Механизмы и клиническое значение печеночного фиброгенеза при перегрузке железом
https://doi.org/10.31550/1727-2378-2022-21-2-23-29
Аннотация
Цель обзора: описать механизмы и клиническое значение печеночного фиброгенеза при перегрузке железом у пациентов с наследственным гемохроматозом и хроническими заболеваниями печени.
Основные положения. Перегрузка железом токсична и может способствовать печеночному фиброгенезу. Развитие фиброза печени является неблагоприятным событием естественного течения как наследственного гемохроматоза, так и хронических заболеваний печени, поскольку может привести к формированию цирроза печени и гепатоцеллюлярной карциномы.
Заключение. Имеющие перегрузку железом больные должны быть стратифицированы по группам риска с целью ранней диагностики фиброза печени и определения оптимальной лечебной тактики
Об авторе
Д. В. ГарбузенкоРоссия
Гарбузенко Дмитрий Викторович — профессор кафедры факультетской хирургии, д. м. н., профессор
454092, г. Челябинск
Список литературы
1. Гарбузенко Д.В. Молекулярные стимулы фиброгенной активации звездчатых клеток печени. Патологическая физиология и экспериментальная терапия. 2022; 66(1): 112–9. [Garbuzenko D.V. Molecular stimuli of fibrogenic activation in hepatic stellate cells. Pathological Physiology and Experimental Therapy. 2022; 66(1): 112–9. (in Russian)]. DOI: 10.25557/0031-2991.2022.01.112-119
2. Mehta K.J., Coombes J.D., Briones-Orta M. et al. Iron enhances hepatic fibrogenesis and activates transforming growth factor-β signaling in murine hepatic stellate cells. Am. J. Med. Sci. 2018; 355(2): 183–90. DOI: 10.1016/j.amjms.2017.08.012
3. Mehta K.J., Farnaud S.J., Sharp P.A. Iron and liver fibrosis: mechanistic and clinical aspects. World J. Gastroenterol. 2019; 25(5): 521–38. DOI: 10.3748/wjg.v25.i5.521
4. Bloomer S.A., Brown K.E. Iron-induced liver injury: a critical reappraisal. Int. J. Mol. Sci. 2019; 20(9): 2132. DOI: 10.3390/ijms20092132
5. Parrow N.L., Fleming R.E. Bone morphogenetic proteins as regulators of iron metabolism. Annu. Rev. Nutr. 2014; 34: 77–94. DOI: 10.1146/annurev-nutr-071813-105646
6. Ruddell R.G., Hoang-Le D., Barwood J.M. et al. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology. 2009; 49(3): 887–900. DOI: 10.1002/hep.22716
7. Bridle K.R., Crawford D.H., Ramm G.A. Identification and characterization of the hepatic stellate cell transferrin receptor. Am. J. Pathol. 2003; 162(5): 1661–7. DOI: 10.1016/S0002-9440(10)64300-3
8. Mandala A., Chen W.J., Armstrong A. et al. PPARα agonist fenofibrate attenuates iron-induced liver injury in mice by modulating the Sirt3 and β-catenin signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 2021; 321(4): 262–9. DOI: 10.1152/ajpgi.00129.2021
9. Brissot P., Pietrangelo A., Adams P.C. et al. Haemochromatosis. Nat. Rev. Dis. Primers. 2018; 4: 18016. DOI: 10.1038/nrdp.2018.16
10. Brissot P., Loréal O. Hemochromatoses. J. Hepatol. 2021; 75(3): 723–4. DOI: 10.1016/j.jhep.2021.04.001
11. Pietrangelo A. Iron and the liver. Liver Int. 2016; 36(suppl.1): 116– 23. DOI: 10.1111/liv.13020
12. Barton J.C., McLaren C.E., Chen W.P. et al. Cirrhosis in hemochromatosis: independent risk factors in 368 HFE p.C282Y homozygotes. Ann. Hepatol. 2018; 17(5): 871–9. DOI: 10.5604/01.3001.0012.3169
13. Buch S., Sharma A., Ryan E. et al. Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis. Aliment. Pharmacol. Ther. 2021; 53(7): 830– 43. DOI: 10.1111/apt.16252
14. Osterreicher C.H., Datz C., Stickel F. et al. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis. Cytokine. 2005; 31(2): 142–8. DOI: 10.1016/j.cyto.2005.03.005
15. Stickel F., Osterreicher C.H., Datz C. et al. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis. Arch. Intern. Med. 2005; 165(16): 1835–40. DOI: 10.1001/archinte.165.16.1835
16. Osterreicher C.H., Datz C., Stickel F. et al. Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis. J. Hepatol. 2005; 42(6): 914–9. DOI: 10.1016/j.jhep.2005.01.023
17. Wood M.J., Gadd V.L., Powell L.W. et al. Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression. Hepatology. 2014; 59(3): 848–57. DOI: 10.1002/hep.26706
