is a hepadnavirus type 1.
FIGURE 332-3
 

HBV is a DNA virus

 

HBV achieves its genomic economy by relying on an efficient strategy of encoding proteins from four overlapping genes: S, C, P, and X.

Like HBV, all have the same distinctive three morphologic forms, have counterparts to the envelope and nucleocapsid virus antigens of HBV, replicate in the liver but exist in extrahepatic sites, contain their own endogenous DNA polymerase, have partially double-strand and partially single-strand genomes, are associated with acute and chronic hepatitis and hepatocellular carcinoma, and rely on a replicative strategy unique among DNA viruses but typical of retroviruses.

Entry of HBV into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide receptor. Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (effected by the DNA polymerase) of minus-strand DNA from a “pregenomic” RNA intermediate. Then, plus-strand DNA is transcribed from the minus-strand DNA template by the DNA-dependent DNA polymerase and converted in the hepatocyte nucleus to a covalently closed circular DNA, which serves as a template for messenger RNA and pregenomic RNA. Viral proteins are translated by the messenger RNA, and the proteins and genome are packaged into virions and secreted from the hepatocyte. Although HBV is difficult to cultivate in vitro in the conventional sense from clinical material, several cell lines have been transfected with HBV DNA. Such transfected cells support in vitro replication of the intact virus and its component proteins.

 

 

Hepatitis B is spread by percutaneous or mucosal exposure to infected blood and various body fluids, as well as through saliva, menstrual, vaginal, and seminal fluids.

Sexual transmission of hepatitis B may occur, particularly in unvaccinated men who have sex with men and heterosexual persons with multiple sex partners or contact with sex workers.

Transmission of the virus may also occur through the reuse of needles and syringes either in health-care settings or among persons who inject drugs.

In addition, infection can occur during medical, surgical and dental procedures, tattooing, or through the use of razors and similar objects that are contaminated with infected blood.


After a person is infected with HBV, the first virologic marker detectable in serum within 1–12 weeks, usually between 8 and 12 weeks, is HBsAg

Entry of HBV into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide receptor. Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (effected by the DNA polymerase) of minus-strand DNA from a “pregenomic” RNA intermediate. Then, plus-strand DNA is transcribed from the minus-strand DNA template by the DNA-dependent DNA polymerase and converted in the hepatocyte nucleus to a covalently closed circular DNA, which serves as a template for messenger RNA and pregenomic RNA. Viral proteins are translated by the messenger RNA, and the proteins and genome are packaged into virions and secreted from the hepatocyte. Although HBV is difficult to cultivate in vitro in the conventional sense from clinical material, several cell lines have been transfected with HBV DNA. Such transfected cells support in vitro replication of the intact virus and its component proteins.


Scheme of typical clinical and laboratory features of acute hepatitis B.
 ALT, alanine aminotransferase.

A graph shows clinical and laboratory features of acute hepatitis B with respect to weeks after exposure.

 

Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond. In typical cases,

HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months. After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Because HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum, and therefore HBcAg is not detectable routinely in the serum of patients with HBV infection. By contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months. Because variability exists in the time of appearance of anti-HBs after HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs. During this “gap” or “window” period, anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs has been implicated in transfusion-associated hepatitis B. In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered. In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than anti-HBs. Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc represent hepatitis B infection in the remote past. Rarely, however, isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg below the detection threshold, and, occasionally, isolated anti-HBc represents a cross-reacting or false-positive immunologic specificity. Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months. Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum. In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class. Infrequently, in ≤1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B. When isolated anti-HBc occurs in the rare patient with chronic hepatitis B whose HBsAg level is below the sensitivity threshold of contemporary immunoassays (a low-level carrier), anti-HBc is of the IgG class. Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely.

