Pathomorphology of liver fibrosis in trepanobioptates of patients with steatohepatitis: main types, sources of development, features of progression

Authors

  • V. A. Tumanskiy Zaporizhzhia State Medical University, Ukraine,
  • S. V. Fen’ Zaporizhzhia State Medical University, Ukraine,

DOI:

https://doi.org/10.14739/2310-1237.2017.3.118299

Keywords:

steatohepatitis, hepatic stellate cells, fibroblasts, liver cirrhosis, biopsy

Abstract

Until recently, among the pathologists, hepatologists and gastroenterologists, a discussion continues on the morphogenesis and gradation of liver fibrosis in non-alcoholic patients (NASH) and alcoholic steatohepatitis (ASH).

Purpose of the study. Studying the main types and sources of liver fibrosis in patients with nonalcoholic and alcoholic steatohepatitis, justifying the gradation of its severity, taking into account the quantitative dynamics of fibrogenic producer cells, the relative area of fibrosis and the deposition of type I, III and IV collagen in the liver.

Material and methods. Histological and histochemical examination of liver fibrosis was performed in 198 patients with NASH of 18-79 years and in 79 patients with ASH of 47-63 years. Immunohistochemical study with measurement of the area of expression of activated αSMA + perisinusoidal stellate cells and αSMA + portal myofibroblasts with F1 (mild), F2 (moderate), F3 (severe) fibrosis and F4 fibrosis / cirrhosis was performed in 80 trepanobioptates of patients with NASH (20 cases in each group), electron microscopic examination of the liver – in 10 deceased patients suffering from NASH.

Results. In patients with NASH and ASH, there are two major types of liver fibrosis progress: the perisinusoidal pericellular and portal-Z3 perisinusoidal fibrosis, the development of which is the new generation of αSMA + star cells and αSMA + portal myofibroblasts of the fibrogenic immunophenotype, with co-expression of fascin and vimentin and absence of desmine expression. As the perisinusoidal pericellular fibrosis progresses from the mild F1 degree, to the severe F3 fibrosis and to the extremely severe F4 fibrosis / cirrhosis of the pericellular type, the area of the Masson-positive extracellular molecular-fibrous matrix (H = 88,70 р = 0,05 ) and the area of αSMA + collagen-producing stellate cells of perisinusoidal-pericellular localization (H = 45,12, p = 0,05). According to the data of photometric morphometry, with increasing severity of portal-Z3 perisinusoidal hepatic fibrosis from F1 to F4, the area of the Masson-positive extracellular molecular-fibrous matrix (N = 76,56 p = 0,05) in areas fibrofacitiously increases, as well as the area of activated αSMA + collagen-producing portal myofibroblasts and perisinusoid stellate cells of Z3 zones of hepatic lobules (H = 43,18, p = 0,05). Activation and increase in the number of CD-68+ macrophages in the centers of intensive hepatocyte steatosis, as well as the appearance of S100 (A4)+ macrophages that activate stellate cells, suggests that the phenomenon of pericellularity of liver fibrosis in NASH and ASH is due to exosomal macrophage involvement in zone of balloon steatonecrosis and necroptosis of hepatocytes, as well as local exosomal-cytokine activation of perisinusoid stellate cells of fibrogenic type.

Conclusion: As the progression of fibrosis from F1 to F4 degree in the liver the area of activated αSMA + fibroblasts, and the area of deposition of collagen I, III and IV type perisinusoidal pericellular or portal-Z3 perisinusoidal localization significantly increase.

References

Stepanov, Yu. M., & Filippova, О. Yu. (2013) Steatoz i steatohepatyt – tryhery pechinkovoho fibrohenezu? [Are steatosis and steatohepatitis triggers of hepatic fibrogenesis?]. Hastroenterolohiia, 2(48), 97–106. [in Ukrainian]

Trautwein, Ch., Friedman, S. L., Schuppan, D., & Pinzani, M. (2015) Hepatic fibrosis: Concept to treatment. J Hepatol. 62(1), 15–24. doi: 10.1016/j.jhep.2015.02.039.

