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Scarring in Alcoholic Liver Disease

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Scarring in Alcoholic Liver Disease RESEARCH UPDATE SCARRING IN ALCOHOLIC for a liver transplant (e.g., because of continued alcohol abuse; concurrent diseases, such as HIV [human immun- LIVER DISEASE odeficiency virus] infection, that would contraindicate a transplant; or advanced age) and who subsequently die of New Insights and Emerging Therapies progressive liver disease. During the past decade, exciting progress has been Scott L. Friedman, M.D. made in the understanding of how liver fibrosis (i.e., hepatic fibrosis) develops in patients with alcoholic liver Like other organs, the liver responds to injury (e.g., disease (ALD). New methods of isolating scar-forming from chronic alcohol ingestion) with scar formation cells in animal and human livers and an improved under- (i.e., fibrosis). Specialized cells known as stellate standing of how growth factors2 drive the liver’s response cells play a major role in the development of liver to injury have been key advances fueling this progress fibrosis. Normally these cells serve as important stor- and have resulted in more realistic hopes for antifibrotic age depots for vitamin A, but during alcoholic injury, therapy in the future. a collection of cellular and molecular mediators This article focuses on new insights about how the liver responds to injury by scar formation, the cell types cause stellate cells to undergo a process of activation and chemical messengers (i.e., cytokines, such as growth that results in dramatic changes in their structure factors) that are involved, and how these insights point and function. Activated stellate cells then become toward effective treatments. primary producers of scar tissue. In turn, accumu- lated scar provokes a series of events that con- tributes to deteriorated liver function. An improved LIVER FIBROSIS: A WOUND-HEALING RESPONSE understanding of the factors that trigger stellate cell activation has led to new therapeutic approaches for The recognition that liver fibrosis represents a general reversing or preventing liver fibrosis more effec- wound-healing response has helped scientists understand tively. KEY WORDS: chronic AODE (alcohol and other the process of fibrosis development. The essential compo- drug effects); alcoholic liver disorder; fibrosis; biologi- nents of this response are a fibrogenic cell type, scar for- mation (i.e., modification of the normal matrix scaffolding cal activation; cell and cell structure; cytokines; liver in which cells are embedded), and growth factors. In the function; treatment method; literature review 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, carring (i.e., fibrosis) is the most severe consequence a medication used to treat various types of cancer and of liver injury from any cause, including injury arthritis), or immunologic or genetic liver disease. Moreover, caused by chronic alcohol ingestion. Although liver S the same general paradigm extends to tissues in other fibrosis is reversible, if it persists because of progressive organs, including the kidney and lung. This broad view alcoholic liver injury, irreversible cirrhosis will develop. has allowed investigators studying different organ systems Under this condition, the fibrous bands crisscrossing the to pool their expertise in search of common features under- liver contract, resulting in a severe distortion of the liver’s lying tissue fibrosis. For example, in all forms of tissue architecture that is characteristic of cirrhosis. As a conse- fibrosis, the same general types of scar component molecules quence of the contraction, the liver’s size diminishes and predominate. These molecules include certain types of its function is compromised, leading to impeded blood collagen that manufacture threadlike fibrils (i.e., collagen flow, reduced ability to detoxify drugs and foreign com- types I and III); specialized compounds known as glyco- pounds, and impaired protein synthesis. (For a brief back- proteins (e.g., fibronectin, laminin, and tenascin); and ground on the function and anatomy of the normal liver, several types of a particular kind of glycoprotein (i.e., see sidebar, p. 311.) Collectively these changes can result proteoglycans, such as dermatan and chondroitin sulfate, in liver failure, often necessitating a liver transplant. which are two constituents of connective tissue). Currently, numerous liver transplants in the United Although the scar in alcoholic fibrosis has the same States are performed in patients with end-stage alcoholic composition as the scar in other chronic liver diseases, its cirrhosis.1 However, the disease exacts a far larger eco- distribution is relatively unique. This distinctive distribution nomic