 J. Magn. Reson. Imaging 2020;51:919-927.

Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants.

BACKGROUND & AIMS: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques for detection of liver fibrosis. Single-center studies have compared the diagnostic performance of MRE vs TE in patients with nonalcoholic fatty liver disease (NAFLD). We conducted a pooled analysis of individual participant data from published studies to compare the diagnostic performance of MRE vs TE for staging of liver fibrosis in patients with NAFLD, using liver biopsy as reference. METHODS: We performed a systematic search of publication databases, from 2005 through 2017. We identified 3 studies of adults with NAFLD who were assessed by MRE, TE, and liver biopsy. In a pooled analysis, we calculated the cluster-adjusted area under the curve (AUROC) of MRE and TE for the detection of each stage of fibrosis. AUROC comparisons between MRE and TE were performed using the Delong test. RESULTS: Our pooled analysis included 230 participants with biopsy-proven NAFLD with mean age of 52.2±13.9 years and a body mass index of 31.9±7.5 kg/m2. The proportions of patients with fibrosis of stages 0, 1, 2, 3, and 4 were: 31.7%, 27.8%, 15.7%, 13.9%, and 10.9%, respectively. The AUROC of TE vs MRE for detection of fibrosis stages ≥1 was 0.82 (95% CI, 0.76-0.88) vs 0.87 (95% CI, 0.82-0.91) (P=.04); for stage≥ 2 was 0.87 (95% CI, 0.82-0.91) vs 0.92 (95% CI, 0.88-0.96) (P=.03); for stage ≥3 was 0.84 (95% CI, 0.78-0.90) vs 0.93 (95% CI, 0.89-0.96) (P=.001); for stage ≥ 4 was 0.84 (95% CI, 0.73-0.94) vs 0.94 (95% CI, 0.89-0.99) (P=.005). CONCLUSION: In a pooled analysis of data from individual participants with biopsy-proven NAFLD, we found MRE to have a statistically significantly higher diagnostic accuracy than TE in detection of each stage of fibrosis. MRE and TE each have roles in detection of fibrosis in patients with NAFLD, depending upon the level of accuracy desired.

Magnetic Resonance Imaging Proton Density Fat Fraction Associates With Progression of Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Markers are needed to predict progression of nonalcoholic fatty liver disease (NAFLD). The proton density fat fraction, measured by magnetic resonance imaging (MRI-PDFF), provides an accurate, validated marker of hepatic steatosis; however, it is not clear whether the PDFF identifies patients at risk for NAFLD progression. We performed a follow-up study of 95 well-characterized patients with biopsy-proven NAFLD and examined the association between liver fat content and fibrosis progression. MRI-PDFF measurements were made at study entry (baseline). Biopsies were collected from patients at baseline and after a mean time period of 1.75 years. Among patients with no fibrosis at baseline, a higher proportion of patients in the higher liver fat group (MRI-PDFF ≥15.7%) had fibrosis progression (38.1%) than in the lower liver fat group (11.8%) (P = .067). In multivariable-adjusted logistic regression models (adjusted for age, sex, ethnicity, and body mass index), patients in the higher liver fat group had a significantly higher risk of fibrosis progression (multivariable-adjusted odds ratio 6.7; 95% confidence interval 1.01-44.1; P = .049). Our findings associate higher liver fat content, measured by MRI-PDFF, with fibrosis progression.

Monitoring Fatty Liver Disease with MRI Following Bariatric Surgery: A Prospective, Dual-Center Study.

