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•	In-Depth Reports Home

In This Report

•	Highlights
•	Introduction
•	Diagnosis
•	Hepatitis A
•	Hepatitis B and D
•	Hepatitis C
•	Autoimmune Hepatitis
•	Symptom Management
•	Outlook
•	Resources
•	References

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Hepatitis

Highlights

Drug Approvals

• In 2005, the FDA approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir worked better than lamivudine. However, questions have been raised about the drug’s possible cancer risks.

Drug Warnings

• In 2004, the FDA issued two drug warnings for patients with hepatitis B (HBV). The HIV drug tenofovir (Viread) should not be used to treat patients who also have HBV as the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate HBV.

Investigative Drugs for Hepatitis B

• Pegylated interferon alfa-2b (Peg-Intron) is being investigated alone and in combination with lamivudine for treatment of HBV. One 2005 study found that a third of patients treated solely with pegylated interferon-alfa-2b became negative for the hepatitis B antigen. Combining the drug with lamivudine did not improve effectiveness. Another 2005 trial found that combination pegylated interferon alfa-2b and lamivudine produced better response and less drug resistance than lamivudine single therapy.

Investigative Drugs for Hepatitis C

• Several new nucleoside analogs are in clinical development. In Phase III trials, viramidine is being tested alone and in combination with pegylated interferon-alfa. In Phase II trials, valopicitabine (NM283) is being studied alone and in combination with pegylated interferons.
• Albuferon. This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is in Phase II trials for patients who have not been treated with or have not responded to standard interferon-alfa.

Research

Liver cancer. According to a 2005 study, interferon therapy can help patients with hepatitis C-induced cirrhosis reduce the risk of developing liver cancer.

Liver transplantation. A 2004 study found that the hepatitis C virus recurs with more severity with liver donations from living donors than livers taken from cadavers.

Introduction

Hepatitis is a disorder in which viruses or other mechanisms produce inflammation in liver cells, resulting in their injury or destruction. The liver is the largest organ in the body, occupying the entire upper right quadrant of the abdomen. It performs over 500 vital functions. Among them are the following:

• It processes all of the nutrients the body requires, including proteins, glucose, vitamins, and fats.
• The liver manufactures bile, the greenish fluid stored in the gallbladder that helps digest fats.
• One of the liver's major contributions to life is to render harmless potentially toxic substances, including alcohol, ammonia, nicotine, drugs, and harmful by-products of digestion.
• Old red blood cells are removed from the blood by the liver and spleen, and the iron contained in them is recycled to the bone marrow to make new red blood cells.

The esophagus, stomach, large and small intestine, aided by the liver, gallbladder and pancreas convert the nutritive components of food into energy and break down the non-nutritive components into waste to be excreted.

Damage to the liver can impair these and many other processes. Hepatitis varies in severity from a self-limited condition with total recovery to a life-threatening or life-long disease. It can occur from many different causes:

• In the most common hepatitis cases, specific viruses incite the immune system to fight off infections (called viral hepatitis). Specific immune factors become over-produced that cause injury.
• Hepatitis can also result from an autoimmune condition, in which abnormal immune factors attack the body's own liver cells.
• Inflammation of the liver can also occur from medical problems, drugs, alcoholism, chemicals, and environmental toxins.

No matter what the cause of hepatitis, it can take either an acute (short term) or chronic form (persistent). In some cases, acute hepatitis develops into a chronic condition, but chronic hepatitis can also occur on its own. Although chronic hepatitis is generally the more serious condition, patients having either condition can experience varying degrees of severity.

Acute Hepatitis. Acute hepatitis can begin suddenly or gradually, but it has a limited course and rarely lasts beyond one or two months. Usually there is only spotty liver cell damage and evidence of immune system activity, but on rare occasions, acute hepatitis can cause severe, even life-threatening, liver damage.

Chronic Hepatitis. The chronic forms of hepatitis persist for prolonged periods. Experts usually categorize chronic hepatitis by indications of severity as one of the following:

• Chronic persistent hepatitis. Chronic persistent hepatitis is usually mild and nonprogressive or slowly progressive, causing limited damage to the liver.
• Chronic active hepatitis. Chronic active hepatitis involves extensive liver damage and cell injury beyond the portal tract.

Click the icon to see an image of aggressive hepatitis.

Viral Hepatitis

Most cases of hepatitis are caused by viruses that infect liver cells and begin replicating. They are defined by the letters A through G:

• Hepatitis A, B, and C are the most common viral forms of hepatitis. Investigators are still looking for additional viruses that may be implicated in hepatitis unexplained by the current known viruses.
• Other hepatitis viruses include hepatitis E and hepatitis G. Like hepatitis A, hepatitis E is caused by contact with contaminated food or water. It is not serious except in pregnant women, when it can be life threatening. Hepatitis G is always chronic with probably the same modes of transmission as hepatitis C, but to date it does not appear to have serious effects.

Scientists don’t know exactly how these viruses actually cause hepatitis (inflammation in the liver). As the virus reproduces in the liver, a number of proteins and enzymes, including many that attach to the surface of the viral protein, are also produced. Some of these may be directly responsible for liver damage. Researchers are investigating elevated levels of specific immune factors, including T-cell sub-types in the liver of hepatitis C and B patients. T-cells are important infection fighters in the immune system, which is some cases can release powerful inflammatory agents (e.g., tumor necrosis factor and interferon gamma) that can cause considerable damage leading to hepatitis B or C.

Autoimmune Chronic Hepatitis

Autoimmune chronic hepatitis accounts for about 20% of all chronic hepatitis cases. Like other autoimmune disorders, this condition develops because a genetically defective immune system attacks the body's own cells and organs (in this case the liver) after being triggered by an environmental agent, probably a virus. Suspects include the measles virus, a hepatitis virus, or the Epstein-Barr virus, which causes mononucleosis. It is also possible that a reaction to a drug or other toxin that affects the liver also triggers an autoimmune response in susceptible individuals. In about 30% of cases, autoimmune hepatitis is associated with other disorders that involve autoimmune attacks on other parts of the body.

Hepatitis Caused by Alcohol and Drugs

Alcohol. About 10% to 35% of heavy drinkers develop alcoholic hepatitis. In the body, alcohol breaks down into various chemicals, some of which are very toxic in the liver. After years of drinking, liver damage can be very severe, leading to cirrhosis in about 10% to 20% of cases. Although heavy drinking itself is the major risk factor for alcoholic hepatitis, genetic factors may play a role in increasing a person's risk for alcoholic hepatitis. Women who abuse alcohol are at higher risk for alcoholic hepatitis and cirrhosis than are men who drink heavily. High-fat diets may also increase the risk in heavy drinkers.

Drugs. Because the liver plays such a major role in metabolizing drugs, hundreds of medications can cause reactions that are similar to those of acute viral hepatitis. Symptoms can appear anywhere from two weeks to six months after starting drug treatment. In most cases, they disappear when the drug is withdrawn; but, in rare circumstances, they may progress to serious liver disease. Among the drugs most prominently cited for liver interactions are halothane, isoniazid, methyldopa, phenytoin, valproic acid, and the sulfonamide drugs. Notably, very high doses of acetaminophen (Tylenol) have been known to cause severe liver damage and even death, particularly when used with alcohol.

Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) affects between 10% and 24% of the population covers a number of conditions, notably nonalcoholic steatohepatitis (NASH). NAFLD has features similar to alcohol- induced hepatitis, particularly a fatty liver, but it occurs in individuals who do not consume significant amounts of alcohol. Severe obesity and diabetes are the major risk factors and may pose a risk for more severe conditions. NAFLD may also occur in conjunction with small intestine surgery or other factors.

NAFLD is usually benign and very slowly progressive. In certain patients, however, it can lead to cirrhosis, liver failure, or liver cancer.

