Liver Fibrosis

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Liver Fibrosis

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.

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nice reading thanks

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Re: Liver Fibrosis

nice reading thanks

goes everywhere you do. Get it on your phone.