Purpose To longitudinally monitor liver fat before and after bariatric surgery by using quantitative chemical shift-encoded (CSE) MRI and to compare with changes in body mass index (BMI), weight, and waist circumference (WC). Materials and Methods For this prospective study, which was approved by the internal review board, a total of 126 participants with obesity who were undergoing evaluation for bariatric surgery with preoperative very low calorie diet (VLCD) were recruited from June 27, 2010, through May 5, 2015. Written informed consent was obtained from all participants. Participants underwent CSE MRI measuring liver proton density fat fraction (PDFF) before VLCD (2-3 weeks before surgery), after VLCD (1-3 days before surgery), and 1, 3, and 6-10 months following surgery. Linear regression was used to estimate rates of change of PDFF (ΔPDFF) and body anthropometrics. Initial PDFF (PDFF0), initial anthropometrics, and anthropometric rates of change were evaluated as predictors of ΔPDFF. Mixed-effects regression was used to estimate time to normalization of PDFF. Results Fifty participants (mean age, 51.0 years; age range, 27-70 years), including 43 women (mean age, 50.8 years; age range, 27-70 years) and seven men (mean age, 51.7 years; age range, 36-62 years), with mean PDFF0 ± standard deviation of 18.1% ± 8.6 and mean BMI0 of 44.9 kg/m2 ± 6.5 completed the study. By 6-10 months following surgery, mean PDFF decreased to 4.9% ± 3.4 and mean BMI decreased to 34.5 kg/m2 ± 5.4. Mean estimated time to PDFF normalization was 22.5 weeks ± 11.5. PDFF0 was the only strong predictor for both ΔPDFF and time to PDFF normalization. No body anthropometric correlated with either outcome. Conclusion Average liver proton density fat fraction (PDFF) decreased to normal (< 5%) by 6-10 months following surgery, with mean time to normalization of approximately 5 months. Initial PDFF was a strong predictor of both rate of change of PDFF and time to normalization. Body anthropometrics did not predict either outcome. Online supplemental material is available for this article. © RSNA, 2018.

Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity.

OBJECTIVES: To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity. STUDY DESIGN: We evaluated children aged 9-17 years with obesity for the presence of NAFLD. Diseases other than NAFLD were excluded by history and laboratories. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction. The diagnostic accuracy of ALT for detecting NAFLD was evaluated. RESULTS: The study included 408 children with obesity that had a mean age of 13.2 years and mean body mass index percentile of 98.0. The study population had a mean ALT of 32 U/L and median hepatic magnetic resonance imaging proton density fat fraction of 3.7%. The estimated prevalence of NAFLD was 26.0% (95% CI 24.2%-27.7%), 29.4% in male patients (CI 26.1%-32.7%) and 22.6% in female patients (CI 16.0%-29.1%). Optimal ALT cut-point was 42 U/L (47.8% sensitivity, 93.2% specificity) for male and 30 U/L (52.1% sensitivity, 88.8% specificity) for female patients. The classification and regression tree model with sex, ALT, and insulin had 80% diagnostic accuracy for NAFLD. CONCLUSIONS: NAFLD is common in children with obesity, but NAFLD and obesity are not concomitant. In children with obesity, NAFLD is present in nearly one-third of boys and one-fourth of girls.

Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD.

Previous studies have shown that gut-microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut-microbiome, have a shared gene-effect with hepatic steatosis and fibrosis. This is a cross-sectional analysis of a prospective discovery cohort including 156 well-characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic-resonance-imaging proton-density-fat-fraction (MRI-PDFF) and fibrosis using MR-elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene-effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy-proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene-effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3-(4-hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold-change of higher-MRE versus lower-MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3-(4-hydroxyphenyl)lactate with hepatic steatosis was RG :0.57,95%CI:0.27-0.80, P < 0.001 and with fibrosis was RG :0.54,95%CI:0.036-1, P = 0.036. Pathway reconstruction linked 3-(4-hydroxyphenyl)lactate to several human gut-microbiome species. In the validation cohort, 3-(4-hydroxyphenyl)lactate was significantly correlated with the abundance of several gut-microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut-microbiome and 3-(4-hydroxyphenyl)lactate that shares gene-effect with hepatic steatosis and fibrosis. (Hepatology 2018).

Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis.

