Categories
Internal Medicine

Hepatitis B

Introduction

Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy.

  • 3.5% of the global population is chronically infected with HBV
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Summary on Hepatitis B infection by Jorge Muniz

Epidemiology

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Geographic distribution of Hepatitis B prevalence, 2005 High: Hepatitis B Surface Antigen Prevalence > 8 % Intermediate: 2-7 % Low: <2% | CDC Travelers’ Health: Yellow Book Chapter 4 – Prevention of Specific Infectious Diseases: Hepatitis, Viral, Type Bmap based on http://i33.tinypic.com/mh37sx.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2127055
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Hepatitis B surface antigen (HBsAg) and HBV DNA are both indicators of ongoing HBV infection. In the majority of infections, both markers are detected. However, in 5–15% of cases, in part depending on genotype, HBsAg is detected but not HBV DNA. This situation corresponds to infections with very low (undetectable) levels of viral DNA. The presence of HBV DNA without detectable HBsAg is the main indicator of OBI. Depending on prevalent genotype and sensitivity of the genomic amplification assay, 5–10% of individuals having been in contact with HBV carry OBI. OBI, occult HBV infection. | Allain J-P, Opare-Sem O. Screening and diagnosis of HBV in low-income and middle-income countries. Nat Rev Gastroenterol Hepatol [Internet]. 2016 Sep 14 [cited 2017 Apr 13];13(11):643–53. Available from: http://www.nature.com/doifinder/10.1038/nrgastro.2016.138

Virology

Viral particles:

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Electron micrograph of circulating forms of HBV particles in the blood is shown at the top and a schematic drawing of Dane particle, the infectious HBV particle, is shown at the bottom with various structural features. | Liang, T. J. (2009). Hepatitis B: the virus and disease. Hepatology (Baltimore, Md.), 49(5 Suppl), S13–S21. https://doi.org/10.1002/hep.22881

3 types of viral particles are visualized in infectious serum by electron microscopy:

  • Spheres & filaments
    • Composed of hepatitis B surface antigen (HBsAg) and host-derived lipids without viral nucleic acids and are therefore noninfectious
  • Infectious HBV virion (Dane particle)
    • Spherical, double-shelled structure 42 nm in diameter, consisting of a lipid envelope containing HBsAg that surrounds an inner nucleocapsid composed of hepatitis B core antigen (HBcAg) complexed with virally encoded polymerase and the viral DNA genome.

Viral genome:

Encodes 4 overlapping open reading frames (ORFs: S, C, P, and X):
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The genome organisation of HBV. The genes overlap. The precore region is labelled PreC. | By T4taylor – Own work based on File:HBV_genome.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10687476
  1. S ORFEncodes viral surface envelope proteins, the HBsAg
    • Structurally & functionally divided into pre-S1, pre-S2, and S regions.
    • The core or C gene has the precore and core regions. Multiple in-frame translation initiation codons are a feature of the S and C genes, which give rise to related but functionally distinct proteins.
  2. C ORFEncodes either viral nucleocapsid (HBcAg) or hepatitis B e antigen (HBeAg) depending on whether translation is initiated from the core or precore regions, respectively
    • HBcAg: Intrinsic property to self-assemble into a capsid-like structure and contains a highly basic cluster of amino acids at its C-terminus with RNA-binding activity
    • HBeAg: Immune tolerogen (promotes persistent infection)
  3. P ORFEncodes polymerase (pol)
    • Polymerase (pol) is functionally divided into 3 domains:
      1. Terminal protein domain (involved in encapsidation and initiation of minus-strand synthesis)
      2. Reverse transcriptase (RT) domain (catalyzes genome synthesis)
      3. Ribonuclease H domain (degrades pregenomic RNA and facilitates replication)
  4. X ORFEncodes HBxAg
    • HBxAg has multiple functions (signal transduction, transcriptional activation, DNA repair, and inhibition of protein degradation)
    • HBxAg is necessary for productive HBV infection in vivo and may contribute to the oncogenic potential of HBV.

Pre-core mutant:

  • HBeAg absent
  • Due to mutation on C gene
  • Infections caused by pre-core mutants:
    • ↑ duration
    • Difficult to treat
    • ↑ risk of cirrhosis

Clinical features

HBV infection leads to a wide spectrum of liver disease ranging from acute hepatitis (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).

