Hepatitis B (HBV)

What is hepatitis?

The term 'hepatitis' simply means inflammation of the liver. Hepatitis may be caused by a virus or a toxin such as alcohol. Other viruses that can cause injury to liver cells include the hepatitis A and hepatitis C viruses। These viruses are not related to each other or to hepatitis B virus and differ in their structure, the ways they are spread among individuals, the severity of symptoms they can cause, the way they are treated, and the outcome of the inphektion.

What is the scope of the problem?

Hepatitis B is an infection of the liver caused by the hepatitis B virus (HBV). It is estimated that 350 million individuals worldwide are infected with the virus, which causes 620,000 deaths worldwide each year. According to the Centers for Disease Control (CDC), approximately 46,000 new cases of hepatitis B occurred in the United States in 2006.

When a person first gets hepatitis B, they are said to have an 'acute' infection. Most people are able to eliminate the virus and are cured of the infection. Some are not able to clear the virus and have 'chronic' infection with hepatitis B that is usually life-long (see below). In the United States an estimated 800,000 to 1.4 million people are chronically infected with hepatitis B.

Hepatitis B is found throughout the world. Some countries have much higher rates of infection than the United States; for example, in Southeast Asia and Sub-Saharan Africa, as many as 15% to 20% of adults are chronically infected with hepatitis B.

What kind of a virus is hepatitis B?

The hepatitis B virus is a DNA virus, meaning that its genetic material is made up of deoxyribonucleic acids. It belongs to a family of viruses known as Hepadnaviridae. The virus is primarily found in the liver but is also present in the blood and certain body fluids.

Hepatitis B virus consists of a core particle (central portion) and a surrounding envelope (outer coat). The core is made up of DNA and the core antigen (HBcAg). The envelope contains the surface antigen (HBsAg). These antigens are present in the blood and are markers that are used in the diagnosis and evaluation of patients with suspected viral hepatitis

How does hepatitis B virus cause liver injury?

The hepatitis B virus reproduces in liver cells, but the virus itself is not the direct cause of damage to the liver. Rather, the presence of the virus triggers an immune response from the body as the body tries to eliminate the virus and recover from the infection। This immune response causes inflammation and may seriously injure liver calls. Therefore, there is a balance between the protective and destructive effects of the immune response to the hepatitis B virus.

How is the hepatitis B virus spread (transmitted)?

Hepatitis B is spread mainly by exposure to infected blood or body secretions. In infected individuals, the virus can be found in the blood, semen, vaginal discharge, breast milk, and saliva. Hepatitis B is not spread through food, water, or by casual contact.

sexual contact is the most common means of transmission, followed by using contaminated needles for injecting illicit drugs, tattooing, body piercing, or acupuncture. Additionally, hepatitis B can be transmitted through sharing toothbrushes and razors contaminated with infected fluids or blood.

Hepatitis B also may be spread from infected mothers to their babies at birth (so-called 'vertical' transmission). This is the most prevalent means of transmission in regions of the world where hepatitis B rates are high. The rate of transmission of hepatitis B from mother to newborn is very high, and almost all infected infants will develop chronic hepatitis B. Fortunately, transmission can be significantly reduced through immunoprophylaxis (see below).

Rarely, hepatitis B can be transmitted through transfused blood products, donated livers and other organs. However, blood and organ donors are routinely screened for hepatitis which typically prevents this type of transmission.

What are the symptoms of acute hepatitis B?

Acute hepatitis B is the period of illness that occurs during the first one to four months after acquiring the virus. Only 30% to 50% of adults develop significant symptoms during acute infection. Early symptoms may be non-specific, including fever, a flu-like illness, and joint pains. Symptoms of acute hepatitis may include:

• fatigue,
  
  
• loss of appetite,
  
  
• nausea,
  
  
• jaundice (yellowing of the skin and eyes), and
  
  
• pain in the upper right abdomen (due to the inflamed liver).

Rarely, acute hepatitis damages the liver so badly it can no longer function. This life-threatening condition is called "fulminant hepatitis." Patients with fulminant hepatitis are at risk of developing bleeding problems and coma resulting from the failure of the liver. Patients with fulminant hepatitis should be evaluated for liver transplantation. Small studies suggest that the drug lamivudine (Epivir), may be of limited assistance in these cases (see below).

