ROLE OF ALLELIC VARIANTS OF HEMOSTASIS GENES IN THE RATE OF PROGRESSION OF FIBROSIS IN CHRONIC LIVER DISEASES


E.E. Starostina (1), S.V. Fastovets (1), L.M. Samokhodskaya (1), T.P. Rozina (1, 2), T.M. Ignatova (2), T.N. Krasnova (1, 2), N.A. Mukhin (1, 2)

(1) Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov, Moscow; (2) SBEI HPE "First MSMU n.a. I.M.. Sechenov" of RMPH, Moscow
The rate of progression of fibrosis in different patients varies and depends on many factors, such as race, gender, age of ingress of infection, genotype, presence of concomitant diseases, bad habits, etc. Currently, the most urgent task is the identification of specific genetic factors of progression of fibrosis that will help to determine the prognosis and tactics of management for these patients. The review describes the available literature data on the effect of polymorphisms of thrombophilia and platelet receptors genes on the course and prognosis of chronic liver diseases.

Literature


  1. Wanless I.R., Nakashima E., Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch. Pathol. Lab. Med. 2000;124(11):1599–607.
  2. Ferrell L. Liver pathology: cirrhosis, hepatitis, and primary liver tumors. Update and diagnostic problems. Mod. Pathol. 2000;13(6):679–704.
  3. Elsharkawy A.M., Oakley F., Mann D.A. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005;10(5):927–39.
  4. Asrani S.K., Larson J.J., Yawn B., Therneau T.M., Kim W.R. Underestimation of liver-related mortality in the United States. Gastroenterology. 2013;145(2):375–82.e1-2.
  5. Lee Y., Friedman S.L. Fibrosis in the liver: acute protection and chronic disease. Prog. Mol. Biol. Transl. Sci. 2010;97:151–200.
  6. Friedman S.L. Hepatic stellate cells. Prog. Liver Dis. 1996;14:101–30.
  7. Martinelli A.L., Ramalho L.N., Zucoloto S. Hepatic stellate cells in hepatitis C patients: relationship with liver iron deposits and severity of liver disease. J. Gastroenterol. Hepatol. 2004;19(1):91–8.
  8. Li D., Friedman S.L. Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J. Gastroenterol. Hepatol. 1999;14(7):618–33.
  9. Poynard T., Bedossa P., Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825–32.
  10. Wright M., Goldin R., Fabre A., Lloyd J., Thomas H., Trepo C., Pradat P., Thursz M. Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study. Gut. 2003;52(4):574–79.
  11. Miyoshi K., Ikebuchi Y., Ishida C., Okamoto K., Murawaki Y. Association between gene polymorphisms of connective tissue growth factor and the progression of chronic liver disease associated with hepatitis C. Intern. Med. 2014;53(14):1461–68.
  12. Poujol-Robert A., Boelle P.Y., Poupon R., Robert A. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology. 2004;39(4):1174–75.
  13. Massard J., Ratziu V., Thabut D., et al. Natural history and predictors of disease severity in chronic hepatitis C. J. Hepatol. 2006;44(Suppl. 1):19–24.
  14. Андреенко Е.Ю., Самоходская Л.М., Балацкий А.В., Макаревич П.И., Бойцов С.А. Прогностическая значимость носительства аллельных вариантов генов, контролирующих систему гемостаза и их сочетания с традиционными факторами риска в раннем развитии ишемической болезни сердца. Кардиоваск. тер. и проф. 2011;8:32–9.
  15. Андреенко Е.Ю. Изучение роли полиморфизма генов, контролирующих систему гемостаза и функцию эндотелия сосудов в раннем развитии ишемической болезни сердца. Дисс. канд. мед. наук. М., 2010.
  16. Садекова О.Н. Генетические маркеры привычного невынашивания беременности I триместра. Дисс. канд. мед. наук. М., 2012.
  17. D'Amico M., Pasta L., Sammarco P. MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, and prothrombin G20210A in hepatocellular carcinoma with and without portal vein thrombosis. J. Thromb. Thrombolysis. 2009;28(1):70–3.
  18. Ramm G.A., Shepherd R.W., Hoskins A.C., Greco S.A., Ney A.D., Pereira T.N., Bridle K.R., Doecke J.D., Meikle P.J., Turlin B., Lewindon P.J. Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment. Hepatology. 2009;49(2):533–44.
  19. Endothelial dysfunction gene polymorphisms and the rate of liver fibrosis in chronic hepatitis C
  20. Таратина О.В., Краснова Т.Н., Самоходская Л.М., Лопаткина Т.Н., Ткачук В.А., Мухин Н.А. Значение полиморфизма генов ренин-ангиотензиновой системы в прогрессировании фиброза печени у больных хроническим гепатитом С. РЖГГК. 2014;24(2):69–77.
  21. Northup P.G., Sundaram V., Fallon M.B., Reddy K.R., Balogun R.A., Sanyal A.J., Anstee Q.M., Hoffman M.R., Ikura Y., Caldwell S.H. Hypercoagulation and thrombophilia in liver disease. J. Thromb. Haemost. 2008;6(1):2–9.
  22. Lisman T., Caldwell S.H., Burroughs A.K., Northup P.G., Senzolo M., Stravitz R.T., Tripodi A., Trotter J.F., Valla D.C., Porte R.J. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J. Hepatol. 2010;53(2):362–71.
  23. Anstee Q.M., Dhar A., Thursz M.R. The role of hypercoagulability in liver fibrogenesis. Clin. Res. Hepatol. Gastroenterol. 2011;35(8–9):526–33.
  24. Tripodi A., Salerno F., Chantarangkul V., Clerici M., Cazzaniga M., Primignani M., Mannuccio Mannucci P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553–58.
  25. Tanaka M., Wanless I.R. Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules. Hepatology. 1998;27(2):488–96.
  26. Wanless I.R., Liu J.J., Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology. 1995;21(5):1232–37.
  27. Wanless I.R., Wong F., Blendis L.M., Greig P., Heathcote E.J., Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology. 1995;21(5):1238–47.
  28. Poynard T., Ratziu V., Benmanov Y., Di Martino V., Bedossa P., Opolon P. Fibrosis in patients with chronic hepatitis C: detection and significance. Semin Liver Dis. 2000;20(1):47–55.
  29. Sterling R.K., Sulkowski M.S. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin. Liver. Dis. 2004;24(Suppl. 2):61–8.
  30. Papatheodoridis G.V., Papakonstantinou E., Andrioti E., Cholongitas E., Petraki K., Kontopoulou I., Hadziyannis S.J. Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut. 2003;52(3):404–9.