18. Kowdley K.V., Brown K.E., Ahn J. et al. ACG Clinical Guideline: hereditary hemochromatosis. Am. J. Gastroenterol. 2019; 114(8): 1202–18. DOI: 10.14309/ajg.0000000000000315
19. Philippe M.A., Ruddell R.G., Ramm G.A. Role of iron in hepatic fibrosis: one piece in the puzzle. World J. Gastroenterol. 2007; 13(35): 4746–54. DOI: 10.3748/wjg.v13.i35.4746
20. Kisseleva T., Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 2021; 18(3): 151–66. DOI: 10.1038/s41575-020-00372-7
21. Rigamonti C., Andorno S., Maduli E. et al. Iron, hepatic stellate cells and fibrosis in chronic hepatitis C. Eur. J. Clin. Invest. 2002; 32(suppl.1): 28–35. DOI: 10.1046/j.1365-2362.2002.0320s1028.x
22. Sikorska K. The iron homeostasis network and hepatitis C virus — a new challenge in the era of directly acting antivirals. Virulence. 2016; 7(6): 620–2. DOI: 10.1080/21505594.2016.1191739
23. Gao Y.H., Wang J.Y., Liu P.Y. et al. Iron metabolism disorders in patients with hepatitis B-related liver diseases. World J. Clin. Cases. 2018; 6(13): 600–10. DOI: 10.12998/wjcc.v6.i13.600
24. Georgopoulou U., Dimitriadis A., Foka P. et al. Hepcidin and the iron enigma in HCV infection. Virulence. 2014; 5(4): 465–76. DOI: 10.4161/viru.28508
25. Shan Y., Lambrecht R.W., Bonkovsky H.L. Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey. Clin. Infect. Dis. 2005; 40(6): 834–41. DOI: 10.1086/428062
26. Sikorska K., Romanowski T., Stalke P. et al. Association of hepcidin mRNA expression with hepatocyte iron accumulation and effects of antiviral therapy in chronic hepatitis C infection. Hepat. Mon. 2014; 14(11): e21184. DOI: 10.5812/hepatmon.21184
27. Sebastiani G., Tempesta D., Alberti A. Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. J. Viral. Hepat. 2012; 19(2): e170–6. DOI: 10.1111/j.1365-2893.2011.01508.x
28. Park S.O., Kumar M., Gupta S. TGF-β and iron differently alter HBV replication in human hepatocytes through TGF-β/BMP signaling and cellular microRNA expression. PLoS One. 2012; 7(6): e39276. DOI: 10.1371/journal.pone.0039276
29. Fujita N., Sugimoto R., Urawa N. et al. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J. Gastroenterol. Hepatol. 2007; 22(11): 1886–93. DOI: 10.1111/j.1440-1746.2006.04759.x
30. Mummadi R., Kasturi K., Sood G. Iron depletion and response to interferon in chronic hepatitis C: a meta-analysis [abstract]. Hepatology. 2007; 46: 365A.
31. Franchini M., Targher G., Capra F. et al. The effect of iron depletion on chronic hepatitis C virus infection. Hepatol. Int. 2008; 2(3): 335–40. DOI: 10.1007/s12072-008-9076-z
32. Costa Matos L., Batista P., Monteiro N. et al. Iron stores assessment in alcoholic liver disease. Scand. J. Gastroenterol. 2013; 48(6): 712–8. DOI: 10.3109/00365521.2013.781217
33. Milic S., Mikolasevic I., Orlic L. et al. The role of iron and iron overload in chronic liver disease. Med. Sci. Monit. 2016; 22: 2144–51. DOI: 10.12659/MSM.896494
34. Ioannou G.N., Weiss N.S., Kowdley K.V. Relationship between transferrin-iron saturation, alcohol consumption, and the incidence of cirrhosis and liver cancer. Clin. Gastroenterol. Hepatol. 2007; 5(5): 624–9. DOI: 10.1016/j.cgh.2007.01.008
35. Costa-Matos L., Batista P., Monteiro N. et al. Liver hepcidin mRNA expression is inappropriately low in alcoholic patients compared with healthy controls. Eur. J. Gastroenterol. Hepatol. 2012; 24(10): 1158–65. DOI: 10.1097/MEG.0b013e328355cfd0
36. Suzuki Y., Saito H., Suzuki M. et al. Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Alcohol. Clin. Exp. Res. 2002; 26(suppl.8): S26–31. DOI: 10.1097/01.ALC.0000026830.27338.23
37. Harrison-Findik D.D., Schafer D., Klein E. et al. Alcohol metabolism mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J. Biol. Chem. 2006; 281(32): 22974–82. DOI: 10.1074/jbc.M602098200
38. Gerjevic L.N., Liu N., Lu S. et al. Alcohol activates TGF-beta but inhibits BMP receptor-mediated Smad signaling and Smad4 binding to hepcidin promoter in the liver. Int. J. Hepatol. 2012; 2012: 459278. DOI: 10.1155/2012/459278
39. Xiong S., She H., Zhang A.S. et al. Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2008; 295(3): 512–21. DOI: 10.1152/ajpgi.90327.2008
40. Kowdley K.V. Iron overload in patients with chronic liver disease. Gastroenterol. Hepatol. (N Y). 2016; 12(11): 695–8.
