Magnetic resonance imaging and spectroscopy for quantification of hepatic steatosis: Urgent need for standardization!
Authors: Boris Guiu, Romaric Loffroy, Patrick Hillon, Jean-Michel Petit
Journal: Journal of Hepatology (2009)

We read with great interest the study by McPherson and colleagues [[6]McPherson S. Jonsson J.R. Cowin G.J. O'Rourke P. Clouston A.D. Volp A. et al.Magnetic resonance imaging and spectroscopy accurately estimate the severity of steatosis provided the stage of fibrosis is considered.J Hepatol. 2009; 51: 389-397Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar] that evaluated the accuracy of magnetic resonance spectroscopy (MRS) and imaging (MRI) for grading the severity of hepatic steatosis. In their study, the authors concluded that, using histology as a reference standard, MRS and MRI gave an accurate evaluation of the severity of steatosis, provided that the stage of fibrosis was considered. Our concerns regarding this study and its conclusion are outlined as follows. The lipid fraction measured using MRS and MRI represents the signal derived from protons contained in fatty acid molecules which contain a variety of functional groups (methene, diallylic, α-methylene to carboxyl, allylic, methylene, and methyl (CH3)) [[3]Guiu B. Loffroy R. Petit J.M. Aho S. Ben Salem D. Masson D. et al.Mapping of liver fat with triple-echo gradient echo imaging: validation against 3.0-T proton MR spectroscopy.Eur Radiol. 2009; PubMed Google Scholar]. Methylene (CH2) is the most abundant group in triglycerides and thus, the most commonly used for fat quantification with MRS. In this paper like in several others performed at 1.5 T or less, MRS was performed using the signal from CH2 + CH3, probably because of the relatively low spectral resolution at such field strengths and the inability to accurately separate CH2 from CH3 peaks. In our experience, with a 3.0-T MR system, the CH3 signal can represent up to 15% of the signal derived from CH2, which could explain substantial differences according to the method used. Since Dixon techniques (in-phase and out-of-phase imaging) were developed to specifically oppose the signal derived from water and that from CH2, the use of CH2 + CH3 for MRS and CH2 for MRI is illogical in this paper which compares both MRS and MRI with histological grading of steatosis. However, to date nothing has been recommended in the literature regarding this issue. With MRS, the peak area is proportional to the concentration of the metabolite containing the relevant nuclei, but is also influenced by T 1 and T 2 relaxation times [3Guiu B. Loffroy R. Petit J.M. Aho S. Ben Salem D. Masson D. et al.Mapping of liver fat with triple-echo gradient echo imaging: validation against 3.0-T proton MR spectroscopy.Eur Radiol. 2009; PubMed Google Scholar, 4Guiu B. Petit J.M. Loffroy R. Ben Salem D. Aho S. Masson D. et al.Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy.Radiology. 2009; 250: 95-102Crossref PubMed Scopus (158) Google Scholar]. Since (1) the T 2 of water and CH2 exhibit considerable interindividual variability [[4]Guiu B. Petit J.M. Loffroy R. Ben Salem D. Aho S. Masson D. et al.Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy.Radiology. 2009; 250: 95-102Crossref PubMed Scopus (158) Google Scholar], (2) iron overload greatly decreases the T 2 of water and (3) fibrosis significantly increases the T 2 of water [[5]Keevil S.F. Alstead E.M. Dolke G. Brooks A.P. Armstrong P. Farthing M.J. Non-invasive assessment of diffuse liver disease by in vivo measurement of proton nuclear magnetic resonance relaxation times at 0.08 T.Br J Radiol. 1994; 67: 1083-1087Crossref PubMed Scopus (16) Google Scholar], quantification of steatosis using MRS must be corrected for T 2 decay to give reliable results. Unfortunately, in the MRS protocol used in this study and described in another paper by the same authors [[1]Cowin G.J. Jonsson J.R. Bauer J.D. Ash S. Ali A. Osland E.J. et al.Magnetic resonance imaging and spectroscopy for monitoring liver steatosis.J Magn Reson Imaging. 2008; 28: 937-945Crossref PubMed Scopus (155) Google Scholar], no correction for T 2 decay was performed. Several spectra should have been acquired with different echo times to correct for T 2 decay via exponential regression analysis of the peak amplitudes at each echo time. Consequently, the absence of correction of T 2 decay is likely to explain the influence of fibrosis on the correlation between MRS and histology. With MRI, in-phase and out-of-phase images (Dixon IP/OP) are not reliable for quantification of liver fat in the case of liver iron overload, which can be present in many chronic liver diseases including hepatitis C, NAFLD, cirrhosis, and hemochromatosis [[7]Westphalen A.C. Qayyum A. Yeh B.M. Merriman R.B. Lee J.A. Lamba A. et al.Liver fat: effect of hepatic iron deposition on evaluation with opposed-phase MR imaging.Radiology. 2007; 242: 450-455Crossref PubMed Scopus (135) Google Scholar]. The shortening of T 2∗ relaxation time largely explains the erroneous determination by Dixon IP/OP. The authors acknowledged this issue and addressed this point by assessing hepatic iron loading on liver biopsy. To our knowledge, an easier and more practical approach would have been to use triple- or multi-echo techniques derived from Dixon IP/OP, which, in correcting for the influence of T 2∗ decay, proved to provide reliable results even in the case of iron overload [4Guiu B. Petit J.M. Loffroy R. Ben Salem D. Aho S. Masson D. et al.Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy.Radiology. 2009; 250: 95-102Crossref PubMed Scopus (158) Google Scholar, 8Yokoo T. Bydder M. Hamilton G. Middleton M.S. Gamst A.C. Wolfson T. et al.Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of low-flip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T.Radiology. 2009; 251: 67-76Crossref PubMed Scopus (263) Google Scholar]. Nowadays, these sequences should replace classical Dixon IP/OP for the determination of liver fat content. In conclusion, there is an urgent need for the standardisation of MRS and MRI. It should improve quality, reproducibility and comparability of their results, and it would also strongly encourage the mentioning of the main acquisition parameters and the method for data analysis, even in clinical papers. Finally, the question should be raised whether the visual grading of steatosis using histology is actually the best reference standard. Given the semi-quantitative nature of histological grading, its inter-observer variability, its overestimation of the degree of steatosis [[2]Franzen L.E. Ekstedt M. Kechagias S. Bodin L. Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.Mod Pathol. 2005; 18: 912-916Crossref PubMed Scopus (96) Google Scholar], and the small quantity of liver tissue examined (about 50–100 mg in a typical biopsy sample vs. 8–27 g in a voxel of MRS) leading to a sampling bias especially when fat is heterogeneously distributed throughout the liver [3Guiu B. Loffroy R. Petit J.M. Aho S. Ben Salem D. Masson D. et al.Mapping of liver fat with triple-echo gradient echo imaging: validation against 3.0-T proton MR spectroscopy.Eur Radiol. 2009; PubMed Google Scholar, 4Guiu B. Petit J.M. Loffroy R. Ben Salem D. Aho S. Masson D. et al.Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy.Radiology. 2009; 250: 95-102Crossref PubMed Scopus (158) Google Scholar], would MRS not be a more appropriate choice?