Hepatitis B

Hepatitis B is a viral infection caused by the hepatitis B virus (HBV), which occurs worldwide and can be transmitted sexually, parenterally, or perinatally. After an incubation period of 1–6 months, most patients develop 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 asymptomatic carriers or develop 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 (indicating seroconversion) is a sign of recovery or successful immunization. Chronic hepatitis with persistent liver inflammation is characterized by persistently elevated HBs antigen, HBV DNA, and transaminase levels. 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 analogues (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 postexposure prophylaxis for newborns of hepatitis B-positive mothers and unvaccinated individuals with recent exposure to those who are hepatitis B-positive.

See also “Acute liver failure.”

• Prevalence: Following the introduction of the hepatitis B vaccine in 1991, rates of acute hepatitis B in the US have declined by approx. 82%. ^[1]
  • In 2016 there were an estimated 862,000 cases (∼ 0.3% of US population) in the US. ^[2][3]
  • In 2015, there were > 257 million cases worldwide (3.5% of the global population). ^[4]
  • The Western Pacific is the most affected region worldwide (6.2% of its population). ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Virus

• Hepatitis B virus (HBV)
  • Member of the Hepadnavirus family
  • Circular, partially double-stranded DNA virus
• See “General virology” for more information on viral structure

Transmission ^[4]

Frequency and patterns of transmission vary worldwide. The following routes of transmission are possible and put a number of different groups at high risk for HBV infection:

• Sexual: transmitted when bodily fluids come in contact with broken skin or mucous membranes (mouth, genitals, or rectum). Risk groups include:
  • Men who have sex with men
  • Individuals with multiple sex partners or sex partners of HBV-positive individuals
  • Sex workers
• Parenteral: due to contaminated needles or instruments that come into contact with the patient's blood. Risk groups include:
  • Persons who inject drugs (shared needles)
  • Health care personnel; with occupational exposure to blood or bodily fluids (e.g., due to needlestick injury ) ^[5][6]
  • Patients undergoing hemodialysis
  • Blood transfusions or organ transplant recipients
  • Individuals undergoing body modifications such as tattooing and body piercings
• Mother-to-child-transmission ^[4]
• Common associations
  • Hepatitis C virus (HCV) and HIV-positive individuals
  • Travelers to regions where HBV is endemic ^[7]

Replication cycle of HBV ^[8][9][10]

HBV carries a DNA polymerase with both DNA and RNA-dependent functions, also known as reverse transcriptase (RT).

1. After entering the host cell's nucleus, reverse transcriptase completes the positive strand of the virus's partially double-stranded relaxed circular DNA (rcDNA).
2. The rcDNA is converted to covalently closed circular DNA (cccDNA) primarily by host enzymes in a process that is not entirely understood.
3. The cccDNA is then transcribed into viral mRNA by host RNA polymerase.
4. The viral mRNA leaves the nucleus and is translated into HBV core proteins and new reverse transcriptase in the cytoplasm.
5. Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into viral rcDNA.
6. New viral DNA genomes are enveloped and leave the cell as progeny virions.

Acute infection ^[11]

• In acute infection, the cellular immune response causes damage to hepatocytes.
• Hepatitis B-infected hepatocytes express viral peptides ; on their surfaces → detection of the HBV-derived peptides by lymphocytes and the subsequent activation of CD8+ T cells that attack the infected hepatocytes → hepatic inflammation with destruction of hepatocytes ^[12]

Chronic infection ^[13]

Caused by viral persistence due to failing immune clearance, which promotes:

• Persistent hepatic inflammation → necrosis, mitosis, and regeneration processes → cirrhosis and cellular dysplasia → HCC
• Integration of HBV DNA into the host genome → altered expression of endogenous genes, chromosomal instability → HCC
• HBV proteins fulfill numerous immune-modulating functions that allow them to elude detection by the immune system and avoid clearance. ^[12]

Acute hepatitis B virus infection

Acute HBV infection is defined as infection acquired in the past 6 months.

