Pathophysiology of Hepatitis B

Hepatitis B is caused by the Hepatitis B virus (HBV). This is a small DNA virus that belongs to a group of hepadnaviruses. The virus is made up of a nucleocapsid and an outer envelope composed mainly of three hepatitis B surface antigens (HBsAgs) that play a central role in the diagnosis of HBV infection (Baumert, et. al 2007). It is thought that this virus causes inflammation of the liver by inducing apoptosis (programmed cell death) which then causes HBV-induced liver injury. (Baumert, et. al 2007).

CDC, 2009 This summary adapted from the Centers for Disease Control is very helpful in understanding the progression of disease. HBsAgs: If there are high levels of these HBsAgs, a person may have an acute or chronic infection. If a person has HBsAg in their blood it means that person is infectious. Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs generally indicates recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B. Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame. IgM antibody to hepatitis B core antigen (IgM anti-HBc):Positivity indicates recent infection with HBV (6 months). Its presence indicates acute infection. Hepatitis B e antigen (HBeAg): A product of the nucleocapsid gene of HBV that is found in serum during acute and chronic hepatitis B. Its presence indicates that the virus is replicating and the infected person has high levels of HBV. Hepatitis B e antibody (HBeAb or anti-HBe): Produced by the immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication. Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is a predictor of long-term

clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV.

If a person is unable to clear the hepatitis B virus from their system after a period of time, the person is said to be chronically infected. Chronic infection, means continuous damage to the liver, which can result in cirrhosis, liver failure, hepatocellular cancer, and even death. Patients infected during childhood are at greatest risk for developing chronic hepatitis B infection. (CDC, 2008)

Hepatitis B
Fact sheet N204 Revised August 2008

Key facts
Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease. The virus is transmitted through contact with the blood or other body fluids of an infected person - not through casual contact. About 2 billion people worldwide have been infected with the virus and about 350 million live with chronic infection. An estimated 600 000 persons die each year due to the acute or chronic consequences of hepatitis B. About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis (scarring of the liver) caused by the chronic infection. The hepatitis B virus is 50 to 100 times more infectious than HIV. Hepatitis B virus is an important occupational hazard for health workers. Hepatitis B is preventable with a safe and effective vaccine. Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It is a major global health problem and the most serious type of viral hepatitis. It can cause chronic liver disease and puts people at high risk of death from cirrhosis of the liver and liver cancer. Worldwide, an estimated two billion people have been infected with the hepatitis B virus (HBV), and more than 350 million have chronic (long-term) liver infections. A vaccine against hepatitis B has been available since 1982. Hepatitis B vaccine is 95% effective in preventing HBV infection and its chronic consequences, and is the first vaccine against a major human cancer. Symptoms Hepatitis B virus can cause an acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. People can take several months to a year to recover from the symptoms. HBV can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer. Who is most at risk for chronic disease? The likelihood that an HBV infection will become chronic depends upon the age at which a person becomes infected, with young children who become infected with HBV being the most likely to develop chronic infections. About 90% of infants infected during the first year of life develop chronic infections; 30% to 50% of children infected between one to four years of age develop chronic infections. About 25% of adults who become chronically infected during childhood die from HBV-related liver cancer or cirrhosis. About 90% of healthy adults who are infected with HBV will recover and be completely rid of the virus within six months. Where is hepatitis B most common? Hepatitis B is endemic in China and other parts of Asia. Most people in the region become infected with HBV during childhood. In these regions, 8% to 10% of the adult population are chronically infected. Liver cancer caused by HBV is among the first three causes of death from cancer in men, and a major cause of cancer in women. High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and Indian sub-continent, an estimated 2% to 5% of the general population is chronically infected. Less than 1% of the population in western Europe and North American is chronically infected.

