Viral hepatitis

1. Viral hepatitis Wei-Min Ke Department of Infectious Diseases Sun Yat-sen University Mar.13, 2009, Friday, Session 8~9 Classroom 503 Mar.20, 2008, Friday, Session 8~9 Classroom 503

2. Ⅰ. Outline • ⒈Definition • Viral hepatitis is one group infectious diseases of liver lesions • caused by several hepatitis virus, • which includes hepatitis viruses A, B, C, D, and E.

3. ⒉ Clinical features of viral hepatitis The manifestations of viral hepatitis are similar, include fatigue, anorexia, hepatomegaly and abnormal liver functions; jaundice only in some patients. Fatigue Anorexia Hepatomegaly Jaundice

4. Hepatitis A and E only are responsible to acute hepatitis, and mainly transmitted by fecal-oral route. Acute hepatitis Fecal-oral route

5. But hepatitis B, C and D can be responsible to acute or chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Acute hepatits Chronic hepatitis Cirrhosis HCC

6. Hepatitis B, C and D are often transmitted by parenteral transmission, • such as transfusion, injection and maternal-infant . • Transfusion Injection Maternal-infant

7. Ⅱ. Etiology The pathogens of viral hepatitis only are hepatitis viruses included hepatitis A, B, C, D, and E. From now on pathogenesis of hepatitis G, transfusion transmitted virus (TTV), Sen virus (SENV) has not been demonstrated to be causative of the liver diseases.

8. ⒈ Virology of Hepatitis A • Hepatitis A virus (HAV) is small RNA virus. • The viral genome is about 7.5 kb in length • and has a single large open-reading frame • that encodes a polyprotein with structural and nonstructural components. Hepatitis A virus particles

9. The virus replicates largely in the liver • and is assembled in the hepatocyte cytoplasm • as a 27-32 nm particle • with a single RNA genome • and an outer capsid protein (HAV Ag). Hepatitis A virus (HAV) found in feces is helpful to confirm the HAV present infection and infectivity. But hepatitis A virus infection is no chronic carrier state.

10. ⒉ Virology of Hepatitis B • Hepatitis B virus (HBV) is a double-shelled, enveloped DNA virus, 42 nm in diameter. Hepatitis B virus

11. The viral genome consists of partially double-stranded DNA, 3.2 kb in length, • and possesses four partially overlapping open-reading frame • that encode the genes for: • ①hepatitis B surface antigen ( S gene, HBsAg), • ②hepatitis B core antigen (C gene,HBcAg), • ③the HBV polymerase (P gene), • ④and a small protein that seems to have transactivating function (X gene, HBxAg).

12. The S gene has three start codons and is capable of producing three different sizes of HBsAg (small, medium, and large S). • The C gene has two start codons and can produce two antigenically distinct products: • the HBcAgretained in hepatocytes until assembled as core particles. • HBeAg secreted into the serum as a small soluble protein.

13. Hepatitis B virus (HBV) consists of three antigen and antibody systems. • HBV replicates in hepatocytes, appears in blood and other body fluids, and spreads mainly by blood.

14. ⒊ Virology of Hepatitis C • ①HCV is an RNA virus that belongs to the family Flaviviridae that includes Dengue fever virus and yellow fever virus. HCV originally was identified by molecular clone techniques in 1989. HCV circulates as a double-shelled enveloped virus, 30 to 60 nm in diameter. Hepatitis C virus

15. The genome is a positively stranded RNA molecule, which is about 9.4 kb in length, contains a single, large open-reading frame, encodes a large polyprotein, post-translationally modified into three structural and several nonstructural polypeptides. The structural proteins include two highly variable envelope antigens (E1 and E2) and a relatively conserved nucleocapsid protein (C).

16. ⒋ Virology of Hepatitis D • The hepatitis delta virus is a unique RNA virus that requires HBV for replication. • The viral genome is a short, 1.7 kb circular single-stranded molecule of RNA that has a single open-reading frame. Hepatitis D virus

17. ⒌ Virology of Hepatitis E • Hepatitis E virus (HEV) is a small nonenveloped, single-stranded RNA virus. The viral genome is 7.2~7.6 kb in length and encodes three open-reading frames, the first (ORF1) for the nonstructural proteins responsible for viral replication, the second (ORF2) for the capsid protein (HEV antigen), and the third (ORF3) for a short protein of unknown function. Hepatitis E virus

18. Ⅲ. Epidemiology China is the high prevalent region of viral hepatitis and anti-HAV-IgG positive rate is about 80%. There are 350 million of HBsAg carriers around the world, about 120 million in our country. The current infections of HCV are 170 million around the world, about 30 million in our country. Prevalent rates of hepatitis D and E in population are about 1% and 17% in our country, respectively.

