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{{InfectiousDisease
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Revision as of 16:27, 18 June 2012



{{#meta: itemprop="medicalWebPageAudiences" content="patient"}}{{#meta: itemprop="medicalWebPageSpecialities" content="cardiology"}}{{#meta: itemprop="medicalWebPageInfoTypes" content="symptoms,diagnosis,treatment,causes,prognosis,complications"}} [[Natural Progression::{{{naturalProgression}}}| ]] Classification Classic::Classification Atypical::

Overview

Hepatitis Main Page

Hepatitis B

Home

Patient Information

Overview

Historical Perspective

Pathophysiology

Causes

Differentiating Hepatitis B from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

CT

MRI

Ultrasound

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hepatitis B On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hepatitis B

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

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NICE Guidance

FDA on Hepatitis B

CDC on Hepatitis B

Hepatitis B in the news

Blogs on Hepatitis B

Directions to Hospitals Treating Hepatitis B

Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [2], João André Alves Silva, M.D. [3], Sara Mehrsefat, M.D. [4]

Overview

Chronic Hepatitis B virus (HBV) is a major global health problem, according to the World Health Organization (WHO).[1][2] Hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family Hepadnaviridae. It is responsible for hepatitis B virus infection in humans, which attacks the liver and causes both acute and chronic disease. During HBV infection, the host's immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host's cell mechanisms to replicate its genome and proteins. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.[3][4] Hepatitis B must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT, and/or elevated AST, such as other viral hepatitis strains, alcoholic hepatitis, and autoimmune hepatitis.[5] Generally, the highest risk for HBV infection is associated with certain lifestyles, occupations, or environments in which contact with blood from infected persons is frequent. The diagnosis of hepatitis B is made by biochemical assessment of liver function.

In the majority of patients with acute and chronic hepatitis B (HBV), symptoms may initially be non-specific and physical examination will be normal.[6] The diagnosis of hepatitis B is made by biochemical assessment of liver function. Initial laboratory evaluation usually reveals increased bilirubin, ALT, AST, and alkaline phosphatase, as well as decreased protein. Prothrombin time may be prolonged in cases of hepatocellular necrosis. Serologic markers, such as Hepatitis B surface antigen (HBsAg); anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis Be antigen; and anti-HBeAg confirm the diagnosis of hepatitis B.[7][8]

In the majority of adult patients, the body is able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B infection. Early antiviral treatment may only be required in fewer than 1% of patients with fulminant hepatitis. Treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Treatment lasts between six months and a year, depending on the medication and genotype. Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. These include the antiviral drugs Lamivudine, Adefovir, Tenofovir, Telbivudine, and Entecavir, as well as immune system modulators such as interferon alpha-2a and pegylated interferon-alpha-2a.[9][10]

Historical Perspective

The first descriptions of hepatitis (epidemic jaundice) are generally attributed to Hippocrates, who identified the disorder during the 5th century BCE.[7] In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman.[11] In 1947, the current nomenclature of hepatitis A (so-called "infectious hepatitis") and hepatitis B (so-called "serum hepatitis") was proposed by MacCallum and Bauer. Throughout the 20th century, advancements in the recognition, isolation, classification, and prevention of hepatitis B were achieved. Today, the focus around HBV remains on the spread of awareness and prevention across the world, especially in endemic areas that would benefit greatly from immunization programs.[12][13]

Pathophysiology

The intracellular hepatitis B virus is a non-cytopathic virus that causes little or no damage to the cell.[1] During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host cell's mechanisms to replicate its own genome and proteins. Different viral antigens and antibodies are detected in serum throughout the course of the disease, such as: HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBC and anti-HBe. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.[3][4]

Causes

The hepatitis B virus is responsible for causing hepatitis B. HBV is a double-stranded DNA virus belonging to the family Hepadnaviridae. The viral particle consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA. HBV DNA polymerase has reverse transcriptase activity. It shows tropism for hepatocytes. Humans are the only natural reservoir of the virus.[14] HBV is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins and ten genotypes (A-J) according to overall nucleotide sequence variation of the genome.[15][16]

Differentiating Hepatitis B from other Diseases

Hepatitis B must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, and/or elevated ALT and AST, such as other forms of viral hepatitis, alcoholic hepatitis, and autoimmune hepatitis.[5][17][18]