  31. Wright M., Goldin R., Hellier S., Knapp S., Frodsham A., Hennig B., Hill A., Apple R., Cheng S., Thomas H., Thursz M. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut. 2003;52(8):1206–10.
  32. Goulding C., O'Brien C., Egan H., Hegarty J.E., McDonald G., O'Farrelly C., White B., Kelleher D., Norris S. The impact of inherited prothrombotic risk factors on individuals chronically infected with hepatitis C virus from a single source. J. Viral. Hepat. 2007;14(4):255–59.
  33. Anstee Q.M., Goldin R.D., Wright M., Martinelli A., Cox R., Thursz M.R. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J.. Thromb. Haemost. 2008;6(8):1336–43.
  34. Xu Z., Westrick R.J., Shen Y.C., Eitzman D.T. Pulmonary fibrosis is increased in mice carrying the factor V Leiden mutation following bleomycin injury. Thromb. Haemost. 2001;85(3):441–44.
  35. Yee T.T., Griffioen A., Sabin C.A., Dusheiko G., Lee C.A.The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut. 2000;47(6):845–51.
  36. Maharshak N., Halfon P., Deutsch V., Peretz H., Berliner S., Fishman S., Zelber-Sagi S., Rozovski U., Leshno M., Oren R. Increased fibrosis progression rates in hepatitis C patients carrying the prothrombin G20210A mutation. World J. Gastroenterol. 2011;17(45):5007–13.
  37. Dik K., de Bruijne J., Takkenberg R.B., Roelofs J.J., Tempelmans M.J., Dijkgraaf M.G., Gelderblom H.C., Reesink H.W., Meijers J.C., Jansen P.L., Levi M. Factor XIII Val34Leu mutation accelerates the development of fibrosis in patients with chronic hepatitis B and C. Hepatol. Res. 2012;42(7):668–76.
  38. Goodman Z.D., Ishak K.G. Histopathology of hepatitis C virus infection. Semin. Liver Dis. 1995;15(1):70–81.
  39. Scheuer P.J., Ashrafzadeh P., Sherlock S., Brown D., Dusheiko G.M. The pathology of hepatitis C. Hepatology. 1992;15(4):567–71.
  40. Bach N., Thung S.N., Schaffner F. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology. 1992;15(4):572–77.
  41. Lefkowitch J.H., Schiff E.R., Davis G.L., Perrillo R.P., Lindsay K., Bodenheimer H.C. Jr, Balart L.A., Ortego T.J., Payne J., Dienstag J.L., et al. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group. Gastroenterology. 1993;104(2):595–603.
  42. Adinolfi L.E., Gambardella M., Andreana A., Tripodi M.F., Utili R., Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33(6):1358–64.
  43. Adinolfi L.E., Ingrosso D., Cesaro G., Cimmino A., D'Anto M., Capasso R., Zappia V., Ruggiero G. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology. 2005;41(5):995–1003.
  44. Toniutto P., Fabris C., Falleti E., Cussigh A., Fontanini E., Bitetto D., Fornasiere E., Minisini R., De Feo T., Marangoni F., Pirisi M. Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver Int. 2008;28(2):257–63.
  45. Martinelli A., Knapp S., Anstee Q., Worku M., Tommasi A., Zucoloto S., Goldin R., Thursz M.. Effect of a thrombin receptor (protease-activated receptor 1, PAR-1) gene polymorphism in chronic hepatitis C liver fibrosis. J. Gastroenterol. Hepatol. 2008;23(9):1403–9.
  46. Asselah T., Bieche I., Laurendeau I., Paradis V., Vidaud D., Degott C., Martinot M., Bedossa P., Valla D., Vidaud M., Marcellin P. Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology. 2005;129(6):2064–75.
  47. Bieche I., Asselah T., Laurendeau I., Vidaud D., Degot C., Paradis V., Bedossa P., Valla D.C., Marcellin P., Vidaud M. Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection. Virology. 2005;332(1):130–44.
  48. Nejjari M., Couvelard A., Mosnier J.F., Moreau A., Feldmann G., Degott C., Marcellin P., Scoazec J.Y. Integrin up-regulation in chronic liver disease: relationship with inflammation and fibrosis in chronic hepatitis C. J. Pathol. 2001;195(4):473–81.
  49. D'Amico M., Pasta F., Pasta L. Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population. Gene. 2015;568(1):85–8.
  50. Vrabelova S., Letocha O., Borsky M., Kozak L. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol. Genet. Metab. 2005;86(1–2):277–85.
  51. Gromadzka G., Rudnicka M., Chabik G., Przybylkowski A., Czlonkowska A. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease. .J Hepatol. 2011;55(4):913–19.
  52. Schaefer M., Weber L., Gotthardt D., Seessle J., Stremmel W., Pfeiffenberger J., Weiss K.H. Coagulation Parameters in Wilson Disease. J. Gastrointestin. Liver Dis. 2015;24(2):183–88.
  53. Pihusch R., Rank A., Gohring P., Pihusch M., Hiller E., Beuers U. Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease. J. Hepatol. 2002;37(5):548–55.
  54. Ben-Ari Z., Panagou M., Patch D., Bates S., Osman E., Pasi J., Burroughs A. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J. Hepatol. 1997;26(3):554–59.
  55. Biagini M.R., Tozzi A., Marcucci R., Paniccia R., Fedi S., Milani S., Galli A., Ceni E., Capanni M., Manta R., Abbate R., Surrenti C. Hyperhomocysteinemia and hypercoagulability in primary biliary cirrhosis. World J. Gastroenterol. 2006;12(10):1607–12.
  56. Kasapoglu B., Turkay C., Yalcin K.S., , Kosar A., Bozkurt A. MTHFR 677C/T and 1298A/C mutations and non-alcoholic fatty liver disease. Clin. Med. 2015;15(3):248–51.
  57. Sazci A., Ergul E., Aygun C., Akpinar G., Senturk O., Hulagu S. Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH). Cell. Biochem. Funct. 2008;26(3):291–96.
  58. Brochado F.M.J., Domenici F.A., Candolo Martinelli Ade L., Zucoloto S., de Carvalho da Cunha S.F., Vannucchi H. Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease. Ann. Nutr. Metab. 2013;63(3):193–99.
  59. Serin E., Guclu M., Atac F.B., Verdi H., Kayaselсuk F., Ozer B., Bilezikсi B., Yilmaz U. Methylenetetrahydrofolate reductase C677T mutation and nonalcoholic fatty liver disease. Dig. Dis. Sci. 2007;52(5):1183–86.
  60. Catalano D., Trovato G.M., Ragusa A., Martines G.F., Tonzuso A., Pirri C., Buccheri M.A., Trovato F.M. Non-alcoholic fatty liver disease (NAFLD) and MTHFR 1298A > C gene polymorphism. Eur. Rev. Med. Pharmacol. Sci. 2014;18(2):151–59.