• Incubation period: 1–6 months ^[4]
• Clinical course: varies significantly ^[14][15]
  • Serum sickness-like syndrome can develop during the prodromal (preicteric) period 1–2 weeks after infection: rash, arthralgias, myalgias, fever ^[16]
  • Subclinical hepatitis (∼ 70% of cases) ^[2]
  • Symptomatic hepatitis (∼ 30% of cases; see also acute viral hepatitis)
    • Fever, skin rash, arthralgias, myalgias, fatigue
    • Nausea, anorexia
    • Jaundice
    • Right upper quadrant pain
  • Symptoms usually resolve after a few weeks, but can last up to 6 months. ^[2]
  • May develop into fulminant hepatitis (∼ 0.5% of cases)

Chronic hepatitis B virus infection ^[15]

Chronic HBV infection is defined as infection persisting for more than 6 months with detection of HBsAg and, possibly, signs and symptoms of liver damage.

• Most patients are inactive, noncontagious carriers. ^[17]
• Potential reactivation of chronic inactive hepatitis can manifest variably in the following ways:
  • Asymptomatic
  • Unspecific symptoms
    • Fatigue, malaise
    • Nausea, poor appetite
    • Unspecific abdominal pain
  • Similar to acute hepatitis
  • Hepatic failure
• The younger when infected, the more likely a patient develops chronic HBV ^[18]
  • 90% of infants
  • ∼ 50% of children between 1 and 5 years
  • Only 5% of adults

Diagnostically relevant virus antigens, DNA, and antibodies ^[19]

Hepatitis B serology

Seroconversion of HBsAg to anti‑HBs indicates acute hepatitis resolution.

HBEAg indicates highly Enfectious.

Testing algorithm

1. Screening: measure HBsAg : and anti‑HBc IgM
2. If HBsAg is positive: measure HBeAg: and HBV DNA to determine transmissibility

During the window period, anti-HBc IgM and anti-HBe may be the only markers available to diagnose an acute HBV infection.

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

Additional tests

Laboratory studies

• Acute hepatitis
  • ↑ AST and ALT
  • AST/ALT ratio < 1 (> 1 in fulminant infection)
  • ↑ GGT
  • ↑ Ferritin
  • ↑ Bilirubin (mixed direct and indirect hyperbilirubinemia)
  • ↑ ALP
• Chronic hepatitis
  • High variability: mildly ↑ or unchanged AST and ALT
  • AST/ALT ratio ≥ 1
  • ↑ GGT
• Cirrhosis
  • ↓ Albumin
  • ↑ INR/PT
  • ↑ Bilirubin
  • ↓ CHE

Abdominal ultrasound ^[20]

• Acute hepatitis
  • ↑ Echogenicity of portal vein radicle walls
  • ↓ Echogenicity of the liver
• Chronic hepatitis
  • ↓ Echogenicity and number of portal vein radicle walls
  • ↑ Liver echogenicity

Liver biopsy

• A biopsy is indicated in the following cases:
  • Diagnosis is uncertain.
  • Exclusion of other possible causes of liver damage in chronic disease or severely affected individuals
  • Assessment of disease severity in patients with active chronic liver disease (i.e., ↑ AST/ALT and detectable levels of HBV DNA)
• See “Pathology” below.

Test of common coinfections ^[21][22]

Coinfection with hepatitis C, hepatitis D, syphilis, and HIV is common and should be tested for accordingly.

Active viral hepatitis ^[23][24]

• Eosinophilic single-cell necrosis (Councilman bodies)
• Bridging necrosis
• Kupffer cell proliferation

Chronic viral hepatitis ^[23][24]

• Formation of lymphoid follicles and mononuclear infiltrates
• Interface hepatitis (piecemeal necrosis)
  • Periportal liver cell necrosis with lymphocytic infiltration
  • The cause of interface hepatitis is a CD8 T-cell‑induced hepatocyte apoptosis.
  • Indicates chronic active hepatitis and poor prognosis
• Fibrous septa ^[25]
• Ground glass hepatocytes ; ^[26]
  • Hepatocytes with swollen transparent cytoplasm due to hyperplasia of the endoplasmic reticulum resulting in a ground glass appearance
  • Pathognomonic for hepatitis B
  • Result from increased production of viral membrane particles (HBsAg)

Ground glass hepatocytes are pathognomonic for HBV, whereas interface hepatitis, fibrous septa, and periportal infiltrates also occur in other types of chronic hepatitis.