Schuppan, D. (2015) Liver fibrosis: common mechanisms and antifibrotic therapies. Clin Res Hepatol Gastroenterol, 39(1), 51–59. doi: 10.1016/j.clinre.2015.05.005.

Caligiuri, A., Gentilini, A., & Marra, F. (2016) Molecular Pathogenesis of NASH. Int J Mol Sci, 17(1575), 1–32. doi: 10.3390/ijms17091575.

Takaki, A., Kawai, D., & Yamamoto, K. (2014) Molecular mechanisms and new treatment strategies for nonalcoholic steatohepatitis (NASH). Int J Mol Sci, 15, 7352–7379. doi: 10.3390/ijms15057352.

Stickel, F., Datz, C., Hampe, J., & Bataller, R. (2017) Pathophysiology and Management of Alcoholic Liver Disease: Update 2016. Gut Liver, 11(2), 173–188. doi: 10.5009/gnl16477.

Scarpellini, E., Lupo, M., Iegri, C., Gasbarrini, A., De Santis, A., & Tack, J. (2014) Intestinal permeability in non-alcoholic fatty liver disease: the gut-liver axis. Rev Recent Clin Trials, 9, 141–147. doi: 10.2174/1574887109666141216104334.

Fukui, H. (2015) Gut Microbiota and Host Reaction in Liver Diseases. Microorganism, 3(4), 759–791. doi: 10.3390/microorganisms3040759.

Kisseleva, T., Uchinami, H., Feirt, N., Quintana-Bustamante, O., Segovia, J. C., Schwa be, R.F., & Brenner, D.A. (2006) Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol, 45(3), 429–438. doi: 10.1016/j.jhep.2006.04.014.

Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A., & Bacon, B. R. (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol, 94, 2467–2474. doi: 10.1111/j.1572-0241.1999.01377.x.

Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 41, 1313–1321. doi: 10.1002/hep.20701.

Kim, S. U., Oh, H. J., Wanless, I. R., Lee, S., Han, K.-H., & Park, Y. N. (2012) The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis. J Hepatol, 57(3), 556–563. doi: 10.1016/j.jhep.2012.04.029.

Castera, L., Yuen Chan, H. L., Arrese, M., Afdhal, N., Bedossa, P., Friedrich-Rust, M., et al. (2015) EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepathol, 63(1), 237–264. doi: 10.1016/j.jhep.2015.04.006.

Chalassi, N., Younossi, Z., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K., et al. (2012) The Diagnosis and Management of Non-Alcoholic Liver Disease: Practice Guidelines by the American Association for the Study of Liver Diseases, American College of Gastroenterology and the American Gastroenterological Association. Am J Gastroenterol, 7(6), 811–826. doi: 10.1038/ajg.2012.128.

Brunt, E. M., Kleiner, D. E., Wilson, L. A., Belt, P., & Neuschwander-Tetri, B. A. (2011) Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology, 53, 810–820. doi: 10.1002/hep.24127.

Lemoinne, S., Cadoret, A., El Mourabit, H., Thabut, D., & Housset, Ch. (2013) Origins and functions of liver myofibroblasts. BBA, 1832(7), 948–954. doi: 10.1016/j.bbadis.2013.02.019.

Lepreux, S., & Desmoulière, A. (2015) Human liver myofibroblasts during development and diseases with a focus on portal (myo)fibroblasts. Front Physiol, 6, 173. doi: 10.3389/fphys.2015.00173.

Karin, D., Koyama, Yu, Brenner, D., & Kisseleva, T. (2016) The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation, 92(3), 84–92. https://doi.org/10.1016/j.diff.2016.07.001.

