Viral hepatitis

1.

Viral Hepatitis

2.

• Viral hepatitis is a group of etiologically
heterogenic
diseases
which
are
mainly
accompanied with affection of liver. It becomes
enlargened
and
accompanied
by
functional
activity and intoxication/
• According to the route of transmission hepatitis
can be enteral (A,E) and parenteral (B,C,D). The
viral hepatitis type F and G is still studied.

3.

• The problem of viral hepatitis remains the urgent,
as these diseases takes the third place after acute
respiratory and acute intestinal infections as to its
spreading.
• Viral hepatitis is a most frequent cause of chronic
hepatitis and liver cirrhosis. In some patients viral
hepatitis may have lethal outcome.

4.

At present following viruses, causing viral hepatitis
are known:
• virus of hepatitis A (VHA);
• virus of hepatitis B (VHB);
• virus of hepatitis E (VHE);
• virus of hepatitis D (VHD), associated with VHB;
• virus of hepatitis C (VHC).
Search for new viruses causing viral hepatitis
continues.

5.

Jaundice and
Cholestasis
Drug
Metabolism
LIVER
DISEASE
CATEGORIES
Hepatocellular
Biosynthetic
Necrosis
Capacity

6.

7.

8. Causes of Acute Hepatitis

Acute Hepatitis
Viral
Viral Hepatitis
Hepatitis
A,A,B/D,
C,EE
B/D, C,
EBV
EBV
CMV & HSV
CMV & HSV
Drugs
Drugs
Ethanol
Ethanol
Tylenol
Tylenol
Halothane
Halothane
Toxins
Vascular
Toxins
Vascular
Jamaica Bush
Bush Tea
Hypotension
Jamaica
Tea Hypotension
Mushrooms
Budd-Chiari
Mushrooms
Budd-Chiari
Metabolic
Metabolic
Autoimmune
Autoimmune
Wilson's Disease
Wilson's
Disease
Hepatitis
Hepatitis
A1AT
A1AT

9. Causes of Chronic Hepatitis

Chronic Hepatitis
Viral Hepatitis
Hep B
Hep C
Drugs
MTX
INH
Amiodarone
Alcohol
NAFLD
Autoimmune
AIH
PBC
PSC
Metabolic
A1AT
HHC
Wilson's
Abbreviations:
NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis
PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis

10. Clinical Stages

• Incubation Period - the time from exposure to
the onset of symptoms, virus shedding may
precede symptoms
• Prodromal Period - symptoms preceding
hepatitis signs such as jaundice
• Icteric Phase - clinically evident signs of
variable duration, may recur
• Post-icteric Phase - clinical and biochemical
recovery of variable duration

11. Human Hepatitis Viruses

Human Hepatitis Viruses
Virus
Genome
HAV
RNA
Genome Envelope
size (kb)
7.5
-
Picornaviridae
hepatovirus
3.2
+
Hepadnaviridae
9.6
+
Flaviviridae
hepacivirus
1.7
+
Unclassified
positive sense,
single stranded, linear
HBV
DNA
Family / genus
partially double
stranded, circular
HCV
RNA
positive sense,
single stranded, linear
HDV
HEV
RNA
positive sense,
single stranded, linear
RNA
positive sense, single
stranded, linear
(viroid), delta virus
7.5
-
Unclassified,
togavirus and
alpha virus-like

12.

