The most serious symptoms of this stage are:

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1 The Natural Progression of Hepatitis C The natural history of hepatitis C looks at the likely outcomes for people infected with the virus if there is no medical intervention. However, the process of trying to predict how hepatitis C will affect the body over time and get a picture of the likely disease progression is complicated by a number of factors: Difficulties in Mapping the Progression of Disease caused by HCV Firstly it has only been 19 years since the virus was identified, and in terms of time to study a disease this is relatively short. Although a great deal has been learnt about what can take place during the first 20 years of infection with hepatitis C, the prognosis from the third decade of infection remains largely uncharted. In order to get a picture of likely progression over time it is necessary to know when people were infected This is problematic as many people with HCV do not know when or how they were infected. Also many people have now had treatment, which may well have changed the course of the disease for them. In order to try and chart a natural history of hepatitis C it means studying the course of an infection without any medical intervention (treatment). One of the main conundrums about HCV infection is that people have such dramatically different outcomes and experiences. While some people clear the virus in the very early stages, most will develop a long term or chronic infection. The course of the disease then is very variable. One person may have no liver damage after twenty years while another person will develop cirrhosis and subsequently liver failure or liver cancer. The range and degree of symptoms also varies significantly. Many people remain asymptomatic (without symptoms) for years, while others will experience fatigue, depression, digestive problems and other symptoms among the many varied extrahepatic (outside of the liver) complications of hepatitis C infection. Confusingly the symptoms people suffer are not necessarily an indication of whether they have liver damage or not. One person may have almost no liver damage and yet their quality of life is severely affected by symptoms, while somebody with extensive scarring of the liver may be symptom free. Existing blood tests for example viral load, liver enzyme levels, or HCV genotype also cannot reliably forecast the outcome of untreated HCV infection. Despite these variations and difficulties an increasing amount has been learnt about how the disease does generally progress. The Progression of Hepatitis C is divided up into four stages: The Acute Stage The Chronic stage Compensated Cirrhosis Decompensated Cirrhosis The period immediately after infection is called the acute phase. This lasts about six months. If the immune system does not manage to clear the virus by then the disease is Scotland

2 considered to have moved into a long-term or chronic phase. This is confirmed when a test for antibodies to the virus is positive and when HCV RNA (viral nucleoprotein) is detectable on at least two occasions over a six month period using the Polymerase Chain Reaction detection system this is a PCR test. It is rare to spontaneously clear the virus once it has reached this chronic stage. Hepatitis C is classified as a liver disease because of the damage it causes to the liver, however the virus affects other body systems and causes symptoms, illnesses and complications outside of the liver. Doctors have previously tended to focus mainly on the state of your liver as opposed to symptoms you feel or other complications caused by the virus because they have often been seen as unconnected or unrelated. This has meant that they have been given less attention and been studied less. The effects of Hepatitis C are described in terms of the changes to the liver as scarring develops. This progression moves from the initial inflammation of the liver caused by the virus hijacking, infecting and killing off liver cells through to the gradual scarring (fibrosis) and then hardening of liver tissue (cirrhosis). Throughout this progression the immune system plays a highly influential role both in stemming the disease but also in accelerating scarring of the liver. Cirrhosis is severe scarring that alters the structure of the liver and over time will seriously undermine the liver s ability to function. Cirrhosis is classified as being either compensated or de-compensated. If the liver can continue to carry out most of its functions despite extensive scarring then this is known as compensated cirrhosis (meaning that the liver can compensate for the damage). If the liver s functions are seriously affected then this is called decompensated cirrhosis. The most serious symptoms of this stage are: Portal Hypertension, (when blood cannot properly flow into the liver and causes bleeding from distended veins (varices) in the oesophagus and the build up of abdominal fluid (ascites) Hepatic Encephalopathy. If blood is forced to bypass the liver it is not filtered for poisons and toxins and there is risk of serious mental confusion leading to coma. Cirrhosis also significantly increases the risk of developing liver cancer. This can develop from either compensated or decompensated cirrhosis. Recent studies suggest that chronic infection with HCV will almost invariably result in cirrhosis. It is the time that this takes that varies. For those people who develop a chronic or long term infection (between 70-80% of those infected with HCV) around 20-30% will develop cirrhosis within 20 years. For some it may be quicker but for others it may take up to sixty years so they may well die of unrelated diseases beforehand. Acute Phase Hepatitis C The term Acute Phase can be confusing, because it only refers to a 6 month period of time after the virus has entered your body. It bears no relation to acuteness of symptoms, or severity of disease. Scotland

