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Viral hepatitis A to E .
- 1. Viral Hepatitis A to E KHUSHI MAWA GROUP 2
- 2. A Long History of Human Misery 500 B.C. written accounts of jaundice in Babylonia 400 B.C.Hippocrates describes epidemic jaundice 1883 jaundice noted to occur after inoculation of human sera 1941 post-vaccination jaundice occurs in >28,000 U.S. soldiers 1947 infectious hepatitis designated Hepatitis A; serum hepatitis designated Hepatitis B 1963 Hepatitis B Surface Antigen identified 1973 Hepatitis A identified by electron microscopy Mid-1970s Hepatitis D recognized Mid-1970s Non-A, Non-B hepatitis described Mid-1980s epidemics of non-hepatitis A enteric hepatitis 1989 Hepatitis C cloned and serological tests developed 1990 Hepatitis E cloned and characterized
- 3. Viral Hepatitis Common Features Early Prodromal Phase serum sickness like syndrome occurs 2-3 weeks before jaundice arthalgias, arthritis, rash, angioneurotic edema, fever Preicteric Phase GI symptoms nausea, vomiting, abdominal pain, anorexia, changes in taste and smell, weight loss generalized malaise, myalgias, headache, fever Icteric Phase fever declines constitutional symptoms improve Convalescent phase full recovery usually within 6 months
- 4. Viral Hepatitis Differential Features Features Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Genome type Ss RNA Ds DNA Ss RNA Ss RNA Ss RNA Genome size 7.5 kB 3.2 kB 9.4 kB 1.7 kB 7.5 kB Incubation period, days (mean) 15-49 (30) 28-160 (70-80) 15-160 (50) 21-140 (35) 15-65 (42) Fecal-oral transmission yes no no no yes Parenteral transmission rare yes yes yes no Sexual transmission no yes, common yes, uncommon yes, uncommon no Fulminant hepatitis <1% <1% rare 2-7.5% ~1%, 30% in pregnancy Chronic hepatitis no 10% 85% 90% with superinfection no
- 5. Acute Hepatitis Evaluation and Recommendations Access for viral hepatitis A, B, C, Hep A IgM, Hep B Surface Ag, Core IgM, Hep C Ab (or PCR) Consider alcohol and drug toxicity, autoimmune hepatitis, ischemia Consider biliary tract disease: CBD stone, PSC Consider other viruses: CMV, EBV, HSV, etc. Hospitalization for excessive anorexia, nausea, vomiting Rising total bilirubin >15 Rising pro time > 15 Rapidly falling transaminases while bilirubin is rising Liver failure: hepatic encephalopathy, ascites Bed rest prn Consider high protein high calorie diet Minimize medications: phenothiazines, ? vitamin K are OK; stop OCPs, Etoh, acetaminophen, etc. Office visit and LFTs twice a week while LFTs rising, and every 1-2 weeks while improving Immunoprophylaxis for contacts of HAV, HBV
- 6. Hepatitis A Picornaviridae Transmitted by fecal oral route, contaminated food, water, shellfish Most infections are sub clinical Incidence peaks in fall and winter 80% infected children are anicteric 10-50% infected college students are anicteric 30-50% U.S. adults are HAV IgG+, but only 3-5% recall prior jaundice High attack rate: 70-90% exposed become infected >60,000 clinical cases per year in U.S. Incubation 15-49 days (mean 30 days) HAV Ag appears in liver at 1-2 weeks HAV then appears in bile and stool Fecal infectivity begins 2-3 weeks before jaundice, lasts 4-5 weeks, ends 2 weeks after peak transaminitis Chronic infection never occurs 60% have normal LFTs at 2 months; 100% normal at 6 months
- 7. Hepatitis A Prevention General prevention Water chlorination Boil water 20 minutes Wash hands Avoid contaminated food HAV Immunoglobulin Can prevent 85-95% infections if given within two weeks of exposure Household and sexual contacts Day care contacts Prison contacts Common source outbreaks HAV Vaccine 90-98% successful with one injection, 100% with two injections Protection begins after 1-2 weeks, may last 20 years Give to all of the above Travelers to endemic areas Homosexuals, IV drug abusers Persons with HCV and HBV Military
