Skip to main content

Integrative Proposal for the Use of Biomarkers in Clinical Practice Management of NAFLD/NASH

  • Chapter
  • First Online:
  • 653 Accesses

Abstract

Identification of non-alcoholic fatty liver disease (NAFLD) and discrimination of the different subgroups of patients, grouped under this umbrella term are key issues in the field of liver diseases. While liver biopsy may still be used to diagnose and stage the disease, noninvasive tools (NITs) to appropriately asses the presence of NAFLD and its severity (i.e. presence of NASH) or degree of progression (i.e. presence of advanced fibrosis or cirrhosis) has been developed and validated in several cohorts during the last decade. These NITs include a wide variety of serum markers (i.e. routinely used serum parameters, biological markers of inflammation or fibrosis, microRNAs as well as lipid metabolites or panels serum proteins), equations combining serum markers and clinical features and advanced imaging techniques, either ultrasound-based or magnetic resonance-based, allowing to evaluate physical properties of the liver. In this chapter, we summarize the concepts reviewed in depth in previous chapters and propose the NITs to be used at present time to evaluate presence and severity of NAFLD in clinical practice.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Younossi ZM, Koenig AB, 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.

    Article  PubMed  Google Scholar 

  2. Younossi ZM. Non-alcoholic fatty liver disease—a global public health perspective. J Hepatol. 2019;70(3):531–44.

    Article  PubMed  Google Scholar 

  3. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123–33.

    Article  CAS  PubMed  Google Scholar 

  4. Bluher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15:288–98.

    Article  PubMed  Google Scholar 

  5. Glovaci D, Fan W, Wong ND. Epidemiology of diabetes mellitus and cardiovascular disease. Curr Cardiol Rep. 2019;21(4):21.

    Article  PubMed  Google Scholar 

  6. Guthold R, Stevens GA, Riley LM, Bull FC. Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. Lancet Glob Health. 2018;6(10):e1077–e86.

    Article  PubMed  Google Scholar 

  7. Younossi Z, Tacke F, Arrese M, Sharma BC, Mostafa I, Bugianesi E, et al. Global perspectives on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Hepatology. 2019;69(6):2672–82.

    Article  PubMed  Google Scholar 

  8. Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2019;16(6):377–86.

    Article  PubMed  Google Scholar 

  9. Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321–50.

    Article  CAS  PubMed  Google Scholar 

  10. Nasr P, Ignatova S, Kechagias S, Ekstedt M. Natural history of nonalcoholic fatty liver disease: a prospective follow-up study with serial biopsies. Hepatol Commun. 2018;2(2):199–210.

    Article  CAS  PubMed  Google Scholar 

  11. Lindenmeyer CC, McCullough AJ. The natural history of nonalcoholic fatty liver disease—an evolving view. Clin Liver Dis. 2018;22(1):11–21.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Arab JP, Barrera F, Arrese M. The evolving role of liver biopsy in non-alcoholic fatty liver disease. Ann Hepatol. 2018;17(6):899–902.

    Article  PubMed  Google Scholar 

  13. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156(5):1264–81. e4

    Article  PubMed  Google Scholar 

  14. Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers. J Hepatol. 2018;68(2):305–15.

    Article  CAS  PubMed  Google Scholar 

  15. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.

    Article  PubMed  Google Scholar 

  16. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018;68(1):349–60.

    Article  PubMed  Google Scholar 

  17. Younossi ZM, Golabi P, de Avila L, Minhui Paik J, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801.

    Article  PubMed  Google Scholar 

  18. Bril F, Cusi K. Nonalcoholic fatty liver disease: the new complication of type 2 diabetes mellitus. Endocrinol Metab Clin N Am. 2016;45(4):765–81.

    Article  Google Scholar 

  19. Younossi ZM, Stepanova M, Ong J, Yilmaz Y, Duseja A, Eguchi Y, et al. Effects of alcohol consumption and metabolic syndrome on mortality in patients with nonalcoholic and alcohol-related fatty liver disease. Clin Gastroenterol Hepatol. 2019;17(8):1625–33. e1

    Article  CAS  PubMed  Google Scholar 

  20. Kim D, Touros A, Kim WR. Nonalcoholic fatty liver disease and metabolic syndrome. Clin Liver Dis. 2018;22(1):133–40.

    Article  PubMed  Google Scholar 

  21. European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–402.

    Article  Google Scholar 

  22. Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis. World J Gastroenterol. 2018;24(30):3361–73.

    Article  PubMed  PubMed Central  Google Scholar 

  23. (NICE) NIfHaCE. Non-alcoholic fatty liver disease (NAFLD): assessment and management 2016 [updated July 2016]. nice.org.uk/guidance/ng49.

  24. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54(3):1082–90.

    Article  PubMed  Google Scholar 

  25. Jimenez-Aguero R, Emparanza JI, Beguiristain A, Bujanda L, Alustiza JM, Garcia E, et al. Novel equation to determine the hepatic triglyceride concentration in humans by MRI: diagnosis and monitoring of NAFLD in obese patients before and after bariatric surgery. BMC Med. 2014;12:137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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(5):1006–16.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017;66(5):1022–30.