The optimal threshold of controlled attenuation parameter (CAP) for the detection of hepatic steatosis using both M and XL probe is unknown in nonalcoholic fatty liver disease (NAFLD). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an accurate and precise method of detecting the presence of hepatic steatosis that is superior to CAP. Thus, the aim of this study was to evaluate the diagnostic accuracy and optimal threshold of CAP for the detection of hepatic steatosis as defined by MRI-PDFF ≥ 5%. This prospective cross-sectional study included 119 adults (59% women) with and without NAFLD who underwent MRI-PDFF and CAP using either M or XL probe when indicated within a 6-month period at the NAFLD Research Center, University of California, San Diego. The mean ( ± standard deviation) age and body mass index were 52.4 (±15.2) years and 29.9 (±5.5) kg/m2 , respectively. The prevalence of NAFLD (MRI-PDFF ≥ 5%) and MRI-PDFF ≥ 10% was 70.6% and 47.1%, respectively. The area under the receiver operating characteristic (AUROC) of CAP for the detection of MRI-PDFF ≥ 5% was 0.80 (95% confidence interval [CI], 0.70-0.90) at the cut-point of 288 dB/m and of MRI-PDFF ≥ 10% was 0.87 (95% CI, 0.80-0.94) at the cut-point of 306 dB/m. When stratified by the interquartile range (IQR) of CAP, we observed that an IQR below the median (30 dB/m) had a robust AUROC compared with an IQR above the median (0.92 [95% CI, 0.85-1.00] versus 0.70 [95% CI, 0.56-0.85]; P = 0.0117), and these differences were statistically and clinically significant. CONCLUSION: The cut-point of CAP for presence of hepatic steatosis (MRI-PDFF ≥ 5%) was 288 dB/m. The diagnostic accuracy of CAP for the detection of hepatic steatosis is more reliable when the IQR of CAP is <30 dB/m. These data have implications for the clinical use of CAP in the assessment of NAFLD. (Hepatology 2018;67:1348-1359).

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.

Hepatic R2* is more strongly associated with proton density fat fraction than histologic liver iron scores in patients with nonalcoholic fatty liver disease.

BACKGROUND: 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. PURPOSE: To identify the most influential covariates for liver R2* values in patients with nonalcoholic fatty liver disease (NAFLD). STUDY TYPE: Retrospective analysis of prospectively acquired data. POPULATION: Baseline data from 204 subjects enrolled in NAFLD/NASH (nonalcoholic steatohepatitis) treatment trials. FIELD STRENGTH: 1.5T and 3T; chemical-shift encoded multiecho gradient echo. ASSESSMENT: Correlation between liver proton density fat fraction and R2*; assessment for demographic, metabolic, laboratory, MRI-derived, and histological covariates of liver R2*. STATISTICAL TESTS: Pearson's and Spearman's correlations; univariate analysis; gradient boosting machines (GBM) multivariable machine-learning method. RESULTS: 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. DATA CONCLUSION: 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. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1456-1466.

Longitudinal evolution of CT and MRI LI-RADS v2014 category 1, 2, 3, and 4 observations.

OBJECTIVES: This study assesses the risk of progression of Liver Imaging Reporting and Data System (LI-RADS) categories, and the effects of inter-exam changes in modality or radiologist on LI-RADS categorization. METHODS: Clinical LI-RADS v2014 CT and MRI exams at our institution between January 2014 and September 2017 were retrospectively identified. Untreated LR-1, LR-2, LR-3, and LR-4 observations with at least one follow-up exam were included. Three hundred and seventy-two observations in 214 patients (149 male, 65 female, mean age 61 ± 10 years) were included during the study period (715 exams total). Cumulative incidence curves for progression to malignant LI-RADS categories (LR-5 or LR-M) and to LR-4 or higher were generated for each index category and compared using log-rank tests with a resampling extension. Relationships between inter-exam changes in LI-RADS category and modality or radiologist, adjusted for inter-exam time intervals, were modeled using mixed effect logistic regressions. RESULTS: Median inter-exam follow-up interval and total follow-up duration were 123 and 227 days, respectively. Index LR-1, LR-2, LR-3, and LR-4 differed significantly in their cumulative incidences of progression to malignant categories (p < 0.0001), which were 0%, 2%, 7%, and 32% at 6 months, respectively. Index LR-1, LR-2, and LR-3 differed significantly in cumulative incidences of progression to LR-4 or higher (p = 0.003). MRI-MRI exam pairs had more stable LI-RADS categorization compared to CT-CT (OR = 0.460, p = 0.0018). CONCLUSIONS: LI-RADS observations demonstrate increasing risk of progression to malignancy with increasing category ranging from 0% for LR-1 to 32% for LR-4 at 6 months. Inter-exam modality changes are associated with LI-RADS category changes. KEY POINTS: • While the majority of LR-2 observations remain stable over long-term follow-up, LR-3 and especially LR-4 observations have a higher risk for category progression. • Category transitions between sequential exams using different modalities (CT vs. MRI) may reflect modality differences rather than biological change. MRI, especially with the same type of contrast agent, may provide the most reproducible categorization, although this needs additional validation. • In a clinical practice setting, in which radiologists refer to prior imaging and reports, there was no significant association between changes in radiologist and changes in LI-RADS categorization.