Clinical Spectrum
•Subclinical Infection – serologic and biochemical evidence
of infection but asymptomatic.
•Clinical Infection – signs and symptoms of hepatitis,
Acute fulminant – massive necrosis
Acute self-limited – complete recovery
Chronic carrier – usually non-progressive
Chronic active – progressive damage +/- symptoms
Cirrhosis and liver failure
Hepatocellular carcinoma

13. Hepatitis A Virus: Morphology and Characteristics

Hepatitis A Virus
Nucleic Acid: 7.5 kb ssRNA
27 nm
Classification: Picornaviridae,
Hepatovirus
One serotype and multiple
genotypes
Nonenveloped, acid and heat stable
In vitro model: monkey and
human cell cultures
In vivo replication: in cytoplasm of
hepatocyte; human and other
higher primates

14. Hepatitis A Virus

27 nm
A member of the family Picornaviridae
(thus related to the polio viruses and
the rhinoviruses)
27–28-nm nonenveloped capsid
Linear RNA genome, essentially
readable mRNA, encoding three genes
Relatively heat stable, but destroyed
by boiling for 5 minutes.

15. Hepatitis A Virus

Transmission route: fecal-oral
27 nm
Clinical presentation
- Jaundice: Adults- 30%, Children- <5%
- Fulminant: <1%
• Diagnostic tests
- Acute infection: IgM anti-HAV
- Chronic infection: Not applicable
• Immunity: IgG anti-HAV
• Case-fatality rate: 0.1 – 2.7%
• Chronic infection: None

16.

Epidemiology
1. Transmission: fecal-oral
a) Food-borne or water-borne
b) Raw or partially cooked shellfish
c) Salads or other raw vegetables
2. Can also be transmitted by blood-blood contact,
especially associated with IV drug abuse
3. Widespread geographical distribution
4. Often virtually 100% of the population is infected
in early childhood, resulting in lasting immunity.

17. Global Prevalence of Hepatitis A

HAV - Epidemiology
Global Prevalence of Hepatitis A Infection
HAV Prevalence
High
Intermediate
Low
Very Low

18. Prevalence of Hepatitis A in the United States

HAV - Epidemiology
Prevalence of Hepatitis A in the
United States
<5
5 - 10
10 - 20
>20 cases
per
100,000
population
CDC

19. Routes of Hepatitis A Transmission

HAV - Epidemiology
Hepatitis A Transmission
• Close personal contact
Household or sexual contact
Daycare centers
• Fecal-oral contamination of food or water
Food handlers
Raw shellfish
Travel to endemic areas
• Blood-borne (rare)
Injecting drug users

20. Serological Course of Acute Hepatitis A

HAV
Typical Serologic Course of Acute
Hepatitis A Virus Infection
Symptoms
ALT
Total anti-HAV
Fecal
HAV
0
1
IgM anti-HAV
2
3
4
5
6
Months after exposure
12
24

21. Age-specific Incidence of Hepatitis A

HAV
Clinical Variants of Hepatitis A
Infection
• Asymptomatic (anicteric) disease
Children under 6 years of age, > 90%
Children from 6-14 years old, 40-50%
• Symptomatic (icteric) disease
Adults and children over 14, 70-80%

22. Clinical Features of Hepatitis A

Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
(average 25)
Clinical illness at
Common
Rare
No
No
15 – 49 days
5% Children
presentation
70-80% Adults

23. Clinical Features of Hepatitis A

Jaundice
Fulminant
Diagnostic tests
Acute infection
Chronic infection
Immunity
Case-fatality rate
Chronic infection
Adults-30%
Children-<5%
<1%
IgM anti-HAV
Not applicable
IgG anti-HAV
0.1 – 2.7%
None

24. Hepatitis E Virus: Morphology and Characteristics

Hepatitis E Virus
Nucleic Acid: 7.5 kb ssRNA
32 nm
Classification:
unclassified, togavirus, and
alphavirus-like
One serotype with genetic
heterogeneity
Non-enveloped, acid stable
Invitro model, no cell culture
system
Invivo replication: in cytoplasm of
hepatocyte;
human and other primates

25. Epidemiology

Hepatitis E
Epidemiology
Suspected from study of waterborne
hepatitis in India in 1980
Confirmed by transmission to chimp and
human in 1983
Endemic mainly in Asia, Middle East,
North Africa

