Download PDF
Semin Liver Dis 2020; 40(04): 331-338
DOI: 10.1055/s-0040-1713006
Review Article

Noninvasive Tests in the Assessment of NASH and NAFLD Fibrosis: Now and Into the Future

Leon A. Adams
1   Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, Western Australia, Australia
2   Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
,
Wah-Kheong Chan
3   Department of Medicine, Gastroenterology and Hepatology Unit, University of Malaysia, Kuala Lumpur, Malaysia
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from “omic” methodologies offer promise for the future.

Keywords

nonalcoholic fatty liver disease - nonalcoholic steatohepatitis - elastography - serum biomarkers


Publication History

Article published online:
11 June 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G. Noninvasive tests do not accurately differentiate nonalcoholic steatohepatitis from simple steatosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018; 16 (06) 837-861
    CrossrefPubMedGoogle Scholar
  • 2 Kleiner DE, Brunt EM, Van Natta M. et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (06) 1313-1321
    CrossrefPubMedGoogle Scholar
  • 3 Ratziu V, Charlotte F, Heurtier A. et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128 (07) 1898-1906
    CrossrefPubMedGoogle Scholar
  • 4 Zhou Y, Orešič M, Leivonen M. et al. Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites. Clin Gastroenterol Hepatol 2016; 14 (10) 1463-1472.e6
    CrossrefPubMedGoogle Scholar
  • 5 Kamada Y, Ono M, Hyogo H. et al; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG興NAFLD). Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis. Hepatol Commun 2017; 1 (08) 780-791
    CrossrefPubMedGoogle Scholar
  • 6 Alkhouri N, Johnson C, Adams L. et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels predict the presence of fibrotic nonalcoholic steatohepatitis (NASH) and NASH cirrhosis. PLoS One 2018; 13 (08) e0202226
    CrossrefPubMedGoogle Scholar
  • 7 Feldstein AE, Lopez R, Tamimi TA. et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res 2010; 51 (10) 3046-3054
    CrossrefPubMedGoogle Scholar
  • 8 Gorden DL, Myers DS, Ivanova PT. et al. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res 2015; 56 (03) 722-736
    CrossrefPubMedGoogle Scholar
  • 9 Kwok R, Tse YK, Wong GL. et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease--the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther 2014; 39 (03) 254-269
    CrossrefPubMedGoogle Scholar
  • 10 Cusi K, Chang Z, Harrison S. et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 60 (01) 167-174
    CrossrefPubMedGoogle Scholar
  • 11 Diab DL, Yerian L, Schauer P. et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clin Gastroenterol Hepatol 2008; 6 (11) 1249-1254
    CrossrefPubMedGoogle Scholar
  • 12 Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50 (04) 1072-1078
    CrossrefPubMedGoogle Scholar
  • 13 Vuppalanchi R, Jain AK, Deppe R. et al. Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12 (12) 2121-30.e1 , 2
    CrossrefPubMedGoogle Scholar
  • 14 Pihlajamäki J, Kuulasmaa T, Kaminska D. et al. Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans. J Hepatol 2012; 56 (03) 663-670
    CrossrefPubMedGoogle Scholar
  • 15 Ajmera V, Perito ER, Bass NM. et al; NASH Clinical Research Network. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology 2017; 65 (01) 65-77
    CrossrefPubMedGoogle Scholar
  • 16 Poynard T, Munteanu M, Charlotte F. et al; FLIP Consortium, the FibroFrance-CPAM Group, the FibroFrance-Obese Group. Diagnostic performance of a new noninvasive test for nonalcoholic steatohepatitis using a simplified histological reference. Eur J Gastroenterol Hepatol 2018; 30 (05) 569-577
    CrossrefPubMedGoogle Scholar
  • 17 Bril F, McPhaul MJ, Caulfield MP. et al. Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. J Investig Med 2019; 67 (02) 303-311
    CrossrefPubMedGoogle Scholar
  • 18 Shen J, Chan HL, Wong GL. et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J Hepatol 2012; 56 (06) 1363-1370
    CrossrefPubMedGoogle Scholar
  • 19 Yang M, Xu D, Liu Y. et al. Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis. PLoS One 2015; 10 (06) e0131664
    CrossrefPubMedGoogle Scholar
  • 20 Lai LL, Chan WK, Sthaneshwar P, Nik Mustapha NR, Goh KL, Mahadeva S. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in non-alcoholic fatty liver disease. PLoS One 2017; 12 (04) e0174982
    CrossrefPubMedGoogle Scholar
  • 21 Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y. et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology 2016; 63 (06) 1875-1887
