Hepatitis virus


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Hepatitis virus

  1. 1. Fe A. Bartolome, MD, FPASMAP Department of Microbiology Our Lady of Fatima University
  2. 2. CASE 1: A 55-year old man was admitted to the hospital with fatigue, nausea, and abdominal discomfort. He had a slight fever, his urine was dark yellow, and his abdomen was distended and tender. He had returned from a trip to Thailand within the previous month.
  3. 3. HEPATITIS A (Infectious Hepatitis) <ul><li>Enterovirus 72 in the Picornavirus family, genus Heparnavirus </li></ul><ul><li>Spread by fecal-oral route </li></ul><ul><li>Incubation period: approx. 1 month </li></ul><ul><li>Period of communicability: before to after symptoms appear </li></ul>
  4. 4. HEPATITIS A (Infectious Hepatitis) <ul><li>Does not cause chronic liver disease </li></ul><ul><li>Rarely causes fatal disease </li></ul><ul><li>Humans serve as reservoir </li></ul><ul><li>Not cytolytic </li></ul>
  5. 5. HEPATITIS A (Infectious Hepatitis) <ul><li>27 nm, naked icosahedral capsid surrounding a positive-sense ssRNA </li></ul><ul><li>Stable to: acid at pH 1, solvents (ether, chloroform), detergents, salt & ground water, drying </li></ul><ul><li>Inactivated by: chlorine treatment of drinking water, formalin, UV radiation </li></ul>
  6. 6. HEPATITIS A (Infectious Hepatitis) <ul><li>Transmission: fecal-oral; possible sexual </li></ul><ul><ul><li>Contaminated food and water </li></ul></ul><ul><ul><li>Dirty hands </li></ul></ul><ul><ul><li>Contaminated shellfish – clams, oysters, mussels </li></ul></ul><ul><li>Only one serotype </li></ul>
  7. 7. HEPATITIS A (Infectious Hepatitis)
  8. 8. <ul><li>No cytopathic effect  damage to liver due to immunopathology </li></ul><ul><li>Interferon limits replication of virus </li></ul><ul><li>NK cells & CTL  lyse infected cells </li></ul><ul><li>Icterus occurs when antibody is detected and CMI responses to the virus occur </li></ul>HEPATITIS A (Infectious Hepatitis)
  9. 9. <ul><li>Clinical: </li></ul><ul><ul><li>Disease in children milder than in adults & usually asymptomatic </li></ul></ul><ul><ul><li>Abrupt onset of symptoms 15 to 50 days after exposure </li></ul></ul><ul><ul><li>(+) jaundice in 2 of 3 adults but only 1 or 2 of 10 children </li></ul></ul><ul><ul><li>Symptoms wane during jaundice period </li></ul></ul><ul><ul><li>(+) viral shedding in stool before onset of symptoms but stops before cessation of symptoms </li></ul></ul>HEPATITIS A (Infectious Hepatitis)
  10. 11. Approach to Diagnosis Hepatitis A (HAV) IgM anti-HAV Negative Positive Assay “total” anti-HAV as clinically indicated (-) Not immune to HAV Acute HAV infection (+) Immune to HAV
  11. 12. <ul><li>Diagnosis: Serology </li></ul><ul><ul><li>IgM anti-HAV : acute HAV infection </li></ul></ul><ul><ul><li>IgG anti-HAV : resolution or previous infection </li></ul></ul>HEPATITIS A (Infectious Hepatitis)
  12. 13. <ul><li>Treatment & Prevention </li></ul><ul><ul><li>Prophylaxis with immune serum globulin given before or early in the incubation period (i.e. < 2 weeks after exposure)  80% to 90% effective in preventing clinical illness </li></ul></ul><ul><ul><li>Active immunization with killed HAV for two doses (initial dose + booster 6-12 months later) </li></ul></ul>HEPATITIS A (Infectious Hepatitis)
  13. 14. <ul><li>Treatment & Prevention </li></ul><ul><ul><li>Active immunization recommended for: </li></ul></ul><ul><ul><ul><li>Travellers to developing countries </li></ul></ul></ul><ul><ul><ul><li>Children 2 – 18 years old </li></ul></ul></ul><ul><ul><ul><li>Men who have sex with men </li></ul></ul></ul>HEPATITIS A (Infectious Hepatitis)
  14. 15. CASE 2: A 28-year-old woman was admitted to the hospital complaining of vomiting, abdominal discomfort, nausea, anorexia, dark urine, and jaundice. She admitted that she was a former heroin addict and that she had shared needles . She was also three months pregnant.