Weight reduction and management of any accompanying medical condition are the primary approaches to nonalcoholic fatty liver disease. To date, however, there is no effective treatment for NAFLD. Drugs, such as fibrates, used to lower triglycerides or those that increase insulin levels, such as metformin, may help protect against liver damage. Other drugs showing some promise include ursodiol and betaine. Vitamin E may help reduce liver injury.

Diagnosis

In people suspected of having or carrying viral hepatitis, physicians will measure certain substances in the blood.

• Bilirubin. Bilirubin is one of the most important factors indicative of hepatitis. It is a red-yellow pigment that is normally metabolized in the liver and then excreted in the urine. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise. (High levels of bilirubin cause the yellowish skin tone, known as jaundice.)
• Liver Enzymes (Aminotransferases). Enzymes known as aminotransferases, including aspartate (AST) and alanine (ALT), are released when the liver is damaged. Measurements of these enzymes, particularly ALT, are the least expensive and most noninvasive tests for determining severity of the underlying liver disease and monitoring treatment effectiveness. Enzyme levels vary, however, and are not always an accurate indicator of disease activity. (For example, they are not useful in detecting progression to cirrhosis.)

Blood is drawn from a vein (venipuncture), usually from the inside of the elbow or the back of the hand. A needle is inserted into the vein, and the blood is collected in an air-tight vial or a syringe. Preparation may vary depending on the specific test.

General Tests to Determine Causes of Viral Hepatitis

Radioimmunoassays. To identify the particular virus causing hepatitis, blood tests called radioimmunoassays are performed. Typically, radioimmunoassays identify particular antibodies, which are molecules in the immune system that attack specific antigens. (Antigens are any molecules that the body considers threatening or dangerous and which can be targeted by antibodies.) Some of these tests can pinpoint hepatitis antigens directly. These tests, however, have limitations:

• There may not be sufficient numbers of antibodies to be detectable by blood tests for up to weeks or months after hepatitis develops. Blood tests that are taken too early, then, may miss these signs of infection.
• Antibodies also persist after patients recover, so a positive antibody test can indicate a previous infection but does not necessarily determine if the infection is active.

The assays for individual hepatitis viruses may differ.

Polymerase Chain Reaction. In some cases of hepatitis C, a polymerase chain reaction (PCR), may be performed. PCR is able to make multiple copies of the virus’ genetic material to the point where it is detectable.

Liver Biopsies

A liver biopsy may be performed for acute viral hepatitis caught in a late stage or for severe cases of chronic hepatitis. No laboratory tests for enzyme or viral levels can truly determine the actual damage to the liver. A biopsy helps determine treatment possibilities, the extent of damage, and the long-term outlook.

The biopsy requires abdominal surgery, most often laparoscopy. This procedure requires general anesthesia and involves the following steps:

• The physician makes one or more small incisions (about 0.5 - 1.0 inch) in the abdomen.
• Carbon dioxide or nitrous oxide is delivered through the incision to inflate the abdomen so that the involved area is visible.
• The surgeon inserts a thin tube, called a laparoscope, which contains a tiny camera. Surgical instruments are also inserted through the incision to remove the liver tissue for biopsy.
• It takes about an hour.

Click the icon to see an explanation of liver biopsy.

A less invasive procedure, called a minilaparoscopy, uses a smaller scope and may prove to reduce the time of the procedure.

Screening for Liver Cancer

Patients with cirrhosis are usually screened for liver cancer using tests for a substance called alpha-fetoproetin (AFP) and ultrasound. It is not known, however, if such screening has much impact on survival, since it is not very sensitive and has a high rate of false positives (suggesting the presence of cancer when it is not actually present). Screening is not necessary in patients without cirrhosis.

Hepatitis A

About one third of the US population has antibodies to hepatitis A, indicating previous infection by the virus. The hepatitis A virus infects up to 200,000 Americans every year and causes symptoms in about 134,000 of them. Almost 30% are children under age 15.

Hepatitis A (formerly called infectious hepatitis) is excreted in feces and transmitted by contaminated food and water. Eating shellfish taken from sewage-contaminated water is a common means of contracting hepatitis A. Infected people can transmit it to others if they do not take strict sanitary precautions. Hepatitis A is infectious for two to four weeks before symptoms develop and for a few days afterward.

Among the people at risk for passing the infection along or being infected are the following:

• International travelers. Hepatitis A is the hepatitis strain people are most likely to encounter in the course of international travel. In fact, in spite of the availability of a vaccine, the increase in travel to underdeveloped countries has kept the incidence of hepatitis A steady in Western nations. The incidence may even be increasing.
• Day care employees and children. It is estimated that between 11% and 16% of hepatitis A cases occur among day care employees and children who attend day care. The risk for children attending day care is very low, however, if hygienic precautions are used, particularly when changing babies and handling diapers.
• Sexually active homosexual men.
• Intravenous drug users.
• Health care, food industry, and sewage workers.

A fly may act as a mechanical vector of diseases such as Hepatitis A, which means the fly carries the infective organism on its feet or mouth parts and contaminates food or water which a person then consumes. A biological vector actually develops an infective organism in its body and passes it along to its host, usually through its saliva. A fly can be a biological vector, as in the transmission of leishmaniasis by the sandfly.

Symptoms of Acute Hepatitis

Symptoms of acute viral hepatitis may begin suddenly or develop gradually. They may be so mild that patients mistake the disease for the flu. They include the following:

• Nearly all patients experience some fatigue and often have mild fever.
• Gastrointestinal problems are very common, including nausea, vomiting, a general feeling of discomfort in the abdomen, or a sharper pain that may occur in the upper right area if the abdomen. This pain tends to increase during jerking movements, such as climbing stairs or riding on a bumpy road.
• GI problems can lead to loss of appetite, weight loss, and dehydration.
• After about two weeks, dark urine and jaundice (a yellowish color in the skin and whites of the eyes) develops in some, but not all, patients. (Children tend not to develop jaundice.)
• About half of all hepatitis patients have light colored stools, muscle pain, drowsiness, irritability, and itching, usually mild.
• Diarrhea and joint aches occur in about a quarter of patients.
• The liver may be tender and enlarged and most people have mild anemia.
• In about 10% of patients, the spleen is enlarged.

Preventing Hepatitis A Infections When Traveling to High-Risk Countries

Travelers should take the following precautions:

• Be vaccinated against hepatitis A and possibly B if traveling for long periods of time to countries where epidemics occur.
• Use only carbonated bottled water for brushing teeth and drinking. (It should be noted that ice cubes can carry infection.) Boiling water is the best method for eliminating infectious agents. There is some debate about how long to boil, but bringing the water to a good boil for at least a minute generally renders it safe to drink.
• Heated food should be hot to the touch and eaten promptly.
• Don’t buy food from street vendors.
• Beware of sliced fruit that may have been washed in contaminated water. Travelers themselves should peel all fresh fruits and vegetables.
• Avoid dairy products.
• Avoid raw or undercooked meat and fish.

Vaccinations for Hepatitis A

Two vaccines (Havrix, Vaqta) are now available and both are very safe and effective for preventing hepatitis A (HAV). They can be given along with immune globulin and other vaccines. A 2001 study also strongly suggested they may be used interchangeably (i.e., if one is given as the first vaccination, the other may be safely used as the booster). A combination vaccine (Twinrix) that contains both Havrix and Engerix-B (a hepatitis B vaccine) is now approved for people with risk factors for both hepatitis A and B.

Click the icon to see a discussion of hepatitis A vaccine.