    CrossrefPubMedGoogle Scholar
  • 22 Gallego-Durán R, Cerro-Salido P, Gomez-Gonzalez E. et al. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease. Sci Rep 2016; 6: 31421
    CrossrefPubMedGoogle Scholar
  • 23 Patel J, Bettencourt R, Cui J. et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2016; 9 (05) 692-701
    CrossrefPubMedGoogle Scholar
  • 24 Angulo P, Hui JM, Marchesini G. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45 (04) 846-854
    CrossrefPubMedGoogle Scholar
  • 25 Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ. Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009; 7 (10) 1104-1112
    CrossrefPubMedGoogle Scholar
  • 26 Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis. Hepatology 2017; 66 (05) 1486-1501
    CrossrefPubMedGoogle Scholar
  • 27 Adams LA, George J, Bugianesi E. et al. Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2011; 26 (10) 1536-1543
    CrossrefPubMedGoogle Scholar
  • 28 Loomba R, Jain A, Diehl AM. et al. Validation of serum test for advanced liver fibrosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2019; 17 (09) 1867-1876.e3
    CrossrefPubMedGoogle Scholar
  • 29 Guillaume M, Moal V, Delabaudiere C. et al. Direct comparison of the specialised blood fibrosis tests FibroMeterV2G and Enhanced Liver Fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres. Aliment Pharmacol Ther 2019; 50 (11-12): 1214-1222
    CrossrefPubMedGoogle Scholar
  • 30 Ducancelle A, Leroy V, Vergniol J. et al. A single test combining blood markers and elastography is more accurate than other fibrosis tests in the main causes of chronic liver diseases. J Clin Gastroenterol 2017; 51 (07) 639-649
    CrossrefPubMedGoogle Scholar
  • 31 Boyle M, Tiniakos D, Schattenberg JM. et al. Performance of the PRO-C3 collagen neo-epitope biomarker in non-alcoholic fatty liver disease. JHEP Rep 2019; 1 (03) 188-198
    CrossrefPubMedGoogle Scholar
  • 32 Bertot LC, Jeffrey GP, de Boer B. et al. Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease. Liver Int 2018; 38 (10) 1793-1802
    CrossrefPubMedGoogle Scholar
  • 33 Ampuero J, Pais R, Aller R. et al. Development and validation of hepamet fibrosis scoring system a simple, noninvasive test to identify patients with nonalcoholic fatty liver disease with advanced fibrosis. Clin Gastroenterol Hepatol 2019
    PubMedGoogle Scholar
  • 34 Daniels SJ, Leeming DJ, Eslam M. et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 2019; 69 (03) 1075-1086
    CrossrefPubMedGoogle Scholar
  • 35 Fagan KJ, Pretorius CJ, Horsfall LU. et al. ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int 2015; 35 (06) 1673-1681
    CrossrefPubMedGoogle Scholar
  • 36 McPherson S, Hardy T, Dufour JF. et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol 2017; 112 (05) 740-751
    CrossrefPubMedGoogle Scholar
  • 37 Wong VW, Vergniol J, Wong GL. et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010; 51 (02) 454-462
    CrossrefPubMedGoogle Scholar
  • 38 Boursier J, Zarski JP, de Ledinghen V. et al; Multicentric Group from ANRS/HC/EP23 FIBROSTAR Studies. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology 2013; 57 (03) 1182-1191
    CrossrefPubMedGoogle Scholar
  • 39 Arena U, Lupsor Platon M, Stasi C. et al. Liver stiffness is influenced by a standardized meal in patients with chronic hepatitis C virus at different stages of fibrotic evolution. Hepatology 2013; 58 (01) 65-72
    CrossrefPubMedGoogle Scholar
  • 40 Wong VW, Irles M, Wong GL. et al. Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease. Gut 2019; 68 (11) 2057-2064
    CrossrefPubMedGoogle Scholar
  • 41 Wong VW, Vergniol J, Wong GL. et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012; 107 (12) 1862-1871
    CrossrefPubMedGoogle Scholar
  • 42 Cassinotto C, Boursier J, de Lédinghen V. et al. Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 2016; 63 (06) 1817-1827
    CrossrefPubMedGoogle Scholar
  • 43 Xu Y, Liu Y, Cao Z. et al. Comparison of FibroTouch and FibroScan for staging fibrosis in chronic liver disease: Single-center prospective study. Dig Liver Dis 2019; 51 (09) 1323-1329
    CrossrefPubMedGoogle Scholar
  • 44 Sigrist RMS, Liau J, Kaffas AE, Chammas MC, Willmann JK. Ultrasound elastography: review of techniques and clinical applications. Theranostics 2017; 7 (05) 1303-1329
    CrossrefPubMedGoogle Scholar
  • 45 Friedrich-Rust M, Nierhoff J, Lupsor M. et al. Performance of acoustic radiation force impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012; 19 (02) e212-e219
    CrossrefPubMedGoogle Scholar
