Predicting the rate of liver fibrosis in patients with chronic hepatitis C virus infection based on the combination of genetic and environmental factors

Cover Page


Cite item

Full Text

Abstract

Rationale: Search for predictors of aggressive course of chronic hepatitis C virus (HCV) infection in individual patients, including genetic studies, is considered  to be a major urgent  goal. High rates of fibrosis progression  in chronic HCV infection is associated with several gene polymorphisms  coding for the components of renin-angiotensin system and involved in the formation of endothelial dysfunction and oxidative stress.

Aim: To develop a predictive  model  to  assess  the  probability  of rapid fibrosis progression  in patients  with chronic HCV infection based on the combination of the known genetic markers, clinical and demographic parameters.

Materials and methods:  One hundred  and  nine  patients  with  chronic  HCV  infection (79 women  and 30 men) of known duration and liver fibrosis were categorized  into the groups with “rapid fibrosis” (n = 54, the rate of fibrosis progression ≥ 0.13 fibrosis units / year) and with “slow fibrosis”  (n = 55, the  rate  of progression < 0.13  fibrosis units / year). Polymorphisms  of the studied genes were assessed by molecular genetic assays. Multivariate analysis of the influence of combination of genetic  variants, as well as of the interaction of genetic, clinical and demographic factors on the rate of fibrosis progression  in the patients with chronic HCV infection was performed by logistic  regression   method. 

Results:  The  rapid rate of fibrosis progression  was significantly associated with patient's  age at the time of infection (Wald statistics  14.955;  p = 0.00011), male gender (Wald statistics  6.787;  p = 0.00918),  (-6)АА genotype  of the  AGT  gene  carriage  (Wald statistics 6.512;  p = 0.01072), 242ТТ-genotype  of the  CYBA gene   (Wald  statistics   4.347;   p = 0.03708),   and 235МТ genotype of the AGT gene  (Wald statistics 4.306; p = 0.03799). The model to predict the probability of rapid fibrosis progression  in individuals with chronic HCV infection included the above mentioned factors; its use was demonstrated with two clinical cases.

Conclusion: The analysis of the AGT  gene  (M235T and  G-6A loci) and  the  СYBA gene  (C242T  locus) polymorphisms  are  relevant to  identify patients  at  risk of rapid  liver fibrosis progression. In this case, 242ТТ genotype of the CYBA gene  and  (-6)AA and  235MT genotypes of the AGT gene  are considered  unfavorable. To refine the prognosis, it is necessary to take into account  demographic parameters (gender  and age at the moment of infection contraction), because male gender and older age of getting the infection would increase the probability of rapidly progressive of hepatitis C.

About the authors

O. V. Taratina

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: taratina.o@gmail.com

Taratina Olesya V. – MD, PhD, Research Fellow, Department of Gastroenterology; Associate Professor, Chair of Gastroenterology, Postgraduate Training Faculty.

61/2–9 Shchepkina ul., Moscow, 129110, +7 (926) 245 66 59

Russian Federation

L. M. Samokhodskaia

Lomonosov Moscow State University

Email: fake@neicon.ru

Samokhodskaia Larisa M. – MD, PhD, Associate Professor, Head of Department of Diagnostic Laboratory, Medical Research and Educational Center.

Leninskie Gory, Moscow, 119991

Russian Federation

T. N. Krasnova

Lomonosov Moscow State University

Email: fake@neicon.ru

Krasnova Tatiana N. – MD, PhD, Associate Professor, Chair of Internal Medicine, Faculty of Fundamental Medicine.

Leninskie Gory, Moscow, 119991

Russian Federation

N. A. Mukhin

Lomonosov Moscow State University

Email: fake@neicon.ru

Mukhin Nikolay A. – MD, PhD, Professor, Member of Russian Academy of Sciences, Head of the Chair of Internal Medicine, Faculty of Fundamental Medicine.

