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Hepatitis A-G

David Kramer, M.D.

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Hepatitis A-G

€ Clinical Classification
• Infectious hepatitis - hepatitis A and E viruses
• Enterically transmitted
• No chronic sequelae
• Infectious hepatitis - hepatitis B, C, D
viruses
• Blood and body fluid transmission
• Serious chronic sequelae
• Possible hepatitis - hepatitis F and G viruses

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Hepatitis A Virus

€ First characterized in 1973


€ RNA virus (member of enterovirus group)
€ Present in large quantity in stool of infected individuals
€ Lesser quantities in serum and saliva
€ Can be grown in vitro
€ Clinical Features
• Incubation period 30 days (range 15-50)
• Often asymptomatic in childhood
• <10% icteric under 6 years of age
• 70-80% icteric in adolescence/adulthood
• Fulminant hepatitis is rare
• <0.5% mortality in children
• No known chronic sequelae or carrier state
€ Prevention
• Immune serum globulin: Given ASAP within 14 days post exposure
• 80-90% efficacy
€ Vaccine
• 94-100% efficacy
• Recommended for high-risk individuals, such as travelers to endemic
areas, homosexual or bisexual men, drug users, chronic liver disease,
children in locales with high endemic rates

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Hepatitis B Virus

€ Member of hepadnavirus family with partly single-stranded DNA


€ Dane particle is probably complete virion and contains HBsAg
€ Incomplete forms (spherical and filamentous particles) also contain HBsAg
€ Virion cores (HBcAg) are contained within the incomplete forms
€ HBeAg exists in serum and on hepatocytes

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Hepatitis B Virus

€ Antigenic and Genetic Variation


• Multiple antigenic specificities of HBsAg are known
- Mutations in "a" determinant inhibit anti-HBs
binding, may cause vaccine failure
• Multiple viral "quasispecies" exist in persistently infected hosts
- Pre-core (HBeAg) and core (HBcAg) mutants may be important in
pathogenesis of persistent infection

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Hepatitis B Virus

Concentration in Various Body Fluids

High Moderate Low/Not Detectable

blood semen urine


serum vaginal fluid feces
wound exudates saliva sweat
tears
breast milk

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Hepatitis B Virus

€ Clinical Features
• Incubation 60-90 days (range 45-180)
• Jaundice relatively uncommon in children
- <10% in under 5 years old - 30-50% over 5 years of age
• Acute mortality 0.5-1%
• Chronic infection common, age-related
- Complications include chronic persistent and chronic active
hepatitis, hepatocellular carcinoma, extrahepatic syndromes
€ Prevention
• Recombinant vaccines are >95% effective in pediatric population
- Prime target is eradication of perinatal transmission; vaccine alone
is 70-95% effective
• HBIG
- >95% efficacy with vaccine in perinatal period - 75% efficacy in
sexual contact exposure
- Anti-HBs titer in IG declining - not indicated

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Hepatitis C

€ Clinical Features
• Incubation 6-7 weeks (range 2-26)
• Jaundice 20-40%, less age dependent
• Persistent infection in most
• 70% develop chronic hepatitis

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Hepatitis D

€ Defective single stranded RNA virus - requires HBV for synthesis of envelope
protein (HBsAg encapsulates genome)
€ Therefore only exists as co-infection with HBV or as superinfection of chronic
HBsAg-positive individual

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Hepatitis D

€ Epidemiology
• Spread most commonly by percutaneous or permucosal exposure
- Perinatal transmission reported but rare
• More prevalent in Mediterranean countries, Romania, some isolated
areas in the Amazon River basin
€ Clinical Features
• Coinfection with HBV
- Fulminant hepatitis more common (2-20%)
- Less commonly become HBsAg carriers
• Superinfection in chronic HBV
- More likely to develop chronic HDV infection
- 70% develop cirrhosis (2-5 times more frequent than
with HBV alone)
• Incubation period probably the same as HBV

