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Fibrosis: Pathophysiology, Diagnosis and Treatment

Free Access

Pathophysiology of Liver Fibrosis

Pinzani M.

Author affiliations

UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK

Corresponding Author

Prof. Massimo Pinzani, MD, PhD, FRCP

UCL Institute for Liver and Digestive Health, Royal Free Hospital

Rowland Hill Street

London NW3 2PF (UK)

E-Mail m.pinzani@ucl.ac.uk

Related Articles for ""

Dig Dis 2015;33:492-497

Abstract

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.

© 2015 S. Karger AG, Basel


Introduction

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. Cirrhosis is defined as an advanced stage of fibrosis, characterized by the formation of regenerative nodules of liver parenchyma that are separated by and encapsulated in fibrotic septa and associated with major angioarchitectural changes [1].

The expansion of knowledge on fibrogenesis and the underlying cellular and molecular mechanisms have brought forward the concept that the predominant profibrogenic mechanisms and the pattern of parenchymal damage evolution depend on the etiology of chronic liver injury. In particular, the concept of etiology-driven fibrosis leading to different prevailing fibrogenic mechanisms implies that targets for antifibrogenic therapy should be classified as ‘core pathways' when likely common to all chronic liver diseases (CLD) and possibly to fibrogenic disorders affecting other organs and tissues, and ‘regulatory pathways' when more specific for a given etiology and/or tissue [2].

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). In addition, these different patterns imply the participation of different cellular effectors of the fibrogenic process [3]. The mechanisms responsible for the fibrogenic evolution of CLD 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 [4].

Accordingly, it is indeed possible to identify disease-specific patterns. For example, portal-central septa and interface hepatitis are typical of chronic viral hepatitis, intercellular fibrosis and the deposition of fibrillar matrix around the sinusoids (capillarization) are distinctive of alcoholic and nonalcoholic steatohepatitis (NASH) and hemochromatosis, while in primary biliary cirrhosis and primary sclerosing cholangitis the coproliferation of reactive bile ductules and periductular myofibroblast-like cells at the portal-parenchymal interface tends to follow a portal-to-portal direction [5]. A sound example of how the evolution of fibrosis can be influenced by the etiology both in quantitative and topographical terms is offered by a recent study in which collagen was measured (as the collagen proportionate area) in cirrhotic explants of different etiologies [6]. Overall, it is more and more clear that we should refer to etiology-driven ‘cirrhoses' and the term ‘advanced chronic liver disease' should replace the word ‘cirrhosis' [7,8].

The knowledge of these aspects of the pathophysiology of CLD provides important insights on the correlation between the time of progression of liver disease, the etiological agents, the dynamics of the necroinflammatory infiltrate, the distribution of fibrosis, and the onset and progression of portal hypertension, depending on the etiological agent leading to cirrhosis.

Established Mechanisms of Liver Fibrogenesis

Studies performed over the past 25 years have highlighted a large number of cellular and molecular mechanisms responsible for liver fibrogenesis. In biological terms, fibrogenesis is a dynamic process characterized by continuous accumulation of fibrillar ECM associated with continuous degradation and remodeling in a context of chronic tissue damage. Fibrosis emerges as an apparently static result when degradation is not sufficient [9]. The principal mechanism leading to liver fibrosis is the chronic activation of the wound-healing reaction. The wound-healing process is normally characterized by an ordered cascade of biological events involving cells and soluble factors aimed at resolving a single tissue injury. In general terms, these events and effectors are disposed in a logical sequence with activation of the next step preceded by the resolution of the previous phase [for a review see [10], [11]]. This process, which is highly efficient in the presence of single acute tissue insult, leads to progressive scarring when the tissue damage is chronic. In other terms, deposition of fibrillar matrix rather than organized tissue regeneration becomes the best option in order to maintain tissue continuity. The modification in ECM composition (predominantly collagen types I and III) have not only obvious mechanical and physical but also biochemical implications, thus contributing to the modulation of several cellular functions (growth, migration, gene expression) through a direct interaction between ECM components and cell adhesion molecules, and by functioning as a reservoir for proinflammatory and profibrogenic mediators [10,11,12].

The reference fibrogenic cell type in the liver is represented by the hepatic stellate cell (HSC). HSCs are characterized by the physiological ability to store retinyl esters in intracytoplasmic lipid droplets and by ultrastructural features of vascular pericytes possibly contributing to the regulation of sinusoidal blood flow [13]. The processes of HSC activation and phenotypical transformation into myofibroblasts, as well as their profibrogenic role, have been extensively clarified and represent an important basis for the understanding of the hepatic fibrogenic process [10,11,12]. It is now evident that distinct ECM-producing cells, each with a distinct localization and a characteristic immunohistochemical and/or electron microscopic phenotype, may contribute to liver fibrosis [10,11]. These include fibroblasts and myofibroblasts of the portal tract, smooth muscle cells localized in vessel walls and myofibroblasts localized around the centrolobular vein. It is also evident that the relative participation of these different cell types is dependent on the development of distinct patterns of fibrosis. In addition to resident mesenchymal cells, myofibroblasts may derive from a population of unique circulating fibroblast-like cells derived from bone marrow stem cells, commonly termed ‘fibrocytes', which has been identified and characterized in recent years [14,15].