3 After the virus has entered your body there are three tests that will show or suggest its presence, HCV Antibodies, PCR and liver function tests (LFTs). Antibodies to the virus can start to be detectable in the blood between 3-12 weeks after infection. Different people s immune systems take different lengths of time to create antibodies, depending on the amount of time it takes for the virus to take hold in the body. This is called the window period. Because it can take 3 months or more for the antibodies to show up in a blood test, it is important to wait this long before having a test if you suspect you have recently been infected. Polymerase chain reaction (PCR) test may be given if infection is strongly suspected for instance if someone has had a needle stick injury then a PCR test will be worth checking 2 weeks after the injury. A PCR test becomes positive sooner than the antibody test. (But as it is more expensive is not usually the first test given). There is an average incubation period of seven to eight weeks before there may be a rise in liver enzymes levels. Liver function tests or LFT s are a set of blood tests measuring specific proteins and enzymes to see how well the liver is performing its various functions. As liver cells are damaged by the virus, enzymes leak into the bloodstream leading to a rise of specific enzyme levels. However, there is not necessarily a rise in enzyme levels even in this acute phase. Symptoms during the Acute Phase Most people do not seem to experience symptoms during the acute phase. For the 25-35% of people who do experience symptoms they are normally vague and non-specific. They can include low-grade fever, fatigue, appetite loss, abdominal pain, nausea and vomiting. About 20% of the people who develop symptoms contract jaundice which is the yellowing of the skin and the whites of the eyes. This is a sign of the liver s function being compromised as bilirubin (the pigment of bile) builds up in the body. Jaundice is a recognised sign of liver problems and as such it may lead to a test for hepatitis C being suggested. The problem for most people is that they are unaware that they have been infected because of this lack of symptoms or vagueness of them. As these symptoms are similar to many other short term infections most people are unlikely to seek medical attention. Even if they do, most doctors will not suspect or test for hepatitis C. In very rare instances some people will develop a severe form of short-term hepatitis in which the liver is rapidly and almost completely destroyed. It is usually fatal as a liver transplant cannot be organised in time. This is called fulminant hepatitis C. Spontaneous clearance of the virus during the acute phase Somewhere between 15% and 30% of people clear the virus completely during the acute phase. This is the spontaneous clearing of HCV by the immune system through elimination of all viral particles in the circulation and destruction all infected cells. Evidence of this infection in the form of antibodies to hepatitis C will possibly always remain in the body, but they will definitely remain for at least for some years. Unlike Scotland

4 some other diseases these antibodies do not provide immunity against a further HCV infection at a later date. Contributory factors to clearing hepatitis C during the acute phase It is not clear exactly why some people clear the virus while others do not, but some common factors are known: a) The younger a person is at the time of HCV infection, the more chance they have of clearing the virus b) Women are more likely to clear the virus than men. c) People who develop symptoms during the acute phase seem to have a greater chance of clearing the virus. d) A healthy immune system, particularly the T cell response to the virus, plays an important part. e) Low alcohol consumption f) Genotype. There is some evidence that people with genotype 3 have a higher chance of clearing the virus than those with genotype 1. g) The amount of virus transmitted at the time of infection. People who contracted the virus through transfusion and so have a higher viral load appear to be at greater risk of developing chronic hepatitis C than people with some other sources of infection. h) Genetics. People with certain genetic makeup are more likely to clear the virus. Does viral clearance mean absolute clearance? Some recent reports, however, have called into question the traditional understanding of viral clearance. A recent study using ultra-sensitive tests was carried out amongst a group of people who had spontaneously cleared the virus and had maintained undetectable HCV viral load in the blood with no clinical signs of hepatitis. The tests revealed the presence of HCV RNA in all participants of the study group, with the majority showing signs of active reproduction by the virus. HCV RNA was found in serum, (the liquid part of blood without the clotting factors) Dendritic cells (specialist cells of the immune system) and in some white blood cells where there were also signs of viral replication. The study is too limited to be conclusive but it challenges assumptions that resolved infections really do mean the complete eradication of HCV from the body. When does acute hepatitis C become chronic hepatitis C? The 70% to 85% of individuals who do not achieve spontaneous viral clearance are considered to be in the chronic phase of Hepatitis C after six months of infection. This is confirmed when HCV antibody testing is positive and HCV RNA viral presence is detectable on at least two occasions over a six month period. So a diagnosis of chronic hepatitis C, means you have passed the time when spontaneous viral clearance is likely or possible. The virus has won the fight for its life against the immune defences inside your body and now has taken up firm residence in your liver cells. Chronic Phase of Hepatitis C The 70% to 85% of individuals who do not manage to clear the virus spontaneously in the acute phase of infection are considered to be in the chronic phase of hepatitis C after Scotland

