Hepatitis B Virus - HBV

Hepatitis B (HBV) is a bloodborne virus and one of the most common infectious diseases in the world. HBV can cause acute or chronic infection. Chronic HBV infection can lead to cirrhosis or liver cancer. Laboratory testing involves serology, which allows for differentiation of acute versus chronic disease.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

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

Criteria for Diagnosis

Acute HBV case definition and case classification (CDC, 2012)

Laboratory Testing

  • Testing and treatment recommendations (CDC, 2016)
  • Differentiate between acute and chronic hepatitis
    • If acute HBV is suspected, test as follows
      •  To determine HBV status
        • HBV core antibody (anti-HBc) IgM
        • HBV surface antigen (HBsAg)
      • To determine alternative or coinfection
    • Interpretation
      • Positive anti-HBc IgM and HBsAg confirm acute HBV
      • If either HBsAg or HBV DNA test is positive, patient is contagious
    • If HBsAg is positive for >6 months – chronic HBV
      • To determine whether active or inactive, test
        • Hepatitis Be antigen (HBeAg)
        • Anti-HBe
        • HBV DNA
      • Interpretation
        • Active chronic disease
          • HBeAg positive, anti-HBe negative, and 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
  • Test all patients with chronic HBV for HCV
  • Test for coinfection/superinfection with hepatitis D (HDV) in patients with known HBV and acute deterioration
  • Liver biopsy (Papatheodoridis, European Association for the Study of the Liver [EASL], 2009; Lok, American Association for the Study of Liver Diseases [AASLD], 2009) 
    • Patients with evidence of active disease – elevated transaminases and DNA >2,000 IU/mL
    • Results may guide therapy in active disease
    • Useful when noninvasive testing does not suggest advanced fibrosis

Differential Diagnosis

Screening

Screening Recommendations for HBV
Population Screening Recommendation
Persons born in regions of high and intermediate HBV prevalence (HBsAG prevalence ≥2%) (eg, Africa, Asia Pacific) CDC, 2016; AASLD, 2018
Injection-drug users CDC, 2016; AASLD, 2018
Men who have sex with men CDC, 2016; AASLD, 2018
Patients with end-stage renal disease AASLD, 2018
All pregnant women CDC, 2016
Infants born to HBsAg-positive mothers CDC, 2016; AASLD, 2018
Donors of blood, plasma, organs, tissues, or semen Code of Federal Regulations (FDA); CDC, 2016; AASLD, 2018
U.S.-born persons not vaccinated as infants whose parents were born in region of high HBV prevalence (≥8%) CDC, 2016; AASLD, 2018
Persons with elevated ALT/AST of unknown etiology CDC, 2016; AASLD, 2018
HIV-positive persons CDC, 2016; AASLD, 2018
Those with household, needle sharing, or sexual contact with individuals known to be HBsAg positive CDC, 2016; AASLD, 2018
Individuals needing immunosuppressive therapy (for transplant or for rheumatologic or gastroenterologic disorders) CDC, 2016; AASLD, 2018
Persons who are sources of exposure through blood or body fluid AASLD, 2018
Unvaccinated patients 19-59 yrs with diabetes mellitus AASLD, 2018
Inmates in correctional facilities AASLD, 2018
Travelers to areas with intermediate or high HBV prevalence CDC, 2016; AASLD, 2018
Persons with >1 sexual partner during previous 6 mos AASLD, 2018
Persons seeking evaluation for sexually transmitted infection CDC, 2016; AASLD, 2018
Staff and residents of facilities for people with developmental disabilities CDC, 2016; AASLD, 2018
Patients with chronic liver disease (eg, HCV) AASLD, 2018
ALT, alanine aminotransferase; AST, aspartate aminotransferase; FDA, U.S. Food and Drug Administration

Sources: CDC, 2016; Terrault, AASLD, 2018

Monitoring

  • Monitor chronic disease at least annually (WHO, 2017)
    • ALT and AST levels
    • HBsAg, HBeAg, anti-HBe, anti-HBs, HBV DNA levels, transaminases
    • AST-to-platelet ratio or transient elastography to assess fibrosis/cirrhosis
  • More frequent monitoring recommended for
    • Patients receiving treatment or after treatment discontinuation
    • Patients who do not yet meet criteria for antiviral therapy

Background

Epidemiology

  • Incidence
    • ~30% of the world population has been exposed (Trepo, 2014)
      • 350 million – chronically infected
    • Endemic in Asia, sub-Saharan Africa, Pacific Islands, and parts of Latin America
    • Chronic disease in U.S. – <2%
      • Cases have decreased by 80% with vaccination
  • 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 within 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
  • HIV infection
  • Needlestick
    • 1-6% risk if blood is HBsAg positive
    • 22-40% risk if blood is HBsAg positive and HBeAg positive
  • Hemodialysis
  • Blood transfusion (predominantly in developing countries)
  • Membership in a high-risk group
    • Infants of HBV-infected mothers
    • Alaskan native and Pacific Islander children
    • Men who have sex with men
    • Children residing in households of first-generation immigrants from countries where HBV infection is endemic