Epidemiology and Demographics

Chronic Hepatitis B (HBV) is a major global health problem. According to the World Health Organization (WHO), more than 2 billion people have been infected with HBV. It is a major cause of chronic liver disease worldwide, affecting an estimated 1.25 million people in the United States, and more than 240 million people worldwide.[1][2]

Risk Factors

Generally, the highest risk for HBV infection is associated with lifestyles, occupations, or environments in which contact with blood from infected patients is frequent. High-risk populations include immigrants/refugees from areas of high HBV endemicity, clients in mental health institutions, injecting drug users, men who have sex with men (MSM), patients receiving hemodialysis, and household contacts of HBV carriers. Perinatal transmission from mother to infant at birth is very efficient. If the mother is positive for both HBsAg and HBeAg, 70%–90% of infants will become infected in the absence of post-exposure prophylaxis.[19]

Screening

High-risk groups should be tested for HBV infection. These include immigrants/refugees from areas of intermediate or high endemicity, patients with chronically elevated aminotransferases, immunocompromised individuals, and people with a history of injection drug use (IDU).[20] Additionally, screening for hepatocellular carcinoma should extend to any HBV carrier over 40 years of age with persistent or intermittent ALT elevation and/or high HBV DNA levels (>2,000 IU/mL).[8]

Natural History, Complications and Prognosis

The course of hepatitis B is extremely variable. Hepatitis B has different clinical manifestations depending on the patient’s age at infection, immune status, and the stage at which the disease is recognized.[1] During the incubation period, patients may experience flu-like symptoms such as nausea, vomiting, and headaches. A person infected with hepatitis B virus may recover completely, become an asymptomatic carrier of the virus, develop chronic disease, or develop fulminant hepatitis. In acute hepatitis B, the incubation period may range from 45 to 120 days, depending on the amount of virus in the inoculum, host factors, and the mode of transmission. These patients may experience the following symptoms: fatigue, nausea, vomiting, anorexia, abdominal pain, and jaundice. In most cases, no special diet or treatment are necessary. The risk of developing chronic hepatitis decreases with age, with infants having the highest risk. Chronic hepatitis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In most cases the prognosis of acute hepatitis is good, with symptoms lasting 2 to 3 weeks. However, in infants and immunocompromised patients, the risk of developing chronic disease is increased.[1][21]

Diagnosis

Diagnostic criteria

The diagnosis of hepatitis is made by biochemical assessment of liver function. A diagnosis is confirmed by the presence of specific antigens and/or antibodies in sera. Three clinically useful antigen-antibody systems have been identified for hepatitis B. These include hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs); antibody (anti-HBc IgM and anti-HBc IgG) to hepatitis B core antigen (HBcAg); and hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe).[1]

Hepatitis B viral antigens and antibodies detectable in the blood following acute infection - CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=14144661

History and symptom

50% of adult patients and the majority of infants and children with acute HBV do not present with symptoms. Symptoms may initially be non-specific.[7] It is critical to obtain an accurate and thorough history in cases of both acute and chronic HBV infections in order to determine modes of infection transmission, as well as to assess risk factors for the progression of HBV-related liver disease.[6][22]

Physical examination

For the majority of patients with acute and chronic hepatitis B (HBV), the physical examination is normal.[6]

Laboratory tests

The diagnosis of hepatitis is made by the biochemical assessment of liver function. An initial laboratory evaluation usually reveals increased bilirubin levels; increased ALT, AST, and alkaline phosphatase; and decreased protein. Prothrombin time may be prolonged in cases of hepatocellular necrosis and hemoglobin may be low. Initial lymphopenia and neutropenia may be followed by lymphocytosis. Serologic markers, such as Hepatitis B surface antigen (HBsAg); anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis B e antigen and anti-HBeAg confirm the diagnosis of hepatitis B. These levels fluctuate throughout the course of the disease.[1][7][8]

Hepatitis B assay results Adapted from World Health Organization[23]

CT

CT scans may diagnose and/or monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in hepatitis B patients.:[24]

MRI

An MRI may be used to diagnose/monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in hepatitis B patients. MRI findings in these patients may include nodular appearance and signs of portal hypertension, such as ascites and splenomegaly.[24]

Ultrasound

Ultrasounds may be used as a screening tool in patients with chronic hepatitis for the early detection of hepatic cirrhosis. HBsAg carriers with cirrhosis should be echographically evaluated every 6 months.