and social toll in patients who are not candidates pattern is important in terms of both disease development (i.e., pathogenesis) and diagnosis. Early fibrosis around 1In the United States, alcoholic cirrhosis accounted for 16.8 percent of the liver transplants performed from October 1, 1987, through December 31, 1993 (Evans 1997). SCOTT L. FRIEDMAN, M.D., is a professor of medicine and 2For a definition of this and other technical terms used in this article, see director of liver research at Mount Sinai School of Medicine, glossary, p. 330. New York, New York. 310 ALCOHOL HEALTH & RESEARCH WORLD RESEARCH UPDATE OVERVIEW OF LIVER STRUCTURE AND FUNCTION Occupying the upper right quadrant of the abdomen and In addition to hepatocytes, several other types of extending into the upper left quadrant, the liver is one of cells with special functions are found in the liver. the largest organs in the human body. Structurally, this Kupffer cells, for example, are specialized immune 31⁄2-pound organ consists of 50,000 to 100,000 func- cells lining the sinusoids. These highly efficient tissue tional units, called lobules, situated within an extensive scavengers (i.e., macrophages) remove more than 99 network of blood vessels and bile ducts known as the percent of the bacteria in the blood and can ingest a portal triad (see figure). Each cylindrical lobule is typic- bacterium in less than 0.01 second. Because blood coming ally several millimeters (mm) in length and up to 2 mm through the portal vein contains a substantial quantity of in diameter. bacteria from the gastrointestinal tract, Kupffer cells are Small branches of the hepatic artery and portal vein key players in disease prevention. running along each lobule’s outer edge supply blood, The sinusoidal endothelial cells have special functions, which flows into the lobule through tiny channels too. Not only do they form the wall lining of the sinusoids, called sinusoids. Like spokes of a wheel, the sinusoids but they also help clear circulating scar (i.e., extracellu- converge in the core of the lobule to form a central lar matrix) molecules from the blood and are a potent “drainage” vein or outflow region. producer of compounds that stimulate cell proliferation Sinusoids serve as the liver’s microcirculatory sys- (i.e., growth factors). tem. The endothelial cells composing the sinusoid walls Stellate cells (also known as lipocytes or as Ito, fat- contain large pore openings. These openings allow storing, or perisinusoidal cells) play an important role in oxygenated blood from the hepatic artery and nutrient- the liver as well. These star-shaped cells are found in the laden blood flowing from the intestine via the portal narrow space between the sinusoid wall and the hepato- vein to bathe the liver’s principal cells (i.e., hepato- cytes (i.e., in the space of Disse). The cells contain cytes), which are arranged in clusters between the sinu- numerous droplets of vitamin A, a nutrient essential for soids. Stacks of thin hepatocyte clusters just one or two normal growth and vision. In fact, stellate cells are the cells thick (i.e., hepatic cellular plates) circle the lob- body’s primary storehouse for vitamin A, and they store ule’s central vein (see figure). enough of this nutrient to supply the body’s needs for Relatively large and metabolically very active, the up to 10 months without any additional dietary intake. hepatocytes are the workhorses that perform the varied In fibrosis, they play a key role in producing scar protein. and vital functions of the liver. These cells process and —Mary Beth de Ribeaux store nutrients, manufacture proteins, and remove tox- ins from the blood before it enters general circulation. Bibliography Hepatocytes also produce bile, which collects between GUYTON, A.C. Textbook of Medical Physiology. 7th edition. adjacent cells and drains into bile ducts for transport to Philadelphia: W.B. Saunders Co., 1986. the gallbladder. Thick, liquid bile stored in the gallblad- der is released intermittently into the small intestine, Mary Beth de Ribeaux is a science editor of Alcohol where it aids in fat digestion. Health & Research World. Liver Liver lobule Hepatic cellular plate Central Hepatocyte vein Kupffer cell Space of Disse Gall bladder Endothelial cell Sinusoid Stellate cell Sinusoid Endothelial cell Stellate cell Branch of hepatic artery Space Branch of portal vein of Disse Hepatocyte Portal triad Bile Kupffer cell duct The liver is situated within the portal triad, an extensive network of blood vessels and bile ducts. VOL. 21, NO. 4, 1997 311 RESEARCH UPDATE alcohol intake. Both genetic determinants and other cofactors Normal Liver Fibrotic Liver affect the extent of this risk. Although genetic factors are not fully understood, they include
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