Quantification of hepatic steatosis with 3-T MR imaging: Validation in ob/ob mice

Purpose: To validate quantitative imaging techniques used to detect and measure steatosis with magnetic resonance (MR) imaging in an ob/ob mouse model of hepatic steatosis. Materials and Methods: The internal research animal and resource center approved this study. Twenty-eight male ob/ob mice in progressively increasing age groups underwent imaging and were subsequently sacrificed. Six ob /+ mice served as control animals. Fat fraction imaging was performed with a chemical shift-based water-fat separation method. The following three methods of conventional fat quantification were compared with imaging: lipid extraction and qualitative and quantitative histologic analysis. Fat fraction images were reconstructed with single- and multiple-peak spectral models of fat and with and without correction for T2* effects. Fat fraction measurements obtained with the different reconstruction methods were compared with the three methods of fat quantification, and linear regression analysis and two-sided and two-sample t tests were performed. Results:Lipid extraction and qualitative and quantitative histologic analysis were highly correlated with the results of fat fraction imaging (r2 = 0.92, 0.87, 0.82, respectively). No significant differences were found between imaging measurements and lipid extraction (P = .06) or quantitative histologic (P = .07) measurements when multiple peaks of fat and T2* correction were included in image reconstruction. Reconstructions in which T2* correction, accurate spectral modeling, or both were excluded yielded lower agreement when compared with the results yielded by other techniques. Imaging measurements correlated particularly well with histologic grades in mice with low fat fractions (intercept, -1.0% ± 1.2 [standard deviation ]). Conclusion: MR imaging can be used to accurately quantify fat in vivo in an animal model of hepatic steatosis and may serve as a quantitative biomarker of hepatic steatosis. © RSNA, 2010

Combination of complex-based and magnitude-based multiecho water-fat separation for accurate quantification of fat-fraction

Multipoint water-fat separation techniques rely on different water-fat phase shifts generated at multiple echo times to decompose water and fat. Therefore, these methods require complex source images and allow unambiguous separation of water and fat signals. However, complex-based water-fat separation methods are sensitive to phase errors in the source images, which may lead to clinically important errors. An alternative approach to quantify fat is through magnitude-based methods that acquire multiecho magnitude images. Magnitude-based methods are insensitive to phase errors, but cannot estimate fat-fraction greater than 50%. In this work, we introduce a water-fat separation approach that combines the strengths of both complex and magnitude reconstruction algorithms. A magnitude-based reconstruction is applied after complex-based water-fat separation to removes the effect of phase errors. The results from the two reconstructions are then combined. We demonstrate that using this hybrid method, 0-100% fat-fraction can be estimated with improved accuracy at low fat-fractions. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc

T1 independent, T2* corrected chemical shift based fat-water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis

Purpose: To determine the precision and accuracy of hepatic fat-fraction measured with a chemical shift-based MRI fat-water separation method, using single-voxel MR spectroscopy (MRS) as a reference standard. Materials and Methods: In 42 patients, two repeated measurements were made using a T 1-independent, T2 *-corrected chemical shift-based fat-water separation method with multi-peak spectral modeling of fat, and T 2-corrected single voxel MR spectroscopy. Precision was assessed through calculation of Bland-Altman plots and concordance correlation intervals. Accuracy was assessed through linear regression between MRI and MRS. Sensitivity and specificity of MRI fat-fractions for diagnosis of steatosis using MRS as a reference standard were also calculated. Results: Statistical analysis demonstrated excellent precision of MRI and MRS fat-fractions, indicated by 95% confidence intervals (units of absolute percent) of [-2.66%,2.64%] for single MRI ROI measurements, [-0.81%,0.80%] for averaged MRI ROI, and [-2.70%,2.87%] for single-voxel MRS. Linear regression between MRI and MRS indicated that the MRI method is highly accurate. Sensitivity and specificity for detection of steatosis using averaged MRI ROI were 100% and 94%, respectively. The relationship between hepatic fat-fraction and body mass index was examined. Conclusion: Fat-fraction measured with T1-independent T 2*-corrected MRI and multi-peak spectral modeling of fat is a highly precise and accurate method of quantifying hepatic steatosis. © 2011 Wiley-Liss, Inc

Noninvasive preclinical and clinical imaging of liver transporter function relevant to drug-induced liver injury

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and drug-induced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug–drug interactions mediated via hepatobiliary transporter perturbation

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R 1 , but evidence for between-site reproducibility of R 1 in small-animal MRI is lacking. Objective: To assess R 1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R 1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1–13 days. R 1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. Results: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R 1 -based MR biomarkers were found to be quite sensitive even to such small errors in R 1 , notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni 2+ in 2% agarose varied between 0.66 s −1 mM −1 at 3 T and 0.94 s −1 mM −1 at 11.7T. Interpretation: While several factors affect the reproducibility of R 1 -based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R 1 -reproducibility