41. Chirumbolo S., Rossi A.P., Rizzatti V. et al. Iron primes 3T3-L1 adipocytes to a TLR4-mediated inflammatory response. Nutrition. 2015; 31(10): 1266–74. DOI: 10.1016/j.nut.2015.04.007
42. Datz C., Müller E., Aigner E. Iron overload and non-alcoholic fatty liver disease. Minerva Endocrinol. 2017; 42(2): 173–83. DOI: 10.23736/S0391-1977.16.02565-7
43. Kowdley K.V., Belt P., Wilson L.A. et al.; NASH Clinical Research Network. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2012; 55(1): 77–85. DOI: 10.1002/hep.24706
44. Britton L.J., Subramaniam V.N., Crawford D.H. Iron and non alcoholic fatty liver disease. World J. Gastroenterol. 2016; 22(36): 8112–22. DOI: 10.3748/wjg.v22.i36.8112
45. Kim C.W., Chang Y., Sung E. et al. Serum ferritin levels predict incident non-alcoholic fatty liver disease in healthy Korean men. Metabolism. 2012; 61(8): 1182–8. DOI: 10.1016/j.metabol.2012.01.007
46. Dongiovanni P., Fracanzani A.L., Fargion S. et al. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J. Hepatol. 2011; 55(4): 920–32. DOI: 10.1016/j.jhep.2011.05.008
47. Gabrielsen J.S., Gao Y., Simcox J.A. et al. Adipocyte iron regulates adiponectin and insulin sensitivity. J. Clin. Invest. 2012; 122(10): 3529–40. DOI: 10.1172/JCI44421
48. Pihan-Le Bars F., Bonnet F., Loréal O. et al. Indicators of iron status are correlated with adiponectin expression in adipose tissue of patients with morbid obesity. Diabetes Metab. 2016; 42(2): 105– 11. DOI: 10.1016/j.diabet.2015.10.007
49. Fernández-Real J.M., Peñarroja G., Castro A. et al. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes. 2002; 51(4): 1000–4. DOI: 10.2337/diabetes.51.4.1000
50. Houschyar K.S., Lüdtke R., Dobos G.J. et al. Effects of phlebotomy induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial. BMC Med. 2012; 10: 54. DOI: 10.1186/1741-7015-10-54
51. Adams L.A., Crawford D.H., Stuart K. et al. The impact of phlebotomy in nonalcoholic fatty liver disease: a prospective, randomized, controlled trial. Hepatology. 2015; 61(5): 1555–64. DOI: 10.1002/hep.27662
52. Nelson J.E., Wilson L., Brunt E.M. et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011; 53(2): 448–57. DOI: 10.1002/hep.24038
53. Eder S.K., Feldman A., Strebinger G. et al. Mesenchymal iron deposition is associated with adverse long-term outcome in non alcoholic fatty liver disease. Liver Int. 2020; 40(8): 1872–82. DOI: 10.1111/liv.14503
Рецензия
Для цитирования:
Гарбузенко Д.В. Механизмы и клиническое значение печеночного фиброгенеза при перегрузке железом. Доктор.Ру. 2022;21(2):23-29. https://doi.org/10.31550/1727-2378-2022-21-2-23-29
For citation:
Garbuzenko D.V. Mechanisms and Clinical Significance of Hepatic Fibrogenesis in Iron Overloa. Title. 2022;21(2):23-29. (In Russ.) https://doi.org/10.31550/1727-2378-2022-21-2-23-29