Hepatic steatosis and reduction in steatosis following bariatric weight loss surgery differs between segments and lobes.

OBJECTIVES: The purpose of this study was to (1) evaluate proton density fat fraction (PDFF) distribution across liver segments at baseline and (2) compare longitudinal segmental PDFF changes across time points in adult patients undergoing a very low-calorie diet (VLCD) and subsequent bariatric weight loss surgery (WLS). METHODS: We performed a secondary analysis of data from 118 morbidly obese adult patients enrolled in a VLCD-WLS program. PDFF was estimated using magnitude-based confounder-corrected chemical-shift-encoded (CSE) MRI in each hepatic segment and lobe at baseline (visit 1), after completion of VLCD (visit 2), and at 1, 3, and 6 months (visits 3-5) following WLS. Linear regressions were used to estimate the rate of PDFF change across visits. Lobar and segmental rates of change were compared pairwise. RESULTS: Baseline PDFF was significantly higher in the right lobe compared to the left lobe (p < 0.0001). Lobar and segmental PDFF declined by 3.9-4.5% per month between visits 1 and 2 (preoperative period) and by 4.3-4.8% per month between visits 1 and 3 (perioperative period), but no significant pairwise differences were found in slope between segments and lobes. For visits 3-5 (postoperative period), lobar and segmental PDFF reduction was much less overall (0.4-0.8% PDFF per month) and several pairwise differences were significant; in each case, a right-lobe segment had greater decline than a left-lobe segment. CONCLUSIONS: Baseline and longitudinal changes in fractional fat content in the 5-month postoperative period following WLS vary across segments, with right-lobe segments having higher PDFF at baseline and more rapid reduction in liver fat content. KEY POINTS: • Baseline and longitudinal changes in liver fat following bariatric weight loss surgery vary across liver segments. • Methods that do not provide whole liver fat assessment, such as liver biopsy, may be unreliable in monitoring longitudinal changes in liver fat following weight loss interventions.

Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease.

BACKGROUND & AIMS: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort. METHODS: We performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3). RESULTS: In the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex. CONCLUSIONS: We identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI.

Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Magnetic resonance imaging (MRI) techniques and ultrasound-based transient elastography (TE) can be used in noninvasive diagnosis of fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective study to compare the performance of magnetic resonance elastography (MRE) vs TE for diagnosis of fibrosis, and MRI-based proton density fat fraction (MRI-PDFF) analysis vs TE-based controlled attenuation parameter (CAP) for diagnosis of steatosis in patients undergoing biopsy to assess NAFLD. METHODS: We performed a cross-sectional study of 104 consecutive adults (56.7% female) who underwent MRE, TE, and liver biopsy analysis (using the histologic scoring system for NAFLD from the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System) from October 2011 through May 2016 at a tertiary medical center. All patients received a standard clinical evaluation, including collection of history, anthropometric examination, and biochemical tests. The primary outcomes were fibrosis and steatosis. Secondary outcomes included dichotomized stages of fibrosis and nonalcoholic steatohepatitis vs no nonalcoholic steatohepatitis. Receiver operating characteristic curve analyses were used to compare performances of MRE vs TE in diagnosis of fibrosis (stages 1-4 vs 0) and MRI-PDFF vs CAP for diagnosis of steatosis (grades 1-3 vs 0) with respect to findings from biopsy analysis. RESULTS: MRE detected any fibrosis (stage 1 or more) with an area under the receiver operating characteristic curve (AUROC) of 0.82 (95% confidence interval [CI], 0.74-0.91), which was significantly higher than that of TE (AUROC, 0.67; 95% CI, 0.56-0.78). MRI-PDFF detected any steatosis with an AUROC of 0.99 (95% CI, 0.98-1.00), which was significantly higher than that of CAP (AUROC, 0.85; 95% CI, 0.75-0.96). MRE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.89 (95% CI, 0.83-0.96), 0.87 (95% CI, 0.78-0.96), and 0.87 (95% CI, 0.71-1.00); TE detected fibrosis of stages 2, 3, or 4 with AUROC values of 0.86 (95% CI, 0.77-0.95), 0.80 (95% CI, 0.67-0.93), and 0.69 (95% CI, 0.45-0.94). MRI-PDFF identified steatosis of grades 2 or 3 with AUROC values of 0.90 (95% CI, 0.82-0.97) and 0.92 (95% CI, 0.84-0.99); CAP identified steatosis of grades 2 or 3 with AUROC values of 0.70 (95% CI, 0.58-0.82) and 0.73 (95% CI, 0.58-0.89). CONCLUSIONS: In a prospective, cross-sectional study of more than 100 patients, we found MRE to be more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. MRI-PDFF is more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.

