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International Journal of Frontiers in Medicine, 2023, 5(6); doi: 10.25236/IJFM.2023.050607.

Risk factors for liver fibrosis progression from early stage to late stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis


Yan Wan, Feifan Liu, Yuanmei Bai, Lijie Zheng, Yuhuan Xie, Peixin Guo

Corresponding Author:
Yuhuan Xie

College of Ethnic Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, China


OBJECTIVE: The risk factors of fibrosis progression from an early stage to a late stage in non-alcoholic fatty liver disease were systematically analyzed, providing evidence for clinical workers to identify, intervene and block the progression of liver fibrosis in patients at an early stage.METHODS: The author independently used PubMed for a literature search on November 21, 2022. Two researchers independently screened the literature and cross-checked it. Any disputes were resolved by consulting the third researcher. The quality of the literature was evaluated using the Newcastle Ottawa Sca, and Then perform statistical analysis through Review Manager 5.4.RESULTS: Nine kinds of literature were included in this study. A meta-analysis of 11 factors associated with advanced fibrosis in patients with early-stage of nonalcoholic fatty liver disease showed that 5 factors were statistically significant, namely diabetes mellitus (OR=4.04, 95%CI 1.51-10.82, P=0.006). High body mass index (MD=1.89, 95%CI 0.78-3.00, P=0.0009); Low platelet count (MD=-45.05, 95%CI -66.49-(-23.26), P=0.0001); High levels of aspartate aminotransferase (MD=14.92, 95%CI 8.53-21.31, P=0.00001); Low serum albumin (MD=-0.37, 95%CI-0.62-(-0.12), P=0.004). CONCLUSIONS: This study found that diabetes mellitus, high body mass index, low platelet count, high aspartate aminotransferase levels, and low serum albumin may be major risk factors for early fibrosis progression in NAFLD.


Nonalcoholic fatty liver disease liver fibrosis; Early liver fibrosis; Advanced liver fibrosis; Risk factors; Meta-analysis

Cite This Paper

Yan Wan, Feifan Liu, Yuanmei Bai, Lijie Zheng, Yuhuan Xie, Peixin Guo. Risk factors for liver fibrosis progression from early stage to late stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis. International Journal of Frontiers in Medicine (2023), Vol. 5, Issue 6: 34-45. https://doi.org/10.25236/IJFM.2023.050607.


[1] M.M. Aydin, K.C. Akcali, Liver fibrosis, Turk J Gastroenterol, 29 (2018) 14-21.

[2] M. Sun, T. Kisseleva, Reversibility of liver fibrosis, Clin Res Hepatol Gastroenterol, 39 Suppl 1 (2015) S60-63.

[3] H. Jiang, J. Chen, R. Gao, Z. Huang, M. Wu, B. Song, Liver fibrosis staging with diffusion-weighted imaging: a systematic review and meta-analysis, Abdom Radiol (NY), 42 (2017) 490-501.

[4] F. Baratta, D. Pastori, F. Angelico, A. Balla, A.M. Paganini, N. Cocomello, D. Ferro, F. Violi, A.J. Sanyal, M. Del Ben, Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study, Clin Gastroenterol Hepatol, 18 (2020) 2324-2331 e2324.

[5] H. Fujii, K. Imajo, M. Yoneda, T. Nakahara, H. Hyogo, H. Takahashi, T. Hara, S. Tanaka, Y. Sumida, Y. Eguchi, K. Chayama, A. Nakajima, N. Nishimoto, N. Kawada, D. Japan Study Group of Nonalcoholic Fatty Liver, HOMA-IR: An independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease, J Gastroenterol Hepatol, 34 (2019) 1390-1395.

[6] D.W. Jun, S.G. Kim, S.H. Park, S.Y. Jin, J.S. Lee, J.W. Lee, M.Y. Kim, D.H. Choi, Y.K. Cho, J.E. Yeon, J.H. Sohn, N.s.g. Korean, External validation of the non-alcoholic fatty liver disease fibrosis score for assessing advanced fibrosis in Korean patients, J Gastroenterol Hepatol, 32 (2017) 1094-1099.

[7] G.J. Park, E. Wiseman, J. George, P.H. Katelaris, F. Seow, C. Fung, M.C. Ngu, Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test, J Gastroenterol Hepatol, 26 (2011) 1411-1416.

[8] H. Cichoz-Lach, K. Celinski, B. Prozorow-Krol, J. Swatek, M. Slomka, T. Lach, The BARD score and the NAFLD fibrosis score in the assessment of advanced liver fibrosis in nonalcoholic fatty liver disease, Med Sci Monit, 18 (2012) CR735-740.

