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Hepatitis B

The disease known as hepatitis B is caused by the infectious Hepatitis B virus (HBV). HBV alone is estimated to have infected 400 million people throughout the globe, making HBV one of the most common human pathogens. Hepatocellular carcinomas (HCC), one of the most common cancers afflicting humans, is primarily caused by chronic HBV infection.. In the last few decades, the correlation between HBV and the development of HCC has been well established. However, the mechanism by which HBV transforms hepatocytes remains elusive. Before HBV can transform a cell, the virus must first infect it. However, the mechanism through which HBV enters hepatocytes has not been resolved despite further understanding of the viral proteins involved. Vaccines are available against HBV, but they may not be 100% effective against all variants of HBV. Furthermore, there is no cure for individuals already infected. Much more research is needed before we fully understand and control the spread of this infectious agent.


The following pages attempt to provide accurate and comprehensible information regarding the various aspects of the hepatitis B virus. Granted, some parts of this site require some scientific background to fully comprehend (i.e. the structural and molecular biology pages), but I have also included a question and answer page for those who feel some information needs clarification. May you find the information you are looking for within.


Hepatitis B Virus General Information


Genome: partial dsDNA


Family:Hepadnaviridae


Related Viruses:Duck Hepatitis B Virus, Ground Squirrel Hepatitis Virus, Snow Goose Hepatitis B Virus, Woodchuck Hepatitis Virus, Wooley Monkey Hepatitis Virus


Satellite Virus: Hepatitis D Virus (Delta Virus)


Incubation Period: 30 - 180 days


Transmission: Blood and Sexual Contact


Acute Attack: Mild or Severe


Serum Diagnosis:anti-HBc, anti-HBs or HBsAg


Treatment: Symptomatic


Prevention:Vaccination with recombinant hepatitis B surface antigens, Hepatitis B Immunoglobulin Post-exposure prophylaxis


History of the Hepatitis B Virus


Viral hepatitis is the term reserved for infections of the liver by one or more of the distinct hepatitis viruses. The terms, hepatitis A and hepatitis B, were first introduced by MacCallum in 1947 in order to categorize infectious (epidemic) and serum hepatitis.These terms were eventually adopted by the World Health Organization Committee on Viral Hepatitis.


Before the viruses causing hepatitis were isolated, transmission was differentiated on the basis of epidemiological observations. Type A hepatitis was considered predominantly transmitted via the fecal-oral route while type B hepatitis was believed to be primarily transmitted parenterally.


In 1963, when searching for polymorphic serum proteins, Blumberg discovered a previously unknown protein in the blood of an Australian aborigine. This protein was denoted as the Australia (Au) antigen. It became apparent that this protein was related to type B hepatitis. By 1968, other investigators, notably Prince, Okochi, and Murakami, had established that the Au antigen (now known as the hepatitis B surface antigen) was only found in the serum of type B hepatitis infected patients.


In 1973, Dane found virus-like particles in the serum of patients suffering from type B hepatitis. These particles were designated as the hepatitis B virus (HBV). Non-related hepatitis viruses were discovered later, but the hepatitis B virus retained its name.


Kaplan confirmed the viral nature of these particles by detecting an endogenous DNA-dependent DNA polymerase within its core. Discovery of this polymerase allowed Robinson to detect and characterize the HBV genome. The HBV genome is unique in the world of viruses due to its compact nature, use of overlapping reading frames, and dependence on a reverse-transcriptional step, though the virion contains primarily DNA. In light of this, the human hepatitis B virus became the archetype of the hepadnavirus family, Hepadnaviridae.


Though the hepatitis B surface antigen (HBsAg) from HBV has been detected in other primates, humans remain its primary reservoir. In the recent past, many related viruses have been found in other species, but each particular virus is species specific. With human HBV as the archetype, the members of the hepadnaviridae family include duck hepatitis B virus (DHBV), ground squirrel hepatitis virus (GSHV), snow goose hepatitis B virus (sgHBV), woodchuck hepatitis virus (WHV), and wooley monkey hepatitis virus. There are likely other viruses that have yet to be isolated which would also be classified as a hepadnaviridae.