Candidates for HAV Vaccinations. Vaccinations for hepatitis A are recommended for the following individuals:

• People in specific populations where outbreaks occur. Indeed, a 2001 study showed that widespread vaccination of children in one county in California led to dramatic decreases in the number of outbreaks among all adults in the community at large. Day care centers are highly associated with such outbreaks, although risks in such centers vary widely depending on the community, so universal immunization in day care centers is not recommended.
• Sexually active homosexual men.
• Patients with any form of chronic hepatitis. (It should be noted that the HAV vaccination should be given to patients before they reach advanced stages of liver disease, when there is a lower rate of response.)
• Health care workers exposed to the virus.
• Travelers to developing countries. (Travelers should also receive immune globulin if they are visiting high-risk areas within four weeks of the vaccination.)
• Experts now recommend routine vaccinations for children and adolescents in high-risk states. These states are Arizona, Alaska, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, Washington, Missouri, Texas, Colorado, Arkansas, Montana, and Wyoming.
• People who have had intimate exposure to patients with hepatitis A may be protected with immune globulin or possibly with the vaccine itself.
• People with chronic liver disease, including those with hepatitis C, should also be vaccinated, particularly if they have not been exposed to hepatitis A, since the infection can cause liver failure in these patients.

Side Effects. Although there are few side effects, allergic responses from the vaccination can occur. Hair loss has been reported in a very few people after a second administration. There may be pain at the injection site. (Havrix causes more pain at the injection site than Vaqta.)

Symptoms of Hepatitis A

Symptoms are usually mild, especially in children and generally appear between two and six weeks after exposure to the virus. Adult patients more likely to have fever, jaundice, and itching that can last one to several months.

General Outlook for People Infected with Hepatitis A

This is the least serious of the common hepatitis viruses. It does not directly kill liver cells and there is no risk for a chronic form. Fulminant hepatitis is the only major concern, but even if it develops, it is almost always less dangerous than with other viral types. Only one in a thousand patients are at risk for death from this complication. If hepatitis A infection occurs in patients with hepatitis C, however, superinfections can occur, even without cirrhosis, leading to a life-threatening form of fulminant hepatitis. (Infection of patients with hepatitis B who do not have cirrhosis does not appear to be as dangerous.)

Specific Tests for Hepatitis A

Radioimmunoassays are generally used to identify IgM antibodies, first produced to fight hepatitis A. They appear early in the course of the disease and usually can be identified as soon as symptoms appear. IgM antibodies disappear during recovery, but those known as IgG antibodies persist, and their presence can be used to indicate a previous infection.

Treatments and Measures to Prevent Transmission of Hepatitis A

The primary goals for managing acute viral hepatitis are to provide adequate nutrition, to prevent additional damage to the liver, and to prevent transmission to others.

Precautions for Preventing Transmission of Hepatitis A. Because hepatitis A (and also hepatitis E) are usually passed through contaminated food, people with these viruses should not prepare food for others; unfortunately, these viruses are most contagious before symptoms appear.

• Using hot water when cleaning utensils or clothing is essential. Heating a contaminated article for a minute kills the virus. Simple household bleach is effective for disinfecting hard surfaces. Sterilizing is not necessary. Still, even with strong precautions, utensils used by the patient for eating and cooking should be kept separate from those used by others.
• Abstain from sexual activity or take strict precautions.
• Abstain from alcohol. Moderate drinking (one or two drinks per evening) after recovery is not harmful for most people.

Hepatitis B and D

Hepatitis B and D were formerly called serum hepatitis. Hepatitis B is mainly transmitted through blood transfusions, contaminated needles, and sexual contact. Blood screening has reduced the risk from transfusions. It can also be passed from cuts, scrapes, and other breaks in the skin. Hepatitis D virus can replicate only by attaching to hepatitis B and therefore cannot exist without the B virus being present.

Risk Factors for Hepatitis B. About 1.2 million Americans are chronically infected with HBV and between 20% and 30% acquired the infection when they were children. Men are at higher risk than women. Among ethnic groups living in the United States, Asians are at highest risk, due to the high rate of HBV in Asian countries. Fortunately, in the US the number of new infections has declined dramatically--by 67% between 1990 and 2002. In 2003, 7526 cases were reported compared to over 20,000 in 1990. The greatest decrease has occurred in children. Among young adults and people living in the Northeast, however, the incidence has increased since 1999. This may indicate that sexual activity is an important route for viral transmission and that the protective effect of the vaccine has not yet reached older, high-risk groups. Also, as with hepatitis A, the increase in travelers to underdeveloped nations may be responsible for the steady rate.

HBV is far more common overseas, and about 600,000 people die each year from conditions, such as liver cancer or cirrhosis, that are related to chronic hepatitis B. Nearly 70% of these infections were acquired during infancy or early childhood.

The following are some people at risk:

• Drug users who share needles.
• Children of infected mothers. Pregnant women with hepatitis B can transmit the virus to their babies. Even if they are not infected at birth, unvaccinated children of infected mothers run a 60% risk of developing it before age five. Children are more likely than adults to become chronic carriers, although between 6% and 12% of children spontaneously recover each year.
• People with multiple sex partners or other high-risk sexual behavior.
• Hospital workers and others exposed to blood products. Contaminated medical instruments, including fingerstick devices used for more than one individual, have been known to transmit the virus.
• Staff members of institutions for mentally impaired people.
• Prisoners.
• Immigrants from areas where the disease rate is high. (International travelers who spend long periods in such areas may also be at risk.)

People at highest risk for becoming chronic carriers of the virus are the following:

• Children infected before they are five, including newborns, most of whom become carriers.
• Infected people with damaged immune systems, such as AIDS patients.

Risk Factors for Hepatitis D. Hepatitis D occurs only in people with hepatitis B. It is not common in the US and the incidence of this hepatitis is declining rapidly overseas. Experts anticipate that it will be extremely rare in the near future. Those who recover from hepatitis B are immune to further infection from both hepatitis B and D viruses.

Symptoms of Hepatitis B

Symptoms appear long after the initial infection, usually four to 24 weeks. Many patients may not even experience them or they may be mild and flu-like. About 10% to 20% of patients have a fever and rash. Nausea is not common. Sometimes there is general aching in the joints. The pain can resemble arthritis, affecting specific joints and accompanied by redness and swelling.

Outlook for Patients with Hepatitis B

The virus does not kill cells directly, but seems to activate cells in the immune system, which cause inflammation and damage in the liver.

Acute Form. Acute hepatitis B is generally mild, but it can be lethal in about 1% of patients. Patients who are coinfected with hepatitis D or C are at risk for serious complications. In patients whose immune systems are severely compromised, such as in AIDS, there is risk of a rapidly progressive form of HBV called fibrosing cholestatic hepatitis. Even patients with mild symptoms can remain chronically infected with the virus.

Chronic Form. About 70% of patients infected with hepatitis B will eventually eliminate the virus without any treatment. The rest will progress to chronic hepatitis. Hepatitis B can also become chronic without an acute stage. The risk for developing a chronic form of hepatitis D is the same as for hepatitis B alone.

The great majority of people with hepatitis B have a good long-term outlook, especially children infected with the virus. Still, about 5% to 10% eventually develop cirrhosis, and worldwide, approximately two million people die each year from hepatitis B, globally making it the ninth leading cause of death. Co-infection with hepatitis D or C increases the risk for cirrhosis. HBV also poses a risk for liver cancer. In Asia about 15% of people who have chronic hepatitis B develop liver cancer, but this high rate is not seen in other parts of the world. Diet may play a role in a higher or lower risk for liver cancer.

Specific Tests for Identifying Hepatitis B

A diagnosis of hepatitis B relies on measuring the liver enzymes aspartate (AST) and alanine (ALT), are released when the liver is damaged, assays to identify the viral DNA, and a liver biopsy.

Physicians then must determine if the condition is chronic but inactive or whether it is more aggressive. This is suggested by identifying a specific antigen called HBsAg, which is a protein that is found in the blood in early stages of hepatitis B and suggests the presence viral replication. Most people develop antibodies to this antigen during convalescence. Their condition is referred to as HBeAG negative or anti-HBe and suggests that infection is on the wane. About 5% to 10% of people do not clear the infection but become carriers of the antigen (called HBsAG-positive). Evidence of its persistence for more than six months suggests that the condition is chronic.

Tests have been developed that can identify specific genetic types of hepatitis B virus (designated A to G). It is not clear how significant they are in treating patients with HBV.

It is important to remember, however, that viral levels are not an accurate measure of actual liver damage. Only a biopsy can determine this.

To diagnose hepatitis D using an antibody test, hepatitis B must already have been identified.

Preventing Hepatitis B and its Transmission

General precautions for preventing hepatitis B when traveling are the same at those for hepatitis A. In infected people, preventing transmission are similar to those for hepatitis C.

Vaccinations for Prevention of Hepatitis B. Several inactivated virus vaccines, including Recombivax HB, GenHevac B, Hepagene, and Engerix-B, can prevent hepatitis B (HBV) and are safe even for infants and children. A triple-antigen hepatitis B vaccine (Hepacare) is proving to be effective for people who do not respond to the standard vaccines. Vaccination programs are also proving to reduce the risk for liver cancer. A combination vaccine (Twinrix) that contains Engerix-B and Havrix, a hepatitis A vaccine, is now approved for people with risk factors for both hepatitis A and B.

Click the icon to see an image discussing hepatitis B vaccine.

Until recently, the vaccine contained a mercury-based preservative called thimerosal. In response to concerns, professional organizations recommended suspending vaccinations in infants with noninfected mothers. In September 1999, a thimerosal-free vaccine became available and medical centers are now urged to continue vaccinations. Unfortunately, even after the thimerosal-free vaccine became available, a number of hospitals still haven't restored vaccination of all infants. This is a safe vaccine and it is reducing the need for hospitalization in children. Parents should be sure their children are immunized.

Candidates for HBV Vaccinations. Experts now recommend that all infants and children not previously vaccinated be immunized by the time they reach seventh grade.

Typical schedules for hepatitis B vaccinations in childhood are as follows:

• All infants should receive the hepatitis B vaccine soon after birth and before hospital discharge. (The first dose may also be given by age 2 months if the mother has no evidence of infection.) The second dose should be given at one to four months (at least four to six weeks after first dose); and the third between six and 18 months (at least 16 weeks after first dose and eight weeks after second dose). (A fourth dose may also be given as part of a combination vaccine.) This is a safe vaccine, even in newborns, and parents should be sure their infants are immunized.
• Infants of mothers infected with HBV should be treated with immune globulin plus the hepatitis vaccine within 12 hours of birth. The second dose should be given at one to two months and the third at six months. Infants should be tested for antibody status at nine to 15 months to see if they are chronic virus carriers or need to be re-vaccinated.
• When it is not known if a mother is infected or not, the infant should receive the vaccine within 12 hours of birth. The mother's blood should then be tested right away. If she is infected, the infant should receive immune globulin as soon as possible (no later than a week).
• Children who are between 11 and 12 and who have not been immunized should receive two or three doses of the vaccine (depending on the brand) given over a few months.

Hepatitis B vaccine protection lasts at least eight to 10 years. Booster shots after that may be recommended depending on continuing risk, such as sexual exposure. In fact, a 2002 study suggested that there is risk for infection in teenagers who were vaccinated in infancy, although protection against chronic hepatitis B may be maintained.

The following adults are at very high risk and should be vaccinated:

• Healthcare and public safety workers who may be exposed to blood products. Such individuals have a risk for hepatitis B virus that ranges from 15% to 30%.
• People in the same household as HBV infected individuals. (Unvaccinated people who have had intimate exposure to people with HBV may be protected with immune globulin, which is sometimes administered with the vaccine.)
• Travelers to developing countries.
• Patients who require transfusions and have not been infected with HBV. (Those with blood clotting disorders should have the vaccination administered under the skin, not injected in the muscle.)
• Sexually active homosexual or heterosexual individuals with multiple partners or who engage in high-risk sexual behavior.
• People with any sexually transmitted diseases.

Other people at risk who would benefit from vaccinations are the following:

• Patients and workers in mental institutions and morticians.
• Patients on hemodialysis. (People on hemodialysis may need larger doses or boosters; they also may need to be re-vaccinated if blood tests indicate they are losing immunity.)
• People who use injected drugs.
• Pregnant women at risk for the virus should be vaccinated; there is no evidence that the vaccine is dangerous to the fetus.
• People receiving treatments or who have conditions that suppress the immune system may need the vaccination, although its benefits for this group are unclear except for those at high risk, such as people with HIV or spleen abnormalities.

The regimen in adults is typically three doses given over six months. One study reported that older adults would benefit from a fourth dose without incurring serious side effects. People with alcoholism may need high doses.

A small percentage of people do not develop immunity even after a vaccine has been given repeatedly. A more potent vaccine is proving to be effective in these people; it loses its effect after five years in about a third of those who receive it.

Soreness at the injection site is the most common side effect. There have been some reports of nerve inflammation after vaccinations for hepatitis B, and there has been some concern about three small studies associating the vaccine with an insignificant increase in multiple sclerosis. Studies in 2001, however, have found no evidence to support these concerns. Nonetheless, some groups oppose the vaccination in children who are not in high-risk groups. It should be strongly stressed that worldwide 65 million people with chronic hepatitis are expected to die from liver disease. And, vaccinations are saving lives. For example, in Taiwan, where infection rates are high and infants are at risk for hepatitis B from infected mothers, vaccination programs have significantly reduced the risk for liver cancer.

Treatments for Chronic Hepatitis B

Four drugs are currently approved in the United States for treatment of chronic hepatitis B: interferon-alfa-2b (Intron), adefovir (Hepsera), lamivudine (Epivir), and entecavir (Baraclude). These drugs block the replication of HBV in the body. A doctor will decide which drug to prescribe based on a patient’s age, disease severity, and other factors. Each drug has various advantages and disadvantages in terms of cost, efficacy, and likelihood of drug resistance. A combination of drugs may also be prescribed.

Interferon Alpha. For many years, interferon alfa-2b (Intron) was the standard drug for hepatitis B. The drug is usually taken by injection every day for 16 weeks. (It does not appear to be effective for hepatitis D.) Unfortunately, even in hepatitis B, the virus recurs in almost all cases, although this recurring mutation may be weaker than the original strain. Administering the drug for longer periods may produce sustained remission in more patients while still being safe. Interferon is also effective in eligible children, although long-term effects are unclear.

Lamivudine and Entecavir. These two drugs are classified as nucleoside analogs. Lamivudine (Epivir or 3TC) is an antiretroviral drug that is used to treat human immunodeficiency virus (HIV) as well as hepatitis B. Lamivudine has reduced viral count in over half of hepatitis B patients who have taken it as sole therapy for about a year. It is less expensive than interferon-alfa and has fewer side effects, but may not be as effective as interferon-alfa for long-term therapy. A major problem with lamivudine is the development of mutated viral strains that become resistant to the drug, particularly in areas where the virus is common. In 2005, the FDA approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir was more effective than lamivudine for treating HBV. However, questions have been raised about the drug’s possible cancer risks. Ongoing studies are assessing this risk.

Adefovir. Adefovir (Hepsera) belongs to a class of antiviral agents called nucleotide analogs. (Nucleotides are related to nucleosides but have a slightly different chemical structure.) Nucleotide analogs block an enzyme involved in the replication of viruses. Adefovir costs more than lamivudine, but may be effective against lamivudine-resistant strains of HBV.

Drug Warnings. In 2004, the FDA issued two drug warnings for patients with HBV. The HIV drug tenofovir (Viread) should not be used to treat patients who are co-infected with HBV as the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate HBV. Patients with lymphoma should be screened for HBV.

Investigative Therapies.

• Telbivudine is a nucleoside analog drug in Phase III trials for treatment of chronic hepatitis B. A 2003 study, presented at a meeting of the American Association for the Study of Liver Diseases, found that telbivudine resulted in significantly better suppression of HBV and normalization of certain liver enzymes compared to lamivudine monotherapy.
• Pegylated interferon alfa-2b (Peg-Intron) is currently approved for treatment of chronic hepatitis C. It is being investigated alone and in combination with lamivudine for treatment of HBV. One 2005 study found that a third of patients treated solely with pegylated interferon-alfa-2b became negative for the hepatitis B antigen (HBeAg). Combining the drug with lamivudine did not improve effectiveness. Another 2005 trial tested a staggered drug regimen where pegylated interferon alfa-2b was administered alone and then later combined with lamivudine. Researchers compared the results with lamivudine single therapy and found that the combination group had better virologic response and less drug-resistance. However, there were more side effects in the combination drug group and the duration of the treatment regimen was longer.
• Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors call T-cells). It appears to be safe for hepatitis B patients when used alone or in combination. It is approved in many countries, but not the United States.
• Vaccines as Treatments. Hepatitis B vaccines are being investigated in combination with drugs, such as lamivudine, for treatment of HBV.

Liver Transplantation. If the disease progresses to the point where it becomes life-threatening, liver transplantation may be an option. It is not foolproof, however. Viral recurrence is high in hepatitis B patients, although it can be significantly reduced using monthly infusions of hepatitis B immune globulin (HBIg), particularly when used with lamivudine. These injections may need to be administered life long. Eventually, about 40% of patients develop resistance to lamivudine. In such events, alternative agents, such as adefovir, are proving to be effective.

Hepatitis C

Each year about 30,000 new cases of hepatitis C occur. It is the most common blood-borne infection in the country. Until blood screening began in 1990, the primary mode of known transmission was through transfusions. It is also transmitted through contaminated needles and possibly through sexual transmission. The cause of transmission is unknown in 40% of cases.

Click the icon to see an image discussing hepatitis C.

About 4 million Americans have had an initial HCV infection and an estimated 2.7 million are currently chronically infected. Hepatitis C also affects 170 million people worldwide. Most people with chronic HCV, however, are unaware that they have it and experts believe that over the next 20 years, there will be a fourfold increase in diagnosed cases in the US. It is currently not possible to predict which patients will develop the chronic form of hepatitis C.

Ethnic Groups. In general, HCV occurs most commonly in non-Caucasian men between the ages of 30 and 49 years. Over 6% of African Americans are infected with HCV, which is about two to three times the risk for Caucasians.

Other High-Risk Groups. Some other specific groups are at higher than normal risk:

• Intravenous drug users. Intravenous drug use has been the greatest risk factor for HCV since the early 1980s. It accounts for 60% of new cases and 20% to 50% of chronic infections. Individuals who engage in this activity have a risk for infection that is between 50% and 80%. Intravenous drug use, particularly in people who also drink alcohol heavily, poses a higher risk for severe complications. Intranasal cocaine use also increases the danger. Needle exchange and educational programs have reduced the risk for HIV transmission and should have similar benefits for preventing HCV.
• People who had transfusions before 1992. Although transfused blood has been tested for both hepatitis B and C since the early nineties, individuals given transfusions before then, even decades before, may still be at risk. Such individuals are urged to be tested. Hepatitis C can exist for decades without symptoms, and nearly 300,000 people who had transfusions before 1992, including many who were children at the time, may have been infected. Of some reassurance was a 1999 study of people who had transfusions when they were children. After an average of 20 years, only 8% tested positive for hepatitis C and only three people showed signs of any liver abnormalities. These results suggest that the virus may be less aggressive in children than adults, but further observations are needed to learn if the infection remains mild beyond age 30.
• Among the homeless and people in prison the HCV prevalence may be as high as 40%.
• Infants of infected mothers. The risk for transmission to an infant during pregnancy is about 2% but increases to 4% to 7% during delivery. The highest rates of infection (20%) are in mothers who are also HIV positive. It is not clear if Cesarean section delivery in infected mothers offers protection. Avoiding fetal scalp monitoring and prolonged labor may reduce the risk. (Breastfeeding does not increase the risk.)
• Organ transplant recipients.
• Sexual transmission. Although HCV can be transmitted sexually, the risk is much less than with hepatitis B or other sexually transmitted diseases. For example, the risk for transmitting the HCV within a monogamous relationship is only about 2% to 3%. The risk is 4% to 6% for partners of people who have high-risk sex (e.g., those with multiple partners or sex workers). Of note, the risk for women becoming infected through sexual transmission may be three times that of men.
• Hospital workers. It should be strongly noted that health care providers in general are at very low risk. The risk of infection from a needle stick is now believed to be about 2%. (It is not yet clear if this poses any significant risk to patients.)
• Children who survive cancer.
• Possibly people who have had body piercing or tattoos with contaminated equipment.

Symptoms of Hepatitis C

Most patients with hepatitis C do not experience symptoms. If they appear at all, symptoms develop about a month or two after a person is infected. Symptoms of progressive chronic viral hepatitis may be very subtle. In some patients, itchy skin is the first symptom. Overall, fatigue is the most common symptom. Many patients do not experience any symptoms at all. In fact, chronic hepatitis C can be present for 10 to 30 years and in some cases cirrhosis or liver failure can develop before patients experience any clear symptom.

Some evidence suggests, however, that patients with chronic hepatitis C often experience an impaired quality of life, mostly from fatigue. Fatigue can impair daily function, vitality, and mood in ways that are similar to other chronic diseases. The severity of the fatigue is not necessarily related to the degree of liver injury. Some patients develop pain in small joints in the body (such as the hand) that may be nearly indistinguishable from symptoms of rheumatoid arthritis, fibromyalgia, or carpal tunnel syndrome. Other nonspecific symptoms include abdominal discomfort, loss of appetite, depression and difficulty in concentration.

Outlook for Patients with Hepatitis C

Acute Form. Acute hepatitis C is rarely recognized, since there are no symptoms in up to 80% of these patients. An estimated 15% and 30% of acute cases clear up without becoming chronic. Early treatment with interferons can significantly reduce the risk for progression to chronic hepatitis.

Chronic Form. About 60% to 85% of infected people develop chronic hepatitis. This poses a risk for cirrhosis, liver cancer, or both.

• Overall, between 10% and 15% of patients with chronic hepatitis C develop cirrhosis. The risk varies widely, however. It is highest for alcohol users, older men, diabetics, and patients co-infected with hepatitis B or HIV.
• Of these patients, 4% eventually develop liver cancer. (Liver cancer rarely develops without cirrhosis first being present.)

Even in patients with cirrhosis, survival rates in one study were nearly 80% at ten years. Still, over 5,000 deaths are currently attributed annually to hepatitis C and the rate continues to climb. Furthermore 140,000 people were hospitalized in 1998 for HCV, leading many experts to believe that hepatitis C is indirectly responsible for many more deaths than reported. [ See In-Depth Report # 75 Cirrhosis.]

Patients with chronic hepatitis C may be also at higher risk for non-liver disorders including the following:

• Cryoglobulinemia (a disorder in which protein clumps form in the blood). This can cause skin rash and ulcers, kidney problems, arthritis, and sensations (such as tingling or pain) in the hands and feet. People with such symptoms may have particular difficulties with interferon, which can have similar side effects.
• Porphyria cutanea tarda (a disorder which causes skin color and texture changes and sensitivity to light.)
• Certain autoimmune disorders, particularly hypothyroidism and rheumatoid arthritis.
• Some experts believe that hepatitis C may infect the central nervous system in certain patients, possibly accounting for the fatigue, depression, or both experienced by patients who have even relatively mild cases.
• Certain non-Hodgkin's lymphomas.

Specific Tests for Identifying Hepatitis C and Determining its Severity

Tests for Liver Enzymes. Blood tests showing elevated liver enzymes, particularly alanine aminotransferase (ALT), plus symptoms of hepatitis (e.g., jaundice, fatigue) are often first signs of acute hepatitis. In chronic hepatitis, however, liver enzymes may be normal or fluctuate. They also can be elevated even after the virus has cleared.

Tests to Identify the Virus. The standard first test for diagnosing hepatitis C is known as enzyme-linked immunosorbent assay (ELISA or EIA). The antibody for hepatitis C is used to identify virus but it may not show up for six weeks to a year after the onset of the disease, so its absence is not necessarily an indication of a healthy liver. A test called an immunoblot assay (called RIBA) may also be used to confirm the presence of the virus. An accurate home test (Hepatitis C Check) is now available. It supplies a lancet for obtaining a drop of blood, which is sent to the laboratory for EIA and possibly RIBA analysis. Results take about a week.

Tests to Identify Genetic Types and Viral Load. Additional tests called HCV RNA assays may be used to confirm the diagnosis. They use a polymerase chain reaction (PCR) to detect the RNA (the genetic material) of the virus. Such tests may be performed if there is some doubt about a diagnosis but the physician still firmly believes the virus is present.

HCV RNA assays also determine virus levels (called viral load). Such levels do not reflect the severity of the condition or speed of progression, as they do for other viruses, such as HIV. However, high viral loads suggest a poorer response to treatment with interferons.

Such techniques may also be used to determine the genotype of the virus, which can be helpful in determining a treatment approach. There are six main genetic types of HCV and more than 90 subtypes. They do not appear to affect the rate of progression of the disease itself, but they can differ significantly in their effects on response to treatment. Genotype 1 is the most difficult to treat and is the cause of up to three quarters of the cases in the US. The other common genetic types are types 2 (15%) and 3 (7%), which are more responsive to treatment.

Liver Biopsy. Only a biopsy can determine the extent of injury in the liver. Some experts are now recommending biopsies for all chronic hepatitis C patients, regardless of severity, because of the risk for liver damage even in patients without symptoms. If a biopsy does not show any scarring and liver enzymes are normal, patients can be assured that the outlook is very favorable.

Prevention of Hepatitis C

No vaccines are available, but immune globulin helps protect against developing hepatitis C after transfusions. Periodic doses of immune globulin in sexual partners of infected people also appear to confer protection. In infected people, preventing transmission is similar to those for hepatitis B.

Treatments for Chronic Hepatitis C

Interferons Alone and in Combination with Ribavirin. Pegylated (PEG) interferon combined with ribavirin (a nucleoside analogue), is now the gold standard for treating for chronic hepatitis C. Interferons are natural proteins that activate certain immune functions in the body and have antiviral properties. Ribavirin is poor at inducing initial responses alone but it can double sustained response rates when combined with an interferon. A number of natural and synthetic interferons are available:

• Natural interferons were the first used for HCV and include interferon alpha-2a (Intron) and Interferon alpha-2b (Roferon). Rebetron is the combination of interferon alpha-2b and ribavirin.
• Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa 2a (Pegasys). Rebetol is a combination of alfa-2b and ribavarin.
• Alfacon-1 (Infergen), also called consensus interferon, is a genetically modified interferon. A combination of alfacon-1 with ribavirin is proving to help some patients who were nonresponsive to ribavirin with interferon.

The combination of pegylated interferon alfa-2b with ribavirin (Rebetol) has achieved the best success rates to date of all interferons and their combinations. It has achieved responses of up to 51% with genotype 1 and nearly 80% with genotype 2 and 3. According to a 2002 comparison study, the Pegasys combination may even produce better results.

PegINF combinations are proving to slow progression of scarring, and have even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Side Effects of the Combination Treatment. The side effects of the combination include those of both interferon and ribavirin. Interferon side effects may occur more often in the combination treatment. Ribavirin used in the combination treatment adds the following specific side effects:

• Hemolytic anemia. This complication is reversible and usually stabilizes after a month or two of treatment. However, some patients may become so anemic that they have to withdraw. Since anemia can worsen heart disease, patients with a history of significant heart problems should not be treated with ribavirin. Other nucleoside analogues, including levovirin and viramidine, are under investigation that may have a lower risk for anemia than ribavirin.
• Skin disorders.
• Coughing and shortness of breath.
• Emotional and neurologic symptoms, such as severe sleep disturbances, depression, and anxiety.
• Gastrointestinal symptoms (heartburn, and weight loss).
• Temporary thyroid dysfunction (either over or under activity). The presence of hypothyroidism (low activity) is, in fact, associated with long-term remission of hepatitis.

Overall, the significant side effects of the combination treatment include flu-like symptoms, blood disorders (e.g., hemolytic anemia and low white blood cell counts), and psychologic and neurologic symptoms (particularly depression). Side effects from the combination result in treatment discontinuation in 10% to 14% of patients. The most frequent reason cited in the US is depression. Of note, combination of both drugs poses a very high risk for birth defects in children whose mothers used the drugs while pregnant.

Determining Treatment Success. Physicians gauge treatment success and approaches based on the patient’s response to the treatments:

• Early Response. These are patients who respond to the drug right away. This means that their viral count drops very rapidly within the first few weeks of treatment and is still undetectable at 12 weeks. (One difficulty in deciding when to stop treatment even in responders is the inability to predict at 12 weeks which of these patients will relapse and which ones will have sustained response.)
• Sustained Response. Patients who are free of the virus longer than six months are considered to be sustained responders. The overall sustained response rates with the current standard combination of pegylated interferon and ribavirin is over 50%, with certain factors predicting higher or lower response rates.
• Relapse. In relapse, the virus comes back again and requires retreatment. This occurs most likely because of the development of mutant strains that may be resistant to the drugs used or because the original dose was too low.
• Nonresponse. Patients are considered to be nonresponders if the virus is still detectable 12 weeks after interferon alone or 24 weeks of combination therapy. Retreating these patients has achieved only a 15% response. Those who achieved a-called breakthrough at some point in the initial treatment may be more likely to response. (During a breakthrough there is a temporary reduction in liver enzymes or disappearance of the virus.) Alfacon-1 (Infergen) may be beneficial for some nonresponding patients. Patients should also ask their physician about any clinical trials that might be appropriate.

People at Risk for Poor Response to Combination Treatment. The following patients have a higher chance for a lower response to combination treatment with interferon and ribavirin:

• People who are at high risk in the first place for aggressive hepatitis C.
• Having a high viral count.
• Having a specific genetic type of the virus affects the response to treatment. Those with genotypes 2 or 3 who are given the current standard treatment (pegylated interferon plus ribavirin) can now achieve a sustained response of over 80%. Unfortunately, the response is lower in those with genotype 1. In one 2003 study, the sustained response rates in patients with genotype 1 were 39% in Caucasian patients and 26% in African Americans (which were the highest response rates reported at that time for this latter group). Young people with type 1 have a much higher response rate than older patients.
• Being African American also poses a risk for poor response. African Americans are less responsive to treatment than Caucasians and Asians. The reasons for this are unclear.

Failure can be due to other, modifiable factors, which should be assessed before stopping treatment, particularly in patients who had interferon alone. They include the following:

• Interferon dose is too low.
• Patient did not comply fully with the treatment.
• Patient was consuming alcohol.
• Treatment time was too short. Some evidence suggests that response can significantly improve for many patients with genotype 1 if treatment time is extended to 48 weeks.

Even if viral levels persist, there is some evidence the interferon treatment may still have benefits. For example, patients with normal liver enzyme levels appear to have almost no risk for liver damage, even if viral levels persist after treatment. Also of note, there is some evidence that interferon still reduces liver scarring and may even reduce the risk for liver cancer in some patients, even if the treatment does not eliminate the virus. More research is needed, however, to confirm these early findings.

Investigative Drugs for Hepatitis C. The current drugs used for HCV still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation then is ongoing to find better solutions. Some showing promise include the following:

• Nucleoside analogs. Several new nucleoside analogs are in clinical development. Viramidine is a drug related to ribavarin. It is being studied in Phase III trials alone and in combination with pegylated interferon-alfa. Valopicitabine (NM283) is being tested in Phase II trials as alone and in combination with pegylated interferons.
• Albuferon. This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is currently being tested in Phase II trials for patients who have not been treated with or have not responded to standard interferon-alfa.
• IMPDH Inhibitors. Mycophenylate mofetil and VX-497 are agents that inhibit an enzyme known by its brief name, IMPDH, which may block replication of the hepatitis C virus. If effective, they would most likely be used in combination with interferon and ribavirin.
• Amantadine (Symmetrel) is an anti-viral agent being investigated in various combinations. For example, triple therapy with amantadine, pegylated interferon, and ribavirin is showing particular promise. In some cases, the side effects of amantadine can be severe, and include vertigo, insomnia, nervousness, and depression. They are particularly disabling among older patients who receive inappropriately high doses.
• Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors call T-cells). It is being used for hepatitis B and is under investigation for hepatitis C in combinations with natural interferons and pegylated interferon.
• Protease Inhibitors. Novel protease inhibitors (similar to those used for HIV) are under investigation for hepatitis C patients who fail other treatments. These agents are based on molecular therapies that target proteins involved in viral reproduction.

Other agents under investigation include vaccines, genetic therapies known as antisense oligonucleotides or monoclonal antibodies, and drugs that will help prevent or reduce progression of liver scarring or progression to liver cancer. Even if successful, none of these agents would be available for some years.

Of interest are studies using phlebotomy (which is simply drawing blood) to reduce iron levels. In one study, maintenance therapy with this procedure reduced liver inflammation and possible slowed progression of cirrhosis.

Liver Transplantation for Hepatitis C. If the disease progresses to the point where it becomes life-threatening, liver transplantation may be an option. In fact, nearly 40% of liver transplant patients are infected with hepatitis C. In any case, liver transplantation is not a cure for hepatitis C. The virus nearly always returns. One study of patients with hepatitis C reported five-year risks for viral recurrence of 80% and for cirrhosis of 10%. A 2004 study found that the hepatitis C virus recurs with more severity with liver donations from living donors than livers taken from cadavers. Retreatment with antiviral agents is being investigated.

Autoimmune Hepatitis

Autoimmune chronic hepatitis typically occurs in women between the ages of 20 and 40 who have other autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia. Some research indicates that the postmenopausal period may be another peak in incidence of AIH among women. About 30% of patients are men, however, and in both genders there is often no relationship to another autoimmune disease. In general, no major risk factors have been discovered for this condition.

Symptoms of Autoimmune Hepatitis

About 85% of people with chronic active autoimmune hepatitis do not have severe symptoms at all. When symptoms occur, they range from minimal to severe, and include fatigue, jaundice, fever, and weight loss. The liver and spleen are often enlarged. In addition, patients with this condition may experience skin disorders, including palmar erythema (red palms) and spider angioma (a blood-red spot, the size of a pinhead, from which tiny blood vessels radiate like spider legs). Itching is not common, however. The abdomen or legs may be swollen due to the accumulation of fluid.

Tests for Autoimmune Chronic Hepatitis

If a patient experiences symptoms of chronic active hepatitis for six months or more and a virus cannot be identified, then autoimmune hepatitis is usually suspected. There are other autoimmune liver diseases, however, that can confuse a diagnosis. To help confirm this condition, test results may show high levels of immune factors called serum globulins or certain antibodies to liver proteins. In some cases, a successful trial of steroid drugs may be the only way to diagnose autoimmune hepatitis.

Outlook for Autoimmune Hepatitis

Autoimmune hepatitis is usually benign and causes little trouble, although there is a very small risk that it can evolve into the active form. One study reported a 10-year survival rate of 95%, which was similar to the same age group in the general population. However, it the condition evolves into the chronic active form, five-year survival rate may be only 50% if the disease is not treated. (The survival rate can be higher in people with milder symptoms and less liver damage.)

Although very uncommon, severe autoimmune hepatitis can be life-threatening and require intensive therapy, including possibly liver transplantation. The risk for liver failure and bleeding in the stomach and esophagus is highest in the early years after disease onset. This risk diminishes over time but is replaced by an increase in liver cancer rates and bleeding in the stomach and intestines. The risk for liver cancer is not as high, however, as with chronic viral hepatitis.

Treatments for Autoimmune Hepatitis

Autoimmune Hepatitis. Patients with autoimmune hepatitis who have mild symptoms and slight inflammation of the liver do not require any treatment except to alleviate symptoms. They should be monitored, however, for any signs of disease progression. Severe autoimmune hepatitis is a life-threatening condition and requires intensive therapy.

Patients with autoimmune hepatitis who have mild symptoms and slight inflammation of the liver do not require any treatment except to alleviate symptoms. They should be monitored, however, for any signs of disease progression. Because of effective treatment options and in spite of a high rate of relapse, long-term survival rates in patients with autoimmune hepatitis are excellent. Drugs that block factors in the immune system and help reduce inflammation and symptoms of autoimmune hepatitis are most often used.

Corticosteroids. Corticosteroids, prednisone and prednisolone, are the standard agents used for autoimmune hepatitis. They produce remission of symptoms in about 80% of patients with autoimmune hepatitis. For most patients, steroids also reduce symptoms within three months, improve liver function within six months, and restore liver health within two years. Between 10% and 20% of patients continue to deteriorate despite steroid treatment, although higher doses may help some of these people. (Steroids are generally not useful for chronic hepatitis B or C, and, in fact, suppressing the immune system in these patients can encourage the viruses to replicate more quickly.)

Treatment usually needs to continue for about two years before the disease is in complete remission. Usually, steroids are stopped when disease symptoms have disappeared, when blood tests show that aminotransferase levels are less than two times normal, and liver biopsies reveal no active cell damage. Steroid medications must be withdrawn very slowly. Patients who are very elderly or who have advanced (decompensated) cirrhosis are not good candidates for this treatment.

Unfortunately, remission rarely lasts more than three years. About half of patients relapse within six months, and only about 20% of patients achieve remission (are disease-free) for more than five years. Re-administering prednisone therapy after relapse achieves another remission in 80% of patients.

Side effects can be very distressing and sometimes serious; they include weight gain, skin problems, moon-shaped face, high blood pressure, diabetes, cataracts, mental disturbances, infections, and osteoporosis.

Investigative Agents. In severe cases, drugs that block the immune system may be used:

• Azathioprine (Imuran) is often prescribed along with steroids to help reduce severe side effects caused by using steroids alone. Azathioprine also suppresses the immune system and helps prevent relapse, but the drug will not induce remission by itself. In one promising study, patients who continued to use azathioprine after prednisolone was withdrawn had no relapses for at least a year. Unfortunately, long-term use of azathioprine may increase the risk for cancer, although studies indicate that this risk is very low.
• Cyclosporine A (Neoral) is another immunosuppressant and may prove to be a safe and effective alternative to corticosteroids.

Some important research is targeting agents that inhibit RNA--the genetic molecules that serve as messengers for regulating cellular processes. In a 2003 animal study, an agent that targeted RNA specifically affecting cell receptors involved in liver injury protected against autoimmune hepatitis in mice.

