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Pathogenesis and Evolution of Liver Fibrosis: Cirrhosis or Cirrhoses?

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Complications of Cirrhosis

Abstract

The word “cirrhosis” identifies the characteristic morphologic alterations of the liver parenchyma common to the advanced stage of all fibrogenic chronic liver diseases associated with the derangement of the hepatic vascular architecture, increase of the intra-hepatic resistance to portal flow, and the development of portal hypertension with its often life-threatening complications.

Current understanding of molecular and cellular mechanisms underlying fibrogenesis and advances in the diagnosis and treatment of chronic liver diseases have made increasingly clear that the term “cirrhosis” is not completely suitable to describe such a dynamic and varied condition and that the categorisation simply based on clinical manifestations does not reflect the biological complexity of the pathophysiological process leading from fibrosis to cirrhosis. Among many experts, there is an increasing concern on the appropriateness of the word “cirrhosis”, which implies almost automatically a rapid and adverse prognosis in an era when increasing therapeutic options are rapidly emerging. In this context perhaps it whould be more appropriate, to address this problem, discussing about “cirrhoses” rather than “cirrhosis”. At least in the pre-clinical phase of cirrhosis when there are no evident clinical manifestations, it is likely that the disease is sustained by different prevalent mechanisms depending on disease etiology. This potentially calls for different morphological classifications, different non-invasive diagnostic and prognostic indicators, different etiology-driven and/or antifibrotic therapies and, most importantly, different expectations on the effective reversibility of fibrosis and cirrhosis.

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References

  1. Millward-Sadler GH, Hanh EG, Wright R. Cirrhosis: an appraisal. In: Wright R, Millward-Sadler GH, Alberti KGMM, Karran S, editors. Liver and biliary disease. 2nd ed. London: Baillière Tindall WB Saunders; 1985. pp. 821–60.

    Google Scholar 

  2. Rappaport AM, McPhee PJ, Fisher MM, Phillips MJ. The scarring of the liver acini (Cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol. 1983;402:107–37.

    Article  CAS  PubMed  Google Scholar 

  3. Reichen J, Egger B, Ohara N, Zeltner TB, Zysset T, Zimmermann A. Determinants of hepatic function in liver cirrhosis in the rat. Multivariate analysis. J Clin Invest. 1988;82:2069–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology. 1995;21:1238–47.

    CAS  PubMed  Google Scholar 

  5. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: in search of a pathophysiological classification of cirrhosis. Hepatology. 2010;51:1445–9.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Tsochatzis EA, Bosch J, Burroughs AK. New therapeutic paradigm for patients with cirrhosis. Hepatology. 2012;56:1983–92.

    Article  CAS  PubMed  Google Scholar 

  7. Hytiroglou P, Snover DC, Alves V, Balabaud C, Bhathal PS, Bioulac-Sage P, et al. Beyond “cirrhosis”: a proposal from the International Liver Pathology Study Group. Am J Clin Pathol. 2012;137:5–9.

    Article  PubMed  Google Scholar 

  8. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Pinzani M, Macias-Barragan J. Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol. 2010;4:459–72.

    Article  PubMed  Google Scholar 

  11. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol. 1980;66:303–53.

    Article  CAS  PubMed  Google Scholar 

  13. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep. 2006;8:145–50.

    Article  CAS  PubMed  Google Scholar 

  15. Calvaruso V, Maimone S, Gatt A, Tuddenham E, Thursz M, Pinzani M, Burroughs AK. Coagulation and fibrosis in chronic liver disease. Gut. 2008;57:1722–7.

    Article  CAS  PubMed  Google Scholar 

  16. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178:5288–95.

    Article  CAS  PubMed  Google Scholar 

  18. Mitchell C, Couton D, Couty JP, et al. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol. 2009;174:1766–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Fabris L, Strazzabosco M. Epithelial-mesenchymal interactions in biliary diseases. Semin Liver Dis. 2011;31:11–32.

    Article  PubMed Central  PubMed  Google Scholar 

  20. OʼHara SP, Tabibian JH, Splinter PL, LaRusso NF. The dynamic biliary epithelia: molecules, pathways, and disease. J Hepatol. 2013;58:575–82.

    Article  PubMed  Google Scholar 

  21. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–29.

    Article  CAS  PubMed  Google Scholar 

  22. Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair. 2008;1:5.

    Article  PubMed Central  PubMed  Google Scholar 

  23. De Alwis NMW, Day CP. Non-alcoholic fatty liver: the mist gradually clear. J Hepatol. 2008;48:S105–12.

    Article  Google Scholar 

  24. Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146:1513–24.

    Article  CAS  PubMed  Google Scholar 

  25. Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol. 2012;11:440–9.

    CAS  PubMed  Google Scholar 

  26. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    Article  CAS  PubMed  Google Scholar 

  27. Otte JM, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology. 2003;124:1866–78.

    Article  CAS  PubMed  Google Scholar 

  28. Coelho AL, Hogaboam CM, Kunkel SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev. 2005;16:553–60.

    Article  CAS  PubMed  Google Scholar 

  29. Brun P, Castagliuolo I, Pinzani M, Palu G, Martines D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2005;289:G571–8.

