Resonance Imaging Proton Density Fat Research Articles

Inter-reader agreement of magnetic resonance imaging proton density fat fraction and its longitudinal change in a clinical trial of adults with nonalcoholic steatohepatitis.

To determine the inter-reader agreement of magnetic resonance imaging proton density fat fraction (PDFF) and its longitudinal change in a clinical trial of adults with nonalcoholic steatohepatitis (NASH). We performed a secondary analysis of a placebo-controlled randomized clinical trial of a bile acid sequestrant in 45 adults with NASH. A six-echo spoiled gradient-recalled-echo magnitude-based fat quantification technique was performed at 3T. Three independent readers measured MRI-PDFF by placing one primary and two additional regions of interest (ROIs) in each segment at both time points. Cross-sectional agreement between the three readers was evaluated using intra-class correlation coefficients (ICCs) and coefficients of variation (CV). Additionally, we used Bland-Altman analyses to examine pairwise agreement between the three readers at baseline, end of treatment (EOT), and for longitudinal change. Using all ROIs by all readers, mean PDFF at baseline, at EOT, and mean change in PDFF was 16.1%, 16.0%, and 0.07%, respectively. The 27-ROI PDFF measurements had 0.998 ICC and 1.8% CV at baseline, 0.998 ICC and 1.8% CV at EOT, and 0.997 ICC for longitudinal change. The 9-ROI PDFF measurements had corresponding values of 0.997 and 2.6%, 0.996 and 2.4%, and 0.994. Using 27 ROIs, the magnitude of the bias between readers for whole-liver PDFF measurement ranged from 0.03% to 0.06% points at baseline, 0.01% to 0.07% points at EOT, and 0.01% to 0.02% points for longitudinal change. Inter-reader agreement for measuring whole-liver PDFF and its longitudinal change is high. 9-ROI measurements have only slightly lower agreement than 27-ROI measurements.

Comparison of conventional sonographic signs and magnetic resonance imaging proton density fat fraction for assessment of hepatic steatosis

This study correlated conventional ultrasonography (US) signs with the magnetic resonance imaging (MRI) proton density fat fraction (PDFF) to evaluate the diagnostic performance of US signs (alone or combined) to predict presence and degree of hepatic steatosis (HS). Overall, 182 subjects met the study inclusion criteria between February 2014 and October 2016. Four US signs were evaluated independently by two radiologists. MRI PDFF was defined as the average of 24 non-overlapping regions of interest (ROIs) within eight liver segments obtained by drawing three ROIs within each segment. The latter acted as the reference standard to evaluate diagnostic accuracy of the US signs and their combinations. Diagnostic performance of US for HS was assessed using receiver operating characteristic (ROC) curve analyses. There was a strongly positive correlation between some combinations of US signs and PDFF (σ = 0.780, p < 0.001). The sensitivity, specificity, PPV, and NPV were 96.6%, 74.8%, 64.8%, and 97.9%, respectively, determined using abnormal hepatorenal echoes to detect grade 1 or higher HS (area under the ROC curve = 0.875). The sensitivity and NPV for detecting HS with US were good and US may be considered a suitable screening tool for exclusion of HS.

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.

Can negligible hepatic steatosis determined by magnetic resonance imaging–proton density fat fraction obviate the need for liver biopsy in potential liver donors?

The purpose of this study is to determine whether magnetic resonance (MR)-proton density fat fraction (PDFF) estimate of negligible hepatic fat percentage (<5%) can exclude significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy and to perform intraindividual comparisons between MR-PDFF techniques for hepatic steatosis quantification. In an ethics-approved retrospective study, 144 liver donor candidates with magnetic resonance spectroscopy (MRS) and 6-echo Dixon magnetic resonance imaging (MRI) between 2013 and 2015 were included. A subset of 32 candidates underwent liver biopsy. Hepatic fat percentage was determined using MR-PDFF and histopathology-determined fat fraction as the reference standard. A receiver operating characteristic analysis with positive predictive value, negative predictive value (NPV), sensitivity, and specificity was performed to discriminate between clinically significant steatosis (≥10%) or not (<10%) at MRS-PDFF and MRI-PDFF thresholds of 5% and 10%. Pearson correlation and Bland-Altman analyses between MRS-PDFF and MRI-PDFF were performed for intraindividual comparison of hepatic steatosis estimation. There was significant association between MRS-PDFF and MRI-PDFF with HP-FP. High NPV of 95% (95% confidence interval [CI], 78%-99%) and 100% (95% CI, 76%-100%) as well as an area under the curve of 0.90 (95% CI, 0.79-1.0) and 0.93 (95% CI, 0.84-1.0) were obtained with a cutoff threshold of 5% MRI-PDFF and MRS-PDFF, respectively, to exclude clinically significant steatosis (≥10%). Intraindividual comparison between MRS-PDFF and MRI-PDFF showed a Pearson correlation coefficient of 0.83. Bland-Altman analysis showed a mean difference of 1% with 95% limits of agreement between -1% and 3%. MR-PDFF estimate of negligible hepatic fat percentage (<5%) has sufficient NPV for excluding clinically significant hepatic steatosis (≥10%) in living liver donor candidates obviating the need for liver biopsy. It may be sufficient to acquire only the multiecho Dixon MRI-PDFF for hepatic steatosis estimation. Liver Transplantation 24 470-477 2018 AASLD.

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

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).