    Article  PubMed  Google Scholar 

  28. Pelusi S, Valenti L. Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease. Liver Int. 2019;39(2):250–6.

    Article  PubMed  Google Scholar 

  29. Bedossa P. Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: why liver biopsy is essential. Liver Int. 2018;38(Suppl 1):64–6.

    Article  PubMed  Google Scholar 

  30. Caldwell S, Lackner C. Perspectives on NASH histology: cellular ballooning. Ann Hepatol. 2017;16(2):182–4.

    Article  PubMed  Google Scholar 

  31. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9.

    Article  CAS  PubMed  Google Scholar 

  32. Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13(4):511–31.

    Article  PubMed  Google Scholar 

  33. Wong VW-S, Adams LA, de Lédinghen V, Wong GL-H, Sookoian S. Noninvasive biomarkers in NAFLD and NASH—current progress and future promise. Nat Rev Gastroenterol Hepatol. 2018;15(8):461–78.

    Article  CAS  PubMed  Google Scholar 

  34. 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(4):1072–8.

    Article  CAS  PubMed  Google Scholar 

  35. Pirola CJ, Sookoian S. Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity. World J Gastroenterol. 2018;24(15):1601–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mayo R, Crespo J, Martinez-Arranz I, Banales JM, Arias M, Minchole I, et al. Metabolomic-based noninvasive serum test to diagnose nonalcoholic steatohepatitis: results from discovery and validation cohorts. Hepatol Commun. 2018;2(7):807–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Arrese M, Eguchi A, Feldstein AE. Circulating microRNAs: emerging biomarkers of liver disease. Semin Liver Dis. 2015;35(1):43–54.

    Article  CAS  PubMed  Google Scholar 

  38. Gjorgjieva M, Sobolewski C, Dolicka D, Correia de Sousa M, Foti M. miRNAs and NAFLD: from pathophysiology to therapy. Gut. 2019;68(11):2065–79

    Google Scholar 

  39. Besutti G, Valenti L, Ligabue G, Bassi MC, Pattacini P, Guaraldi G, et al. Accuracy of imaging methods for steatohepatitis diagnosis in non-alcoholic fatty liver disease patients: a systematic review. Liver Int. 2019;39(8):1521–34.

    Article  PubMed  Google Scholar 

  40. Gallego-Duran R, Cerro-Salido P, Gomez-Gonzalez E, Pareja MJ, Ampuero J, Rico MC, et al. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease. Sci Rep. 2016;6:31421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Agbima U, Asranib SK. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol. 2019;13(4):361–74.

    Article  CAS  Google Scholar 

  42. Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, 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 

  43. Loomba R, Jain A, Diehl AM, Guy CD, Portenier D, Sudan R, et al. Validation of serum test for advanced liver fibrosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2019;17(9):1867–76.e3.

    Article  CAS  PubMed  Google Scholar 

  44. Ampuero J, Pais R, Aller R, Gallego-Duran R, Crespo J, Garcia-Monzon C, et al. Development and validation of hepamet fibrosis scoring system—a simple, non-invasive test to identify patients with nonalcoholic fatty liver disease with advanced fibrosis. Clin Gastroenterol Hepatol. 2019.

    Google Scholar 

  45. Yin M, Glaser KJ, Talwalkar JA, Chen J, Manduca A, Ehman RL. Hepatic MR elastography: clinical performance in a series of 1377 consecutive examinations. Radiology. 2016;278(1):114–24.

    Article  PubMed  Google Scholar 

  46. Wong VW, Adams LA, de Ledinghen V, Wong GL, Sookoian S. Noninvasive biomarkers in NAFLD and NASH—current progress and future promise. Nat Rev Gastroenterol Hepatol. 2018;15(8):461–78.

    Article  CAS  PubMed  Google Scholar 

  47. Alkhouri N, Lawitz E, Noureddin M. Looking into the crystal ball: predicting the future challenges of fibrotic NASH treatment. Hepatol Commun. 2019;3(5):605–13.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Boursier J, Zheng MH, Wong VW, Michalak S, Li YY, Chan AWH, et al. PS-201 external validation in NAFLD cohorts of the FibroScan-based FAST score combining liver stiffness, controlled attenuation parameter and AST to identify patients with active NASH (NAS ≥ 4) and significant fibrosis (F ≥ 2). J Hepatol. 2019;70:e133–e40.

    Google Scholar 

  49. Boursier J, Guillaume M, Leroy V, Irles M, Roux M, Lannes A, et al. New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD. J Hepatol. 2019;71(2):389–96.

    Article  PubMed  Google Scholar 

  50. Petta S, Wong VW, Camma C, Hiriart JB, Wong GL, Vergniol J, et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther. 2017;46(6):617–27.

