1. Viral Hepatitis
Richard J. Ziegler

2. Introduction (1)
Hepatitis with an infectious etiology is primarily a viral disease.
At least seven viruses cause hepatitis; three are also associated with primary hepatocellular carcinoma.
Acute infections caused by these viruses cannot be distinguished clinically from each other, but serum enzyme changes allow differentiation from other liver disease.

3. Introduction (2)
Several viruses produce chronic infections associated with “carrier” individuals.
Routes of infection are unique for each virus.
Vaccines and human gamma globulin preparations are available for protection from some of these viruses.

4. Clinical Disease Majority of infections are asymptomatic.
Disease includes anorexia, nausea, vomiting, right upper quadrant pain, and increased serum levels of liver enzymes AST and ALT.
Jaundice occurs late in the disease and is frequently not present.

5. Hepatitis Viruses
Enterically transmitted hepatitis is caused by Hepatitis A (HAV) and Hepatitis E (HEV) viruses.
Parenterally transmitted hepatitis is caused by Hepatitis B (HBV), Hepatitis C (HCV), and Hepatitis D (HDV) viruses.
Mosquito bite transmitted hepatitis is caused by the Yellow Fever virus.
Other viruses like HSV, CMV, EBV, and rubella can cause acute hepatitis as part of their systemic disease.

6. Viral Hepatitis - Historical Perspectives
Enterically
transmitted
“Infectious” A E
Viral hepatitis
NANB
Parenterally
transmitted
“Serum” B D C
F, G, TTV
? other 2

7. Type of Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces
virus
blood-derived
blood-derived
blood-derived
body fluids
body fluids
body fluids
Route of
fecal-oral
percutaneous
percutaneous
percutaneous
fecal-oral
transmission
permucosal
permucosal
permucosal
Chronic no
yes
yes
yes no
infection
Prevention
pre/post-
pre/post-
blood donor
pre/post-
ensure safe
exposure
exposure
screening;
exposure
drinking
immunization
immunization
risk behavior
immunization;
water
modification
risk behavior
modification 3

8. Hepatitis A Virus 6

9. Introduction to HAV Hepatitis
HAV exists in only one serotype.
Clinical disease is milder or asymptomatic in young children.
Virus shedding precedes symptoms by about two weeks.
A general review of HAV and its clinical disease may be found at:

10. Hepatitis A - Clinical Features
Incubation period: Average 30 days
Range days
Jaundice by <6 yrs, <10% age group: yrs, 40%-50% >14 yrs, 70%-80%
Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis
Chronic sequelae: None 7

11. Hepatitis A Infection Typical Serological Course Total anti-HAV Titre
Symptoms
Titre
ALT
Fecal
HAV
IgM anti-HAV 1 2 3 4 5 6 12 24
Months after exposure 9

12. Hepatitis A Virus Transmission
Close personal contact (e.g., household contact, sex contact, child day care centers)
Contaminated food, water (e.g., infected food handlers in restaurants, raw shellfish)
Blood exposure (rare) (e.g., injecting drug use, transfusion) 11

14. Laboratory Diagnosis
Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA or ELISA for HAV antigen in feces.
Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.

15. Hepatitis A Vaccination Strategies
Epidemiologic Considerations
Many cases occur in community-wide outbreaks
no risk factor identified for most cases
highest attack rates in 5-14 year olds
children serve as reservoir of infection
Persons at increased risk of infection
travelers
homosexual men
injecting drug users 18

16. HAV Vaccines
Havrix and VAQTA are formalin inactivated virion preparations that can be used for individuals 12 mos. and older.
Twinrix vaccine is used to protect those 18 and older from both HAV and HBV and is a combination of Havrix and Energix-B (a purified recombinant surface antigen preparation of HBV).

17. Hepatitis A Prevention - Immune Globulin
Pre-exposure
travelers to intermediate and high HAV-endemic regions
Post-exposure (within 14 days)
Routine
household and other intimate contacts
Selected situations
institutions (e.g., day care centers)
common source exposure (e.g., food prepared by infected food handler) 27

18. HAV Active and Passive Immunizations Details
Details are found at the following websites: and

19. Introduction to HEV Hepatitis
HEV is not endemic in USA.
Disease is usually associated with travel to an endemic area.
A general review of HEV and its clinical disease may be found at:

20. Hepatitis E Virus 26 26 26

21. Hepatitis E - Clinical Features
Incubation period: Average 40 days
Range days
Case-fatality rate: Overall, 1%-3% Pregnant women, %-25%
Illness severity: Increased with age
Chronic sequelae: None identified 27 27 27

22. Hepatitis E Virus Infection
Typical Serologic Course
Symptoms
ALT
IgG anti-HEV
Titer
IgM anti-HEV
Virus in stool 1 2 3 4 5 6 7 8 9 10 11 12 13
Weeks after Exposure 28 28 28