Fausther, M., Lavoie, E. G., & Dranoff, J. A. (2013) Contribution of Myofibroblasts of Different Origins to Liver Fibrosis. Curr Pathobiol Rep, 1(3), 225–230. doi: 10.1007/s40139-013-0020-0.

Xu, J., Liu, X., Koyama, Y., Wang, P., Lan, T., Kim, I-G., et al. (2014) The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies Front Pharmacol, 5, 167. doi: 10.3389/fphar.2014.00167.

Liu, X., Xu, J., Brenner, D. A., & Kisseleva, T. (2013) Reversibility of Liver Fibrosis and Inactivation of Fibrogenic Myofibroblasts. Curr. Pathobiol. Rep, 1, 209–214. doi: 10.1007/s40139-013-0018-7.

Dranoff, J. A., & Wells, R. G. (2010) Portal fibroblasts: Underappreciated mediators of biliary fibrosis. Hepatology, 51(4), 1438–1444. doi: 10.1002/hep.23405.

Wells, R. G. (2014) The Portal Fibroblast – Not Just a Poor Man’s Stellate Cell. Gastroenterology, 147(1), 41–47. doi: 10.1053/j.gastro.2014.05.001.

Bosselut, N., Housset, C., Marcelo, P., Rey, C., Burmester, T., Vinh, J., et al. (2010) Distinct proteomic features of two fibrogenic liver cell populations: hepatic stellate cells and portal myofibroblasts. Proteomics, 10(5), 1017–1028. doi: 10.1002/pmic.200900257.

Ji, J., Yu, F., Ji, Q., Li, Z., Wang, K., Zhang, J., et al. (2012) Comparative proteomic analysis of rat hepatic stellate cell activation: a comprehensive view and suppressed immune response. Hepatology, 56(1), 332–349. doi: 10.1002/hep.25650.

Perepelyuk, M., Terajima, M., Wang, A. Y., Georges, P. C., Janmey, P. A., Yamauchi, M., & Wells, R. G. (2013) Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol, 304(6), 605–614. doi: 10.1152/ajpgi.00222.2012.

Olsen, A. L., Sackey, B. K., Marcinkiewicz, C., Boettiger, D., & Wells, R. G. (2012) Fibronectin extra domain-A promotes hepatic stellate cell motility but not differentiation into myofibroblasts. Gastroenterology, 142(4), 928–937. e3. doi: 10.1053/j.gastro.2011.12.038.

Fen’, S. V. (2017) Immunogistokhimicheskaya kharakteristika deponirovaniya kollagena I, III, IV tipa v dinamike progressirovaniya osnovnykh tipov fibroza pecheni u bol'nykh nealkogol'nym steatogepatitom [Immunohistochemical characteristics of collagen I, III, IV type deposition in the dynamics of progressing of the basic types of liver fibrosis in patients with non-alcohol steatohepatitis]. Morphologiya, 11(3), 29–38.[in Russian]

Chen, L., Li J., Zhang, J., Dai, C., Liu, X., Wang, J., et al. (2015) S100A4 promotes liver fibrosis via activation of hepatic stellate cells. J Hepatol, 62(1), 156–164. doi: 10.1016/j.jhep.2014.07.035.

Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., et al. (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity, 41(1), 14–20. doi: 10.1016/j.immuni.2014.06.008.

Xue, J., Schmidt, S. V., Sander, J., Draffehn, A., Krebs, W., Quester, I., et al. (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity, 40(2), 274–288. doi: 10.1016/j.immuni.2014.01.006.

Tumansky, V.A., & Shebeko, Yu. A. (2012) Perisinusoidal'no-centrolobulyarnyj fibroz pecheni: osobennosti morfogeneza i parametry progressii [Perisinusoidal-centrolobular liver fibrosis: features of morphogenesis and progression parameters]. Pathologia, 3, 59–64. [in Russian]

Szabo, G., & Petrasek, J. (2015) Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol, 12, 387–400. doi: 10.1038/nrgastro.2015.94.

