Hepatic Fibrosis -- Role of Hepatic Stellate Cell Activation

Scott L. Friedman, MD

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In This Article

Abstract and Introduction

Abstract

Hepatic fibrosis is a reversible wound healing response characterized by accumulation of extracellular matrix (ECM), or "scar," that follows chronic but not self-limited liver disease. The ECM components in fibrotic liver are similar regardless of the underlying cause. Activation of hepatic stellate cells is the central event in hepatic fibrosis. These perisinusoidal cells orchestrate an array of changes including degradation of the normal ECM of liver, deposition of scar molecules, vascular and organ contraction, and release of cytokines. Not only is hepatic fibrosis reversible, but it is also increasingly clear that cirrhosis may be reversible as well. The exact stage at which fibrosis/cirrhosis becomes truly irreversible is not known. Antifibrotic therapies will soon be a clinical reality. Emerging therapies will be targeted to those patients with reversible disease. The paradigm of stellate cell activation provides an important framework for defining therapeutic targets.

Introduction

Hepatic fibrosis is a wound healing response comprising reversible scarring that occurs in almost all patients with chronic, but not self-limited liver injury. Ultimately, hepatic fibrosis leads to cirrhosis, characterized by nodule formation and organ contraction. The causes of cirrhosis are multiple and include congenital, metabolic, inflammatory, and toxic liver diseases. In all circumstances, the composition of the hepatic scar is similar. Moreover, the cells and soluble factors participating in this response in liver are also similar to those in parenchymal injury to kidney, lung, or skin. Fibrosis occurs earliest in regions where injury is most severe.

In normal liver, hepatic stellate cells (HSCs) are nonparenchymal, quiescent cells whose main functions is to store vitamin A and probably to maintain the normal basement membrane-type matrix. However, numerous in vivo and in vitro studies indicate that in response to liver injury, HSCs undergo an "activation" process in which they lose vitamin A, become highly proliferative, and synthesize "fibrotic" matrix rich in type I collagen. This understanding has helped to identify underlying mechanisms, and will likely lead to new therapies for fibrotic diseases of many organs, including liver.[1]

The following article describes in greater detail the cellular and molecular events underlying liver fibrosis, and how these new insights provide a framework for new concepts of diagnosis and treatment of hepatic fibrosis.

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