Clinical features cannot separate the viral causes of hepatitis, so serology does the work: it identifies which virus is responsible and, for the chronic infections, whether the virus is still replicating.
Hepatitis A
Acute HAV infection is diagnosed by IgM anti-HAV, which becomes detectable around the onset of symptoms, on average about 4 weeks after infection, and can persist for 4-6 months. IgG anti-HAV appears during convalescence, remains detectable for life and confers lasting immunity; it is what screening tests measure, and a positive result indicates past infection or vaccination rather than current disease.
Hepatitis B
HBV has several markers, and the pattern they form over time is what distinguishes the phases of infection.
- HBsAg is the surface antigen and the main test for current infection, whether acute or chronic. It can be detected 1-2 weeks after exposure and as late as 11-12 weeks. Transient HBsAg positivity can follow vaccination and is clinically insignificant.
- IgM anti-HBc appears around the onset of illness and is the best marker of acute infection, distinguishing recent infection from a resolved one.
- Total anti-HBc, mostly of the IgG class, develops in every HBV infection, appears shortly after HBsAg and persists for life; it indicates infection at some time in the past.
- Anti-HBs is the protective antibody: with anti-HBc it indicates recovery and immunity, and alone it indicates vaccination.
In some people the HBsAg level is so low that IgM anti-HBc is used instead to establish infection. HBeAg indicates active replication and high infectivity, and anti-HBe usually appears as replication falls. Of the two, PCR for HBV DNA is the more sensitive and quantitative measure of replication, and in immunocompetent adults with chronic hepatitis B it is the level of replication, not the HBsAg titre, that correlates with liver damage. People infected with a pre-core mutant HBV do not express HBeAg, so a negative HBeAg does not exclude active replication.
Hepatitis C
For HCV the gold standard is assay of HCV RNA, which is detectable even before the aminotransferases rise and before antibody appears. Quantification of HCV RNA does not measure disease severity, but it is used to monitor the antiviral response. Anti-HCV is the screening test — an antibody test measuring total IgM and IgG against the virus, not an IgM-only test. Detectable anti-HCV without detectable HCV RNA indicates an infection that has resolved or been cured. Detection of IgG anti-HBc in a person with HCV simply reflects a past or present HBV infection alongside it.
Hepatitis D
HDV requires HBV, so its serology is read together with the HBV markers. Anti-HBc of the IgM class accompanies hepatitis B acquired at the same time as HDV (co-infection), whereas anti-HBc of the IgG class accompanies HDV superinfection of an established chronic hepatitis B. Anti-HDV and HDV RNA demonstrate HDV infection directly.
The acute panel and its pitfalls
Four serological tests are used in a patient with acute hepatitis: IgM anti-HAV, HBsAg, IgM anti-HBc, and anti-HCV (a total antibody test, not an IgM-only test).
Some results mislead. Low titres of rheumatoid factor and antinuclear antibodies are found rarely, but a high rheumatoid factor can cause a false-positive IgM anti-HBc, and it can also cause a false-positive HCV screening test, in which case HCV RNA has to be measured to settle the question.
Chronic hepatitis
To identify chronic hepatitis B, a positive HBsAg together with a negative IgM anti-HBc indicates chronic rather than acute infection. When HBsAg is positive, the next step is to test HBeAg and anti-HBe, with HBV DNA being more reliable and correlating with liver damage. Patients presenting with fulminant hepatitis should also be tested for HDV. For HCV, a positive anti-HCV supports the diagnosis, but HCV RNA establishes it.