Inflammation of the Liver

The word "hepatitis" literally means "inflammation of the liver." Inflammation is the body's response to injury or infection in vascular tissue (tissue with blood vessels).

Although the "classic signs" of inflammation are redness, swelling, heat, pain, and the formation of exudate (such as pus), in hepatitis C infection, there may be no visible signs of inflammation.

So what is it about infection with the hepatitis C virus (HCV) that actually damages the liver? In fact, the virus itself does relatively little damage. For the most part, it's the body's own inflammatory response to infected liver cells that results in the tissue damage characteristic of chronic HCV infection.

Inflammation and Immunity: What's the Difference?

There are significant difference between the immune response and the inflammatory response. Additionally, there are differences between the acute inflammatory response and chronic inflammation.

The first response of the body to an antigen (foreign invader) such as the hepatitis C virus is the inflammatory response. The inflammatory response is:

Rapid. The inflammatory response can begin within seconds of injury or invasion

Nonspecific. The response is the generally the same regardless of the type of antigen

Self-Limiting. The inflammatory process stops after the antigen is eliminated.
Because the inflammatory response is rapid, nonspecific and can be perpetuated by different factors, an exaggerated or prolonged inflammatory response can be difficult to control and can cause significant tissue damage.

The immune response also begins after the detection of an antigen, and complements the activity of the inflammatory response. However, the immune response has significant differences from the inflammatory response, in that it is:

Slow. The immune response can develop over days to weeks

Specific. The immune system creates antibodies which target individual types of antigens

Ongoing. With a few exceptions, the persistence of antibodies after the resolution of infection provides protection against future infection by the same antigen.
The hepatitis C virus is an example of an antigen that is able to defeat the immune system's ability to provide lasting immune protection. People who "clear" hepatitis C infection, either spontaneously or with medications, are not immune and can be reinfected if subsequently exposed.

Triggering the Inflammatory Response

The hepatitis C virus seems to have a preference for infecting liver cells (hepatocytes). Once HCV binds to a hepatocyte, it injects its genetic material (RNA) into the cell. The viral RNA takes control of the cell's metabolic processes, and causes the cell to assemble more copies of the virus (a process called viral replication).

The infected liver cell is doomed, but it performs one last service - it generates cytokines, which are chemical signals that attract the attention of the body's immune system. Cytokines warn nearby cells of the infection and also play a role in initiating the inflammatory and immune responses.

One of the cytokines expressed by infected cells is interferon. Interferon communicates with nearby cells, instructing them to begin producing proteins that prevent the virus from replicating. In addition, interferon acts as a regulator of body's immune response to infection, increasing and decreasing the immune response as needed.

The Role of the White Blood Cell

The "soldiers" of immune defense are white blood cells (WBC's), also called leukocytes.

When a physician orders a laboratory blood test called a "CBC with Diff" (complete blood count with differential), the tests results report a breakdown of the WBC count by different WBC types, such as:

Neutrophils. These fast-acting WBC's are usually the first to arrive at the site of an infection, and specialize in attacking and digesting bacteria. They have a life-span of about 12 hours.

Eosinophils. These cells also phagocytize (ingest) foreign particles, but specialize in digesting antigens that have attached to antibodies, which are proteins produced by other specialized WBC's that bind with and neutralize antigens. Eosinophils are also highly active during allergic reactions and parasitic infections.

Basophils. These rare cells migrate to the site of injury or infection and release substances (histamines) that increase the inflammatory response by attracting other leukocytes.

Monocytes. These cells, also called macrophages (literally "big eaters") can either circulate freely in the blood stream or become lodged in tissues. Moncytes ingest foreign particles, secrete chemicals to attract other leukocytes, and initiate the process of scar tissue formation to isolate and repair the damaged or infected region.

Lymphocytes. While the types of WBC's mentioned above all contribute to the inflammatory response, lymphocytes are critical to the immune response. They are programmed to respond to specific threats by analyzing foreign particles and creating responses that will protect the person from future infection - the phenomenon of immunity. The subtypes of lymphocytes include:

Cytotoxic T lymphocytes. These cells act directly against the infectious agent

Helper and Suppressor T lymphocytes. These cells work to either stimulate the immune response or decrease it as the infection resolves


B lymphocytes. When triggered, these cells produce antibodies, proteins that neutralize antibodies by binding with them, and provide long term protection against future infection.
The Process of Inflammation

The interplay of immune and inflammatory response is extremely complex, involving a large number of chemical and mechanical processes. What follows is a very abbreviated description of the process.

Once infected with the hepatitis C virus, the infected hepatocytes release cytokines. These chemical messengers trigger a series of changes in the walls of blood vessels that allows various leukocytes to pass through the vessel wall and migrate to the site of infection, attracted by the cytokines released by the infected cells.

When leukocytes arrive at the infected cell, they release chemicals onto the surface of the cell that causes it to swell and burst. Fragments of the destroyed cells are engulfed by the leukocytes and digested.

Additionally, changes in the vascular wall allows fluid in the blood vessels to "leak" through the wall of the vessel into surrounding tissue, transporting plasma proteins and fluids to the site of injury, resulting in edema and exudate, or pus.

These fluids and plasma proteins assist to control the inflammatory and immune response, and flush away cellular fragments from destroyed cells.

So What Goes Wrong?

If the immune and inflammatory responses are so effective at eliminating infections, why does hepatitis C infection become chronic in 85% of cases?

The answer is that although the hepatitis C virus is a very simple "organism," over time it has developed traits that allow it to effectively resist the body's immune and inflammatory defense systems.

Once the virus attaches to the surface of a cell, it inserts its RNA (the genetic material of the virus) into the cell. Inside the cell, the viral RNA is acted upon by substances called proteases, which begin to make copies of the RNA.

The rate at which new viruses are replicated is staggering - it is estimated that between 100 billion (1011) and 1 trillion (1012) viruses are replicated per day.

The process of copying the viral RNA is imperfect, and tends to introduce variations into the RNA sequence at the rate of one error per genome per replication cycle.

The result of this rapid, error-prone replication process is a subtle variation in the genome, or genetic blueprint, of newly-produced HCV viruses. These genetic mutations are called genotypes and quasispecies.

Although the immune system is capable of producing an effective immune response to HCV infection, the response is highly specific, that is, the immune cells are not able to defend against a wide variety of slightly different HCV particles.

Since the replication process rapidly generates virus particles with many subtle genetic variations, some of the virus variants can escape the host’s immune response.

The strength of the host’s immune response is sometimes referred to as “immune pressure.” People who generate a stronger immune response exert more immune pressure on the virus, and this tends to drive the virus to develop a broader range of quasispecies than those who have a weaker immune response.

In addition, there is study evidence to suggest that when HCV infects a cell it is capable of regulating some of the cellular responses to infection. The hepatitis C virus appears to be able to modify the infected cell's reaction, causing an increase in the expression of factors that favor viral reproduction, and decreasing the production of chemical factors which could lead to its destruction.

The Progression to Fibrosis

The liver has an amazing ability to heal itself. For example, when a liver is transplanted in to a recipient, it can grow to nearly full size in a few weeks. However, when the inflammatory response progresses and worsens, there can be damage to the reticulum, or supporting framework of the liver.

When the supporting framework is damaged, the repair must be accomplished by the formation of scar tissue. The presence of scar tissue on liver biopsy indicates the development of liver fibrosis. In time, scar tissue can cause changes to the physical architecture of the liver - a condition called cirrhosis.

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