Skip to main content
Log in

Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date

  • Leading Article
  • Published:
Pharmaceutical Medicine Aims and scope Submit manuscript

Abstract

Nonalcoholic fatty liver disease (NAFLD) has now become a worldwide health issue due to the obesity epidemic, affecting approximately 90% of the obese population and 15–40% of the general population. It is the most common form of chronic liver disease in the United States. NAFLD constitutes a spectrum of diseases ranging in severity from mild, such as fatty liver, progressing into nonalcoholic steatohepatitis (NASH), then fibrosis, and ending with cirrhosis. NASH and increasing fibrosis stage are associated with increased morbidity and mortality; the fibrosis stage is therefore a critical element of risk stratification needed to determine therapeutic approach and also the response to treatment. Liver biopsy is considered the ‘gold standard’ in the diagnosis of NAFLD. However, it is not practical for widespread clinical use because it is invasive, costly, and associated with complications including occasional death. These limitations have driven the development of noninvasive tests that can accurately predict the fibrosis stage in those with NAFLD. In this review, we provide a concise overview of different non-invasive measurements used for NAFLD/NASH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Courtesy of David E. Kleiner, M.D., Ph.D. National Cancer Institute

Similar content being viewed by others

References

  1. Albhaisi S, Sanyal A. Recent advances in understanding and managing non-alcoholic fatty liver disease. F1000Res. 2018;7:F1000 Faculty Rev-720.

    Article  CAS  Google Scholar 

  2. Siddiqui MS, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology. 2018;67(5):2001–12.

    Article  PubMed  Google Scholar 

  3. Isabela Andronescu C, Roxana-Purcarea M, Aurel Babes P. The role of noninvasive tests and liver biopsy in the diagnosis of nonalcoholic fatty liver disease. J Med Life. 2018;11(3):243–6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kleiner DE, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.

    Article  PubMed  Google Scholar 

  5. Perumpail BJ, et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–76.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sayiner M, et al. Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis. Ther Adv Gastroenterol. 2018;11:1756284818811508.

    Article  CAS  Google Scholar 

  7. Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010;5(6):463–6.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sanyal AJ, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54(1):344–53.

    Article  PubMed  Google Scholar 

  9. Diamond DL, et al. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics. PLoS Pathog. 2010;6(1):e1000719.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Fernando H, et al. (1)H and (3)(1)P NMR lipidome of ethanol-induced fatty liver. Alcohol Clin Exp Res. 2010;34(11):1937–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Min HK, et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012;15(5):665–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ganz M, Szabo G. Immune and inflammatory pathways in NASH. Hepatol Int. 2013;7(Suppl 2):771–81.

    Article  PubMed  Google Scholar 

  13. Masarone M, et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2018;2018:9547613.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Puri P, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology. 2009;50(6):1827–38.

    Article  CAS  PubMed  Google Scholar 

  15. Sherriff JL, et al. Choline, its potential role in nonalcoholic fatty liver disease, and the case for human and bacterial genes. Adv Nutr. 2016;7(1):5–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ferslew BC, et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2015;60(11):3318–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chow MD, Lee YH, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med. 2017;56:34–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li T, Apte U. Bile acid metabolism and signaling in cholestasis, inflammation, and cancer. Adv Pharmacol. 2015;74:263–302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bell LN, et al. Serum proteomic profiling in patients with drug-induced liver injury. Aliment Pharmacol Ther. 2012;35(5):600–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bell LN, et al. Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease. Hepatology. 2010;51(1):111–20.

    Article  CAS  PubMed  Google Scholar 

  21. Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2018;33(1):33–43.

    Article  CAS  Google Scholar 

  22. Ajmera V, et al. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology. 2017;65(1):65–77.

    Article  CAS  PubMed  Google Scholar 

  23. Neuman MG, Cohen LB, Nanau RM. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014;28(11):607–18.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Perito ER, et al. Association between cytokines and liver histology in children with nonalcoholic fatty liver disease. Hepatol Commun. 2017;1(7):609–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wan X, et al. Role of NLRP3 inflammasome in the progression of NAFLD to NASH. Can J Gastroenterol Hepatol. 2016;2016:6489012.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Loomba R, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017;25(5):1054–1062.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boursier J, Diehl AM. Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog. 2015;11(1):e1004559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sookoian S, Pirola CJ. Cell-free DNA methylation as liquid biopsy for the assessment of fibrosis in patients with nonalcoholic steatohepatitis: a gap between innovation and implementation. Hepatobiliary Surg Nutr. 2017;6(2):117–21.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mann J, Reeves HL, Feldstein AE. Liquid biopsy for liver diseases. Gut. 2018;67(12):2204–12.