  • 46 Lee MS, Bae JM, Joo SK. et al. Prospective comparison among transient elastography, supersonic shear imaging, and ARFI imaging for predicting fibrosis in nonalcoholic fatty liver disease. PLoS One 2017; 12 (11) e0188321
    CrossrefPubMedGoogle Scholar
  • 47 Leong WL, Lai LL, Nik Mustapha NR. et al. Comparing point shear wave elastography (ElastPQ) and transient elastography for diagnosis of fibrosis stage in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2019
    PubMedGoogle Scholar
  • 48 Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013; 37 (03) 544-555
    CrossrefPubMedGoogle Scholar
  • 49 Loomba R, Cui J, Wolfson T. et al. Novel 3D magnetic resonance elastography for the noninvasive diagnosis of advanced fibrosis in NAFLD: a prospective study. Am J Gastroenterol 2016; 111 (07) 986-994
    CrossrefPubMedGoogle Scholar
  • 50 Imajo K, Kessoku T, Honda Y. et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology 2016; 150 (03) 626-637.e7
    CrossrefPubMedGoogle Scholar
  • 51 Petta S, Vanni E, Bugianesi E. et al. The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 2015; 35 (05) 1566-1573
    CrossrefPubMedGoogle Scholar
  • 52 Chan WK, Treeprasertsuk S, Goh GB. et al. Optimizing use of Nonalcoholic Fatty Liver Disease Fibrosis Score, Fibrosis-4 Score, and Liver Stiffness Measurement to identify patients with advanced fibrosis. Clin Gastroenterol Hepatol 2019; 17 (12) 2570-2580.e37
    CrossrefPubMedGoogle Scholar
  • 53 Petta S, Wai-Sun Wong V, Bugianesi E. et al. Impact of obesity and alanine aminotransferase levels on the diagnostic accuracy for advanced liver fibrosis of noninvasive tools in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2019; 114 (06) 916-928
    CrossrefPubMedGoogle Scholar
  • 54 Boursier J, de Ledinghen V, Leroy V. et al. A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis. J Hepatol 2017; 66 (06) 1158-1165
    CrossrefPubMedGoogle Scholar
  • 55 Chalasani N, Abdelmalek MF, Loomba R. et al. Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with NASH. Liver Int 2019; 39 (05) 924-932
    CrossrefPubMedGoogle Scholar
  • 56 Jayakumar S, Middleton MS, Lawitz EJ. et al. Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: analysis of data from a phase II trial of selonsertib. J Hepatol 2019; 70 (01) 133-141
    CrossrefPubMedGoogle Scholar
  • 57 Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL. et al. Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH. Liver Int 2017; 37 (12) 1887-1896
    CrossrefPubMedGoogle Scholar
  • 58 Siddiqui MS, Yamada G, Vuppalanchi R. et al. Diagnostic accuracy of non-invasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol 2019
    PubMedGoogle Scholar
  • 59 Boursier J, Vergniol J, Guillet A. et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol 2016; 65 (03) 570-578
    CrossrefPubMedGoogle Scholar
  • 60 Treeprasertsuk S, Björnsson E, Enders F, Suwanwalaikorn S, Lindor KD. NAFLD fibrosis score: a prognostic predictor for mortality and liver complications among NAFLD patients. World J Gastroenterol 2013; 19 (08) 1219-1229
    CrossrefPubMedGoogle Scholar
  • 61 Kamarajah SK, Chan WK, Nik Mustapha NR, Mahadeva S. Repeated liver stiffness measurement compared with paired liver biopsy in patients with non-alcoholic fatty liver disease. Hepatol Int 2018; 12 (01) 44-55
    CrossrefPubMedGoogle Scholar
  • 62 Pavlides M, Banerjee R, Tunnicliffe EM. et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int 2017; 37 (07) 1065-1073
    CrossrefPubMedGoogle Scholar
  • 63 Newsome PN, Sasso M, Deeks JJ. et al. 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 Gastroenterol Hepatol 2020; 5 (04) 362-373 [Erratum in Lancet Gastroenterol Hepatol 2020;5(04):e3
    Google Scholar
  • 64 Boursier J, Anty R, Vonghia L. et al. Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH. Aliment Pharmacol Ther 2018; 47 (10) 1387-1396
    CrossrefPubMedGoogle Scholar
  • 65 Chuah KH, Wan Yusoff WNI, Sthaneshwar P, Nik Mustapha NR, Mahadeva S, Chan WK. MACK-3 (combination of hoMa, Ast and CK18): a promising novel biomarker for fibrotic non-alcoholic steatohepatitis. Liver Int 2019; 39 (07) 1315-1324
    CrossrefPubMedGoogle Scholar
  • 66 Banerjee R, Pavlides M, Tunnicliffe EM. et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepatol 2014; 60 (01) 69-77
    CrossrefPubMedGoogle Scholar
  • 67 McDonald N, Eddowes PJ, Hodson J. et al. Multiparametric magnetic resonance imaging for quantitation of liver disease: a two-centre cross-sectional observational study. Sci Rep 2018; 8 (01) 9189
    CrossrefPubMedGoogle Scholar