Advertisement

Non-invasive Quantitative Magnetic Resonance Imaging and Spectroscopic Biomarkers in Nonalcoholic Fatty Liver Disease and Other Cardiometabolic Diseases Associated with Ectopic Fat Deposition

  • Gavin Hamilton
  • Michael S. Middleton
  • Elhamy R. Heba
  • Claude B. SirlinEmail author
Chapter

Abstract

Obesity is associated with ectopic fat deposition in various organs and tissues that may adversely affect their structure, and their metabolic function. In the context of developing new drugs for nonalcoholic fatty liver disease and related cardiometabolic conditions (obesity, type 2 diabetes, cardiovascular disease, metabolic syndrome), non-invasive quantitative imaging biomarkers have been developed to estimate hepatic steatosis, percentage and type of fat accumulation in skeletal muscle, and absolute and relative amounts of muscle, and subcutaneous and visceral body fat. Advanced magnetic resonance imaging (MRI) is widely considered to be well suited, and the preferred non-invasive method to estimate proton density fat fraction (PDFF), an accurate and precise biomarker of hepatic steatosis. Magnetic resonance spectroscopy (MRS) is currently the only non-invasive method to assess intramyocellular lipid (IMCL), a biomarker of fat accumulation within skeletal muscle cells. Finally, semi-automated MRI is emerging as the leading method to formulate an overall body composition profile (BCP), which provides a snapshot of fat and muscle composition in the body.

Keywords

Intramyocellular lipid (IMCL) Magnetic resonance imaging (MRI) Magnetic resonance spectroscopy (MRS) Nonalcoholic fatty liver disease (NAFLD) Proton density fat fraction (PDFF) Quantitative imaging biomarker (QIB) 