  15. 16. <ul><li>Caused by a hepadnavirus with a DNA genome </li></ul><ul><li>Spread parenterally by blood or needles, by sexual contact or perinatally </li></ul><ul><li>Has median incubation period of approx. 3 months, after which icteric symptoms start insidiously </li></ul><ul><li>Is followed by chronic hepatitis in 5% - 10% of patients </li></ul>HEPATITIS B (Serum Hepatitis)
  16. 17. <ul><li>Is causally related to primary hepatocellular carcinoma </li></ul><ul><li>Infects the liver and, to a lesser extent, the kidneys and pancreas of only humans and chimpanzees </li></ul><ul><li>Stable to: treatment with ether, acid, freezing, and moderate heating </li></ul>HEPATITIS B (Serum Hepatitis)
  17. 18. <ul><li>Virion also called a Dane particle </li></ul><ul><li>Structure: enveloped, with icosahedral nucleocapsid core containing a partially double-stranded circular DNA genome </li></ul><ul><ul><li>Polymerase with reverse transcriptase & ribonuclease H activity </li></ul></ul><ul><ul><li>HBcAg </li></ul></ul><ul><ul><li>HBeAg </li></ul></ul><ul><ul><li>HBsAg (Australia antigen) – with 3 glycoproteins (S [major component], M, and L) </li></ul></ul><ul><ul><li>X protein – acts as transactivator of transcription and as a protein kinase </li></ul></ul>HEPATITIS B (Serum Hepatitis)
  18. 19. <ul><li>Replication – unique features: </li></ul><ul><ul><li>With distinctly defined tropism for the liver </li></ul></ul><ul><ul><li>Small genome  necessitates economy </li></ul></ul><ul><ul><li>Replicates through an RNA intermediate </li></ul></ul><ul><ul><li>Produces and releases antigenic decoy particles </li></ul></ul><ul><ul><li>Binds to polymerized human serum albumin & other serum proteins </li></ul></ul><ul><ul><li>Partial DNA strand completed by being formed into a complete ds DNA circle  delivered to nucleus </li></ul></ul>HEPATITIS B (Serum Hepatitis)
  19. 20. <ul><li>Major source of infection: blood </li></ul><ul><li>Other sources: semen, saliva, milk, vaginal & menstrual secretions, and amniotic fluid </li></ul><ul><li>Most efficient way to acquire virus: injection of virus into the blood stream </li></ul><ul><li>Common but less efficient routes: sexual contact and birth </li></ul>HEPATITIS B (Serum Hepatitis)
  20. 21. <ul><li>Mother-to-child infection: </li></ul><ul><ul><li>Can be transmitted from a chronically-infected mother to her child during the birthing process </li></ul></ul><ul><ul><li>One of the most common modes of transmission for Asians </li></ul></ul>HEPATITIS B (Serum Hepatitis)
  21. 22. <ul><li>Blood-borne infection: </li></ul><ul><ul><li>Includes: </li></ul></ul><ul><ul><ul><li>Wound-to-wound contact </li></ul></ul></ul><ul><ul><ul><li>Blood transfusion </li></ul></ul></ul><ul><ul><ul><li>Reusing syringes or medical services </li></ul></ul></ul><ul><ul><ul><li>Sharing razors or toothbrushes contaminated by blood </li></ul></ul></ul><ul><ul><ul><li>Reusing or sharing needles for tattoos, piercings, acupuncture, or injection drugs </li></ul></ul></ul>HEPATITIS B (Serum Hepatitis)
  22. 23. <ul><li>HBV is NOT spread through: </li></ul><ul><ul><li>Sharing of food or water </li></ul></ul><ul><ul><li>Sharing eating utensils or drinking glasses </li></ul></ul><ul><ul><li>Tears, sweat, urine, or stool </li></ul></ul><ul><ul><li>Coughing or sneezing </li></ul></ul><ul><ul><li>Hugging or kissing </li></ul></ul><ul><ul><li>Breastfeeding </li></ul></ul><ul><ul><li>Mosquitoes </li></ul></ul>HEPATITIS B (Serum Hepatitis)