Acute Hepatitis B:

2⁄3 present as mild, asymptomatic and subclinical illness that usually goes undetected while 1⁄3 develop clinical features of hepatitis (range from mild constitutional symptoms of fatigue and nausea, to more marked symptoms and jaundice, and rarely to acute liver failure)
  • Clinical incubation period: 2–3 months, length of the incubation period correlating, to some extent, with the level of virus exposure)
  • Short preicteric/prodromal period (days to few weeks):
    • Constitutional symptoms: Fever, fatigue, anorexia, nausea, and body aches
    • ↑ Serum ALT levels rise + ↑ HBsAg and detectable HBV DNA
  • Icteric phase (variable period averaging 1–2 weeks):
    • Jaundice or dark urine
    • Viral levels decrease
  • Convalescent-phase:
    • Jaundice resolves but constitutional symptoms may last for weeks or even months
    • HBsAg is cleared followed by the disappearance of detectable HBV DNA from serum

Chronic Hepatitis B:

Chronic hepatitis B has a variable and dynamic course.
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The five phases of chronic hepatitis B infection as defined by European Association for the Study of the Liver. Hepatitis B virus serology (HBsAg: hepatitis B surface antigen; HBsAb: hepatitis B surface antibody; HBeAg: hepatitis B e antigen; HBeAb: hepatitis B e antibody; HBcAb IgM: hepatitis B virus core immunoglobulin M antibody; HBcAb IgG: hepatitis B core antibody IgG) | Gwilz – CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=65950825
  • Early phase:
    • ↑ HBeAg, HBsAg, and HBV DNA
    • ↑ (mild-to-moderate) serum aminotransferase levels
  • With time, disease activity can resolve with:
    • Persistence of high levels of HBeAg & HBV DNA, the “immune tolerance phase
    • Loss of HBeAg & fall of HBV DNA to low/undetectable levels “inactive carrier state
  • Other patients continue to have chronic hepatitis B, although some lose HBeAg and develop anti-HBe (HBeAg-negative chronic hepatitis B).
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Hepatitis B disease phases and treatment indications | Hepatitis B virus infection. (2018). Nature Reviews Disease Primers, 4, 18036. Retrieved from https://doi.org/10.1038/nrdp.2018.36

The overall prognosis of patients with chronic hepatitis is directly related to the severity of disease.

  • Severe chronic hepatitis & cirrhosis: 5-year survival rate (50%)
  • Evidence of chronic hepatitis:
    • ↑ ALT
    • Liver biopsy (inflammation and/or fibrosis)
  • Asymptomatic or nonspecific symptoms (fatigue and mild right upper quadrant discomfort)
  • Severe disease/cirrhosis
    • Significant constitutional symptoms
    • Jaundice
    • Peripheral stigmata of end-stage liver disease:
      • Spider angiomata, palmar erythema, splenomegaly, gynecomastia, ftor hepaticus
      • More advanced cirrhosis:
        • Ascites, peripheral oedema, encephalopathy, gastrointestinal bleeding
      • ↑ ALT & AST (may not correlate with severity of liver disease)
      • Bilirubin, prothrombin time, and albumin (abnormal levels with progressive disease)
      • ↓ Platelet count is often a poor prognostic sign.
  • Acute exacerbations with markedly elevated serum ALT
    • Commonly in HBeAg-negative chronic hepatitis B
    • D/D acute hepatitis B and chronic hepatitis B with a flare:
      • Anti-HBc IgM (can be detected occasionally in patients with chronic hepatitis B with exacerbation)
      • Alpha-fetoprotein (AFP) (used as a marker for HCC, is often elevated in parallel with ALT during acute exacerbation)
        • Unlikely to exceed 400 ng/mL. In patients with AFP much greater than this level, development of HCC should be suspected.

Extrahepatic Manifestations of Hepatitis B (1-10% HBV-infected cases):

Immune complex–mediated injury related to high level of HBV-antigenemia is thought to be the cause.
  • Serum-sickness–like syndrome: Occurs in the setting of acute hepatitis B, often preceding the onset of jaundice.
    • Clinical features:
      • Fever, skin rash, and polyarteritis
        • Symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B.
      • Course of this syndrome often parallels the duration and level of HBV viremia: rapid clearance of the virus leads to rapid resolution of the illness.
  • Acute necrotizing vasculitis (polyarteritis nodosa) (30-50% cases are HBV carriers):
    • (Early) Constitutional symptoms, high fever, anemia, and leukocytosis
    • (Late) Multisystem involvement:
      • Arthritis, renal disease (proteinuria and hematuria), heart disease (pericarditis and congestive heart failure), hypertension, gastrointestinal disease (acute abdominal pain and bleeding), skin involvement (vasculitic lesions), and neurological disorders (mononeuritis multiplex and central nervous system abnormalities).
  • HBV-associated nephropathy (M/C membranous glomerulonephritis):
    • 30%–60% of children with this disorder experience spontaneous remission, especially with HBeAg seroconversion
    • 30% of adults with this condition can progress to renal failure with as many as 10% requiring dialysis or renal transplant
  • Papular acrodermatitis of childhood (Gianotti-Crosti syndrome):
    • Distinct skin manifestation of acute HBV infection in childhood with maculopapular, erythematous, and nonpruritic lesions involving the face and extremities
    • Syndrome lasts about 15–20 days and can either precede or follow the onset of jaundice in acute hepatitis B.
    • Generalized lymphadenopathy and hepatomegaly have been described.

Occult/latent HBV Infection:

  • Seronegative occult or latent HBV infections:
    • HBsAg-negative who are either seronegative for all HBV markers or positive for anti-HBc and/or anti-HBs.
    • Positive for HBV DNA by PCR either in the liver or serum or both

Complications

Acute Hepatitis B:

Patients with acute liver failure due to hepatitis B require careful management and monitoring and should be referred rapidly to a tertiary medical center with the availability of liver transplantation.
  • Acute liver failure (1% cases)
  • Fulminant hepatitis: Sudden appearance of fever, abdominal pain, vomiting, and jaundice, followed by disorientation, confusion, and coma.
    • HBsAg and HBV DNA levels generally fall rapidly as liver failure develops, and some patients are HBsAg-negative by the time of onset of hepatic coma.

Chronic hepatitis B:

1⁄3 cases develop a long-term consequence of the disease
  • Cirrhosis
  • End-stage liver disease
  • HCC

Diagnosis

HBV serology:

nrgastro.2016.138-f1
A positive anti-HBc test result indicates either a previous or ongoing HBV infection. The presence of hepatitis B surface antigen (HBsAg) indicates acute or chronic infection, which in the presence of hepatitis B e antigen (HBeAg) is typically associated with a high viral load. Appearance of anti-HBe indicates nonreplicative chronic infection with low viral load. Anti-HBc associated with anti-HBs indicates recovery. Anti-HBs also develops in those who have been vaccinated against HBV. Anti-HBc associated with low-level HBV DNA indicates OBI. Negative anti-hepatitis B core antigen (anti-HBc) with detectable HBV DNA suggests window period infection or, rarely, primary OBI. OBI, occult HBV infection. | Allain J-P, Opare-Sem O. Screening and diagnosis of HBV in low-income and middle-income countries. Nat Rev Gastroenterol Hepatol [Internet]. 2016 Sep 14 [cited 2017 Apr 13];13(11):643–53. Available from: http://www.nature.com/doifinder/10.1038/nrgastro.2016.138
Serological markerSignificance
HBsAgViremia
(can be positive in acute/chronic/cirrhosis/carrier case)↑ risk of vertical transmission
HBeAg↑ infectivity
HBcAgNever released in blood
Anti-HBsPatient immune.
Virus not present.
Anti-HBe↓ infectivity
Anti-HBc (Most important diagnostic marker)
(IgM)Acute Hep. B
(IgG)+ HBsAgChronic Hep. B
+ Anti-HBsRemote recovered
Replication markers:
HBV DNAQuantitative marker of replication
(Cut off for significant replication = >1000 copies/ml)Most reliable, sensitive & best marker of replication
HBeAgQualitive marker of replication
Absent in pre-core mutants
Other (indirect) markers:
DNA Polymerase 
SGOT/SGPTIndicate liver damage by replication
hbv-serology
The Calgary Guide | http://calgaryguide.ucalgary.ca/
PhaseSerology
Incubation period (1st Window Period)HBsAg + HBcAg
Acute (symptomatic) Hep. BHBsAg + (IgM) Anti-HBc
(2nd) Window Period(IgM) Anti-HBc
Recovering Acute Hep. B(IgM) Anti-HBc + Anti-HBs
Remote recovered(IgG) Anti-HBc + Anti-HBs
Chronic Hep. B(IgG) Anti-HBc + HBsAg
Post VaccinationAnti-HBs

Management

nrdp201835-f7
Approved treatment agents for chronic HBV infection | Hepatitis B virus infection. (2018). Nature Reviews Disease Primers, 4, 18036. Retrieved from https://doi.org/10.1038/nrdp.2018.36

Pharmacological management:

Indicated for immune-active form (↑ ALT/AST) or fibrosis on liver biopsy
  • ILATE:
    • Interferon (IFN)-α2b
    • Lamivudine
    • Adefovir
    • Tenofovir
    • Entecavir

Summary

nrdp201836-i1
Hepatitis B virus can cause a lifelong chronic infection, which is associated with the development of cirrhosis and hepatocellular carcinoma. This illustrated PrimeView highlights the global perspective on the management and prevention of chronic hepatitis B infection. | Hepatitis B virus infection. (2018). Nature Reviews Disease Primers, 4, 18036. Retrieved from https://doi.org/10.1038/nrdp.2018.36

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