After six months 70% to 85% of those infected will have failed to clear the virus spontaneously. After this period the HCV virus enters what is known as the ‘chronic phase’. This is when hepatitis C becomes a chronic or long-term infection. The diagnosis is confirmed when over a six month period HCV RNA viral presence is detectable on at least two occasions.
A diagnosis of chronic HCV means the battle between the virus and the immune system that occurs during the acute stage has finally been won by the virus. It is now highly unlikely that the virus can be cleared without treatment.
How the disease then progresses varies significantly from person to person. After many years some people will have minimal liver damage with no scarring while others can progress to cirrhosis (extensive scarring of the liver) within less than ten years. On average it takes about twenty years for significant liver scarring to develop.
It is still not known whether chronic HCV infection inevitably leads to cirrhosis. At present it is thought that this is a very likely outcome, although for some people it may take at least 50 years or more. They may well die of other unrelated diseases or conditions before cirrhosis develops. The rate of progression of liver damage cannot be accurately determined by liver enzyme levels, viral load or by genotype.
The symptoms experienced and the damage done to the liver varies dramatically from person to person. Some people will have few, if any, symptoms for many years. While for others the symptoms can have quite noticeable effects on their health.
It was originally thought that the virus only infected liver cells. But recently it has become clear that HCV also infects parts of the immune system, some blood cells and probably the brain. This means that hepatitis C is not just a liver disease but is a systemic disease prone to affecting other organs in the body.
HCV causes damage to the liver mainly in the form of inflammation, which then leads to scarring or fibrosis. How the virus affects the various functions of the liver is discussed in the section The Liver & hepatitis C.
Liver damage and fibrosis during the chronic stage
HCV results in the death of liver cells. It is uncertain whether the virus kills the cells or if it is the immune system’s response to invasion by the virus. At present it is thought that it is probably a combination of the two, but that the immune system’s response is what causes 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 can cause the fibroelastic sheath (Glisson’s capsule) surrounding the liver to stretch, which may be the cause of pain in the liver area.
Inflammation begins the processes that lead to fibrosis. Fibrosis is not a disease but is a condition caused by the body’s response to liver damage. 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 store 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 reaction occurs amongst different liver cells. This leads stellate cells to dispense with vitamin A altering their function.
Infected and inflamed liver cells release chemical signals called ‘cytokines’. These activate leukocytes (white blood cells) from outside the liver which travel to the area of infection. On arrival they team up with Kupffer cells (specialised white blood cells that neutralise and remove bacteria, viruses, parasites and tumour cells from the liver) and produce further chemical signals. These signals cause stellate cells to begin producing and laying down collagen fibres in the extra cellular matrix, which is the area between the cells.
Collagen is a fibrous protein which is fundamental to the formation of scar tissue. The body’s use of collagen in an area of injury is an attempt to limit the spread of infection to other cells. As an infection or injury resolves, the collagen matrix enclosing the injury is normally dissolved. The activated stellate cells then die off, allowing the tissue to return to normal.
In a chronic illness such as hepatitis C the collagen matrix grows too fast and cannot be properly dissolved. This results in a build up of scar tissue around cells. Liver cells lose vital access to the 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
A further possible cause of fibrosis is due to damage by free radicals. Free radicals are highly reactive chemical substances. They are the by-product of a cell’s normal reactions such as energy generation and the breakdown of fats. During these reactions oxygen is transformed into the free radical superoxide. Normally cells have mechanisms for protecting themselves from the dangers of free radicals. When too many are generated, or if they are not controlled properly, there is a danger that they will cause cell and tissue damage.
Free radicals are of concern for people with HCV for a number of reasons:
- Chronic liver inflammation may lead to over-production of free radicals within the liver.
- 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.
- If the liver function is already impaired and this had led to an overload of iron, the free radicals may interact with the iron causing further damage.
The liver is famed for its ability to regenerate, so why doesn't liver regeneration prevent liver damage in hepatitis? In Greek mythology the liver’s 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 Mount Olympia and sharing it with mankind. Zeus sent an eagle to the rock. By day the bird pecked away at Prometheus’s liver. By night as the eagle slept Prometheus’s liver grew back so that it was a fresh tasty meal again for the eagle the next morning.
Hepatitis C is usually characterised by a 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 harmful agents which are capable of damaging its cell structure. Either there is regeneration with complete restoration of the liver structure 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. But if the injury is repetitive s the case with HCV infection - the liver cannot effectively cope. It does not have the time and space to heal actually itself properly.