The Difference of Hypoxic Inducible Factor-1α, Vascular Endothelial Growth Factor, and Transforming Growth Factor-β1 Based on Liver Fibrosis Severity in Patients with Chronic Hepatitis B
DOI:
https://doi.org/10.3889/oamjms.2021.5639Keywords:
Chronic Hepatitis B, Hypoxic Inducible Factor-1α, Liver Fibrosis, Transforming Growth Factor-β1, Vascular Endothelial Growth FactorAbstract
BACKGROUND: Hepatitis B is a global health problem. The disease damages hepatocytes and creates tissue hypoxic condition. Hypoxia triggers production of several mediators such as hypoxic inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-β1. The mediators act in liver fibrosis and cirrhosis, and hepatocellular carcinoma.
AIM: The objective of the study was to determine the difference in serum HIF-1α, VEGF, and TGF-β1 levels based on liver fibrosis severity in patients with chronic hepatitis B.
MATERIALS AND METHODS: This cross-sectional study was performed in Haji Adam Malik Hospital Medan, Indonesia, from January to July 2020. Subjects were chronic hepatitis B patients aged 18 years or older. Exclusion criteria were other chronic diseases, malignancies, or pregnancy. Liver fibrosis was determined using shear wave elastography and categorized as follow: F1, F2, F3, and F4. Serum HIF-1α, VEGF, and TGF-β1 levels were measured using enzyme-linked immunosorbent assay. Specimens were obtained from venous blood.
RESULTS: A total of 63 patients were enrolled in this study with mean age of 40.3 (SD 11.69) years. Subjects were dominated by males (58.7%). There were no differences in serum HIF-1α, VEGF, and TGF-β1 levels based on liver fibrosis grading and also based on hepatitis B envelope antigen (HBeAg) status and gender. Associations between liver fibrosis grading, HBeAg, and gender were absent. There was a positive correlation between liver fibrosis severity and age (r = 0.311, p = 0.013).
CONCLUSION: Serum HIF-1α, VEGF, and TGF-β1 levels were not different among chronic hepatitis B patients based on liver fibrosis severity.
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Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30(12):2212-9. https://doi.org/10.1016/j.vaccine.2011.12.116 PMid:22273662
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965-2013. Lancet. 2015;386(10003):1546-55. https://doi.org/10.1016/s0140-6736(15)61412-x PMid:26231459
Liaw Y. Antiviral therapy of chronic hepatitis B: Opportunities and challenges in Asia. J Hepatol. 2009;51(2):403-10. PMid:19467727
Kementerian Kesehatan Republik Indonesia. Badan Penelitian dan Pengembangan Kesehatan Kementerian Kesehatan Republik Indonesia, Riset Kesehatan Dasar 2013. Jakarta: Kementerian Kesehatan Republik Indonesia; 2013. Available from: https://www.kemkes.go.id/resources/download/general/ hasil%20riskesdas%202013.pdf. [Last accessed on 2020 Dec 05]. https://doi.org/10.6066/jtip.2013.24.2.121
Lesmana CR, Lesmana LA. Perjalanan Penyakit Hepatitis B: Hepatitis B di Indonesia Dari Molekul Sampai Terapi. Jakarta: Digestive Disease and GI Oncology Centre Mediastra Hospital; 2015.
Makhlouf MM, Awad A, Zakhari MM, Fouad M, Saleh WA. Vascular endothelial growth factor level in chronic liver diseases. J Egypt Soc Parasitol. 2002;32(3):907-21. PMid:12512823
Kim SJ, Choi IK, Park KH, Yoon SY, Oh SC, Seo JH, et al. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: Correlations with clinical parameters and survival. Jpn J Clin Oncol. 2004;34(4):184-90. https://doi.org/10.1093/jjco/hyh039 PMid:15121753
Nova F, Siregar GA, Sungkar T. Comparison of serum vascular endothelial growth factor (VEGF) in degrees Child Pugh cirrhosis patients. Indian J Appl Res. 2019;9:37-9.
