- Clinical science
Hepatitis B virus (HBV) is a common viral infection worldwide and can be transmitted sexually, parenterally, or perinatally. After an incubation period of 1–6 months, most patients present with an asymptomatic or mild inflammation of the liver, which usually resolves spontaneously within a few weeks or months. However, 5% of all adult patients and 90% of infants born to a hepatitis B-positive mother develop chronic hepatitis. Chronically infected individuals may be either asymptomatic carriers or exhibit ongoing hepatic inflammation with an increased risk of liver cirrhosis and hepatocellular carcinoma. Serologic testing, which is decisive for diagnosing HBV, initially involves measurement of HBs antigen. An increase in serum anti‑HBs (also known as seroconversion) is a sign of recovery or successful immunization. Chronic hepatitis is indicated by persistently elevated HBs antigen levels, as well as high HBV DNA and transaminase levels in cases of persistent liver inflammation. Treatment of acute hepatitis B consists of supportive measures. In the case of fulminant hepatitis, liver transplantation may be necessary. For chronic hepatitis B, pegylated interferon alpha and nucleoside/nucleotide analogs (e.g., tenofovir) are used to reduce viral replication and infectivity. Prophylactic immunization with a recombinant vaccine is recommended for all age groups. Other preventative measures include post-exposure prophylaxis for newborns of hepatitis B-positive mothers and unvaccinated individuals with recent exposure to those who are hepatitis B-positive.
- More than 248 million people worldwide are chronically infected.
- ∼ 600,000 deaths annually from HBV-related liver disease
- High prevalence in Asia, Africa, and the Amazon basin
- United States
- In 2014, there were 20,000 new hepatitis B infections and ∼ 2 million people with chronic hepatitis B.
- Acute hepatitis B has declined by ∼ 82% after the introduction of the hepatitis B vaccine in 1991.
Epidemiological data refers to the US, unless otherwise specified.
The frequency and patterns of transmission vary worldwide.
- Needlestick injury
- Contaminated instruments and shared needles
- Contaminated blood products
- IV drug users
- Individuals whose close contacts have chronic HBV infection
- Infants of HBV-positive mothers
- Professions with exposure to human blood and/or seminal/vaginal fluids
- Individuals with multiple sex partners or sex partners of HBV-positive people
- Patients undergoing hemodialysis; organ or blood transfusion recipients
- Hepatitis C virus (HCV) or HIV-positive individuals
Individuals whose medical history indicates a high risk for HBV infection should be tested!
Hepatocytes infected by the hepatitis B virus express viral peptides on their surfaces; → lymphocytes recognize HBV-derived peptides and become activated (CD8+ cytotoxic T cells) → lymphocytes attack liver cells (cellular immune response) → hepatic inflammation with destruction of hepatocytes
- After entering the host cell's nucleus, host DNA polymerase completes the positive strand of the partially double-stranded viral DNA, producing cccDNA.
- The cccDNA is then transcribed into viral mRNA by host RNA polymerase.
- The viral mRNA leaves the nucleus, and in the cytoplasm is translated by host mRNA polymerase into HBV core proteins and reverse transcriptase.
- Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into partially double-stranded viral DNA.
- New viral DNA genomes are enveloped and leave the cell as progeny virions.
If clearance of the virus fails
- Persistent hepatic inflammation with necrosis, mitosis, and regeneration processes → cirrhosis, cellular dysplasia → HCC
- Integration of HBV DNA into the host genome → altered expression of endogenous genes, chromosomal instability → HCC
- 1–6 months
Acute HBV infections are defined as infections that were acquired in the past 6 months.
- Serum sickness-like syndrome can develop during the prodromal (preicteric) period; : rash, polyarthritis, fever
- Subclinical hepatitis (70% of cases)
- Symptomatic hepatitis (30% of cases; see also )
- ∼ 0.5% of cases) (
- Most adults will clear infection
Recovery rates in adults are very good, with less than 5% of cases progressing to chronic infections. In contrast, the risk of developing chronic hepatitis is considerably higher in infants infected perinatally (90%) and young children (20–50%)!
- Most patients are inactive, non-contagious carriers.
- Potential reactivation of chronic inactive hepatitis: may be asymptomatic , imitate acute hepatitis; , or result in hepatic failure
- , stigmata of chronic liver disease (25% of cases)
- Extrahepatic manifestations (10–20% of cases)
Diagnostically relevant virus antigens, DNA, and antibodies
|HBV antigen/DNA||Description||Corresponding antibodies|
| || || |
| || || |
| || || |
|Acute infection||↑||∅||↑||∅||↑ IgM||∅–↑||↑ (ALT > AST)|
|∅||∅||∅||∅||↑ IgM first, then IgG||∅–↑||↑ (ALT > AST)|
|Resolved prior infection||∅||↑||∅||↑||↑ IgG||∅||∅|
Virus persistence (chronic infection)
Active chronic infection
|↑||∅||↑||∅||↑ IgG|| |
HBV DNA > 2000 IU/mL
|Normal or ↑|
Inactive chronic infection
|↑||↑ IgG||HBV DNA ≤ 2000 IU/mL||Normal|
- Testing algorithm
- Laboratory studies
- Abdominal ultrasound
- Liver biopsy (see “Pathology” below)
- Test of common coinfections (e.g., hepatitis C/D, syphilis, HIV)
HBeAg indicates Infectivity due to viral Existence(/persistence)!
Chronic viral hepatitis
- Formation of lymphoid follicles and mononuclear infiltrates
- Piecemeal necrosis: periportal liver cell necrosis with lymphocytic infiltration; ; indicates chronic active hepatitis and poor prognosis
- Fibrous septa
- Ground glass hepatocytes
|Differential diagnosis of viral hepatitis|
|Pathogen||Viral family||Transmission route||Incubation period (days)||Symptoms/Signs||Serological diagnosis||Treatment||Prevention||Complications|
|Hepatitis A virus (HAV)|| || || || || || |
|Hepatitis B virus (HBV)|| || || |
|Hepatitis C virus (HCV)|| || || |
|Hepatitis D virus (HDV)|| || || || |
Hepatitis E virus (HEV)
| || || || || |
Hepatitis viruses A and E usually only cause AcutE hepatitis!
The differential diagnoses listed here are not exhaustive.
Acute hepatitis B
- Supportive care
- For treatment of acute liver failure, see “Complications” below
Chronic hepatitis B
- Indication: chronic active hepatitis B (see “Diagnostics” above) with evidence of liver inflammation (ALT ≥ 2 times upper limit) or cirrhosis
- Nucleoside/nucleotide analogs : indicated for patients with both decompensated and compensated liver disease and nonresponders to interferon treatment
- Pegylated interferon alfa (PEG-IFN-a) : especially in younger patients with compensated liver disease
- Coinfection with HDV is best treated with PEG-IFN-a.
- Surgical treatment
Hepatitis D virus infection
- Epidemiology: 5% of all chronically infected HBV patients are carriers of the hepatitis D virus.
- Pathogen: Hepatitis D virus (HDV)
- Incomplete viral particle resembling a viroid
- Defective single-stranded RNA virus
- Utilizes the HBsAg coat of HBV for propagation
- Transmission: sexual, parenteral, perinatal (only possible in combination with HBV )
- Definition: rapidly worsening liver function resulting in coagulopathy and
- Viral hepatitis: hepatitis A, B, E, or B + D, CMV
- Vascular disorders: ischemic hepatitis ,
- Pregnancy-related: , acute fatty liver of pregnancy
- Others: Wilson's disease ,
- Clinical features
- Laboratory findings: ↑ PT with INR ≥ 1.5, often ↑↑ ALT and AST, ↑ bilirubin level, and platelet count ≤ 150,000/mm3
- Further diagnostics: depending on the suspected underlying cause
- Early transfer to a liver transplant center
- Intravenous N-acetylcysteine
- Address/prevent complications: e.g., cerebral edema, encephalopathy, coagulopathy, renal failure, and infection
- Address underlying cause: e.g., antiviral treatment for hepatitis B, steroids for autoimmune hepatitis, or delivery for HELLP syndrome
- is the only therapeutic option for patients without sufficient regeneration of hepatocytes.
- Prognosis: The mortality rate without liver transplantation ranges from 30% (acetaminophen toxicity) to 80% (non-acetaminophen-related liver failure).
- Liver cirrhosis
- Post‑hepatitis syndrome
- Reactivation of previous HBV infection due to immunosuppression
We list the most important complications. The selection is not exhaustive.
- Pre-exposure vaccination: recommended for all unvaccinated individuals (see )
Post-exposure prophylaxis (PEP)
- Goal: prevention of HBV infection
- Indication: exposure to HBV (e.g., percutaneous, ocular, mucosal)
- Documented vaccine responder with HBsIgG ≥ 10 mIU/mL: no intervention needed
- Documented non-responder : Administer two doses of hepatitis B immune globulin (HBIG) separated by 1 month
- Unvaccinated individuals or incompletely vaccinated: simultaneous administration of hepatitis B immune globulin (HBIG) and hepatitis B vaccine (see also ) and completion of original vaccination series
Vaccinated with 3 doses of hepatitis B vaccine but postvaccination anti-HBs status is unknown or anti-HBs <10 mIU/mL:
1 dose of HBIG and
- Administration of 3 consecutive doses of the hepatitis B vaccine and retest of anti-HBs level or alternatively
- Administration of 1 dose of the vaccine and retest for anti-HBs in 1-2 months and if needed 2 additional doses and then retest anti-HBs level.
- 1 dose of HBIG and
Whereas maternal hepatitis B; infections rarely cause fetal complications during pregnancy, the risk of perinatal transmission is high, especially if the maternal viral load is increased. If an infant becomes infected, the risk of developing chronic hepatitis is 90%.
- Maternal screening for HBsAg should be performed on all women at the first prenatal visit.
- Management for HBsAg-positive mothers
- Newborn immunization: within 12 hours of birth (first dose of hepatitis B vaccine series plus 1 dose of HBIG)
- Breastfeeding: allowed as long as passive‑active postexposure prophylaxis was given
- Infected newborns:
Interferon therapy is contraindicated during pregnancy!