Hepatitis B virus (HBV) is a unique, coated DNA virus belonging to the Hepadnaviridae family of viruses, (partly double-stranded; icosahedral capsid with an envelope; virion-also called Dane particles as the main characteristics). It is not related to the hepatitis A virus or the hepatitis C virus. HBV primarily infect liver cells. The name of the family comes from hepa- meaning liver; dna- referring to deoxyribonucleic acid, the virus' genetic material; and viridae- meaning virus. Other viruses in this family can also cause hepatitis in certain animals e.g. mammalian and avian hepadnaviruses are known to exist. The Hepadnaviridae are very similar to one another. Accordingly, several animal models have been developed to study the hepatitis B virus and to evaluate new drugs to treat hepatitis B virus.The genes of the hepatitis B virus contain genetic codes to make a number of protein products, including hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), hepatitis B e antigen (HBeAg), and DNA polymerase.
These four proteins are important because their tests are used to diagnose hepatitis B virus. The hepatitis B virus consists simply of a core particle (central portion) and a surrounding envelope (outer coat). The core is made up of the HBcAg, whereas the envelope is made up of the HBsAg. The core particle contains the hepatitis B virus DNA, HBeAg, and DNA polymerase. The HBeAg serves as a marker of the virus' ability to spread the infection. The DNA polymerase is an important part of the virus' uniqueness of its reproduction. Of relevant importance here is that, the human immunodeficiency virus (HIV) also reproduces using this same process. As a result, many drugs that have been developed to inhibit this process of reproduction to treat HIV infection may also be effective in treating chronic hepatitis B viral infection.
HOW HBV CAUSES INJURY TO THE LIVER:
The hepatitis B virus itself does not directly cause damage to the liver. Rather, the body's immune (protective) response to the virus (a foreign material) paradoxically causes the damage. Thus, in a hepatitis B viral infection, the body's immune response to the virus is responsible for both the elimination of the hepatitis B virus from the body and recovery from the infection. Yet, at the same time, the injury to the liver cells is caused by that same immune response to the hepatitis B virus in the liver cells.
Therefore, there is a balance between the protective and destructive effects of the immune system's response to the hepatitis B virus. How this balance is achieved determines the outcome in an individual infected with hepatitis B virus. Therefore, an acute hepatitis B viral infection can lead to recovery (the usual outcome), to acute liver failure (rarely), and sometimes to chronic infection. The chronic infection can result in a healthy carrier state (in which the affected person harbors the virus but remains healthy) or progress to cirrhosis (severe scarring, or fibrosis, of the liver) and its complications, including liver cancer.
Hepatitis B virus is spread or acquired through exposure to infected blood or the body's secretions. The highest concentrations of hepatitis B virus are found in the blood, semen, vaginal discharge, breast milk, and saliva. There are only low concentrations of hepatitis B virus in the urine and none in the feces. Therefore, hepatitis B is not spread through food or water or by casual contact. Furthermore, hepatitis B virus is no longer or rarely transmitted by blood transfusions in most countries because all blood for transfusion is screened (tested) to exclude contamination with hepatitis B virus. In much of the developing world, (sub-Saharan Africa, most of Asia, and the Pacific), most people become infected with HBV during childhood, and 8% to 10% of people in the general population become chronically infected. In these regions liver cancer caused by HBV figures among the first three causes death by cancer in men.
High rates of chronic HBV infection are also found in the Amazon and the southern parts of Eastern and Central Europe. In the Middle East and Indian sub-continent, about 5% are chronically infected.
TRANSMISSION –IN SUMMARY:
Hepatitis B virus is transmitted by contact with blood or body fluids of an infected person in the same way as human immunodeficiency virus (HIV), the virus that causes AIDS. However, HBV is 50 to 100 times more infectious than HIV.
The main ways of getting infected with HBV are
Worldwide, most infections occur from infected mother to child, from child to child contact in household settings, and from reuse of non sterilized needles and syringes.
In many industrialized countries (e.g. Western Europe and North America, the pattern of transmission is different. In these countries, mother-to-infant and child-to-child transmission accounted for up to one third of chronic infections before childhood hepatitis B vaccination programmes were implemented.