About the Autors


E.E. Starostina - Postgraduate Student, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov, Moscow; e-mail: starostinaee@gmail.com
S.V. Fastovets - Postgraduate Student, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov, Moscow; e-mail: s.v.fastovets@gmail.com.
L.M. Samokhodskaya – PhD in Medical Sciences, Associate Professor, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov, Moscow; e-mail: slm@fbm.msu.ru
T.P. Rozina - PhD in Medical Sciences, Associate Professor, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov; SBEI HPE "First MSMU n.a. I.M.. Sechenov" of RMPH, Moscow; e-mail: alrozin@ya.ru
T.M. Ignatova – Doctor of Medical Scineces, Leading Researcher, SBEI HPE "First MSMU n.a. I.M.. Sechenov" of RMPH, Moscow; e-mail: tmignatova@gmail.com
T.N. Krasnova - PhD in Medical Sciences, Associate Professor, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov; SBEI HPE "First MSMU n.a. I.M.. Sechenov" of RMPH, Moscow; e-mail: krasnovamgu@yandex.ru
N.A. Mukhin – Doctor of Medical Sciences, Prof., Acad. of RAS, Faculty of Fundamental Medicine MSU n.a. M.V. Lomonosov; SBEI HPE "First MSMU n.a. I.M.. Sechenov" of RMPH, Moscow; e-mail: moukhin-nephro@yandex.ru


Similar Articles


Бионика Медиа