5 six months of infection. This is when hepatitis C becomes a chronic or long-term infection. The diagnosis of chronic hepatitis C is confirmed when HCV antibody testing is positive and HCV RNA viral presence is detectable on at least two occasions over a six month period. The intense battle that goes on inside the body during the acute stage between the virus and the immune system has been won by the virus. It is now highly unlikely that the virus can be cleared without treatment. How the disease then progresses will vary significantly from person to person. In terms of liver damage some people infected will have minimal liver damage with no scarring after many years while a few people 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 a matter of debate whether chronic HCV infection inevitably leads to cirrhosis. At present it is thought that this is the case, but that 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 tests. Symptoms people experience as with liver damage vary dramatically. Some people will have few, if any, symptoms for many years, while for others the symptoms can be severely debilitating. It was originally thought that the virus only infected liver cells. However, recently it has become clear that HCV also infects parts of the immune system and some blood cells. This means that hepatitis C is not just a liver disease but is a systemic disease, in that it can affect other organs in the body. HCV triggers damage to the liver firstly in the form of inflammation, which then leads to scarring or fibrosis of the liver. This is discussed in the sections on liver damage. Other sections include symptoms during the chronic stage and the complications that can occur outside of the liver: the extra-hepatic manifestations of the disease. How the virus affects the functions of the liver is discussed in the sections on the Liver. Symptoms during the Chronic Stage There is no set symptom pattern with hepatitis C. For some people symptoms are severe enough to significantly and consistently affect their quality of life whilst other people experience none at all. Sometimes they will be vaguely noticeable, but for many people they come and go and the severity varies. People who have cleared the virus with treatment often only realise that they were experiencing symptoms in retrospect when they are feeling better. Symptoms related to the chronic stage of the disease can include: Fatigue with non-refreshing sleep Depression Short-term memory problems Difficulty concentrating Mood swings Digestive problems Joint and muscle aches and pains Scotland

6 Headaches Flu-like symptoms Discomfort or pain in the liver area Abdominal pain. Itching Research has tended to focus on looking at liver damage rather than symptoms or associated extra-hepatic illnesses (illnesses outside of the liver). And it is only recently that the medical profession has started to accept that symptoms and associated illness are indeed caused by the virus, although the reasons for them are not totally understood yet. These symptoms are referred to by doctors as non-specific symptoms when they don t relate directly to liver damage or any of the associated illnesses the virus can trigger. The cause of many of these non-specific symptoms is not clear, but there is some evidence to show that hepatitis C may infect neural tissue and this could at least be part of an explanation for some symptoms. One study has confirmed that fatigue, depression and feelings of anger caused by HCV are more severe and more intractable than when these symptoms are experienced by people with non liver-related chronic diseases. Brain fog (confusion and impaired memory) has been reported by many people with HCV. A study amongst people with chronic hepatitis C and those who had cleared the virus showed greater cognitive impairment amongst those with chronic HCV infection. HCV has been found in cerebrospinal fluid and it is believed this might be linked to brain fog, but more research is needed to pin this link down. The study, although small, revealed several things that suggests an underlying mechanism for cognitive impairment: Those with HCV demonstrated greater cognitive impairment than those who had cleared the virus The choline/creatine ratio on MRI brain scanning was higher in this group and a significantly higher ratio was found in the white matter and basal ganglia of the brain in people with hepatitis C as opposed to hepatitis B Autopsied brain tissue showed HCV replication HCV was found in the cerebral spinal fluid of 8 out of 13 individuals. Scotland