Estimating of hepatic fat amount using MRI proton density fat fraction in a real practice setting.

The recently developed magnetic resonance imaging (MRI) proton density fat fraction (PDFF) allows measurement of the fat in all segments of hepatic tissue. However, it is time consuming and inconvenient to measure each segment repeatedly. Moreover, volume of each segment also should be adjusted with arithmetic mean of the selected segments when total amount of liver fat is estimated. Therefore, we try to develop a clinically-relevant and applicable method of estimating hepatic fat in PDFF image.A total of 164 adults were enrolled. We addressed the measurement frequency and segment selection to determine the optimal method of measuring intrahepatic fat. Total hepatic fat was estimated by the weighted mean of each segment reflecting their respective segmental volumes. We designed 2 models. In Model 1, we determined the segment order by which the mean was closest to the whole weighted mean. In Model 2, we determined the segment order by which the arithmetic mean of the selected segments was closest to the whole weighted mean.Fat fraction (FF) was most important risk factor of hepatic heterogeneity in multivariable analysis (β = 0.534, P < .001). In severe fatty liver (FF > 22.1%), intrahepatic fat variability was 2.47% (1.16-6.26%). The arithmetic mean total intrahepatic FF was 12.66%. But the weighted mean that applied to each segmental volume was 12.90%. In Model 1, arithmetic mean of segments 4 and 5 was closest to the total estimated hepatic fat amount. However, when we added segment 8, the mean of segments 4, 5, and 8 was significantly different from the estimated total hepatic fat amount (P = .0021). In Model 2, arithmetic mean of segments 4 and 5 was closest to the total estimated hepatic fat amount. There was a significant reduction in variability between segment 4 and segments 4 and 5 (P < .0001).Averaging the mean hepatic FF of segments 4 and 5 was the most reasonable method for estimating total intrahepatic fat in practice.

Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis

We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0-1 vs 2-3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91-0.98), and grade 0-2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93-0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2-3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71-0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63-0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.

Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique

Liver biopsy analysis is the standard method used to diagnose nonalcoholic fatty liver disease (NAFLD). Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis, but is expensive. Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity, specificity, and quantitative accuracy, and results vary among technicians. A new quantitative ultrasound (QUS) technique can identify steatosis in animal models. We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis, comparing findings with those from magnetic resonance imaging proton density fat fraction (MRI-PDFF) analysis as a reference. We performed a prospective, cross-sectional analysis of a cohort of adults (N = 204) with NAFLD (MRI-PDFF, ≥5%) and without NAFLD (controls). Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California, San Diego, from February 2012 through March 2014. QUS parameters and backscatter coefficient (BSC) values were calculated. Patients were assigned randomly to training (n = 102; mean age, 51 ± 17 y; mean body mass index, 31 ± 7 kg/m(2)) and validation (n = 102; mean age, 49 ± 17 y; body mass index, 30 ± 6 kg/m(2)) groups; 69% of patients in each group had NAFLD. BSC (range, 0.00005-0.25 1/cm-sr) correlated with MRI-PDFF (Spearman ρ = 0.80; P < .0001). In the training group, the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 (95% confidence interval, 0.95-1.00; P < .0001). The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93% and 87% sensitivity, 97% and 91% specificity, 86% and 76% negative predictive values, and 99% and 95% positive predictive values, respectively. QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis, based on a cross-sectional analysis that used MRI-PDFF as the reference. With further validation, QUS could be an inexpensive, widely available method to screen the general or at-risk population for NAFLD.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Predicting Hepatic Steatosis in a Racially and Ethnically Diverse Cohort of Adolescent Girls

To develop a risk assessment model for early detection of hepatic steatosis using common anthropometric and metabolic markers. This was a cross-sectional study of 134 adolescent and young adult females, age 11-22 years (mean 13.3±2 years) from a middle school and clinics in Madison, Wisconsin. The ethnic distribution was 27% Hispanic and 73% non-Hispanic; the racial distribution was 64% Caucasian, 31% African-American, and 5% Asian, Fasting glucose, fasting insulin, alanine aminotransferase (ALT), body mass index (BMI), waist circumference (WC), and other metabolic markers were assessed. Hepatic fat was quantified using magnetic resonance imaging proton density fat fraction (MR-PDFF). Hepatic steatosis was defined as MR-PDFF>5.5%. Outcome measures were sensitivity, specificity, and positive predictive value (PPV) of BMI, WC, ALT, fasting insulin, and ethnicity as predictors of hepatic steatosis, individually and combined, in a risk assessment model. Classification and regression tree methodology was used to construct a decision tree for predicting hepatic steatosis. MR-PDFF revealed hepatic steatosis in 16% of subjects (27% overweight, 3% nonoverweight). Hispanic ethnicity conferred an OR of 4.26 (95% CI, 1.65-11.04; P=.003) for hepatic steatosis. BMI and ALT did not independently predict hepatic steatosis. A BMI>85% combined with ALT>65 U/L had 9% sensitivity, 100% specificity, and 100% PPV. Lowering the ALT value to 24 U/L increased the sensitivity to 68%, but reduced the PPV to 47%. A risk assessment model incorporating fasting insulin, total cholesterol, WC, and ethnicity increased sensitivity to 64%, specificity to 99% and PPV to 93%. A risk assessment model can increase specificity, sensitivity, and PPV for identifying the risk of hepatic steatosis and guide the efficient use of biopsy or imaging for early detection and intervention.