Scarring in Alcoholic Liver Disease: New Insights and Emerging Therapies

Article excerpt

Like other organs, the liver responds to injury (e.g., from chronic alcohol ingestion) with scar formation (i.e., fibrosis). Specialized cells known as stellate cells play a major role in the development of liver fibrosis. Normally these cells serve as important storage depots for vitamin A, but during alcoholic injury, a collection of cellular and molecular mediators cause stellate cells to undergo a process of activation that results in dramatic changes in their structure and function. Activated stellate cells then become primary producers of scar tissue. In turn, accumulated scar provokes a series of events that contributes to deteriorated liver function. An improved understanding of the factors that trigger stellate cell activation has led to new therapeutic approaches for reversing or preventing liver fibrosis more effectively. KEY WORDS: chronic AODE (alcohol and other drug effects); alcoholic liver disorder fibrosis; biological activation; cell and cell structure; cytokines; liver function; treatment method; literature review

Scarring (i.e., fibrosis) is the most severe consequence of liver injury from any cause, including injury caused by chronic alcohol ingestion. Although liver fibrosis is reversible, if it persists because of progressive alcoholic liver injury, irreversible cirrhosis will develop. Under this condition, the fibrous bands crisscrossing the liver contract, resulting in a severe distortion of the liver's architecture that is characteristic of cirrhosis. As a consequence of the contraction, the liver's size diminishes and its function is compromised, leading to impeded blood flow, reduced ability to detoxify drugs and foreign compounds, and impaired protein synthesis. (For a brief background on the function and anatomy of the normal liver, see sidebar, p. 311.) Collectively these changes can result in liver failure, often necessitating a liver transplant.

Currently, numerous liver transplants in the United States are performed in patients with end-stage alcoholic cirrhosis.' However, the disease exacts a far larger economic and social toll in patients who are not candidates for a liver transplant (e.g., because of continued alcohol abuse; concurrent diseases, such as HIV [human immunodeficiency virus] infection, that would contraindicate a transplant; or advanced age) and who subsequently die ol progressive liver disease.

During the past decade, exciting progress has been made in the understanding of how liver fibrosis (i.e., hepatic fibrosis) develops in patients with alcoholic liver disease (ALD). New methods of isolating scar-forming cells in animal and human livers and an improved understanding of how growth factors2 drive the liver's response to injury have been key advances fueling this progress and have resulted in more realistic hopes for antifibrotic therapy in the future.

This article focuses on new insights about how the liver responds to injury by scar formation, the cell types and chemical messengers (i.e., cytokines, such as growth factors) that are involved, and how these insights point toward effective treatments.

LIVER FIBROSIS: A WOUND-HEALING RESPONSE

The recognition that liver fibrosis represents a general wound-healing response has helped scientists understand the process of fibrosis development. The essential components of this response are a fibrogenic cell type, scar formation (i.e., modification of the normal matrix scaffolding in which cells are embedded), and growth factors. In the liver, the same fibrotic reaction occurs regardless of the type of injury, whether the damage results from alcohol, viral hepatitis, drugs toxic to the liver (e.g., methotrexate, a medication used to treat various types of cancer and arthritis), or immunologic or genetic liver disease. Moreover, the same general paradigm extends to tissues in other organs, including the kidney and lung. This broad view has allowed investigators studying different organ systems to pool their expertise in search of common features underlying tissue fibrosis. …