INFO: Liver Fibrosis' Role in Hepatitis C

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Liver Fibrosis Article Date: 2/26/2004 Reviewed 7/15/05 by V. J. , RN, BSN, MA When infected by the hepatitis C virus, liver cells (hepatocytes) trigger a series of events that initiate both an inflammatory and an immune response. Since hepatitis C infection tends to become chronic in most cases, the inflammatory process in turn progresses from acute to chronic inflammation. In time, chronic inflammation leads to the formation of microscopic areas of scar tissue in the liver tissue, known as fibrosis. If the scar tissue causes disruption in the structure of the liver, the condition is called cirrhosis. In its early stages, fibrosis is reversible, but cirrhosis, once developed, may be permanent. In this article, we will provide an overview of some of the mechanisms of fibrosis as well as factors that contribute to the progression of fibrosis to cirrhosis. The Key Players: Stellate and Kupffer Cells Hepatic Stellate Cells. Under normal conditions, stellate ("star-shaped") cells are reservoirs of fat and vitamin A in the liver. They also contain filaments that can contract and regulate blood flow through the liver. When activated by liver damage and

the chemical by-products of inflammation, stellate cells transform and become capable of creating strands of collagen, a substance fundamental to the formation of scar tissue. These collagen strands are deposited in areas of inflammation in an effort to contain the spread of viral infection. Kupffer Cells. Kupffer cells are specialized leukocytes (white blood cells) in the liver. They can move rapidly around the liver, and are responsible for the removal of particulate matter from the circulating blood, such as old or damaged red blood cells, bacteria, viruses, parasites and tumor cells. When leukocytes from outside the liver are drawn to the area of infection by chemical signals called cytokines released by infected liver cells, they cooperate with Kupffer cells to produce chemical signals that cause stellate cells to begin producing collagen fibers.

In addition, Kupffer cells produce oxygen free-radicals. As we shall see, oxygen free-radicals play a major role in the progression and development of fibrosis. The Pathophysiology of Fibrosis The deposition of collagen in an area of injury is not an abnormal event. By attempting to enclose an injured or infected area with scar tissue, the body attempts to limit the spread of infection to other cells. Normally, as an infection or injury resolves, the collagen matrix enclosing the injury is dissolved as activated stellate cells die off, allowing the tissue to return to normal. Unfortunately, in a chronic illness such as hepatitis C infection, ongoing infection and inflammation causes the

collagen matrix to grow more rapidly than it can be dissolved. The result is a surplus of scar tissue, which can eventually progress to cirrhosis. The deposition of collagen has direct effects on liver function, specifically: The presence of collagen fibers around individual hepatocytes impair the cells' ability to receive nutrition and results in shrinkage of the cell (hepatocellular atrophy). The accumulation of collagen fibers in the hepatic sinusoids (microscopic blood channels in the liver) obstructs the passage of substances from the blood to the hepatocytes, decreasing the liver's ability to remove drugs, toxins and metabolic waste products. Fibrosis around the veins of the liver restricts blood flow, increasing vascular resistance and contributing to the

development of portal hypertension. Portal hypertension, in turn, contributes to the development of esophageal varices, edema and ascites. Impaired blood flow through the liver forces arterial blood to bypass the filtering cells of the liver, further decreasing the efficiency of the liver and contributing to the death of hepatic cells. The Assessment of Fibrosis Normally, a liver biopsy is performed to accurately assess the progression of fibrosis in liver disease. The following terms are often used to describe the changes in liver tissue associated with HCV

infection: Portal Inflammation: the portal areas are tiny tracts of connective tissue within the liver that contain branches of the portal vein, the hepatic artery and bile ducts. Piecemeal Necrosis: this term describes necrosis (cellular death) and inflammation around the portal areas. Fibrosis: the deposition of collagen fibers in the cell structure of the liver, forming scar tissue. The early stages of fibrosis are confined to the portal tracts. Bridging Fibrosis: an intermediate stage of fibrosis characterized by expansion of collagenous (scar) tissue to the portal tracts and bridging between portal areas. Cirrhosis: a term used to describe significant deformation of the liver

structure due to scarring. Contributing Factors Although the exact sequence of physical and chemical events leading to the development of fibrosis and cirrhosis is not precisely defined, researchers have identified factors which play important roles in the progression of disease. Antioxidants. Normally, the liver is well equipped with a range of antioxidants. These are chemicals that can protect the liver from the damaging effect of oxygen free-radicals, which are byproducts of many cellular and metabolic processes. However, in chronic liver disease, there appears to be a significant depletion of antioxidants. This is important because a surplus of oxygen free-radicals can create a condition known as oxidative stress, which