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Hepatitis E

€ Single stranded RNA virus


€ Similar to caliciviruses in structure but may be a separate virus family
€ Genome has been cloned and sequenced but virus has not been grown in
vitro
€ Epidemiology
• Primarily transmitted by drinking contaminated water
- Person-to-person transmission uncommon
- Vertical transmission reported
• Endemic countries include Mexico, Indian subcontinent, southern
Russia, SE Asia, and northern and eastern Africa
€ Clinical Features
• Incubation period 40 days (range 15-60)
• Mortality increased in pregnant women (15-25% vs. 0.5-3%)
• No known sequelae

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Hepatitis F Virus

€ Awaiting Confirmation
• Original stool samples from 5 patients with sporadic non A, non B
hepatitis in France
• Stool extract infective for rhesus monkeys
• 27-37 nm virus-like particles (ds DNA) excreted in stool, found in liver
biopsy, and immunoreactive by ELISA
• So far, data not replicated
J Virol 1994; 68:7810-15

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Hepatitis G Virus

€ Microbiology
• ss RNA virus in Flavivirus family
• May not be primarily hepatotropic

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Hepatitis G Infection

€ Clinical Manifestations
• Relatively common infection, little evidence for clinical disease
• Does not appear to cause clinical hepatitis
• Very commonly found in individuals with HBV, HCV, HIV-1, and HTLV-1
infections compared to general population, but does not appear to alter
the clinical course

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Chronic Hepatitis

€ Indications for Interferon Therapy


• Hepatitis B
- Persistent ALT elevation
- Positive HBsAg, HBeAg, HBV DNA in serum
- Chronic hepatitis on biopsy
- Compensated liver disease
• Hepatitis C
- Persistent ALT elevation
- Anti-HCV in serum
- Chronic hepatitis on biopsy

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Interferon Therapy

Characteristics of Favorable Responders

Hepatitis B Hepatitis C

Short disease duration Short disease duration

High ALT Young age

Active disease with fibrosis Absent or minimal fibrosis

Low HBV DNA Low HCV RNA

HBeAg +, HDV- Genotype 2 or 3 or low quasi spe-


cies

N Engl J Med 1997; 347-56

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Hepatitis A-G Supplementary Outline

I. Hepatitis A
• Description of agent
I. RNA virus - member of enterovirus group
II. Present in large quantity in the stool of infected patients, with lesser quantities in serum and saliva
III. Can be cultivated in vitro
• Epidemiology
I. Younger age groups have higher disease rates
II. Personal contact and day care centers are most important exposure groups nationally
• Clinical Features
I. Incubation period averages 30 days after exposure, with range 15-50 days
II. Fecal shedding of virus diminishes rapidly with onset of clinical symptoms
III. Jaundice is relatively uncommon in young children
(1) <10% icteric in cases under 6 years of age
(2) 70-80% icteric in adolescence/adulthood
(3) Illness often diagnosed retrospectively in a child
after parent becomes icteric one month after the child's
self-limited illness with malaise and vomiting
IV. Fulminant hepatitis is rare but does occur
V. No known instances of chronic/persistent hepatitis
• Serologic Diagnosis
I. IgM anti-HAV useful for diagnosis of acute disease
II. IgG anti-HAV indicative of prior (>3 months) infection
• Prevention
I. Immune serum globulin
(1) Give as soon as possible after exposure
(2) Efficacy 80-90%
(3) Probably no efficacy if given >14 days after exposure
II. Vaccine
(1) 94-100% efficacy in large trials
(2) Recommended for select high risk groups
I. Travelers to endemic areas (unprotected risk 3-5/1000 per month of stay)
II. Homosexual or bisexual men
III. Injecting drug users Individuals with chronic liver disease
IV. Children residing in endemic areas
I. Alaska Natives and American Indians
II. Vaccines not yet approved under 2 years of age

