Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis

Andrea Dennis, Matt D Kelly, Carolina Fernandes, Sofia Mouchti, Jonathan A Fallowfield, Gideon Hirschfield, Michael Pavlides, Stephen Harrison, Manu V Chakravarthy, Rajarshi Banerjee, Arun Sanyal, Andrea Dennis, Matt D Kelly, Carolina Fernandes, Sofia Mouchti, Jonathan A Fallowfield, Gideon Hirschfield, Michael Pavlides, Stephen Harrison, Manu V Chakravarthy, Rajarshi Banerjee, Arun Sanyal

Abstract

Introduction: Late stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. The well-reported limitations with biopsy, such as associated risks and sampling error, coupled with patient preference, are driving investigation into non-invasive alternatives. MRI-derived biomarkers proton density fat fraction (PDFF) and iron-corrected T1 mapping (cT1) are gaining traction as emerging alternatives to biopsy for NASH. Our aim was to explore the correlations between cT1 and PDFF (from LiverMultiScan®), with the histological components on the NAFLD-NASH spectrum in a large cohort of cross-sectional data, in order to calibrate the measurement to histology, and to infer what might constitute a clinically meaningful change when related to the FDA's criteria.

Materials and methods: In a retrospective analysis of data combined from three previously published observational NASH studies, in which adult participants who underwent liver biopsy on suspicion of NAFLD or NASH and had an MRI scan measuring cT1 and PDFF (LiverMultiScan®, Perspectum Ltd, UK), associations between imaging biomarkers and histology were tested using Spearman's rank correlation coefficient (rs), and further exploration of the relationships between the imaging variables and histology were performed using linear regression.

Results: N = 264 patients with mean age of 54 (SD:9.9), 39% female, and 69% with BMI ≥ 30kg.m-2 were included in the analysis. cT1 and PDFF both correlated with all features of the NAFLD activity score (NAS). cT1 was also positively correlated with Kleiner-Brunt fibrosis. Partial correlations, adjusting for steatosis, revealed cT1 correlated with inflammation and fibrosis, whereas PDFF did not, and both were still associated with the NAS, but correlation was weaker with PDFF than cT1. An estimated difference of 88 ms in cT1, or 21% relative difference in PDFF was related to a two-point difference in overall NAS.

Conclusion: The correlations between cT1 and PDFF with the histopathological hallmarks of NASH demonstrate the potential utility of both cT1 and PDFF as non-invasive biomarkers to detect a pharmacodynamic change in NASH, with cT1 showing superiority for detecting changes in inflammation and fibrosis, rather than liver fat alone.

Trial registration: ClinicalTrials.gov NCT01543646 NCT03142867.

Keywords: MRI; NAFLD; NASH; imaging; non-invasive biomarkers.

Conflict of interest statement

Perspectum Ltd is a privately funded commercial enterprise that develops medical devices to address unmet clinical needs, including LiverMultiScan®. RB is the CEO and founder of Perspectum. AD, SM, CF, and MK are employees of Perspectum. MP is a shareholder in Perspectum. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Dennis, Kelly, Fernandes, Mouchti, Fallowfield, Hirschfield, Pavlides, Harrison, Chakravarthy, Banerjee and Sanyal.

Figures

Figure 1
Figure 1
Flow diagram of patient inclusion from the three trials RIAL/NICOLA, CALM, and PREVALENCE.
Figure 2
Figure 2
Example PDFF and cT1 parametric maps for patients with NAS = 1 (A) cT1 = 684ms, PDFF = 6.5%; NAS = 3 (B) cT1 = 833ms, PDFF = 16.9%; and NAS = 5 (C) cT1 = 916ms, PDFF = 18.5%.
Figure 3
Figure 3
Box plots showing relationships between cT1 and PDFF with NAS (top row) and fibrosis (bottom row).