Treatment

Medical therapy

The majority of adults are able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B infection. Symptomatic treatment may be indicated. Early antiviral treatment may only be required in fewer than 1% of patients, whose hepatitis B takes a very aggressive course, such as in cases of fulminant hepatitis. Treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected patients with persistently elevated serum alanine aminotransferase and HBV DNA levels are candidates for therapy. Treatment lasts from six months to a year, depending on the medication and genotype. Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. These include antiviral drugs (e.g., Lamivudine, Adefovir, Tenofovir, Telbivudine and Entecavir) and immune system modulators, including interferon alpha-2a and pegylated interferon-alpha-2a.[9][10][25][26]

Surgery

Surgery is usually not indicated for the treatment of hepatitis B. However, for patients with advanced liver damage secondary to HBV infection or liver failure in fulminant hepatitis, liver transplantation may be beneficial.

Primary Prevention

The risk of transmission of hepatitis B may be diminished by following measures proposed by the WHO. These include vaccination of all infants within 24 hours of birth; vaccination of members of certain risk groups, such as travelers to endemic areas and healthcare workers (if they have not been vaccinated yet); avoidance of sexual contact with a person who has acute or chronic hepatitis B; and avoiding sharing personal items such as razors or toothbrushes. The HBV vaccine is effective in preventing HBV infections when it is administered either before or shortly after exposure.[1][27][28]

Vaccination

The Hepatitis B vaccine is the most effective tool in preventing the transmission of HBV and HDV. Vaccines are composed of the surface antigen of HBV (HBsAg) and are produced by two different methods, including plasma-derived and recombinant DNA. The primary hepatitis B immunization series conventionally consists of three doses of vaccine. Vaccination of infants and, in particular, delivery of hepatitis B vaccine within 24 hours of birth is 90–95% effective in preventing infection with HBV, as well as decreasing HBV transmission if followed by at least two other doses. WHO recommends universal hepatitis B vaccination for all infants, and further advises that the first dose should be given as soon as possible after birth.[1][29] This strategy has resulted in a dramatic decrease in the prevalence of CHB among young children in regions of the world where universal infant vaccination programs have been implemented. A small proportion of vaccinated children (5–10%) have a poor response to vaccination, and will remain susceptible as adults to acquisition of HBV infection.[1][30]

Vertical transmission

Hepatitis B virus (HBV) infection in a pregnant woman poses a serious risk to the fetus. Without postexposure immunoprophylaxis, approximately 40% of infants born to HBV-infected mothers in the United States will develop chronic HBV infection, approximately one-fourth of whom will eventually die from chronic liver disease.[31]

Secondary Prevention

Hepatitis B Immunoglobulin (HBIG) is a form of passive immunization when given shortly before or soon after exposure to hepatitis B virus. It is also administered in combination with HBV vaccines to newborns of HBsAg-positive mothers.[1][28]