19. ⒈ Hepatitis A ⑴ Sources of infection in hepatitis A • Hepatitis A is transmitted in acute phase of the disease. • Fecal shedding of virus occurs before 2 weeks of the onset of disease and it can persist to 30 days after onset of the disease. • There is no evidence for the existence of a chronic form hepatitis A, and a carrier state.

20. ⑵ Route of transmission in hepatitis A • Investigation of the source of hepatitis A cases reveals that most are due to direct person-to-person exposure and, • to lesser extent, to direct fecal contamination of food or water.

21. Consumption of shellfish from contaminated waterways is a well-known but uncommon source of hepatitis A. • 310,000 of patients with hepatitis A were reported in Shanhai city in 1988 due to contaminated blood clam(毛蚶). Blood clam

22. ⑶ Susceptibility and Immunity in hepatitis A • High-risk groups for acquiring hepatitis A include travelers to developing areas of the world, children in day care centers. • The baby under 6 months of age is not susceptible to hepatitis A, because they acquire anti-HAV IgG from your mother, and anti-HAV IgG is immune protective. • Along with the increase of age the rate of covert infection increases, the susceptibility to hepatitis A is decreased. • Generally, the immunity to hepatitis A can maintain for life.

23. ⒉Hepatitis B ⑴ Sources of infection in hepatitis B • The patients with acute or chronic hepatitis B and HBV carrier all can be regarded to the source of infection. • However, chronic hepatitis B and HBV carrier are important as the sources of infection.

24. ⑵ Routes of transmission in hepatitis B Hepatitis B is spread predominantly by the parenteral route or by intimate person contact. Investigations of the source of hepatitis B reveal that most adult cases are due to sexual or parenteral contact. intimate person contact

25. Blood transfusion and plasma products are now rarely infections for hepatitis B because of the institution of routine screening of blood donations for HBsAg and anti-HBc. Transfusion

26. Maternal-infant spread of hepatitis B is another important mode of transmission not only in endemic areas of the world, but also in the country among immigrants from the endemic areas. Routine screening of pregnant women and prophylaxis of newborns are now recommended. Intrafamilial spread of hepatitis B also can occur, although the mode of spread in this situation is not well defined.

27. ⑶ Susceptibility and Immunity in hepatitis B Human without anti-HBs is susceptible to hepatitis B virus. • By covert infection near 50% of human at 30 years of age acquire anti-HBs. • When the infection occurs in new neonate, they easily become to chronic carrier, because their immunity is not mature.

28. ⑷Epidemic features of hepatitis B • Low epidemic region with <2% of HBsAg carrier rate is found in north American, western Europe and Australia. • Moderate epidemic region with 2~7% of HBsAg carrier rate is reported in Eastern Europe, Mediterranean, Japan and Pre-Soviet Union. • High epidemic region with 8~20% of HBsAg carrier rate is reported in tropic Africa, Southeast Asia and China.

30. ⒊Hepatitis C • ⑴ Sources of infection in hepatitis C • The sources of infection are acute or chronic hepatitis C. 3.2% of anti-HCV positive rate among population in our country. ⑵ Routes of transmission in hepatitis C Hepatitis C is spread predominantly by the parenteral route. At highest risk are injection drug users and persons with multiple parenteral exposures. Sexual transmission of hepatitis C occurs but is not common.

31. Maternal-infant spread occurs in about 5% of cases, usually to infants whose mothers have high levels of HCV RNA in serum. Other potential sources of HCV are needlestick accidents. Since the introduction of routine screening of blood for anti-HCV, post-transfusion hepatitis C has become rare. needlestick accidents

32. ⑶Susceptibility and Immunity in hepatitis C Humans are susceptible to HCV generally, no protective immunity to in different species after infection. ⒋ Hepatitis D Hepatitis D is linked to hepatitis B, and consequently its epidemiology is similar. HDV can be spread by the parenteral route and sexually.

33. ⒌Hepatitis E ⑴ Sources of infection in hepatitis E The source of infection only is acute case of hepatitis E. ⑵ Route of transmission in hepatitis E HEV is spread by the fecal-oral route, and most cases can be traced to exposure to contaminated water under poor sanitary conditions . Large outbreaks have been described from India, Pakistan, China, Northern and central Africa, and Central American. 119,000 of patients with hepatitis E were reported in south region of Xinjian in 1986 to 1988 due to contaminated source.

