Hepatitis B Virus

Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. The virus can cause potentially life-threatening liver disease. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Management of acute hepatitis is typically supportive. Administration of antivirals or liver transplantation may be necessary in fulminant and chronic cases.

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Classification

Dna virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Structure

  • Taxonomy: Hepadnaviridae family, Orthohepadnavirus genus
  • DNA: circular (icosahedral) and partially double stranded
  • Small (30–42 nm)
  • 8 different genotypes are known.
Structure of hepatitis b virus

Structure of hepatitis B virus (HBV):
The virus particle (virion) is made up of an outer lipid envelope. The nucleocapsid (core) encloses the viral DNA and a DNA polymerase, which has reverse transcriptase activity. The outer envelope contains proteins, which help the virus bind to and enter target cells.

Image: “Hepatitis B Virus (HBV)” by Mansouri, N., et al. License: CC BY 3.0, edited by Lecturio.

Features

  • Causes acute and chronic hepatitis
  • Infection is preventable by vaccination (95% efficiency).
  • One of the most common causes of liver cirrhosis
Electron micrograph of the hepatitis b virus

Electron micrograph of the hepatitis B virus (HBV)

Image: “Hepatitis-B virions” by CDC. License: Public Domain

Epidemiology and Pathogenesis

Epidemiology

  • Hepatitis B virus (HBV) is the most common viral hepatitis worldwide.
  • Highest prevalence: Asia, sub-Saharan Africa, South America, and the Middle East
  • In the United States: 
    • Approximately 2 million people have chronic HBV. 
    • Very low prevalence in children < 12 years of age

Transmission

  • The only reservoir for HBV: humans
  • Unprotected sexual intercourse: ⅔ of cases
  • Parenteral: e.g., shared IV drug needles, accidental needle sticks
  • Mother to child: most common in high-prevalence areas

Host risk factors

  • Persons who inject drugs (PWIDs)
  • Unprotected sex with multiple partners
  • Men who have sex with men (MSM)
  • HIV infection
  • Hemodialysis
  • Infants born to HBV-positive mothers
  • Professions with exposure to human blood or seminal/vaginal fluids 
  • Individuals on hemodialysis or recipients of organ/blood transfusion

Pathophysiology

  • HBV infects liver cells expressing viral peptides on the surface → peptides activate lymphocytes (CD8+ cytotoxic T cells) → WBCs mount a cellular immune response against infected liver cells → destruction of hepatocytes → liver inflammation
  • Primary replication:
    • Exposure to infectious bodily fluids → replication in the mucosa → bloodstream (1st viremia)
    • Reaches the liver due to tissue tropism (hepatotropic due to receptor recognition)
    • Viral uptake by hepatocytes via a receptor on the plasma membrane
    • Replication occurs in hepatocytes and Kupffer cells (hepatic macrophages):
      • After cell entry → a double-stranded relaxed circular DNA (rcDNA) positive strand is completed by the viral polymerase
      • The RNA polymerase of the host transcribes DNA into viral mRNA.
      • Viral mRNA is reverse transcribed into viral rcDNA → viral mRNA and reverse transcriptase are packaged into a capsid → new viral DNA genomes are enveloped
    • Newly enveloped virus particles are excreted into the bloodstream and infect bodily fluids.
    • Hepatic injury is immune related (no viral cytotoxicity):
      • Immunologic response to infection
      • Accompanied by portal and periportal lymphocytic infiltration→ varying degree of necrosis
Hepatitis b virus (hbv) replication

Hepatitis B virus (HBV) replication:
The HBV is phagocytosed to replicate by utilizing the replication machinery of the host cell.

Image: “HBV replication” by Graham Beards. License: Public Domains

Clinical Presentation

Acute infection

  • Incubation time: 1–6 months 
  • ⅔ of individuals with acute infection are asymptomatic.
  • ⅓ of individuals develop symptoms of acute hepatitis: 
    • Nausea and vomiting
    • Jaundice
    • Fever
    • Tiredness
    • Dark urine
    • Abdominal pain 
    • Myalgias and arthralgias
  • Symptom duration: often only a few weeks
  • Death is rare.

Chronic infection

  • Approximately 5% of cases show persistent viral infection.
  • Only 30% of the cases with persistent viral infection develop chronic hepatitis.
  • Can lead to acute-on-chronic exacerbation
  • Acute reactivation:
    • Asymptomatic
    • May mimic the course of acute infection 
    • May develop liver failure 
  • Cirrhosis
  • Hepatocellular carcinoma (HCC)
  • Extrahepatic manifestations:
    • Vasculitis: 
      • Panarteritis nodosa
      • Sicca syndrome
      • Raynaud syndrome
      • Uveitis
    • Neuritis and polyneuropathy
    • Glomerulonephritis
    • Skin rashes

Diagnosis

Viral markers

  • Hepatitis B surface antigen (HBsAg): 
    • Increased in acute hepatitis B, chronic hepatitis B, and asymptomatic carriers
    • Detectable 4 weeks after exposure → false negative results possible
  • Hepatitis B surface antibody (anti-HBs):
    • Corresponding antibody to HBsAg
    • Marker for recovery from infection
  • Hepatitis B core antigen (HBcAg): not routinely used in HBV testing
  • Hepatitis B core antibody (anti-HBc):
    • Corresponding antibody to HBcAg
    • Common screening parameter indicating contact to HBV
    • Total Anti-HBc: does not differentiate between acute, chronic, or past infection
    • Anti–HBc-IgM: acute HBV infection
    • Anti–HBc-IgG: always detectable after contact to HBV (unspecific)
  • Hepatitis B envelope antigen (HBeAG): indicator of active viral replication
  • Hepatitis B e antibody (anti-HBe):
    • Corresponding antibody to HBeAg
    • Indicates the transition to recovery from HBV infection 
  • HBV DNA:
    • Measure of viral load
    • Used to monitor efficacy of antiviral therapy
    • > 20 IU/mL indicates replication of the virus → individual is contagious

Laboratory evaluation

Screening for HBV infection:

  • Perform in the following cases: symptoms of acute hepatitis, high risk of exposure, and/or increased risk for severe disease course
  • HBsAg:
    • Detectable 1–6 months after infection
    • Early infection may not be discovered.
  • Anti-HBc: IgM and IgG
  • If both positive → acute or chronic HBV infection

Acute hepatitis B:

  • ↑ HBsAg anti–HBc-IgM
  • ↑ Transaminases 

HBV-vaccinated individuals:

  • Anti-HBs positive
  • Anti-HBc negative

Chronic hepatitis B:

  • ↑ HBsAg for > 6 months
  • Anti-HBe and Anti-HB not elevated!
  • HBeAg may be elevated.
  • ↑ HBV DNA 

Additional parameters

  • Hallmark of early acute disease is ↑ transaminases:
    • ALT and AST: 1000–2000 IU/mL
    • ALT > AST
  • Gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP): usually ↑ but < 3x the upper limit of normal
  • Erythrocyte sedimentation rate (ESR): may be ↑
  • Signs of severe disease: 
    • Hemolysis
    • Thrombocytopenia
    • ↑ INR
Laboratory parameters of hbv infection

Laboratory parameters of hepatitis B virus (HBV) infection:
The chart shows the typical course of important markers in diagnosis of HBV infection after viral exposure.

Image by Lecturio.

Management and Prevention

Management

Acute hepatitis B:

  • No specific therapy available
  • Treatment is supportive.

Chronic hepatitis B:

  • 1st-line treatment: 
    • Pegylated interferon alfa (PEG-IFN-α)
    • Entecavir (ETV)
    • Tenofovir disoproxil fumarate (TDF) 
    • Indications: 
      • HBV DNA positivity with clinical complications
      • Cirrhosis
      • Acute liver failure
      • Reactivation of chronic HBV during or after chemotherapy
      • Immunosuppression
    • Treatment goals:
      • Reversal of liver disease 
      • ↓ DNA levels of HBV
      • Seroconversion to anti-HBe
    • Contraindications:
      • Mental illness
      • Decompensated cirrhosis (e.g., ascites, encephalopathy)
      • Autoimmune conditions
      • Leukopenia or thrombocytopenia
      • Kidney dysfunction
  • Liver transplantation: the only curative treatment option in cases of end-stage liver disease 

Prevention

Screening:

Screening for HBV infection is recommended by the CDC for the following groups:

  • Individuals from areas with medium-to-high HBV prevalence
  • Needle injuries (e.g., medical staff, IV drug users)
  • Pregnant individuals
  • Newborns of mothers with known, active HBV infection

Vaccination:

  • HBV vaccine: active, leads to long-term immunity
  • For infants:
    • 3-dose series
    • Administered at 0, 1, and 6 months
  • For adults: 2-dose series (1 month apart) 
  • Hepatitis A + B combination vaccine is also available as 3-dose series.

Postexposure prophylaxis (PEP):

Options dependent on immunization status:

  • Active immunization (hepatitis B vaccination)
  • Passive immunization (hepatitis B immune globulin)
  • Combined active and passive immunization
  • No immunization

Hepatitis Viruses Comparative Table

Comparison table of hepatitis viruses

Anti-HBc: hepatitis B core antibody
Anti-HBs: hepatitis B surface antibody
HBcAg: hepatitis B core antigen
HBsAg: hepatitis B surface antigen
HBV: hepatitis B virus
HCC: hepatocellular carcinoma
HCV: hepatitis C virus
HDV: hepatitis D virus

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Alcoholic liver disease (ALD): liver pathology occurring due to prolonged, excessive alcohol consumption. The 1st stage is asymptomatic fatty liver, which is reversible. The 2nd stage is alcoholic hepatitis, which most commonly presents with jaundice, fever, and RUQ pain. Liver cirrhosis occurs in the 3rd stage. Diagnosis is established by history, liver function tests, and imaging studies. 
  • Drug-induced liver injury (DILI): occurs when ingested drugs directly injure the hepatocytes in a predictable, dose-dependent way, or through idiosyncratic reactions. The presentation can be acute or chronic. Severe toxicity manifests as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests. Management consists of early diagnosis, discontinuation of the drug, and supportive therapy.
  • Autoimmune hepatitis (AIH): liver inflammation occurring when the immune system attacks the liver cells. Clinical presentation may range from asymptomatic to symptoms of acute liver failure. Diagnosis is established via blood testing for the characteristic autoantibodies (especially anti-smooth muscle antibodies) and liver biopsy. Management includes corticosteroids and azathioprine. 
  • Wilson disease: an autosomal recessive disorder from a mutation in the ATP7B gene, which regulates copper transport within hepatocytes. Neuropsychiatric manifestations differentiate Wilson disease from other causes of hepatitis. In early stages, Wilson disease may be confused with hepatic encephalopathy. Kayser-Fleischer rings and low ceruloplasmin levels help separate Wilson disease from other causes of hepatitis.
  • Nonalcoholic fatty liver disease (NAFLD): a spectrum of liver pathology arising from accumulation of triglycerides in hepatocytes. The disease ranges from fatty liver/hepatic steatosis to nonalcoholic steatohepatitis, which has fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and, possibly, primary liver cancer. Management is through lifestyle modifications (e.g., diet, exercise).

References

  1. Sorrell, M.F., Belongia, E.A., Costa, J., et al. (2009). National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 150(2), 104–10. https://pubmed.ncbi.nlm.nih.gov/19124811/
  2. Centers for Disease Control and Prevention. (2020). Hepatitis B information for health professionals: hepatitis B FAQs for health professionals. Retrieved January 27, 2021, from https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview
  3. Te, H.S., Jensen, D.M. (2010). Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis. 14(1), 1–21, vii. https://pubmed.ncbi.nlm.nih.gov/20123436/
  4. World Health Organization. (2011). Weekly epidemiological record (WER): global routine vaccination coverage. 86(46), 509–20. http://www.who.int/wer/2011/wer8646/en/index.html
  5. Pyrsopoulos, N. (2020). Hepatitis B. Emedicine. Retrieved January 28, 2021, from https://emedicine.medscape.com/article/177632-overview#a3
  6. Lok, A. (2020). Hepatitis B virus: Overview of management. Retrieved January 27, 2021, from https://www.uptodate.com/contents/hepatitis-b-virus-overview-of-management

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