Today however, the majority of infections in these countries are acquired during young adulthood by sexual activity, and injecting drug use. In addition, hepatitis B virus is the major infectious occupational hazard of health workers, and most health care workers have received hepatitis B vaccine. Hepatitis B virus is not spread by contaminated food or water, and cannot be spread casually in the workplace. High rates of chronic HBV infection are also found in the Amazon and the southern parts of Eastern and Central Europe. In the Middle East and Indian sub-continent, about 5% are chronically infected. In U.S., adolescents and young adults account for the majority of reported cases of hepatitis B infection. Sexual contact (intercourse) being the most common means of transmission. The virus also can be spread by hepatitis B virus-contaminated blood or body fluid in several different ways. These ways include intravenous drug use, skin-popping (injecting under the skin), tattooing, body piercing, and acupuncture using non-sterile instruments. Additionally, hepatitis B virus can be transmitted through the sharing of toothbrushes and razors. Finally, blood-sucking insects such as mosquitoes and bed bugs that are common in the tropics have reportedly spread hepatitis B virus.
Young children who become infected with HBV are the most likely to develop chronic infection. About 90% of infants infected during the first year of life and 30% to 50% of children infected between 1 to 4 years of age develop chronic infection. The risk of death from HBV-related liver cancer or cirrhosis is approximately 25% for persons who become chronically infected during childhood.
SYMPTOMS OF ACUTE HEPATITIS B:
Acute hepatitis B is the initial, rapid onset, short duration of illness that results from infection with hepatitis B virus. About 70% of adults with acute hepatitis B have few or no symptoms. The remaining 30% develop significant symptoms two to four months following exposure to the hepatitis B virus. This period of time between the exposure and the first symptoms is what is usually referred to as the incubation period. The most common symptoms of acute hepatitis B includes; fatigue, loss of appetite, nausea, and abdominal pain over the region of the liver. Jaundice (yellow skin) often accompanies these other symptoms. When this happens, the infection is commonly termed as acute icteric (jaundiced) hepatitis. Occasionally, individuals with acute hepatitis B develop the so-called prodromal symptoms. These are symptoms that start just the onset of the commonly showing symptoms. Sometimes, the prodromal symptoms resemble an allergic reaction, such as skin rash, pain and swelling of the joints, and low-grade fever. Other times, the prodromal symptoms resemble the symptoms of the flu. Rarely (in less than 0.5% of adults), individuals with acute hepatitis B can develop acute liver failure (fulminant hepatitis). These patients are extremely ill with the symptoms of acute hepatitis already described and the additional problems of confusion or coma (encephalopathy) and bruising or bleeding (coagulopathy). In fact, up to 80% of people with fulminant hepatitis can die within days to weeks.
DETERMINANT OF THE OUTCOME OF THE ACUTE HBV:
The individual's ability to eliminate (clear) the hepatitis B virus from the body and recover from acute hepatitis B depends on the strength of the body's immune response to the infection. The stronger the immune response, the greater is the likelihood of eliminating the virus and recovering. By the same token, however, the stronger the immune response, the more likely is the occurrence of acute liver injury and symptoms. On the other hand, a weaker immune response results in less liver injury and fewer symptoms. At the same time, however, the weaker immune response results in less viral elimination (clearance) and a greater likelihood of developing chronic hepatitis B viral infection. Indeed, most infants and children who acquire acute hepatitis B viral infection are asymptomatic, but their rate of developing chronic hepatitis B virus is greater than 95%. Most adults (about 95%), particularly those with acute, symptomatic, icteric hepatitis B (with jaundice), will recover completely from the infection within two to three months. They also will develop immunity, that is, protection from a subsequent hepatitis B viral infection. Moreover, these individuals rarely develop chronic liver disease. In contrast, those adults with few or no symptoms during their episode of acute hepatitis B, as compared to other adults with symptoms, are less likely to clear the infection and are more likely to develop chronic hepatitis B.
CHRONIC HEPATITIS B INFECTION:
The diagnosis of chronic hepatitis B can be made, by definition, only after six months from the onset of acute hepatitis B. It is often difficult to suspect the diagnosis of chronic hepatitis B based just on the patient's symptoms. The reason for this difficulty is that those individuals, who develop chronic hepatitis B, are usually the same individuals who had few or no symptoms to signal the onset of their acute hepatitis B.
