Progressive accumulation of fibrillar extracellular matrix (ECM) in the liver is the consequence of reiterated liver tissue damage due to infective (mostly hepatitis B and C viruses), toxic/drug-induced, metabolic and autoimmune causes, and the relative chronic activation of the wound-healing reaction. The process may result in clinically evident liver cirrhosis and hepatic failure. Although cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrotic development related to the underlying disorders causing the fibrosis. These different patterns of fibrogenic evolution are related to different factors and particularly: (1) the topographic localization of tissue damage, (2) the relative concentration of profibrogenic factors and (3) the prevalent profibrogenic mechanism(s). The mechanisms responsible for the fibrogenic evolution of chronic liver diseases can be summarized in three main groups: chronic activation of the wound-healing reaction, oxidative stress-related molecular mechanisms, and the derangement of the so-called ‘epithelial-mesenchymal' interaction leading to the generation of reactive cholangiocytes and peribiliary fibrosis. Most of the knowledge on the cell and molecular biology of hepatic fibrosis derives from in vitro studies employing culture of activated hepatic stellate cells isolated from rat, mouse or human liver. It is now evident that other ECM-producing cells, i.e. fibroblasts and myofibroblasts of the portal tract and circulating ‘fibrocytes', are likely to contribute to liver fibrosis. More recently, the attention is progressively shifting to the profibrotic microenvironment of the liver with increasing interest for the role of immune cells and specific subsets of macrophages regulating the progression or the regression of fibrosis, the role of intestinal microbiota and the influence of tissue stiffness. Other major areas of development include the role of tissue hypoxia and the establishment of an anaerobic proinflammatory environment and the influence of epigenetic modification in conditioning the progression of fibrosis.

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;402:107-137.
Mehal WZ, Iredale J, Friedman SL: Scraping fibrosis: expressway to the core of fibrosis. Nat Med 2011;17:552-553.
Pinzani M, Rombouts K: Liver fibrosis: from the bench to clinical targets. Dig Liver Dis 2004;36:231-242.
Pinzani M, Rombouts K, Colagrande S: Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 2005;42(suppl 1):S22-S36.
Germani G, Hytiroglou P, Fotiadu A, Burroughs AK, Dhillon AP: Assessment of fibrosis and cirrhosis in liver biopsies: an update. Semin Liver Dis 2011;31:82-90.
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;49:1236-1244.
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.
Rosselli M, Macnaughtan J, Jalan R, Pinzani M: Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Gut 2013;63:1234-1241.
Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655-1669.
Wynn TA: Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524-529.
Pinzani M, Macias-Barragan J: Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 2010;4:459-472.
Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005;115:209-218.
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;66:303-353.
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.
Quan TE, Cowper SE, Bucala R: The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 2006;8:145-150.
Novo E, Parola M: Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 2008;1:5.
De Alwis NMW, Day CP: Non-alcoholic fatty liver: the mist gradually clear. J Hepatol 2008;48:S105-S112.
Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA: Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014;14:181-194.
Machado MV, Cortez-Pinto H: Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 2012;11:440-449.
Olsen AL, Bloomer SA, Chan EP, Gaça MD, Georges PC, Sackey B, Uemura M, Janmey PA, Wells RG: Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Am J Physiol Gastrointest Liver Physiol 2011;301:G110-G118.
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;170:1942-1953.
Chen Y, Choi SS, Michelotti GA, Chan IS, Swiderska-Syn M, Karaca GF, Xie G, Moylan CA, Garibaldi F, Premont R, Suliman HB, Piantadosi CA, Diehl AM: Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology 2012;143:1319-1329.
Mann DA: Epigenetics in liver disease. Hepatology 2014;60:1418-1425.
Schnabl B, Brenner DA: Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513-1524.
Machado MV, Cortez-Pinto H: Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 2012;11:440-449.
Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004;4:499-511.
Otte JM, Rosenberg IM, Podolsky DK: Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 2003;124:1866-1878.
Coelho AL, Hogaboam CM, Kunkel SL: Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev 2005;16:553-560.
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-G578.
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-G525.
Seki E, Brenner DA: Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 2008;48:322-335.
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;132:517-524.
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;35:749-755.
Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al: Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-117.
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;122:1303-1313.
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;126:1740-1749.
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;37:1519-1526.
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;46:690-698.
Dufour JF, DeLellis R, Kaplan MM: Reversibility of hepatic fibrosis in autoimmune hepatitis. Ann Intern Med 1997;127:981-985.
Wakim-Fleming J, Mullen KD: Long-term management of alcoholic liver disease. Clin Liver Dis 2005;9:135-149.
Dixon JB, Bhathal PS, Hughes NR, O'Brien PE: Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647-1654.
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.
Desmet VJ, Roskams T: Cirrhosis reversal: a duel between dogma and myth. J Hepatol 2004;40:860-867.
Wanless IR, Nakashima E, Sherman M: Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000;124:1599-1607.
Desmet VJ: Milestones in liver disease: scoring chronic hepatitis. J Hepatol 2003;38:382-386.
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;3:928-931.
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;24:692-698.
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;126:1795-1808.
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;55:1174-1182.
Popov Y, Schuppan D: Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009;50:1294-1306.
Shuppan D, Pinzani M: Antifibrotic therapy: lost in translation? J Hepatol 2012;56(suppl):S66-S74.
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