How do I interpret hepatitis B serology results, including HBsAg (Hepatitis B surface antigen), anti-HBs (Hepatitis B surface antibody), HBeAg (Hepatitis B e-antigen), anti-HBe (Hepatitis B e-antibody), and anti-HBc (Hepatitis B core antibody)?

Interpretation of Hepatitis B Serology

The most accurate way to interpret hepatitis B serology is through systematic analysis of five key markers: HBsAg, anti-HBs, total anti-HBc, IgM anti-HBc, and HBeAg/anti-HBe, which together determine infection status, stage, and immunity.

Key Serological Markers and Their Significance

Primary Diagnostic Markers:

1. HBsAg (Hepatitis B Surface Antigen)

   • Indicates active HBV infection (acute or chronic)
   • First marker to appear (30 days average after exposure; range 6-60 days)
   • Persistence beyond 6 months indicates chronic infection
   • All HBsAg-positive individuals should be considered infectious 1

2. Anti-HBc (Total Antibody to Hepatitis B Core Antigen)

   • Appears at onset of symptoms
   • Persists for life in most cases
   • Indicates current or past HBV infection 1

3. IgM Anti-HBc

   • Indicates acute or recently acquired infection
   • Present for up to 6 months after acute infection
   • Used to distinguish acute from chronic infection
   • Should only be tested in patients with clinical evidence of acute hepatitis 1

4. Anti-HBs (Antibody to Hepatitis B Surface Antigen)

   • Indicates recovery and immunity from HBV infection
   • Appears during convalescence (3-4 months after infection)
   • Also present after successful vaccination
   • Levels ≥10 mIU/mL are considered protective 2

5. HBeAg/Anti-HBe (Hepatitis B e-Antigen/Antibody)

   • HBeAg indicates active viral replication and high infectivity
   • Anti-HBe typically indicates decreased viral replication 1

Systematic Interpretation Algorithm

Step 1: Check HBsAg Status

• If positive: Active infection (acute or chronic)
• If negative: No active infection (susceptible, immune, or resolved)

Step 2: If HBsAg Positive, Determine Acute vs. Chronic

• Check IgM anti-HBc:
  • Positive: Acute hepatitis B infection
  • Negative: Chronic hepatitis B infection

Step 3: If HBsAg Negative, Determine Immunity Status

• Check anti-HBs and anti-HBc:
  • Both negative: Susceptible (never infected, not immune)
  • Anti-HBs positive, anti-HBc negative: Immune due to vaccination
  • Anti-HBs positive, anti-HBc positive: Immune due to resolved natural infection
  • Anti-HBs negative, anti-HBc positive: Four possible interpretations (see below)

Common Serological Patterns and Their Interpretation

HBsAg	Total anti-HBc	IgM anti-HBc	Anti-HBs	HBeAg	Anti-HBe	Interpretation
+	+	+	-	+/-	-/+	Acute infection
-	+	+	-	-	+/-	Acute resolving infection
-	+	-	+	-	+/-	Recovered from past infection and immune
+	+	-	-	+	-	Chronic infection with high viral replication
+	+	-	-	-	+	Chronic infection with lower viral replication
-	-	-	+	-	-	Immune due to vaccination
-	+	-	-	-	+/-	Four possibilities: resolved infection with waned antibodies, "low-level" chronic infection, false positive anti-HBc, or resolving acute infection [1]

Special Considerations and Pitfalls

1. Isolated anti-HBc (HBsAg negative, anti-HBs negative, anti-HBc positive):

   • May represent:
     • Resolved infection with waned anti-HBs
     • False-positive anti-HBc
     • "Low-level" chronic infection (occult HBV)
     • Window period during acute infection resolution 1
   • Consider HBV DNA testing to rule out occult infection

2. Window Period:

   • Period between disappearance of HBsAg and appearance of anti-HBs
   • Anti-HBc is the only detectable marker during this time
   • Can last several weeks to months

3. Reactivation Risk:

   • Patients with resolved HBV infection (HBsAg negative, anti-HBc positive) can experience reactivation when immunosuppressed
   • Monitor closely in patients receiving immunosuppressive therapy 1, 2

4. False Results:

   • Transient HBsAg positivity can occur for up to 18 days after vaccination (clinically insignificant) 1
   • IgM anti-HBc can persist at low levels in chronic infection during viral replication 1
   • False-positive IgM anti-HBc can occur; limit testing to those with clinical evidence of acute hepatitis 1

Clinical Applications

1. Screening:

   • Initial screening: HBsAg and anti-HBs
   • Complete evaluation: Add total anti-HBc, IgM anti-HBc if acute infection suspected

2. Monitoring Chronic Infection:

   • HBsAg, HBeAg/anti-HBe, HBV DNA levels
   • Liver function tests (ALT/AST)

3. Post-vaccination Testing:

   • Anti-HBs ≥10 mIU/mL indicates immunity
   • No other markers should be positive

4. Pre-immunosuppression Evaluation:

   • Test for HBsAg, anti-HBc, and anti-HBs
   • Consider prophylactic antiviral therapy for HBsAg-positive or anti-HBc-positive patients 2

By following this systematic approach to interpreting hepatitis B serology, clinicians can accurately diagnose acute and chronic infections, assess immunity status, and make appropriate management decisions to reduce morbidity and mortality from HBV infection.