Moreover, most individuals with chronic hepatitis B infection remain symptom free (asymptomatic) for many years, even up to two or three decades. During this time, the patient's liver blood tests usually are at most mildly abnormal and the inflammation and scarring (fibrosis) of the liver progresses little, if at all. Occasionally, however, these individuals with otherwise inactive chronic hepatitis B may develop flares (reactivation) of acute symptoms, elevated liver blood tests, and inflammation of the liver. These flares resemble acute hepatitis, but they can cause progression of the chronic liver scarring (fibrosis). They tend to occur in men who acquired the chronic infection at a young age.
At some point, however, the chronic hepatitis can progress to CIRRHOSIS (severe scarring, or fibrosis) of the liver. These patients then can develop the symptoms and signs (abnormal findings on physical examination) of cirrhosis. For example, they can become weak, fatigued, and susceptible to infections. They can also lose muscle mass, especially in the shoulders and upper legs. In fact, they can develop poor nutrition and weight loss from abnormal digestion, malabsorption, or abnormal liver metabolism of nutrients.
Thus, deficiencies can occur, for example, of vitamin A, which causes impaired vision at night, or of vitamin D, which causes thinning of the spine or hip bones (osteopenia). Patients with cirrhosis also often develop visible evidence (stigmata) of cirrhosis, including swollen breasts (gynecomastia), small (atrophic) testicles, red palms (palmar erythema), and characteristic dilated vessels on the skin (spider angioma).
ADVANCED LIVER CIRRHOSIS:
Ultimately, the progression of cirrhosis leads to what is commonly known as advanced cirrhosis, which is characterized by the development of certain complications. Advanced cirrhosis is sometimes referred to as cirrhosis or chronic liver failure. Some authorities also use the term, decompensated cirrhosis, as synonymous with advanced cirrhosis. Others, however, reserve the term, decompensated cirrhosis, for advanced cirrhosis that includes specifically any of the complications that result primarily from portal hypertension. (Some of the complications of advanced cirrhosis can have multiple causes.) This difference in terminology matters little because the important consideration in any particular case is to simply specify which of the complications of cirrhosis apply.
Accordingly, the complications of cirrhosis that indicate the presence of advanced cirrhosis are complications that include those resulting primarily from portal hypertension (fluid retention, encephalopathy, GI bleeding, hypersplenism, and the hepatorenal syndrome), as well as coagulopathy, jaundice, and the hepatopulmonary syndrome. Portal hypertension is the term for the increased pressure in the portal venous system that occurs in patients with advanced cirrhosis. (The portal venous system drains blood from the intestinal and abdominal organs to the liver.) The most common complications of cirrhosis that result primarily from portal hypertension are fluid retention, hepatic (liver) encephalopathy, and gastrointestinal (GI) bleeding. The retention of fluid leads to swollen ankles (edema) and a swollen abdomen( ascites).
Sometimes, the fluid in the abdomen becomes infected (spontaneous bacterial peritonitis), causing fever and abdominal pain. The hepatic encephalopathy causes drowsiness, confusion, and even coma. Widened (dilated) veins (varices) in the esophagus and stomach that burst can cause GI bleeding. As a result, the patient may vomit bright red blood or defecate dark (even tarry) blood. Some patients develop hypersplenism, a complication that is due, in part at least, to portal hypertension. These patients have an enlarged spleen (splenomegaly), decreased red blood cells (anemia), decreased white blood cells (leukopenia), and decreased platelets (thrombocytopenia). The anemia causes weakness; the leukopenia contributes to infections; and the thrombocytopenia impairs the clotting of blood. Patients with portal hypertension also can develop a serious problem with the functioning of their kidneys without actual damage to the kidneys themselves (hepatorenal syndrome).
In advanced cirrhosis also, other important complications can occur besides those due primarily to portal hypertension. For example, some patients are prone to easy bruising and bleeding, largely because the impaired function of the liver causes abnormalities in the blood clotting process (coagulopathy). Patients with advanced cirrhosis can also develop jaundice because the damaged liver is unable to adequately eliminate a yellow compound, called bilirubin. More rarely, some patients can develop difficulty with breathing because certain hormones released in advanced cirrhosis cause abnormal functioning of the lungs (hepatopulmonary syndrome).
