What is the serologic marker for chronic Hepatitis D (Hepatitis D virus)?

Serologic Marker for Chronic Hepatitis D

The primary serologic marker for chronic Hepatitis D is high-titer anti-HDV IgG antibodies, often accompanied by persistent anti-HDV IgM, with confirmation of chronic infection requiring detection of serum HDV RNA. 1

Diagnostic Approach to Chronic HDV Infection

Primary Serologic Markers

Anti-HDV IgG antibodies at high titers are the hallmark of chronic HDV infection. 1 The European Association for the Study of the Liver (EASL) guidelines emphasize that chronic hepatitis D (CHD) is diagnosed by detecting high anti-HDV IgG levels in serum. 1

• Anti-HDV IgM antibodies frequently persist in chronic infection, distinguishing it from resolved acute infection where IgM typically wanes. 1, 2
• In chronic HDV, both IgM and IgG anti-HDV antibodies remain detectable over time, whereas in self-limited acute infection, IgM disappears during convalescence. 2

Confirmatory Molecular Testing

HDV RNA detection by nucleic acid amplification testing (NAAT) is essential to confirm active viral replication and establish chronic infection. 1

• The definition of chronic HDV infection requires positive HDV RNA for more than 6 months. 3
• HDV RNA quantification (viral load) should be performed using reverse-transcription PCR assays. 1
• At least two HDV RNA tests performed 3-6 months apart are necessary because HDV RNA levels can fluctuate and may become temporarily undetectable. 1

Additional Hepatitis D Markers

The Infectious Diseases Society of America (IDSA) guidelines list the following HDV markers available for testing: 1

• Hepatitis D total antibodies
• Hepatitis D IgM antibody
• Hepatitis D IgG antibody
• Hepatitis D antigen
• Hepatitis D virus RNA, quantitative (viral load)

Critical Distinction: Acute vs. Chronic HDV

Antibody Titer Patterns

An anti-HDV total antibody titer ≥100 by serial dilution is an excellent marker for differentiating chronic from acute HDV infection among viremic patients. 3 This threshold demonstrates strong agreement (kappa = 0.91) in distinguishing infection chronicity. 3

Temporal Antibody Patterns

• In self-limited acute HDV infection: IgM anti-HDV is transient, appearing 10-15 days after presentation, with IgG developing weeks later during convalescence; both antibodies eventually wane. 2
• In chronic HDV infection: Brisk IgM antibody response occurs early, IgG anti-HDV becomes detectable within approximately 15 days, and both antibodies persist indefinitely. 2

Essential Concurrent HBV Testing

Because HDV requires HBV for replication, all patients must be HBsAg-positive, and comprehensive HBV characterization is mandatory. 1

EASL guidelines strongly recommend testing: 1

• HBeAg/anti-HBe status - active HBV coinfection worsens HDV outcomes
• HBV DNA quantification - determines degree of HBV replication
• Anti-HBc IgM - distinguishes HBV/HDV coinfection (both acute) from HDV superinfection (acute HDV in chronic HBV carrier)

Common Pitfalls and Caveats

Seronegative Hepatitis D

Approximately 8.4% of chronic HDV infections may be seronegative (anti-HDV antibodies negative despite HDV RNA positivity). 4 This critical finding emphasizes that:

• Patients with chronic HBV and elevated ALT but negative HBV DNA should undergo HDV RNA testing even if anti-HDV antibodies are negative. 4
• Relying solely on serologic markers will miss a significant proportion of chronic HDV cases. 4

Poor Correlation Between Serology and Viremia

High-titer total anti-HDV (≥1000) and IgM anti-HDV show only moderate agreement (kappa = 0.41) with HDV RNA positivity. 3 Among chronic HDV patients with detectable HDV RNA:

• Only 50% have high-titer (≥1000) total anti-HDV. 3
• IgM anti-HDV and high-titer total anti-HDV are not reliable markers of active viral replication. 3

IgM Anti-HDV as a Marker of Liver Damage

IgM anti-HDV predominantly reflects HDV-induced liver damage rather than viral replication per se. 5 The antibody:

• Disappears with resolution of HDV disease (spontaneous or treatment-induced). 5
• Persists in patients with ongoing hepatitis. 5
• Consists mainly of monomeric 7S IgM rather than pentameric 19S forms. 5

HDV RNA Fluctuations

HDV viral load declines over time in a significant proportion of patients, particularly those with cirrhosis, and may be associated with worse prognosis. 1 This paradoxical finding means:

• A single negative HDV RNA does not exclude chronic infection
• Serial testing is mandatory for accurate diagnosis
• Declining viral load in cirrhotic patients may indicate advanced disease rather than improvement

Optimal Specimen Collection

Per IDSA guidelines, optimal specimens for HDV testing are: 1

• Serology: Plasma (EDTA or PPT) or serum (clot or SST), room temperature, transport within 2 hours
• HDV RNA: Plasma (EDTA or PPT) or serum (SST), room temperature, transport within 2 hours