Development of a non-invasive model to improve the accuracy of determining liver fibrosis stage in nonalcoholic fatty liver disease

Yu.M. Stepanov, N.V. Nedzvetskaya, V.B. Yagmur, I.A. Klenina, N.Yu. Oshmyanskaya


Background. The differentiation of mild (F1-F2) and advanced fibrosis (F3-F4), as well as the exclusion of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), are extremely important for prediction of the disease course. Integrative analyses of serum markers have been proposed as promising alternatives to biopsy method. Our study was targeted to develop a new model for determining the stage of fibrosis based on a more efficient combination of serological markers and to compare it with well-established algorithms. Materials and methods. Sixty patients with biopsy-proven NAFLD, including 26 (43 %) men and 34 (57 %) women, with average age of 37.10 ± 12.4 and 44.30 ± 7.25 years, respectively, were recruited for the study. Particularly, advanced fibrosis was diagnosed in 8 patients, 28 had mild fibrosis and 24 didn’t have any fibrosis according to morphological study. The following fibrosis markers were calculated: aspartate aminotransferase and alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the 4 factor (FIB-4). Among many variables, hyaluronic acid, α2-macroglobulin, apolipoprotein A1, fibronectin, and haptoglobin were included in comprehensive study. Integrative model have been built up to determine the stage of fibrosis. The models were compared with the area under the receiver operating characteristic (AUROC) curves. Results. The ROC analysis showed that the FIB-4 demonstrated the largest AUROC, for the F2 — 0.72, F3 — 0.8, F4 — 0.82, respectively. Obtained results of the APRI were significantly higher for mild and advanced fibrosis (F2 — 0.74, F3 — 0.82). The AAR values were reliable only for liver cirrhosis (AUROC 0.89). A strong direct correlation was determined between the stage of fibrosis and the level of hyaluronic acid, α2-macroglobulin and fibronectin (r = 0.72, 0.93 and 0.71, p < 0.05, respectively). Whereas, we observed a moderate negative linear correlation between fibrosis stage and the indices of both apolipoprotein A1 and haptoglobin (r = –0.61; r = –0.35, respectively, p < 0.05). The positive correlation was determined between activity of the inflammatory process and the content of hyaluronic acid, α2-macroglobulin and fibronectin (r = 0.54, 0.67 and 0.55 at p < 0.05), while the reverse moderate relation observed for apolipoprotein A1 and hapthoglobin (r = –0.56 and –0.33, p < 0.05). Conclusions. The analysis of obtained results showed that α2-macroglobulin, apolipoprotein A1, hyaluronic acid, and fibronectin had the greatest diagnostic validity among non-invasive markers of fibrosis. Every of them get the AUROC level higher than 0.75 for minimal fibrosis and, moreover, for moderate, significant fibrosis and cirrhosis they had an area more than 0.9.


nonalcoholic fatty liver disease; liver fibrosis; liver biopsy; non-invasive diagnostic methods

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Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000 Jan 18;132(2):112-7. PMID: 10644271.

Powell EE, Jonsson JR, Clouston AD. Dangerous liaisons: the metabolic syndrome and nonalcoholic fatty liver disease. Ann Intern Med. 2005 Nov 15;143(10):753-4. PMID: 16287799.

Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011 Aug;34(3):274-85. doi: 10.1111/j.1365-2036.2011.04724.x.

Turola E, Petta S, Vanni E, et al. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis. Dis Model Mech. 2015 Sep 1;8(9):1037-46. doi: 10.1242/dmm.019950.

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, WymerM. Global epidemiology of nonalcoholic fatty liver disease. Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431.

Marchesini G, Mazzotti A. NAFLD incidence and remission: only a matter of weight gain and weight loss? J Hepatol. 2015 Jan;62(1):15-7. doi: 10.1016/j.jhep.2014.10.023.

Bruno S, Maisonneuve P, Castellana P, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ. 2005 Apr 23;330(7497):932. doi: 10.1136/bmj.38391.663287.E0.

Lonardo A, Trande P. Are there any sex differences in fattyliver? A study of glucose metabolism and body fat distribution. J Gastroenterol Hepatol. 2000 Jul;15(7):775-82. PMID: 10937684.