LIVER CANCER (HEPATOCELLULAR CARCINOMA)-DUE TO ADVANCED CIRRHOSIS:
Finally, liver cancer can develop in chronic HBV infected patients as a complication of advanced cirrhosis. This primary (originating in the liver) cancer of the liver is most likely to occur in people with active hepatitis B virus reproduction. The way in which the cancer develops is not yet fully understood. It is thought, however, that the hepatitis B virus DNA somehow becomes incorporated into the liver cell DNA of the patient. The most common symptoms and signs of liver cancer are abdominal pain and swelling, an enlarged liver, weight loss, and fever. In addition, the liver tumors can produce and release a number of substances, including ones that cause increased red blood cells (erythrocytosis), low blood sugar (hypoglycemia), and high blood calcium (hypercalcemia). The most useful diagnostic screening tests for liver cancer are an alpha-fetoprotein blood test and an ultrasound imaging study of the liver.
HBV INVOLVEMENT OF ORGANS OUSTIDE THE LIVER-(EXTRA-HEPATIC):
Rarely, chronic hepatitis B infection can lead to disorders that affect organs other than the liver. The deposit of specific hepatitis B virus immune complexes in the various organs usually causes these disorders. A hepatitis B virus immune complex is the entity that results from the binding together of a hepatitis B virus antibody and a hepatitis B virus antigen. (An antigen is a substance that is foreign to the body and an antibody is a specialized protein that is produced by white blood cells in response to the antigen. Hepatitis B virus immune complexes that settle, or deposit, in the small arteries throughout the body can result in an inflammation of these vessels (vasculitis), called polyarteritis nodosa. This condition can cause a wide range of symptoms, including muscle weakness, nerve damage (neuropathy), deep skin ulcers, kidney problems with loss of protein in the urine, (proteinuria), and sometimes kidney failure, high blood pressure, unexplained fevers, and abdominal pain. The hepatitis B virus immune complexes can cause damage to the kidneys in yet another way. That is, the immune complexes can be deposited in the glomeruli(filtering elements) of the kidney, causing glomeronephritis, which is a different disease from polyarteritis nodosa.
DIAGNOSIS OF HBV:
Hepatitis B is diagnosed from the results of specific hepatitis B virus tests (serologies) that reflect the various components of the hepatitis B virus. These serological tests differ from the standard liver tests (such as the ALT and AST) that can become abnormal when the liver is damaged from whatever cause, including hepatitis B viral infection. HBsAg AND anti-HBs:
The diagnosis of hepatitis B infection is made primarily by detecting the hepatitis B surface antigen (HBsAg) in the blood. The presence of HBsAg means that there is active hepatitis B viral infection and the absence of HBsAg means that there is no active hepatitis B viral infection. Following an exposure to hepatitis B virus, HBsAg becomes detectable in the blood within four weeks. In individuals who recover from acute hepatitis B viral infections, the elimination, or clearance, of HBsAg occurs within four months after the onset of symptoms. Chronic hepatitis B viral infection is defined as the persistence of HBsAg for more than six months.
After the HBsAg is eliminated from the body, the antibodies to HBsAg (anti-HBs) usually appear. These anti-HBs provide immunity to subsequent hepatitis B viral infection. Likewise, individuals who are successfully vaccinated against hepatitis B virus have measurable anti-HBs in the blood.
The hepatitis B core antigen can only be found in the liver and cannot be detected in the blood. The presence of large amounts of hepatitis B core antigen in the liver indicates an ongoing reproduction of the virus. This means that the virus is active. The antibody to hepatitis B core antigen, known as the hepatitis B core antibody (anti-HBc), however, is detectable in the blood. As a matter of fact, two types of anti-HBc antibodies (IgM and IgG) are produced.
IgM anti-HBc is a marker (indicator) for acute hepatitis B infection. The IgM anti-HBc is found in the blood during the acute infection and lasts for up to six months after the onset of symptoms. IgG anti-HBc develops during the course of the acute hepatitis B viral infection and persists for life, regardless of whether the individual recovers or develops the chronic infection. Accordingly, only the IgM type of anti-HBc can be specifically used to diagnose an acute hepatitis B viral infection. Moreover, determining just the total anti-HBc (without separating its two components) is not very helpful.
HBeAg, anti-HBe, AND PRE-CORE MUTATIONS:
Hepatitis B e antigen (HBeAg) and its antibody, anti-HBe, are useful markers to determine the likelihood of spread of the virus (transmissibility) by persons affected with chronic hepatitis B viral infection. Detecting both HBeAg and anti-HBe in the blood is usually mutually exclusive. Accordingly, the presence of HBeAg means ongoing viral activity and the ability to infect others, whereas the presence of anti-HBe signifies a more inactive state of the virus and less risk of transmission.