References

  1. 1.
    Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473–81.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270–87.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Caprio S. Development of type 2 diabetes mellitus in the obese adolescent: a growing challenge. Endocr Pract. 2012;18(5):791–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Karlas T, Wiegand J, Berg T. Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae. Best Pract Res Clin Endocrinol Metab. 2013;27(2):195–208.PubMedCrossRefGoogle Scholar
  5. 5.
    Hui E, Xu A, Bo Yang H, Lam KS. Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: role of adipokines. J Diabetes Investig. 2013;4(5):413–25.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713–23.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH. Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci (Lond). 2009;116(7):539–64.CrossRefGoogle Scholar
  8. 8.
    Oni ET, Agatston AS, Blaha MJ, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis. 2013;230(2):258–67.PubMedCrossRefGoogle Scholar
  9. 9.
    Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2(11):901–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Lettner A, Roden M. Ectopic fat and insulin resistance. Curr Diab Rep. 2008;8(3):185–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Hardy OT, Czech MP, Corvera S. What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes. 2012;19(2):81–7.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Shimabukuro M, Kozuka C, Taira S, et al. Ectopic fat deposition and global cardiometabolic risk: new paradigm in cardiovascular medicine. J Med Investig. 2013;60:1–2):1-14.CrossRefGoogle Scholar
  13. 13.
    Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(7):1712–23.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917–23.CrossRefGoogle Scholar
  15. 15.
    Targher G, Byrne CD. Clinical Review: Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab. 2013;98(2):483–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Ballestri S, Lonardo A, Bonapace S, et al. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(7):1724–45.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Perseghin G. Muscle lipid metabolism in the metabolic syndrome. Curr Opin Lipidol. 2005;16(4):416–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Pan DA, Lillioja S, Kriketos AD, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997;46(6):983–8.Google Scholar
  19. 19.
    Petersen KF, Shulman GI. Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. Am J Cardiol. 2002;90(5A):11G–8G.PubMedCrossRefGoogle Scholar
  20. 20.
    Perseghin G, Scifo P, De Cobelli F, et al. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes. 1999;48(8):1600–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Jacob S, Machann J, Rett K, et al. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes. 1999;48(5):1113–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51(10):2944–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Teranishi T, Ohara T, Maeda K, et al. Effects of pioglitazone and metformin on intracellular lipid content in liver and skeletal muscle of individuals with type 2 diabetes mellitus. Metabolism. 2007;56(10):1418–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Bradford V, Dillon J, Miller M. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease. Hepat Med. 2014;6:1–10.PubMedGoogle Scholar
  25. 25.
    Rabl C, Campos GM. The impact of bariatric surgery on nonalcoholic steatohepatitis. Semin Liver Dis. 2012;32(1):80–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Lim EL, Hollingsworth KG, Aribisala BS, et al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54(10):2506–14.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Mazza A, Fruci B, Garinis GA, et al. The role of metformin in the management of NAFLD. Exp Diabetes Res. 2012;2012:716404.PubMedCrossRefGoogle Scholar
  28. 28.
    Ozturk ZA, Kadayifci A. Insulin sensitizers for the treatment of non-alcoholic fatty liver disease. World J Hepatol. 2014;6(4):199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. J Hepatol. 2011;55(6):1383–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Scorletti E, Bhatia L, McCormick KG, et al. Design and rationale of the WELCOME trial: a randomised, placebo controlled study to test the efficacy of purified long chain omega-3 fatty treatment in non-alcoholic fatty liver disease. Contemp Clin Trials. 2014;37(2):301–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623.Google Scholar
  32. 32.
    Ratziu V. Targeting non-alcoholic fatty liver disease through 11-βHSD1 inhibition. Lancet Diabetes Endocrinol. 2014;2:354–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Schwenzer NF, Springer F, Schraml C, et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51(3):433–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(23):7392–402.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    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(4):729–49.Google Scholar
  36. 36.