Leninskie Gory, Moscow, 119991

Russian Federation

References

  1. WHO. Global hepatitis report. Geneva: World Health Organization; 2017. 83 p. Available from: http://apps.who.int/iris/bitstream/10665/255016/1/9789241565455-eng.pdf?ua=1.
  2. Рекомендации по диагностике и лечению взрослых больных гепатитом C. М.; 2017. 69 с. Доступно на: http://www.iia-rf.ru/upload/iblock/6d9/6d96c71786128fcab695c11afea3338c.pdf.
  3. Poynard T, Bedossa P, Opolon P. Natural his- tory of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825–32. doi: https://doi.org/10.1016/S0140-6736(96)07642-8.
  4. Asselah T, Bièche I, Paradis V, Bedossa P, Vidaud M, Marcellin P. Genetics, genomics, and proteomics: implications for the diagnosis and the treatment of chronic hepatitis C. Semin Liver Dis. 2007;27(1):13–27. doi: 10.1055/s-2006-960168.
  5. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. AASLD/IDSA Recommendations for testing, managing, and treating hepatitis C. Updated: July 6, 2016. Changes made September 16, 2016. Available from: https://www.hcvguidelines.org/.
  6. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol. 2017;66(1):153–94. doi: 10.1016/j.jhep.2016.09.001.
  7. Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, Shorthouse C, Purdie DM, Jonsson JR. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology. 2000;31(4):828–33. doi: 10.1053/he.2000.6253.
  8. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology. 2003;37(3): 493–503. doi: 10.1053/jhep.2003.50127.
  9. Самоходская ЛМ, Игнатова ТМ, Абдуллаев СМ, Краснова ТН, Некрасова ТП, Мухин НА, Ткачук ВА. Прогностическое значение комбинации аллельных вариантов генов цитокинов и гемохроматоза у больных хроническим гепатитом С. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2007;17(2):50–6.
  10. Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT, Rowland CM, Catanese JJ, Leong DU, Sninsky JJ, Layden TJ, Wright TL, White T, Cheung RC. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007;46(2):297–306. doi: 10.1002/hep.21695.
  11. Семенова НА, Рязанцева НВ, Новицкий ВВ, Бычков ВА, Чечина ОЕ. Роль полиморфизма гена IL6-174C/G в развитии хронической HCV-инфекции. Бюллетень сибирской медицины. 2010;(5):93–6.
  12. Romero-Gomez M, Eslam M, Ruiz A, Maraver M. Genes and hepatitis C: susceptibility, fibrosis progression and response to treatment. Liver Int. 2011;31(4):443–60. doi: 10.1111/j.1478-3231.2011.02449.x.
  13. Fontana RJ, Litman HJ, Dienstag JL, Bonkovsky HL, Su G, Sterling RK, Lok AS; HALT-C Trial Group. YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C. Liver Int. 2012;32(4):665–74. doi: 10.1111/j.1478-3231.2011.02686.x.
  14. do O NT, Eurich D, Schmitz P, Schmeding M, Heidenhain C, Bahra M, Trautwein C, Neuhaus P, Neumann UP, Wasmuth HE. A 7-gene signature of the recipient predicts the progression of fibrosis after liver transplantation for hepatitis C virus infection. Liver Transpl. 2012;18(3):298–304. doi: 10.1002/lt.22475.
  15. Щекотова АП, Кривцов АВ, Булатова ИА, Загородских ЕБ. Эндотелиальная дисфункция и полиморфизм гена эндотелиальной синтазы азота (NOS3) при хронических заболеваниях печени. Современные проблемы науки и образования. 2012;(2). [Электронный журнал]. Доступно на: https://scienceeducation.ru/ru/article/view?id=6047.
  16. Таратина ОВ, Краснова ТН, Самоходская ЛМ, Лопаткина ТН, Ткачук ВА, Мухин НА. Значение полиморфизма генов ренинангиотензиновой системы в прогрессировании фиброза печени у больных хроническим гепатитом С. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2014;24(2):69–77.
  17. Таратина ОВ, Краснова ТН, Самоходская ЛМ, Лопаткина ТН, Ткачук ВА, Мухин НА. Полиморфизм генов эндотелиальной дисфункции и скорость прогрессирования фиброза печени при хроническом гепатите С. Терапевтический архив. 2014;86(4):45–51.
  18. King LY, Johnson KB, Zheng H, Wei L, Gudewicz T, Hoshida Y, Corey KE, Ajayi T, Ufere N, Baumert TF, Chan AT, Tanabe KK, Fuchs BC, Chung RT. Host genetics predict clinical deterioration in HCV-related cirrhosis. PLoS One. 2014;9(12):e114747. doi: 10.1371/journal.pone.0114747.
