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Viral Hepatitis

April 5, 2012 Group B4: Shruti Kumar, Rachel Nodine , Andrew Savoie , Austin Stokes, Moon Won . Viral Hepatitis. Overview. Virology & Epidemiology Pathogenesis & Clinical Manifestations Diagnosis, Treatment & Prevention Board Question Review References . Virology & Epidemiology .

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Viral Hepatitis

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  1. April 5, 2012 Group B4: Shruti Kumar, Rachel Nodine, Andrew Savoie, Austin Stokes, Moon Won Viral Hepatitis

  2. Overview • Virology & Epidemiology • Pathogenesis & Clinical Manifestations • Diagnosis, Treatment & Prevention • Board Question Review • References

  3. Virology & Epidemiology

  4. HAV • RNA picornavirus • Transmitted via fecal/oral route • outbreaks: food handlers and drinking fecal-contaminated water, close person-person contact (day care workers) • No carrier state • Incubation short (wks) • Key features: • Asymptomatic • Acute • Alone (no carriers)

  5. 2009 HAV Statistics • 1,987 cases nationwide • Accounting for asymptomatic infections and underreporting: 21,000 new infections • Incidence: 0.6 per 100,000 • Highest in 20-29 age group

  6. HBV • DNA hepadnavirus • Transmitted via sexual, maternal-fetal, & parenteral routes (present in all body fluids) • healthcare workers, infants, teens are at greater risk • Carrier state • Incubation long (months) • Risk of hepatocellular carcinoma (HCC) • virus acts as oncogene

  7. 2009 HBV Statistics • 3,371 cases nationwide • Accounting for asymptomatic infections and underreporting: 38,000 new infections • Incidence: 1.1 per 100,000 • Highest in 30-39 age group

  8. HCV • RNA flavivirus • Transmission via blood, IV drug use, & post-transfusion • Carrier state • Incubation long • Risk of HCC due to chronic inflammation • Key features: • Chronic • Cirrhosis • Carcinoma • Carrier

  9. 2009 HCV Statistics • 781 cases nationwide • Accounting for asymptomatic infections and underreporting: 16,000 new infections • Incidence: 0.3 per 100,000 • Highest in 20-29 age group

  10. HDV • RNA delta virus • Transmission via parenteral, sexual, maternal-fetal route • Carrier state • Key features • Defective virus that Depends on HbsAg as envelope

  11. HEV • RNA hepevirus • Transmission is fecal-oral especially w/ waterborne epidemics (consumption of contaminated water or undercooked seafood) • Endemic to Asia, India, Africa, Central America • Short incubation period • Key features: • Enteric • Expectant mothers (high mortality in pregnancy) • Epidemic

  12. Pathogenesis & Clinical Manifestations

  13. Transmission • Hepatitis A & E – F/Otransmission • B, C, & D – blood-to-blood contact • note: B is only DNA Virus

  14. General Pathogenesis • Hepatocytes AST & ALT • Pericanicular cells  GGT & AP • Bile canaliculi bilirubin • Hepatitis viruses invade hepatocytes • AST & ALT are highly elevated • GGT, AP, & bilirubin are mildly elevated • as disease progresses, GGT, AP, & bilirubin increases • BOTH conjugated & unconjugated bilirubin are increased • Viral hepatitis: ALT > AST • Alcoholic hepatitis: AST > ALT • AST is present in mitochondria, & alcohol is a mitochondrial poison • Gallstones are opposite!

  15. General Pathogenesis (cont.) • Virus infected cells lyse &hepatocytes rupture releases ALT & AST = very high AST & ALT • Primary mechanism of damage is due to host immune system • Necrotic cells lyse  releasing AST & ALT • Some pericanicular cells will also be destroyed via inflammatory/immune response mildly elevated GGT & AP. • As the infection worsens (2 wks)  liver swells, canaliculi narrow  backup of bilirubin into the blood. • Therefore ALS & AST rise high & fast followed by increases in GGT, AP and bilirubin 2 wks later.

  16. Acute Hepatitis • Mild to severe course followed by complete resolution • can be caused by ALL 5 types of hepatitis • incubation period depends on virus • Clinical course • Systemic flu-like symptoms • fatigue, low grade fever, muscle/joint aches, cough, runny nose, & pharyngitis • 2 weeks later, patient develops jaundice (scleral icterus) due to increased bilirubin (BOTH conjugated & unconjugated) withpainful hepatomegaly & high blood levels of LFT enzymes • Conjugated bilirubin in urine  dark urine

  17. Chronic Hepatitis • Chronic hepatitis • Growth of virus  systemic flu-like symptoms • Difficult to diagnose • often enlarged, tender liver & elevated LFT enzymes are the only clue for diagnosis • Chronic Hepatitis • Symptoms lasting greater than 6 months