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016
  2. 2.0 2.1 Center for Disease Control and Prevention. Guidelines for Hepatitis Sureveillance and Case Management 2009.http://www.cdc.gov/hepatitis/Statistics/SurveillanceGuidelines.htm
  3. 3.0 3.1 Zhang YY, Hu KQ (2015). "Rethinking the pathogenesis of hepatitis B virus (HBV) infection". J Med Virol. 87 (12): 1989–99. doi:10.1002/jmv.24270. PMID 25989114.
  4. 4.0 4.1 Chang KM, Liu M (2016). "Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics". Curr Opin Pharmacol. 30: 93–105. doi:10.1016/j.coph.2016.07.013. PMID 27570126.
  5. 5.0 5.1 Centers for Disease Control and Prevention. Viral Hepatitis http://www.cdc.gov/hepatitis/ Accessed on October 4th, 2016
  6. 6.0 6.1 6.2 Rotman Y, Brown TA, Hoofnagle JH (2009). "Evaluation of the patient with hepatitis B." Hepatology. 49 (5 Suppl): S22–7. doi:10.1002/hep.22976. PMC 2881483. PMID 19399815.
  7. 7.0 7.1 7.2 7.3 Center for Disease Control and Prevention. Hepatitis B Epidemiology and Prevention of Vaccine-Preventable Diseases 2012.http://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html
  8. 8.0 8.1 8.2 AASLD guidelines for treatment of chronic hepatitis B. Hepatology (2016)http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/full Accessed on October 10th, 2016
  9. 9.0 9.1 Vargas HE, Dodson FS, Rakela J (2002). "A concise update on the status of liver transplantation for hepatitis B virus: the challenges in 2002". Liver Transpl. 8 (1): 2–9. doi:10.1053/jlts.2002.29765. PMID 11799479.
  10. 10.0 10.1 Omata M (1990). "Significance of extrahepatic replication of hepatitis B virus". Hepatology. 12 (2): 364–6. PMID 2202639.
  11. Hussey, Hugh H. (1981). "The Hepatitis B Saga". JAMA: The Journal of the American Medical Association. 245 (13): 1317. doi:10.1001/jama.1981.03310380021018. ISSN 0098-7484.
  12. Mahoney FJ (1999). "Update on diagnosis, management, and prevention of hepatitis B virus infection". Clin Microbiol Rev. 12 (2): 351–66. PMC 88921. PMID 10194463.
  13. Neefe, John R., Sydney S. Gellis, and Joseph Stokes. "Homologous serum hepatitis and infectious (epidemic) hepatitis: Studies in volunteers bearing on immunological and other characteristics of the etiological agents." The American journal of medicine 1.1 (1946): 3-22.
  14. Zuckerman AJ (1996). "Hepatitis Viruses". In Baron S; et al. Baron's Medical Microbiology (4th ed.). University of Texas Medical Branch. ISBN 0-9631172-1-1.
  15. Magnius LO, Norder H (1995). "Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene". Intervirology. 38 (1–2): 24–34. PMID 8666521. |access-date= requires |url= (help)
  16. Lin CL, Kao JH (2011). "The clinical implications of hepatitis B virus genotype: Recent advances". J Gastroenterol Hepatol. 26 Suppl 1: 123–30. doi:10.1111/j.1440-1746.2010.06541.x. PMID 21199523.
  17. Cohen JA, Kaplan MM (1979). "The SGOT/SGPT ratio--an indicator of alcoholic liver disease". Dig Dis Sci. 24 (11): 835–8. PMID 520102.
  18. Williams AL, Hoofnagle JH (1988). "Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis". Gastroenterology. 95 (3): 734–9. PMID 3135226.
  19. Center for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Hepatitis B 2012.http://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html
  20. U.S Preventive Services Task Force. Hepatitis B. (2016) https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=hepatitis+b Accessed on October 10th, 2016
  21. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434.
  22. Lok AS, McMahon BJ (2009). "Chronic hepatitis B: update 2009". Hepatology. 50 (3): 661–2. doi:10.1002/hep.23190. PMID 19714720.
  23. "WHO".
  24. 24.0 24.1 Bialecki ES, Di Bisceglie AM (2005). "Diagnosis of hepatocellular carcinoma". HPB (Oxford). 7 (1): 26–34. doi:10.1080/13651820410024049. PMC 2023919. PMID 18333158.
  25. McGory RW, Ishitani MB, Oliveira WM, Stevenson WC, McCullough CS, Dickson RC; et al. (1996). "Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization". Transplantation. 61 (9): 1358–64. PMID 8629297.
  26. Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W; et al. (2005). "Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence". Liver Transpl. 11 (4): 402–9. doi:10.1002/lt.20402. PMID 15776431.
  27. Morbidity and Mortality Weekly Report. A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. (2006). http://www.cdc.gov/mmwr/PDF/rr/rr5516.pdf Accessed on October 4th, 2016
  28. 28.0 28.1 Centers for Disease Control and Prevention. Prevention and Control of Infections with Hepatitis Viruses in Correctional Settings http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5201a1.htm Accessed on October 4th 2016
  29. Ni JD, Xiong YZ, Wang XJ, Xiu LC. Does increased hepatitis B vaccination dose lead to a better immune response in HIV- infected patients than standard dose vaccination: a meta-analysis? Int J STD AIDS. 2013;24(2):117–22.
  30. Liu CJ, Liou JM, Chen DS, Chen P J.Natural course and treatment of dual hepatitis B virus and hepatitis C virus infections. J Formos Med Assoc Taiwan. 2005;104(11):783–91.
  31. Centers for Disease Control and Prevention. Viral Hepatitis - Hepatitis B Information. Perinatal Transmission (2016) http://www.cdc.gov/hepatitis/hbv/perinatalxmtn.htm Accessed on October 5th, 2016


Template:WH Template:WS

Historical Perspective

Hepatitis Main Page

Hepatitis B

Home

Patient Information

Overview

Historical Perspective

Pathophysiology

Causes

Differentiating Hepatitis B from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

CT

MRI

Ultrasound

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hepatitis B On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hepatitis B

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hepatitis B

CDC on Hepatitis B

Hepatitis B in the news

Blogs on Hepatitis B

Directions to Hospitals Treating Hepatitis B

Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [6], Sara Mehrsefat, M.D. [7]

Overview

The first descriptions of hepatitis (epidemic jaundice), recorded in the 5th century BCE, are generally attributed to Hippocrates.[1] In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman.[2] In 1947, the current nomenclature of hepatitis A (so-called infectious hepatitis) and hepatitis B (so-called serum hepatitis) was proposed by MacCallum and Bauer. Throughout the 20th century, advancements in the recognition, isolation, classification, and prevention of hepatitis B were achieved. Today, the focus around HBV remains on the spread of awareness and prevention across the world, especially in endemic areas that would benefit greatly from immunization programs.[3][4]

Historical Perspective

Early History

  • The first descriptions of hepatitis (epidemic jaundice), recorded in the 5th century BCE, are generally attributed to Hippocrates.[1]
  • In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman. Lurman's paper, which is regarded as a classic example of an epidemiological study, definitively identified contaminated lymph as the source of hepatitis outbreak.[2] Lurman described a form of hepatitis that was transmitted by direct inoculation of blood or blood products during a smallpox outbreak in Bremen, Germany. Thousands of shipyard employees were vaccinated against smallpox with a preparation made from human lymph. Between several weeks and 8 months later, 15% of the workers became ill with jaundice, while unvaccinated workers remained healthy.[3]
  • During the early 20th century, similar outbreaks of jaundice occurring after longer incubation periods were documented in clinics treating patients with syphilis, diabetes, and tuberculosis.[3]
  • In the 1920s, reports from clinics in Germany and the United States referred to the treatment of syphilis with intravenous therapy.[5] At the time, the so-called "salvarsan icterus" was thought to be a direct effect of the treatment for syphilis, rather than an artifact of the use of contaminated needles and syringes.
  • In 1926, Flaum, Malmros, and Persson published a paper on the role of syringes and needles in the transmission of the disease, in which they documented the distinctive incubation period of the infection compared to the so-called spontaneous catarrhal jaundice (now known as Hepatitis A). In their paper, they introduced the possibility that two different viruses might cause hepatitis.[5] Further evidence supporting the notion of the existence of at least two separate etiological agents causing hepatitis came during World War II, when jaundice epidemics were clearly distinguished among United States military personnel based on differences in transmission and incubation periods.[2]
  • In 1947, the current nomenclature of hepatitis A (so-called infectious hepatitis) and hepatitis B (so-called serum hepatitis) was proposed by MacCallum and Bauer. By this time, it was already known that in comparison with hepatitis A, hepatitis B:[3]
    • Was transmitted by percutaneous exposure to blood products
    • Had a longer incubation period (2-6 months)
    • Occurred more often in adults
  • In the 1960’s and 1970’s, Krugman et al. performed studies confirming these previously observed differences as well as the occurrence of homologous immunity after infection with hepatitis B.[5]
  • In 1965, the hepatitis B virus was discovered by Baruch Blumberg. He identified the Australia antigen (later known to be hepatitis B surface antigen or HBsAg) in blood collected from Australian aborigines.[6] In 1970, the virus particle was identified with electron microscopy by D.S. Dane et al.[7]
  • In 1970, the virus particle was identified with electron microscopy by D.S. Dane et al.[7]
  • In 1972, hepatitis B virus was classified into four subtypes: adr, adw, ayr, and yaw. This initial classification was based on the envelope protein of the virus. The four subtypes were noted to have different geographical distributions, which helped trace the route of infections.[8][9]

Discovery and Vaccine

  • By the early 1980s the genome of the hepatitis B virus had been sequenced.
  • Since 1982, a vaccine against hepatitis B has been available.[6]
  • Recent discoveries have allowed hepatitis B virus to be classified not only according to serotype, but according to genotype. Today, HBV is classified into ten genotypes (A-J) according to the variation of the nucleotide sequence of the genome.[10]

Global Health

  • In 1992, the Global Advisory Group to the World Health Organization (WHO) recommended that hepatitis B vaccine be incorporated into national immunization programs in all countries by 1997.
  • Since 2007, World Hepatitis Day has taken place on July 28. The intention of the day is to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis, and treatment. It has been led by the World Hepatitis Alliance.
  • On May 2010, the World Hepatitis Alliance received global endorsement from the World Health Organization.[11]

References

  1. 1.0 1.1 Center for Disease Control and Prevention.Epidemiology and Prevention of Vaccine Preventable Diseases 2012. http://www.cdc.gov/vaccines/pubs/pinkbook/hepa.html
  2. 2.0 2.1 2.2 Hussey, Hugh H. (1981). "The Hepatitis B Saga". JAMA: The Journal of the American Medical Association. 245 (13): 1317. doi:10.1001/jama.1981.03310380021018. ISSN 0098-7484.
  3. 3.0 3.1 3.2 3.3 Mahoney FJ (1999). "Update on diagnosis, management, and prevention of hepatitis B virus infection". Clin Microbiol Rev. 12 (2): 351–66. PMC 88921. PMID 10194463.
  4. Neefe, John R., Sydney S. Gellis, and Joseph Stokes. "Homologous serum hepatitis and infectious (epidemic) hepatitis: Studies in volunteers bearing on immunological and other characteristics of the etiological agents." The American journal of medicine 1.1 (1946): 3-22.
  5. 5.0 5.1 5.2 "Evolution of Concepts of Hepatitis".
  6. 6.0 6.1 Alter HJ, Blumberg BS (1966). "Further studies on a "new" human isoprecipitin system (Australia antigen)". Blood. 27 (3): 297–309. PMID 5930797. Retrieved 2012-02-08. Unknown parameter |month= ignored (help)
  7. 7.0 7.1 Dane DS, Cameron CH, Briggs M (1970). "Virus-like particles in serum of patients with Australia-antigen-associated hepatitis". Lancet. 1 (7649): 695–8. PMID 4190997. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  8. Mazzur S, Burgert S, Blumberg BS (1974). "Geographical distribution of Australia antigen determinants d, y and w." Nature. 247 (5435): 38–40. PMID 4128782.
  9. Yamanaka T, Akahane Y, Suzuki H, Okamoto H, Tsuda F, Miyakawa Y; et al. (1990). "Hepatitis B surface antigen particles with all four subtypic determinants: point mutations of hepatitis B virus DNA inducing phenotypic changes or double infection with viruses of different subtypes". Mol Immunol. 27 (5): 443–9. PMID 1694959.
  10. Enomoto M, Tamori A, Nishiguchi S (2006). "Hepatitis B virus genotypes and response to antiviral therapy". Clin Lab. 52 (1–2): 43–7. PMID 16506363.
  11. World Health Organization. Viral hepatitis (2010). http://apps.who.int/gb/ebwha/pdf_files/EB126/B126_R16-en.pdf Accessed on October 5th, 2016


Template:WH Template:WS

Pathophysiology

Hepatitis Main Page

Hepatitis B

Home

Patient Information

Overview

Historical Perspective

Pathophysiology

Causes

Differentiating Hepatitis B from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

CT

MRI

Ultrasound

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hepatitis B On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hepatitis B

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hepatitis B

CDC on Hepatitis B

Hepatitis B in the news

Blogs on Hepatitis B

Directions to Hospitals Treating Hepatitis B

Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [8]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [9], Sara Mehrsefat, M.D. [10]

Overview

The intracellular hepatitis B virus is a non-cytopathic virus that causes little or no damage to the cell.[1] During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host's cell mechanisms to replicate its genome and proteins. Different viral antigens and antibodies may be detected in serum throughout the course of the disease, including HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBC, and anti-HBe. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.[2][3]

Pathogenesis

Immunopathogenesis

The host immune response is primarily responsible for both hepatocellular damage and viral clearance in patients with HBV infection. While the innate immune response does not play a significant role in these processes, the adaptive immune response (particularly virus-specific cytotoxic T lymphocytes) contributes to nearly all of the liver injury associated with HBV infection.[1][2][3]

Life Cycle

  • Several cellular receptors have been identified, including the transferrin receptor, the asialoglycoprotein receptor molecule, and the human liver endonexin. However, the mechanism by which HBsAg binds to a specific receptor to enter cells has not yet been established. Viral nucleocapsids enter the cell and reach the nucleus, where the viral genome is delivered.[1][4][5][6]
  • In the nucleus, second-strand DNA synthesis is completed and the gaps in both strands are repaired to yield a covalently closed circular (ccc) supercoiled DNA molecule that serves as a template for the transcription of four viral RNAs that are 3.5, 2.4, 2.1, and 0.7 kb long.[4][7]
  • These transcripts are polyadenylated and transported to the cytoplasm, where they are translated into the viral nucleocapsid and precore antigen (C, pre-C), polymerase (P), envelope L (large), M (medium), S (small)), and transcriptional transactivating proteins (X).[4][8]
  • The new, mature, viral nucleocapsids can then follow either of two different intracellular pathways. One of these pathways leads to the formation and secretion of new virions, while the other leads to the amplification of the viral genome inside the cell nucleus. In the virion assembly pathway, the nucleocapsids reach the ER, where they associate with the envelope proteins and bud into the lumen of the ER, at which point they are secreted via the Golgi apparatus out of the cell.[1]

HBV Antigens and Antibodies

Nomenclature Full Name Description[1]
HBV Hepatitis B Virus (complete infectious virion) The 42 nm, double-shelled particle, that consists of a 7 nm thick outer shell and a 27 nm inner core. The core contains a small, circular, partially double-stranded DNA molecule and an endogenous DNA polymerase. This is the prototype agent for the family epadnaviridae.
HBsAg Hepatitis B Surface Antigen (envelope antigen) The complex of antigenic determinants found on the surface of HBV and of 22 nm particles and tubular forms.
HBcAg Hepatitis B Core Antigen The antigenic specificity.
HBeAg Hepatitis B e Antigen The antigenic determinant that is closely associated with the nucleocapsid of HBV. It also circulates as a soluble protein in serum.
Anti-HBs
Anti-HBc
Anti-HBe
Antibody to HBsAg
Antibody to HBcAg
Antibody to HBeAg
Specific antibodies that are produced in response to their respective antigenic determinants.

Transmission

Coinfections

Hepatitis D

HIV

  • About 10% of people living with HIV in the United States are coinfected with HBV.[12]
  • HIV-positive patients who are coinfected with HBV are at increased risk for serious, life-threatening health complications. HIV/HBV coinfection can also complicate the management of HIV infection.[12]
  • Hepatitis B is preventable through vaccination. HBV vaccination is recommended for people who are at risk for or living with HIV and who have tested negative for HBV.
  • Persons infected with HIV are more likely to develop persistent infection with HBV.[1]
  • HIV infection is one of the factors that may reduce the immunogenicity of hepatitis vaccines, along with age (>40 years), gender, weight, genetics, hemodialysis, immunosuppression, and tobacco smoking.[1]

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Zhang YY, Hu KQ (2015). "Rethinking the pathogenesis of hepatitis B virus (HBV) infection". J Med Virol. 87 (12): 1989–99. doi:10.1002/jmv.24270. PMID 25989114.
  3. 3.0 3.1 3.2 3.3 3.4 Chang KM, Liu M (2016). "Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics". Curr Opin Pharmacol. 30: 93–105. doi:10.1016/j.coph.2016.07.013. PMID 27570126.
  4. 4.0 4.1 4.2 Nathanson, Neal (1997). Viral pathogenesis. Philadelphia: Lippincott-Raven. ISBN 0781702976.
  5. Plotkin, Stanley (1999). Vaccines. Philadelphia: W.B. Saunders Co. ISBN 0721674437.
  6. Guidotti LG, Martinez V, Loh YT, Rogler CE, Chisari FV (1994). "Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice". J Virol. 68 (9): 5469–75. PMC 236947. PMID 8057429.
  7. Plotkin, Stanley (1999). Vaccines. Philadelphia: W.B. Saunders Co. ISBN 0721674437.
  8. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434.
  9. Petersen NJ, Barrett DH, Bond WW, Berquist KR, Favero MS, Bender TR; et al. (1976). "Hepatitis B surface antigen in saliva, impetiginous lesions, and the environment in two remote Alaskan villages". Appl Environ Microbiol. 32 (4): 572–4. PMC 170308. PMID 791124.
  10. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434.
  11. Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  12. 12.0 12.1 AIDS. Hepatitis B and AIDS. (2015) https://www.aids.gov/hiv-aids-basics/staying-healthy-with-hiv-aids/potential-related-health-problems/hepatitis-b/ Accessed on October 5th, 2016


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Natural History, Complications & Prognosis


Diagnosis

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Treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [11]