26. Epidemiology

Hepatitis E
Epidemiology
Fecal-oral transmission (human to human)
Contaminated water supplies in tropical or
subtropical developing countries
Mainly young adults
Can infect primates, swine, sheep, rats
Swine may be reservoir of infection in North
America (attenuated virus)
Maternal-infant transmission occurs and is
often fatal

27. Clinical Characteristics

Hepatitis E
Clinical Characteristics
Similar to hepatitis A
Can cause severe acute hepatitis
Subclinical infection is common
Attenuated virus from animal reservoirs
Low-dose infections often asymptomatic
No chronic infection
Up to 20% mortality among pregnant
women (esp. third trimester)

28. Clinical Features of Hepatitis E

Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
Clinical Illness at
presentation
Jaundice
Common
Unknown
No
Yes, unknown frequency
15 – 60 (days)
70 – 80% in adults
Common

29. Course of Acute Infection

Hepatitis E
Course of Acute Infection
Viral Replication
IgM Antibody
IgG Antibody
ALT
Viremia
Symptoms
Virus in Stool
0
10
20
30
40
50
Time After Infection (days)
60
1
2
(years)

30. Clinical Features of Hepatitis E

Fulminant
Diagnostic tests
Acute infection
Chronic infection
Immunity
Case-fatality rate
Chronic infection
<1%, in pregnancy up to
30%
IgG anti-HEV (seroconversion)
Not applicable
Not applicable
0.5 – 4%
1.5 – 21% in pregnant women
None

31. Hepatitis C Virus: Morphology and Characteristics

Hepatitis C Virus
Nucleic Acid: 9.6 kb ssRNA
Classification: Flaviviridae,
Hepacivirus
40-60 nm
Genotypes: 1 to 6
Enveloped
In vitro model: primary
hepatocyte and T cell cultures;
replicon system
In vivo replication: in cytoplasm,
hepatocyte and lymphocyte;
human and other primates

32. Prevalence

HCV - Epidemiology
Prevalence
Worldwide
170 million ( 3%)
United States
Anti-HCV positive
HCV RNA positive
3.9 million (1.8%)
2.7 million (1.4%)
Alter MJ et al., New Engl J Med 1999; 341:556
Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.)
Hepatitis C. New York: Academic Press, 2000:185

33. Current Likelihood of Transmission

HCV - Epidemiology
Current Likelihood of Transmission
Transfusion
~ 1 in 1,000,000
Maternal-Infant
Mother HIV-negative
~ 5%
Mother HIV-positive
15 - 20%
Heterosexual partner
~1 in 1,000 per yr
Needlestick injury
HCV-positive source
HCV status unknown
Terrault NA, Hepatology 2002 ;36(Suppl 1):S99
Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106
~ 5%
~ 1%

34. Outcome Following Hepatitis C Infection

HCV - Natural History
Outcome Following Hepatitis C Infection
Acute hepatitis C
55 - 85%
Chronic infection
70%
Chronic hepatitis
20%
1 - 4%/yr
HCC
Cirrhosis
Time
(yr)
4 - 5%/yr
10
20
Decompensation
30

35. Diagnostic Tests

HCV - Diagnosis
Diagnostic Tests
• Hepatitis C antibody tests
• Qualitative HCV RNA tests
• Quantitative HCV RNA tests
• Genotyping

36. Acute hepatitis C infection

HCV - Diagnosis
Acute HCV Infection
1000
HCV RNA positive
800
Anti-HCV
ALT
600
(IU/L)
Symptoms
400
200
Normal
ALT
0
0
2
4
6
8
10
12
24
1
2
3
Weeks
4
5
Months
Time After Exposure
Hoofnagle JH, Hepatology 1997; 26:15S
6
7

37. Antibody tests for hepatitis C

HCV - Diagnosis
HCV Antibody Test
• Indicates past or present infection
• Inexpensive, sensitive and specific
• Poor positive predictive value in low
prevalence populations
• Low sensitivity in immunosuppressed
patients

