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Magnetic resonance elastography biomarkers for detection of histologic alterations in nonalcoholic fatty liver disease in the absence of fibrosis

  • Magnetic Resonance
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Abstract

Objectives

To investigate associations between histology and hepatic mechanical properties measured using multiparametric magnetic resonance elastography (MRE) in adults with known or suspected nonalcoholic fatty liver disease (NAFLD) without histologic fibrosis.

Methods

This was a retrospective analysis of 88 adults who underwent 3T MR exams including hepatic MRE and MR imaging to estimate proton density fat fraction (MRI-PDFF) within 180 days of liver biopsy. Associations between MRE mechanical properties (mean shear stiffness (|G*|) by 2D and 3D MRE, and storage modulus (G′), loss modulus (G″), wave attenuation (α), and damping ratio (ζ) by 3D MRE) and histologic, demographic and anthropometric data were assessed.

Results

In univariate analyses, patients with lobular inflammation grade ≥ 2 had higher 2D |G*| and 3D G″ than those with grade ≤ 1 (p = 0.04). |G*| (both 2D and 3D), G′, and G″ increased with age (rho = 0.25 to 0.31; p ≤ 0.03). In multivariable regression analyses, the association between inflammation grade ≥ 2 remained significant for 2D |G*| (p = 0.01) but not for 3D G″ (p = 0.06); age, sex, or BMI did not affect the MRE-inflammation relationship (p > 0.20).

Conclusions

2D |G*| and 3D G″ were weakly associated with moderate or severe lobular inflammation in patients with known or suspected NAFLD without fibrosis. With further validation and refinement, these properties might become useful biomarkers of inflammation. Age adjustment may help MRE interpretation, at least in patients with early-stage disease.

Key Points

• Moderate to severe lobular inflammation was associated with hepatic elevated shear stiffness and elevated loss modulus (p =0.04) in patients with known or suspected NAFLD without liver fibrosis; this suggests that with further technical refinement these MRE-assessed mechanical properties may permit detection of inflammation before the onset of fibrosis in NAFLD.

• Increasing age is associated with higher hepatic shear stiffness, and storage and loss moduli (rho = 0.25 to 0.31; p ≤ 0.03); this suggests that age adjustment may help interpret MRE results, at least in patients with early-stage NAFLD.

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Abbreviations

BMI:

Body mass index

MMDI:

Multimodel direct inversion

MRE:

Magnetic resonance elastography

MRI:

Magnetic resonance imaging

NAFLD:

Nonalcoholic fatty liver disease

NAS:

Nonalcoholic fatty liver disease activity score

NASH:

Nonalcoholic steatohepatitis

PDFF:

Proton density fat fraction

ROI:

Region of interest

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Acknowledgements

The authors wish to thank GE Healthcare which provides research support to the University of California, San Diego, CA and the University of Wisconsin, Madison, WI.

Funding

This study has received funding by National Institutes of Health (NIH) grants (K23DK090303, R01DK083380, R01DK088925, R01DK100651, K24DK102595, R01DK106419, EB001981, EB017197), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (U01DK061718), and Mayo Clinic Center for Individualized Medicine Imaging Biomarker Discovery Program.

Author information

Authors and Affiliations

  1. Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Yali Qu & Bin Song

  2. Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA, 92093-0888, USA

    Yali Qu, Michael S. Middleton, Jonathan C. Hooker, Yesenia Covarrubias, Kathryn J. Fowler, Yingzhen N. Zhang, Ethan Sy, Kang Wang, Adrija Mamidipalli & Claude B. Sirlin

  3. NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

  4. Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

  5. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Kevin J. Glaser, Jun Chen, Meng Yin & Richard L. Ehman

  6. Computational and Applied Statistics Laboratory, the San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA

    Tanya Wolfson & Anthony C. Gamst

  7. Department of Pathology, University of California San Diego, La Jolla, CA, USA

    Mark A. Valasek

  8. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA

    Jeffrey B. Schwimmer

  9. Department of Gastroenterology, Rady Children’s Hospital San Diego, San Diego, CA, USA

    Jeffrey B. Schwimmer

  10. Departments of Radiology, Medical Physics, Biomedical Engineering, Medicine, and Emergency Medicine, University of Wisconsin, Madison, WI, USA

    Scott B. Reeder

Authors
  1. Yali Qu
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  2. Michael S. Middleton
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  3. Rohit Loomba
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  7. Tanya Wolfson
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  8. Yesenia Covarrubias
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  9. Mark A. Valasek
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  11. Yingzhen N. Zhang
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  12. Ethan Sy
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  13. Anthony C. Gamst
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  14. Kang Wang
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  15. Adrija Mamidipalli
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  16. Jeffrey B. Schwimmer
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  17. Bin Song
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  18. Scott B. Reeder
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  19. Meng Yin
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  20. Richard L. Ehman
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  21. Claude B. Sirlin
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Corresponding author

Correspondence to Claude B. Sirlin.