23. Epidemiologic Features
Hepatitis E -
Epidemiologic Features
Most outbreaks associated with fecally contaminated drinking water.
Several large epidemics have occurred in the Indian subcontinent and the USSR, China, Africa and Mexico.
In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown.
Minimal person-to-person transmission. 29 29 29

25. Prevention and Control Measures for Travelers to HEV-Endemic Regions
Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler.
IG prepared from donors in Western countries does not prevent infection.
Unknown efficacy of IG prepared from donors in endemic areas.
Vaccine? 31 31 31

26. Hepatitis B Virus 28

27. Introduction to HBV Hepatitis
Virion is called the “Dane particle”.
Viral antigens HBs, HBc, and HBe and HBV replication are important (see ).
Reverse transcription is involved in replication

28. Introduction (2)

29. Introduction (3)
Virus infection may lead to acute disease or be asymptomatic.
Development of a chronic carrier state is inversely related to the age of infection (perhaps 90% in infected neonates).
350 million carriers worldwide.

30. Introduction (4) Hepatocellular necrosis is immune-mediated.
HBV is associated with PHC (primary hepatocelluar carcinoma).
HBx protein has been implicated in PHC.
Passive and active immunization as well as antiviral treatment is available.

32. Hepatitis B - Clinical Features
Incubation period: Average days
Range days
Clinical illness (jaundice): <5 yrs, <10% yrs, 30%-50%
Acute case-fatality rate: 0.5%-1%
Chronic infection: <5 yrs, 30%-90% yrs, 2%-10%
Premature mortality from chronic liver disease: 15%-25% 29

33. Spectrum of Chronic Hepatitis B Diseases
1. Chronic Persistent Hepatitis - asymptomatic
2. Chronic Active Hepatitis - symptomatic exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma

34. Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titre
anti-HBs
HBsAg
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
100
Weeks after Exposure 30

35. Progression to Chronic HBV Infection
Typical Serologic Course
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titre
IgM anti-HBc 4 8 12 16 20 24 28 32 36 52
Years
Weeks after Exposure 31

36. Outcome of Hepatitis B Virus Infection
by Age at Infection
100
100 80
Chronic Infection (%) 80 60 60
Chronic Infection
Symptomatic Infection (%) 40
Chronic Infection (%) 40 20 20
Symptomatic Infection
Birth
1-6 months
7-12 months
1-4 years
Older Children
and Adults
Age at Infection 34

37. Global Patterns of Chronic HBV Infection
High (>8%): 45% of global population
lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-7%): 43% of global population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%): 12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups 35

39. Concentration of Hepatitis B Virus in Various Body Fluids
Low/Not
High
Moderate
Detectable
blood
semen
urine
serum
vaginal fluid
feces
wound exudates
saliva
sweat
tears
breastmilk 1 1 1

40. Hepatitis B Virus Modes of Transmission
Sexual - sex workers and homosexuals are particular at risk.
Parenteral - IVDA, Health Workers are at increased risk.
Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. 2 2 2

41. Diagnosis
A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.
HBsAg - used as a general marker of infection.
HBsAb - used to document recovery and/or immunity to HBV infection.
anti-HBc IgM - marker of acute infection.
anti-HBcIgG - past or chronic infection.
HBeAg - indicates active replication of virus and therefore infectiveness.
Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV.
HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

42. Treatment (1)
Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.
Epivir (Lamivudine) - a oral, nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.
Entecavir (Baraclude) – a recently FDA approved, oral nucleoside transcriptase inhibitor
Hepsera (Adefovir dipivoxil) – an oral, nucleoside reverse transcriptase inhibitor with same problems as lamivudine.

43. Treatment (2)
The latest treatment recommendations are at:
Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg negative.

44. Prevention
Vaccination - highly effective recombinant vaccines (see below) are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.
Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive.
Other measures - screening of blood donors, blood and body fluid precautions.

45. Vaccines (1)
Two HBV recombinant subunit vaccines containing HBsAg are available (Recombivax HB and Energix-B).
Twinrix, a combination of Havrix and Energix-B is available for those 18 years old and older.
Comvax, a combined HBV-H.influenzae type b conjugate vaccine may be used between 6 weeks and 70 years.
Pediarix, a combined HBV-diptheria, tetanus, and acellular pertusis-inactivated poliovirus vaccine can not be used before 6 weeks or at an age >7 years.

46. Vaccines (2)
Vaccination for HBV is discussed at:
Vaccination for HAV and HBV is discussed at:

47. Table 2                                                                                            

48. Introduction to HDV Hepatitis
HDV is a defective virus that contains delta antigen and requires HBV for replication.
The clinical disease is more severe than HBV hepatitis.