    Article  CAS  PubMed  Google Scholar 

  30. Lambrecht J, et al. Prospects in non-invasive assessment of liver fibrosis: liquid biopsy as the future gold standard? Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt A):1024–36.

    Article  CAS  PubMed  Google Scholar 

  31. Vincent R, Sanyal A. Recent advances in understanding of NASH: MicroRNAs as both biochemical markers and players. Curr Pathobiol Rep. 2014;2(3):109–15.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gerhard GS, DiStefano JK. Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol. 2015;7(2):226–34.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–54.

    Article  CAS  PubMed  Google Scholar 

  34. Sterling RK, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–25.

    Article  CAS  PubMed  Google Scholar 

  35. Vallet-Pichard A, Mallet V, Pol S. FIB-4: a simple, inexpensive and accurate marker of fibrosis in HCV-infected patients. Hepatology. 2006;44(3):769 (author reply 769–770).

    Article  PubMed  Google Scholar 

  36. Shah AG, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McPherson S, et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59(9):1265–9.

    Article  PubMed  Google Scholar 

  38. Adams LA, 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):1536–43.

    Article  CAS  PubMed  Google Scholar 

  39. Sun W, et al. Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: a meta-analysis study. Hepatol Res. 2016;46(9):862–70.

    Article  CAS  PubMed  Google Scholar 

  40. Sumida Y, et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Siddiqui MS, et al. Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease. Liver Int. 2016;36(4):572–9.

    Article  CAS  PubMed  Google Scholar 

  42. Cai D, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wai CT, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–26.

    Article  PubMed  Google Scholar 

  44. Harrison SA, et al. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57(10):1441–7.

    Article  CAS  PubMed  Google Scholar 

  45. Cichoz-Lach H, et al. The BARD score and the NAFLD fibrosis score in the assessment of advanced liver fibrosis in nonalcoholic fatty liver disease. Med Sci Monit. 2012;18(12):CR735–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruffillo G, et al. Comparison of NAFLD fibrosis score and BARD score in predicting fibrosis in nonalcoholic fatty liver disease. J Hepatol. 2011;54(1):160–3.

    Article  PubMed  Google Scholar 

  47. Raszeja-Wyszomirska J, et al. Validation of the BARD scoring system in Polish patients with nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol. 2010;10:67.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kaswala DH, Lai M, Afdhal NH. Fibrosis assessment in nonalcoholic fatty liver disease (NAFLD) in 2016. Dig Dis Sci. 2016;61(5):1356–64.

    Article  CAS  PubMed  Google Scholar 

  49. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121(1):91–100.

    Article  CAS  PubMed  Google Scholar 

  50. Sanal MG. Biomarkers in nonalcoholic fatty liver disease-the emperor has no clothes? World J Gastroenterol. 2015;21(11):3223–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cheah MC, McCullough AJ, Goh GB. Current modalities of fibrosis assessment in non-alcoholic fatty liver disease. J Clin Transl Hepatol. 2017;5(3):261–71.

    PubMed  PubMed Central  Google Scholar 

  52. Ratziu V, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Cales P, et al. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol. 2009;50(1):165–73.

    Article  PubMed  Google Scholar 

  54. Cales P, et al. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology. 2005;42(6):1373–81.

    Article  PubMed  Google Scholar 

  55. Fagan KJ, et al. ELF score ≥ 9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int. 2015;35(6):1673–81.

    Article  PubMed  Google Scholar 

  56. Parkes J, Roderick P, Harris S, Day C, Mutimer D, Collier J, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut. 2010;59:1245–51.

    Article  CAS  PubMed  Google Scholar 

  57. Nobili V, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136(1):160–7.

    Article  CAS  PubMed  Google Scholar 

  58. Glen J, et al. Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance. BMJ. 2016;354:i4428.

    Article  PubMed  Google Scholar 

  59. Vassiliadis E, et al. Circulating levels of a collagen type v propeptide fragment in a carbon tetrachloride reversible model of liver fibrosis. Biomark Insights. 2012;7:159–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sand JM, et al. MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis–validation of two novel biomarker assays. PLoS One. 2013;8(12):e84934.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Leeming DJ, et al. Protein fingerprinting of the extracellular matrix remodelling in a rat model of liver fibrosis—a serological evaluation. Liver Int. 2013;33(3):439–47.