Schattenberg, J. M., & Lee, M. S. (2016) Extracellular Vesicles as Messengers Between Hepatocytes and Macrophages in Nonalcoholic Steatohepatitis. Gastroenterology,150(4), 815–818. doi: http://dx.doi.org/10.1053/j.gastro.2016.02.064.

Hirsova, P., Ibrahim, S. H., Krishnan, A., Verma, V. K., Bronk, S. F., Werneburg, N. W., et al. (2016) Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology, 150, 956–967. doi: 10.1053/j.gastro.2015.12.037.

Sato, K., Meng, F., Glaser, S., & Alpini, G. (2016) Exosomes in liver pathology. J Hepatol, 65(1), 213–221. doi: 10.1016/j.jhep.2016.03.004.

Momen-Heravi, F., Saha, B., Kodys, K., Catalano, D., Satishchandran, A., & Szabo, G. (2015) Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med, 13(261), 1–13. doi: 10.1186/s12967-015-0623-9.

Verma, V. K., Li, H., Wang, R., Hirsova, P., Mushref, M., Liu, Y., et al. (2016) Alcohol stimulates macrophage activation through caspase dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol, 64, 651–660. doi: 10.1016/j.jhep.2015.11.020.

Pradere, J. P., Kluwe, J., De Minicis, S., Jiao, J. J., Gwak, G. Y., Dapito, D. H., et al. (2013) Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology, 58(4), 1461–1473. doi:10.1002/hep.26429.

Charrier, A., Chen, R., Chen, L., Kemper, S., Hattori, T., Takigawa, M., & Brigstock, D. R. (2014) Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver. Surgery, 156, 548–555. doi: 10.1016/j.surg.2014.04.014.

Chen, L., & Brigstock, D. R. (2016) Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC-derived exosomes. FEBS Lett, 590(23), 4263–4274. doi: 10.1002/1873-3468.12448.

Chen, L., Charrier, A., Zhou, Y., Chen, R., Yu, B., Agarwal, K., et al. (2014) Epigenetic regulation of connective tissue growth factor by microRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology, 59, 1118–1129. doi: 10.1002/hep.26768.

Marra, F., & Tacke, F. (2014) Roles for chemokines in liver disease. Gastroenterology, 147, 577–594. doi: 10.1053/j.gastro.2014.06.043.

Tacke, F., & Zimmermann, H. W. (2014) Macrophage heterogeneity in liver injury and fibrosis. J Hepatol, 60, 1090–1096. doi: 10.1016/j.jhep.2013.12.025.

Sasaki, R., Devhare, P. B., Steele, R., Ray, R., & Ray, R. B. (2017) Hepatitis C virus-induced CCL5 secretion from macrophages activates hepatic stellate cells. Hepatology, 66(3), 746–757. doi: 10.1002/hep.29170.

Havryliuk, A. O. (2012) Histolohichni i imunohistokhimichni oznaky ymovirnoho prohresuvannia fibrozu pechinky u khvorykh na khronichnyi virusnyi hepatyt B, C i B+C [Histologic and immunohistochemical signs of probable progression of liver fibrosis in patients with chronic viral hepatitis B, C and B + C]. Svit medytsyny ta biolohii, 3, 25–29. [in Ukrainian].

Barnes, M. A., Roychowdhury, S., & Nagy, L. E. (2014) Innate immunity and cell death in alcoholic liver disease: Role of cytochrome P4502E1. Redox Biology, 2, 929–993. doi.org/10.1016/j.redox.2014.07.007.

How to Cite

1.
Tumanskiy VA, Fen’ SV. Pathomorphology of liver fibrosis in trepanobioptates of patients with steatohepatitis: main types, sources of development, features of progression. Pathologia [Internet]. 2017Dec.22 [cited 2024Apr.21];(3). Available from: http://pat.zsmu.edu.ua/article/view/118299

Issue

Section

Original research