- 8. Hepatitis B Hepadnaviridae Transmission route is variable HBV is found in blood and all body fluids except stool Western societies: percutaneous, hetero/homosexual contact is most common Non-western societies: perinatal transmission is most common Epidemiology Worldwide 2 billion people have markers of infection 400 million have chronic infection (5%) U.S. 1.25 million chronic infections (50% Asian) 200 thousand acute infections per year 250 deaths/year from fulminant HBV 4000 deaths/year from chronic HBV 800 deaths/year from HBV related hepatomas
- 9. Hepatitis B 90% cases are self-limited with spontaneous resolution >50% are anicteric 10% become chronic <1% are fulminant (10% if E Ag mutant) 3-5% in U.S. have HBV markers Surface Ag appears 1-12 weeks after exposure Clinical hepatitis and Core IgM occur 4 weeks after Surface antigen E Ag indicates period of infectivity S Ab indicates resolving infection Rare window period occurs when Surface Ag disappears and before Surface Ab appears; Core Ab will be positive Extrahepatic manifestations Arthralgias and rash (25%) Angioneurotic edema, polyarteritis nodosa, mononeuritis, membranoproliferative GN, arthritis, Raynauds phenomena, Type II mixed essential cryroglobulinemia, Guillan Barre Syndrome, pancreatitis, pericarditis
- 10. Chronic Hepatitis B Persistent Surface Ag, E Ag, DNA > 6 months Risk of chronicity is dependent on host age and immune status 90% perinatal infection 30% childhood infection age < 6 years 5% adult acute infection 30% with HIV co-infection Prognosis is dependent on HBV stage Immune tolerant: Surface Ag +, E Ag +, DNA +, ALT normal Prognosis good, hepatoma risk low Integrated state: Surface Ag +, E Ag -, DNA , ALT usually normal Prognosis good, hepatoma risk low Chronic active hepatitis: Surface Ag +, E Ag +, DNA +, ALT >2x normal 20% develop cirrhosis in 5 years 10% per year lose E Ag 1% per year lose S Ag Increased risk of hepatoma 400 x
- 11. Hepatitis B Prevention Modify risk factors Eliminate high risk behavior; use condoms Incidence of acute HBV has decreased by 40% in U.S. over 15 years Screen pregnant mothers for HBV Surface Ag HBIG + HBV vaccination at birth prevents 80-90% perinatal transmission Hepatitis B Immune Globulin Perinatal exposure Needle stick exposure Sexual, mucosal or percutaneous exposures HBV Vaccination Perinatal exposure Persons with sexual, mucosal, percutaneous exposures Persons with HCV or IV drug abuse Homosexuals Health care workers Hemodialysis Universal vaccination for children
- 12. Hepatitis B Treatment Who to treat? Chronic active disease > 6 months Surface Ag +, DNA +, E Ag + or (if E Ag mutant) ALT > 100, and/or active hepatitis on biopsy Goal of treatment Stop viral replication, HBV DNA becomes neg Convert E Ag pos to neg, E AB becomes pos Improvement in histology, prevention of progression to cirrhosis With successful treatment, loss of Surface Ag may occur in 1-2% per year
- 13. Hepatitis B Treatment Alpha-interferon 2b 5 mu sq qd for 16 weeks 40 % will have successful response and lose E Ag, 10% lose Surface Ag Hepatitis flare is common during treatment Favorable pretreatment variables Low HBV DNA < 200 pg/ml High ALT > 100 Active hepatitis on biopsy Shorter duration of infection Others: female, lack of immunosuppression, HBV E Ag +, h/o jaundice, horizontal transmission Pros Short, finite duration of treatment Effective, viral response persists in 95% Cons Expensive: $2000 per month Numerous side effects May cause cirrhosis to decompensate
- 14. Hepatitis B Treatment Nucleoside Analogues Lamivudine Inhibits HBV reverse transcription Minimal side effects YMDD escape mutants occur 15-30% per year Adefovir Inhibits HBV reverse transcription Active against lamivudine resistance Minimal side effects (proteinuria, increased Cr) resistance is rare so far..1.8-2.5% at 2 years Famciclovir Inhibits DNA polymerase Less effective than lamivudine, numerous resistance mutations Minimal side effects Entecavir Active against lamivudine resistance; phase 2 trials Emtricitabine some cross resistance with lamivudine mutants, phase 2 trials Clevudine phase 1-2 trials B-L-Thymodine B-nucleoside, phase 1-2 trials
- 15. Hepatitis C Flaviviridae Transmission is primarily percutaneous; sexual and perinatal infection can occur Transfusional HCV risk is now low: 1:1,935,000 50-90% of IV drug abusers have HCV 10% needle stick injuries transmit HCV 4% sexual partners have HCV; Risk of sexual transmission <0.5%/year Perinatal transmission 1-10% 100 million chronic carriers world wide (>3%) 4 million with chronic HCV in U.S. (1.5-2%) 30 thousand new HCV cases per year in U.S. (incidence decreasing) 10 thousand deaths/year from HCV (incidence increasing) Acute hepatitis is rare Fulminant hepatitis is extremely rare 15% can spontaneously resolve infection 85% develop chronic infection HCV RNA becomes + 2 weeks after exposure incubation period is 6-7 weeks HCV Ab becomes + by 12 weeks in most
- 16. Hepatitis C Factors Associated with Disease Progression Age > 40 Male Alcohol > 50 gm/d Immunosuppression: HIV, transplant, etc. Infection by blood transfusion Co-infection with HBV Genotype 1
- 17. Hepatitis C Goals of Therapy Biochemical response normal ALT Virological response loss of HCV RNA End of treatment response loss of HCV RNA at end of treatment Early Virological response (EVR) HCV RNA neg or 2 log reduction at 12 weeks Overall 67 % with EVR achieve SVR 80% who are HCV RNA neg achieve SVR 40% who are RNA +, but have 2 log reduction achieve SVR Patients w/o EVR Only 1.6% achieve SVR Sustained virological response (SVR) Undetectable HCV RNA 6 months after treatment ends 95% have persistent SVR over 10 years 80% have reduction in fibrosis
- 18. Hepatitis C Treatment Peg-interferon a-2b (Peg Intron) 1.5 ug/kg/wk sq Peg-interferon a-2a (Pegasys) 180 ug/wk sq Ribaviron 1000-1200 mg/d for genotype 1 800 mg/d for genotype non-1 Treat genotype 1: 48 weeks; genotype non-1: 24 weeks Cost: $ 2000-2500 per month Treatment SVR (%) Peg Intron overall 54 genotype 1 42 geno non-1 82 Pegasys overall 57 genotype 1 46 geno non-1 76
- 19. Hepatitis E Related to Rubella virus Endemic in equatorial regions of world India, Africa, Central America, Asia May account for 50% hepatitis cases in endemic areas Antibodies found in pigs, other mammals Fecal oral transmission Contaminated water Household transmission rates are low 1-2% Rare in U.S. except travelers to endemic regions 1-2% U.S. blood donors have HEV Ab (?cross reactivity) Incubation period is 15-60 days (mean 40) HEV IgM + at 27-39 days 1-4% overall mortality; 20-30% mortality if pregnant
- 20. Other Viruses Causing Hepatitis Hepatitis G and GB related to HCV TT Virus post-transfusional hepatitis in Japan Sanban, Yonban, TLMV related to TT virus, post-transfusional hepatitis in Japan Giant Cell Hepatitis paramyxovirus; 7 small series ~100 patents Herpes Viruses HSV 1 and 2 90% are immunosupressed or in last trimester of pregnancy HSV 6 and 7 case reports Cytomegalovirus after transfusion or transplant Epstein Barr Virus 11% become jaundiced Rift Valley Fever Virus Yellow Fever Virus Lassa Virus Marburg Virus Ebola Virus Adenoviures Enteorviruses Coxsackie Viruses SARS 60% have hepatitis, virus found in liver by PCR