[9] H.W. Lee, B.K. Kim, S.U. Kim, J.Y. Park, D.Y. Kim, S.H. Ahn, K.J. Kim, K.H. Han, Prevalence and Predictors of Significant Fibrosis Among Subjects with Transient Elastography-Defined Nonalcoholic Fatty Liver Disease, Dig Dis Sci, 62 (2017) 2150-2158.

[10] K. Kodama, T. Kawaguchi, H. Hyogo, T. Nakajima, M. Ono, M. Seike, H. Takahashi, Y. Nozaki, M. Kawanaka, S. Tanaka, K. Imajo, Y. Sumida, Y. Kamada, H. Fujii, Y. Seko, T. Takehara, Y. Itoh, A. Nakajima, N. Masaki, T. Torimura, T. Saibara, Y. Karino, K. Chayama, K. Tokushige, Clinical features of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without advanced fibrosis, J Gastroenterol Hepatol, 34 (2019) 1626-1632.

[11] K. Kakisaka, Y. Suzuki, Y. Fujiwara, T. Abe, M. Yonezawa, H. Kuroda, K. Ishida, T. Sugai, Y. Takikawa, Evaluation of ballooned hepatocytes as a risk factor for future progression of fibrosis in patients with non-alcoholic fatty liver disease, J Gastroenterol, 53 (2018) 1285-1291.

[12] S. Gomez de la Cuesta, R. Aller de la Fuente, C. Tafur Sanchez, O. Izaola, C. Garcia Sanchez, N. Mora, J.M. Gonzalez Hernandez, D. de Luis Roman, Analytical, anthropometric and dietary factors associated with the development of fibrosis in patients with nonalcoholic fatty liver disease, Rev Esp Enferm Dig, 110 (2018) 292-298.

[13] S. McPherson, E. Henderson, A.D. Burt, C.P. Day, Q.M. Anstee, Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease, J Hepatol, 60 (2014) 1055-1062.

[14] V. Subramanian, R.D. Johnston, P. Kaye, G.P. Aithal, Regional anthropometric measures associated with the severity of liver injury in patients with non-alcoholic fatty liver disease, Aliment Pharmacol Ther, 37 (2013) 455-463.

[15] V. Kumar, X. Xin, J. Ma, C. Tan, N. Osna, R.I. Mahato, Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis, Advanced Drug Delivery Reviews, 176 (2021).

[16] E.-J. Rhee, Nonalcoholic Fatty Liver Disease and Diabetes: An Epidemiological Perspective, Endocrinology and Metabolism, 34 (2019).

[17] T. Alkayyali, L. Qutranji, E. Kaya, A. Bakir, Y. Yilmaz, Clinical utility of noninvasive scores in assessing advanced hepatic fibrosis in patients with type 2 diabetes mellitus: a study in biopsy-proven non-alcoholic fatty liver disease, Acta Diabetol, 57 (2020) 613-618.

[18] F.E. Mózes, J.A. Lee, E.A. Selvaraj, A.N.A. Jayaswal, M. Trauner, J. Boursier, C. Fournier, K. Staufer, R.E. Stauber, E. Bugianesi, R. Younes, S. Gaia, M. Lupșor-Platon, S. Petta, T. Shima, T. Okanoue, S. Mahadeva, W.K. Chan, P.J. Eddowes, G.M. Hirschfield, P.N. Newsome, V.W. Wong, V. de Ledinghen, J. Fan, F. Shen, J.F. Cobbold, Y. Sumida, A. Okajima, J.M. Schattenberg, C. Labenz, W. Kim, M.S. Lee, J. Wiegand, T. Karlas, Y. Yılmaz, G.P. Aithal, N. Palaniyappan, C. Cassinotto, S. Aggarwal, H. Garg, G.J. Ooi, A. Nakajima, M. Yoneda, M. Ziol, N. Barget, A. Geier, T. Tuthill, M.J. Brosnan, Q.M. Anstee, S. Neubauer, S.A. Harrison, P.M. Bossuyt, M. Pavlides, Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis, Gut, 71 (2022) 1006-1019.

[19] S.A. Polyzos, J. Kountouras, C.S. Mantzoros, Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics, Metabolism, 92 (2019) 82-97.

[20] M. Hedenstierna, A. Nangarhari, A. El-Sabini, O. Weiland, S. Aleman, Cirrhosis, high age and high body mass index are risk factors for persisting advanced fibrosis after sustained virological response in chronic hepatitis C, J Viral Hepat, 25 (2018) 802-810.

[21] S. Petta, V. Di Marco, C. Camma, G. Butera, D. Cabibi, A. Craxi, Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index, Aliment Pharmacol Ther, 33 (2011) 1350-1360.

[22] P. Stal, Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance, World J Gastroenterol, 21 (2015) 11077-11087.

