·                    Incubation:                

·                    The incubation period for viral hepatitis varies depending on which hepatitis virus causes the disease.

·                     For hepatitis A, the incubation period is 2 to 6 weeks.

·                     For hepatitis B, , the incubation period is between 1 and 5 months

·                    For hepatitis C, it is estimated that the incubation period is 2 to 26 weeks.

Duration:

·                    Children with hepatitis A usually have mild symptoms or are without symptoms. They may be more fatigued than  normal, but they are rarely jaundiced. Almost all previously healthy persons who develop hepatitis A will  completely recover from their illness in a few weeks or months without long-term complications.

·                    With hepatitis B, 90% to 95% of patients recover from their illness completely within 6 months, without long-term  complications. In some cases, however, persons with either hepatitis B or C can go on to develop chronic  hepatitis and cirrhosis (chronic degeneration) of the liver. Some persons with hepatitis B or C may also              become lifelong carriers of these viruses and can spread them to other people.

Contagiousness:

·                         Hepatitis A is contagious, and its virus can be spread in contaminated food or             water, as well as in unsanitary  conditions in child-care facilities or schools.             Toilets and sinks used by an infected person should be cleaned with antiseptic             cleansers. All persons who live with or care for someone with hepatitis should              wash their  hands after contact with the infected person. In addition, when               traveling to countries where hepatitis A is            prevalent, your child should              be vaccinated with at least two doses of the hepatitis A vaccine.

·                         Hepatitis B is highly contagious. Its virus can be found in virtually all body fluids,             though its main routes of infection are through sexual contact, contaminated             blood transfusions, and shared needles for drug injections. Household              contact with adults with hepatitis B can put people at risk for contracting                           hepatitis. Frequent hand washing and good hygiene practices can reduce                                 this risk. Use of the hepatitis B vaccine can greatly decrease the incidence             of this infection. Ask your child's doctor about this vaccine.

·                    Hepatitis C is contagious and can be spread through shared drug needles, contaminated blood products, and, less commonly, through sexual contact. Hepatitis C can be spread from mother to fetus during pregnancy, however, the risk of passing hepatitis C to the fetus is about 5%. If you are pregnant, contact your doctor if you think you may have been exposed to hepatitis C.

Over the past several years, improved medical technology has almost eliminated the risk of catching hepatitis from contaminated blood products and blood transfusions. But, as tattoos and acupuncture have become more popular, the risk of developing hepatitis from improperly sterilized equipment used in these procedures has increased.

 Signs and Symptoms:

Hepatitis is an inflammatory process involving the liver. Hepatitis, in its early stages, may cause flu-like symptoms. These symptoms may include malaise (a general ill feeling), fever, muscle aches, loss of appetite, nausea, vomiting, diarrhea, and jaundice. Some people may have no symptoms at all and may not even know they're infected.

If hepatitis progresses, its symptoms begin to point to the liver as the source of illness. Chemicals normally secreted by the liver begin to build up in the blood. This causes jaundice (a yellowing of the skin and whites of the eyes), foul breath, and a bitter taste in the mouth. Urine turns dark or "tea-colored," and stools become white, light, or "clay-colored." There also can be abdominal pain, which may be centered below the right ribs (over a tender, swollen liver) or below the left ribs (over a tender spleen).

Description:

The word hepatitis simply means an inflammation of the liver, without pinpointing a specific cause. Someone with hepatitis may be suffering from one of several disorders, including a viral infection of the liver; liver injury caused by a toxin (poison); liver damage caused by interruption of the organ's normal blood supply; or trauma.

Most commonly, hepatitis is caused by one of three viruses: the hepatitis A virus; the hepatitis B virus; or the hepatitis C virus. In some cases, mononucleosis can also result in hepatitis.

In children, the most common form of hepatitis is hepatitis A, also called "infectious hepatitis." This form is caused by the hepatitis A virus (HAV), which lives in the stools of infected individuals. When someone touches or eats anything that is contaminated with HAV-infected stool, the virus can pass into the body through the mouth. This makes it easy for HAV to spread in overcrowded, unsanitary living conditions. HAV also spreads in contaminated water, milk, and foods, especially in shellfish. Because hepatitis A can be a mild infection, particularly in children, it is possible for some people to be unaware that they have had the illness. In fact, although medical tests show that about 40% of urban Americans have had hepatitis A, only about 5% recall being sick.

Hepatitis B, also called "serum hepatitis," is caused by the hepatitis B virus (HBV). HBV spreads through infected body fluids, such as blood, saliva, semen, vaginal fluids, tears, breast milk, and urine. Infections may occur through a contaminated blood transfusion (uncommon in the United States), shared contaminated needles or syringes for injecting drugs, or sexual activity with an HBV-infected person. HBV-infected mothers can also pass the virus to their newborn babies.

Hepatitis C is spread by direct contact with an infected person's blood. It can be spread by sharing drug needles or getting a tattoo or body piercing with unsterilized tools, blood transfusions (especially ones that occurred before 1992; since then the U.S. blood supply has been routinely screened for the disease), or from mother to newborn. Hepatitis C is also a common threat in kidney dialysis centers. Less commonly, it is spread through sexual contact. Rarely, people living with an infected person can contract the disease by sharing items that might contain that person's blood, such as razors or toothbrushes.

There are other viruses that can cause hepatitis, including Hepatitis E. These viruses are known as "non-ABC hepatitis" because most of them have not been completely identified.

All of these viral hepatitis conditions can be diagnosed and followed through the use of readily available blood tests.

Prevention:

In general, to prevent viral hepatitis you should follow good hygiene and avoid crowded, unhealthy living conditions. If you travel to areas of the world where sanitation is poor and water quality is uncertain, extra care is necessary, particularly when drinking and swimming. Never eat shellfish from waters contaminated by sewage. You should also remind children to wash their hands thoroughly after using the toilet and before eating. If someone in the family develops hepatitis, antiseptic cleansers should be used to clean any toilet, sink, potty-chair, or bedpan used by that person.

Since contaminated needles and syringes are a major source of hepatitis infection, you should encourage drug awareness programs in your community and schools. At home, speak to your children frankly and frequently about the dangers of drug use. Also encourage abstinence and safe sex for teens, in order to eliminate their risk of hepatitis infection through sexual contact.

A hepatitis A vaccine is available, and is especially recommended for travelers, sexually active individuals, and people in high-risk occupations, such as health care and child care personnel. If you are planning to travel abroad, consult your doctor in advance so you and your family have enough time to complete the required immunizations. The vaccine is especially useful for staff of child care facilities or schools, family members of infected persons, or sexual partners of someone with hepatitis A.

There is also a hepatitis B vaccine, which should be given to both children and adults as part of routine immunization. Talk to your child's doctor about vaccinations for hepatitis.

Hepatitis C

 is transmitted predominantly through blood to blood contact (such as through sharing drug injecting equipment). There is a very small risk of transmission through sexual contact or from mother to child. A specific laboratory test for hepatitis C has been available only since early 1990. There are at least nine different genotypes or strains of hepatitis C. Previous infection with one strain of the virus does not protect against re-infection with the same or a different strain. The seroconversion 'window period' ranges from two to twenty-six weeks, during which time antibodies cannot be detected. There is currently no vaccine available to protect against hepatitis C.

The liver

The liver is vital to the body's good health. It has a number of functions which include:

·        manufacturing and storing bile (which is used to break down fats in the digestive system);

·        storing sugar and controlling the amount of sugar in the blood;

·        manufacturing protein and other substances;

·        and removing toxins, drugs and hormones etc from our bloodstream.

If enough liver cells are not functioning well, a number of important body systems will eventually suffer.

How does hepatitis C affect people?

Hepatitis C infection involves an initial (acute) phase of infection, which is usually not noticed and lasts two to six months. During this phase, levels of the virus in the blood rise dramatically until the body's immune response starts producing antibodies. Although the antibodies fight the virus, in 75% of cases the virus is not eliminated and following the acute phase of infection, these people are left with a long-term chronic infection.

Some people with this chronic infection do not have any noticeable liver damage or symptoms. They remain well, but their blood is infectious and they should take care to reduce any risk of transmitting the virus to others.

A majority of people infected with hepatitis C will eventually develop liver damage that will result in symptoms which typically include tiredness, nausea or abdominal discomfort. Sometimes symptoms may be disproportionately disabling compared to the amount of liver damage.

Over a twenty-year period, chronic infection may result in permanent scarring of the liver called cirrhosis. This is not life threatening in itself, but after a further five to ten years, extensive cirrhosis may result in liver failure or cancer of the liver. Liver failure may be treated by liver transplantation. A small number of people with hepatitis C develop liver cancer (hepatocellular carcinoma).

The available evidence thus far suggests that if 100 people are infected with the virus the outcome will be as follows:

·        about 15 to 35 people will clear the virus spontaneously within two to six months of infection and will neither develop a chronic infection nor risk developing advanced liver disease. They can, however, be re-infected with hepatitis C if they are re-exposed.

·        about 65 to 85 people will develop chronic hepatitis C infection.

·        about 5 to 10 people with chronic hepatitis C infection will have progressed to cirrhosis after 20 years of infection (rising to 20 people after 40 years of infection). Among the factors associated with an increased risk of cirrhosis are alcohol consumption, HIV or hepatitis B co-infection, older age at the time of infection, and being male.

·        about 3 to 5 people with hepatitis C-related cirrhosis will be at risk of liver failure or hepatocellular carcinoma after 30 to 40 years of infection. Among people with cirrhosis, the risk of liver cancer is 1 to 3 per cent a year.

·        the majority of people with chronic hepatitis C infection will probably not progress to advanced liver disease but their quality of life may be diminished.

New and Future Treatments for Chronic Hepatitis C

Treatment of chronic hepatitis C is presently based on the use of interferon-alpha. Interferon-alpha is a protein that is given by injection, usually three times a week. The addition of ribivirin, a non-specific, orally administered anti-viral agent, improves the efficacy of interferon-alpha. Although interferon-alpha with or without ribivirin works for some patients with hepatitis C, most do not achieve a "sustained response" of undetectable virus in blood 6 months after stopping therapy. Interferon-alpha is also associated with myriad adverse events and is relatively expensive. Ribavirin may also cause side effects. Better drugs are unequivocally needed for the treatment of chronic hepatitis C. What will they likely be?

Longer Acting Interferon-alpha

The next drug available for the treatment of chronic hepatitis C will be peginterferon-alpha (sometimes called "pegylated interferon"). The active agent in peginterferon-alpha is the same old interferon-alpha. However, the protein is attached to polyethylene glycol (antifreeze), an inert compound that slows the elimination from the body. More constant blood levels of interferon-alpha are achieved with less frequent injections, usually once a week. This results in enhanced compliance and clinically superior anti-viral activity.

Published studies have shown that peginterferon-alpha alone results in "sustained response" rates of 30% to almost 40%. The side effect profile is similar to unmodified interferon-alpha. Preliminary data show that addition of oral ribavirin to pegylated interferon-alpha results in "sustained response" rates of approximately 50%. Hence, pegylation enhances the efficacy of interferon-alpha for the treatment of chronic hepatitis C.

The United States Food and Drug Administration (FDA) has recently approved peginterferon-alpha-2b (Peg-Intron, Schering-Plough) for the treatment of chronic hepatitis C. Peginterferon-alpha-2a (Pegasys, Hoffmann La Roche) will likely be approved in the near future. Within a year, the FDA will likely approve the combination of peginterferon-alphas with ribavirin. Clinical trials of peginterferon-alpha with a compound called VX-497 (Vertex Pharmaceuticals) are also in progress. VX-497 has some features similar to ribavirin and inhibits a cellular enzyme know as inosine monophosphate dehydrogenase that may responsible for some of its effects.

An even longer acting form on interferon-alpha is currently in early stage clinical testing. This is a fusion protein between albumin and interferon alpha (Albuferon, Human Genome Sciences). Data on its clinical efficacy are not yet available. It is also probable that other long acting preparations of interferon-alpha will be developed in the next few years.

Drugs that Affect the Immune Response Against the Virus

Several drugs known as "immune modifiers" or "immunomodulators" that alter the immune response are being tested in clinical trials for chronic hepatitis C. Some are being studied along with interferon-alpha. There drugs alter the inflammatory response against liver cells infected with the virus; however, their mechanisms of action are poorly understood. Compounds of this type currently being tested in humans include thymosin-alpha-1 (Zadaxin, SciClone Pharmaceuticals) and histamine dihydrocholoride (Ceplene, Maxim Pharmaceuticals).

Therapeutic vaccines are also being developed to enhance the immune response against the hepatitis C virus. In contrast to a preventive vaccine, which is likely to be a very long way off for hepatitis C, a therapeutic vaccine is administered to already-infected individuals to stimulate the immune system to fight the infection. Several therapeutic vaccines are in preclinical development for hepatitis C. The most promising of these are DNA vaccines involving injection of DNA copies of the hepatitis C virus's RNA genome, which are taken up by certain immune system cells. These cells then express viral proteins, stimulating an immune response against the virus. These theoretically appealing therapeutic vaccine for hepatitis C remain to be shown effective in human subjects

Specific Agents Against Hepatitis C Virus Proteins

A new generation of drugs to treat hepatitis C will be those designed specifically to inhibit functions of the hepatitis C virus. One target for such drugs is the hepatitis C virus RNA genome. Ribozymes are catalytic RNA molecules, some of which can cut other RNA molecules. A ribozyme (Hepatazyme, Ribozyme Pharmaceuticals) has been designed to cleave the hepatitis C virus RNA genome in a region that the virus needs to survive. Its efficacy in cutting hepatitis C virus RNA has been established in the test tube and the drug is now in early clinical trials. ISIS-14803 (Isis Pharmaceuticals) is a antisense inhibitor complementary to a conserved sequence of the hepatitis C virus RNA. This molecule binds to the viral RNA and inhibits the expression of proteins required for replication. ISIS-14803 is currently in early stage clinical trials. A small molecule known as VP-50406 (ViroPharma) has also been demonstrated to inhibit hepatitis C virus RNA in the laboratory and is in early stage clinical development. Inhibitors of a unique structure of the hepatitis C virus RNA necessary for protein synthesis, known as the internal ribosome entry site or IRES, are also under study in the laboratory.

Three favorite targets of the hepatitis C virus for pharmaceutical chemists are its N3S RNA polymerase, NS3 RNA helicase and NS5B RNA polymerase. Compounds directed against these targets are in various stages of preclinical development. The targets are all enzymes (proteins that catalyze chemical reactions) essential for hepatitis C virus replication. They are expressed in cells infected with the virus but not in mature viral particles themselves. Armed with knowledge of the three-dimensional structures of these enzymes deduced using X-ray crystallography, scientists can identify molecules that inhibit their activities.

NS3 has two parts with distinct enzymatic activities. One part is a protease that cuts a larger precursor protein encoded by the hepatitis C virus RNA into smaller functional proteins. Inhibition of NS3 would result in a failure of the virus to make the smaller proteins necessary for its replication. The other part of NS3 is a RNA helicase that unwinds the hepatitis C viral RNA. RNA unwinding is necessary for its efficient replication and translation into protein. Specific inhibitors of NS3's enzymatic activities would theoretically not influence critical host cell functions, limiting the side effect profiles. NS5B of the hepatitis C virus is an essential RNA-dependent RNA polymerase that copies the virus's RNA genome. Animal cells do not copy RNA; they make RNA copies from DNA. Therefore, specific inhibitors of the NS5B should not affect host cell processes.