Pathophysiology

Phases of Chronic HBVa
Phase HBeAg Anti-HBe HBV DNA Transaminases
Immune tolerant
  • Seen almost exclusively when infection is acquired perinatally or in early childhood
  • Minimal histologic damage
Positive Negative High – >20,000 IU/mL Normal
Immune active
  • Moderate to severe liver inflammation and possible liver fibrosis​
  • Loss of HBeAg and seroconversion to anti-HBe often occur
Positive Negative Moderately high – >2,000 IU/mL Elevated
Inactive
  • Follows seroconversion from HBeAg positive to HBeAg-antibody (anti-HBe) positive
  • Favorable long-term outcome with low risk of progression to HCC or cirrhosis
Negative Positive Absent or low – <2,000 IU/mL Normal
aThe 2017 EASL guidelines propose a new classification system for chronic HBV that has not yet been adopted by other organizations.

HCC, hepatocellular carcinoma

Source: McMahon, 2008

  • 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 if mother is HBsAg positive
      • 70-90% risk 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 more likely to be 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 discomfort in right-upper quadrant
    • 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 (HCC)
      • Cirrhosis may present with jaundice, ascites, splenomegaly, encephalopathy, or variceal bleeding
    • Annual incidence of HCC
      • <1% for noncirrhotic HBV-infected “carriers”
      • 2-3% for patients with cirrhosis
    • Annual incidence of cirrhosis
      • 2-6% for HBeAg-negative patients
      • 8-10% for HBeAg-positive chronic hepatitis patients

Prevention

  • Vaccination recommended for
    • Persons residing in communities with an increased prevalence of infection
    • Persons traveling to a country with high prevalence rates
    • Persons at risk for infection through sexual contact (eg, men having sex with men, persons with multiple sexual partners, sex partners of people with HBV)
    • Persons with sexually transmitted disease
    • Injection drug users
    • Healthcare workers or others at risk of percutaneous or mucosal exposure
    • All neonates and children
    • HIV-positive patients
    • Residents of correctional facilities
    • Residents and staff of facilities for people with developmental disabilities
    • Persons with HCV or chronic liver disease
    • Persons with end-stage renal disease
    • Unvaccinated adults 19-59 years with diabetes mellitus
  • Immediate short-term protection (3-6 months) against HBV can be obtained with hepatitis B IgG

ARUP Laboratory Tests

Evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes HAV IgM, HBV core antibody IgM, HBsAg, HCV antibody

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation testing will be added

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

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation testing will be added

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

Do not use for blood donor screening, associated reentry protocols, or for screening human cell, tissues, and cellular and tissue-based products

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

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

Monitor HBV therapy; order in conjunction with HBV DNA, HBsAg, HBV surface antibody, and HBe antibody

Order only when a patient is known to be positive for HBsAg

Monitor HBV therapy

Order in conjunction with HBV DNA, HBsAg, HBV surface antibody, and HBe antigen

Monitor confirmed chronic hepatitis B infection

Order for HBV screening in pregnant women (prenatal testing)

Reflex pattern: if results for HBsAg screen are reactive (≥1.0), then HBsAg prenatal confirmation testing will be added

Detect and quantify HBV

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

Detect and quantify HBV

Determine antiviral drug resistance

Reflex pattern: if HBV quantitative NAAT result is ≥3.0 log IU/mL (1,000 IU/mL), then HBV genotype by sequencing will be added

Initial screening for hepatobiliary inflammation

Panel includes albumin; alkaline phosphatase (ALP); AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

Noninvasive assessment of liver fibrosis in patients with chronic viral hepatitis B or C (with or without HIV coinfection) and in patients with hepatic steatosis

Test can performed only if the patient has a FibroScan score

Result based on both a panel of serum biomarkers (FibroMeter) and the FibroScan Vibration Controlled Transient Elastography (VCTE), a noninvasive, diagnostic ultrasound-based test that measures liver fibrosis

Related Tests

Detect acute or chronic HBV infection

Indicate stage of infection

Monitor patients with chronic HBV infection and known positive HBsAg

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

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

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

Determine antiviral drug resistance by DNA sequencing

Diagnose HDV infection in patient with documented acute or chronic HBV and risk for HDV infection

Consider ordering HBV core IgM antibody to determine whether HDV infection is a coinfection or a superinfection with HBV

Determine whether HDV infection is acute rather than chronic

Consider ordering HBV core IgM antibody to determine whether HDV infection is a coinfection or a superinfection with HBV

Confirm and quantify presence of HDV

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer: Medical Director, Automated Core Laboratory, ARUP Laboratories
Contributor
Contributor

Lehman

Christopher M. Lehman, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, University of Utah Health Hospital Clinical Laboratory, ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories
Medical Director, Serologic Hepatitis and Retrovirus and Immunology Core Laboratory
Co-Medical Director, Microbial Immunology, at ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®