has been associated with the progression of fibrosis. Hepatic Iron Stores. Iron can accumulate in the liver as a result of genetic disease, such as hemochromatosis, or as the result of repeated blood transfusions. Iron overload is associated with liver injury, including fibrosis, cirrhosis and liver cancer. A surplus of hepatic iron has been identified as a "pro-fibrogenic co-factor" in the presence of alcohol abuse, viral hepatitis, or hepatotoxic drugs. Age. Age has been associated with increased vulnerability to the detrimental effects of oxidative stress, and this appears to be related to a decreased availability of antioxidant resources. Age is considered a significant determinant in the rate of progression from inflammation to fibrosis and cirrhosis. Obesity and NASH. Nonalcoholic steatohepatitis (NASH) is a serious liver disease that is characterized by fatty deposits in the liver and inflamed liver tissues. As we have seen, liver inflammation leads to scarring (fibrosis) and cirrhosis. Steatosis (fatty liver, also called Non-alcoholic Fatty Liver Disease or NAFLD), a precursor to NASH, is highly correlated with obesity. Steatosis has been found in 70% of people who exceed their ideal body weight by 10%, and in 100% of people who are morbidly obese. Steatosis is usually a harmless and non-progressive condition, but in some people, steatosis develops into NASH. Studies have found that the incidence of NASH in obese people ranges from about 10% to 70% varying with age and degree of obesity. Is There Treatment For

Liver Fibrosis? Obviously, the best way to prevent the progression of fibrosis / cirrhosis in the context of HCV infection is to eradicate the hepatitis C virus. Unfortunately, the currently available medications (the interferons or peginterferon / ribavirin combinations) fail to eliminate the virus in a percentage of patients, so anti-fibrotic therapies are under investigation. Interferon. Studies are evaluating the effect of interferon as a possible anti-fibrotic therapy, regardless of the effect on the hepatitis C virus. However, the efficacy of this treatment is not conclusive, and the drug often produces side effects that are intolerable. Antioxidants. Studies have examined the effect of antioxidant therapy on the development of fibrosis, but the data is not clear-cut.

Different studies have used differing doses of drugs for varying periods of time, often on patients with advanced cirrhosis. Animal studies are limited in that they do not necessarily replicate the clinical condition of human patients. Some of the antioxidants under investigation include: Silymarin, also known as Milk Thistle Sho-Saiko-To, a Japanese herbal medicine S-adenosyl-methionine, also known as SAMe alpha-Tocopherol, also known as

Vitamin E. Other therapies under investigation include halofuginone, phosphodiesterase inhibitors, and endothelin-A-receptor or angiotensin antagonists. Alcohol Accelerates Fibrosis Alcohol use has been shown to correlate highly with progressive fibrosis in the context of HCV infection, suggesting that abstinence from alcohol can reduce the rate of fibrotic progression to cirrhosis. Source Meyer U. The Liver. Biozentrum, Univeristy of Basel, Switzerland. Stalnikowitz D and Weissbrod A. Liver fibrosis and inflammation. A review. ls of Hepatology 2003; 2(4): October-December: 159-163. Fibrosis. The Merck Manual of Diagnosis and Therapy, Section 4, Chapter 41. 2004. http://www.merck.com/Chronic Hepatitis C: Current Disease Management. National Digestive Diseases Information Clearinghouse, National Institutes of Health. Yadav D et al. Serum and liver micronutrient antioxidants and serum oxidative stress in patients with chronic hepatitis C. Am J Gastroenterol. 2002 Oct;97(10):2634-9. Parola M and Robino G. Oxidative stress-related molecules and liver fibrosis. Journal of Hepatology 35 (2001) 297-306. NASH: Who is at Risk? The Hepatitis Neighborhood.

http://www.hepatitisneighborhood.com/. Schuppan D, et al. Hepatitis C and liver fibrosis. Cell Death Differ. 2003 Jan;10 Suppl 1:S59-67. Poynard, T et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997 Mar 22;349(9055):825-32Reviewed 7/15/05 by V. J. , RN, BSN, MA http://www.hepatitisneighborhood.com/content/understanding_hepatitis/complications_of_Hepatitis C_1608.aspx?randStr=