    Article  CAS  PubMed  Google Scholar 

  62. Luo Y, et al. An evaluation of the collagen fragments related to fibrogenesis and fibrolysis in nonalcoholic steatohepatitis. Sci Rep. 2018;8(1):12414.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Nielsen MJ, et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res. 2013;5(3):303–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Karsdal MA, et al. Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy. Am J Physiol Gastrointest Liver Physiol. 2016;311(6):G1009–17.

    Article  PubMed  Google Scholar 

  65. Nielsen MJ, et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int. 2015;35(2):429–37.

    Article  CAS  PubMed  Google Scholar 

  66. Leeming DJ, et al. Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension. Aliment Pharmacol Ther. 2013;38(9):1086–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Leeming DJ, et al. Pro-C5, a marker of true type V collagen formation and fibrillation, correlates with portal hypertension in patients with alcoholic cirrhosis. Scand J Gastroenterol. 2015;50(5):584–92.

    Article  PubMed  Google Scholar 

  68. Cassinotto C, et al. Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology. 2016;63(6):1817–27.

    Article  PubMed  Google Scholar 

  69. Sarvazyan A, et al. An overview of elastography—an emerging branch of medical imaging. Curr Med Imaging Rev. 2011;7(4):255–82.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Tang A, et al. Ultrasound elastography and MR elastography for assessing liver fibrosis: part 2, diagnostic performance, confounders, and future directions. AJR Am J Roentgenol. 2015;205(1):33–40.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zhao H, et al. Noninvasive assessment of liver fibrosis using ultrasound-based shear wave measurement and comparison to magnetic resonance elastography. J Ultrasound Med. 2014;33(9):1597–604.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Sigrist RMS, et al. Ultrasound elastography: review of techniques and clinical applications. Theranostics. 2017;7(5):1303–29.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Barr RG, et al. Elastography assessment of liver fibrosis: society of radiologists in ultrasound consensus conference statement. Radiology. 2015;276(3):845–61.

    Article  PubMed  Google Scholar 

  74. Laurent S, Jennifer O, Cécile B, Céline F, Véronique M, Sebastian M. Non-invasive assessment of liver fibrosis by vibration-controlled transient elastography (Fibroscan®). In: Liver biopsy. Hirokazu Takahashi; IntechOpen: 2011. https://doi.org/10.5772/20729.

    Google Scholar 

  75. de Ledinghen V, et al. Feasibility of liver transient elastography with FibroScan using a new probe for obese patients. Liver Int. 2010;30(7):1043–8.

    Article  PubMed  CAS  Google Scholar 

  76. Li Q, et al. Current status of imaging in nonalcoholic fatty liver disease. World J Hepatol. 2018;10(8):530–42.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepatic Med. 2010;2:49–67.

    Article  Google Scholar 

  78. Raizner A, et al. Hepatic inflammation may influence liver stiffness measurements by transient elastography in children and young adults. J Pediatr Gastroenterol Nutr. 2017;64(4):512–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ferraioli G, et al. Liver ultrasound elastography: an update to the world federation for ultrasound in medicine and biology guidelines and recommendations. Ultrasound Med Biol. 2018;44(12):2419–40.

    Article  PubMed  Google Scholar 

  80. Ferraioli G, et al. Point shear wave elastography method for assessing liver stiffness. World J Gastroenterol. 2014;20(16):4787–96.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Woo H, et al. Comparison of the reliability of acoustic radiation force impulse imaging and supersonic shear imaging in measurement of liver stiffness. Radiology. 2015;277(3):881–6.

    Article  PubMed  Google Scholar 

  82. Mariappan YK, Glaser KJ, Ehman RL. Magnetic resonance elastography: a review. Clin Anat. 2010;23(5):497–511.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Huwart L, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135(1):32–40.

    Article  PubMed  Google Scholar 

  84. Morisaka H, et al. Comparison of diagnostic accuracies of two- and three-dimensional MR elastography of the liver. J Magn Reson Imaging. 2017;45(4):1163–70.

    Article  PubMed  Google Scholar 

  85. Pavlides M, et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int. 2017;37(7):1065–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Decaris ML, et al. Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology. 2017;65(1):78–88.

    Article  CAS  PubMed  Google Scholar 

  87. Banerjee R, et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepatol. 2014;60(1):69–77.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Choe YG, et al. Apolipoprotein B/AI ratio is independently associated with non-alcoholic fatty liver disease in nondiabetic subjects. J Gastroenterol Hepatol. 2013;28(4):678–83.