HBV has been estimated by the World Health Organization (WHO) to have infected over two billion people worldwide. Approximately 500 million are chronic carriers. Transmission of HBV is primarily through blood and/or sexual contact, though other methods of transmission have been suggested. The large reservoir of infected individuals has sustained a satellite virus known as the hepatitis D virus (HDV). HDV can only replicate in cells already infected with HBV since HDV uses hepatitis B surface proteins to package its own RNA. However, the nature of HDV is quite different from HBV. Therefore, it will only be mentioned briefly in this website.


Epidemiology


The hepatitis B virus is globally distributed among humans. The various strains of HBV are quite species specific. Though HBs has been found in other primates, humans remain the principal reservoir. Many individuals are affected worldwide, but the prevalence of HBV has been decreasing in developed countries, thanks to the availability of the hepatitis B vaccine, increasing knowledge of how the virus is spread as well as screening of donated blood before use.


The hepatitis B virus is primarily found in the blood of infected individuals. Virus titres, as high as ten billion virions per millilitre of blood, have been reported in HBe-positive carriers. However, HBV has also been detected in other bodily fluids including urine, saliva/nasopharyngeal fluids, semen, and menstrual fluids. This virus has not been detected in feces, perhaps due to inactivation and degradation within the intestinal mucosa or by the bacterial flora.


Transmission of HBV is done most efficiently via percutaneous introduction (i.e. needlestick injury). Sexual transmission is also possible though inefficient. There are other potential routes of transmission, but their efficiency is not easily measured. Children of mothers with active HBV are also at risk of acquiring HBV. Uninfected individuals living with an HBV carrier are at greater risk of contracting HBV than those not living with a carrier. This is likely due to the fact that HBV can survive even on a dry surface for over a week. However, it should be remembered that for HBV to infect, it still must gain entry into the bloodstream of an uninfected individual.


Higher Risk Groups


DIAGNOSIS


Clinical Phases During Acute Infection


Acute viral hepatitis infection can be broken into four stages: i) incubation period, which is the time between initial viral entry into the cell to first day of symptoms; ii) prodromal or pre-icteric period; iii) the icteric phase; and iv) recovery.


Symptoms during the onset of acute hepatitis B viral infection vary, depending on the individual. Many children and some adults infected with the virus never show any discernible symptoms. However, most infected individuals experience a certain level of jaundice which tends to develop soon after the virus can be detected in the blood. Often, jaundice is preceded by mild fevers, fatigue, malaise, loss of appetite, and sometimes nausea and vomiting.


During the icteric or blood-borne phase, an infected individual's urine tends to have a dark, golden-brown appearance. This is often followed by the lightening of the stool as well as the yellowing of the skin, typically seen in jaundice. Jaundice is considered clinically apparent once total bilirubin levels are greater than 2-4mg/dl


Signs of Liver Trouble


There are some common signs that suggest one may have a liver problem. However, not all liver problems are attributable to the Hepatitis B virus. Hepatitis A, C, D, E, G viruses, as well as alcohol, chemical, bacterial, and other conditions can damage one's liver. The following is a list of the common symptoms of liver problem:

If one suspects one has a liver condition, it is highly recommended that one sees a doctor and be tested to determine whether one's concerns are well-founded. Early detection may help simplify treatment


Blood Tests for Diagnosing Hepatitis B


A variety of serological assays may be employed to differentiate the type of viral infection as well as disciminate between chronic and acute hepatitis B virus (HBV) infection. The most sensitive and specific methods used commercially in diagnosis are radioimmunoassays (RIA) and enzyme-linked immunosorbent assays (ELISA). Both assays make use of specific antibodies against various HBV proteins and can detect HBsAg proteins as low as 0.25 ng/mL and anti-HBs antibodies at a level of 1 mIU/mL. PCR has also been used in detecting low levels of HBV DNA present in both blood and liver tissue samples.


Reference Ranges in Clinical Biochemistry Tests


These are average ranges and times I have managed to compile, but may not exactly match those used by all medical centres.


