Liver Fibrosis
Article Date: 2/26/2004


When infected by the hepatitis C virus, liver cells (hepatocytes) trigger a
series of events that initiates both an inflammatory and an immune response.

Since hepatitis C infection tends to become chronic in most cases, it follows
that the inflammatory process would progress 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 and 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 impairs 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), 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. 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.
Annals 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.





Sandra Tara Balduf (Ane)

Frontline Hepatitis Awareness

Support for patients and educational materials

http://frontline-hepatitis-awareness.com

1-866-Hep-GoGo 866-437-4646




[Non-text portions of this message have been removed]