    Article  CAS  PubMed  Google Scholar 

  89. Gray J, et al. A proteomic strategy to identify novel serum biomarkers for liver cirrhosis and hepatocellular cancer in individuals with fatty liver disease. BMC Cancer. 2009;9:271.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Higuchi N, et al. Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease. Exp Ther Med. 2011;2(6):1077–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang YL, et al. Intervening TNF-alpha via PPARgamma with gegenqinlian decoction in experimental nonalcoholic fatty liver disease. Evid Based Complement Alternat Med. 2015;2015:715638.

    PubMed  PubMed Central  Google Scholar 

  92. Lim JW, Dillon J, Miller M. Proteomic and genomic studies of non-alcoholic fatty liver disease—clues in the pathogenesis. World J Gastroenterol. 2014;20(26):8325–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lorena D, et al. Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells: modulation by mechanical stress and role in cell adhesion. Lab Invest. 2004;84(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  94. Rashid ST, et al. Proteomic analysis of extracellular matrix from the hepatic stellate cell line LX-2 identifies CYR61 and Wnt-5a as novel constituents of fibrotic liver. J Proteome Res. 2012;11(8):4052–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fitzpatrick E, Dhawan A. Noninvasive biomarkers in non-alcoholic fatty liver disease: current status and a glimpse of the future. World J Gastroenterol. 2014;20(31):10851–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Younossi ZM, et al. A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease. Hepatology. 2005;42(3):665–74.

    Article  CAS  PubMed  Google Scholar 

  97. Rodriguez-Suarez E, et al. Non-alcoholic fatty liver disease proteomics. Proteom Clin Appl. 2010;4(4):362–71.

    Article  CAS  Google Scholar 

  98. Sirota JC, et al. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism. 2013;62(3):392–9.

    Article  CAS  PubMed  Google Scholar 

  99. Haukeland JW, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol. 2006;44(6):1167–74.

    Article  CAS  PubMed  Google Scholar 

  100. Bell LN, et al. Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease. Hepatology. 2010;51(1):111–20.

    Article  CAS  PubMed  Google Scholar 

  101. Alkhouri N, et al. Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2009;43(10):985–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Graham TE, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354(24):2552–63.

    Article  CAS  PubMed  Google Scholar 

  103. Christou GA, Tselepis AD, Kiortsis DN. The metabolic role of retinol binding protein 4: an update. Horm Metab Res. 2012;44(1):6–14.

    Article  CAS  PubMed  Google Scholar 

  104. Yoneda M, et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol. 2007;42(7):573–82.

    Article  CAS  PubMed  Google Scholar 

  105. Yu C, et al. Serum proteomic analysis revealed diagnostic value of hemoglobin for nonalcoholic fatty liver disease. J Hepatol. 2012;56(1):241–7.

    Article  CAS  PubMed  Google Scholar 

  106. Kamada Y, et al. Serum fucosylated haptoglobin as a novel diagnostic biomarker for predicting hepatocyte ballooning and nonalcoholic steatohepatitis. PLoS One. 2013;8(6):e66328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yoneda M, et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol. 2008;8:53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Kaneda H, et al. Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2006;21(9):1459–65.

    CAS  PubMed  Google Scholar 

  109. Yoneda M, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. J Gastroenterol. 2007;42(5):375–81.

    Article  CAS  PubMed  Google Scholar 

  110. Gabrielli GB, et al. Serum laminin P1 in chronic viral hepatitis: correlations with liver histological activity and diagnostic value. Clin Chim Acta. 1996;252(2):171–80.

    Article  CAS  PubMed  Google Scholar 

  111. Krishnan A, et al. Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis. Lab Invest. 2012;92(12):1712–25.

    Article  CAS  PubMed  Google Scholar 

  112. D’Amico F, et al. Liver immunolocalization and plasma levels of MMP-9 in non-alcoholic steatohepatitis (NASH) and hepatitis C infection. Acta Histochem. 2010;112(5):474–81.

    Article  PubMed  CAS  Google Scholar 

  113. Wanninger J, et al. MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis. Exp Mol Pathol. 2011;91(2):603–7.

    Article  CAS  PubMed  Google Scholar 

  114. Kwak MS, et al. Serum bilirubin levels are inversely associated with nonalcoholic fatty liver disease. Clin Mol Hepatol. 2012;18(4):383–90.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Mansouri A, et al. MnSOD overexpression prevents liver mitochondrial DNA depletion after an alcohol binge but worsens this effect after prolonged alcohol consumption in mice. Dig Dis. 2010;28(6):756–75.