    Article  CAS  PubMed  Google Scholar 

  30. Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidences in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G518–25.

    Article  CAS  PubMed  Google Scholar 

  31. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–35.

    Article  CAS  PubMed  Google Scholar 

  32. Medina J, Arroyo AG, Sanchez-Madrid F, Moreno-Otero R. Angiogenesis in chronic inflammatory liver disease. Hepatology. 2004;39:1185–95.

    Article  CAS  PubMed  Google Scholar 

  33. Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50:604–20.

    Article  PubMed  Google Scholar 

  34. Corpechot C, Barbu V, Wendum D, et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology. 2002;35:1010–21.

    Article  CAS  PubMed  Google Scholar 

  35. Yoshiji H, Kuriyama S, Yoshii J, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut. 2003;52:1347–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Medina J, Caveda L, Sanz-Cameno P, et al. Hepatocyte growth factor activates endothelial pro-angiogenic mechanisms relevant in chronic hepatitis C-associated neoangiogenesis. J Hepatol. 2003;38:660–7.

    Article  CAS  PubMed  Google Scholar 

  37. Shimoda K, Mori M, Shibuta K, Banner B, Barnard G. Vascular endothelial growth factor/vascular permeability factor mRNA expression in patients with chronic hepatitis C and hepatocellular carcinoma. Int J Oncol. 1999;14:353–9.

    CAS  PubMed  Google Scholar 

  38. Medina J, Sanz-Cameno P, Garcia-Buey L, Martin-Vilchez S, Lopez-Cabrera M, Moreno-Otero R. Evidence of angiogenesis in primary biliary cirrhosis: an immunohistochemical descriptive study. J Hepatol. 2005;42:124–31.

    Article  CAS  PubMed  Google Scholar 

  39. Novo E, Cannito S, Zamara E, et al. Vascular endothelial growth factor and angiopoietin-1 as hypoxia-dependent autocrine and paracrine factors stimulating migration and chemotaxis of activated human hepatic stellate cells. Am J Pathol. 2007;170:1942–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Aleffi S, Petrai I, Bertolani C, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42:1339–48.

    Article  CAS  PubMed  Google Scholar 

  41. Pinzani M, Rombouts K. Liver fibrosis: from the bench to clinical targets. Dig Liver Dis. 2004;36:231–42.

    Article  CAS  PubMed  Google Scholar 

  42. Hall A, Germani G, Isgrò G, et al. Fibrosis distribution in explanted cirrhotic livers. Histopathology. 2012;60:270–7.

    Article  PubMed  Google Scholar 

  43. Calvaruso V, Burroughs AK, Standish R, et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology. 2009;49:1236–44.

    Article  PubMed  Google Scholar 

  44. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis. A systematic review of 118 studies. J Hepatol. 2006;44:217–31.

    Article  PubMed  Google Scholar 

  45. Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol. 2007;46:927–34.

    Article  CAS  PubMed  Google Scholar 

  46. Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254–61.

    Article  CAS  PubMed  Google Scholar 

  47. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133:481–8.

    Article  CAS  PubMed  Google Scholar 

  48. Groszmann RJ, Bosch J, Grace N, Conn HO, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol vs placebo in the prevention of the first variceal hemorrhage. Gastroenterology. 1990;99:1401–7.

    CAS  PubMed  Google Scholar 

  49. Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R, Bandi JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology. 1998;114:1296–303.

    Article  CAS  PubMed  Google Scholar 

  50. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet. 2003;361(9361):952–4.

    Article  PubMed  Google Scholar 

  51. Krogsgaard K, Gluud C, Henriksen JH, Christoffersen P. Correlation between liver morphology and portal pressure in alcoholic liver disease. Hepatology. 1984;4:699–703.

    Article  CAS  PubMed  Google Scholar 

  52. Van Leeuwen DJ, Howe SC, Scheuer PJ, Sherlock S. Portal hypertension in chronic hepatitis: relationship to morphological changes. Gut. 1990;31:339–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol. 2006;44:111–7.

    Article  PubMed  Google Scholar 

  54. Sreenivasan P, Inayat I, Jain D, Bari K, Garcia-Tsao G. Histological-clinical correlation in cirrhosis—Validation of a histological classification of the severity of cirrhosis. Hepatology. 2007;46(Suppl 1):579A (Abstract).

    Google Scholar 

  55. Calvaruso V, Burroughs AK, Standish R, Manousou P, Grillo F, Leandro G, Maimone S, Pleguezuelo M, Xirouchakis I, Guerrini GP, Patch D, Yu D, O’Beirne J, Dhillon AP. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology. 2009;49:1236–44.

    Article  PubMed  Google Scholar 

  56. Germani G, Dhillon A, Andreana L, Calvaruso V, Manousou P, Isgró G, Burroughs AK. Histological subclassification of cirrhosis. Hepatology. 2010;52:804–5.