  19. Самоходская ЛМ, Старостина ЕЕ, Яровая ЕБ, Краснова ТН, Мухин НА, Ткачук ВА, Садовничий ВА. Математическая модель прогноза скорости фиброза печени у больных с хроническим гепатитом С на основе комбинаций геномных маркеров. Вестник Российской академии медицинских наук. 2015;70(6):651–61. doi: http://dx.doi.org/10.15690/vramn548.
  20. Mueller JL, King LY, Johnson KB, Gao T, Nephew LD, Kothari D, Simpson MA, Zheng H, Wei L, Corey KE, Misdraji J, Lee JH, Lin MV, Gogela NA, Fuchs BC, Tanabe KK, Gordon FD, Curry MP, Chung RT. Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study. Clin Transplant. 2016;30(4):452–60. doi: 10.1111/ctr.12710.
  21. Самоходская ЛМ, Балацкий АВ, Садекова ОН, Таратина ОВ, Колотвин АВ. Молекулярно-генетический анализ предрасположенности человека к мультифакторным заболеваниям. М.: Изд-во МГУ; 2011. 388 c.
  22. Yee LJ. Host genetic determinants in hepatitis C virus infection. Genes Immun. 2004;5(4): 237–45. doi: 10.1038/sj.gene.6364090.
  23. Richardson MM, Powell EE, Barrie HD, Clouston AD, Purdie DM, Jonsson JR. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet. 2005;42(7):e45. doi: 10.1136/jmg.2005.032557.
  24. Pradat P, Trepo E, Potthoff A, Bakshi R, Young B, Trepo C, Lagier R, Moreno C, Lemmers A, Gustot T, Degre D, Adler M, Wedemeyer H. The cirrhosis risk score predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology. 2010;51(1):356–7. doi: 10.1002/hep.23223.
  25. Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011;25(2):195–206. doi: 10.1016/j.bpg.2011.02.005.
  26. Таратина ОВ, Краснова ТН, Самоходская ЛМ, Сагинова ЕА, Мухин НА, Ткачук ВА. Роль структурного полиморфизма генов ренин-ангиотензиновой системы и эндотелиальной дисфункции в прогрессировании фиброза печени при хроническом гепатите С. В: Варфоломеев СД, ред. Постгеномные исследования и технологии. М.: МАКС Пресс; 2011. с. 347–76.
  27. Таратина ОВ, Самоходская ЛМ, Краснова ТН, Мухин НА. Связь полиморфизма генов ренин-ангиотензиновой системы и эндотелиальной дисфункции с формированием и тяжестью портальной гипертензии у больных хроническим гепатитом С. Альманах клинической медицины. 2016;44(6):698–712. doi: 10.18786/2072-0505-2016-44-6-698-712.
  28. Patin E, Kutalik Z, Guergnon J, Bibert S, Nalpas B, Jouanguy E, Munteanu M, Bousquet L, Argiro L, Halfon P, Boland A, Müllhaupt B, Semela D, Dufour JF, Heim MH, Moradpour D, Cerny A, Malinverni R, Hirsch H, Martinetti G, Suppiah V, Stewart G, Booth DR, George J, Casanova JL, Bréchot C, Rice CM, Talal AH, Jacobson IM, Bourlière M, Theodorou I, Poynard T, Negro F, Pol S, Bochud PY, Abel L; Swiss Hepatitis C Cohort Study Group; International Hepatitis C Genetics Consortium; French ANRS HC EP 26 Genoscan Study Group. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology. 2012;143(5):1244–52.e1–12. doi: 10.1053/j.gastro.2012.07.097.
  29. Marcolongo M, Young B, Dal Pero F, Fattovich G, Peraro L, Guido M, Sebastiani G, Palù G, Alberti A. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology. 2009;50(4):1038–44. doi: 10.1002/hep.23111.
  30. De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys. 2007;462(2):266–72. doi: 10.1016/j.abb.2007.04.016.
  31. Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112(9):1383–94. doi: 10.1172/JCI18212.
  32. De Minicis S, Seki E, Oesterreicher C, Schnabl B, Schwabe RF, Brenner DA. Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology. 2008;48(6):2016–26. doi: 10.1002/hep.22560.
  33. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4(3): 181–9. doi: 10.1038/nri1312.
  34. de Mochel NS, Seronello S, Wang SH, Ito C, Zheng JX, Liang TJ, Lambeth JD, Choi J. Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology. 2010;52(1): 47–59. doi: 10.1002/hep.23671.
  35. Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. J Clin Invest. 1990;86(5):1729–37. doi: 10.1172/JCI114898.
