Metabolic-associated fatty liver disease: Noninvasive diagnosis and assessment of liver fibrosis

Metabolically associated fatty liver disease as one of the most common liver pathologies in the world, which ranges from simple steatosis to more severe forms such as steatohepatitis, which can progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. The stage of fibrosis in hepatic tissue is associated with an increased risk of overall mortality, cardiovascular disease, hepatocellular carcinoma and extrahepatic malignancies, especially in the elderly, when there is an increased predisposition to metabolic disorders, which may lead to the development of fatty liver dystrophy and progression of fibrosis. Histologic methods of liver examination, including liver biopsies are highly informative, making this method of diagnosing liver pathology crucial in verifying the diagnosis; however, these procedures may have rare but potentially serious complications. In this regard, the relevance of using various non-invasive methods to assess the severity of fibrotic processes in liver tissue, including existing scales and algorithms such as FIB-4 and NAFLD Fibrosis Score, BARD and BAAT scales, APRI index and ultrasound elastography is undeniable. This review study examines the use of modern non-invasive approaches to assess the degree of fibrosis in patients with metabolically associated fatty liver disease, including elderly patients. Thus, as a first step the use of calculated fibrosis indices, such as FIB-4 index, NFS scale, followed, if necessary, by ultrasound diagnostic methods, especially liver elastography, is very relevant.

1. Geier A, Tiniakos D, Denk H, Trauner M. From the origin of NASH to the future of metabolic fatty liver disease. Gut. 2021;70(8):1570–1579. https://doi.org/10.1136/gutjnl-2020-323202.

2. Battistella S, D’Arcangelo F, Grasso M, Zanetto A, Gambato M, Germani G et al. Liver transplantation for Nafld: indications and post-transplant management. Clin Mol Hepatol. 2023;29:286–301. https://doi.org/10.3350/cmh.2022.0392.

3. Wong R, Cheung R. Trends in the prevalence of metabolic dysfunctionassociated fatty liver disease in the United States, 2011–2018. Clin Gastroenterol Hepatol. 2022;20(3):610–613. https://doi.org/10.1016/j.cgh.2021.01.030.

4. Kim D, Konyn P, Sandhu K, Dennis B, Cheung A, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased allcause mortality in the United States. J Hepatol. 2021;75(6):1284–1291. https://doi.org/10.1016/j.jhep.2021.07.035.

5. Wang TY, Wang RF, Bu ZY, Targher G, Byrne CD, Sun DQ, Zheng MH. Association of metabolic dysfunction-associated fatty liver disease with kidney disease. Nat Rev Nephrol. 2022;18(4):259–268. https://doi.org/10.1038/s41581-021-00519-y.

6. Gheorghe G, Bungău S, Ceobanu G, Ilie M, Bacalbaşa N, Bratu O et al. The non-invasive assessment of hepatic fibrosis. J Formos Med Assoc. 2021;120(2):794–803. https://doi.org/10.1016/j.jfma.2020.08.019.

7. Riazi K, Azhari H, Charette J, Underwood F, King, JA, Afshar E et al. The prevalence and incidence of NAFLD worldwide:a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851–861. https://doi.org/10.1016/S2468-1253(22)00165-0.

8. Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YuV, Tkacheva ON, Troshina EA et al. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2022;32(4):104–140. (In Russ.) https://doi.org/10.22416/1382-4376-2022-32-4-104-140.

9. McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. 2010;51(4):1450–1460. https://doi.org/10.1002/hep.23533.

10. Midia M, Odedra D, Shuster A, Midia R, Muir J. Predictors of bleeding complications following percutaneous image-guided liver biopsy: a scoping review. Diagn Interv Radiol. 2019;25(1):71–80. https://doi.org/10.5152/dir.2018.17525.

11. Neuberger J, Patel J, Caldwell H, Davies S, Hebditch V, Hollywood C et al. Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology. Gut. 2020;69(8):1382–1403. https://doi.org/10.1136/gutjnl-2020-321299.

12. Campos-Murguía A, Ruiz-Margáin A, González-Regueiro J, MacíasRodríguez R. Clinical assessment and management of liver fibrosis in nonalcoholic fatty liver disease. World J Gastroenterol. 2020;26(39):5919–5943. https://doi.org/10.3748/wjg.v26.i39.5919.

13. Hagström H, Nasr P, Ekstedt M. Hammar U, Stål P, Hultcrantz R, Kechagias S. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265–1273. https://doi.org/10.1016/j.jhep.2017.07.027.

14. Bassal T, Basheer M, Boulos M, Assy N. Nonalcoholic fatty liver disease – a concise review of noninvasive tests and biomarkers. Metabolites. 2022;12(11):1073. https://doi.org/10.3390/metabo12111073.