Abdelmoaty MA, Bogdady AM, Attia MM, Zaky NA. Circulating vascular endothelial growth factor and nitric oxide in patients with liver cirrhosis: A possible association with liver function impairment. Indian J Clin Biochem. 2009;24(4):398-403. https://doi.org/10.1007/s12291-009-0071-5 PMid:23105867
Assy N, Paizi M, Gaitini D, Baruch Y, Spira G. Clinical implication of VEGF serum levels in cirrhotic patients with or without portal hypertension. World J Gastroenterol. 1999;5(4):296-300. https://doi.org/10.3748/wjg.v5.i4.296 PMid:11819451
Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344(7):495-500. PMid:11172192
Rousselet MC, Michalak S, Dupré F, Croué A, Bedossa P, SaintAndré JP, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology. 2005;41(2):257-64. https://doi.org/10.1002/hep.20535 PMid:15660389
Mulherin SA, Miller WC. Spectrum bias or spectrum effect? Subgroup variation in diagnostic test evaluation. Ann Intern Med. 2002;137:598-602. https://doi.org/10.7326/0003-4819-137-7-200210010-00011 PMid:12353947
Shiha G, Ibrahim A, Helmy A, Sarin SK, Omata M, Kumar A, et al. Asian-pacific association for the study of the liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: A 2016 update. Hepatol Int. 2017;11(1):1-30. https://doi.org/10.1007/s12072-016-9760-3 PMid:27714681
Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut. 2007;56(7):968-73. https://doi.org/10.1136/gut.2006.111302 PMid:17255218
McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49 Suppl 5:S45-55. PMid:19399792
Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39 Suppl 10:S60-3. PMid:26206574
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209-18. PMid:15690074
Matak P, Heinis M, Mathieu JR, Corriden R, Cuvellier S, Delga S, et al. Myeloid HIF-1 is protective in Helicobacter pylorimediated gastritis. J Immunol. 2015;194(7):3259-66. https://doi.org/10.4049/jimmunol.1401260 PMid:25710915
Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge. Cancer Sci. 2018;109(3):560-71. https://doi.org/10.1111/cas.13483 PMid:29285833
Corrado C, Fontana S. Hypoxia and HIF signaling: One axis with divergent effects. Int J Mol Sci. 2020;21(16):5611. https://doi.org/10.3390/ijms21165611 PMid:32764403
Verrecchia F, Mauviel A. Transforming growth factor-beta and fibrosis. World J Gastroenterol. 2007;13(22):3056-62. https://doi.org/10.3748/wjg.v13.i22.3056 PMid:17589920
Latasa MU, Boukaba A, García-Trevijano ER, Torres L, Rodríguez JL, Caballería J, et al. Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: Role in liver regeneration. FASEB J. 2001;15(7):1248-50. https://doi.org/10.1096/fj.00-0556fjev1 PMid:11344103
Roth KJ, Copple BL. Role of hypoxia-inducible factors in the development of liver fibrosis. Cell Mol Gastroenterol Hepatol. 2015;1(6):589-97. PMid:28210703
Kron P, Linecker M, Limani P, Schlegel A, Kambakamba P, Lehn JM, et al. Hypoxia-driven Hif2a coordinates mouse liver regeneration by coupling parenchymal growth to vascular expansion. Hepatology. 2016;64(6):2198-209. https://doi.org/10.1002/hep.28809 PMid:27628483
Xie F, Dong J, Zhu Y, Wang K, Liu X, Chen D, et al. HIF1a Inhibitor rescues acute-on-chronic liver failure. Ann Hepatol. 2019;18(5):757-64. https://doi.org/10.1016/j.aohep.2019.03.007 PMid:31402229
Mesarwi OA, Shin MK, Bevans-Fonti S, Schlesinger C, Shaw J, Polotsky VY. Hepatocyte hypoxia inducible factor-1 mediates the development of liver fibrosis in a mouse model of nonalcoholic fatty liver disease. PLoS One. 2016;11(12):e0168572. https://doi.org/10.1371/journal.pone.0168572 PMid:28030556
