Hepatitis D Virus

Hepatitis D virus (HDV) is a small enveloped, single-stranded RNA virus. Hepatitis D virus is considered a satellite virus, as it requires the presence of hepatitis B virus (HBV) for assembly and secretion. Therefore, in order for an individual to contract hepatitis D, coinfection or superinfection with HBV is required. Like HBV, HDV is transmitted parenterally, through unprotected sexual intercourse, or perinatally. Clinical presentation is that of a classical viral hepatitis, including coinfection of HDV and HBV, which is considered the most serious form of hepatitis because of the high mortality rate. For acute cases, management is supportive, whereas for chronic cases, pegylated interferon alfa (PEG-IFN-α) is needed.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses have a genome formed by either DNA or RNA. Viruses of the RNA genome can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as mRNA, which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA-dependent RNA polymerase, a viral enzyme, to transcribe the genome into mRNA.

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General Characteristics

Structure

  • Family: Kolmioviridae, genus: Deltavirus
  • Single-stranded circular RNA (ssRNA)
  • Negative-sense genome
  • Small (approximately 36 nm in diameter)
  • Incomplete or defective virus particle → resembles viroid
  • Envelope contains hepatitis B surface antigen (HbsAg)
  • 8 species of hepatitis D virus (HDV) are known.

Features

  • Causes acute or chronic hepatitis
  • Difference from classical satellite virus: HDV does not have sequence similarity with hepatitis B virus (HBV) → can replicate independently of HBV but requires HBV for complete virion assembly and secretion
  • Relies on host-cell machinery for replication
  • Lowers HBV replication in most individuals (mechanism incompletely understood)
Hepatitis D virus (HDV)_

Hepatitis D virus (HDV):
The hepatitis D virion consists of single-stranded circular RNA (HDV RNA), a single HDV-encoded antigen (HDAg), and a lipoprotein envelope (HbsAg), which is provided by the hepatitis B virus (HBV).

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Epidemiology

  • Prevalence:
    • About 5% of individuals with hepatitis B worldwide have HDV coinfection (15–20 million people total)
    • Adults >> children, especially in areas of high HBV vaccination
    • Highest: Mongolia, Republic of Moldova, Western and Central Africa
    • Prevalence decreases due to increasing HBV vaccination rates
  • HDV–HBV coinfection/superinfection is the most severe form of chronic viral hepatitis → rapid progression toward hepatocellular carcinoma (HCC) and liver-related death

Pathogenesis

Transmission

Transmission of hepatitis D is similar to that of hepatitis B.

  • Unprotected sexual intercourse
  • Parenterally (shared IV drug needles, accidental needle sticks) 
  • Mother to child (most common in high-prevalence areas)

Host risk factors

  • Persons who inject drugs (PWIDs)
  • Individuals who have unprotected sex with multiple partners
  • Men who have sex with men (MSM)
  • HIV infection
  • Hemodialysis
  • Infants born to HBV-positive mothers
  • Professions with exposure to human blood, seminal fluids, and/or vaginal fluids 
  • Individuals on hemodialysis or recipients of organs or blood transfusions

Pathophysiology

  • Infection with HDV can only occur as coinfection or superinfection with HBV.
  • HDV infects liver cells → expresses viral peptides on their surfaces via a bile transporter
  • HDV recognizes its receptor by the large HbsAg
  • After entering the hepatocyte, HDV is uncoated → makes use of the host cellular RNA polymerases to replicate
  • Peptides activate lymphocytes (CD8+ cytotoxic T cells) → WBCs mount a cellular immune response against infected liver cells → destruction of hepatocytes  → liver inflammation

Clinical Presentation

General

  • HDV infection is clinically indistinguishable from other forms of viral hepatitis.
  • 90% of cases are asymptomatic.
  • Incubation period: 
    • Coinfection: 1–6 months
    • Superinfection: 2–8 weeks
  • Possible symptoms: 
    • Nausea, vomiting
    • Jaundice
    • Fever
    • Tiredness
    • Dark urine
    • Abdominal pain 
    • Myalgias, arthralgias

Coinfection

  • Only if individual is anti-Hbs-negative at time of infection
  • Clinically not distinguishable from classical hepatitis B
  • Individuals may be asymptomatic during the initial infection.
  • Higher incidence of liver failure in PWIDs

Superinfection

  • Can present as severe acute hepatitis (unrecognized HBV carrier state) or exacerbation of chronic hepatitis B
  • Accelerates progression to more severe disease (cirrhosis, HCC) in all ages 
  • HBV replication is reduced by HDV infection (mechanism incompletely understood)

Diagnosis and Management

Diagnosis

  • Viral markers (serum)
    • HbsAg: has to be positive for diagnosis of HDV
    • Early markers: anti-HDV IgM and HDV RNA 
    • Late marker: anti-HDV IgG 
    • IgM antibodies to hepatitis B core antigen (IgM anti-HBc): acute HBV/HDV coinfection
  • Additional laboratory testing:
    • ALT and AST levels 
    • Signs of severe disease: 
      • Hemolysis
      • Thrombocytopenia
      • Elevated INR

Management

  • Acute disease: supportive, no specific therapy available 
  • Chronic disease: conventional or pegylated interferon alfa (PEG-IFN-α)
    • Given for at least 48 weeks
    • Efficiency approximately 20%
    • Effective only as long as administered
    • Contraindications: decompensated cirrhosis, active psychiatric conditions, autoimmune diseases

Prevention

  • Prevention of HDV is based on stopping the spread of HBV 
  • Vaccination against HBV is the most effective way to prevent HDV:
    • For all infants and children up to 18 years (recommended by WHO and CDC)
    • For adults, especially those in high-risk groups.
    • 3 doses required to complete hepatitis B vaccine series
    • 2-dose series for adolescents and adults available
    • Babies born to infected mothers: must receive 1st dose within the 1st 12 hours of life
  • Further measures:
    • Safety measures for handling blood products
    • Safe injection practices
    • Postexposure prophylaxis: hepatitis B immune globulin or hepatitis B vaccine

Comparison of Hepatitis Viruses

Comparison table of hepatitis viruses

Anti-HBc antibodies: antihepatitis B core antibodies
Anti-HBs antibodies: antihepatitis B surface antibodies
HBcAg: hepatitis B core antigen
HBsAg: hepatitis B surface antigen
HBV: hepatitis B virus
HCC: hepatocellular carcinoma
HCV: hepatitis C virus
HDV: hepatitis D virus

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Differential Diagnosis

  • Alcoholic liver disease (ALD): liver pathology that occurs because of prolonged excessive alcohol consumption. The 1st stage is an asymptomatic fatty liver, which is reversible. The 2nd stage is alcoholic hepatitis, which most commonly presents with jaundice, fever, and RUQ pain. The 3rd stage is cirrhosis of the liver. Diagnosis is established by history, liver-function tests, and imaging studies. 
  • Drug-induced liver injury (DILI): occurs when drugs ingested cause injury to the hepatocytes directly in a predictable dose-dependent way or through idiosyncratic reactions. The presentation of DILI can be acute or chronic, with severe toxicity manifesting as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests. Management consists of early diagnosis and discontinuing the drug, as well as supportive therapy.
  • Autoimmune hepatitis (AIH): liver inflammation that occurs when the body’s immune system attacks its own liver cells. Clinical presentation ranges from asymptomatic to symptoms of acute liver failure. Diagnosis is established via testing the blood for characteristic autoantibodies (especially, anti–smooth muscle antibodies) and liver biopsy. Management includes corticosteroids and azathioprine. 
  • Wilson disease: autosomal recessive disorder from a mutation in the ATP7B gene, which regulates copper transport within hepatocytes. Neuropsychiatric manifestations of Wilson disease help differentiate it from other causes of hepatitis. In early stages, Wilson disease may be confused with hepatic encephalopathy. Kayser-Fleischer rings, low ceruloplasmin levels help separate Wilson disease from other causes of hepatitis.
  • Nonalcoholic fatty liver disease (NAFLD): spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis which has fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and possibly, primary liver cancer. Management is with lifestyle modifications (diet and exercise).

References

  1. Roy P. (2021). Hepatitis D. Emedicine. Retrieved January 28, 2021, from https://emedicine.medscape.com/article/178038-overview#a6
  2. Rizzetto M, Verme G. (1985). Delta hepatitis—present status. J Hepatol 1:187–193.
  3. Samuel D, Zignego AL, Reynes M, et al. (1995). Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis. Hepatology 21:333–339.
  4. Abbas Z, Afzal R. (2013). Life cycle and pathogenesis of hepatitis D virus: a review. World J Hepatol 5:666–675.
  5. Negro F, Lok A. (2020). Diagnosis of hepatitis D virus infection. UptoDate. Retrieved January 28, 2021, from https://www.uptodate.com/contents/diagnosis-of-hepatitis-d-virus-infection
  6. Bichko V, Netter HJ, Wu TT, Taylor J. (1994). Pathogenesis associated with replication of hepatitis delta virus. Infectious Agents and Disease 3(2-3):94–97.
  7. Stockdale AJ, Kreuels B, Henrion M, Giorgi E, Kyomuhangi I, de Martel C, Hutin Y, Geretti AM. (2020). The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. Journal of Hepatology 73:523–532. https://doi.org/10.1016/j.jhep.2020.04.008
  8. World Health Organization (WHO). Hepatitis D factsheet. Retrieved August 7, 2021, from https://www.who.int/news-room/fact-sheets/detail/hepatitis-d

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