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(3) Duration of vaccine immunity unknown - at least 4 years, perhaps up to 20 years by antibody kinetic modeling
II. Hepatitis B
• Description of agent
I. Member of hepadnavirus family with partly single stranded DNA
II. Dane particle (42 nm) is probably the complete virion and contains HBsAg
III. HBsAg also present in blood as 22 nm spherical and filamentous particles
IV. Virion cores are within the incomplete forms above and contain HBcAg and HBeAg
V. Multiple antigenic specificities of HBsAg have been described
(1) Mutations in "a" determinant can inhibit binding of anti-HBs antibody, resulting in vaccine failure in individuals
exposed to these strains (termed "escape mutants")
(2) Multiple viral quasispecies can exist in persistently infected hosts
I. Approximately half of chronic HBV carriers eventually lose HBeAg
II. This process may result from infection with mutation to quasispecies, pre-core variants (HBeAg negative) that
infect but do not kill hepatocytes, allowing continuing infection of other hepatocytes
(3) HBcAg gene codes for both humoral and cytotoxic T cell epitopes; mutations here may facilitate persistence of
infection
• Epidemiology
I. Virus has highest concentrations in blood, serum, and wound exudate, followed by semen, vaginal fluid, and saliva, then
by urine, feces, sweat, tears, and breast milk
II. Incidence of infection has been decreasing the past 10 years, most dramatically due to declines in homosexual men and
injecting drug users, with further decline likely related to vaccine use
III. Heterosexual contact is the most common mode of transmission, followed by injecting drug use
(1) Impact of routine infant vaccination is still undetermined
• Clinical Features
I. Incubation period 60-90 days, ranging from 45-180
II. Jaundice relatively uncommon, especially in young children
a. <10% icteric under 5 years of age
b. 30-50% with jaundice over 5 years
3. Acute mortality (fulminant hepatitis) approximately 0.5-1.0%
4. Chronic infection is common, especially in infected at young age
a. 90% of perinatal infections become carriers
b. 10% of older children/adults become carriers
5. Complications of chronic infection are significant
a. Chronic persistent hepatitis
b. Chronic active hepatitis
c. Hepatocellular carcinoma
d. Extrahepatic (immune mediated) syndromes
(1) Urticaria
(2) Arthritis and arthralgia

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(3) Papular acrodermatitis of childhood
(4) Membranous (and other) glomerulonephritis
(5) Vasculitis
(6) Aplastic anemia, thrombocytopenia
D. Serologic Diagnosis
1. HBsAg, IgM anti-HBc for acute
infection
a. Note presence of "window period" at 6 to 8 months after infection when HBsAg declines but anti-HBs is not yet
detectable
2. anti-HBs indicative of prior infection (usually >6-7 months previously), but presence of anti-
HBs does not rule out chronic HBV carrier state (uncommonly HBsAg carriers will have concomitant
anti-HBs)
3. Anti-HBs but not anti-HBc develops after vaccination
E. Prevention
1. Immune serum globulin no longer has significant anti-HBsAg activity and is unlikely to be protective
2. Hepatitis B immune globulin is highly effective
a. When combined with vaccine is >95% effective in preventing perinatal transmission
b. Approximately 75% effective in sexual contact exposure
3. Recombinant hepatitis B vaccines have improved efficacy over serum-derived vaccine
a. 70-95% efficacy alone in perinatal exposures
b. 95% of unexposed infants develop anti-HBs
c. Duration of immunity still unknown probably at least 10 years
III. Hepatitis C virus
A. Description of agent
1. Single stranded RNA virus in Flavivirus family
2. Mutations in hypervariable region contribute to organism's ability to establish persistent infection
B. Epidemiology
1. Most common cause of transfusion-associated hepatitis
2. Incidence is falling, related mostly to declines in injecting drug abusers and in development of screening assays for blood
donors
3. Has been transmitted by one IVIG product (manufacturing process has now been changed)
4. Vertical transmission has been documented, but the magnitude of this mode is not yet known
5. Almost half of HCV cases have no clear risk factors but occur in individuals of low socioeconomic level; half of these have
exposure to high-risk individuals in the distant past
C. Clinical Features
1. Incubation period 6-7 weeks (range 2-26 weeks) in transfusion-related cases
2. Jaundice in only 20-40%; most infections are subclinical
3.Fulminant hepatitis uncommon
4. Most individuals develop persistent infection; 70% develop chronic hepatitis