In addition to chronic wound healing, the involvement of oxidative stress has been documented in all fibrogenic disorders characterized by chronic tissue damage and the overexpression of critical genes related to ECM remodeling and inflammation [for a review see [16]]. Oxidative stress resulting from the presence of free radicals as well as by decreased efficiency of antioxidant defenses does not represent simply a potentially toxic consequence of chronic tissue injury, but actively contributes to excessive tissue remodeling and fibrogenesis. Accordingly, reactive oxygen species (ROS) or reactive aldehydes (in particular 4-hydroxy-2,3-nonenal; HNE) released by damaged or activated neighboring cells can directly affect the behavior of myofibroblasts by an upregulation of profibrogenic genes, including procollagen type I, MCP-1 and tissue inhibitor of metallopeptidase-1 (fig. 1) [16]. Along these lines, oxidative stress likely represents a predominant profibrogenic mechanism in conditions such as chronic alcoholic hepatitis and NASH. In these settings, perisinusoidal fibrosis may develop independently of evident tissue necrosis and inflammation due to the direct profibrogenic action of ROS, HNE and acetaldehyde in the case of chronic alcohol abuse [17].

Fig. 1

ROS and related mediators as profibrogenic stimuli. Oxidative stress resulting from the presence of free radicals as well as by decreased efficiency of antioxidant defenses actively contributes to excessive tissue remodeling and fibrogenesis. ROS or reactive aldehydes (in particular HNE) released by damaged or activated neighboring cells can directly affect the behavior of myofibroblasts by an upregulation of profibrogenic genes, including procollagen type I, MCP-1 and tissue inhibitor of metallopeptidase-1 (TIMP1). PDGF = Platelet-derived growth factor; KC = Kupffer cell; SEC = sinusoidal endothelial cell; ASH = alcoholic steatohepatitis; coll = collagen.

http://www.karger.com/WebMaterial/ShowPic/313084

Emerging Mechanisms of Liver Fibrogenesis

More recently, attention has been 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 [18], the role of intestinal microbiota [19] and the influence of tissue stiffness [20]. Other major areas of development include the role of tissue hypoxia [21], the establishment of an anaerobic proinflammatory environment [22] and the influence of epigenetic modification in conditioning the progression of fibrosis [23].

Among these emerging mechanisms, the alterations of mechanisms of innate immunity in the establishment of a systemic proinflammatory and profibrogenic environment affecting the progression of CLD seems to have a central role. The symbiotic relationship existing between the gut microflora and human host plays an important role in modulating immunological homeostasis and is integral to health. In CLD, a combination of dysbiosis (e.g. an imbalance between pathogenic and nonpathogenic bacterial species), increased intestinal permeability, altered gut defenses and reduced immunological surveillance leads to increased migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or other extraintestinal organs or sites [24]. Multiple lines of investigation suggest that bacterial translocation contributes to CLD, particularly in NASH [25]. In particular, the attention is focused on bacterial by-products termed pathogen-associated molecular patterns (PAMPs). PAMPs are lipoproteins, bacterial DNA and double-stranded RNA, which are recognized by pattern recognition receptors (PRRs) present on a wide variety of cells, including fibroblasts [26]. The interaction between PAMPs and PRRs serves as a first line of defense during infection and activates numerous proinflammatory cytokine and chemokine responses. In this context, it is particularly relevant that fibroblasts, myofibroblasts and vascular pericytes express a variety of PRRs, including Toll-like receptors (TLRs), and that their ligands can directly activate these cell types and promote their differentiation into collagen-producing myofibroblasts [27,28]. In addition, upon stimulation with the TLR4 ligand lipopolysaccharide (LPS) or the TLR2 ligand lipoteichoic acid, fibroblasts activate mitogen-activated protein kinase pathways, translocate NF-κB and secrete substantial amounts of proinflammatory cytokines and chemokines [29]. The interaction between PAMPs and PRRs, particularly TLRs, is in addition important for the establishment of a proinflammatory/profibrogenic condition in a defined vascular district, i.e. the portal circulation, with activation of HSC-expressing TLRs by an excessive amount of PAMPs reaching the liver as a consequence of abnormal intestinal permeability in conditions such as chronic alcohol abuse, diabetes and obesity [30,31].

The Reversibility of Fibrosis and Cirrhosis

Although a regression has been shown in animal models of cirrhosis, this possibility is not yet fully substantiated in humans. Evidence of either fibrotic or cirrhotic regression has now been reported in CLD of different etiologies, including viral hepatitis [32,33,34,35,36,37,38,39], autoimmune hepatitis [38], alcoholic and nonalcoholic steatohepatitis [40,41,42]. However, when these results were examined by experienced liver pathologists, there was agreement only for a variable degree of fibrosis regression in cirrhosis but not for a reversal of cirrhosis in most cases [43]. Along these lines, there is no convincing evidence that the abnormalities of the intrahepatic vasculature regress in human cirrhotic liver. In fact, the available evidence suggests that the so-called veno-portal adhesions persist even in cases of extensive fibrosis regression, and evident ‘arterialized' sinusoids appear in the context of intrahepatic arteriovenous shunts [44].