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Guarantor

The scientific guarantor of this publication is Claude B. Sirlin.

Conflict of Interest

The authors of this manuscript declare relationships with the following companies:

K. J. G. has intellectual property rights and a financial interest in MR elastography technology; institution has intellectual property rights and a financial interest in MR elastography technology.

J. C. has intellectual property rights and a financial interest in MR elastography technology; his institution has intellectual property rights and a financial interest in MR elastography technology. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board as is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

S. B. R. reports that his institution, the University of Wisconsin, receives research support from GE Healthcare.

M. Y. has intellectual property rights and a financial interest in MR elastography technology; her institution has intellectual property rights and a financial interest in MR elastography technology. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

R. L. E. has intellectual property rights and a financial interest in MR elastography technology. His institution has intellectual property rights and a financial interest in MR elastography technology. He reports grants from Resoundant Inc. His research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

C. B. S. reports grants from GE, Siemens, Philips, Bayer, Foundation of NIH, and Gilead; personal consultation fees from Blade, Boehringer, and Epigenomics; consultation under the auspices of the University to AMRA, BMS, Exact Sciences, GE Digital, IBM-Watson, and Pfizer; lab service agreements from Enanta, Gilead, ICON, Intercept, Nusirt, Shire, Synageva, Takeda; royalties from Wolters Kluwer for educational material outside the submitted work; honoraria to the institution from Medscape for educational material outside the submitted work; ownership of stock in Livivos; serving on advisory board to Quantix Bio.

J. B. S. reports grant funding from Intercept, Genfit, and Seraphina.

M. S. M. reports consultation to Arrowhead, Glympse, Kowa, Median, and Novo Nordisk; lab service agreements under auspices of UCSD from Alexion, AstraZeneca, Bristol-Myers Squibb, Celgene, Enanta, Galmed, Genzyme, Gilead, Guerbet, Intercept, Ionis, Janssen, Janssen, NuSirt, Organovo, Pfizer, Roche, Sanofi, Shire, Synageva, and Takeda; stockholder Pfizer; and co-founder Quantix Bio.

K. J. F. reports grants from Bayer, Median, Pfizer, and GE, consulting for Epigenomics and GE.

R. L. reports grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, pH Pharma, and Siemens. He serves as a consultant or advisory board member for Alnylam/Regeneron, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Inipharm, Intercept, Ionis, Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Promethera, Sagimet, 89 bio, and Viking Therapeutics. He also reports a financial interest in Liponexus, Inc.

Statistics and Biometry

Dr. Anthony Gamst and Tanya Wolfson kindly provided statistical advice for this manuscript and were included as authors.

Informed Consent

Written informed consent was obtained from all subjects in this study.

Ethical Approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

Some study subjects or cohorts have been previously reported in the following articles (1−4). The prior articles included patients with fibrosis and so differed in their population cohorts. Also, the prior articles either did not report MRE results (1, 3) or reported only a single MRE-measured parameter (shear stiffness) (2, 4).

  1. 1.

    Luo RB, Suzuki T, Hooker JC, et al How bariatric surgery affects liver volume and fat density in NAFLD patients. Surg Endosc 2018;32:1675-1682. doi: https://doi.org/10.1007/s00464-017-5846-9

  2. 2.

    Loomba R, Sirlin CB, Ang B, et al Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015;61:1239-1250. doi: https://doi.org/10.1002/hep.27647

  3. 3.

    Middleton MS, Heba ER, Hooker CA, et al Agreement between magnetic resonance imaging proton density fat fraction measurements and pathologist-assigned steatosis grades of liver biopsies from adults with nonalcoholic steatohepatitis. Gastroenterology 2017;153:753-761. doi: https://doi.org/10.1053/j.gastro.2017.06.005

  4. 4.

    Caussy C, Chen J, Alquiraish MH, et al Association between obesity and discordance in fibrosis stage determination by magnetic resonance vs transient elastography in patients with nonalcoholic liver disease. Clin Gastroenterol Hepatol 2018;16:1974-1982.e7. doi: https://doi.org/10.1016/j.cgh.2017.10.037.

Methodology

  • Retrospective

  • Cross-sectional study

  • Performed at one institution

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Qu, Y., Middleton, M.S., Loomba, R. et al. Magnetic resonance elastography biomarkers for detection of histologic alterations in nonalcoholic fatty liver disease in the absence of fibrosis. Eur Radiol 31, 8408–8419 (2021). https://doi.org/10.1007/s00330-021-07988-6

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  • DOI: https://doi.org/10.1007/s00330-021-07988-6

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