Hepatitis C part 1

What is hepatitis C?

Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). It is difficult for the human immune system to eliminate the virus from the body, and infection with HCV usually becomes chronic. Over decades, chronic infection with HCV damages the liver and can cause liver failure in some people. In the U.S., the number of new cases of infection with HCV has declined over the last 10 years from a peak of some 200,000 annually to about 19,000 in 2006. When the virus first enters the body, there usually are no symptoms, so these numbers are estimates. Up to 85% of newly infected people fail to clear the virus and become chronically infected. In the U.S., more than three million people are chronically infected with HCV. Infection is most common among people who are 40 to 60 years of age, reflecting the high rates of infection in the 1970s and 1980s. There are 8,000 to 10,000 deaths each year in the U.S. related to HCV. HCV is the leading cause of liver transplantation in the U.S and is a risk factor for liver cancer.

What is the nature (biology) of the hepatitis C virus?

'Hepatitis' means inflammation of the liver. HCV is one of several viruses that can cause hepatitis. It is unrelated to the other common hepatitis viruses (for example, hepatitis A or hepatitis B). HCV is a member of the Flaviviridae family of viruses. Other members of this family of viruses include those that cause yellow fever and dengue.

Viruses belonging to this family all have ribonucleic acid (RNA) as their genetic material. All hepatitis C viruses are made up of an outer coat (envelope) and contain enzymes and proteins that allow the virus to reproduce within the cells of the body, in particular, the cells of the liver. Although this basic structure is common to all hepatitis C viruses, there are at least six distinctly different strains of the virus which have different genetic profiles (genotypes). In the U. S., genotype 1 is the most common form of HCV. Even within a single genotype there may be some variations (genotype 1a and 1b, for example). Genotyping is important to guide treatment because some viral genotypes respond better to therapy than others. The genetic diversity of HCV is one reason that it has been difficult to develop an effective vaccine since the vaccine must generate viral proteins from each genotype

How does liver damage occur in hepatitis C infection?

The presence of HCV in the liver triggers the human immune system, which leads to inflammation. Over time (usually decades), prolonged inflammation may cause scarring. Extensive scarring in the liver is called cirrhosis. When the liver becomes cirrhotic, the liver fails to perform its normal functions, (liver failure), and this leads to serious complications and even death. Cirrhotic livers also are more prone to become cancerous.

How is hepatitis C virus spread and how can transmission be prevented?

HCV is spread (transmitted) most efficiently through inadvertent exposure to infected blood.

• The most common route of transmission is needles shared among users of illicit drugs.
• Accidental needle-sticks in healthcare workers also have transmitted the virus.
• The average risk of getting HCV from a stick with a contaminated needle is 1.8% (range 0% to 10%).
• Prior to 1992, some people acquired the infection from transfusions of blood or blood products. Since 1992, all blood products are screened for HCV, and cases of HCV due to blood transfusion now are extremely rare.
• HCV also can be passed from mother to unborn child. Approximately 4 of every 100 infants born to HCV-infected mothers become infected with the virus.
• A small number of cases are transmitted through sexual intercourse. The risk of transmission of HCV from an infected individual to a non-infected spouse or partner without the use of condoms over a lifetime has been estimated to be 1% to 4%
• Finally, there have been some outbreaks of HCV when instruments or sharp tool have been re-used without appropriate cleaning between patients.

Transmission of HCV can be prevented in several ways.

• Programs have been aimed at avoiding needle sharing among drug addicts. Needle exchange programs and educational interventions have reduced high-risk behaviors. However, the population of drug addicts is a difficult population to reach, and rates of HCV remain high among addicts (30% of younger users).
• Among healthcare workers, safe needle-usage techniques have been developed to reduce accidental needle-sticks. Newer syringes have self-capping needle systems that avoid the need to manually replace a cap after drawing blood and reduce the risk of needle-sticks.
• There is no clear way to prevent transmission of the HCV from mother to child.
• Persons with multiple sexual partners should use barrier precautions such as condoms to limit the risk of HCV as well as other sexually-transmitted diseases.
• Monogamous couples should consider the low risk of transmission when deciding whether to use condoms during intercourse. Some couples may decide to use them and some may not.
• Screening tests for blood products have almost eliminated the risk of transmission through transfusion, estimated by the CDC to be less than one in two million transfused blood products.
• People with HCV should not share razors or toothbrushes with others.
• It is critical that physicians and clinics follow manufacturer's directions for sterilizing/cleaning instruments and that disposable sharp instruments be discarded properly.

It is important to realize that HCV is not spread by casual contact. Thus, shaking hands, kissing, and hugging are not behaviors that increase the risk of transmission. There is no need to use special isolation procedures when dealing with infected patients.

What are the symptoms of hepatitis C infection?

About 75% of people have no symptoms when they first acquire HCV infection. The remaining 25% may complain of fatigue, loss of appetite, muscle aches or fever. Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection.

Over time, the liver in people with chronic infection may begin to experience the effects of the persistent inflammation caused by the immune reaction to the virus. Blood tests may show elevated levels of liver enzymes, a sign of liver damage, which is often the first suggestion that the infection may be present. Patients may become easily fatigued or complain of nonspecific symptoms.

As cirrhosis develops, symptoms increase and may include :

• weakness,
• loss of appetite,
• weight loss,
• breast enlargement in men,
• a rash on the palms,
• difficulty with the clotting of blood, and
• spider-like blood vessels on the skin.

In patients with advanced cirrhosis, the liver begins to fail. This is a life-threatening problem. Confusion and even coma (encephalopathy) may result from the inability of the liver to process certain toxic substances.