The most obvious problem when discussing the issue of fibrosis regression in cirrhosis or even cirrhosis reversal is the lack of a clear and common language and, ultimately: (a) the precise distinction of advanced fibrosis (‘precirrhosis') from true cirrhosis and (b) the possibility of staging cirrhosis. The problem is fundamentally based on the use of semiquantitative scoring systems for staging fibrosis and, in particular, in the fact that cirrhosis is always represented by the highest score and is indeed considered as an end stage of CLD [45]. Indeed, cirrhosis appears in a very broad spectrum of variants (early, fully developed, ‘active' and ‘inactive') and more than one study has documented the transition from micronodular to macronodular cirrhosis following the discontinuation of the causative agent [46,47]. While it is doubtful that an accurately defined cirrhosis is able to reverse to normal, there is sound evidence concerning the capacity of the healing liver to reabsorb scar tissue following an effective causative treatment (i.e. sustained viral response, abstinence from alcohol, etc.). However, scar tissue in the liver of patients with CLD lasting 30 or more years is likely characterized by different stages of biochemical and biological evolution. Indeed, fibrotic deposition related to recent disease and characterized by the presence of thin reticulin fibers, often in the presence of a diffuse inflammatory infiltrate, is likely fully reversible, whereas long-standing fibrosis, branded by extensive collagen cross-linking by tissue transglutaminase, presence of elastin, dense acellular/paucicellular ECM and decreased expression and/or activity of specific metalloproteinases, is not [48]. In other words, present within the same liver are different types of scar tissue with different potential and dynamics of reversibility once the etiological agent is eradicated and/or antifibrogenic strategy is established. In addition, substantial experimental evidence suggests that long-term fibrogenesis occurring in human CLD is characterized by a progressive resistance to apoptosis of HSCs/myofibroblasts with the consequent immovability of a critical mass of profibrogenic cells [49].

Conclusions

In spite of the intense and continuative research activity in the area of liver fibrosis, there is still a profound discrepancy between the wealth of pharmacological targets and promising agents for the treatment of liver fibrosis and the actual testing in clinical trials [50,51]. At present there is not a single compound approved for antifibrotic therapy in CLD. Reasons are manifold, including the usually slow progression of liver fibrosis, requiring high numbers of well-stratified patients to be followed up for a long period of time, and the lack of sensitive and specific surrogate markers or imaging technologies for liver fibrosis progression or regression that would permit a rapid clinical screening for potential antifibrotic agents. In addition, the concept of etiology-driven fibrosis leading to different prevailing fibrogenic mechanisms implies that targets for antifibrogenic therapy should be labelled as directed at ‘core pathways' or ‘regulatory pathways' [32,33].

In addition to these key difficulties in patient stratification and study design, it is important to reconsider the methodology that we employ for the identification of drug targets. Until now we have used in vitro methods, i.e. HSC (often mouse or rat HSC) cultured on plastic dishes, assuming that the observed molecular pathways are similar if not identical to those responsible for liver fibrosis in humans. In addition, most if not all of the animal models employed as confirmatory tools have very little in common with human liver disease. Therefore, it is necessary to establish in vitro models exclusively employing human cells possibly cultured in a 3D (rather than 2D) environment, and to select animal models able to answer specific pathophysiological questions. This would be essential in order to be able to translate complex basic acquisitions into effective clinical tools.

Disclosure Statement

The author declares no conflict of interest.


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Author Contacts

Prof. Massimo Pinzani, MD, PhD, FRCP

UCL Institute for Liver and Digestive Health, Royal Free Hospital

Rowland Hill Street

London NW3 2PF (UK)

E-Mail m.pinzani@ucl.ac.uk


Article / Publication Details

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Abstract of Fibrosis: Pathophysiology, Diagnosis and Treatment

Published online: July 06, 2015
Issue release date: July 2015

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ISSN: 0257-2753 (Print)
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References

  1. 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.
  2. Mehal WZ, Iredale J, Friedman SL: Scraping fibrosis: expressway to the core of fibrosis. Nat Med 2011;17:552-553.
  3. Pinzani M, Rombouts K: Liver fibrosis: from the bench to clinical targets. Dig Liver Dis 2004;36:231-242.
  4. Pinzani M, Rombouts K, Colagrande S: Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 2005;42(suppl 1):S22-S36.
  5. 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.
  6. 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.
  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.
  8. 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.
  9. Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134:1655-1669.
  10. Wynn TA: Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524-529.
  11. Pinzani M, Macias-Barragan J: Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 2010;4:459-472.
  12. Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005;115:209-218.
  13. 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.
  14. 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.
    External Resources
  15. Quan TE, Cowper SE, Bucala R: The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 2006;8:145-150.
  16. Novo E, Parola M: Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 2008;1:5.
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