    Article  PubMed  Google Scholar 

  57. Shiratori Y, Imazeki F, Moriyama M, Yano M, Arakawa Y, Yokosuka O, et al. Histological improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517–24.

    Article  CAS  PubMed  Google Scholar 

  58. Kweon YO, Goodman ZD, Dienstag JL, Shiff ER, Brown NA, Burkardt E, et al. Decreasing fibrogenesis: an immunoistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001;35:749–55.

    Article  CAS  PubMed  Google Scholar 

  59. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105–17.

    Article  CAS  PubMed  Google Scholar 

  60. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303–13.

    Article  CAS  PubMed  Google Scholar 

  61. Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126:1740–9.

    Article  CAS  PubMed  Google Scholar 

  62. Serpaggi J, Carnot F, Nalpas B, Canioni D, Guéchot J, Lebray P, Vallet-Pichard A, Fontaine H, Bedossa P, Pol S. Direct and indirect evidence for the reversibility of cirrhosis. Hum Pathol. 2006;37:1519–26.

    Article  PubMed  Google Scholar 

  63. Hui CK, Leung N, Shek TW, Yao H, Lee WK, Lai JY, Lai ST, Wong WM, Lai LS, Poon RT, Lo CM, Fan ST, Lau GK, Hong Kong Liver Fibrosis Study. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology. 2007;46:690–8.

    Article  PubMed  Google Scholar 

  64. Dufour JF, DeLellis R, Kaplan MM. Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med. 1997;127:981–5.

    Article  CAS  PubMed  Google Scholar 

  65. Wakim-Fleming J, Mullen KD. Long-term management of alcoholic liver disease. Clin Liver Dis. 2005;9:135–49.

    Article  PubMed  Google Scholar 

  66. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–54.

    Article  PubMed  Google Scholar 

  67. Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis, and cirrhosis. Surgery. 2004;135:48–58.

    Article  PubMed  Google Scholar 

  68. Desmet VJ, Roskams T. Reversal of cirrhosis: evidence based medicine? Gastroenterology. 2003;125:629–30.

    Article  CAS  PubMed  Google Scholar 

  69. Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol. 2004;40:860–7.

    Article  PubMed  Google Scholar 

  70. Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med. 2000;124:1599–607.

    CAS  PubMed  Google Scholar 

  71. Desmet VJ. Milestones in liver disease. Scoring chronic hepatitis. J Hepatol. 2003;38:382–6.

    Article  PubMed  Google Scholar 

  72. Popper H. What are the major types of hepatic cirrhosis? In: Ingelfinger F, Relman A, Finland M, editors. Controversies in internal medicine. Philadelphia: WB Saunders; 1966. pp. 233–43.

    Google Scholar 

  73. Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E. The Copenhagen study group for liver disease. Conversion of micronodular into macronodular cirrhosis. Hepatology. 1983;3:928–31.

    Article  CAS  PubMed  Google Scholar 

  74. Hayasaka A, Ilda S, Suzuki N, Kondo F, Miyazaki M, Yonemitsu H. Pyridinoline collagen cross-links in patients with chronic viral hepatitis and cirrhosis. J Hepatol. 1996;24:692–8.

    Article  CAS  PubMed  Google Scholar 

  75. Issa R, Zhou X, Constandinou CM, Fallowfield J, Millward-Sadler H, Gaca MD, Sands E, Suliman I, Trim N, Knorr A, Arthur MJ, Benyon RC, Iredale JP. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology. 2004;126:1795–808.

    Article  CAS  PubMed  Google Scholar 

  76. Novo E, Marra F, Zamara E, Valfrè di Bonzo L, Monitillo L, Cannito S, Petrai I, Mazzocca A, Bonacchi A, De Franco RS, Colombatto S, Autelli R, Pinzani M, Parola M. Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans. Gut. 2006;55:1174–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sheila Sherlock Chair of Hepatology, UCL Institute for Liver and Digestive Health, Royal Free Hospital U3, Pond Street, NW3 2QG, London, UK

    Prof Massimo Pinzani MD, PhD, FRCP

  2. Institute for Liver and Digestive Health, Sheila Sherlock Liver Centre, University College London, Royal Free Hospital, Pond Street, NW3 2QG, London, UK

    Dr Francesca Saffioti MD & Prof Massimo Pinzani MD, PhD, FRCP

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  1. Dr Francesca Saffioti MD
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Correspondence to Massimo Pinzani MD, PhD, FRCP .

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Editors and Affiliations

  1. Department of Transplant, Mayo Clinic, Jacksonville, Florida, USA

    Andrew P. Keaveny

  2. Institut de Malalties Digestives i Metaboliques, University of Barcelona, Barcelona, Spain

    Andrés Cárdenas

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Saffioti, F., Pinzani, M. (2015). Pathogenesis and Evolution of Liver Fibrosis: Cirrhosis or Cirrhoses?. In: Keaveny, A., Cárdenas, A. (eds) Complications of Cirrhosis. Springer, Cham. https://doi.org/10.1007/978-3-319-13614-1_1

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