  36. Bataller R, Sancho-Bru P, Ginès P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal. 2005;7(9–10):1346–55. doi: 10.1089/ars.2005.7.1346.
  37. Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM, Angus PW. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut. 2005;54(12):1790–6. doi: 10.1136/gut.2004.062398.
  38. Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol. 2008;23(9):1327–38. doi: 10.1111/j.1440-1746.2008.05461.x.
  39. Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol. 2010;7(8):425–36. doi: 10.1038/nrgastro.2010.97.
  40. Kanno K, Tazuma S, Chayama K. AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl(4). Biochem Biophys Res Commun. 2003;308(1):177–83. doi: https://doi.org/10.1016/S0006-291X(03)01357-3.
  41. Wei HS, Li DG, Lu HM, Zhan YT, Wang ZR, Huang X, Zhang J, Cheng JL, Xu QF. Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4). World J Gastroenterol. 2000;6(4):540–5. doi: 10.3748/wjg.v6.i4.540.
  42. Yang L, Bataller R, Dulyx J, Coffman TM, Ginès P, Rippe RA, Brenner DA. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005;43(2):317–23. doi: 10.1016/j.jhep.2005.02.034.
  43. Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, Namisaki T, Kitade M, Yamazaki M, Tsujinoue H, Fukui H. Combination of interferon-beta and angiotensin-converting enzyme inhibitor, perindopril, attenuates the murine liver fibrosis development. Liver Int. 2005;25(1):153–61. doi: 10.1111/j.1478-3231.2005.01038.x.
  44. Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, Sakuta S. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology. 2002;36(4 Pt 1):1022. doi: 10.1053/jhep.2002.32679.
  45. Rimola A, Londoño MC, Guevara G, Bruguera M, Navasa M, Forns X, García-Retortillo M, García-Valdecasas JC, Rodes J. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation. 2004;78(5):686–91. doi: 10.1097/01.TP.0000128913.09774.CE.
  46. Yoshiji H, Noguchi R, Fukui H. Combined effect of an ACE inhibitor, perindopril, and interferon on liver fibrosis markers in patients with chronic hepatitis C. J Gastroenterol. 2005;40(2):215–6. doi: 10.1007/s00535-004-1523-6.
  47. Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Aihara Y, Douhara A, Yamao J, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Fujimoto M, Uemura M, Fukui H. Combination of branchedchain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis. Mol Med Rep. 2012;5(2):539–44. doi: 10.3892/mmr.2011.676.
  48. Corey KE, Shah N, Misdraji J, Abu Dayyeh BK, Zheng H, Bhan AK, Chung RT. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int. 2009;29(5):748–53. doi: 10.1111/j.1478-3231.2009.01973.x.
  49. Abu Dayyeh BK, Yang M, Dienstag JL, Chung RT. The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C Trial cohort. Dig Dis Sci. 2011;56(2):564–8. doi: 10.1007/s10620-010-1507-8.
  50. Bataller R, Sancho-Bru P, Ginès P, Lora JM, Al-Garawi A, Solé M, Colmenero J, Nicolás JM, Jiménez W, Weich N, Gutiérrez-Ramos JC, Arroyo V, Rodés J. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125(1):117–25. doi: https://doi.org/10.1016/S0016-5085(03)00695-4.
  51. Jeunemaitre X. Genetics of the human renin angiotensin system. J Mol Med (Berl). 2008;86(6): 637–41. doi: 10.1007/s00109-008-0344-0.
  52. Forrest EH, Thorburn D, Spence E, Oien KA, Inglis G, Smith CA, McCruden EA, Fox R, Mills PR. Polymorphisms of the renin-angiotensin system and the severity of fibrosis in chronic hepatitis C virus infection. J Viral Hepat. 2005;12(5):519–24. doi: 10.1111/j.1365-2893.2005.00630.x.
  53. Codes L, Asselah T, Cazals-Hatem D, Tubach F, Vidaud D, Paraná R, Bedossa P, Valla D, Marcellin P. Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy. Gut. 2007;56(3):390–5. doi: 10.1136/gut.2006.101931.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2017 Taratina O.V., Samokhodskaia L.M., Krasnova T.N., Mukhin N.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies