HCV results in the death of liver cells. It is not yet clear whether it is the virus itself that kills the cells or the immune systems ultimately unhelpful response to the invasion by the virus. At present it is thought that it is probably a combination of the two but that the immune system does the most damage. The death of liver cells triggers the dispatching of inflammatory cells to the affected area. Inflammation leads to the enlargement of the liver (hepatomegaly) in over 60% of people infected with HCV and often results in abdominal pain. The inflammation can also cause the fibroelastic sheath (Glissons capsule) that surrounds the liver to stretch, which may lead to pain in the liver area.
Inflammation begins the processes that lead to fibrosis. Fibrosis is not a disease in itself, but the bodys response to the damage to the liver. Inflammation triggers a reaction by a group of cells in the liver called stellate (literally star-shaped) or fat cells. When the liver is functioning normally stellate cells are the storage site for fat and vitamin A in the liver. They also help regulate the flow of blood through the liver. But when the liver is inflamed by the presence of HCV, a complex interplay takes places amongst different liver cells, which leads stellate cells to dispense with vitamin A and to alter their function.
Infected and inflamed liver cells release chemical signals (called cytokines) which activate leukocytes (white blood cells) from outside the liver to travel to the area of infection. On arrival they team up with Kupffer cells (Kuppfer cells are specialised white blood cells that are the incinerators of the liver, neutralising and removing bacteria, viruses, parasites and tumour cells) to produce further chemical signals that cause stellate cells to begin producing and laying down collagen fibres in the extra cellular matrix. This is the area between the cells.
Collagen is a fibrous protein which is fundamental to the formation of scar tissue. The deposition of collagen in an area of injury is an attempt 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.
In a chronic illness such as hepatitis C the collagen matrix grows more rapidly than it can be dissolved. This results in a build up of scar tissue around cells. Liver cells lose access to the flow of blood carrying nutrients and oxygen and so die. A vicious circle results in which inflammation and fibrogenic cells stimulate each other leading to increased fibrosis.
Free Radicals and Fibrosis
Another possible cause of fibrosis is damage by free radicals. Free radicals are highly reactive chemical substances that are the by-product of a cells normal reactions such as energy generation, the breakdown of fats and inflammation. During these reactions oxygen is transformed into the free radical superoxide. Normally cells have mechanisms for protecting themselves from the dangers of free radicals but when too many are generated or if they are not controlled properly then they can cause cell and tissue damage.
Free radicals are of concern for people with HCV for a number of reasons:
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Chronic liver inflammation may lead to overproduction of free radicals within the liver.
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There is evidence that free radicals play a role in liver fibrosis. Free radicals can chemically alter fat in the body. This is called lipid peroxidation. The free radicals attack the cell membrane and can injure and eventually kill cells. If this happens to liver cells, this will lead to fibrosis.
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If the liver function is already impaired and this had led to an overload of iron then the free radicals may interact with the iron causing further damage
Why doesn't liver regeneration prevent liver damage in hepatitis.The liver is famed for its ability to regenerate. In Greek mythology the livers self healing ability was exploited by Zeus to punish Prometheus, the Titan God. Zeus, the king of the Gods, ordered Prometheus to be chained to a rock in the Caucasian mountains as a punishment for stealing the holy fire from Olympia- the home of the Gods- and sharing it with mankind. Zeus sent an eagle to the rock. By day the bird pecked away at Prometheuss liver. By night as the eagle slept Prometheuss liver grew back so that it was a fresh tasty meal again for the eagle the next morning.
Hepatitis C is usually characterised by degeneration of the liver through slow but progressive scarring. So why can't the liver repair itself in the presence of HCV? The liver has two responses to injurious agents which are capable of damaging its cell structure. Either there is regeneration with complete restoration of liver architecture and function or there is sustained scarring of liver tissue leading to damage. When the liver is damaged by a single strong injury, regeneration is highly likely even if a large area is affected. However, if the injury is repetitive and of small intensity, as is the case with HCV infection, the liver cannot effectively cope with such a long-term sustained attack. It does not have the time and space to heal itself properly.
Effect of fibrosis on liver function
Scarring can start to have an effect on many of the livers numerous functions.
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The liver cells that are deprived of nutrition and oxygen shrink. This is called hepatocellular atrophy.
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The accumulation of collagen fibres in the sinusoids (microscopic blood channels in the liver) obstructs the passage of necessary substances from the blood to the liver cells, decreasing the liver's ability to remove drugs, toxins and metabolic waste products. (Possibly one of the cause of headaches and other toxic type symptoms).
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Impaired blood flow through the liver may force arterial blood to bypass the filtering cells of the liver, increasing toxicity and further decreasing the efficiency of the liver.