In some individuals infected with hepatitis B virus, the genetic material for the virus has undergone a particular 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 most specific marker of hepatitis B virus reproduction is the measurement of hepatitis B virus DNA in the blood. You remember that DNA is the genetic material of hepatitis B virus. High levels of hepatitis B virus DNA indicate an ongoing reproduction of the virus and viral activity. Low or undetectable levels of hepatitis B virus DNA are associated with the inactive phase of hepatitis B viral infection. Several different laboratory tests (assays) are available to measure hepatitis B virus DNA.
The PCR- (polymerase chain reaction) is the most sensitive method (assay) for determining the level of hepatitis B virus DNA. This means that the PCR is the best method for detecting minute amounts of the hepatitis B virus marker. This method works by amplifying the material that is being measured up to a billion times for its detection. The PCR method, therefore, can measure as few as 50 to 100 copies (particles) of hepatitis B virus per milliliter of blood. This test, however, is actually too sensitive for practical diagnostic use.
The purpose of measuring hepatitis B virus DNA usually is to determine whether the hepatitis B viral infection is active or inactive (quiescent). This distinction can be made based on the amount of hepatitis B virus DNA in the blood. High levels of DNA indicate an active infection, while low levels indicate a dormant, or inactive, infection. Thus, patients with dormant disease have about a million viral particles per milliliter of blood, whereas patients with active disease have several billion particles per milliliter. Therefore, anyone who is HBsAg positive, even if the hepatitis B viral infection is inactive, will have detectable levels of hepatitis B virus DNA by the PCR method because it is so sensitive.
For practical purposes, hepatitis B virus DNA can be measured using a so-called hybridization method (assay), which is a less sensitive test than the PCR. Unlike the PCR method, the hybridization assay measures the viral material without amplification. Thus this test can detect hepatitis B virus DNA only when many viral particles are present in the blood, meaning that the infection is active. In other words, from a practical point of view, if hepatitis B virus DNA is detected with a hybridization assay, this means that the hepatitis B viral infection is active.
PREVENTION AND TREATMENT:
Liver cancer is almost always fatal, and usually develops between 35 and 65 years of age, when people are maximally productive and with family responsibilities. The loss of a mother or a father can be devastating to the entire family. In developing countries, most people with liver cancer die within months of diagnosis. In industrialized countries, surgery and chemotherapy can prolong life up to a few years. Chronic hepatitis B in some patients can be treated with drugs such as interferon or lamivudine, which can help some patients. However, interferon or lamivudine therapies are very costly and therefore few individuals can afford them and will never be available to most patients in developing countries due to their costs. Patients with cirrhosis are sometimes given liver transplants, with varying success. It is preferable to prevent this disease with vaccine than to try to cure it.
SAFETY AND EFFECTIVENESS OF THE HBV CACCINES:
The vaccine is given as a series of three intramuscular doses. It has been said that the vaccine is 95% effective in preventing children and adults from developing chronic infection if they have not yet been infected. In many countries where 8% to 15% of children used to become chronically infected with HBV, the rate of chronic infection has been reduced to less than 1% in immunized groups of children. And the reports are showing that. Since 1982, over one billion doses of hepatitis B vaccine have been used worldwide.
All countries have been urged by world bodies to add hepatitis B vaccine into their national immunization programmes. As of March 2000, 116 countries had included hepatitis B vaccine in their national programmes including most countries in Eastern and South- East Asia, the Pacific Islands Australia, North and South America,Western Europe and the Middle East. However, many low income countries in sub-Saharan Africa, the Indian subcontinent and in the Newly Independent States do not use the vaccine. The price of the hepatitis B vaccine has been one of the main obstacles to its introduction in many of these countries.
The Global Alliance for Vaccines and Immunization (GAVI) was created in 1999. It is a unique coalition of public and private institutions. The main mission of GAVI is to vaccinate as many children as possible against vaccine-preventable diseases. GAVI has introduced a new approach to international health funding: the Global Fund for Children's vaccines (GFCV). This fund will help 74 low-income countries including those in the sub-Saharan Africa, Asia and Southern America to reinforce their national vaccine programmes and introduce hepatitis B, yellow fever and haemophilus influenzae type b (Hib) vaccines into their national immunization programmes.