Carter-Kent C, Zein NN, Feldstein AE. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am J Gastroenterol. 2008 Apr;103(4):1036-42. doi: 10.1111/j.1572-0241.2007.01709.x.

Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999 Nov;107(5):450-5. PMID: 10569299.

Younossi ZM. Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008 Jul;28(1):2-12. doi: 10.1111/j.1365-2036.2008.03710.x.

Tarantino G. Should nonalcoholic fatty liver disease be regarded as a hepatic illness only? World J Gastroenterol. 2007 Sep 21;13(35): 4669-72. doi: 10.3748/wjg.v13.i35.4669.

Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002 Nov;123(5):1705-25. PMID: 12404245.

Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. 2007 Feb;11(1):75-104, ix. doi: 10.1016/j.cld.2007.02.011.

Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med. 2000 Nov 16;343(20):1467-76. doi: 10.1056/NEJM200011163432007.

Abenavoli L, Peta V. Role of adipokines and cytokines in non-alcoholic fatty liver disease. Rev Recent Clin Trials. 2014;9(3):134-40. PMID: 25514909.

Sanyal AJ, American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002 Nov;123(5):1705-25. PMID: 12404245.

Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 2002 Dec;8(12):1114-22. doi: 10.1053/jlts.2002.36740.

Rifai K, Cornberg J, Mederacke I, et al. Clinical feasibility of liver elastography by acoustic radiation force impulse imaging (ARFI). Dig Liver Dis. 2011 Jun;43(6):491-7. doi: 10.1016/j.dld.2011.02.011.

Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: a review and update. Dig Dis Sci. 2010 Mar;55(3):560-78. doi: 10.1007/s10620-009-1081-0.

Bril F, Barb D, Portillo-Sanchez P, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017 Apr;65(4):1132-44. doi: 10.1002/hep.28985.

Di Martino M, Pacifico L, Bezzi M, et al. Comparison of magnetic resonance spectroscopy, proton density fat fraction and histological analysis in the quantification of liver steatosis in children and adolescents. World J Gastroenterol. 2016 Oct 21;22(39):8812-9. doi: 10.3748/wjg.v22.i39.8812.

Shukla A, Kapileswar S, Gogtay N, et al. Simple biochemical parameters and a novel score correlate with absence of fibrosis in patients with nonalcoholic fatty liver disease. Indian J Gastroenterol. 2015 Jul;34(4):281-5. doi: 10.1007/s12664-015-0580-5.

Rossi E, Adams LA, Ching HL, Bulsara M, MacQuillan GC, Jeffrey GP. High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis. Clin Chem Lab Med. 2013 May;51(5):1107-14. doi: 10.1515/cclm-2012-0584.

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 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004.

Oh MK, Winn J, Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008 Sep 1;28(5):503-22. doi: 10.1111/j.1365-2036.2008.03752.x.

Adams LA, Angulo P. Role of liver biopsy and serum markers of liver fibrosis in non-alcoholic fatty liver disease. Clin Liver Dis. 2007 Feb;11(1):25-35, viii. doi: 10.1016/j.cld.2007.02.004.

Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008 Sep;48(3):792-8. doi: 10.1002/hep.22429.

Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American association for the study of liver diseases, American college of gastroenterology, and the American gastroenterological association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762.

Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145-71. doi: 10.1146/annurev-pathol-121808-102132.

Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010 Apr;7(4):195-203. doi: 10.1038/nrgastro.2010.21.

Armstrong MJ, Houlihan DD, Bentham L, et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J Hepatol. 2012 Jan;56(1):234-40. doi: 10.1016/j.jhep.2011.03.020.

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 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004.

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 Sep;65(3):570-8. doi: 10.1016/j.jhep.2016.04.023.

Dyson JK, Anstee QM, McPherson S. Non-alcoholic fatty liver disease: A practical approach to diagnosis and staging. Frontline Gastroenterol. 2014 Jul;5(3):211-218. doi: 10.1136/flgastro-2013-100403.

Demir M, Lang S, Schlattjan M, Drebber U, et al. NIKEI: a new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD. PLoS One. 2013;8(3):e58360. doi: 10.1371/journal.pone.0058360.

Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015 Aug;149(2):389-97.e10. doi: 10.1053/j.gastro.2015.04.043.

Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015 May;61(5):1547-54. doi: 10.1002/hep.27368.

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