In this secondary analysis of a randomized, double-blinded, placebo-controlled clinical trial, we performed three-way comparisons of MRI-PDFF, MRS-PDFF (a quantitative measurement of the liver fat content), and the liver histology–determined steatosis grade (an ordinal scale that allows the assessment of liver fat) at two time points 24 weeks apart. MRS is the only reference standard for measuring liver fat quantity noninvasively, and MRI-PDFF provides a reliable and robust estimate of the liver fat content as shown in previous cross-sectional studies. In this longitudinal study, we have shown that liver MRI-PDFF correlates strongly with the MRS-measured liver fat content both at the baseline and at the end of the trial at week 24 in 50 patients with biopsy-proven NAFLD. In addition, changes in the liver MRI-PDFF and MRS-measured liver fat content reflected changes in clinical/biochemical parameters such as weight and liver enzymes longitudinally at two time points. Moreover, the liver MRI-PDFF and MRS-determined liver fat content correlated with the histology-determined steatosis grade at two time points (weeks 0 and 24). Our data suggest that liver MRI-PDFF is a reliable method for accurately quantifying liver fat and a sensitive method for monitoring changes in the liver fat content in patients with NAFLD in the setting of a clinical trial. The small amounts of changes in the liver fat content that were appreciated by MRI-PDFF but not by liver histology were associated with corresponding changes in body weight and serum ALT, AST, and GGT levels, and this suggests clinical significance for dynamic changes in the liver fat content.
Liver biopsy remains the gold standard for the diagnosis of NAFLD and is used for the assessment of changes in the histology-determined steatosis grade after interventions. Because of the subjective assessment of the steatosis grade on histology as well as its sampling variability, it is not able to reliably capture small increases or decreases in liver fat. Noninvasive biomarkers such as imaging studies have been increasingly used for assessments of changes in liver fat in patients with NAFLD. Ultrasound is the most commonly used method because of its availability, low cost, and minimal risk to the patients. It measures the fat content of the liver indirectly by assessing the liver texture and echogenicity. However, ultrasound is both machine- and operator-dependent and lacks the ability to accurately quantify the liver fat content. In addition, it is hard to perform on obese patients and lacks sensitivity. Computed tomography is more precise than ultrasound, but it has its own disadvantages, including interference due to iron deposition, fibrosis, or edema and, most importantly, the risks associated with exposure to ionizing radiation as well as a sensitivity lower than that of MRI.[37, 38]
MRS remains the only noninvasive reference standard for detecting and quantifying the biochemical fat content in the liver and has been used in several research studies, but it has limited clinical applicability or availability.[17, 39] MRS measures PDFF biochemically, and MRI estimates PDFF. MRS evaluates the liver fat content in only a single 2 × 2 × 2 cm3 cube (voxel) within the liver. However, this technique relies on factors that lead to estimates of the fat content that are platform- and imaging protocol–dependent. An MRI-based assessment of liver fat can provide an image as well as the liver fat content for each segment of the liver. However, conventional MRI-based methods of liver fat assessment are limited because of T1 bias, T(2)* decay, eddy currents, and multifrequency signal-interference effects of protons in fat and, therefore, may not provide an accurate estimation of the liver fat content. MRI-PDFF, a novel biomarker, eliminates the biases seen with conventional MRI techniques and has shown a robust correlation with MRS.[19-21, 40]
MRI-PDFF has improved biases seen with conventional MRI techniques. MRI-PDFF is independent of the field strength, scanner platform, and parameters and correlates highly with hepatic triglyceride. In addition, in contrast to MRS, MRI-PDFF can be used with any MRI platform. We have shown that MRI-PDFF correlates highly (Pearson r correlation coefficient = 0.98) with MRS. In addition, it has excellent repeatability when the test is repeated on the same day (Pearson r correlation coefficient = 0.99). In this study, we have extended our previous finding that MRI-PDFF correlates with MRS-PDFF and histology-determined steatosis grades in a cross-sectional analysis to a longitudinal analysis in which subjects were assessed for changes in their liver fat over a 24-week time period in the setting of a randomized controlled trial.