Transmission Hepatitis B virus is transmitted between people by contact with the blood or other body fluids (i.e. semen and vaginal fluid) of an infected person. Modes of transmission are the same for the human immunodeficiency virus (HIV), but HBV is 50 to 100 times more infectious Unlike HIV, HBV can survive outside the body for at least 7 days. During that time, the virus can still cause infection if it enters the body of a person who is not infected. Common modes of transmission in developing countries are: perinatal (from mother to baby at birth) early childhood infections (inapparent infection through close interpersonal contact with infected household contacts) unsafe injections practices blood transfusions sexual contact In many developed countries (e.g. those in western Europe and North America), patterns of transmission are different than those mentioned above. Today, the majority of infections in these countries are transmitted during young adulthood by sexual activity and injecting drug use. HBV is a major infectious occupational hazard of health workers. HBV is not spread by contaminated food or water, and cannot be spread casually in the workplace. The virus incubation period is 90 days on average, but can vary from about 30 to 180 days. HBV may be detected 30 to 60 days after infection and persist for widely variable periods of time. Treatment There is no specific treatment for acute hepatitis B. Care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids that are lost from vomiting and diarrhoea. Chronic hepatitis B can be treated with drugs, including interferon and anti-viral agents, which can help some patients. Treatment can cost thousands of dollars per year and is not available to most patients in developing countries. Liver cancer is almost always fatal, and often develops in people at an age when they are most productive and have family responsibilities. In developing countries, most people with liver cancer die within months of diagnosis. In higher income countries, surgery and chemotherapy can prolong life for up to a few years in some patients. Patients with cirrhosis are sometimes given liver transplants, with varying success. Prevention All infants should receive the hepatitis B vaccine: this is the mainstay of hepatitis B prevention. The vaccine can be given as either three or four separate doses, as part of existing routine immunization schedules. In areas where mother-to-infant spread of HBV is common, the first dose of vaccine should be given as soon as possible after birth (i.e. within 24 hours). The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. After age 40, protection following the primary vaccination series drops below 90%. At 60 years old, protective antibody levels are achieved in only 65 to 75% of those vaccinated. Protection lasts at least 20 years and should be lifelong. All children and adolescents younger than 18 years old and not previously vaccinated should receive the vaccine. People in high risk groups should also be vaccinated, including: persons with high-risk sexual behaviour; partners and household contacts of HBV infected persons; injecting drug users; persons who frequently require blood or blood products; recipients of solid organ transplantation; those at occupational risk of HBV infection, including health care workers; and international travellers to countries with high rates of HBV.

The vaccine has an outstanding record of safety and effectiveness. Since 1982, over one billion doses of hepatitis B vaccine have been used worldwide. In many countries where 8% to 15% of children used to become chronically infected with HBV, vaccination has reduced the rate of chronic infection to less than 1% among immunized children. As of December 2006, 164 countries vaccinate infants against hepatitis B during national immunization programmes - a major increase compared with 31 countries in 1992, the year that the World Health Assembly passed a resolution to recommend global vaccination against hepatitis B.

Pathophysiology
The virus does not directly kill hepatocytes. [9] The host's immune response to viral antigens is thought to be the cause of the liver injury in HBV infection. [10] The cellular immune response, rather than the humoral immune response, seems to be primarily involved in disease pathogenesis. Induction of antigen-specific T-lymphocyte response is thought to occur when host T lymphocytes are presented with viral epitopes by antigen-presenting cells in lymphoid organs. These antigen-specific T cells mature and expand and then migrate to the liver. In acute HBV infection, most HBV DNA is cleared from hepatocytes through non-cytocidal effects of inflammatory byproducts of CD8+ T lymphocytes, stimulated by CD4+ T lymphocytes, notably interferon-gamma and tumour necrosis factor-alfa. These cause down-regulation of viral replication, and trigger direct lysis of infected hepatocytes by HBV-specific CD8+ cytotoxic T cells. [11] In contrast, people with chronic HBV infection display weak, infrequent, and narrowly focused HBV-specific T-cell responses, and the majority of mononuclear cells in livers of chronic HBV-infected people are non-antigenspecific. [12]

Life cycle of HBVFrom Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med. 2004; 350:1118-1129; used with permission

Due to the presence of HBV in extrahepatic sites, as well as the presence of covalently closed circular DNA (cccDNA) within hepatocytes, eradication of the virus is an unrealistic goal based on the currently available drugs. Covalently closed circular DNA serves as a template for transcription of pregenomic messenger RNA, a vital initial step in HBV replication. [13] [14][15] [16] The continued presence of cccDNA within hepatocytes is considered as a marker of viral persistence. Unfortunately, current therapies have not been effective in eradicating cccDNA and are only able to decrease levels. [17] [18] [19] [20] [21] [22] [23] Persistence of even low levels of cccDNA in the hepatocyte nucleus has been shown to correlate with viral rebound after discontinuation of therapy. In addition, the integration of HBV DNA to the hepatocyte nucleus during replication process could explain increased risk for hepatocellular carcinoma.