38. Qualitative tests for HCV RNA

HCV - Diagnosis
Qualitative HCV RNA (PCR)
• Confirms diagnosis of HCV infection
• Useful in the early diagnosis of acute
hepatitis C
• Demonstrates the presence of active
infection
• “Gold standard” for documenting
response to treatment

39. Clinical Features of Hepatitis C

Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
Clinical Illness at
presentation
No
Common
Yes, rare
Yes, low frequency
14 – 160 (days)
5 - 10%

40. Clinical Features of Hepatitis C

Jaundice
Fulminant
Diagnostic tests
Acute infection
Chronic infection
>6 months
Immunity
Case-fatality rate
Chronic infection
5 – 10%
Rare
HCV RNA (anti-HCV)
HCV RNA (anti-HCV),
Unknown
1 – 2%
60 – 85%

41.

Hepatitis B Virus: Morphology and Characteristics
Hepatitis B Virus
Nucleic Acid: 3.2 kb DNA
Classification: Hepadnaviridae
Multiple serotypes and genotypes
A-F
42 nm
Enveloped
22 nm
In vitro model: primary
hepatocyte culture and
transfection of cloned HBV DNA
HBsAg
42 nm
HBcAg
HBV DNA
In vivo replication: in cytoplasm,
cccDNA in nucleus; hepatocyte
and other tissues, human and
other primates
4

42. Epidemiology of Hepatitis B

HBV - Epidemiology
Prevalence of HBsAg Carrier State
>8%
2-8%
<2%
WHO

43. Risk factors for hepatitis B infection

HBV - Epidemiology
Risk Factors for Infection
Percutaneous
Injection drug use
Transfusion or transplant
Occupational exposure
Parenteral practices
Permucosal
Perinatal
Sexual
Household contact

44. Clinical Outcome of Acute Hepatitis B

HBV - Natural History
Outcome of Acute HBV Infection
Recovery
Subclinical
Hepatitis
Acute Hepatitis
Acute Infection
Chronic Infection
Fulminant
Hepatitis
Death

45. Risk of chronic infection

HBV - Epidemiology
Risk of Chronic Infection
100
80
%
60
Risk 40
20
0
Neonates
Infants
Children
Age at Infection
Adults

46. Clinical Outcome of Chronic Hepatitis B

HBV - Natural History
Outcome of Chronic HBV Infection
Chronic HBV Infection
Inactive Carrier
State
Chronic Hepatitis
Cirrhosis
HCC

47. Serological Markers of Acute HBV Infection

HBV - Diagnosis
Acute Infection
HBV DNA
HBeAg
Anti-HBe
Anti-HBs
Anti-HBc
HBsAg
0
Anti-HBc IgM
2
Months
4
6
Years

48. Serological Markers of Chronic HBV Infection

HBV - Diagnosis
Serological Markers of Chronic HBV Infection
Chronic Infection
HBV DNA
HBeAg
Anti-HBe
HBsAg
Anti-HBc IgG
Anti-HBc IgM
Months
Years

49. Clinical Significance of Serological Markers for HBV Infection

HBV - Diagnosis
Serological Markers
Clinical Significance
HBsAg
Acute/Chronic infection
Anti-HBc IgM
Acute infection
HBeAg
High infectivity
Anti-HBe
Low infectivity
Anti-HBs
Immunity
Anti-HBc IgG and HBsAg
Chronic infection
Anti-HBc IgG and anti-HBs
Resolved infection

50. Clinical Features of Hepatitis B

Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
Clinical Illness at
presentation
Not likely
Common
Common
Common
60-180 (days)
10 - 15%

51. Clinical Features of Hepatitis B

Jaundice
Fulminant
Diagnostic tests
Acute infection
Chronic infection
Immunity
Case-fatality rate
Chronic infection
5 –20%
<1%
HBsAg, IgM anti-HBc
HBsAg, IgG anti-HBc
IgG anti-HBc, anti-HBs
1 – 3%
>90% infants
<5% adults