15. Cataldo I, Sarcognato S, Sacchi D, Cacciatore М, Baciorri F, Mangia A et al. Pathology of non-alcoholic fatty liver disease. Pathologica. 2021;113(3):194–202. https://doi.org/10.32074/1591-951X-242.

16. Kleiner D, Brunt E, Van Natta M, Behling C, Contos MJ, Cummings O et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321. https://doi.org/10.1002/hep.20701.

17. Sterling R, Lissen E, Clumeck N, Sola R, Correa M, Montaner J et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–1325. https://doi.org/10.1002/hep.21178.

18. Peleg N, Issachar A, Sneh-Arbib O, Shlomai A. AST to Platelet Ratio Index and fibrosis 4 calculator scores for non-invasive assessment of hepatic fibrosis in patients with nonalcoholic fatty liver disease. Dig Liver Dis. 2017;49(10):1133–1138. https://doi.org/10.1016/j.dld.2017.05.002.

19. McPherson S, Hardy T, Dufour J, Petta S, Romero-Gomez M, Allison M et al. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol. 2017;112(5):740–751. https://doi.org/10.1038/ajg.2016.453.

20. Sumida Y, Yoneda M, Hyogo H, Itoh Y, Ono M, Fujii H et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2. https://doi.org/10.1186/1471-230X-12-2.

21. Lazebnik LB, Golovanova EV, Turkina SV, Raikhelson KL, Okovityy SV, Drapkina OM et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Experimental and Clinical Gastroenterology. 2021;1(1):4–52. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-185-1-4-52.

22. Angulo P, Hui J, Marchesini G, Bugianesi E, George J, Farrell G et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–854. https://doi.org/10.1002/hep.21496.

23. Wu Y, Kumar R, Wang M, Singh M, Huang J, Zhu Y, Lin S. Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease. World J Gastroenterol. 2021;27(34):5753–5763. https://doi.org/10.3748/wjg.v27.i34.5753.

24. Li G, Zhang X, Lin H, Liang YL, Wong GLH, Wong VWS. Non-invasive tests of non-alcoholic fatty liver disease. Chin Med J. 2022;135(05):532–546. https://doi.org/10.1097/CM9.0000000000002027.

25. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004.

26. Harrison S, Oliver D, Arnold H, Gogia S, Neuschwander-Tetri B. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57(10):1441–1447. https://doi.org/10.1136/gut.2007.146019.

27. 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(5):1486–1501. https://doi.org/10.1002/hep.29302.

28. Cichoż-Lach H, Celiński K, Prozorow-Król B, Swatek J, Słomka M, Lach T. 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):CR735–740. https://doi.org/10.12659/msm.883601.

29. Chen X, Goh G, Huang J, Wu Y, Wang M, Kumar R et al. Validation of noninvasive fibrosis scores for predicting advanced fibrosis in metabolicassociated fatty liver disease. J Clin Transl Hepatol. 2022;10(4):589–594. https://doi.org/10.14218/JCTH.2021.00311.

30. Sun W, Cui H, Li N, Wei Y, Lai S, Yang Y 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):862–870. https://doi.org/10.1111/hepr.12647.

31. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok ASF. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–526. https://doi.org/10.1053/jhep.2003.50346.

32. Kolhe KM, Amarapurkar A, Parikh P, Chaubal A, Chauhan S, Khairnar H et al. Aspartate transaminase to platelet ratio index (APRI) but not FIB-5 or FIB-4 is accurate in ruling out significant fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) in an urban slum-dwelling population. BMJ Open Gastroenterol. 2019;6(1):e000288. https://doi.org/10.1136/bmjgast-2019-000288.

33. Pitisuttithum P, Chan WK, Piyachaturawat P, Imajo K, Nakajima A, Seki Y et al. Predictors of advanced fibrosis in elderly patients with biopsyconfirmed nonalcoholic fatty liver disease: the GOASIA study. BMC Gastroenterol. 2020;20(1):88. https://doi.org/10.1186/s12876-020-01240-z.

34. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118(6):1117–1123. https://doi.org/10.1016/s0016-5085(00)70364-7.

35. Anty R, Iannelli A, Patouraux S, Bonnafous S, Lavallard V, Senni-Buratti M et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of nonalcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol Ther. 2010;32(11-12): 1315–1322. https://doi.org/10.1111/j.1365-2036.2010.04480.x.

36. Kruger FC, Daniels CR, Kidd M, Swart G, Brundyn K, van Rensburg C, Kotze M. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J. 2011;101(7):477–480. https://pubmed.ncbi.nlm.nih.gov/21920102/.

37. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104–1112. https://doi.org/10.1016/j.cgh.2009.05.033.

38. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127(6):1704–1713. https://doi.org/10.1053/j.gastro.2004.08.052.