    Machann J, Stefan N, Schick F. (1)H MR spectroscopy of skeletal muscle, liver and bone marrow. Eur J Radiol. 2008;67(2):275–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189–94.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Glover GH. Multipoint Dixon technique for water and fat proton and susceptibility imaging. J Magn Reson Imaging. 1991;1(5):521–30.PubMedCrossRefGoogle Scholar
  39. 39.
    Fishbein MH, Gardner KG, Potter CJ, Schmalbrock P, Smith MA. Introduction of fast MR imaging in the assessment of hepatic steatosis. Magn Reson Imaging. 1997;15(3):287–93.PubMedCrossRefGoogle Scholar
  40. 40.
    Yokoo T, Shiehmorteza M, Hamilton G, et al. Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T. Radiology. 2011;258(3):749–59.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hu HH, Li Y, Nagy TR, Goran MI, Nayak KS. Quantification of absolute fat mass by magnetic resonance imaging: a validation study against chemical analysis. Int J Body Compos Res. 2011;9(3):111–22.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Reeder SB, Hu HH, Sirlin CB. Proton density fat-fraction: a standardized MR-based biomarker of tissue fat concentration. J Magn Reson Imaging. 2012;36(5):1011–4.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Longo R, Ricci C, Masutti F, et al. Fatty infiltration of the liver. Quantification by 1H localized magnetic resonance spectroscopy and comparison with computed tomography. Investig Radiol. 1993;28(4):297–302.CrossRefGoogle Scholar
  44. 44.
    Thomsen C, Becker U, Winkler K, et al. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging. 1994;12(3):487–95.PubMedCrossRefGoogle Scholar
  45. 45.
    Longo R, Pollesello P, Ricci C, et al. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1995;5(3):281–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288(2):E462–8.Google Scholar
  47. 47.
    Hamilton G, Middleton MS, Bydder M, et al. Effect of PRESS and STEAM sequences on magnetic resonance spectroscopic liver fat quantification. J Magn Reson Imaging. 2009;30(1):145–52.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Pineda N, Sharma P, Xu Q, et al. Measurement of hepatic lipid: high-speed T2-corrected multiecho acquisition at 1H MR spectroscopy--a rapid and accurate technique. Radiology. 2009;252(2):568–76.PubMedCrossRefGoogle Scholar
  49. 49.
    Schick F, Eismann B, Jung WI, et al. Comparison of localized proton NMR signals of skeletal muscle and fat tissue in vivo: two lipid compartments in muscle tissue. Magn Reson Med. 1993;29(2):158–67.PubMedCrossRefGoogle Scholar
  50. 50.
    Boesch C, Slotboom J, Hoppeler H, Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR-spectroscopy. Magn Reson Med. 1997;37(4):484–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Kreis R, Boesch C. Spatially localized, one- and two-dimensional NMR spectroscopy and in vivo application to human muscle. J Magn Reson B. 1996;113(2):103–18.PubMedCrossRefGoogle Scholar
  52. 52.
    Boesch C, Decombaz J, Slotboom J, Kreis R. Observation of intramyocellular lipids by means of 1H magnetic resonance spectroscopy. Proc Nutr Soc. 1999;58(4):841–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis. 2007;11(1):37–54.. viiiPubMedCrossRefGoogle Scholar
  54. 54.
    Graif M, Yanuka M, Baraz M, et al. Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease. Investig Radiol. 2000;35(5):319–24.CrossRefGoogle Scholar
  55. 55.
    Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123(3):745–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Mottin CC, Moretto M, Padoin AV, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14(5):635–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Barry CT, Mills B, Hah Z, et al. Shear wave dispersion measures liver steatosis. Ultrasound Med Biol. 2012;38(2):175–82.Google Scholar
  58. 58.
    Limanond P, Raman SS, Lassman C, et al. Macrovesicular hepatic steatosis in living related liver donors: correlation between CT and histologic findings. Radiology. 2004;230(1):276–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Kodama Y, Ng CS, Wu TT, et al. Comparison of CT methods for determining the fat content of the liver. AJR Am J Roentgenol. 2007;188(5):1307–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Lee SW, Park SH, Kim KW, et al. Unenhanced CT for assessment of macrovesicular hepatic steatosis in living liver donors: comparison of visual grading with liver attenuation index. Radiology. 2007;244(2):479–85.PubMedCrossRefGoogle Scholar
  61. 61.
    Birnbaum BA, Hindman N, Lee J, Babb JS. Multi-detector row CT attenuation measurements: assessment of intra- and interscanner variability with an anthropomorphic body CT phantom. Radiology. 2007;242(1):109–19.CrossRefGoogle Scholar
  62. 62.
    Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med. 2009;361(9):849–57.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hamilton G, Yokoo T, Bydder M, et al. In vivo characterization of the liver fat (1)H MR spectrum. NMR Biomed. 2011;24(7):784–90.PubMedCrossRefGoogle Scholar
  64. 64.
    Ren J, Dimitrov I, Sherry AD, Malloy CR. Composition of adipose tissue and marrow fat in humans by 1H NMR at 7 Tesla. J Lipid Res. 2008;49(9):2055–62.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Bydder M, Girard O, Hamilton G. Mapping the double bonds in triglycerides. Magn Reson Imaging. 2011;29(8):1041–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Hu HH, Kan HE. Quantitative proton MR techniques for measuring fat. NMR Biomed. 2013;26(12):1609–29.PubMedCrossRefGoogle Scholar