49. Hepatitis D (Delta) Virus
 antigen
HBsAg
RNA 19 19 19

50. Hepatitis D - Clinical Features
Coinfection
severe acute disease.
low risk of chronic infection.
Superinfection
usually develop chronic HDV infection.
high risk of severe chronic liver disease.
may present as an acute hepatitis. 20 20 20

51. Hepatitis D Virus Modes of Transmission
Percutanous exposures
injecting drug use
Permucosal exposures
sex contact 21 21 21

52. HBV - HDV Coinfection Typical Serologic Course Titre
Symptoms
ALT Elevated
Titre
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Time after Exposure 22 22 22

53. HBV - HDV Superinfection
Typical Serologic Course
Jaundice
Symptoms
Total anti-HDV
ALT
Titre
HDV RNA
HBsAg
IgM anti-HDV
Time after Exposure 23 23 23

55. Hepatitis D - Prevention
HBV-HDV Coinfection
Pre or postexposure prophylaxis to prevent HBV infection.
HBV-HDV Superinfection
Education to reduce risk behaviors among persons with chronic HBV infection. 25 25 25

56. Introduction to HCV Hepatitis (1)
HCV is a flavivirus, an enveloped, s.s. + sense RNA virus.
It is the most common cause of transfusion-associated hepatitis and blood-borne infections in USA.
Acute form of the disease is milder than hepatitis caused by HAV and HBV and is rarely recognized clinically.
70% of those infected develop chronic disease, a high percentage of which is asymptomatic.

57. Introduction (2)
6 HVC genotypes and over 50 subtypes exist; positive chronic infection treatment response depends on genotype (types 2 and 3 respond best)
HCV accounts for an estimated 1/3 PHC (primary hepatocellular carcinoma) cases.
Several HCV nonstructural proteins interact with cell cycle proteins e.g. p53 or their promotors.

58. Hepatitis C Virus capsid envelope protein protease/helicase
RNA-dependent
RNA polymerase
c22
33c
c-100 5’ 3’
core E1 E2
NS2
NS3
NS4
NS5
hypervariable
region 7 7 7

59. Hepatitis C - Clinical Features
Incubation period: Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice): % (20-30%)
Chronic hepatitis: 70%
Persistent infection: %
Immunity: No protective antibody
response identified 8 8 8

60. Chronic Hepatitis C Infection
All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, end stage liver disease, and hepatocellular carcinoma.
10-20% of those infected progress past the chronic persistent hepatitis stage to the more serious disease stages.

61. Hepatitis C Virus Infection
Typical Serologic Course
anti-HCV
Symptoms
Titre
ALT
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure 10 10 10

62. Risk Factors Associated with Transmission of HCV
Transfusion or transplant from infected donor
Injecting drug use
Hemodialysis (yrs on treatment)
Accidental injuries with needles/sharps
Sexual/household exposure to anti-HCV-positive contact
Multiple sex partners
Birth to HCV-infected mother 11 11 11

63. 14 14 14

64. Laboratory Diagnosis
HCV antibody - generally used with HCV-RNA test to diagnose chronic hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears.
HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in diagnosing chronic infection and monitoring the response to antiviral therapy.

65. Treatment (1)
Since symptoms during acute infection are rare, it is rarely diagnosed or treated; if diagnosed, a short course combination treatment similar to those for chronic HCV hepatitis is recommended.
Presently, the optimal treatment for chronic infection uses a 24 or 48 wk. course of the combination of subcutaneous pegylated (polyethylene glycol-conjugated) alpha interferon and oral ribivirin.

66. Treatment (2)
An excellent discussion of the current thoughts concerning the management of chronic hepatitis C infection is found at:

67. Prevention of Hepatitis C
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions 15 15 15

68. Yellow Fever Virus Hepatitis
Yellow fever virus (YFV) is a flavivirus the same family as HCV.
YFV is acquired through the bite of a mosquito therefore it is an arbovirus.
Urban yellow fever involves person to person transmission by domestic mosquitoes.
Jungle yellow fever involves monkey to human transfer by arboreal mosquitoes.

69. Yellow Fever Clinical Disease (1)
Short 3-6 day incubation period.
Disease may be mild or severe.
Initial symptoms include: fever, chills, headache, dizziness, myalgia, and backache followed by nausea, vomiting and bradycardia.
Symptoms may resolve or proceed to high fever, jaundice, and renal dysfunction.

70. Clinical disease (2) Patients either die or recover completely.
Illness occurs in Africa and Central and South America.

71. Prevention and Treatment
An excellent live, attenuated virus vaccine using the 17D strain of the virus is available.
No antiviral drug therapy is available.