Bozova S, Elpek GO. Hypoxia-inducible factor-1alpha expression in experimental cirrhosis: Correlation with vascular endothelial growth factor expression and angiogenesis. APMIS. 2007;115(7):795-801. https://doi.org/10.1111/j.1600-0463.2007.apm_610.x PMid:17614845
Akiyoshi F, Sata M, Suzuki H, Uchimura Y, Mitsuyama K, Matsuo K, et al. Serum vascular endothelial growth factor levels in various liver diseases. Dig Dis Sci. 1998;43(1):41-5. https://doi.org/10.1023/a:1018863718430 PMid:9508533
El-Assal ON, Yamanoi A, Soda Y, Yamaguchi M, Igarashi M, Yamamoto A, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: Possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology. 1998;27(6):1554-62. https://doi.org/10.1002/hep.510270613 PMid:9620326
Yang L, Inokuchi S, Roh YS, Song J, Loomba R, Park EJ, et al. Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocytespecific deletion of TAK1. Gastroenterology. 2013;144(5):1042- 54. https://doi.org/10.1053/j.gastro.2013.01.056 PMid:23391818
Mu M, Zuo S, Wu R, Deng K, Lu S, Zhu J, et al. Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signalling pathway. Drug Des Devel Ther. 2018;12:4107-15. https://doi.org/10.2147/dddt.s186726 PMid:30584275
Fan W, Liu T, Chen W, Hammad S, Longerich T, Hausser I, et al. ECM1 prevents activation of transforming growth factor β, hepatic stellate cells, and fibrogenesis in mice. Gastroenterology. 2019;157(5):1352-67. https://doi.org/10.1053/j.gastro.2019.07.036 PMid:31362006
Mantaka A, Koulentaki M, Samonakis D, Sifaki-Pistolla D, Voumvouraki A, Tzardi M, et al. Association of smoking with liver fibrosis and mortality in primary biliary cholangitis. Eur J Gastroenterol Hepatol. 2018;30(12):1461-9. https://doi.org/10.1097/meg.0000000000001234 PMid:30106760
Yang JD, Abdelmalek MF, Pang H, Guy CD, Smith AD, DiehlAM, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology. 2014;59(4):1406-14. https://doi.org/10.1002/hep.26761 PMid:24123276
Gao Y, Zou G, Ye J, Pan G, Rao J, Li F, et al. Relationship between hepatitis B surface antigen, HBV DNA quantity and liver fibrosis severity. Zhonghua Gan Zang Bing Za Zhi. 2015;23(4):254-7. PMid:26133815
Chen Y, Li Y, Li N, Fan X, Li C, Zhang P, et al. A noninvasive score to predict liver fibrosis in HBeAg-positive hepatitis B patients with normal or minimally elevated alanine aminotransferase levels. Dis Markers. 2018;2018:3924732. https://doi.org/10.1155/2018/3924732 PMid:30405859
Petta S, Eslam M, Valenti L, Bugianesi E, Barbara M, Cammà C, et al. Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: An age-dependent risk profiling study. Liver Int. 2017;37(9):1389-96. https://doi.org/10.1111/liv.13397 PMid:28235154
Klisic A, Abenavoli L, Fagoonee S, Kavaric N, Kocic G, Ninić A. Older age and HDL-cholesterol as independent predictors of liver fibrosis assessed by BARD score. Minerva Med. 2019;110(3):191-8. https://doi.org/10.23736/ s0026-4806.19.05978-0 PMid:30784251
van Santen DK, van der Loeff MF, van Dissel JC, Martens JP, van der Valk M, Prins M. High proportions of liver fibrosis and cirrhosis in an ageing population of people who use drugs in Amsterdam, the Netherlands. Eur J Gastroenterol Hepatol. 2018;30(10):1168- 76. https://doi.org/10.1097/meg.0000000000001213 PMid:30028776
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