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5. Extrahepatic manifestations similar to HBV have been described
D. Serologic diagnosis
1. Second generation ELISA as screening test
a. Sensitivity and specificity approximately 90%
b. 80% seroconvert within 4-8 weeks after clinical symptoms begin
2. Second generation RIBA (recombinant immunoblot assay) is confirmatory
test
a. Estimated sensitivity 98%
b. Most high-risk ELISA II + patients are RIBA II +; less than half low-risk patients are RIBA II +
E. Prevention
1. Immune serum globulin is ineffective in prevention
2. No specific prevention method available

IV. Hepatitis D
A. Description of agent
1. Defective ss RNA virus
2. Requires HBsAg to act as genome capsule
3. Exists as co-infection (acquired simultaneously) with hepatitis B or as superinfection of chronic HBsAg-
positive individual
B. Epidemiology
1. Percutaneous or permucosal exposure, similar to hepatitis B and C
2. Perinatal transmission has been reported
3. Certain geographic areas have higher rates
a. Mediterranean area
b. Romania
c. Isolated areas in Amazon River basin
C. Clinical Features
1. Incubation period probably the same as HBV
2. Co-infection with HBV
a. Fulminant hepatitis more common (than with HBV infection alone) - 2-20%
b. Less likely to become chronic HBsAg carrier (<10% in adults)
3. Superinfection in HBsAg carrier
a. More likely to develop HDV carrier state than if co-infection
b. More likely to develop cirrhosis than with HBV alone 70% vs. 15-30%
D. Serologic Diagnosis
1. IgM anti-HDV is present transiently in most with acute HDV infection
a. 40-50% positive within 2 weeks of infection
b. Persists at a low level in chronic HDV infection
2. IgG anti-HDV develops in both co-and superinfected cases

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E. Prevention
1. No specific prophylactic measures available
2. Prevention of HBV infection will prevent HDV

V. Hepatitis E
A. Description of agent

1. 32 nm ss RNA virus
2. Smaller 27-30 nm virus-like particles also present - may represent degradation products
3. Similar to caliciviruses but may represent a separate family
4. Genome has been cloned and sequenced
B. Epidemiology
1. Primarily transmitted in contaminated water
2. Person-to-person transmission less common than with hepatitis A
3. Parenteral and vertical transmission have been reported
4. Endemic countries include Mexico, Indian subcontinent, southern Russia, SE Asia, and northern and eastern Africa
C. Clinical Features
1. Incubation period 40 days (range 15-60)
2. Anicteric cases occur; frequency unclear
3. Mortality increased in pregnant women (15-25% vs. 0.5-3%)
4. No known chronic infections or other sequelae
D. Serologic diagnosis
1. IgM anti-HEV develops acutely, then fades
2. IgG response persists
3. Since HEV testing not readily available, should consider diagnosis in traveler to endemic area who is negative for hepatitis
A, B, and C
E. Prevention
1. No specific measures available

VI. Hepatitis F
A. Proposed new agent for sporadic, enterically transmitted non A, non B hepatitis
B. ds DNA viral particles in stools of 5 patients from France (F is for France), transmitted to experimental animals
C. Unconfirmed findings to date

VII. Hepatitis G
A. ss RNA Flavivirus agent
B. Appears to be enterically transmitted
C. May not be hepatotropic agent
1. Individuals with HGV and liver disease almost always have another etiologic agent as cause

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2. Patients with concomitant HGV and HBV or HCV have clinical courses
consistent with course of HBV or HCV alone (especially with regard to interferon response)