What determines the outcome of acute hepatitis B?

The body's immune response is the major determinant of the outcome in acute hepatitis B. Individuals who develop a strong immune response to the infection are more likely to clear the virus and recover. However, these patients also are more likely to develop more severe liver injury and symptoms due to the strong immune response that is trying to eliminate the virus. On the other hand, a weaker immune response results in less liver injury and fewer symptoms but a higher risk of developing chronic hepatitis B. People who recover and eliminate the virus will develop life-long immunity, that is, protection from subsequent infection from hepatitis B.

Most infants and children who acquire acute hepatitis B viral infection have no symptoms। In these individuals, the immune system fails to mount a vigorous response to the virus. Consequently, the risk of an infected infant developing chronic hepatitis B is greater than 95%. In contrast, only 5% of adults who have acute hepatitis B develop chronic hepatitis B.

What are the symptoms of chronic hepatitis B?

The liver is a vital organ that has many functions. These include a role in the immune system, production of clotting factors, producing bile for digestion, and breaking down toxic substances, etc. Patients with chronic hepatitis B develop symptoms in proportion to the degree of abnormalities in these functions. The signs and symptoms of chronic hepatitis B vary widely depending on the severity of the liver damage. They range from few and relatively mild signs and symptoms to signs and symptoms of severe liver disease such as cirrhosis or liver failure.

Most individuals with chronic hepatitis B remain symptom free for many years or decades. During this time, the patient's blood tests usually are normal or only mildly abnormal. Some patients may deteriorate and develop inflammation or symptoms, putting them at risk for developing cirrhosis.

Cirrhosis of the liver due to hepatitis B

Inflammation from chronic hepatitis B can progress to cirrhosis (severe scarring) of the liver. Significant amounts of scarring and cirrhosis lead to liver dysfunction.

Symptoms may include:

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

Decreased absorption of vitamins A and D can cause impaired vision at night and thinning of bones (osteoporosis). Patients with liver cirrhosis also are at risk of infections because the liver plays an important role in the immune system.

Hepatitis B virus and primary liver cancer (hepatocellular carcinoma)

Patients with chronic hepatitis B are at risk of developing liver cancer The way in which the cancer develops is not fully understood. Symptoms of liver cancer are nonspecific. Patients may have no symptoms, or they may experience abdominal pain and swelling, an enlarged liver, weight loss, and fever. The most useful diagnostic screening tests for liver cancer are a blood test for a protein produced by the cancer called alpha-fetoprotein and an ultrasound imaging study of the liver. These two tests are used to screen patients with chronic hepatitis B, especially if they have cirrhosis or a family history of liver cancer.

How is hepatitis B diagnosed?

Infection with hepatitis B is suspected when the medical history and the physical examination reveal risk factors for the infection or symptoms and signs that are suggestive of hepatitis B. Abnormalities in the liver tests (blood tests) also can raise suspicion; however, abnormal liver tests can result from many conditions that affect the liver. The diagnosis of hepatitis B can be made only with specific hepatitis B virus blood tests. These tests are known as hepatitis 'markers' or 'serology.'

Markers found in the blood can confirm hepatitis B infection and differentiate acute from chronic infection. These markers are substances produced by the hepatitis B virus (antigens) and antibodies produced by the immune system to fight the virus. Hepatitis B virus has three antigens for which there are commonly-used tests - the surface antigen (HBsAg), the core antigen (HBcAg) and the e antigen (HBeAg).

HBsAg and anti-HBs

The presence of hepatitis B surface antigen (HBsAg) in the blood indicates that the patient is currently infected with the virus. HBsAg appears an average of four weeks after initial exposure to the virus. Individuals who recover from acute hepatitis B infections clear the blood of HBsAg within approximately four months after the onset of symptoms. These individuals develop antibodies to HBsAg (anti-HBs). Anti-HBs provides complete immunity to subsequent hepatitis B viral infection. Similarly, individuals who are successfully vaccinated against hepatitis B produce anti-HBs in the blood.