39. Lichtinghagen R, Pietsch D, Bantel H, Manns M, Brand K, Bahr M. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013;59(2):236–242. https://doi.org/10.1016/j.jhep.2013.03.016.

40. Vali Y, Lee J, Boursier J, Spijker R, Löffler J, Verheij J et al. Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis. J Hepatol. 2020;73(2):252–262. https://doi.org/10.1016/j.jhep.2020.03.036.

41. Li G, Zhang X, Lin H, Liang LY, Wong GLH, Wong VWS. Non-invasive tests of non-alcoholic fatty liver disease. Chin Med J. 2022;135(05):532–546. https://doi.org/10.1097/CM9.0000000000002027.

42. Altamirano J, Qi Q, Choudhry S, Abdallah M, Singal AK, Humar A et al. Noninvasive diagnosis: non-alcoholic fatty liver disease and alcoholic liver disease. Transl Gastroenterol Hepatol. 2020;5:31. https://doi.org/10.21037/tgh.2019.11.14.

43. Poynard T, Imbert-Bismut F, Munteanu M, Messous D, Myers RP, Thabut D et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp. Hepatol. 2004;3(1):8. https://doi.org/10.1186/1476-5926-3-8.

44. Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L 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. https://doi.org/10.1186/1471-230X-6-6.

45. 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):305–315. https://doi.org/10.1016/j.jhep.2017.11.013.

46. Vali Y, Lee J, Boursier J, Spijker R, Verheij J, Brosnan MJ et al. FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis. J Clin Med. 2021;10(11):2415. https://doi.org/10.3390/jcm10112415.

47. Wong VWS, Vergnoil J, Wong GLH, Foucher J, Chan HLY, Le Bail B et al. Diagnosis of Fibrosis and Cirrhosis Using Liver Stiffness Measurement in Nonalcoholic Fatty Liver Disease. Hepatology. 2010;51(2):454–462. https://doi.org/10.1002/hep.23312.

48. Yoneda M, Yoneda M, Mawatari H, Fujita K, Endo H, Iida H et al. Noninvasive assessment of liver fibrosis by measurement of stifness in patients with nonalcoholic fatty liver disease (NAFLD). Dig Liver Dis. 2008;40(5):371–378. https://doi.org/10.1016/j.dld.2007.10.019.

49. Kwok R, Tse YK, Wong GLH, Ha Y, Lee AU, Ngu MC 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(3):254–269. https://doi.org/10.1111/apt.12569.

50. Myers RP, Pomier-Layrargues G, Kirsch R, Pollett A, Duarte-Rojo A, Wong D et al. Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients. Hepatology. 2012;55(1):199–208. https://doi.org/10.1002/hep.24624.

51. Salles N, Dussarat P, Foucher J, Villars S, de Lédinghen V. Non-invasive evaluation of liver fibrosis by transient elastography and biochemical markers in elderly inpatients. Gastroenterol Clin Biol. 2009;33(2):126–132. https://doi.org/10.1016/j.gcb.2008.12.003.

52. Mitkov VV, Mitkova MD. Ultrasound shear wave elastography. Ultrasound and Functional Diagnostics. 2015;(2):94–108. (In Russ.) Avalaible at: https://elibrary.ru/tuidch.

53. Yoneda M, Suzuki K, Kato S, Fujita K, Nozaki Y, Hosono K et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology. 2010;256(2):640–647. https://doi.org/10.1148/radiol.10091662.

54. Palmeri ML, Wang MH, Rouze NC, Abdelmalek MF, Guy CD, Moser B et al. Noninvasive evaluation of hepatic fibrosis using acoustic radiation forcebased shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol. 2011;55(3):666–672. https://doi.org/10.1016/j.jhep.2010.12.019.

55. Liu H, Fu J, Hong R, Li F. Acoustic Radiation Force Impulse Elastography for the Non-Invasive Evaluation of Hepatic Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review & Meta-Analysis. PLoS One. 2015;10(7):e0127782–e0127782. https://doi.org/10.1371/journal.pone.0127782.

56. Ferraioli G, Wong V, Castera L, Berzigotti A, Sporea I, Dietrich CF 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):2419–2440. https://doi.org/10.1016/j.ultrasmedbio.2018.07.008.

57. 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):328–357. https://doi.org/10.1002/hep.29367.

58. Lazebnik LB, Radchenko VG, Golovanova EV, Zvenigorodskaya LA, Konev YuV, Seliverstov PV et al. Nonalcoholic fatty liver disease: clinic, diagnostics, treatment (Recommendations for therapists, 2nd edition). Experimental and Clinical Gastroenterology. 2017;(2):22–37. (In Russ.) Available at: https://www.nogr.org/jour/article/view/377/377.