  23. 24. <ul><li>High-Risk Groups: </li></ul><ul><ul><li>People from endemic regions </li></ul></ul><ul><ul><li>Babies of mothers with chronic HBV infection </li></ul></ul><ul><ul><li>IV drug abusers </li></ul></ul><ul><ul><li>People with multiple sexual partners (homosexual and heterosexual) </li></ul></ul><ul><ul><li>Hemophiliacs and other patients requiring blood and blood product treatments </li></ul></ul><ul><ul><li>Health care personnel </li></ul></ul><ul><ul><li>Hemodialysis patients and blood and organ recipients </li></ul></ul>HEPATITIS B (Serum Hepatitis)
  24. 25. Spread of virus: HEPATITIS B (Serum Hepatitis) Source Infection Blood Ab Prevent spread and disease Liver Viremia CMI Symptoms, Resolution HBsAg Ab Immune complexes Immune complex disease Mother’s milk Vaginal secretions Blood Semen Saliva Rash, polyarthritis, fever, GN
  25. 26. Symptoms of typical acute HBV infection: Fever, rash, arthritis (15%) Jaundice Dark urine Malaise (95%) Anorexia (90%) Nausea (80%) RUQ pain (60%) Itching (10%) EXPOSURE Incubation Period Pre-icteric Icteric Convalescent period
  26. 27. Clinical outcomes of acute HBV infection: Fulminant hepatitis (1%) HBsAg+ > 6 mos (9%) Extrahepatic disease: Polyarteritis nodosum Glomerulonephritis Cirrhosis Hepatic cell carcinoma
  27. 29. Approach to Diagnosis of HBV infection Hepatitis B (HBV) HBsAg Negative Positive Assay anti-HBs (total) (-) Consider immunization for appropriate populations Assay IgM anti-HBc (+) Recovered or immunized (-) Chronic HBV infection (+) Acute or reactivated HBV infection
  28. 30. Laboratory Diagnosis of HBV infection: <ul><li>Acute and chronic infection can be distinguished by the presence of HBsAg and HBeAg in the serum and the pattern of antibodies to the individual antigens. </li></ul><ul><li>The detection of HBeAg is the BEST correlate to the presence of infectious virus. </li></ul><ul><li>During the symptomatic phase, detection of antibodies to HBeAg and HBsAg is obscured because the antibody is complexed with antigens in the serum. </li></ul><ul><li>The best way to diagnose recent acute infection, especially during the period when neither HBsAg nor anti-HBs can be detected (window period), is to measure anti-HBc IgM. </li></ul>
  29. 31. Laboratory Diagnosis of HBV infection:c <ul><li>What are the tests which you have to take? </li></ul><ul><ul><li>ALT blood test – to determine whether treatment against HBV is needed </li></ul></ul><ul><ul><li>HBV DNA level – direct measure of HBV viral load; helps evaluate treatment response </li></ul></ul><ul><ul><li>HBeAg and anti-HBe tests </li></ul></ul><ul><ul><ul><li>HBeAg seroconversion (loss of HBeAg) and development of anti-Hbe is a sign that the treatment is working </li></ul></ul></ul>
  30. 32. Serologic test results in four stages of HBV infection 1 IgM is found in the acute stage; IgG is found in subsequent stages.
  31. 33. How will you know if you are protected from HBV? Quick Test Results Results Interpretation HBsAg (+) Anti-HBs (-) Chronic HBV infection if HBsAg remains (+) for six months HBsAg (-) Anti-HBs (+) Immune to HBV HBsAg (-) Anti-HBs (-) Unprotected; need vaccination HBsAg (+) Anti-HBs (+) (rare) Chronic HBV infection
  32. 34. Simplified Diagnostic Approach in Patients Presenting with Acute Hepatitis Serologic Tests of Patient’s Serum Diagnostic Interpretation HBsAg IgM Anti-HAV IgM anti-HBc + + + + -- -- -- -- -- -- + + + + -- -- + -- -- + -- + + -- Acute hepatitis B Chronic hepatitis B Acute hep A superimposed on chronic HBV Acute hepatitis A and B Acute hepatitis A Acute hep A and hep B (HBsAg below detection level) Acute hepatitis B (HBsAg below detection level) Test for acute hepatitis C (anti-HCV)
  33. 35. Hepatitis B: Serologic Tests of Candidate for HBV Vaccine
  34. 36. CASE 3: A 65-year-old man was admitted with jaundice, nausea, and vomiting 6 months after undergoing coronary artery bypass grafting.
  35. 37. <ul><li>Predominant cause of NANBH and major cause of post-transfusion hepatitis </li></ul><ul><li>Member of Hepaciviridae in the Flaviviridae family </li></ul><ul><li>Enveloped, positive-sense RNA virus; labile to drying </li></ul><ul><li>Genome encodes two glycoproteins (E1, E2) that undergo variation due to hypervariable regions within their genes </li></ul><ul><li>Infects only humans and chimpanzees </li></ul>HEPATITIS C (NANB Post-transfusion Hepatitis)
  36. 38. <ul><li>Binds to cells using CD81 surface receptors OR coats itself with LDL or VLDL  uptake into hepatocytes  remain in the ER and is cell-associated </li></ul><ul><li>Bind to : </li></ul><ul><ul><li>TNFR  inhibit apoptosis </li></ul></ul><ul><ul><li>Protein kinase R (PKR)  inhibit interferon α </li></ul></ul><ul><li>CMI responsible to producing tissue damage </li></ul><ul><li>Antibodies not protective </li></ul>HEPATITIS C (NANB Post-transfusion Hepatitis)
  37. 39. <ul><li>Transmission: </li></ul><ul><ul><li>Primarily in infected blood and sexually </li></ul></ul><ul><ul><li>Others: semen, vaginal secretions, transfusion, needlestick injury, shared drug paraphernalia, and breast-feeding </li></ul></ul><ul><ul><li>Almost all (>90%) HIV-infected individuals who are or were IV drug users are infected with HCV </li></ul></ul>HEPATITIS C (NANB Post-transfusion Hepatitis)
  38. 40. HEPATITIS C (NANB Post-transfusion Hepatitis) <ul><li>Clinical : </li></ul><ul><ul><li>Acute disease similar to HAV and HBV infection but with less intense inflammatory response and milder symptoms </li></ul></ul><ul><ul><li>CHRONIC AND PERSISTENT HEPATITIS IS THE HALLMARK OF INFECTION </li></ul></ul>
  39. 41. HEPATITIS C (NANB Post-transfusion Hepatitis) Recovery and clearance (15%) Persistent infection (85%) Chronic hepatitis Liver failure (6%) Cirrhosis (20%) Hepatocellular carcinoma (4%)
  40. 43. Approach to Diagnosis of HCV infection Hepatitis C (HCV) Anti-HCV (-) Not exposed to HCV (If poor immune status or recent exposure, assay for HCV RNA by PCR) (+) Assay HCV RNA by PCR <ul><li>(-) </li></ul><ul><li>Recovered HCV infection or </li></ul><ul><li>Below detection limit of PCR assay used or </li></ul><ul><li>False (+) anti- HCV </li></ul>(+) Active HCV infection
  41. 44. HEPATITIS C (NANB Post-transfusion Hepatitis) <ul><li>Diagnosis and detection of HCV infection are based on ELISA recognition of antibody. </li></ul><ul><ul><li>Seroconversion occurs within 7 to 31 weeks of infection </li></ul></ul><ul><li>Recombinant interferon- α alone or with ribavirin is the only known treatment </li></ul>
  42. 45. HEPATITIS D (“Delta Agent”) <ul><li>Unique feature: uses HBV and target cell proteins to replicate and produce its one protein  HBsAg essential for packaging the virus </li></ul><ul><li>Resemble plant virus satellite agents and viroids in size, genomic structure, and requirements for helper virus for replication </li></ul><ul><li>Responsible for causing 40% of the fulminant hepatitis infections </li></ul>
  43. 46. HEPATITIS D (“Delta Agent”) <ul><li>Circular, ssRNA genome that forms a rod shape as a result of its extensive base-pairing </li></ul><ul><li>Binds to and internalized by hepatocytes in the same manner as HBV </li></ul><ul><li>Replication process unusual  forms an RNA structure called a ribozyme  cleaves the RNA circle to produce an mRNA </li></ul>
  44. 47. HEPATITIS D (“Delta Agent”) Consequences of HDV infection: Co-infection: HBV +  Incubation Superinfection: Chronic HBV +  Incubation Acute hepatitis Cirrhosis Fulminant hepatitis Chronic delta infection
  45. 49. Comparison of Types of HDV Infections
  46. 50. HEPATITIS E (Enteric NANBH) <ul><li>Predominantly spread by fecal-oral route </li></ul><ul><li>Resembles Calicivirus or the Norwalk agent in size and structure </li></ul><ul><li>Symptoms and course of disease similar to HAV but symptoms may occur later than HAV and response to IgG may be poor </li></ul><ul><li>Causes fulminant infection in pregnant women </li></ul>
  47. 51. HEPATITIS G <ul><li>Flavivirus similar to HCV </li></ul><ul><li>MOT: </li></ul><ul><ul><li>Contaminated blood or blood products </li></ul></ul><ul><ul><li>Sexual contact </li></ul></ul><ul><li>75% cleared from plasma; 25% chronic </li></ul><ul><li>Site of replication: mononuclear cells  not hepatotropic  no increase in serum transaminases </li></ul><ul><li>No pathologic effect </li></ul><ul><li>Commonly co-infects patients with HIV  protects against HIV disease </li></ul>
  48. 52. Important Properties of Hepatitis Viruses 1 Interrupted, circular dsDNA 2 Circular, negative-sense ssRNA
  49. 53. Comparative Features of Hepatitis Viruses
  50. 54. Comparative Features of Hepatitis Viruses