Patients who fail to clear the virus during an acute episode develop chronic hepatitis B. The diagnosis of chronic hepatitis B is made when the HBsAg is present in the blood for at least six months. In chronic hepatitis B, HBsAg can be detected for many years, and anti-HBs does not appear.

Anti-HBc

In acute hepatitis, a specific class of early antibodies (IgM) appears that is directed against the hepatitis B core antigen (anti-HBc IgM). Later, another class of antibody, anti-HBc IgG, develops and persists for life, regardless of whether the individual recovers or develops chronic infection. Only anti-HBc IgM can be used to diagnose an acute hepatitis B infection.

HBeAg, anti-HBe, and pre-core mutations

Hepatitis B e antigen (HBeAg) is present when the hepatitis B virus is actively multiplying, whereas the production of the antibody, anti-HBe, (also called HBeAg seroconversion) signifies a more inactive state of the virus and a lower risk of transmission.

In some individuals infected with hepatitis B virus, the genetic material for the virus has undergone a structural change, called a pre-core mutation. This mutation results in an inability of the hepatitis B virus to produce HBeAg, even though the virus is actively reproducing. This means that even though no HBeAg is detected in the blood of people with the mutation, the hepatitis B virus is still active in these persons and they can infect others.

Hepatitis B virus DNA

The best marker of hepatitis B virus reproduction is the level of hepatitis B virus DNA in the blood. Detection of hepatitis B virus DNA in a blood sample signals that the virus is actively multiplying. In acute hepatitis, HBV DNA is present soon after infection, but is eliminated over time in patients' who clear the infection. In chronic hepatitis, levels of HBV DNA often continue to be elevated for many years and then decrease as the immune system controls the virus. HBV DNA levels are sometimes referred to as the 'viral load'.

How are the hepatitis B blood tests interpreted?

The following table gives the usual interpretation for sets of results from hepatitis B blood (serological) tests.

Most Likely Status*	Tests	Results
Susceptible, not infected, not immune	HBsAg anti-HBc anti-HBs	negative negative negative
Immune due to natural infection	HBsAg anti-HBc anti-HBs	negative positive positive
Immune do to hepatitis B vaccination	HBsAg anti-HBc anti-HBS	negative negative positive
Acutely infected	HBsAg anti-HBc IgM anti-HBc anti-HBs	positive positive positive negative
Chronically infected	HBsAg anti-HBc IgM anti-HBc anti-HBs	positive positive negative negative

*Interpretation of the hepatitis B virus blood tests should always be made by an experienced clinician with knowledge of the patient's medical history, physical examination, and results of the standard liver blood tests.

What is the role of a liver biopsy in chronic hepatitis B?

During a liver biopsy, a small sample of liver tissue is collected and examined under the microscope. This test is valuable because this sample reflects the health of the liver. It can show the amount of liver injury (inflammation or cirrhosis). Liver biopsy is not routinely needed to diagnose hepatitis B, but it is used for monitoring the progression of liver damage in people with chronic hepatitis and helping to choose or evaluate treatment options.

What is the natural course of chronic hepatitis B?

The course of chronic hepatitis B is variable and depends on several factors. These factors are the patient's age at which the infection began, the extent of viral multiplication, and the immune system's ability to control the infection.

The infection can progress from an:

• immune tolerant phase (in which the immune system ignores the virus)
  
  
• immune clearance phase (in which the immune system attempts to eliminate the virus)
  
  
• quiescent phase (in which the virus is less active)

What medications are used to treat hepatitis B?

Acute infection

Acute infection with hepatitis B usually does not require treatment. In rare cases, however, the infection may cause life-threatening liver failure. Patients with liver failure due to acute hepatitis B should be evaluated for liver transplantation. Small studies suggest that the drug lamivudine (Epivir) may be effective in this setting.

Chronic infection

If a person is chronically infected with hepatitis B and has few signs or symptoms of complications, medications usually are not used. These patients are watched carefully and given periodic blood tests. One test measures the 'viral load,' that is, the amount of viral DNA in the blood. Doctors will recommend treatment if there are signs that the virus is beginning to cause damage or if the viral load is high. Another reason to prescribe medication is if the patient has a positive test for the Hepatitis B e-antigen (HBeAg) in the blood. HBeAg is associated with an increased risk of progression of liver disease and its complications.