  18. Hepatitis A Pathogenesis clinical manifestations Clinical Course ~ MILD acute hepatitis, NEVER chronic Milder in childrenthan adults 1-4% of adults develop fulminant hepatitis 1% death rate from HAV infx • feces  hand  mouth  hepatocytes

  19. Hepatitis B pathogenesis clinical manifestations Incubation – 6 weeks  6 months Acute hepatitis fever, fatigue, jaundice, nausea, muscle aches, & RUQ pain Fulminant hepatitis ~ severe acute hepatitis w/ rapid destruction of liver Chronic hepatitis (4 types) Asymptomatic carrier ~ patient NEVER develops anti-HBsAg Abs & harbors virus w/out liver injury (about 200 mil worldwide) Chronic-persistent hepatitis ~ patient has low-grade “smoldering” hepatitis Chronic active hepatitis patient has acute hepatitis state that continues without normal recovery (lasting longer than 6-12 mo) Co-infection &superinfectionw/ HDV • uses reverse transcriptase of minus strand DNA from a pregenomic RNA intermediate • plus-strand DNA is transcribed from the minus-strand DNA template by DNA –dependent DNA polymerase & converted into the hepatocyte nucleus to cccDNA which serves as a template for mRNA & pregenomic RNA • viral proteins are translated by mRNA and the proteins & genomes are packed into virons & secreted from the hepatocyte

  20. Hepatitis C pathogenesis clinical manifestations acute infection is usually asymptomatic some patients develop classic symptoms fever, fatigue, jaundice, nausea, muscle aches, & RUQ pain 85% of exposed  chronic hepatitis 20% develop cirrhosis • incubation 6-12 wks • MCC cause of blood-borne infection in US

  21. Hepatitis D & Hepatitis E hepatitis d hepatitis E Pathogenesis: feces  water/food  mouth  hepatocytes Clinical course: HEV in pregnant women is associated w/ fulminant hepatitis. • Coinfection – HBV + HDV • transmitted together in IV drug use, blood transfusions, & sex  acute hepatitis • HBsAbs will be protective against BOTH • Superinfection – HBV then HDV • causes acute hepatitis in chronically infected HBV Pt • high incidence of fulminant hepatitis, cirrhosis & 5-15% mortality

  22. Diagnosis, Treatment & Prevention

  23. Hepatitis A • Acute infection • Anti-HAV IgM • Recovery/Vaccination • Anti-HAV IgG • No antiviral treatment, supportive care only • Vaccination • Recommended for children ≥1 year old • Passive: immunoglobulin (HAVIG) for pre- and post-exposure prophylaxis • Active: protective antibodies in 1 month

  24. Hepatitis B • HBsAg: 2-8w after exposure, 1st marker of infection • Persistence > 6months defines chronic HBV • HBeAg and HBV-DNA: infective particles • Appear after HBsAg and disappear before Anti-HBs • Anti-HBc-IgM: present during acute infection, converted to IgG by 6months • IgG found in both recovery and chronic states • Anti-HBs: protective antibody, marker of immunization after vaccine • Anti-HBe: in both acute and chronic infections, low infectivity

  25. Hepatitis B (cont.) • Treatment • Acute: usually cleared spontaneously • Chronic: reduce risk of cirrhosis and liver cancer • Antivirals: lamivudine, adefovir, tenofovir, entecavir, telbivudine • IFN-α for patients without cirrhosis • PEGylated IFN lasts longer • Prevention • Vaccines • Active: recombinant, HBsAG from yeast, recommended for newborns and high-risk adults • Passive: HBIG, prevention of infection after exposure • infants of infected mothers, spouses of infected patients

  26. http://upload.wikimedia.org/wikipedia/en/5/59/HBV_serum_markers.pnghttp://upload.wikimedia.org/wikipedia/en/5/59/HBV_serum_markers.png

  27. Hepatitis C • Diagnosed via • Antibody enzyme immunoassay (ELISA) • Looks for antibodies to HCV in patient serum • Confirmed with recombinant immunoblot assay (RIBA) • RT-PCR • Can measure viral load in blood as early as 1-2w post infection • No virus = recovery from past infection • Viral RNA for >6mo defines chronic infection • Genotyping • Predict response to IFN therapy • Treated with [PEG-IFN-α + ribavirin + protease inhibitor] • No vaccine • Prevention with education about needle sharing

  28. Hepatitis D & Hepatitis E • HDV • Anti-HDV-IgM: active infection (requires HBV) • IgG is not a protective antibody • Serology – NOT helpful • anti-HDV IgM & IgG are in serum for only short period of time • Treatment - same as chronic HBV (control HBV infection) • Prevention is also established with HBV prevention techniques (HBV vaccine) • HEV • anti-HEV- IgM indicates active infection, IgG indicates

  29. Board Review Questions

  30. Board Review Questions • A 22 year old Caucasian male with fever and joint pain is found to have atypical lymphocytes on his blood smear. This patient’s symptoms are caused by an enveloped virus having partially double-stranded circular DNA. An enzyme packed in its virion has RNA dependent DNA polymerase activity. This patient is most likely infected with: • Parvovirus B-19 • Hepatitis B virus • Rotavirus • Hepatitis A virus • Hepatitis C virus

  31. Board Review Question 1 • A 22 year old Caucasian male with fever and joint pain is found to have atypical lymphocytes on his blood smear. This patient’s symptoms are caused by an enveloped virus having partially double-stranded circular DNA. An enzyme packed in its virion has RNA dependent DNA polymerase activity. This patient is most likely infected with: • Parvovirus B-19 • Hepatitis B virus • Rotavirus • Hepatitis A virus • Hepatitis C virus

  32. Board Review Question 2 • A 25 year old male with a several month history of fluctuating levels of ALT and AST is found to have high titers of IgG directed against hepatitis C envelope protein. These antibodies do not confer effective immunity against the infection because: • The antibodies do not have neutralizing properties • Envelope proteins vary their antigenic structure • Envelope proteins have low immunogenicity • Envelope proteins are lost after recurrent replications

  33. Board Review Question 2 • A 25 year old male with a several month history of fluctuating levels of ALT and AST is found to have high titers of IgG directed against hepatitis C envelope protein. These antibodies do not confer effective immunity against the infection because: • The antibodies do not have neutralizing properties • Envelope proteins vary their antigenic structure • Envelope proteins have low immunogenicity • Envelope proteins are lost after recurrent replications

  34. Board Review Question 3 • A 23 year old pregnant woman is found to have chronic viral hepatitis B on liver biopsy. The presence of which of the following serologic markers is more likely to increase the risk of vertical transmission of the virus? • HBcAg • HBsAg • HBeAg • Anti-HBsAgIgG • Anti-HBeAgIgM

  35. Board Review Question 3 • A 23 year old pregnant woman is found to have chronic viral hepatitis B on liver biopsy. The presence of which of the following serologic markers is more likely to increase the risk of vertical transmission of the virus? • HBcAg • HBsAg • HBeAg • Anti-HBsAgIgG • Anti-HBeAgIgM

  36. Board Review Question 4 • A 25 year old man is hospitalized with fever, anorexia, and fatigue. He admits to IV drug abuse and many episodes of unprotected sex over the past few years. His condition is treated and he is discharged from the hospital. The patient follows up with his physician regularly over the next 8 months, and the following serologic marker dynamics are obtained (see the graph below). • This patient most likely: • Had acute hepatitis B and has successfully recovered • Had an exacerbation of preexisting hepatitis B • Had acute hepatitis B that has progressed to chronic hepatitis with low infectivity • Had acute hepatitis B that has progressed to chronic hepatitis with high infectivity • Was vaccinated against HBV during the hospitalization

  37. Board Review Question 4 • A 25 year old man is hospitalized with fever, anorexia, and fatigue. He admits to IV drug abuse and many episodes of unprotected sex over the past few years. His condition is treated and he is discharged from the hospital. The patient follows up with his physician regularly over the next 8 months, and the following serologic marker dynamics are obtained (see the graph below). • This patient most likely: • Had acute hepatitis B and has successfully recovered • Had an exacerbation of preexisting hepatitis B • Had acute hepatitis B that has progressed to chronic hepatitis with low infectivity • Had acute hepatitis B that has progressed to chronic hepatitis with high infectivity • Was vaccinated against HBV during the hospitalization

  38. Board Review Question 5 • A 25 year old female recently returned from her travels abroad during monsoon season in Thailand. She has also realized that she is pregnant and feels fatigued frequently. Her primary care physician attributes her fatigue to stress she is experiencing from the pregnancy. She subsequently develops loss of appetite, abdominal pain, hepatomegaly, and nausea/vomiting. Which of the following types of hepatitis could be attributed to her symptoms? • Hepatitis A • Hepatitis B • Hepatitis C • Hepatitis D • Hepatitis E

  39. Board Review Question 5 • A 25 year old female recently returned from her travels abroad during monsoon season in Thailand. She has also realized that she is pregnant and feels fatigued frequently. Her primary care physician attributes her fatigue to stress she is experiencing from the pregnancy. She subsequently develops loss of appetite, abdominal pain, hepatomegaly, and nausea/vomiting. Which of the following types of hepatitis could be attributed to her symptoms? • Hepatitis A • Hepatitis B • Hepatitis C • Hepatitis D • Hepatitis E

  40. References • Harrison’s Principles of Internal Medicine 18thed, Vol 2; p. 2537-2539; 2579. • Pathoma – p. 119. • Clinical Microbiology Made Ridiculously Simple, 4th edition; p. 246-255. • Rapid Review Pathology 3e, Edward Goljan • Viral Hepatitis 01-18-2012, Bonnie Buxton • USMLE World QBANK

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