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Ch. 20 Hepatitis A-E
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  1. Ch. 20Hepatitis A-E

  2. Hepatitis Viruses Five medically important Hepatitis viruses: - HAV - HBV - HCV - HDV - HEV EPV, CMV & yellow fever viruses also infect the liver

  3. Viral Hepatitis - Overview

  4. Hepatitis Viruses

  5. HEPATITIS A VIRUS

  6. Hepatitis A Virus: Structure and Classification • RNA Picornavirus • Separate genus because of differences with other enteroviruses • Naked icosahedral capsid • SS RNA (7478 nucleotides) • Single serotype worldwide • Humans only reservoir

  7. HEPATITIS A VIRUS TRANSMISSION • Fecal-oral transmission • Close personal contact(e.g., household contact, sex contact, child day-care centers) • Contaminated food, water(e.g., infected food handlers, contaminated raw oysters) • Blood exposure (rare <<<1%)(e.g., injection drug use, rarely by transfusion)

  8. Hepatitis A: Pathogenesis • Incubation 4 weeks (range 2-6 weeks) • Oral cavityGI tractliver via blood • Replicates in hepatocytes (little damage to cells) released via bile to intestines 7-10 days prior to clinical symptoms • Liver damage and clinical syndrome result of immune response and not direct effect of virus

  9. Hepatitis A: Clinical Features • An acute illness with: • discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting) • jaundice or elevated serum aminotransferase levels, dark urine, light stool • Adults usually more symptomatic • Patients are infective while they are shedding the virus in the stool- usually before the onset of symptoms • Most cases resolve spontaneously in 2-4 weeks • Complete recovery 99%

  10. Hepatitis A Diagnosis • Detection of IgM antibody • IgG positive 1-3 weeks later; suggests prior infection or vaccination.

  11. Hepatitis A Treatment • Supportive- no specific role of antiviral therapy • Lifelong immunity likely after infection or vaccination

  12. PREVENTING HEPATITIS A • Hygiene (e.g., hand washing) • Sanitation (e.g., clean water sources) • Hepatitis A vaccine (pre-exposure) • Immune globulin (pre- and post-exposure)

  13. Hepatitis B Virus

  14. Hepatitis B: Structure • Member of the hepadnavirus group • Virion also referred to as Dane particle • 42nm enveloped virus (HBsAg) • Core antigens located in the center (nucleocapsid) • Core antigen (HbcAg) • e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg) • 22nm spheres and filaments other forms- no DNA in these forms so they are not infectious (composed of surface antigen)- these forms outnumber the actual virions

  15. Structure and Replication • Circular partially double stranded DNA of virus • Initial replication to complete circular DNA with subsequent transcription to make several mRNAs some of which are translated into viral proteins • One of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion • Some DNA integrates into host genome causing carrier state

  16. Hepatitis B Virus Modes of Transmission • Sexual • Parenteral • Perinatal

  17. HBV Pathogenesis • Virus enters hepatocytes via blood • Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome • 5 % become chronic carriers (HBsAg> 6 months) • Higher rate of hepatocellular ca in chronic carriers, especially those who are “e” antigen positive • HBsAb likely confers lifelong immunity • HBeAb indicates low transmissibility

  18. Hepatitis B Clinical Features • Incubation Period: 6 weeks to 6 months (av. 120 days) • Preicteric or Prodromal phase from initial symptoms to onset of jaundice usually lasts from 3 to 10 days: Non-specific, insidious onset of malaise, anorexia, fever, headache, myalgias, skin rashes, arthralgias, arthritis, and dark urine beginning 1-2 days before onset of jaundice.

  19. Hepatitis B Clinical Features • Icteric phase usually lasts from 1-3 weeks: jaundice, light or gray stools, hepatic tenderness, hepatomegaly. • Convalescence phase may persist for weeks or months: Malaise, fatigue. Jaundice, anorexia, and other symptoms disappear.

  20. Hepatitis B Symptoms • About 50%-60% of adults with HBV infection have no signs or symptoms. • Those who do have symptoms might experience: • Jaundice • Fatigue • Abdominal pain • Loss of appetite • Nausea, vomiting • Joint pain

  21. Current Treatment Options for HBV • Pegylated Interferon alfa (Intron A) • Lamivudine (Epivir HBV) • Adefovir dipivoxil (Hepsera)

  22. Hepatitis B Vaccine • Infants: several options that depend on status of the mother • If mother HBsAg negative: birth, 1-2m,6-18m • If mother HBsAg positive: vaccine and Hep B immune globulin within 12 hours of birth, 1-2m, <6m • Adults • 0, 1, 6 months • Vaccine recommended in • All those aged 0-18 • Those at high risk

  23. Hepatitis D (Delta) Virus d antigen HBsAg RNA

  24. Hepatitis D Structure • Defective virus that requires co-infection with hepatitis B for replication • Enveloped with SS RNA genome • Only antigen encoded in the delta antigen

  25. Hepatitis D Virus Modes of Transmission • Percutaneous exposures • injecting drug use • Permucosal exposures • sex contact

  26. Hepatitis D:Pathogenesis • Pathogenesis • Immune mediated • Co-infection- infection with B at the same time (more severe) • Superinfection: acquisition of Hep D in chronically Hep B

  27. Hepatitis C Virus

  28. Hepatitis C Structure and Classification • Member of the flavivirus family (other members yellow fever and dengue) • Enveloped single stranded RNA virus • Humans and chimpanzees only known reservoirs • 6 serotypes (genotypes) and multiple subtypes based on high variability of envelope glycoproteins

  29. Exposures Known to Be Associated With HCV Infection • Injecting drug use • Transfusion, transplant from infected donor • Occupational exposure to blood • Mostly needle sticks • Iatrogenic (unsafe injections) • Birth to HCV-infected mother • Sex with infected partner • Multiple sex partners

  30. Hep C: Pathogenesis • Blood-borne pathogen that infects hepatocytes • Much like Hep A and B, liver damage and clinical illness due more to elicited immune response as opposed to direct cytopathic effect of the virus • Likely cytotoxic T cells that mediate most of the damage • Like other chronic liver diseases (Hep B and chronic alcoholism), can cause hepatocellular ca (HCC) • Some genotypes more amenable to therapy- i.e. 3a

  31. Hepatitis C: Clinical Features • Acute infection asymptomatic in over 80% of patients, when present, acute illness usually mild • Acute symptoms include jaundice, nausea, abdominal pain, loss of appetite, dark urine

  32. Chronic Hepatitis C Factors Promoting Progression or Severity • Increased alcohol intake • Age > 40 years at time of infection • HIV co-infection • Other • Male gender • Chronic HBV co-infection

  33. Hepatitis C: Diagnosis • ELISA-a serological test which is usually. positive within 2-5 months after infection • 3rd generation assays now 99% specific and sensitive • Confirmatory testing • PCR (positive 1-2 weeks post infection) both quantitative and qualitative (I.e. ye/no) available • RIBA (recombinant immunoblot assay)- looks for 2 or more antibodies to HCV viral antigens • Genotype testing done when treatment anticipated

  34. Hepatitis C Therapy • Standard of care is pegylated interferon alpha and ribavirin • Many barriers to treatment as the above regimen is difficult to take and has many systemic side effects (fatigue, myalgias, depression, anemia to name a few) • Overall response rate to treatment is 40-50% (higher for non 1 genotypes)

  35. Hepatitis E Virus

  36. Hepatitis E • Non-enveloped single stranded RNA virus • Resembles Calicivirus or Norwalk agent • Similar illness to Hep A except high mortality in pregnant women

  37. Hepatitis E - Clinical Features • Incubation period: Average 40 days • Range 15-60 days • Case-fatality rate: Overall, 1%-3% Pregnant women, 15%-25% • Illness severity: Increased with age • Chronic sequelae: None identified

  38. HIV and AIDS Acquired Immunodeficiency Syndrome Disease caused by an infectious agent: a retrovirus

  39. AIDS Definition • AIDS is currently defined as the presence of one of 25 conditions indicative of severe immunosuppression • OR • HIV infection in an individual with a CD4+ cell count of <200 cells per cubic mm of blood • AIDS is therefore the end point of an infection that is continuous, progressive and pathogenic • With the prevalence of HIV in the developing world, HIV and its complications will be with us for generations

  40. Important Properties The virus only grows on T4 cells that are proliferating in response to an immune stimulus -- Therefore difficult to grow in culture Human immunodeficiency viral particles are seen at medium magnification in this electron micrograph (CDC)

  41. HIV - The Virus Retrovirus Three genes GAG – POL – ENV Three polyproteins Six regulatory genes TAT – REV – NEF –VIF – VPR – VPU

  42. HIV - The Virus Retrovirus Two glycoproteins: gp160gp120 and gp41 gp41 is fusogen that spans the membrane ENV gene

  43. HIV - The Virus p24: nucleocapsid Retrovirus Group-Specific Antigens p17: inner surface - myristoylated p9: nucleocapsid associated with RNA GAG gene Polyprotein