FIGURE 3

 

Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond. In typical cases, HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months. After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Because HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum, and therefore HBcAg is not detectable routinely in the serum of patients with HBV infection. By contrast, anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months. Because variability exists in the time of appearance of anti-HBs after HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs. During this “gap” or “window” period, anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs has been implicated in transfusion-associated hepatitis B. In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered. In some persons, years after HBV infection, anti-HBc may persist in the circulation longer than anti-HBs. Therefore, isolated anti-HBc does not necessarily indicate active virus replication; most instances of isolated anti-HBc represent hepatitis B infection in the remote past. Rarely, however, isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg below the detection threshold, and, occasionally, isolated anti-HBc represents a cross-reacting or false-positive immunologic specificity. Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first 6 months after acute infection, whereas IgG anti-HBc is the predominant class of anti-HBc beyond 6 months. Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum. In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class. Infrequently, in ≤1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B. When isolated anti-HBc occurs in the rare patient with chronic hepatitis B whose HBsAg level is below the sensitivity threshold of contemporary immunoassays (a low-level carrier), anti-HBc is of the IgG class.

Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely.

FIGURE 3

 

What do the different hepatitis B serologic markers mean?

  • Hepatitis B surface antigen (HBsAg): The presence of HBsAg, a protein on the surface of HBV, indicates that the person is infectious. It can be detected in high levels in serum during acute or chronic HBV infection. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make hepatitis B vaccine.
  • Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B.
  • Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame.
  • IgM antibody to hepatitis B core antigen (IgM anti-HBc): Positivity indicates recent infection with HBV (≤6 months). Its presence indicates acute infection.
  • Hepatitis B e antigen (HBeAg): The presence indicates that the virus is replicating and the infected person has high levels of HBV. HBeAg is a secreted product of the nucleocapsid gene of HBV that is found in serum during acute and chronic hepatitis B.
  • Hepatitis B e antibody (HBeAb or anti-HBe): Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV. HBeAb is produced by the immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication.
  • HBV DNA:  HBV DNA concentration correlates with levels of HBV virus particles. HBV DNA is measured as IU/mL or copies/ml by the polymerase chain reaction assay. HBV viral DNA can be detected and quantified in serum. There are several commercial assays that can detect and quantify HBV DNA, some to limits as low as 10 IU/ml.

How do I interpret hepatitis B serologic test results?

The following table provides interpretations for different combinations and results of hepatitis B serologic markers.

Table. Antibody and Antigen Biomarkers for Hepatitis B Infection (6)

Clinical state HBsAg Total Anti-HBs Total anti-HBc Action
Table. Antibody and Antigen Biomarkers for Hepatitis B Infection 
Chronic infection Positive Negative Positive Link to hepatitis B-directed care
Acute Positive Negative Positive
(IgM anti-HBc)
Link to hepatitis B-directed care
Resolved infection Negative Positive Positive Counseling, reassurance
Immune (immunization) Negative Positive Negative Reassurance
Susceptible
(never infected and no evidence of immunization)
Negative Negative Negative Vaccinate
*Isolated core antibody Negative Negative Positive Depends on situation

*can be a result of:

1 False positive: Repeat testing required
2 Past infection: No action needed
3 Occult HBV infection: Needs to be known if patient ever becomes immunosuppressed or given chemotherapy or treated with antiviral therapy for hepatitis C virus infection. Consider monitoring HBV DNA.
4 Passive transfer to infant born to HBsAg-positive mother No specific action needed.

How long does it take for blood to test HBsAg-positive after exposure to HBV?

HBsAg will be detected in an infected person’s blood an average of 4 weeks (range: 1–9 weeks) after exposure to the virus. About 1 of 2 patients will no longer be infectious by 7 weeks after onset of symptoms, and all patients who do not remain chronically infected will be HBsAg-negative by 15 weeks after onset of symptoms (12).

 

 

Prvention

immunization.

Currently, for hepatitis A, B, and E, active immunization with vaccines is the preferable approach to prevention.

 

Content 4

Infection in adulthood leads to chronic hepatitis in less than 5% of cases.

Content 11

 

 

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