Strengths and Limitations
We would like to highlight the following strengths of the study. First, the randomized, placebo-controlled study design allowed a systematic assessment of a defined group of patients with biopsy-proven NAFLD and a predefined MRI fat mapping protocol as well as cross-validation of MRI-PDFF by MRS-PDFF for each subject both before and after 24 weeks of treatment. Second, the NASH-CRN histological scoring system was used for characterization of liver histology. Third, the radiologist and pathologists were blinded to histological and MR data, respectively. Fourth, all patients underwent extensive liver fat mapping, and liver fat changes were compared in colocalized ROIs before and after 24 weeks of treatment. To our knowledge, this study illustrates one of the most extensive liver fat phenotypings performed in a clinical trial assessing the efficacy of a drug versus a placebo in the treatment of NASH. This provides a strong rationale for using MRI-PDFF in future clinical trials in NASH. However, we acknowledge the following limitation of this study. This study was not designed to assess the role of MRI-PDFF in screening for NAFLD or detecting NAFLD because we did not have a control group and it would have been unethical to subject normal individuals with normal liver fat content according to MRI-PDFF to a liver biopsy assessment. However, it is highly likely that MRI-PDFF could be used for screening for hepatic steatosis in future studies.
Further Advantages of MRI-PDFF Over MRS-PDFF
MRI-PDFF can be applied to any commercially available platform, whereas MRS-PDFF remains a research tool requiring special coils, is time-consuming, is not routinely available, and will likely not be used in clinical practice because of the complexities of its logistics and the lack of required expertise at most clinical imaging centers. MRS-PDFF requires trained research technologists and is usually analyzed by a physicist using specialized software. In comparison, MRI-PDFF can be determined with routine modern scanners by any MR technologist. MRI-PDFF maps can be generated online within seconds and can be analyzed after minimal training in recognizing segments and avoiding artifacts. Because of the complexity of MRS and the ease of MRI, NASH-CRN, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, has decided to include MRI-PDFF but not MRS-PDFF in its active clinical trials.
Emerging Need to Assess Changes in Liver Fat in Lipid-Lowering Trials in Cardiovascular Disease
Newer lipid-lowering therapies are emerging, and some of the novel lipid-lowering agents have been shown to increase the liver fat content. Lomitapide, a microsomal triglyceride transfer protein inhibitor, has been shown to reduce LDL cholesterol in patients with familial hypercholesterolemia, and in doing so, it has been shown to increase the liver fat content. Another lipid-lowering agent, mipomersen, an apolipoprotein B synthesis inhibitor, also showed efficacy in lowering LDL cholesterol concentrations in patients with homozygous familial hypercholesterolemia, but a concomitant increase in the liver fat content was noted. Therefore, there is an emerging, unmet need for the accurate, noninvasive quantification of changes in the liver fat content, and MRI-PDFF provides a clinically useful tool in such settings.
In conclusion, using a randomized controlled trial, here we show that MRI-PDFF correlates well with MRS-PDFF and is more sensitive than the histology-determined steatosis grade in quantifying longitudinal changes in the liver fat content. MRI-PDFF allows fat mapping of the entire liver and can be determined with any clinical MRI platform, whereas MRS measures fat biochemically in a small ROI and is largely a research tool with limited clinical availability; MRI-PDFF may be used as an imaging biomarker to quantify changes in liver fat in future clinical trials.
Future studies are needed to examine the role of additional MR-based biomarkers beyond liver fat quantification for the assessment of other histological features seen in patients with NASH, including lobular inflammation, ballooning degeneration, and fibrosis. However, we propose that a new standard has emerged for the quantification of liver fat in the setting of clinical trials in NASH.