Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents

Michele Di Martino, Lucia Pacifico, Mario Bezzi, Rossella Di Miscio, Beatrice Sacconi, Claudio Chiesa, Carlo Catalano, Michele Di Martino, Lucia Pacifico, Mario Bezzi, Rossella Di Miscio, Beatrice Sacconi, Claudio Chiesa, Carlo Catalano

Abstract

Aim: To establish a threshold value for liver fat content between healthy children and those with non-alcoholic fatty liver disease (NAFLD) by using magnetic resonance imaging (MRI), with liver biopsy serving as a reference standard.

Methods: The study was approved by the local ethics committee, and written informed consent was obtained from all participants and their legal guardians before the study began. Twenty-seven children with NAFLD underwent liver biopsy to assess the presence of nonalcoholic steatohepatitis. The assessment of liver fat fraction was performed using MRI, with a high field magnet and 2D gradient-echo and multiple-echo T1-weighted sequence with low flip angle and single-voxel point-resolved ¹H MR-Spectroscopy (¹H-MRS), corrected for T1 and T2* decays. Receiver operating characteristic curve analysis was used to determine the best cut-off value. Lin coefficient test was used to evaluate the correlation between histology, MRS and MRI-PDFF. A Mann-Whitney U-test and multivariate analysis were performed to analyze the continuous variables.

Results: According to MRS, the threshold value between healthy children and those with NAFLD is 6%; using MRI-PDFF, a cut-off value of 3.5% is suggested. The Lin analysis revealed a good fit between the histology and MRS as well as MRI-PDFF.

Conclusion: MRS is an accurate and precise method for detecting NAFLD in children.

Keywords: Children; Magnetic resonance imaging-PDFF; Magnetic resonance spectroscopy; Non-alcoholic fatty liver disease; Obesity.

Conflict of interest statement

Conflict-of-interest statement: Nothing to disclosure.

Figures

Figure 1
Figure 1
Subcutaneous and visceral fat measurement technique. A: Sagittal T1-weighted localizer MR image used to select levels for analysis (L1-L2, L2-L3, L3-L4, L4-L5, L5-S1); B: Axial T1-weighted MR image with water suppression at the L4-L5 level. Contrast was manually adjusted to select signal from subcutaneous (red) and visceral (green) adipose tissue. Area of this fat was calculated by the workstation and summarized with that of other levels.
Figure 2
Figure 2
Mean lipid content for MR-Spectroscopy. A-C: MRI-PDFF reveals a hepatic fat fraction of 7%, MRS quantified 6.5% of liver steatosis and histological analysis 30% of liver steatosis; D-F: Severe hepatic steatosis in a 8-year-old girl: MRII-PDFF 25%, MRS 50% and histologic analysis 90% of liver steatosis respectively.
Figure 3
Figure 3
Receiver operating characteristic curve analysis of MR Spectrscopy (A) and MR imaging-PDFF (B) for discrimination of healthy from non-alcoholic fatty liver disease children.
Figure 4
Figure 4
Evaluation of magnetic resonance imagingestimated-proton density fat fraction at medium and high level of hepatic steatosis. A, B: Differences between liver fat fraction estimated by using 1H MR spectroscopy and triple-echo sequence compared with histology were plotted against means, with 95% confidence intervals (Bland-Altman plot); C: All data points were within limits of agreement (dotted lines), corresponding to 1.96 SDs from mean. MRS: MR-Spectroscopy.