The natural history of HBV infection has been classified into 4 phases, [8] which are influenced by age of infection, host genetic factors, presence of other viruses, HBV mutations, and level of immunosuppression.

In neonates with immature immune systems, 95% of those infected become asymptomatic chronic HBV carriers, compared with 30% of children infected over the age of 6 years. [24] Most (70%) of primary infections with HBV in adults are asymptomatic and self-limiting, with clearance of virus from the blood and liver, and lasting immunity to re-infection.

However, about 30% of adults with acute HBV may have symptomatic icteric hepatitis. [24] Patients who develop chronic HBV have a 10% to 30% risk of developing cirrhosis, particularly older patients with high levels of HBV DNA, or patients with hepatitis C, hepatitis D, or HIV co-infection. [25]

Hepatitis B is the inflammation of the liver caused by hepatitis B virus. This is considered to be more serious than hepatitis Adue to the possibility of severe complications such as massive damage and hepatocarcinoma of the liver. Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease.About 2 billion people worldwide have been infected with the virus and about 350 million live with chronic infection. An estimated 600 000 persons die each year due to the acute or chronic consequences of hepatitis B. About 25% of adults who become chronically infected during childhood later die from liver cancer or cirrhosis (scarring of the liver) caused by the chronic infection. The hepatitis B virus is 50 to 100 times more infectious than HIV. Hepatitis B virus is an important occupational hazard for health workers.

Hepatitis B is preventable with a safe and effective vaccine. Etiologic Agent:

The disease is caused by Hepatitis B virus 1. This virus has very limited tissue tropism 2. HBV infects the liver and possibly the pancreas. 3. HbsAg appears in the blood 30 to 60 days after exposure and persists for variable periods of time.
Incubation Period:

The incubation period is 50 to 189 days or two to five months with a mean equal to 90 days.
Period of Communicability:

The patient is capable of transmitting the virus during the latter part of the incubation period and during the acute phase. The virus may persist in the blood for many years.
Mode of Transmission: 1. Hepatitis B can be directly transmitted by person to person contact via infected body fluids. 2. 3. It can be transmitted though contaminated needles and syringes. Transmission can occur through infected blood or body fluids introduced at birth.

4. It can also be transmitted through sexual contact. HBV transmission does not occur. 1. 2. 3. by fecal-oral route by food-borne or water-borne transmission by arthropod (mosquito) transmission.

Pathogenesis: 1. 2. 3. 4. 5. 6. 7. HBV can cause acute or chronic hepatitis. Production of virus and high level of HbsAg is continuous and the particles are found in the blood until the infections is resolved. The virus must be delivered into the liver to establish infection. The virus replicates and large amount of HbsAg is released into the blood. Initiation of virus replication may be as short as three days from acquisition, but symptoms may not be observed for 45 days or much longer. Replication of the virus is not cytopathic and proceeds to relatively long periods without causing liver damage. During the acute phase of infection, the liver parenchyma shows degenerative changes consisting of cellular swelling and necrosis, especially in hepatocytes. Prodormal period

Clinical Manifestations:
1.

Fever, malaise, and anorexia. Nausea, vomiting, abdominal discomfort, fever and chills. Jaundice, dark urine, and pale stools. Recovery is indicated by a decline of fever and improved appetite.

2. Fulminant hepatitis may be fatal and manifested by severe symptoms like ascitis and bleeding. Diagnostics Procedures: 1. 2. 3. 4. 5. 6. 7. 1. 2. 3. 4. 5. 6. 7. 8. 9. Compliment fixation test Radio-immunoassay-hemaglutinin test Liver function test Bile examination in blood and urine Blood count Serum transaminase SGOT, SGPT, ALT HbsAg Blood donors must be screened to exclude carriers. Caution must be observed in giving care to patients with known HBV. Hands and other skin areas must be washed immediately and thoroughly after contact with body fluids. Avoid injury with sharp objects or instruments. Use disposable needles and syringes only once and discard properly. Avoid sharing of toothbrush, razor, and other instruments that may be contaminated with blood. Observe safe sex. Have adequate rest, sleep, and exercise and eat nutritious food. Hepatitis B vaccine is recommended for pre-exposure.

Prevention:

10. Hepatitis Immune Globulin (HBIg) should be administered within 72 hours to those exposed directly to hepatitis B virus either by ingestion, by prick or by inoculation.

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