In chronic hepatitis B, the goal of treatment is to reduce the risk of complications including cirrhosis and liver failure. However, it takes decades for complications to occur, which makes it difficult to study the effect of medications. As a substitute for waiting years to find out what happens, scientists have used tests like the viral load or liver function tests to evaluate if medicines are working. This is logical because it is known that people who have large amounts of the virus in their blood are at highest risk to get cirrhosis. Up to one-third of people with very high viral loads (more than one million viral copies per milliliter of blood) will develop cirrhosis over a decade, compared to only 4.5% of those with low viral loads (fewer than 300 viral copies per milliliter).

Medications can reduce the number of viruses in the body and may be able to eliminate the virus from the bloodstream. Logically, this should lead to them having a low rate of progression to cirrhosis (<1%>

The medications in current use for chronic hepatitis B include the interferons and nucleoside/nucleotide analogues. New agents are being developed although they are still under investigation and considered experimental. There are no accepted guidelines that tell how every patient should be treated. As a result, treatment is individualized.

Is there a preferred treatment for chronic hepatitis B?

There are no clear guidelines to recommend which agent to use first in treating chronic hepatitis B। Interferon is given for a defined period of time and may have a more prolonged response after the medication is discontinued than NAs. However, interferon is given as an injection, and side effects often are troublesome. NAs are given as a pill and have few side effects, but the duration of treatment is unclear, and prolonged therapy may be required. NAs may be preferred in patients with unstable disease and cirrhosis because they are thought to be less likely to cause serious flares of hepatitis with more severe liver disease.

What are the effects of alcohol on hepatitis B virus?

Agents that damage the liver are particularly harmful in patients who already have hepatitis B. For this reason, it is recommended that persons with hepatitis B avoid drinking alcohol.

What can be done to prevent hepatitis B?

Hepatitis B is a preventable disease. Vaccination and post-exposure prophylaxis have significantly reduced rates of infection. Risk can also be reduced by avoiding unprotected sex, contaminated needles, and other sources of infection.

How effective is vaccination for hepatitis B?

The hepatitis B vaccine contains a protein (antigen) that stimulates the body to make protective antibodies. Examples of hepatitis B vaccines available in the United States include hepatitis b vaccine-injection (Engerix-B, Recombivax-HB). Three doses (given at 0, 1, and 6 months) are necessary to assure protection. There are also combination vaccines on the market that provide protection against hepatitis B and other diseases.

Examples include:

• Hepatitis-b-hepatitis-a vaccine - injection (Twinrix), which provides protection against both hepatitis A and hepatitis B.
  
  
• Haemophilus B/hepatitis B vaccine - injection (Comvax) provides protection against hepatitis B and Haemophilus influenzae type b (a cause of meningitis).
  
  
• Pediarix provides protection against hepatitis B, tetanus, pertussis (whooping cough), and polio.

Hepatitis B vaccines are effective and safe. Up to 95% of vaccinated individuals form effective antibodies when they get the vaccine and are protected from hepatitis B. In healthcare workers, high-risk public safety workers, dialysis patients, and sexual partners of infected persons, a blood test for antibodies is recommended after vaccination to ensure that the person produced antibodies. For the few who do not form antibodies, revaccination may improve response, especially in infants. However, a small proportion of individuals will never respond to hepatitis B vaccination. Side effects from the vaccine are usually mild and include soreness at the site of injection. The risk of serious allergic reactions (anaphylaxis) is less than one per million doses. Vaccination has reduced the number of new cases of hepatitis B by more than 75% in the United States.

Adults in high risk situations also are advised to receive hepatitis B vaccine. This includes:

• health care workers
  
  
• dentists
  
  
• intimate and household contacts of patients with chronic hepatitis B infection
  
  
• public safety workers who may be exposed to blood
  
  
• men who have sex with men
  
  
• individuals with multiple sexual partners
  
  
• dialysis patients
  
  
• injection drug users
  
  
• persons with chronic liver disease
  
  
• residents and staff in institutions that care for persons with developmental disabilities
  
  
• persons infected with HIV
  
  
• persons who require repeated transfusions or blood products.