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).

MRI proton density fat fraction is robust across the biologically plausible range of triglyceride spectra in adults with nonalcoholic steatohepatitis.

BACKGROUND: Proton density fat fraction (PDFF) estimation requires spectral modeling of the hepatic triglyceride (TG) signal. Deviations in the TG spectrum may occur, leading to bias in PDFF quantification. PURPOSE: To investigate the effects of varying six-peak TG spectral models on PDFF estimation bias. STUDY TYPE: Retrospective secondary analysis of prospectively acquired clinical research data. POPULATION: Forty-four adults with biopsy-confirmed nonalcoholic steatohepatitis. FIELD STRENGTH/SEQUENCE: Confounder-corrected chemical-shift-encoded 3T MRI (using a 2D multiecho gradient-recalled echo technique with magnitude reconstruction) and MR spectroscopy. ASSESSMENT: In each patient, 61 pairs of colocalized MRI-PDFF and MRS-PDFF values were estimated: one pair used the standard six-peak spectral model, the other 60 were six-peak variants calculated by adjusting spectral model parameters over their biologically plausible ranges. MRI-PDFF values calculated using each variant model and the standard model were compared, and the agreement between MRI-PDFF and MRS-PDFF was assessed. STATISTICAL TESTS: MRS-PDFF and MRI-PDFF were summarized descriptively. Bland-Altman (BA) analyses were performed between PDFF values calculated using each variant model and the standard model. Linear regressions were performed between BA biases and mean PDFF values for each variant model, and between MRI-PDFF and MRS-PDFF. RESULTS: Using the standard model, mean MRS-PDFF of the study population was 17.9 ± 8.0% (range: 4.1-34.3%). The difference between the highest and lowest mean variant MRI-PDFF values was 1.5%. Relative to the standard model, the model with the greatest absolute BA bias overestimated PDFF by 1.2%. Bias increased with increasing PDFF (P < 0.0001 for 59 of the 60 variant models). MRI-PDFF and MRS-PDFF agreed closely for all variant models (R2 = 0.980, P < 0.0001). DATA CONCLUSION: Over a wide range of hepatic fat content, PDFF estimation is robust across the biologically plausible range of TG spectra. Although absolute estimation bias increased with higher PDFF, its magnitude was small and unlikely to be clinically meaningful. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:995-1002.

Optimization of region-of-interest sampling strategies for hepatic MRI proton density fat fraction quantification.

BACKGROUND: Clinical trials utilizing proton density fat fraction (PDFF) as an imaging biomarker for hepatic steatosis have used a laborious region-of-interest (ROI) sampling strategy of placing an ROI in each hepatic segment. PURPOSE: To identify a strategy with the fewest ROIs that consistently achieves close agreement with the nine-ROI strategy. STUDY TYPE: Retrospective secondary analysis of prospectively acquired clinical research data. POPULATION: A total of 391 adults (173 men, 218 women) with known or suspected NAFLD. FIELD STRENGTH/SEQUENCE: Confounder-corrected chemical-shift-encoded 3T MRI using a 2D multiecho gradient-recalled echo technique. ASSESSMENT: An ROI was placed in each hepatic segment. Mean nine-ROI PDFF and segmental PDFF standard deviation were computed. Segmental and lobar PDFF were compared. PDFF was estimated using every combinatorial subset of ROIs and compared to the nine-ROI average. STATISTICAL TESTING: Mean nine-ROI PDFF and segmental PDFF standard deviation were summarized descriptively. Segmental PDFF was compared using a one-way analysis of variance, and lobar PDFF was compared using a paired t-test and a Bland-Altman analysis. The PDFF estimated by every subset of ROIs was informally compared to the nine-ROI average using median intraclass correlation coefficients (ICCs) and Bland-Altman analyses. RESULTS: The study population's mean whole-liver PDFF was 10.1 ± 8.9% (range: 1.1-44.1%). Although there was no significant difference in average segmental (P = 0.452) or lobar (P = 0.154) PDFF, left and right lobe PDFF differed by at least 1.5 percentage points in 25.1% (98/391) of patients. Any strategy with ≥4 ROIs had ICC >0.995. 115 of 126 four-ROI strategies (91%) had limits of agreement (LOA) <1.5%, including four-ROI strategies with two ROIs from each lobe, which all had LOA <1.5%. 14/36 (39%) of two-ROI strategies and 74/84 (88%) of three-ROI strategies had ICC >0.995, and 2/36 (6%) of two-ROI strategies and 46/84 (55%) of three-ROI strategies had LOA <1.5%. DATA CONCLUSION: Four-ROI sampling strategies with two ROIs in the left and right lobes achieve close agreement with nine-ROI PDFF. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:988-994.