VIII. Interferon therapy for chronic HBV and HCV A. Most data from studies of adults
B. Indicated for chronic hepatitis due to these two agents
C. Favorable response more likely in selected circumstances
1. Hepatitis B - short duration of disease, high ALT, active disease with fibrosis on biopsy, low HBV DNA levels, positive e
antigen, absence of HDV infection
2. Hepatitis C - short duration of disease, young age (in adult population), absent or minimal fibrosis on biopsy, low HCV RNA
levels, genotype 2 or 3 or low level of quasispecies present
D. Studies of interferon in children with chronic hepatitis B
1. Some children will respond with clearance of HBV DNA and normalization of ALT (40% response rate in white children)
2. Asian children and those with perinatally-acquired disease may have poorer responses
3. Interferon alpha-2b has been studied most; interferon gamma may not have benefit
4. Interferon beta possibly beneficial
in children not responding to interferon alpha (40% response rate in one uncontrolled study)

Selected Bibliography

General References

1. Brown KE, Tisdale J, Barrett J, et al. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 336:1059-64.
2. Jackson LA, Stewart LK, Solomon SL, et al. Risk of infection with hepatitis A, B or C, cytomegalovirus, varicella or measles
among child care providers. Pediatr Infect Dis J 1996; 15:584-9.
3. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. N Engl J Med 1997; 336:196204.
4. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334:1685-
90.

5. Sjogren MH. Serologic diagnosis of viral


hepatitis. Med Clin NAmer 1996; 80:929-56.

Specific Viruses

1. Alter HJ, Nadatsuji Y, Metpolder J, et al. The incidence of transfusion-associated hepatitis G virus infection and its relation
to liver disease. N Engl J Med 1997; 336:747-54.
2. Alter MJ. Review of serologic testing for hepatitis C virus infection and risk of posttransfusion hepatitis C. Arch Pathol Lab
Med 1994; 118:342-5.
3. Alter MJ, Gallagher M, Morris TT, et al. Acute non-A-E hepatitis in the United States and the role of hepatitis G virus
infection.

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N Engl J Med 1997; 336:741-6.
4. Breese JS, Mast EE, Coleman PJ, et al.
Hepatitis C virus infection associated with
administration of intravenous immune
globulin: A cohort study. JAMA 1996;
276:1563-7.
5. Carman W, Thomas H, Domingo E. Viral genetic variation: Hepatitis B virus as a clinical example. Lancet 1993; 341:349-52.
6. Committee on Infectious Diseases. Prevention of hepatitis A infections: Guidelines for use of hepatitis A vaccine and immune
globulin. Pediatrics 1996; 98:1207-15.
7. Deka N, Sharma MD, Mukerjee R. Isolation of the novel agent from human stool samples that is associated with sporadic
non-A, non-B hepatitis. J Virol 1994; 68:7810-15.
8. Mast EE, Krawczynski K. Hepatitis E: An overview. Annu Rev Med 1996; 47:257-66.
9. Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vaccination of neonates and infants: Emerging safety data from
the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 1996; 15:771-6.
10. Nowicki MJ, Balistreri WF. The hepatitis C
virus: Identification, epidemiology, and
clinical controversies. J Pediatr
Gastroenterol 1995; 20:248-74.

Therapy of Chronic Hepatitis

1. Hirschman SZ. Current therapeutic approaches to viral hepatitis. Clin Infect Dis 1995; 20:741-6.
2. Fried MW. Therapy of chronic viral hepatitis. Med Clin NAmer 1996; 80:957-72.
3. Hoofnagle JH, Di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med 1997; 336:347-56.
4. Ruiz-Moreno M, Fernandez P, Leal A, et al. Pilot interferon-~ trial in children with chronic hepatitis B who had previously
not responded to interferon-~ therapy. Pediatrics 1997; 99:222-5.
5. Vajro P, Tedesco M, Fontanella A, et al.
Prolonged and high dose recombinant
interferon alpha-2b alone or after prednisone
priming accelerates termination of active
viral replication in children with chronic
hepatitis B infection. Pediatr Infect Dis J
1996; 15:223-31.

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