[23] M. Naldi, M. Baldassarre, M. Domenicali, M. Bartolini, P. Caraceni, Structural and functional integrity of human serum albumin: Analytical approaches and clinical relevance in patients with liver cirrhosis, J Pharm Biomed Anal, 144 (2017) 138-153.

[24] F. Tabata, Y. Wada, S. Kawakami, K. Miyaji, Serum Albumin Redox States: More Than Oxidative Stress Biomarker, Antioxidants (Basel), 10 (2021).

[25] R. Spinella, R. Sawhney, R. Jalan, Albumin in chronic liver disease: structure, functions and therapeutic implications, Hepatol Int, 10 (2016) 124-132.

[26] M. Ruart, L. Chavarria, G. Camprecios, N. Suarez-Herrera, C. Montironi, S. Guixe-Muntet, J. Bosch, S.L. Friedman, J.C. Garcia-Pagan, V. Hernandez-Gea, Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury, J Hepatol, 70 (2019) 458-469.

[27] M. Yoneda, H. Fujii, Y. Sumida, H. Hyogo, Y. Itoh, M. Ono, Y. Eguchi, Y. Suzuki, N. Aoki, K. Kanemasa, K. Imajo, K. Chayama, T. Saibara, N. Kawada, K. Fujimoto, Y. Kohgo, T. Yoshikawa, T. Okanoue, D. Japan Study Group of Nonalcoholic Fatty Liver, Platelet count for predicting fibrosis in nonalcoholic fatty liver disease, J Gastroenterol, 46 (2011) 1300-1306.

[28] N. Gotlieb, N. Schwartz, S. Zelber-Sagi, G. Chodick, V. Shalev, O. Shibolet, Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis, World J Gastroenterol, 26 (2020) 5849-5862.

[29] H.T. Gozdas, N. Ince, Elevated mean platelet volume to platelet ratio predicts advanced fibrosis in chronic hepatitis C, Eur J Gastroenterol Hepatol, 32 (2020) 524-527.

[30] F. Liu, H. Zhou, L. Cao, Z. Guo, C. Dong, L. Yu, Y. Wang, C. Liu, J. Qiu, Y. Xue, X. Liu, Y. Xu, Risk of reduced platelet counts in patients with nonalcoholic fatty liver disease (NAFLD): a prospective cohort study, Lipids Health Dis, 17 (2018) 221.

[31] M. Yoshida, R. Tateishi, S. Hiroi, M. Fujiwara, Y. Kitanishi, K. Iwasaki, T. Takeshima, A. Igarashi, Changes in Platelet Counts and Thrombocytopenia Risk in Patients with Chronic Liver Disease with Different Etiologies Using Real-World Japanese Data, Adv Ther, 39 (2022) 992-1003.

[32] W.J. Zhou, J. Yang, G. Zhang, Z.Q. Hu, Y.M. Jiang, F. Yu, Association between red cell distribution width-to-platelet ratio and hepatic fibrosis in nonalcoholic fatty liver disease: A cross-sectional study, Medicine (Baltimore), 98 (2019) e16565.

[33] J. Hu, Y. Zheng, H. Ying, H. Ma, L. Li, Y. Zhao, Alanyl-Glutamine Protects Mice against Methionine- and Choline-Deficient-Diet-Induced Steatohepatitis and Fibrosis by Modulating Oxidative Stress and Inflammation, Nutrients, 14 (2022).

[34] T. Li, Y. Yan, B. Wang, H. Qian, X. Zhang, L. Shen, M. Wang, Y. Zhou, W. Zhu, W. Li, W. Xu, Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis, Stem Cells Dev, 22 (2013) 845-854.

[35] S. Gawrieh, L.A. Wilson, O.W. Cummings, J.M. Clark, R. Loomba, B. Hameed, M.F. Abdelmalek, S. Dasarathy, B.A. Neuschwander-Tetri, K. Kowdley, D. Kleiner, E. Doo, J. Tonascia, A. Sanyal, N. Chalasani, N.C.R. Network, Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels, Am J Gastroenterol, 114 (2019) 1626-1635.

[36] W. Qingbo, L. Jinhua, Effects of swimming under different loads on some inflammatory factors of blood serum of rats with hyperlipemia, Journal of Physical Education 16 (2009) 105-109.

[37] G. Yunlong, W. Xiong-jian, Nonalcoholic fatty liver disease driven by metabolic disease, Journal Of Gannan Medical University, 42 (2022) 758-764.

[38] F. Mansour-Ghanaei, F. Joukar, S.N. Mobaraki, S. Mavaddati, S. Hassanipour, M. Sepehrimanesh, Prevalence of non-alcoholic fatty liver disease in patients with diabetes mellitus, hyperlipidemia, obesity and polycystic ovary syndrome: A cross-sectional study in north of Iran, Diabetes Metab Syndr, 13 (2019) 1591-1596.