• Clinical science

Hepatitis B (Hepatitis B infection)

Abstract

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.

Epidemiology

  • 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.

References:[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Virus

Transmission

The frequency and patterns of transmission vary worldwide.

  1. Sexual
  2. Parenteral
    • Needlestick injury
    • Contaminated instruments and shared needles
    • Contaminated blood products
  3. Perinatal

High-risk groups for HBV infection

  • 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!
References:[5][6][7][8]

Pathophysiology

Acute infection

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

  • Replication cycle
    1. After entering the host cell's nucleus, host DNA polymerase completes the positive strand of the partially double-stranded viral DNA, producing cccDNA.
    2. The cccDNA is then transcribed into viral mRNA by host RNA polymerase.
    3. The viral mRNA leaves the nucleus, and in the cytoplasm is translated by host mRNA polymerase into HBV core proteins and reverse transcriptase.
    4. Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into partially double-stranded viral DNA.
    5. New viral DNA genomes are enveloped and leave the cell as progeny virions.

Chronic infection

If clearance of the virus fails

References:[9][10]

Clinical features

Incubation period

  • 1–6 months

Acute infection

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 acute viral hepatitis)
    • Fever, skin rash, arthralgias, myalgias, fatigue
    • Nausea
    • Jaundice
    • Right upper quadrant pain
    • Symptoms usually resolve after 1–3 months
  • Fulminant hepatitis (∼ 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%)!

Chronic infection

Chronic HBV infections are defined as infections persisting for more than 6 months with detection of HBsAg and possibly symptoms of liver damage.

  • Most patients are inactive, non-contagious carriers.
  • Potential reactivation of chronic inactive hepatitis: may be asymptomatic , imitate acute hepatitis; , or result in hepatic failure
  • Cirrhosis, stigmata of chronic liver disease (25% of cases)
  • Extrahepatic manifestations (10–20% of cases)

References:[7][11][12][13]

Diagnostics

Diagnostically relevant virus antigens, DNA, and antibodies

HBV antigen/DNA Description Corresponding antibodies
  • HBsAg
  • Surface antigen
  • Protein on the surface of HBV; first evidence of infection
  • Anti‑HBs
    • Indicates immunity to HBV due to vaccination or resolved infection
    • Usually appears 1–3 months after infection.
  • HBcAg HBcAg is not part of the serological testing, because HBcAg forms the nucleocapsid of the virus particle which lies beneath the viral surface. Therefore HBcAg circulates as a part of the virus but is covered by the HBsAg. It does not circulate as a free protein in significant quantity in the blood.
  • Core antigen
  • Anti‑HBc
    • Anti-HBC IgM indicates recent infection with HBV (≤ 6 months)
    • Anti-HBc IgG indicates resolved or chronic infections
  • HBeAg
  • Envelope antigen
  • Protein secreted by the virus that indicates viral replication and infectivity

Hepatitis B serology

HBsAg Anti-HBs

HbeAg

Anti-HBe Anti-HBc HBV DNA Transaminases
Acute infection IgM ∅–↑ (ALT > AST)

“Window period”

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
Vaccination
  • Testing algorithm
    • Screening: HBsAg (detectable 1–5 months after infection) and anti‑HBc IgM ;
    • If HBsAg is positive → measure HBeAg and HBV DNA; ;
    • Seroconversion of HBsAg to anti‑HBs indicates acute hepatitis resolution.

Additional tests

Seroconversion of HBsAg to anti‑HBs indicates immune clearance of HBV!

HBeAg indicates Infectivity due to viral Existence(/persistence)!
References:[14][3][10][12][13][15][16][17][18]

Pathology

Acute viral hepatitis

Chronic viral hepatitis

Ground glass hepatocytes are only present in HBV, while piecemeal necrosis, fibrous septa, and periportal infiltrates also occur in other types of chronic hepatitis!

References:[19][20][21][22][23]

Diff:

References:[19][20][21][22][23]

Differential diagnoses

Differential diagnosis of viral hepatitis
Pathogen Viral family Transmission route Incubation period (days) Symptoms/Signs Serological diagnosis Treatment Prevention Complications
Hepatitis A virus (HAV)
  • Picornavirus
    • Non-enveloped virus
    • Positive sense, single-stranded, linear RNA
  • Fecal-oral
  • 15–50
  • Supportive
Hepatitis B virus (HBV)
  • Parenteral, sexual, perinatal
  • 30–180
  • Often asymptomatic
  • Serum sickness-like reaction in prodrome phase
  • Acute hepatitis (see above)
  • Stigmata of cirrhosis in chronic cases
  • HBsAg
  • Anti-HBc
  • HBeAg
  • Safe sex; screening of blood products; use of sterile instruments and needles
  • HBV vaccination, post-exposure prophylaxis
Hepatitis C virus (HCV)
  • Flavivirus
    • Enveloped virus
    • Positive sense, single-stranded, linear RNA
  • Parenteral (rarely sexual or perinatal)
  • 14–180
  • Often asymptomatic
  • Acute hepatitis (see above)
  • Stigmata of cirrhosis in chronic cases
  • Use of sterile instruments and needles; safe sex
  • No vaccination for HCV available
Hepatitis D virus (HDV)
  • Deltavirus
    • Enveloped virus
    • Negative sense, single-stranded, circular RNA
  • Always coinfection with HBV
    • HDV is a defective virus that requires the HBsAg for entry into hepatocytes
  • Parenteral (rarely sexual, perinatal)
  • Coinfection: 45–160
  • Superinfection: 14–56
  • Peginterferon-α
  • Prevention of HBV infection (see “Prevention” below)

Hepatitis E virus (HEV)

  • Hepevirus
    • Non-enveloped virus
    • Positive sense, single-stranded, linear RNA
  • Fecal-oral
  • 15–64
  • Acute: supportive
  • Chronic (rare): ribavirin

Hepatitis viruses A and E usually only cause AcutE hepatitis!
References:[5][24][25][26][27][10][28][29][30]

The differential diagnoses listed here are not exhaustive.

Treatment

Acute hepatitis B

Chronic hepatitis B

References:[10][31]

Complications

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 )
  • Course
    • Coinfection: more severe acute hepatitis, but 90% rate of convalescence
    • Superinfection of a chronic HBsAg carrier: ↑ risk of liver cirrhosis
    • In rare cases, fulminant hepatitis

Acute liver failure

Long-term complications

References:[5][32][33][34][35][36]

We list the most important complications. The selection is not exhaustive.

Prevention

  • Pre-exposure vaccination: recommended for all unvaccinated individuals (see immunization schedule)
  • Post-exposure prophylaxis (PEP)
    • Goal: prevention of HBV infection
    • Indication: exposure to HBV (e.g., percutaneous, ocular, mucosal)
    • Administration
      • 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 perinatal hepatitis B) 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.

References:[37][38]

Special patient groups

Perinatal hepatitis B

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
    • In mild disease and/or low HBV DNA levels, therapy may be delayed until after birth
    • In severe disease; (e.g., cirrhosis) and/or high HBV DNA, therapy with nucleoside/nucleotide analogs (especially tenofovir) is commonly recommended
    • Delivery: spontaneous vaginal delivery possible
  • 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:
    • Usually asymptomatic, but up to 90% risk developing chronic infection and significant risk of cirrhosis and progression to hepatocellular carcinoma if left untreated
    • Serum studies:
      • Normal or only slightly elevated transaminases
      • High viral replication rate

Interferon therapy is contraindicated during pregnancy!
References:[39]