Liver Transplantation and Autoimmune Hepatitis. If all therapies fail and the disease becomes life threatening, liver transplantation may be performed. Liver transplantation is problematic, however. In one study, half of patients who received a transplant required re-transplantation within a year. Autoimmune hepatitis recurred in 25% of patients studied. (According to one 2000 study, transplantation in these patients may improve accompanying autoimmune disorders in half of patients who experienced it.) Children who develop autoimmune hepatitis after liver transplantation may respond to corticosteroid and azathioprine therapy.

Symptom Management

The primary goals for managing viral hepatitis are to provide adequate nutrition, to prevent additional damage to the liver, and to prevent transmission to others. For mild cases of acute viral hepatitis, no drug therapy or other treatment is either available or necessary. Hospitalization is needed only for people at high risk for complications, such as pregnant women, elderly people, patients with other serious conditions, or those who have severe nausea and vomiting and need to have fluids administered intravenously.

The following tips may be useful:

• In some cases, the physician may prescribe drugs that have minimal impact on the liver to alleviate the symptoms of hepatitis, such as nausea or severe itching.
• All patients should abstain from alcohol and sexual contact during the acute phase.
• Although most patients with hepatitis experience fatigue and require more rest than usual, they can be as physically active as they want without affecting recovery. In fact, patients should be encouraged to be as active as they can.
• Depression is common, particularly in people used to an active life. Patients should be reassured that in the great a majority of hepatitis cases, recovery is complete.
• The liver processes many types of medications, so as soon as hepatitis is diagnosed, the patient should stop taking all drugs, including over-the-counter medications, except those a physician specifically prescribes or recommends. Of special note, ibuprofen (Advil, Motrin) apparently increases liver enzymes in hepatitis C patients and therefore should be avoided. Ibuprofen is one the common painkillers known as nonsteroidal anti-inflammatory drugs (NSAIDs). Other NSAIDs include aspirin and naproxen. The usual alternative to an NSAID is acetaminophen (Tylenol). It should be noted that acetaminophen also can be toxic in the liver, particularly when drinking alcohol.

After the onset of acute hepatitis, periodic visits to the physician for repeat blood tests are necessary, the frequency of which depends on how well the patient feels. If symptoms still occur after three months and laboratory tests still indicate active presence of the virus, the patient should be evaluated every month. If symptoms persist beyond six months, a liver biopsy may be required to determine any liver damage.

Dietary Factors to Protect the Liver. In general, no vitamins or special diets have been proven to be particularly beneficial. The following may be helpful however:

• Eating many small snacks during the day, with larger ones in the morning, may help prevent weight loss while reducing the severity of nausea. Patients might be able to tolerate high-caloric drinks to supplement their regular diet.
• One small Japanese study suggested that vitamin E might help protect against liver damage in patients with hepatitis C.
• Thiamine binds to iron and helps reduce iron load in the liver. One small study suggested it may be helpful for patients with chronic hepatitis B. Pork is high in the vitamin, but more healthful sources include dried fortified cereals, oatmeal, corn, nuts, cauliflower, sunflower seeds and vitamin pills.
• Some research suggests that supplements of omega-3 fatty acids (found in fish oil and evening primrose oil) may help protect the diseased liver.
• In one Norwegian study, higher coffee intake was associated with a lower risk for cirrhosis.

Outlook

In most cases of acute viral hepatitis, recovery is complete and the liver returns to normal within two to eight weeks. In a small number of cases of hepatitis B or C, the condition can be prolonged and recovery may not occur for a year. About 5% to 10% of these patients will experience a flare-up of symptoms in a milder form before full recovery. A few of these patients may go on to develop chronic hepatitis. People who have been infected with a hepatitis virus continue to produce antibodies to that specific virus. This means that they cannot be reinfected with the same hepatitis virus again. Unfortunately, they are not protected from other types.

Serious consequences of acute viral hepatitis are rare, but can be life threatening if they occur. Pregnant women with acute hepatitis B, C, or E are at higher risk for complications of acute hepatitis.

In very rare cases, within two months of onset of acute hepatitis, a very serious condition known as fulminant hepatitis can develop. In this event, the liver fails with catastrophic consequences. The following events may develop:

• A large swollen abdomen (known as ascites) and a peculiar hand-flapping tremor (called asterixis).
• These symptoms may be followed by stomach and intestinal bleeding and mental confusion, stupor, or coma caused by brain injury (encephalopathy).

No medications, including corticosteroids, have any effect against the condition itself. Liver transplantation is currently the only life-saving treatment for fulminant acute hepatitis and has survival rates of up to 60%. Without liver transplantation, the chance of survival is only 20%.

Other serious and rare consequences of acute viral hepatitis are aplastic anemia (which can be fatal), pancreatitis, hypoglycemia, and polyarteritis, a serious inflammation of blood vessels.

General Prognosis for Chronic Hepatitis

Chronic Persistent Hepatitis. Chronic persistent hepatitis is usually mild and nonprogressive or slowly progressive, causing limited damage to the liver. Cell injury in such cases is usually limited to the region of portal tracts, which contains vessels that carry blood to the liver from the digestive tract. In some cases, however, more extensive liver damage can occur over long periods of time and progress to chronic active hepatitis.

Chronic Active Hepatitis. If damage to the liver is extensive and cell injury occurs beyond the portal tract, chronic active hepatitis can develop. Significant liver damage has usually occurred by this time. Nearly every bodily process is affected by a damaged liver, including digestive, hormonal, and circulatory systems. Symptoms can significantly impair daily life.

• Cirrhosis. If liver cells are destroyed between the portal tract and the central veins in the liver, progressive cell damage can build a layer of scar tissue over the liver, resulting in the condition known as cirrhosis. In such cases, the entire liver is threatened with malfunction and failure. If cirrhosis develops, the average survival time is about 10 years. The risk for cirrhosis is much higher in patients with hepatitis C than in those with hepatitis B. [For more information, seeWell-Connected report #75, Cirrhosis.]
• Liver Cancer. The risk for liver cancer in patients with cirrhosis is about 14% but varies widely depending on the cause of hepatitis. (Liver cancer is rare in patients who do not develop cirrhosis.)

Click the icon to see an image of cirrhosis of the liver.

Liver Transplantation

Liver transplantation may be indicated in the following patients:

• Those who have developed life-threatening cirrhosis and who have a life expectancy of more than 12 years.
• Patients with liver cancer that has not spread beyond the liver may also be candidates.

Current five-year survival rates after liver transplantation are between 55% and 80%, depending on different factors. Patients also report improved quality of life and mental functioning after liver transplantation. Unfortunately, in about half of all chronic hepatitis patients, the disease recurs after transplantation.

Patients should consider medical centers that have performed more than 50 transplants per year and produced better-than-average results. Unfortunately, in 2003 with 18,000 Americans waiting for a liver donor, only 4,244 liver transplantations were performed. And, given the large number of people with hepatitis C, this situation will almost certainly worsen over the following years.

Resources

• www.cdc.gov/hepatitis -- Centers for Disease Control and Prevention
• www.hepfi.org -- Hepatitis Foundation International
• www.liverfoundation.org -- American Liver Foundation
• www.aasld.org -- American Association for the Study of Liver Diseases
• www.gastro.org -- American Gastrointestinal Association
• www.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
• www.immunize.org -- Immunization Action Coalition
• www.hivandhepatitis.com -- Hepatitis and HIV
• www.unos.org -- United Network for Organ Sharing
• www.medhelp.org/perl6/Hepatitis -- Patient-to-patient support forum

References

Centers for Disease Control and Prevention. Incidence of Acute Hepatitis B: United States, 1990-2002. MMWR. 2004; 52:1252-1254.

Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142(4):240-250.

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