Vowels (A and E) are bowels (transmitted fecal-orally) and usually only cause AcutE hepatitis.

Recovery rates of hepatitis B infection in adults are very good, with less than 5% of cases progressing to chronic infection. In contrast, the risk of developing chronic hepatitis is considerably higher in infants infected perinatally (90%) and young children (20–50%).

The differential diagnoses listed here are not exhaustive.

Lifestyle changes

• Weight loss ^[40]
• Cessation of substance use (including alcohol)
• Discontinuation of hepatotoxic medication

Antiviral treatment

Acute hepatitis B

• Pharmacological treatment is generally not indicated, and supportive care suffices.
• For treatment of acute liver failure, see “Complications” below. ^[28]

Chronic hepatitis B ^[28]

• Nucleoside/nucleotide analogs (NAs): Indicated in patients with both decompensated and compensated liver disease and patients who do not respond to interferon treatment
  • Tenofovir (TDF or TAF) is preferred due to:
    • High efficiency
    • Low rates of drug resistance
  • Entecavir
  • Telbivudine, lamivudine, and adefovir are no longer preferred due to:
    • High rates of drug resistance
    • Lower antiviral potency
    • More severe side effects
• Pegylated interferon alfa (PEG-IFN-α) ; : recombinant interferon alpha conjugated with polyethylene glycol (PEG) with antiviral and antineoplastic properties ^[41]
  • Mechanism of action
    • Interferons bind to specific cell-surface receptors → ↑ transcription and ↑ translation of various genes → ↑ protein products with immune-modulating effect (e.g., antiviral, antiproliferative, and antineoplastic)
    • Pegylation → ↑ interferon molecule size → slower absorption, ↑ half-life, and ↓ clearance rate → ↑ biologic activity
  • Treatment duration: shorter than nucleoside/nucleotide analogue regimen
  • Contraindications
    • Decompensated cirrhosis
    • Psychiatric conditions ^[42]
    • Pregnancy
    • Autoimmune conditions
    • Leukopenia or thrombocytopenia
  • Adverse effects are common and may considerably reduce patient tolerance.
    • Flu-like symptoms
    • Arthralgia, myalgia
    • Leukopenia, thrombocytopenia
    • Major depressive disorder

Liver transplantation indications

• End-stage liver disease due to HBV
• Fulminant hepatic failure (emergency transplantation)

Special populations ^[28]

Hepatitis D virus infection ^[45][46]

• Epidemiology: 5% of all chronically infected HBV patients are carriers of the hepatitis D virus.
• Etiology: Hepatitis D virus (HDV)
  • Incomplete viral particle resembling a viroid
  • Defective single-stranded RNA delta virus
  • Requires the HBsAg coat of HBV for entry into host cells
• Transmission: sexual, parenteral, perinatal
• Incubation period
  • Coinfection: 1–6 months
  • Superinfection: 2–8 weeks
• Clinical features: similar to acute HBV infection
• Course
  • Coinfection with HBV usually leads to more severe acute hepatitis ^[32]
  • Superinfection of a chronic HBsAg carrier increases risk of liver cirrhosis and accelerates disease progression.
• Treatment: See “Coinfection with hepatitis D” above.
• Complications: identical to those of hepatitis B (see below)

Remember the 3 D's of hepatitis D: Defective Deltavirus Dependent on HBV HBsAg coat for entry.

Acute hepatic failure

• Epidemiology: Affects ∼ 1% of acute HBV infections ^[47]
• Diagnosis: evidence of hepatic injury (e.g., ↑ transaminases, ↑ bilirubin), hepatic encephalopathy, and coagulopathy (INR > 1.5).
• Management: See “Acute liver failure.”

Long-term complications of hepatitis B ^[15]

• Liver cirrhosis
• Hepatocellular carcinoma (HCC) ^[48]
• Extrahepatic manifestations (10–20% of cases) ^[49]
  • Polyarteritis nodosa (strong correlation: in 36% of cases, hepatitis B virus is the causative agent) ^[38]
  • Glomerulonephritis
    • Membranous glomerulonephritis (more common)
    • Membranoproliferative glomerulonephritis type 1 (less common)
  • Aplastic anemia
• Reactivation of previous HBV infection due to immunosuppression
• Post‑hepatitis syndrome
  • Chronic fatigue, weakness
  • Nausea, loss of appetite
  • Possible upper quadrant pain

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

Screening ^[2]

• The CDC recommends screening for the following population groups:
  • All pregnant women (HBsAg)
  • Individuals from areas with intermediate or high HBV prevalence ^[50]
  • Unvaccinated children of parents born in countries with high HBV prevalence
  • Household and sexual contacts of HBV-positive individuals
  • Men who have sex with men
  • IV drug users
  • Individuals receiving immunosuppressive treatment (e.g., transplant recipients or HIV-positive individuals receiving ART)
  • Infants born to mothers with confirmed HBV infection or unknown HBV status
  • Individuals with elevated ALT/AST of unknown etiology
  • Hemodialysis patients
  • Blood, plasma, organ, tissue, and semen donors
• Individuals who test positive should be provided with counseling and referral to a medical specialist that can conduct a thorough clinical evaluation and provide appropriate care.

Hepatitis B preexposure prophylaxis

General lifestyle measures ^[51]

• Regular, thorough hand-washing
• Condom use
• Covering wounds and cuts carefully to minimize the risk of contact.
• Cleaning up spilled possibly infectious blood with a mixture of water and bleach solution (9 parts water, 1 part bleach)
• Avoiding illegal street drugs (especially IV drugs) or making sure to use new, fresh, sterile equipment
• Making sure that procedures like body piercings, tattoos, and acupuncture are done with sterile needles
• Not sharing sharp items such as razors, toothbrushes, nail clippers, and earrings or body rings
• Discarding tampons and sanitary napkins into plastic bags

Recommendations for active hepatitis B immunization ^[7]

• Infants
  • Active hepatitis B immunization is recommended for all infants as part of the general recommended immunization schedule; immunization should begin at birth.
    • Infants ≥ 2,000 grams should receive their first vaccine dose in the form of a single-antigen HepB vaccine within 24 hours of birth.
    • Infants ≤ 2,000 grams should receive their first vaccine dose delayed, either at the time of hospital discharge or when 1 month of age. ^[52]
  • The final dose of the vaccine series should be administered after 24 weeks.
• Children and adolescents
  • All unvaccinated children and adolescents aged < 19 years should be vaccinated.
  • Catch-up vaccination is recommended for children and adolescents at any age.
• Adults
  • Unvaccinated adults at risk for HBV infection (especially high-risk groups for HBV infection)
    • The presence of a specific risk factor should not be a requirement for vaccination.
  • Those requesting protection from HBV

Hepatitis B postexposure prophylaxis ^[7]

Exposure is defined as percutaneous or mucosal contact with blood or body fluids.

• Depending on immunization status, affected individuals will either receive:
  • Active immunization (i.e., hepatitis B vaccination)
  • Passive immunization (i.e., hepatitis B immune globulin)
  • Combined active and passive immunization
  • No intervention

Administration

PEP recommendations differ for HBV exposure in health care personnel (HCP) and general population.

• HCP
  • Completely vaccinated individuals with documented response do not require any intervention.
  • Unvaccinated/partly vaccinated individuals will receive 1 dose of HBIG and active immunization if exposed to bodily fluids of a patient with unknown or positive HBsAg status.
  • A completely vaccinated HCP with unknown response and patient should receive postexposure testing, regardless of source patient HBsAg status.
    • If patient is negative and HCP anti-HBs is < 10 mIU/ml, HCP should receive a dose of hepatitis B vaccine.
    • If patient is positive or status is unknown and HCP anti-HBs is < 10 mIU/ml, HCP should receive 1 dose of HBIG and revaccination with hepatitis B vaccine
• General population
  • Completely vaccinated individuals with documented response do not require any intervention.
  • Previously vaccinated and unvaccinated individuals should receive active immunization if exposed to a source with unknown HBsAg status.
  • When source is HBsAg positive, exposed unvaccinated/previously vaccinated individuals should receive full vaccine series with simultaneous administration of HBIG.