52. Hepatitis D Virus: Morphology and Characteristics

Hepatitis D Virus
Nucleic Acid: 1.7 kb ssRNA
Classification: unclassified,
related to viroids; deltavirus
HBV envelope
One serotype, three genotypes
35-37nm
In-vitro model: primary
hepatocyte culture and
transfection of cloned HDV DNA
In-vivo replication: in nucleus,
requires HBV for assembly and
infection

53. Transmission of hepatitis D virus (HDV)

HDV
Epidemiologic Patterns
Pattern
Distribution
Modes of transmission
Endemic
Mediterranean
Middle East
Central & South
America
Africa
Intra-familial
Sexual
Non-endemic North America
Northern Europe
Injection drug use
Transfusion of clotting
factor concentrates

54. Modes of HDV infection

HDV
Coinfection
B
D
Superinfection
B
D

55. HDV Co-infection

HDV
HDV - Coinfection
ALT
HDV RNA
IgM anti-HDV
IgG anti-HDV
HDAg
IgM anti-HBc
HBsAg
IgG anti-HBc
anti-HBs
Months

56. HDV Superinfection

HDV
HDV - Superinfection
ALT
HDV RNA
IgM anti-HDV
IgG anti-HDV
HDAg
HBV DNA
HBsAg, IgG anti-HBc
Years

57. Clinical sequelae of HDV infection

HDV
Clinical Sequelae
Coinfection
Superinfection
Acute hepatitis
Acute
exacerbation
Uneventful
recovery
Fulminant
hepatitis
Chronic
hepatitis
Cirrhosis
and HCC

58. Clinical Features of Hepatitis D

Transmission
Oral
Percutaneous
Sexual
Perinatal
Incubation period
Clinical Illness at
presentation
No
Common
Yes, rare
No
21 – 45 (days)
10%, higher with
superinfection

59. Clinical Features of Hepatitis D

Jaundice
Fulminant
Diagnostic tests
Acute infection
Chronic infection
Immunity
Case-fatality rate
Chronic infection
Unknown
2 – 7.5%
IgM anti-HDV
IgG anti-HDV, HBsAg +
Not applicable
1 – 2%
Superinfection – 80%
Coinfection < 5%

60. Hepatitis E vs. Hepatitis A

Hepatitis E
Hepatitis E vs. Hepatitis A
HEV
HAV
Fecal-oral transmission
Yes
Yes
Transmission in family
No
Yes
Developing
countries
Worldwide
Young adults
All
Subclinical infection
Yes
Yes
Chronic infection
No
No
Distribution
Ages infected

61. Prevalence In Groups at Risk

HCV - Epidemiology
Prevalence In Groups at Risk
Recipients of clotting factors before 1987
75 - 90%
Injection drug users
70 - 85%
Long-term hemodialysis patients
10%
Individuals with > 50 sexual partners
10%
Recipients of blood prior to 1990
5%
Infants born to infected mothers
5%
Long-term sexual partners of HCV positive
1 - 5%
Health workers after random needlesticks
1 - 2%
CDC, MMWR 1998;47(No. RR-19):1

62. Vaccination of selected high-risk groups in adults

HBV - Vaccine
Indications in Adults
Sexual and household contacts of
carriers
Sexually active individuals with multiple
sex partners and men who have sex
with men
Injection drug users
Hemodialysis patients
Recipients of clotting factor concentrates
Families of adoptees from endemic areas
CDC and WHO

63. Vaccination of selected high-risk groups in adults

HBV - Vaccine
Indications in Adults (con’t.)
Health care and public safety workers
with occupational risks
Persons in institutions for the
developmentally disabled or in long-term
correctional facilities
Travelers to countries endemic for
hepatitis B who plan to stay > 6 months
Transplant candidates before transplantation
Patients with chronic liver disease
CDC and WHO