Increased pressure in the blood vessels of the liver (portal hypertension) may cause fluid to build up in the abdominal cavity (ascites) and result in engorged veins in the swallowing tube (esophageal varices) that tear easily and can bleed suddenly and massively. Portal hypertension also can cause kidney failure or an enlarged spleen resulting in a decrease of blood cells and the development of anemia, increased risk of infection and bleeding.

In advanced cirrhosis, liver failure causes decreased production of clotting factors. Patients with advanced cirrhosis often develop jaundice because the damaged liver is unable to eliminate a yellow compound, called bilirubin that is formed from the hemoglobin of old red blood cells.

What conditions outside the liver are associated with hepatitis C?

Most of the signs and symptoms of HCV relate to the liver. Less commonly, HCV causes conditions outside of the liver.

• An example is when the body produces unusual antibodies called 'cryoglobulins'. These cryoglobulins cause inflammation of the arteries (vasculitis) which may damage the skin, joints, and kidneys. Patients with cryoglobulinemia may have joint pain, arthritis, a raised purple rash on the legs, generalized pain or swelling. In addition, these patients may develop Raynaud's phenomenon, in which the fingers and toes turn color (white, then purple, then red) and become painful at cold temperatures.
• Two skin conditions, lichen planus and porphyria cutanea tarda, have been associated with chronic infection with HCV.
• For reasons that are unclear, diabetes is three times more common among patients with chronic HCV infection than in the general population.
•  Low platelet counts may occur as a result of antibody-mediated platelet destruction.
• HCV also is associated with B-cell lymphoma, a cancer of the lymph system.

What is the usual progression of chronic infection with the hepatitis C virus?

Our understanding of the natural progression (history) of HCV infection still is evolving.

Of 100 people infected with HCV, it is estimated that 75 to 85 will become chronically infected, 60 to 70 will develop liver disease, 5 to 20 will develop cirrhosis and 1 to 5 will die from complications of liver disease like cirrhosis or liver cancer.

Scientists are learning more about what causes some people to have milder problems and others to have serious complications. Drinking alcohol or acquiring other hepatitis viruses are risk factors for severe disease. Thus, persons who have chronic hepatitis C should avoid drinking and should be vaccinated against the other hepatitis viruses (A and B).

Liver cancer (hepatocellular carcinoma) is associated with cirrhosis due to chronic HCV infection. Some experts recommend screening patients with HCV and cirrhosis for liver cancer every six months with abdominal ultrasound and a blood test for alpha-fetoprotein (a marker for liver cancer). The effectiveness of this screening is unclear.

Who is at high risk and should be tested for hepatitis C infection?

Currently, screening for HCV is not recommended as part of a routine physical examination.

• Rather, testing should be done in individuals at high risk for infection including current and past users of injectable drugs and persons exposed to infected blood or organs from infected persons.
• Children born to chronically infected mothers should be tested to determine if they carry the virus.
• Persons with abnormal levels of liver enzymes in the blood also should be tested.

These are not the only circumstances under which tests may be done. In general, testing is recommended when exposure to the virus is suspected.

What are the diagnostic tests for hepatitis C virus and how are they used to diagnose hepatitis C virus infection?

Several diagnostic tests currently are available for the diagnosis of HCV. They can be categorized according to the way the tests are used.

Screening tests

Screening tests are tests that are used to diagnose a condition or disease among individuals not known to have the disease. It is particularly useful for individuals who have risk factors for the condition or disease. The first step in screening for HCV is to test blood for the antibody to HCV using an enzyme-linked immunosorbent assay (ELISA). If the ELISA test is negative (does not find the antibody), the patient is assumed to be free of HCV. It takes several weeks (up to six months) for antibodies to develop after the initial infection with HCV, so this screening test may miss a few newly-infected individuals. However, in HCV physicians usually are looking for chronic infection so missing a few recently-infected individuals is not of much importance.

The ELISA test for HCV antibody is not perfect and may sometimes be positive in people who are not currently infected. Thus, if the ELISA test for HCV antibody is positive, additional testing is done to confirm the diagnosis with another type of test for the antibody. One such test is called the recombinant immunoblot assay (RIBA). It is read as either 'positive', 'negative' or 'indeterminate'. Indeterminate means that the result is unclear. Another option is to use molecular tests to measure the amount of HCV ribonucleic acid (RNA) in the blood.

Molecular tests for hepatitis C virus

As previously described, HCV is an RNA virus, meaning that it contains RNA. Several tests (assays) are available to measure the amount of HCV RNA in a person's blood. These tests are referred to as molecular tests because they examine the virus at the molecular level. A single negative test for RNA does not mean that there is no infection because the virus may appear in the blood intermittently or may exist in small amounts. Newer tests have helped by detecting smaller and smaller amounts of virus in the blood.

Testing for RNA is useful in determining whether or not a patient has circulating virus in the blood (viremia). Hence, it can be used to confirm that a positive ELISA truly reflects active hepatitis C virus infection.

RNA testing also should be done in individuals who may have been recently exposed to HCV. HCV RNA testing is more sensitive (that is, will detect more cases) than the conventional ELISA testing in this setting. The reason for this greater sensitivity is that it may take a person several weeks after exposure to HCV to develop the antibodies, whereas HCV RNA becomes detectable one to three weeks after exposure. Finally, HCV RNA testing may be helpful to assess a patient's virologic response to treatment at certain time points during antiviral therapy (see treatment of HCV below).