34. ⑶Susceptibility and Immunity in hepatitis E Covert infection is common in children and clinical infection is often in adult. • Although anti-HEV IgG only persists in 6~12 months in circulation but re-infection can not be seen.

35. Ⅳ. Pathogenesis • ⒈ Pathogenesis of Hepatitis A • Although HAV has a cytopathic effect in tissue culture, • more evidence indicates that hepatocyte injury is secondary to host immune response.

36. ⒉ Pathogenesis of Hepatitis B • Clinical observations suggest that the immune response of the host in hepatitis B is more important than viral factors in the pathogenesis of liver injury. • ⑴In HBV acute infection • Specific immune responses to multiple viral antigens can be demonstrated in both major histocompatibility complex class II and I restricted T cells .

37. ⑵In HBV chronic infection • The patients fail to clear virus, both CD4+ and CD8+ T cell are markedly reduced in chronic infection. • ⑶HBV infection in infants • Infants with immature immune system, who acquire HBV infection at birth, • have a very high rate of chronic infection and replication typically has only mild liver injury.

38. ⑷Severe form hepatitis B • HBV induced fulminant liver failure is associated with a vigorous immune response, low levels of virus, and massive hepatocellular necrosis.

39. ⒊ Pathogenesis of Hepatitis C Mechanisms of viral persistence and of hepatocellular injury in patients with chronic HCV infection are poorly understood. In generally, viral infection can produce cellular injury by direct cytopathogenicity and indirect immune-mediated injury.

40. ⒋ Pathogenesis of Hepatitis D • There are some evidences that HDV Ag and HDV RNA may be directly cytotoxic to hepatocytes. ⒌Pathogenesis of Hepatitis E • Mechanisms of hepatocellular injury may be similar to hepatitis A.

41. Ⅴ. Pathology • There aren’t morphological features distinguishing the different etiological types of hepatitis. • Same pathologic changes can be seen in different viral hepatitis, but same viral hepatitis can occur different pathologic changes.

42. ⒈Acute viral hepatitis(1) • Hepatocyte ballooning, degeneration, and acidophilic body formation are present. • These changes are most prominent near the terminal hepatic venule, • and in mild cases, the injury is confined to this area alone. Acidophilic body formation

43. ⒉Chronic viral hepatitis • The range of histology findings is broad, from minimal periportal lymphocytic inflammation to active hepatitis with bridging fibrosis. • The simplified system in which inflammation is graded from 0 to 4 . • and fibrosis is staged from 0 to 4 have been developed by Scheuer.

44. Stage1 Stage3 Stage4 Stage2 According to liver biopsy sections: Fibrin morphometrical measurements in fibrosis S1, S2, S3, S4 are 8.3%, 11.4%, 14.9%, 20.7% respectively. Correspondingly, the liver parenchyma morphometrical measurements in fibrosis S1, S2, S3, S4 are 91.7%, 88.6%, 85.1%, 79.3% respectively.

45. ⒊Severe form hepatitis • ⑴Acute severe form hepatitis • Massive or submassive forms of hepatic necrosis are more than two-thirds of hepatic parenchyma. Massive necrosis

46. ⑵Subacute severe form hepatitis • Submassive forms of hepatic necrosis are less than 50% of hepatic parenchyma. Submassive necrosis

47. ⑶Chronic severe form hepatitis • Massive or submassive forms of hepatic necrosis occur on the basis of chronic liver diseases. Chronic severe form hepatitis

48. ⒋Cirrhosis(active and inactive) • Active cirrhosis:distort the hepatic architecture with obvious inflammation. • Inactive cirrhosis:distort the hepatic architecture with slight inflammation . End-stage cirrhosis

49. Ⅵ.Manifestations The average incubation periods 4 weeks(2~6weeks) in hepatitis A; three months(1~6 months) in hepatitis B; 6 weekss (2 weeks~6 months) in hepatitis C 4~20 weeks in hepatitis D 6 weeks (2~9weeks) in hepatitis E • The spectrum of diseases in viral hepatitis is very variable, from asymptomatic to fatal disease.

50. ⒈Acute hepatitis • ⑴ Icteric form of acute hepatitis ①Prodromal stage • The prodromal stage of illness is marked by the onset of fatigue, nausea, poor appetite, and vague right upper quadrant pain. • Less common symptoms include fever, headache, arthralgias, myalgias, and diarrhea. • The duration persists 5~7 days.