References

    1. Marra F, Lotersztajn S. Pathophysiology of NASH: Perspectives for a Targeted Treatment. Curr Pharm Des (2013) 19:5250–69. 10.2174/13816128113199990344
    1. Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease— meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (2016) 64(1):73–84. 10.1002/hep.28431
    1. Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol (2018) 15(1):11–20. 10.1038/nrgastro.2017.109
    1. Cholankeril G, Ahmed A. Alcoholic Liver Disease Replaces Hepatitis C Virus Infection as the Leading Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol (2018) 16(8):1356–8. 10.1016/j.cgh.2017.11.045
    1. Noureddin M, Nissen AV, Bresee C, Todo T, Kim I, Alkhouri N, et al. NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol (2018) 113(11):1649–59. 10.1038/s41395-018-0088-6
    1. Pournik O, Alavian S, Ghalichi L, Seifizarei B, Mehrnoush L, Aslani A, et al. Inter-observer and Intra-observer Agreement in Pathological Evaluation of Non-alcoholic Fatty Liver Disease Suspected Liver Biopsies. Hepat Mon2 (2014) 14(1):e15167. 10.5812/hepatmon.15167
    1. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology (2005) 128:1898–906. 10.1053/j.gastro.2005.03.084
    1. Center for Drug Evaluation and Research (CDER) F Nonalcoholic Steatohepatitis with Compensated Cirrhosis : Developing Drugs for Treatment Guidance for Industry Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry. Draft Guidance (2019) 49(5):1456–66. 10.1002/jmri.26312
    1. Permutt Z, Le T, Peterson M, Seki E, Brenner D, Sirlin C, et al. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease – MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther (2012) 36(1):22–9. 10.1111/j.1365-2036.2012.05121.x
    1. Tang A, Desai A, Hamilton G, Wolfson T, Gamst A, Lam J, et al. Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease. Radiology (2015) 274(2):416–25. 10.1148/radiol.14140754
    1. Idilman IS, Aniktar H, Idilman R, Kabacam G, Savas B, Elhan A, et al. Hepatic steatosis: quantification by proton density fat fraction with MR imaging versus liver biopsy. Radiol (2013) 267(3):767–75. 10.1148/radiol.13121360
    1. Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, et al. Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease. Gastroenterol (2017) 27 152(3):598–607.e2. 10.1053/j.gastro.2016.10.026
    1. Tang A, Tan J, Sun M, Hamilton G, Bydder M, Wolfson T, et al. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis. Radiol (2013) 267(2):422–31. 10.1148/radiol.12120896
    1. Middleton MS, Heba ER, Hooker CA, Bashir R, Fowler KJ, Sandrasegaran K, 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 Michael. Gastroenterology (2017) 153(3):753–61. 10.1053/j.gastro.2017.06.005
    1. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le T-A, et al. Utility of Magnetic Resonance Imaging Versus Histology for Quantifying Changes in Liver Fat in Nonalcoholic Fatty Liver Disease Trials. Hepatology (2013) 58(6):1930–40. 10.1002/hep.26455
    1. Kang GH, Cruite I, Shiehmorteza M, Wolfson T, Gamst AC, Hamilton G, et al. Reproducibility of MRI-Determined Proton Density Fat Fraction Across Two Different MR Scanner Platforms. J Magn Reson Imaging (2011) 34(4):928–34. 10.1002/jmri.22701
    1. Bachtiar V, Wilman H, Jacobs J, Newbould R, Kelly C, Gyngell M, et al. Reliability and reproducibility of multiparametric magnetic resonance imaging of the liver. PLoS One (2019) 14(4):e0214921. 10.1371/journal.pone.0214921
    1. Yokoo T, Hamilton G, Hernando D, Hu HH, Kukuk GM, Middleton MS, et al. linearity, Bias, and Precision of hepatic Proton Density Fat Fraction Measurements by Using Mr imaging: A Meta-Analysis. Radiology (2017) 000(0). 10.1148/radiol.2017170550
    1. Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol (2016) 65(6):1006–16. 10.1016/j.jhep.2016.06.005
    1. Glazer H, Levitt R, Lee J, Emami B, Gronemeyer S, Murphy W. Differentiation of radiation fibrosis from recurrent pulmonary neoplasm by magnetic resonance imaging. AJR Am J Roentgenol (1984) 143(4):729–30. 10.2214/ajr.143.4.729
    1. Mozes FE, Tunnicliffe EM, Pavlides M, Robson MD. Influence of fat on liver T (1) measurements using modified Look–Locker inversion recovery (MOLLI) methods at 3T. J Magn Reson Imaging (2016) 44(1):105–11. 10.1002/jmri.25146
    1. Tunnicliffe EM, Rajarshi B, Pavlides M, Neubauer S, Robson MD. A model for hepatic fibrosis: the competing effects of cell loss and iron on shortened modified Look-Locker inversion recovery T1 (shMOLLI-T1) in the liver. J Magn Reson Imag (2016) Jul 45(2):450–62. 10.1002/jmri.25392
    1. Pavlides M, Banerjee R, Tunnicliffe EM, Kelly C, Collier J, Wang LM, et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int (2017) 37(7):1065–73. 10.1111/liv.13284
    1. Eddowes P, McDonald N, Davies N, Semple S, Kendall T, Hodson J, et al. Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther (2017) 47(5):631–44. 10.1111/apt.14469
    1. Banerjee R, Pavlides M, Tunnicliffe EM, Piechnik SK, Sarania N, Philips R, et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepatol (2014) 61(1):69–77. 10.1016/j.jhep.2013.09.002