Of course, one cannot accurately predict the adverse event profile of a given drug until it is tested in human. Drugs designed as best as possible against specific viral targets may still prove to have side effects. However, well-designed drugs directed against the hepatitis C virus RNA, NS3 protease, NS3 RNA helicase and NS5AB RNA polymerase are very likely to be more effective and better tolerated than currently available treatments for hepatitis C. The timeline from the laboratory to the clinic is likely to be several years.

Drugs that Affect the Liver's Response to Injury

Chronic hepatitis (inflammation of the liver) can lead to fibrosis (scarring) and cirrhosis (fibrosis plus abnormal regeneration of liver cells). Virtually all of the serious complications of chronic hepatitis C result from cirrhosis. For this reason, several groups are developing drugs to prevent fibrosis and cirrhosis. Recent data suggest that fibrosis, and perhaps even early cirrhosis, may be reversible to some extent.

Very little is known about why the liver becomes fibrotic in response to chronic inflammation. Furthermore, it is not known why some individuals infected with the hepatitis C virus develop significant fibrosis or cirrhosis while others never do. Some drugs that may prevent liver fibrosis and cirrhosis are in early clinical trials. IP-501 (Interneuron Pharmaceuticals) is an orally administered anti-fibrotic compound being tested for the treatment of including alcoholic and hepatitis C-induced cirrhosis. Animal models suggest that IP-501 is effective in preventing the development of alcohol-induced cirrhosis, however the exact mechanism by which this compound works is not fully understood. Clinical trials of IP-501 in alcohol-induced liver disease and chronic hepatitis C are underway. Preliminary studies in humans have also shown that interleukin-10 (Schering-Plough) may prevent liver fibrosis in chronic hepatitis C. Clinical trials of interleukin-10 need to be carried out on a larger scale to demonstrate safety and efficacy. Increasing scientific effort is being devoted to the study of liver fibrosis in response to injury and exciting new drugs to prevent it will hopefully be available someday.

Re-grow a Damaged Liver?

When a liver is damaged beyond repair, the only hope today is orthotopic liver transplantation. However, considerable research effort is being devoted to the study of stem cells. Stem cells are undifferentiated cells, such as those in the early embryo that can be directed to form many different tissues of the body. In the past few of years, investigators have shown that liver stem cells reside in the bone marrow. Theoretically, these bone marrow stem cells can be isolated and grown into hepatocytes and bile duct cells in the laboratory. Some animal studies have also shown that expression of the enzyme telomerase in liver cells enhance their ability to regenerate. Although considerable challenges remain to be overcome, this early stage research provides promise that liver transplantation may someday be a thing of the past.

Pharacogenomics

Some drugs work in some patients but not in others. Similarly, some drugs have side effects in some patients while others tolerate them well. For example, less than half of patients with chronic hepatitis C have a "sustained response" to treatment with interferon-alpha and many experience intolerable side effects. Most of this is a result of different individuals' different genetic make-ups.

Pharmacogenomics is the science of understanding the correlation between an individual patient's genetic make-up and response to a drug. The discipline is evolving rapidly as a result of the extensive work recently completed on sequencing the entire human genome. Phamacogenomics aims to identify genetic markers that predict response to a drug. The genetic markers commonly assessed are known a single nucleotide polymorphisms (SNPs) and haplotypes. SNPs are changes at a single base of DNA between individuals. Haplotypes are linear arrays of slightly different forms of particular genes on a chromosome. By studying populations of patients and their responses to a drug, inheritance of a collection of SNPs or different haplotypes can be correlated with successful treatment, unsuccessful treatment or development of side effects. This knowledge can them be used to "customize" drug therapy for a particular patient based on first examining their DNA.