References

    1. Giorgio V, Prono F, Graziano F, Nobili V. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr. 2013;13:40.
    1. Widhalm K, Ghods E. Nonalcoholic fatty liver disease: a challenge for pediatricians. Int J Obes (Lond) 2010;34:1451–1467.
    1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58:1538–1544.
    1. Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic fatty liver disease. Hepatology. 2009;50:1282–1293.
    1. Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:27–38.
    1. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le TA, Bettencourt R, Changchien C, Brenner DA, Sirlin C, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology. 2013;58:1930–1940.
    1. Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34:spcone.
    1. Yokoo T, Shiehmorteza M, Hamilton G, Wolfson T, Schroeder ME, Middleton MS, Bydder M, Gamst AC, Kono Y, Kuo A, et al. Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T. Radiology. 2011;258:749–759.
    1. Meisamy S, Hines CD, Hamilton G, Sirlin CB, McKenzie CA, Yu H, Brittain JH, Reeder SB. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology. 2011;258:767–775.
    1. Hines CD, Frydrychowicz A, Hamilton G, Tudorascu DL, Vigen KK, Yu H, McKenzie CA, Sirlin CB, Brittain JH, Reeder SB. T(1) independent, T(2) (*) corrected chemical shift based fat-water separation with multi-peak fat spectral modeling is an accurate and precise measure of hepatic steatosis. J Magn Reson Imaging. 2011;33:873–881.
    1. Hamilton G, Yokoo T, Bydder M, Cruite I, Schroeder ME, Sirlin CB, Middleton MS. In vivo characterization of the liver fat ¹H MR spectrum. NMR Biomed. 2011;24:784–790.
    1. Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, Dziura J, Taksali SE, Kursawe R, Shaw M, et al. Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? Hepatology. 2009;49:1896–1903.
    1. Chabanova E, Bille DS, Thisted E, Holm JC, Thomsen HS. (1)H MRS assessment of hepatic steatosis in overweight children and adolescents: comparison between 3T and open 1T MR-systems. Abdom Imaging. 2013;38:315–319.
    1. Tang A, Tan J, Sun M, Hamilton G, Bydder M, Wolfson T, Gamst AC, Middleton M, Brunt EM, Loomba R, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. Radiology. 2013;267:422–431.
    1. Larson-Meyer DE, Newcomer BR, VanVrancken-Tompkins CL, Sothern M. Feasibility of assessing liver lipid by proton magnetic resonance spectroscopy in healthy normal and overweight prepubertal children. Diabetes Technol Ther. 2010;12:207–212.
    1. Idilman IS, Aniktar H, Idilman R, Kabacam G, Savas B, Elhan A, Celik A, Bahar K, Karcaaltincaba M. Hepatic steatosis: quantification by proton density fat fraction with MR imaging versus liver biopsy. Radiology. 2013;267:767–775.
    1. Demerath EW, Ritter KJ, Couch WA, Rogers NL, Moreno GM, Choh A, Lee M, Remsberg K, Czerwinski SA, Chumlea WC, et al. Validity of a new automated software program for visceral adipose tissue estimation. Int J Obes (Lond) 2007;31:285–291.
    1. Ross R, Freeman J, Hudson R, Janssen I. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. J Clin Endocrinol Metab. 2002;87:5044–5051.
    1. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16.
    1. Guiu B, Petit JM, Loffroy R, Ben Salem D, Aho S, Masson D, Hillon P, Krause D, Cercueil JP. Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology. 2009;250:95–102.
    1. Villanova N, Moscatiello S, Ramilli S, Bugianesi E, Magalotti D, Vanni E, Zoli M, Marchesini G. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42:473–480.
    1. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–1350.
    1. Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, Chiesa C. Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology. 2014;59:461–470.
    1. Santoro N, Caprio S. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in obese adolescents: a looming marker of cardiac dysfunction. Hepatology. 2014;59:372–374.
    1. Sagi R, Reif S, Neuman G, Webb M, Phillip M, Shalitin S. Nonalcoholic fatty liver disease in overweight children and adolescents. Acta Paediatr. 2007;96:1209–1213.
    1. Taksali SE, Caprio S, Dziura J, Dufour S, Calí AM, Goodman TR, Papademetris X, Burgert TS, Pierpont BM, Savoye M, et al. High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype. Diabetes. 2008;57:367–371.
    1. Maffeis C, Manfredi R, Trombetta M, Sordelli S, Storti M, Benuzzi T, Bonadonna RC. Insulin sensitivity is correlated with subcutaneous but not visceral body fat in overweight and obese prepubertal children. J Clin Endocrinol Metab. 2008;93:2122–2128.
    1. Fonvig CE, Bille DS, Chabanova E, Nielsen TR, Thomsen HS, Holm JC. Muscle fat content and abdominal adipose tissue distribuition investigated by magnetic resonance spectroscopy and imaging in obese children and youths. Pediatr Rep. 2012;4:e11.
    1. Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, Lundbom N, Rissanen A, Ridderstråle M, Groop L, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137:865–872.
    1. Longo R, Pollesello P, Ricci C, Masutti F, Kvam BJ, Bercich L, Crocè LS, Grigolato P, Paoletti S, de Bernard B. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1995;5:281–285.
    1. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol. 1999;276:E977–E989.
    1. van Werven JR, Marsman HA, Nederveen AJ, Smits NJ, ten Kate FJ, van Gulik TM, Stoker J. Assessment of hepatic steatosis in patients undergoing liver resection: comparison of US, CT, T1-weighted dual-echo MR imaging, and point-resolved 1H MR spectroscopy. Radiology. 2010;256:159–168.
    1. Chalasani N. Nonalcoholic fatty liver disease liver fat score and fat equation to predict and quantitate hepatic steatosis: promising but not prime time! Gastroenterology. 2009;137:772–775.
    1. Springer F, Machann J, Claussen CD, Schick F, Schwenzer NF. Liver fat content determined by magnetic resonance imaging and spectroscopy. World J Gastroenterol. 2010;16:1560–1566.
    1. Reeder SB, Robson PM, Yu H, Shimakawa A, Hines CD, McKenzie CA, Brittain JH. Quantification of hepatic steatosis with MRI: the effects of accurate fat spectral modeling. J Magn Reson Imaging. 2009;29:1332–1339.
    1. Machann J, Thamer C, Schnoedt B, Stefan N, Haring HU, Claussen CD, Fritsche A, Schick F. Hepatic lipid accumulation in healthy subjects: a comparative study using spectral fat-selective MRI and volume-localized 1H-MR spectroscopy. Magn Reson Med. 2006;55:913–917.
    1. Cowin GJ, Jonsson JR, Bauer JD, Ash S, Ali A, Osland EJ, Purdie DM, Clouston AD, Powell EE, Galloway GJ. Magnetic resonance imaging and spectroscopy for monitoring liver steatosis. J Magn Reson Imaging. 2008;28:937–945.
    1. Yokoo T, Bydder M, Hamilton G, Middleton MS, Gamst AC, Wolfson T, Hassanein T, Patton HM, Lavine JE, Schwimmer JB, 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;251:67–76.
    1. Africa JA, Newton KP, Schwimmer JB. Lifestyle Interventions Including Nutrition, Exercise, and Supplements for Nonalcoholic Fatty Liver Disease in Children. Dig Dis Sci. 2016;61:1375–1386.
    1. Rehm JL, Wolfgram PM, Hernando D, Eickhoff JC, Allen DB, Reeder SB. Proton density fat-fraction is an accurate biomarker of hepatic steatosis in adolescent girls and young women. Eur Radiol. 2015;25:2921–2930.

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