    Article  PubMed  Google Scholar 

  116. Kessova IG, et al. Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology. 2003;38(5):1136–45.

    Article  CAS  PubMed  Google Scholar 

  117. Jayaraman A, et al. Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis. Biotechnol Bioeng. 2005;91(4):502–15.

    Article  CAS  PubMed  Google Scholar 

  118. Yamaguchi H, et al. Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways. J Biol Chem. 2004;279(38):39431–7.

    Article  CAS  PubMed  Google Scholar 

  119. Zhu C, et al. Mechanism of the promotion of steatotic HepG2 cell apoptosis by cholesterol. Int J Clin Exp Pathol. 2014;7(10):6807–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Sabapathy K, et al. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell. 2004;15(5):713–25.

    Article  CAS  PubMed  Google Scholar 

  121. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev. 2008;60(3):311–57.

    Article  CAS  PubMed  Google Scholar 

  122. Al Sharif M, et al. Modes-of-action related to repeated dose toxicity: tissue-specific biological roles of PPAR gamma ligand-dependent dysregulation in nonalcoholic fatty liver disease. PPAR Res. 2014;2014:432647.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ehx G, et al. Liver proteomic response to hypertriglyceridemia in human-apolipoprotein C-III transgenic mice at cellular and mitochondrial compartment levels. Lipids Health Dis. 2014;13:116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Binas B, Erol E. FABPs as determinants of myocellular and hepatic fuel metabolism. Mol Cell Biochem. 2007;299(1–2):75–84.

    Article  CAS  PubMed  Google Scholar 

  125. Vilar-Gomez E, et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology. 2016;63(6):1875–87.

    Article  CAS  PubMed  Google Scholar 

  126. Neuschwander-Tetri BA, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65.

    Article  CAS  PubMed  Google Scholar 

  127. Poynard T, et al. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Daniels SJ, et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology. 2019;69(3):1075–86.

    Article  CAS  PubMed  Google Scholar 

  129. Peleg N, et al. AST to platelet ratio index and fibrosis 4 calculator scores for non-invasive assessment of hepatic fibrosis in patients with non-alcoholic fatty liver disease. Dig Liver Dis. 2017;49(10):1133–8.

    Article  CAS  PubMed  Google Scholar 

  130. Patel YA, et al. Identifying nonalcoholic fatty liver disease advanced fibrosis in the veterans health administration. Dig Dis Sci. 2018;63(9):2259–66.

    Article  CAS  PubMed  Google Scholar 

  131. Adams LA, et al. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem. 2005;51(10):1867–73.

    Article  CAS  PubMed  Google Scholar 

  132. Boursier J, et al. The combination of a blood test and Fibroscan improves the non-invasive diagnosis of liver fibrosis. Liver Int. 2009;29(10):1507–15.

    Article  PubMed  Google Scholar 

  133. Papastergiou V, Tsochatzis E, Burroughs AK. Non-invasive assessment of liver fibrosis. Ann Gastroenterol. 2012;25(3):218–31.

    PubMed  PubMed Central  Google Scholar 

  134. Martinez SM, et al. Noninvasive assessment of liver fibrosis. Hepatology. 2011;53(1):325–35.

    Article  PubMed  Google Scholar 

  135. Baranova A, et al. Non-invasive markers for hepatic fibrosis. BMC Gastroenterol. 2011;11:91.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arun J. Sanyal.

Ethics declarations

Funding

The authors declare no funding information.

Conflicts of interest

Dr Albhaisi has no conflicts of interest. Dr Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect, Exalenz, and Hemoshear. He has served as a consultant to AstraZeneca, Nitto Denko, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Fibrogen, Jannsen, Gilead, Lilly, Poxel, Artham, Cymabay, Boehringer Ingelheim, Novo Nordisk, Bird Rock Bio, Novartis, Pfizer, Jannsen, and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Afimmune, ChemomAb, Nordic Bioscience, and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, AstraZeneca, Mallinckrodt, Cumberland, and Novartis. He receives royalties from Elsevier and UptoDate.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Albhaisi, S., Sanyal, A.J. Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date. Pharm Med 33, 451–463 (2019). https://doi.org/10.1007/s40290-019-00305-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40290-019-00305-z

Navigation