Cross-sectional correlation between hepatic R2* and proton density fat fraction (PDFF) in children with hepatic steatosis.

PURPOSE: To determine the relationship between hepatic proton density fat fraction (PDFF) and R2* in vivo. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board (IRB)-approved, cross-sectional study, we conducted a secondary analysis of 3T magnetic resonance imaging (MRI) exams performed as part of prospective research studies in children in whom conditions associated with iron overload were excluded clinically. Each exam included low-flip-angle, multiecho magnitude (-M) and complex (-C) based chemical-shift-encoded MRI techniques with spectral modeling of fat to generate hepatic PDFF and R2* parametric maps. For each technique and each patient, regions of interest were placed on the maps in each of the nine Couinaud segments, and composite whole-liver PDFF and R2* values were calculated. Pearson's correlation coefficients between PDFF and R2* were computed for each MRI technique. Correlations were compared using Steiger's test. RESULTS: In all, 184 children (123 boys, 61 girls) were included in this analysis. PDFF estimated by MRI-M and MRI-C ranged from 1.1-35.4% (9.44 ± 8.76) and 2.1-38.1% (10.1 ± 8.7), respectively. R2* estimated by MRI-M and MRI-C ranged from 32.6-78.7 s-1 (48.4 ± 9.8) and 27.2-71.5 s-1 (42.2 ± 8.6), respectively. There were strong and significant correlations between hepatic PDFF and R2* values estimated by MRI-M (r = 0.874; P < 0.0001) and MRI-C (r = 0.853; P < 0.0001). The correlation coefficients (0.874 vs. 0.853) were not significantly different (P = 0.15). CONCLUSION: Hepatic PDFF and R2* are strongly correlated with each other in vivo. This relationship was observed using two different MRI techniques. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:418-424.

LI-RADS Version 2018 Ancillary Features at MRI.

The Liver Imaging Reporting and Data System (LI-RADS) standardizes performance of liver imaging in patients at risk for hepatocellular carcinoma (HCC) as well as interpretation and reporting of the results. Developed by experts in liver imaging and supported by the American College of Radiology, LI-RADS assigns to observations categories that reflect the relative probability of benignity, HCC, or other malignancy. While category assignment is based mainly on major imaging features, ancillary features may be applied to improve detection and characterization, increase confidence, or adjust LI-RADS categories. Ancillary features are classified as favoring malignancy in general, HCC in particular, or benignity. Those favoring malignancy in general or HCC in particular may be used to upgrade by a maximum of one category up to LR-4; those favoring benignity may be used to downgrade by a maximum of one category. If there are conflicting ancillary features (ie, one or more favoring malignancy and one or more favoring benignity), the category should not be adjusted. Ancillary features may be seen at diagnostic CT, MRI performed with extracellular agents, or MRI performed with hepatobiliary agents, with the exception of one ancillary feature assessed at US. This article focuses on LI-RADS version 2018 ancillary features seen at MRI. Specific topics include rules for ancillary feature application; definitions, rationale, and illustrations with clinical MRI examples; summary of evidence and diagnostic performance; pitfalls; and future directions. ©RSNA, 2018.