    Article  CAS  PubMed  Google Scholar 

  51. Agbim U, Asrani SK. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol. 2019;13(4):361–74.

    Article  CAS  PubMed  Google Scholar 

  52. Bertot LC, Jeffrey GP, Wallace M, MacQuillan G, Garas G, Ching HL, et al. Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma. Hepatol Commun. 2017;1(1):53–60.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Arrese M, Feldstein AE. Nash-related cirrhosis: an occult liver disease burden. Hepatol Commun. 2017;1(2):84–6.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Procopet B, Berzigotti A. Diagnosis of cirrhosis and portal hypertension: imaging, non-invasive markers of fibrosis and liver biopsy. Gastroenterol Rep (Oxf). 2017;5(2):79–89.

    Article  Google Scholar 

  55. Zhang YN, Fowler KJ, Ozturk A, Potu CK, Louie AL, Montes V, et al. Liver fibrosis imaging: a clinical review of ultrasound and magnetic resonance elastography. J Magn Reson Imaging. 2019;

    Google Scholar 

  56. Stefan N, Haring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7(4):313–24.

    Article  PubMed  Google Scholar 

  57. Tapper EB, Loomba R. Noninvasive imaging biomarker assessment of liver fibrosis by elastography in NAFLD. Nat Rev Gastroenterol Hepatol. 2018;15(5):274–82.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Castera L. Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: non-invasive tests are enough. Liver Int. 2018;38(Suppl 1):67–70.

    Article  PubMed  Google Scholar 

  59. Valery PC, Powell EE. Engaging primary care clinicians in the assessment of NAFLD. Nat Rev Gastroenterol Hepatol. 2019;16(8):458–60.

    Article  PubMed  Google Scholar 

  60. Alexander M, Loomis AK, Fairburn-Beech J, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med. 2018;16(1):130.

    Article  PubMed  PubMed Central  Google Scholar 

  61. American Diabetes A. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S34–45.

    Article  Google Scholar 

  62. Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65(8):1359–68.

    Article  CAS  PubMed  Google Scholar 

  63. Arab JP, Barrera F, Gallego C, Valderas JP, Uribe S, Tejos C, et al. High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients. Ann Hepatol. 2016;15(5):721–8.

    PubMed  Google Scholar 

  64. Bertot LC, Jeffrey GP, de Boer B, MacQuillan G, Garas G, Chin J, 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):1793–802.

    Article  CAS  PubMed  Google Scholar 

  65. Bril F, McPhaul MJ, Caulfield MP, Castille JM, Poynard T, Soldevila-Pico C, 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(2):303–11.

    Article  PubMed  Google Scholar 

  66. Rowe IA, Parker R. The diagnosis of nonalcoholic fatty liver disease should carry important prognostic information. Nat Rev Gastroenterol Hepatol. 2019;16:449–50.

    Article  PubMed  Google Scholar 

  67. Younossi ZM, Stepanova M, Rafiq N, Henry L, Loomba R, Makhlouf H, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease. Hepatol Commun. 2017;1(5):421–8.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Mazzotti A, Caletti MT, Brodosi L, Di Domizio S, Forchielli ML, Petta S, et al. An internet-based approach for lifestyle changes in patients with NAFLD: two-year effects on weight loss and surrogate markers. J Hepatol. 2018;69(5):1155–63.

    Article  PubMed  Google Scholar 

  69. Forlano R, B H, Mullish BH, Katertsidis N, Giannakeas N, Tzallas A, et al. A mobile application for the management and follow-up of patients with non-alcoholic fatty liver disease. J Hepatol. 2018;68:S605–842.

    Google Scholar 

  70. Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, 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 

Download references

Acknowledgements

Conflict of interest: The authors declare not to have conflict of interests related to this scientific work.

Funding: Financial support and sponsorship: This article was partially supported by the Chilean government through the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1191145 to M.A., 1200227 to JPA and 1191183 to F.B.) and the Comisión Nacional de Investigación Científica y Tecnológica (grant CONICYT PIA/Basal PFB12, Basal Centre for Excellence in Science and Technology to M.A.).

J.M. Banales received support from the Spanish Ministry of Economy and Competitiveness (FIS PI15/01132, FIS PI18/01075 and Miguel Servet Programme CON14/00129), cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), CIBERehd (ISCIII), BIOEF (EiTB Maratoia BIO15/CA/016/BD), Department of Health of the Basque Country (2017111010), “Fundación Científica de la Asociación Española Contra el Cancer” (AECC Scientific Foundation) and La Caixa Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Arrese .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Benítez, C., Arab, J.P., Barrera, F., Banales, J.M., Arrese, M. (2020). Integrative Proposal for the Use of Biomarkers in Clinical Practice Management of NAFLD/NASH. In: Romero-Gomez, M. (eds) NAFLD and NASH. Springer, Cham. https://doi.org/10.1007/978-3-030-37173-9_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-37173-9_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-37172-2

  • Online ISBN: 978-3-030-37173-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics