第二十四章病毒性肝炎

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涂崔宓
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1 Fudan University PhD : 138 : Tel: Fax: yjzheng@shmu.edu.cn

2 HAV HBV HCV HDV HEV

3 HAV HBV HCV HDV HEV TTV HGV/GBV-C SENV HFV CMV EBV

4 ( / / ) (1947, MacCallum) HAV HBV ( ) ENANBH (1850S) HAV NANBH (1965,Blumberg) (1973, Feinstone) HCV clone (1977,Mosley) HBV (1970, Dane) (1988,Hoµghton) SEN-V TTV (1997, Nishizawa) ENANBH (1980S) HDV (1983, Rizzetto) Next virus? HFV HGV/GBV-C (1995, Nishizawa) ( 1983, Balayan ) HEV 20 (Epidemic jaundice) 1943 JAMA(Catarrhal jaundice) 1942 Voget Cameron 1947 MacCallum1973 WHO (1988, Purcell) HEV (1991, Reyes) HEV? (1995, Clayson) HEV (1997,Meng)

5 HAV/HBV/HCV/HDV HAV HEV HBV HCV HDV

7 Order Family Genus Type Species Mono -negavirales Caudovirales Nidovirales ( ) ICTV classification Picornaviridae ( RNA ) Arenaviridae ( ) Enterovirus Rhinovirus Hepatovirus () Cardiovirus Aphthovirus Parechovirus Arenavirus Ophiovirus Tenuivirus Deltavirus Poliovirus Human rhinovirus A Hepatitis A virus Encephalomyocarditis virus Foot-and-mouth disease virus Human parechovirus Lymphocytic choriomeningitis virus Citrus psorosis virus Rice stripe virus Hepatitis delta virus Hepeviridae Hepevirus Hepatitis E virus Hepadnaviridae ( DNA ) Flaviviridae () Orthohepadnavirus Avihepadnavirus Flavivirus Pestivirus Hepacivirus Hepatitis B virus Duck hepatitis B virus Yellow fever virus Bovine viral diarrhea virus Hepatitis C virus

8 Viral hepatitis(b15-b19) in ICD-10

9 WHO 140 / /3

10 12090/

11 Annual reported hepatitis cases in China million cases in

12 Annual reported morbidity in China

16 Fudan University PhD : 138 : Tel: Fax: yjzheng@shmu.edu.cn

18 HAV

19 Pathogenesis of enteroviruses

20 15~ %~0.4%

21 HAV 1~21~2

22 -HAV IgM -HAV IgM HAV HAV -HAV IgG -HAV IgG HAV ALT HAV HAV

25 Anti-HAV prevalence High Intermediate Low Very low CDC, 1999

28 90% ~

29 HAIG 90% 3~5 HAIG

30 Fudan University PhD : 138 : Tel: Fax: yjzheng@shmu.edu.cn

31 Hepatitis E (HEV), (>50 ), 30~70% ;?!, 40 (15~60 ) (1~5%) (20%, ) ; ;

32 ?! HEV HEV HEV HEV HEV HEV () ( ) SPF DPI HEV RNA 11% 43.5% HAV HEV 2003 Lancet 3HEV RNA 2003 J Gen Virol: HEV RNA;

the Program for Monitoring Emerging Diseases 4

33 the Program for Monitoring Emerging Diseases >24,

34 HEV

35 Genome organization of HEV Methyl transferase RDRP Polycysteine region Transmemberane Sequence ORF3 Hydrophobic Region ORF1 Papain like cysteine protease Helicase ORF2 Signal peptide rhev Particle HEV HEV 7.5kb, 3

36 . ( ) (%) 1955~ ~ ~ ~ ~ ~ NA 1981~ ~ ~ NA 1988~ NA

37 Non-ABC >25% HEV HEV RT- PCR(+) HEV RT-PCR(+)

38 HEV HEV HEV HEV

39 Distribution of Genotypes LEGEND Genotype I Genotype II Genotype III Genotype IV HEV Genotypes

40 % % - (. ) 46.5% - non-abc ( 90 ) 17.2% - (1992) >20 -, , 12,

41 IV 3 5

42 % % - (. ) 46.5% - non-abc ( 90 ) 17.2% - (1992) >16 -, , 12,

43 HEV I IV, III (2006) China

44 HAV IgM (53.03%) HBsAg (41.08%) 31.12% 19.07% 20.97% 1.80% 1.04% 8.73% HEV IgM (17.55%) 5.98% Others 11.28% (,%) HCV 5 (0.47) HAV+HCV 3 (0.28) HBsAg+HCV 2 (0.19) HCV+HEV 2 (0.19) HBsAg+HCV+HEV 1 (0.09) 106 (10.06)

45 ( ) 3

46 ( ) II I IV III

47 (%) /? / %) NA / %) NA / % 9.1 9/ %) NA /1675 (8.7%)

48 HEV (n=8626)

49 HEV 2:1 ( ) 15~40 HEV

50 ( ) 16, 46, ( 4767 *) 26, ( 1720 *) * HEV IgM EIA

52 HEV HEV 127/ /97=0.3% HEV HEV 0.3%

53 (150bp) 31 4, 4 A D, %/ 3.4~ ~14.4 A D IV ( ) A 2004/ D 2004/ /2004 B/C 2002/2005

54 (HEV IgG) / ( ) / ( ) / ( ) /69 <5 1.84( ) / ( ) /145 >15 OR 95%CI (%) / / ( ) / ( ) / ( ) /69 <5 1.84( ) / ( ) /145 >15 OR 95%CI (%) /

55 IV HEV

56 2006;193(12): IF=4.953) (JKF201001) (2005AA2Z3H20)

58 -HEV IgM HEV -HEV IgG HEV IgM 10

60 -HEV5%~26% -HEV17.2% HEV 20%

62 100 n=8 GMT(IU) (5IU) W Weeks 62W

63 HAV HEV HAV HEV RNA HEV 27-32nm 27 34nm ( ) 3 VP1 3 T= HEV a, B A, B, RNA 7.5kb I,II,III,IV 1

64 Fudan University PhD : 138 : Tel: Fax: yjzheng@shmu.edu.cn

65 Global Disease Burden Estimated 2 billion people infected with HBV More than 350 million have chronic HBV infection Approximately 88% of the world's population live in areas where the prevalence of chronic HBV infection is high (>8% HBsAg +) or moderate (2-7% HBsAg +) Estimated HBV-related deaths in 2002 Approximately 93% of deaths were the result of chronic infection The worldwide prevalence of HBV infection is falling due not only to vaccine, but to better hygiene and to the AIDS campaign which addresses the dangers of promiscuity and of shared syringes and needles. WHO believe that by 2001 there will be an 80% fall in carrier rate, but the reservoir of those patients already infected will still have to be treated.

66 Deaths from Vaccine-Preventable Diseases Diphtheria Pneumococcus Tetanus Pertussis Polio Meningococcus Measles Rotavirus Yellow Fever Hib Hepatitis B 4 Million Deaths to Be Prevented (2000 estimates)

Epidemiology of Chronic Infection Most HBV infections occur in perinatal period/early childhood Infections at this early age lead to high proportion chronic infections Large proportion of chronic

67 Epidemiology of Chronic Infection Most HBV infections occur in perinatal period/early childhood Infections at this early age lead to high proportion chronic infections Large proportion of chronic infections unrecognized and lead to longterm complications (cirrhosis and HCC) ~21% of HBV-related deaths result from infection in perinatal period ~48% from infection in early childhood (age <5 years)

68 25% 80%~90%

69 HBV (Dane )HBV 42nm 22nm HBV HBsAg 22nm 40nm ~ 500nm

70 HBV HBVDNA S C P X S SS1 S2 HBV HBsAg pre-sl pre-s2 C CC HBcAg HBeAg P DNA Xx HBxAg 8 A-H

71 HBV -HBsAg a,d/y,w(1-4)/r, q(+/-) Adw2,4;ayw1-4;adrq+ adrq- ayr

72 Distribution of HBV genotypes and HBsAg subtypes across the world HBV genoty HBsAg Geographical distribution pe A adw2 Europe, North America, Africa ayw1 Africa B adw2 Far East ayw1 Far East C Adrq- Pacific adr/ayr adw adr Far East Japan, Indonesia Far East, Pacific D ayw4 United States ayw2/ay w3 Worldwide E ayw4 Africa F adw2 South America adw4 ayw4 Polynesia, Alaska, Central and South America South America

73 HBsAg -HBs HBcAg -HBc e HBeAg -HBe HBV HBV HBV Pre-S1 Pre-S2 x HBV-DNA DNA

74 DNA HBV -HBc -HBc IgM HBsAg HBeAg -HBe -HBs ALT HBV

75 Tests Results Interpretation Tests Results Interpretation HBsAg anti-hbc anti-hbs HBsAg anti-hbc anti-hbs HBsAg anti-hbc anti-hbs Interpretation of the Hepatitis B Panel susceptible immune due to natural infection immune due to hepatitis B vaccination HBsAg anti-hbc IgM anti-hbc anti-hbs HBsAg anti-hbc IgM anti-hbc anti-hbs HBsAg anti-hbc anti-hbs acutely infected chronically infected four interpretations possible * * 1. May be recovering from acute HBV infection. 2. May be distantly immune and test not sensitive enough to detect very low level of anti-hbs in serum. 3. May be susceptible with a false anti-hbc. 4. May be undetectable level of HBsAg present in the serum and the person is actually a carrier.

76 HBV DNA -HBs

77 HBV HBV % 30%~50% 1 80%~90% 1~4 30%~50% 1% 5%~10% HBV HBsAg 6 HBV -HBs -HBc 60% 30% 2% HBsAg

78 HBV HBV HBsAg HBeAg

79 Concentration of HBV in body fluids High Moderate Low / not detectable Blood Serum Wound exudates Semen Vaginal fluid Saliva Urine Feces Sweat Tears Breast milk

80 Transmission of HBV Transmitted by exposure to HBV-infected blood or serous body fluid (serum, wound exudates, semen, vaginal fluid) Mode of transmission: Person-to-person Direct Indirect (via infected object) Cannot be transmitted though intact skin or mucous membranes Extremely infectious times more infectious than HIV Sexually transmitted disease

81 Parenteral Transmission of HBV Receipt of infected blood or blood products Use of contaminated medical instruments and injection equipment in health care settings Use of contaminated injection equipment by injection drug users Use of contaminated equipment for tattooing, ritual scaring, acupuncture, body piercing, body scarring

82 80% HBV HBV

83 HBV-HBs HBV 50%~60% 70%

84 1992 HBsAg 9.75%8.08%10.49% 30~40 HBsAg

86 WHO Strategy 1991 WHO WHO Priorities for hepatitis B immunization in order of importance are: routine infant vaccination; prevention of perinatal HBV transmission (the birth dose); catch-up vaccination for older age groups. Vaccination of infants and children is highest priority for hepatitis B programs

87 3 doses of hepatitis B vaccine 90% 95% effective in preventing HBV infection and chronic sequelae To prevent perinatal HBV transmission, 1st dose vaccine should be given within 24 hours after birth the birth dose

89 Hepatitis B Vaccine Made from HBsAg by genetic engineering (no human blood products are used in current vaccines) Hep B is given to infants because It can prevent onset of chronic disease in infants and Adult vaccination has been operationally difficult The vaccine can be given in a variety of schedules, usually with DPT1, DPT2, and DPT3 Among the safest of EPI vaccine The only cancer and STD vaccine available (hepatoma) Now HPV!

90 HBIG 3~6 HBsAg HBeAg 6 24

91 Fudan University PhD EM : 138 : Tel: Fax: yjzheng@shmu.edu.cn

92 NANB 1989 HCV (HCC) WHO3% 1.7 HCV

93 50nm 6 HCV ( 1a 2b 3c ) 1 HCV 70 HCV quasispecies

94 Genome NS3 / NS5B RNA RNA HCV

95 ( ) (<20%) 60%-85% Agerelated 10%-70% <5%-20% Mortality from CLD 1%-5%

96 HCV Symptoms +/- anti-hcv HCV RNA Titer ALT Normal Years Months Time after Exposure

97 HCV Symptoms +/- anti-hcv HCV RNA Titer ALT Normal Years Months Time after Exposure

98 HCV -HCV HCV -HCV -HCV HCV RNA HCV RNA

99 HCV Resolved Exposure (Acute phase) 15% (15) 85% (85) Stable Chronic 80% (68) Slowly Progressive 20% (17) Cirrhosis 75% (13) HIV and Alcohol 25% (4) HCC Transplant Death

100 HCV

101

102 HCV

103 1% 1%~2.4% 2.5%~4.9% 5% 1515

104 World Health Organization, ( ) US 3-44 M Americas M Western Europe 5 M Africa M Eastern Europe 10 M Far East Asia 60 M South East Asia M Australia 0.2 M

105 1a, 1b 2a, 2b, 3a 1b 2a, 2b, 2c, 3a 4 4 1b, 3a 2a 1b, 6 1b 3b 5a 1b, 3a

106 -HCV3.2% 3.6% 2.9% 2.5% 2.7% 3.2% 3.3% 3.8% 4.6% -HCV 1 2.0% % HCV 1b 2a 1b 1a 2b 3b6

107 -HCV ALT1993 HCV HCV HCV RNA

108 Comparison between HBV and HCV

109

110

111 Fudan University PhD : 138 : Tel: Fax: yjzheng@shmu.edu.cn

112 1977 HBcAg HBV HBcAg delta 1980 HBV HBV HBsAg HBsAg

113 RNA 36~43nm HDV RNA HDAg HBV HBsAg HDV RNA 1.7kb HDV DNA HDV HBV

114 Schematic representation of viral particles found in serum of HBV - HDV infected people Infectious HBV particle: Infectious HDV particle: 42 nm outer envelope containing lipid and three forms of HBsAg 27 nm nucleocapsid containing 180 copies of core protein and reverse transcriptase and HBV DNA nm outer envelope containing lipid and three forms of HBsAg 19 nm nucleocapsid containing 60 copies of delta antigen and HDV genomic RNA Empty noninfectious particles: 22 nm filaments and spheres made of lipid and mainly one form of HBsAg

115 HDV HDV/HBV HDVHBV HDV/HBV HBV HDV 80% HDV 60%~70% 5~10

116

117 -HDV HDV -HDV HDV RNA HDAg HDV HDV

118 HDV HBV

119 HDV 1000 HBsAgHDV HBV HDV HDV

120

121 HBsAg HDV

概述病毒性肝炎在我国危害极大病毒性肝炎在我国各类传染病中发病率最高我国乙肝病毒感染者逾 1.2 亿 ~ 10% 乙型肝炎患者近 3 千万每年近 30 万人死于肝炎或肝癌 2

概述病毒性肝炎在我国危害极大病毒性肝炎在我国各类传染病中发病率最高我国乙肝病毒感染者逾 1.2 亿 ~ 10% 乙型肝炎患者近 3 千万每年近 30 万人死于肝炎或肝癌 2 病毒性肝炎 1 概述病毒性肝炎在我国危害极大病毒性肝炎在我国各类传染病中发病率最高我国乙肝病毒感染者逾 1.2 亿 ~ 10% 乙型肝炎患者近 3 千万每年近 30 万人死于肝炎或肝癌 2 病原学 3 能引起肝功能损害的病毒有很多, 病毒性

第二十四章 病毒性肝炎

第二十四章病毒性肝炎