Hepatitis B Virus - HBV

Diagnosis

Indications for Testing

  • New onset of jaundice, anorexia, or dark urine
  • Known exposure to hepatitis
  • Suspicion of chronic hepatitis (elevated liver enzymes)
  • Initial screening for acute hepatitis indicates HBV infection

Laboratory Testing

  • Testing and treatment recommendations (CDC, 2008)
  • Differentiation between acute and chronic hepatitis
    • Acute suspected HBV – confirmed if HBV core antibody (anti-HBc) IgM and HBV surface antigen (HBsAg) positive
    • Chronic HBV – HBsAg positive for >6 months
      • Two patterns in active chronic disease – hepatitis B e antigen (HBeAg) positive, anti-HBe negative, high HBV DNA; or HBeAg negative, anti-HBe positive and high HBV DNA
      • Pattern in chronic but inactive HBV – HBeAg negative, anti-HBe positive and undetectable or low HBV DNA
    • If either the surface antigen or DNA test is positive – carrier is contagious
  • All individuals with chronic HBV should be tested for HCV
  • Acute deterioration in patient with known HBV – test for coinfection/superinfection with hepatitis D (HDV)
  • Liver biopsy (EASL, 2009; AASLD, 2009)
    • In active disease – treatment may help
    • Useful in patients where advanced fibrosis not suggested by noninvasive testing
    • Patients should have evidence of active disease – elevated transaminases and DNA >2000 IU/mL

Histology

  • Immunohistochemistry for biopsy material – consider HbsAg or HBcAg

Differential Diagnosis

Screening

Screening recommendations for HBV (CDC, 2008; AASLD, 2009)

Population

Screening 
recommendation

Persons born in regions of high and intermediate HBV prevalence (>2%) (eg, Africa, Asian-Pacific)

CDC 2008

Injection-drug abusers

CDC 2008

Men who have sex with men

CDC 2008

Hemodialysis

CDC 2001

All pregnant women

CDC 2005

Infants born to HBsAg-positive mothers

CDC 2005, 2007, 2008

Donors of blood, plasma, organs, tissue, and semen

Code of Federal Regulations (FDA)

US-born persons not vaccinated as infants whose parents were born in region of high HBV prevalence (>8%)

CDC 2008

Persons with elevated ALT/AST of unknown etiology

CDC 2008

HIV-positive persons

CDC 2004

Household, needle-sharing or sex contacts of persons known to be HBsAg positive

CDC 2005

Persons who are sources for exposures (needle-stick, sexual assault)

CDC 2004

Persons needing immunosuppressive therapy (transplant, rheumatology, and gastroenterology)

CDC 2008

Monitoring

  • Monitor chronic disease every 6 months
    • HBsAg, HBeAg, anti-HBe, anti-HBs, HBV DNA, transaminases
      • May need more frequent monitoring for those in immune-active phase
      • Less frequent monitoring for those in inactive phase

Clinical Background

Hepatitis B (HBV) is a blood-borne virus and one of the most common infectious diseases in the world.

Epidemiology

  • Incidence
    • 1/3 of world population has been exposed
      • 350 million – chronically infected
    • Endemic in Asia, sub-Saharan Africa, Pacific Islands, and parts of Latin America
    • U.S. cases have dropped 80% with vaccination
      • Prevalence of chronic disease <2%
  • Transmission
    • Parenteral – common infection route in low-prevalence regions
    • Sexual – common infection route in low-prevalence regions
    • Vertical perinatal – main infection route in endemic regions
    • Horizontal – from chronically infected person in a household
  • Ethnicity – more common in Alaskan native population

Organism

  • DNA virus of Hepadnaviridae family
  • Eight HBV subgroups (A-H) based on genetic differences
    • Genotypes tend to be geographically based
    • Genotype A most common in U.S.
    • Genotype may be associated with disease progression and response to treatment
    • Each subgroup may have subtypes (eg, A1, A2, A3)
  • Infection not directly cytotoxic to hepatocytes
    • Severity of injury is modulated by host immune responses
  • High titers of HBV are present in blood; moderate titers are present in vaginal secretions, semen, and saliva

Risk Factors

  • Parenteral drug abuse
  • Multiple sex partners (more than 1 partner during the preceding 6 months)
  • Sexual transmission from HBV-positive partner
  • Infants of HBV-infected mothers
  • Persons infected with HIV
  • Alaskan native and Pacific Islander children
  • Children residing in households of first-generation immigrants from countries where HBV infection is endemic
  • Needlestick
    • 1-6% risk if blood is HBsAg(+)
    • 22-40% risk if blood is HBsAg(+) and HBeAg(+)
  • Hemodialysis

Pathophysiology

  • Phases of chronic HBV (NIH, 2007)

    Phases of Chronic HBV

    Phase

    HBeAg

    Anti-HBe

    HBV DNA

    Transaminases

    Immune-tolerant

    • Occurs over a prolonged period when infection is acquired perinatally or in early childhood
    • Minimal histologic damage
    • Mild or no liver necroinflammation
    • No or slow progression to fibrosis
    PositiveNegativeHigh – >2000 IU/mLNormal

    Immune-active

    • Lasts several months to years
    • Moderate to severe liver necroinflammation
    • Rapid progression to fibrosis may occur
    • Loss of HBeAg and seroconversion to anti-HBe often occur
    PositiveNegativeModerately high – >2000 IU/mLElevated

    Inactive

    • Follows seroconversion from HBeAg positive to anti-HBe antibody positive
    • Favorable long-term outcome with low risk of progression to hepatocellular carcinoma (HCC) or cirrhosis
    NegativePositiveAbsent or low – <2000 IU/mLNormal
    HBsAg clearanceNegativePositiveAbsent or low – <1000 IU/mLNormal
    ReactivatedNegativePositive or negativeModerately highElevated
  • Infants and young children are at the greatest risk for becoming chronically infected
    • 95% of perinatal transmission occurs at time of birth
    • 5-20% risk of vertical transmission if mother is HBsAg positive
      • 70-90% risk of vertical transmission if mother is HBsAg and HBeAg positive
    • 90% of exposed infants will develop chronic hepatitis
    • 30% of exposed children ages 1-5 will develop chronic hepatitis
    • Only 5% of exposed adults will develop chronic hepatitis
  • Breast feeding does not increase risk and need not be discontinued by an infected mother

Clinical Presentation

  • Acute HBV
    • Likelihood of developing symptoms is age dependent
      • Children generally asymptomatic
      • ~50% of adolescents have symptoms
    • Incubation period of 2 weeks to 4 months
      • Approximately 50% of those infected usually have symptoms appear 25 to 180 days following exposure
    • Mildest attacks are asymptomatic anicteric and detectable only by an increase in serum transaminase levels
    • Influenza-like symptoms – fatigue, malaise, fever, anorexia
    • Jaundice and gastrointestinal symptoms (usually within 10 days of symptom onset)
    • May develop acute fulminant hepatic failure requiring transplantation (~1% of cases)
      • Rapidly progressive hepatitis with signs of liver failure – coagulopathy, encephalopathy, cerebral edema
  • Chronic HBV
    • Most common presentations are fatigue or vague, right-upper quadrant discomfort
    • Patients may have systemic symptoms associated with deposition of circulating hepatitis B antigen-antibody immune complexes (ie, arthritis, leukocytoclastic vasculitis, glomerulonephritis, cryoglobulinemia, and generalized vasculitis)
    • Long-term consequences include cirrhosis and hepatocellular carcinoma
      • Cirrhosis may present with jaundice, ascites, splenomegaly, encephalopathy, or variceal bleeding
    • Annual incidence for HCC is <1% for noncirrhotic HBV-infected “carriers” and 2-3% for patients with cirrhosis
    • Annual incidence of cirrhosis is 2-6% for HBeAg-negative and 8-10% for HBeAg positive chronic hepatitis patients

Prevention

  • Vaccination recommended for the following
    • Persons residing in communities with an increased prevalence of infection
    • Persons traveling to a country with high prevalence rates
    • Health care workers
    • All neonates and children
    • HIV-positive patients
    • Residents of correctional facilities
  • Immediate short-term protection (3-6 months) against HBV can be obtained with hepatitis B IgG

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Initial screening for hepatobiliary inflammation

Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

   
Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457
Method: Qualitative Chemiluminescent Immunoassay

Order when patient has had clinical acute hepatitis of unknown origin for less than 6 months

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody

Positive HAV IgM indicates current or recent infection; false positives are common

   
Hepatitis B Virus Surface Antigen with Reflex to Confirmation 0020089
Method: Qualitative Chemiluminescent Immunoassay 

For acute onset of hepatitis, order along with HBV core IgM, HAV IgM, and HCV antibodies to diagnose viral causative agent

   
Hepatitis B Virus Surface Antibody 0020090
Method: Quantitative Chemiluminescent Immunoassay
Quantification of HBV surface antibodies provides useful means of monitoring post-liver-transplant therapy with hepatitis B immunoglobulin in HBV-positive patients and ascertaining response to HBV vaccines    
Hepatitis B Virus Core Antibody, IgM 0020092
Method: Qualitative Chemiluminescent Immunoassay

For acute onset of hepatitis, order along with HBV surface antigen, HAV IgM, and HCV antibodies to diagnose viral causative agent

   
Hepatitis B Virus Core Antibodies (Total) 0020091
Method: Qualitative Chemiluminescent Immunoassay
Useful screening tool in patients about to undergo immunosuppression to identify candidates for prophylactic nucleoside analog therapy to prevent severe life-threatening HBV reactivation Tests for IgG and IgM antibodies but does not differentiate between them  
Hepatitis Be Virus Antigen 0020094
Method: Qualitative Enzyme Immunoassay

Monitor HBV therapy; order along with HBV DNA, HBV surface antigen, HBV surface antibody and HBe antibody

Order only when a patient is known to be positive for HBV surface antigen

Surrogate marker for HBV replication and infectivity
Hepatitis Be Virus Antibody 0020095
Method: Qualitative Enzyme Immunoassay

Monitor HBV therapy; order along with HBV DNA, HBV surface antigen, HBV surface antibody and HBe antibody

Treatment-induced HBeAg seroconversion is an important therapeutic milestone in HBeAg-positive patients and is also an important therapeutic goal

   
Hepatitis B Virus Surface Antigen with Reflex to Confirmation, Prenatal  2007573
Method: Qualitative Chemiluminescent Immunoassay 

Order for HBV screening in pregnant women

   
Hepatitis B Virus DNA Quantitative, Real-Time PCR 0056025
Method: Quantitative Real-Time Polymerase Chain Reaction

Assess viral response to treatment as measured by changes in the HBV DNA levels

Monitor HBV therapy; order along with HBV surface antigen, HBV surface antibody, HBe antigen, and HBe antibody

Monitor patients who were infected with HBV prior to liver transplantation

Viral loads are predictive of future risk of developing cirrhosis and HCC

   
Hepatitis B Virus DNA Quantitative, Real-Time PCR with Reflex to Genotyping 2004722
Method: Quantitative Real-Time Polymerase Chain Reaction/Sequencing

Determine viral load for therapeutic considerations

Genotyping may be helpful in selecting antiviral therapies

   
Hepatitis B Surface Antigen by Immunohistochemistry 2003917
Method: Immunohistochemistry

Aid in histologic diagnosis of HBV

Stained and returned to client pathologist; consultation available if needed

Gold standard for diagnosis of HBV infection

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Hepatitis B Virus Surface Antigen, Confirmation 0020128
Method: Chemiluminescent Immunoassay

Indicates acute or chronic infection

Hepatitis B Virus Panel, Chronic with Reflex to HBsAg Confirmation 0020454
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Enzyme Immunoassay

Indicates stage of infection; should only be ordered if patient has HBV surface antigen

Hepatitis B Virus Surface Antigen Confirmation, Prenatal  2007575
Method: Chemiluminescent Immunoassay

Order for confirmation of HBV in prenatal testing

Hepatitis C Virus Antibody by CIA 2002483
Method: Qualitative Chemiluminescent Immunoassay
Hepatitis B Virus Genotype by Sequencing 2001567
Method: Polymerase Chain Reaction/Sequencing

May be unsuccessful if the HBV viral load is less than log 3.0 or 1,000 IU/mL of plasma