Centers that serve high-risk individuals are encouraged to provide the vaccine to their clients. Such centers include dialysis units, drug treatment facilities, sexually transmitted diseasesprevalence of hepatitis B in their population. Travelers who visit these countries for a prolonged period of time (usually six months) and those who may be exposed to blood or semen should consider vaccination. clinics and correctional facilities. Some countries have a high

What is post-exposure immunoprophylaxis for hepatitis B virus?

Unvaccinated individuals who are exposed to a known case of hepatitis B or to a person at high risk for hepatitis B should be evaluated by a physician. Examples of such exposures include needle stick injuries in health care workers or sexual intercourse with an infected person. If the exposure is significant, the physician will recommend vaccination and also may recommend an injection of hepatitis B immune globulin (HBIG). HBIG is prepared from the plasma of blood donors and contains antibodies to hepatitis B. Vaccination and HBIG can substantially reduce the risk of disease in persons exposed to hepatitis B if given within one week of a needle stick or two weeks of sexual intercourse.

Vaccination provides long-term immunity in people who respond to the vaccine. There is no need for HBIG if an exposure occurs to a vaccinated person who is known to respond to the vaccine; however, a blood test might be drawn to verify that the person did respond to the vaccine.

How is transmission of hepatitis B virus from mother to newborn infant prevented?

Infected mothers can pass hepatitis B to their newborn infants। All pregnant women should have blood tested to determine if they are infected. Infants born to infected mothers should receive HBIG and hepatitis B vaccine at birth. This is 85% to 95% effective in eliminating the risk of hepatitis B in the infant.

What is new in the treatment of hepatitis B virus?

New agents are under development to treat hepatitis B. Many of these are nucleoside/nucleotide analogues that investigators hope will be more effective than older agents. Experts also are working on treatment guidelines and the use of multi-drug therapy. Vaccination remains the key to preventing hepatitis B and holds the most promise for reducing disease burden.

Hepatitis B At A Glance

• The hepatitis B virus is a DNA virus belonging to the Hepadnaviridae family of viruses. Hepatitis B virus is not related to the hepatitis A virus or the hepatitis C virus.
  
  
• Some people with hepatitis B never clear the virus and are chronically infected. Approximately 350 million individuals in the world and one million in the United States are chronically infected with hepatitis B. Many of these people appear healthy but can spread the virus to others.
  
  
• Hepatitis B infection is transmitted through sexual contact, contact with contaminated blood (for example, through shared needles used for illicit, intravenous drugs), and from mother to child. Hepatitis B is not spread through food, water, or casual contact.
  
  
• Serologic (blood) markers specifically for hepatitis B virus are used to diagnose hepatitis B viral infection. The blood tests can also identify people who are at highest risk for complications.
  
  
• Injury to the liver by hepatitis B virus is caused by the body's immune response as the body attempts to eliminate the virus.
  
  
• In the United States, 95% of adults who get hepatitis B are able to clear the virus and cure themselves of infection. The remaining 5% of adults with acute hepatitis B go on to develop chronic hepatitis B. Those who acquire the infection in childhood are much more likely to have chronic infection. Chronic hepatitis B may lead to cirrhosis or liver failure. Approximately 15% to 25% of persons with chronic infection will die prematurely as a result of the infection.
  
  
• Progression of chronic hepatitis B viral infection occurs insidiously (subtly and gradually), usually over several decades. The course is determined primarily by the age at which the hepatitis B viral infection is acquired and the interaction between the virus and the body's immune system.
  
  
• Treatment with interferons or nucleoside/nucleotide analogues suppresses viral reproduction in about 40% to 90% of patients with chronic hepatitis B. The medications are also effective in reducing inflammation and improving blood tests. This can delay or reduce complications such as cirrhosis. However, most people do not have a permanent response and relapse is common. The medications do not cure the infection.
  
  
• Liver transplantation should be considered for patients with impending liver failure due to acute (initial) infection or advanced cirrhosis.
  
  
• Hepatitis B is preventable through vaccination. All children should receive the vaccine. In addition, adults at high risk for hepatitis B should be vaccinated. Unvaccinated people who are exposed to hepatitis B should be evaluated by a physician to determine if they need specific immune globulin (HBIG).