  67. 67.
    Bottomley PA. Spatial localization in NMR spectroscopy in vivo. Ann N Y Acad Sci. 1987;508:333–48.Google Scholar
  68. 68.
    Granot J. Selected volume excitation using stimulated echoes (VEST): applications to spatially localized spectroscopy and imaging. J Magn Reson Imaging. 1986;70:488–92.Google Scholar
  69. 69.
    Frahm J, Merboldt K-D, Hänicke W. Localized proton spectroscopy using stimulated echoes. J Magn Reson Imaging. 1987;72:502–8.Google Scholar
  70. 70.
    Keevil SF. Spatial localization in nuclear magnetic resonance spectroscopy. Phys Med Biol. 2006;51(16):R579–636.PubMedCrossRefGoogle Scholar
  71. 71.
    Middleton M, Hamilton G, Sirlin CB. Effect of saturation bands on quantitative liver fat proton MR spectroscopy. In Proceedings of the RSNA Annual Meeting, Chicago, IL; 2011.Google Scholar
  72. 72.
    De Graff R, Rothman DL. In vivo detection and quantification of scalar coupled 1H NMR resonances. Concepts Magn Reson. 2001;13:32–76.CrossRefGoogle Scholar
  73. 73.
    in ‘t Zandt H, van Der Graaf M, Heerschap A. Common processing of in vivo MR spectra. NMR Biomed. 2001;14:224–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Vanhamme L, Sundin T, Hecke PV, Huffel SV. MR spectroscopy quantitation: a review of time-domain methods. NMR Biomed. 2001;14(4):233–46.PubMedCrossRefGoogle Scholar
  75. 75.
    Mierisova S, Ala-Korpela M. MR spectroscopy quantitation: a review of frequency domain methods. NMR Biomed. 2001;14(4):247–59.PubMedCrossRefGoogle Scholar
  76. 76.
    Szczepaniak LS, Babcock EE, Schick F, et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Phys. 1999;276(5 Pt 1):E977–89.Google Scholar
  77. 77.
    Thomas EL, Potter E, Tosi I, et al. Pioglitazone added to conventional lipid-lowering treatment in familial combined hyperlipidaemia improves parameters of metabolic control: relation to liver, muscle and regional body fat content. Atherosclerosis. 2007;195(1):e181–90.PubMedCrossRefGoogle Scholar
  78. 78.
    Reeder SB, Pineda AR, Wen Z, et al. Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL): application with fast spin-echo imaging. Magn Reson Med. 2005;54(3):636–44.PubMedCrossRefGoogle Scholar
  79. 79.
    Kawamitsu H, Kaji Y, Ohara T, Sugimura K. Feasibility of quantitative intrahepatic lipid imaging applied to the magnetic resonance dual gradient echo sequence. Magn Reson Med Sci. 2003;2:47–50.PubMedCrossRefGoogle Scholar
  80. 80.
    Qayyum A, Goh JS, Kakar S, Yeh BM, Merriman RB, Coakley FV. Accuracy of liver fat quantification at MR imaging: comparison of out-of-phase gradient-echo and fat-saturated fast spin-echo techniques-initial experience. Radiology. 2005;237:507–11.PubMedCrossRefGoogle Scholar
  81. 81.
    Bydder M, Yokoo T, Hamilton G, et al. Relaxation effects in the quantification of fat using gradient echo imaging. Magn Reson Imaging. 2008;26(3):347–59.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Yokoo T, Bydder M, Hamilton G, 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(1):67–76.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Heba ER, Desai A, Zand KA, Hamilton G, Wolfson T, Schlein AN, Gamst A, Loomba R, Sirlin CB, Middleton MS. Accuracy and the effect of possible subject-based confounders of magnitude-based MRI for estimating hepatic proton density fat fraction in adults, using MR spectroscopy as reference. J Magn Reson Imaging. 2016;43:398–406.PubMedCrossRefGoogle Scholar
  84. 84.
    Zand KA, Shah A, Heba E, Wolfson T, Hamilton G, Lam J, Chen J, Hooker JC, Gamst AC, Middleton MS, Schwimmer JB, Sirlin CB. Accuracy of multiecho magnitude-based MRI (M-MRI) for estimation of hepatic proton density fat fraction (PDFF) in children. J Magn Reson Imaging. 2015;42:1223–32.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Yu H, Shimakawa A, McKenzie CA, et al. Multiecho water-fat separation and simultaneous R2* estimation with multifrequency fat spectrum modeling. Magn Reson Med. 2008;60(5):1122–34.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Yu H, Shimakawa A, Hines CD, et al. Combination of complex-based and magnitude-based multiecho water-fat separation for accurate quantification of fat-fraction. Magn Reson Med. 2011;66(1):199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Meisamy S, Hines CD, Hamilton G, et al. Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. Radiology. 2011;258(3):767–75.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Boesch C, Machann J, Vermathen P, Schick F. Role of proton MR for the study of muscle lipid metabolism. NMR Biomed. 2006;19(7):968–88.PubMedCrossRefGoogle Scholar
  89. 89.
    Szczepaniak L, Dobbins RL, Stein DT, JD MG. Bulk magnetic susceptibility effects on the assessment of intra- and extramycellular lipids in vivo. Magn Reson Med. 2002;47:607–10.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Gavin Hamilton
    • 1
  • Michael S. Middleton
    • 1
  • Elhamy R. Heba
    • 1
  • Claude B. Sirlin
    • 1
    Email author
  1. 1.Liver Imaging Group, Department of RadiologyUniversity of California, San DiegoSan DiegoUSA

Personalised recommendations