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Review
. 2005 Feb;115(2):209-18.
doi: 10.1172/JCI24282.

Liver fibrosis

Ramón Bataller  1 , David A Brenner
Affiliations
Review

Liver fibrosis

Ramón Bataller et al. J Clin Invest. 2005 Feb.

Erratum in

  • J Clin Invest. 2005 Apr;115(4):1100

Abstract

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

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Figures

Figure 1
Figure 1
Changes in the hepatic architecture (A) associated with advanced hepatic fibrosis (B). Following chronic liver injury, inflammatory lymphocytes infiltrate the hepatic parenchyma. Some hepatocytes undergo apoptosis, and Kupffer cells activate, releasing fibrogenic mediators. HSCs proliferate and undergo a dramatic phenotypical activation, secreting large amounts of extracellular matrix proteins. Sinusoidal endothelial cells lose their fenestrations, and the tonic contraction of HSCs causes increased resistance to blood flow in the hepatic sinusoid. Figure modified with permission from Science & Medicine (S28).
Figure 2
Figure 2
Expression of collagen α1(I) in a model of cholestasis-induced liver fibrosis. Transgenic mice with green fluorescence protein reporter gene under the direction of the collagen α1(I) promoter/enhancers were subjected to bile duct ligation for 2 weeks. (A) Collagen α1(I) was markedly expressed by activated HSCs, but not hepatocytes, in the hepatic parenchyma. Magnification, ×200. (B) Collagen α1(I) is markedly expressed by myofibroblasts around proliferating bile ducts. HSCs proliferate to initiate collagen deposition in the hepatic parenchyma. Magnification, ×40.
Figure 3
Figure 3
Cellular mechanisms of liver fibrosis. Different types of hepatotoxic agents produce mediators that induce inflammatory actions in hepatic cell types. Damaged hepatocytes and biliary cells release inflammatory cytokines and soluble factors that activate Kupffer cells and stimulate the recruitment of activated T cells. This inflammatory milieu stimulates the activation of resident HSCs into fibrogenic myofibroblasts. Activated HSCs also secrete cytokines that perpetuate their activated state. If the liver injury persists, accumulation of activated HSCs and portal myofibroblasts occurs, synthesizing large amounts of ECM proteins and leading to tissue fibrosis. ECM degradation is inhibited by the actions of cytokines such as TIMPs. Apoptosis of damaged hepatocytes stimulates the fibrogenic actions of HSCs. If the cause of the liver injury is removed, fibrosis is resolved. This phase includes apoptosis of activated HSCs and regeneration of hepatocytes. Collagen is degraded by increased activity of MMPs induced by decreased TIMP expression. CCL21, C-C chemokine ligand 21; MCP-1, monocyte chemoattractant protein–1; MIP-2, macrophage inflammatory protein–2; NS3, HCV nonstructural protein 3; NS5, HCV nonstructural protein 5; PAF, platelet-activating factor.
Figure 4
Figure 4
Reversibility of liver fibrosis in a patient with chronic hepatitis B virus infection after successful treatment with lamivudine. A decrease in smooth muscle actin immunostaining, a marker of fibrogenic myofibroblasts, can be seen in paired liver biopsies before (A) and after (B) therapy. Dark brown granules represent areas stained for smooth muscle actin. Magnification, ×40. Reproduced with permission from Journal of Hepatology (S2).
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