    1. McDonald N, Eddowes PJ, Hodson J, Semple SI, Davies NP, Kelly CJ, et al. Multiparametric magnetic resonance imaging for quantitation of liver disease: a two-centre cross-sectional observational study. Sci Rep (2018) 8(1):9189. 10.1038/s41598-018-27560-5
    1. Pavlides M, Banerjee R, Sellwood J, Kelly CJ, Robson MD, Booth JC, et al. Multiparametric magnetic resonance imaging predicts clinical outcomes in patients with chronic liver disease. J Hepatol (2016) 64:308–15. 10.1016/j.jhep.2015.10.009
    1. Levick C, Phillips-hughes J, Collier J, Banerjee R, Cobbold J, Wang LM, et al. Non-invasive assessment of portal hypertension by multi-parametric magnetic resonance imaging of the spleen : A proof of concept study. PLoS One (2019) 14(8):1–16. 10.1371/journal.pone.0221066
    1. Harrison SA, Dennis A, Fiore MM, Kelly MD, Kelly CJ, Paredes AH, et al. Utility and variability of three non-invasive liver fibrosis imaging modalities to evaluate efficacy of GR-MD-02 in subjects with NASH and bridging fibrosis during a phase-2 randomized clinical trial. PLoS One (2018) 13(9):1–12. 10.1371/journal.pone.0203054
    1. Harrison S, Rossi S, Paredes A, Trotter J, Bashir M, Guy C, et al. NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients with Nonalcoholic Steatohepatitis. Hepatology (2020) 71(4):1198–212. 10.1002/hep.30590
    1. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Articles Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis : a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet (2019) 6736(19):1–13. 10.1016/S0140-6736(19)32517-6
    1. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, 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(4):1239–50. 10.1002/hep.27647
    1. Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A, et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol (2016) 9(5):692–701. 10.1177/1756283X16656735
    1. Loomba R, Neuschwander-tetri BA, Sanyal A, Chalasani N, Diehl AM, Terrault N, et al. Multicenter validation of association between decline in MRI-PDFF and histologic response in nonalcoholic steatohepatitis. Hepatology (2020) 72(4):0–3. 10.1002/hep.31624
    1. Newsome PN, Sasso M, Deeks JJ, Paredes A, Boursier J, Chan W, et al. Articles FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis : a prospective derivation and global validation study. Lancet Gastro Hep (2020) 1253(19):1–12. 10.1016/S2468-1253(19)30383-8
    1. Bedossa P, Poitou C, Veyrie N, Bouillot J, Basdevant A, Paradis V, et al. Histopathological Algorithm and Scoring System for Evaluation of Liver Lesions in Morbidly Obese Patients. Hepatology (2012) 56:1751–9. 10.1002/hep.25889
    1. Kleiner DE, Brunt EM. Nonalcoholic Fatty Liver Disease : Pathologic Patterns and Biopsy Evaluation in Clinical. Semin Liver Dis (2012) 32(1):1–13. 10.1055/s-0032-1306421
    1. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver Fibrosis, but no Other Histologic Features, Associates with Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology (2015) 149(2):389–97. 10.1053/j.gastro.2015.04.043
    1. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis — new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol (2013) 10(11):1–10. 10.1038/nrgastro.2013.149
    1. Loomba R, Bedossa P, Guy C, Taub R, Bashir M, Harrison S. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to predict treatment response on NASH liver biopsy: a secondary analysis of the resmetirom randomized placebo controlled Phase 2 clinical trial 2020. J Hepatol (2020) 73:S19–57. 10.1016/S0168-8278(20)30656-5
    1. Hutton C, Gyngell M, Milanesi M, Bagur A, Brady M. Validation of a standardized MRI method for liver fat and T2 * quantification. PLos One (2018) 13(9):1–12. 10.1371/journal.pone.0204175
    1. Bagur AT, Robson MD, Brady M, Hutton C, Irving B, Gyngell ML. Magnitude - intrinsic water – fat ambiguity can be resolved with multipeak fat modeling and a multipoint search method. Magn Reson Med (2019) 13(9):460–75. 10.1002/mrm.27728
    1. Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. Gastroenterol Hepatol Assoc (2019) 2(10):1–16. 10.1001/jamanetworkopen.2019.12565
    1. Mojtahed A, Kelly CJ, Herlihy AH, Kin S, Wilman HR, Mckay A, et al. Reference range of liver corrected T1 values in a population at low risk for fatty liver disease — a UK Biobank sub-study, with an appendix of interesting cases. Abdom Radiol (2019) 44(1):72–84. 10.1007/s00261-018-1701-2
    1. Bashir M, Wolfson T, Gamst A, Fowler K, Ohliger M, Shah S, et al. Hepatic R2* is more strongly associated with proton density fat fraction than histologic liver iron scores in patients with nonalcoholic fatty liver disease. J Magn Reson Imaging (2018) 49(5):1456–66. 10.1002/jmri.26312
    1. Younossi Z, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Positive Results from REGENERATE: A Phase 3 International, Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for NASH. J Hepatol (2019) 70(1):e5. 10.1016/S0618-8278(19)30006-4

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj