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 – screen for HBV core antibody (anti-HBc) IgM, hepatitis A (HAV) IgM, hepatitis C (HCV) antibody, and HBV surface antigen (HBsAg)
      • Confirmed if anti-HBc IgM and HBsAg positive
    • Chronic HBV – HBsAg positive for >6 months
      • Active chronic disease
        • Hepatitis Be antigen (HBeAg) positive, anti-HBe negative, high HBV DNA; or HBeAg negative, anti-HBe positive, and high HBV DNA
      • Inactive chronic disease
      • HBeAg negative, anti-HBe positive, and undetectable or low HBV DNA
    • If either the surface antigen or DNA test is positive – patient is contagious
  • All patients 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)
    • Patients should have evidence of active disease – elevated transaminases and DNA >2000 IU/mL
    • In active disease – results of biopsy may guide therapy
    • Useful in patients where advanced fibrosis not suggested by noninvasive testing

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
    • ~30% of world population has been exposed (Trepo, 2014)
      • 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 and Pacific Islander populations

Organism

  • DNA virus of Hepadnaviridae family
  • At least 10 HBV subgroups (A-J) based on genetic differences
    • Genotypes tend to be geographically based
    • Genotype A most common in North America, Northern Europe
    • 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 (>1 partner during the preceding 6 months)
  • HBV-positive partner
  • Infants of HBV-infected mothers
  • HIV infection
  • Alaskan native and Pacific Islander children
  • Men who have sex with men (MSM)
  • 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
  • Blood transfusion (predominantly in developing countries)

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
  • Breastfeeding 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
      • Adults and adolescents have higher rate of being symptomatic
    • Incubation period of 2 weeks to 4 months
    • Mildest disease is 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 presentation is fatigue or vague, right-upper quadrant discomfort
    • Patients may have systemic symptoms associated with deposition of circulating hepatitis B antigen-antibody immune complexes (eg, 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
    • Healthcare 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 abnormalities

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 to evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

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

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

Can be ordered as part of the acute hepatitis panel which includes HAV IgM, HBV core antibody IgM, HBV surface antigen, and HCV antibody

   
Hepatitis B Virus Surface Antibody 0020090
Method: Quantitative Chemiluminescent Immunoassay

Monitor post-liver transplant therapy with hepatitis B immunoglobulin in HBV-positive patients and ascertain response to HBV vaccines

   
Hepatitis B Virus Core Antibody, IgM 0020092
Method: Qualitative Chemiluminescent Immunoassay

Can be ordered as part of the acute hepatitis panel which includes HAV IgM, HBV core antibody IgM, HBV surface antigen, and HCV antibody to determine if patient has acute HBV infection

   
Hepatitis B Virus Core Antibodies (Total) 0020091
Method: Qualitative Chemiluminescent Immunoassay

Determine exposure to HBV infection

May be helpful in determining which patients are at risk for HBV reactivation and would benefit from prophylactic nucleoside analog therapy prior to initiation of immunosuppression therapy 

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 in conjunction 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 in conjunction with HBV DNA, HBV surface antigen, HBV surface antibody and HBe antigen    
Hepatitis Be Virus Antigen and Antibody Panel 2012141
Method: Qualitative Enzyme Immunoassay

Monitor confirmed chronic hepatitis B infection

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

Order for HBV screening in pregnant women (prenatal testing)

   
Hepatitis B Virus by Quantitative PCR 0056025
Method: Quantitative Polymerase Chain Reaction

Monitor treatment

Quantitative range – 1.3-8.2 log IU/mL (20-170,000,000 IU/mL)

If virus is not detected, the test result will be reported as <1.3 log IU/mL (<20 IU/mL); if virus is detected but number of copies not accurately quantified, the test result will be reported as not quantified

   
Hepatitis B Virus (HBV) by Quantitative PCR with Reflex to HBV Genotype by Sequencing 2004722
Method: Quantitative Polymerase Chain Reaction/Sequencing

Determine viral load for therapeutic considerations

Genotyping may be helpful in selecting antiviral therapies

Limit of quantification is 1.3 log IU/mL (20 IU/mL)

Reflex pattern – if HBV Quantitative PCR result is ≥3.0 log IU/mL (1000 IU/mL), then HBV genotype by sequencing will be added

   
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

Detect acute or chronic HBV infection

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

Indicates stage of infection

Use to monitor patients with chronic HBV infection and known positive HBV surface antigen

Reflex pattern – if results for HBsAg are repeatedly reactive with an index value of 1.00-50.00, then HBsAg confirmation will be added

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

Order for confirmation of HBV in prenatal testing (prenatal testing)

Hepatitis C Virus Antibody by CIA 2002483
Method: Qualitative Chemiluminescent Immunoassay

Preferred single screening test for one time screening of population born between 1945-1965 and individuals at risk for HCV

Positive results require confirmation by molecular testing

Hepatitis B Virus Genotype by Sequencing 2001567
Method: Polymerase Chain Reaction/Sequencing

HBV RT polymerase and HBsAg encoding regions are sequenced

Resistance and surface antigen mutations are reported

In addition, the major HBV genotypes are identified

Mutations in viral subpopulations <20% of total may not be detected