AST (Aspartate Aminotransferase) or SGOT (Serum Glutamic-Oxalocetic Transaminase)


5-54 U/L | This enzyme is found mainly in heart, kidney, liver, muscle, and pancreatic tissues. Tissue damage releases this enzyme and elevated levels can be detected in the blood. Vitamin B deficiency and pregnancy may actually decrease levels of this enzyme found in the blood.


ALT (Alanine Aminotransferase) or SGPT (Serum Glutamic-Pyruvic Transaminase)


0-36 U/L | This enzyme is found mainly in the liver, but can also be seen in lower amounts in heart, muscle, and other tissues. Increased levels of this enzyme in the blood can be attributed to liver damage, kidney infection, chemical toxins, or even a cardiac infarction (heart attack).


Alkaline Phosphatase (during growth and pregnancy)


40-120 U/L | This enzyme is primarily found in bone and liver tissue. Growing children typically have an increased level of this enzyme in their blood compared to adults.


for children: 40-400 U/L


GGT (Gamma Glutamyltransferase)


3-59 U/L | This enzyme is primarily found in liver cells and is quite sensitive to alcohol consumption. Elevated levels of this enzyme are found in liver disease, bile-duct obstruction, and drug abuse, to name a few.


LDH (Lactose Dehydrogenase)


135-225 U/L | This enzyme is primarily found in brain, heart, kidney, liver, lung, and skeletal muscle tissues. Increased levels are associated with cell death. Decreased levels can be associated with malnutrition or low tissue/organ activity.


Albumin


35-50 g/L This protein is synthesized in the liver and is involved in maintaining blood protein base levels. Liver damage may result in low levels of albumin produced. When albumin levels drop to extremely low levels, fluid from the blood may leak into surrounding tissues, resulting in swelling known as edema.


Bilirubin (non-neonatal) - Total (conjugated and unconjugated)


1-17 µmol/L | Bilirubin is a byproduct of red blood cell breakdown. It is actually formed when the hemoglobin ring is opened through other enzyme activities. Bilirubin is typically excreted into the bile, giving bile its pigmentation. Increased levels are associated with liver disease, mononucleosis, toxicity due to some types of drugs, and hemolytic anemia.


Bilirubin (non-neonatal) - Direct (conjugated)


0-5 µmol/L


PT (Prothrombin Coagulation Time)


10-12s


Clinical Types

Acute Hepatitis


The clinical course of HBV runs similarly to that of Hepatitis A Virus (HAV), but tends to be more severe and may be associated with serum-sickness-like syndrome. The mildest attacks are asymptomatic and are detectable only by an increase in serum transaminase levels. Alternatively, patients may be anicteric, but may suffer from gastrointestinal and influenza-like symptoms. These patients are likely to remain undiagnosed unless a clear history of exposure is available. The severity of infection may vary from the asymptomatic and icteric (from which recovery is typical) through to fulminant, fatal viral hepatitis. Icteric attacks in adults are marked by a prodromal period (typically three to four days, but may last up to two or three weeks) during which patients feel sickly, suffer from digestive symtoms such as anorexia and nausea and may, in the later stages, have mild pyrexia. Other common symptoms are rigors, loss of desire to drink alcohol or smoke, malaise, and occasionally, severe headaches. The prodromal period is followed by the darkening of urine and lightening of feces, followed by the development of jaundice.


Cirrhosis


Cirrhosis can be characterized anatomically by widespread nodules in the liver combined with fibrosis. These excessive nodules and fibroids result in the distortion of the normal liver architecture and interfere with blood flow through the liver. Cirrhosis may also result in the inability of the liver to perform its functions as abnormalities progressively develop.


Fulminant Hepatitis


This is a rare form of the disease which usually overwhelms the patient within ten days. This form may develop so quickly that jaundice is inconspicuous and may be confused with acute psychosis or meningo-encephalitis. On the other hand, the patient may become deeply jaundiced. Forboding signs may be repeated vomiting, fetor hepaticus, confusion, and drowsiness. The 'flapping' tremor may only be transient, but rigidity is usual. These are then supervened by coma, indicating likely acute liver failure. The patient's temperature rises, jaundice deepens, and liver shrinks, possibly accompanied by widespread hemorrhages.


The levels of serum bilirubin and transaminase are poor prognostic indicators because transaminase levels may actually decrease as the patient's clinical condition worsens. Prothrombin is the best indicator of prognosis. Frequency of the fulminant course varies, depending upon the type of viral hepatitis and prevalence of hepatitis B carriage.


Post-Hepatitis Syndrome


Adult patients feel less-than-perfect for variable spans of time following acute hepatitis. Typically, this period lasts for a few weeks, but may extend into months. Common features are anxiety, fatigue, failure to regain weight, anorexia, alcohol intolerance, and right upper abdominal discomfort. The edges of the liver may be tender. Serum transaminase levels may be up to three times that of normal. Hepatic histology reveals mild, residual portal zone cellularity and fibrosis, and sometimes fatty changes in the liver cells. These conditions do not differ from patients found to be recovering normally and who are now symptom-free. Thus, a liver biopsy should not be done within six months after acute hepatitis as there may be difficulty in distinguishing the residual changes from developing chronic hepatitis.


Prolonged Cholestasis


Occasionally, prolonged jaundice is of the cholestatic type. The onset is acute, and as the jaundice deepens within the first three weeks, the patient begins to itch. After the first few weeks, the patient feels well, gains weight, and is asymptomatic apart from icterus and slight hepatomegaly. Jaundice persists for 8 - 29 weeks, after which recovery is complete.


Relapses


In 1.8% - 15% of cases, some of the original attack is duplicated, but typically in a milder form. Often, relapse is simply shown by an increase in serum transaminases and bilirubin. Relapses may be a result of premature activity or intake of large amounts of alcohol. Multiple relapses may occur. However, full recovery may follow, though in some patients, relapses may indicate progression to chronic hepatitis.


Hepatocellular Carcinoma (HCC)


Hepatocellular carcinoma is the technical term for liver cancer. This form of the disease develops after a long time in individuals suffering from chronic hepatitis B infection. What events trigger the development of this disease are currently unknown.


Treatment: Acute Infection


At present, there are no specific treatments for benign acute viral hepatitis. Current therapy should be aimed to support and to maintain comfort. As with most forms of hepatitis, alcohol consumption should be minimized, if not eliminated altogether. This helps the liver recover. Use of adrenocorticosteroids, recommended by some, appears to have no effect curing the underlying disease. Furthermore, it appears that use of steroids in early treatment of hepatitis B virus (HBV) infection may result in the development of a persistent infection. Therapeutic effectiveness of interferon use on the prognosis and course of acute HBV infection remain unknown.


Treatment: Chronic Infection


A number of elements has been used in the treatment of chronic HBV. The goals of treatment are three-fold: to eliminate infectivity and transmission of HBV to others, to arrest the progression of liver disease and improve the clinical prognosis, and to prevent the development of hepatocellular carcinoma (HCC).


Currently, there are several treatments being used. Interferon alpha use is most common, but now lamivudine (3TC), and others are being looked at as potential therapeutic agents. Combinations of antiviral drugs are being used with some success.


Antivirals:The following list includes those which are still in their experimental stages.



Immune System Modulators:



Mixed Treatments:


None of these treatments can be called a cure. A true cure for this disease still remains elusive.


Alternative Treatments


Since there is no cure, many individuals have sought other sources of therapy for their damaged liver. Though many swear by these alternative treatments, they should be taken with caution. One should remember that though these alternative treatments come from natural sources, harmful side-effects may also follow. Most alternative treatments do not target the virus. They typically boost the liver's health.


Healthy Diet


Eating a balanced and healthy diet will minimize any excess damage done to an infected liver and may even expedite liver recovery. It should be remembered that virtually everything we eat must pass through the liver.



Note: The above suggestions should be used as a guideline when eating, but should not be taken as the "be-all-and-end-all".


Liver Transplants

Liver transplants are sometimes required by those with extensive liver damage due to viral (or non-viral) causes. However, there are many factors to consider before getting a liver transplant. First and foremost, transplantation is a complex operation that requires a suitable donor. Also, there is usually a long waiting list for those wishing to receive a transplant. Moreover, transplanting a liver into a chronically hepatitis B infected individual presents the likelihood that the newly transplanted liver may become reinfected unless certain preventive measures are taken like Hepatitis-B immunoglobin. Transplant operations tend to be relatively expensive procedures. Not all hospitals may be able to perform such an operation.Despite these problems, for some individuals, liver transplants may offer the only hope for a healthy life.


New Therapy of Hepatitis-B

SciClone Pharmaceuticals today announced that results from the Company's Taiwan phase 3 trial published in Hepatology (May 1998) demonstrate that ZADAXIN(R) thymosin alpha 1 is effective and safe in the treatment of chronic hepatitis B. Importantly, the ZADAXIN complete virologic response rate (the conversion from both hepatitis B virus positive to negative and hepatitis B e antigen positive to negative) in the study continues to increase even when measured one year after the end of treatment.


The publication on the study's primary site data, written by Professor Yun-Fang Liaw, M.D. and his colleagues of the Chang Gung Memorial Hospital, Taiwan, included 98 Asian patients with chronic hepatitis B. At the start of the study, patients were randomized to receive 1.6 mg of ZADAXIN two times per week for 26 weeks, 52 weeks or no treatment. Patients were followed for a total of 18 months.


The publication highlights that patients receiving ZADAXIN showed:


Professor Liaw and his co-workers, commenting on this recent Hepatology article, said: ``Thymosin alpha 1 is safe and effective in the treatment of chronic hepatitis B. The thymosin alpha 1 response rate is statistically significant in the six month treatment group when compared to control. It also reduces liver inflammation. Thymosin alpha 1 therapy offers renewed hope in the fight against chronic hepatitis B.''


Hepatitis B is a potentially deadly liver disease and one of the most common causes of death in the world. According to the World Health Organization, approximately 350 million people, or 5% of the world's population, are chronic carriers of the hepatitis B virus in their blood. These carriers of the hepatitis B virus have a 200-fold increased chance of developing serious liver disease, including liver cancer, the most common cancer in the world, and cirrhosis. Currently, ZADAXIN and interferon (a drug that produces a sustained response in less than one third of Asian patients treated and causes debilitating side effects) are the only established therapies for hepatitis B in certain Asian markets, including the People's Republic of China.


SciClone markets ZADAXIN in the People's Republic of China, the Philippines and Singapore for the treatment of hepatitis B. The drug also has been approved in Peru and Kuwait for treatment of hepatitis B and in Argentina and Italy as an influenza vaccine adjuvant. SciClone's exclusive Japanese partner, Schering-Plough K.K., recently launched a Phase 3 study of ZADAXIN in Japan for hepatitis B. SciClone has 18 ZADAXIN hepatitis B marketing applications pending in Asia, Latin American and the Middle East. SciClone intends to file a ZADAXIN hepatitis B marketing application in Taiwan during the second quarter.


SciClone Pharmaceuticals, Inc. is an international biopharmaceutical company that acquires, develops and commercializes specialist-oriented drugs for treating chronic and life-threatening diseases, including hepatitis B, hepatitis C, cystic fibrosis, cancer and immune system disorders.


Hepatitis B Carrier Fact Sheet

Hepatitis B Virus infects the liver. The virus is in blood, semen, menstrual blood and other body fluids.5 to 10% of adults and about 90% of babies who get hepatitis B will go on to "carry" or keep the virus for the rest of their lives. These people are called "hepatitis B Carriers". They may not be sick, but they can pass the virus on to others and make others sick with hepatitis B.


People who are hepatitis B carriers can lead normal, healthy lives Most hepatitis B carriers do not feel sick or look sick. However, carriers have a higher risk o becoming sick with liver disease and liver cancer. Carriers need to have the regular care of the doctor.


There are simple ways that hepatitis B carriers can stay healthy


There are things carriers can do to keep form infecting other with hepatitis B



People who are not close contacts are not at risk for getting hepatitis B. carriers do not have to talk about their infection with anyone that is not a close contact. It is okay to share meals with family and friends.


Vaccination and good hygiene can protect close infection with hepatitis B

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