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Viral Hepatitis - Historical Perspectives

“Infectious” A Enterically
E
transmitted
Hepatitis A-E Viruses
Viral hepatitis NANB
An Overview

Parenterall
“Serum” B D C y
transmitted
F, G, TTV
? other

Characteristics of Hepatitis Viruses Characteristics of Hepatitis Viruses


virus
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
VIRUS HAV HBV HCV HDV HEV
Family Picornaviridae Hepadnaviridae Flaviviridae Unclassified Unclassified
Transmission Fecal oral parenteral parenteral parenteral Fecal-oral
Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Hepatitis E- Prevalence high high moderate Low, regional
like regional
Virion 27nm, 42nm, spherical 60nm, 35nm, 30-32 Fulminant dse rare rare rare frequent In
icosahedral spherical spherical icosahedral pregnancy
Chronic dse never often often often never
Envelope no Yes (HBsAg) yes Yes (HBsAg) no Oncogenic no yes yes ? no

Genome ssRNA dsDNA ssRNA ssRNA ssRNA

Genome 7.5kb 3.2 kb 9.4 kb 1.7kb 7.6 kb


size
Stability Heat & acid Acid sensitive Ether and acid Acid sensitive Heat stable
stable sensitive

Type of Hepatitis HEPATITIS A VIRUS (HAV)


A B C D E • This picornavirus is the 
Source of feces blood/ blood/ blood/ feces
causative agent of 
virus blood-derived blood-derived blood-derived infectious hepatitis. 
body fluids body fluids body fluids – single strand, 3’‐
polyadenylated, positive 
Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral
sense RNA genome 
transmission permucosal permucosal permucosal
– surrounded by a naked 
Chronic no yes yes yes no (unenveloped) icosahedral
infection capsid that is around 28 nm 
in diameter 
Prevention pre/post- pre/post- blood donor pre/post- ensure safe
– at the 5’ end of the RNA 
exposure exposure screening; exposure drinking
immunization immunization risk behavior immunization; water
strand is a viral protein called 
modification risk behavior VPg. 
modification – only one serotype of HAV.

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Hepatitis A ‐ Clinical Features Clinical Manifestations
Asymptomatic or mild, nonspecific illness‐ majority  
below 5 yo
 Incubation period: Average 30 days
Symptomatic
Range 15‐50 days
 Jaundice by <6 yrs,  <10% Pre‐icteric‐fever,vomiting,profound anorexia & 
age group: 6‐14 yrs, 40%‐50% abdominal discomfort.Mild & unnoticed in infants & 
>14 yrs, 70%‐80%  young children.(+)Diarrhea in children, constipation 
 Complications: Fulminant hepatitis 0.15% in adults
Relapsing hepatitis  3‐20%
Icteric phase‐ jaundice/dark urine after systemic 
 Chronic sequelae: None symptoms x a week. Subtle & unnoticed in young 
kids. Appetite.Well‐being gradually return to normal 
Extrahepatic‐ none

Hepatitis A Infection Prevention


Typical Serological Course
Symptoms Total anti-HAV

Titre ALT Preexposure Immunization:


2 doses, starting 12 months old, 6‐12months 
Fecal
HAV apart
IgM anti-HAV

0 1 2 3 4 5 6 12 24
Months after exposure

Prevention Hepatitis B
Postexposure Immunization:   

Time since exposure Future exposure Age of patient Recommended


• DS DNA Virus
/week likely prophylaxis • Hepadnavirus
IG:0.02 ml/kg
• May exist in multiple forms:
</= 2 wk No All age
– Spherical particles (22nm)
Yes >/= 1yo – Tubular of filamentous forms
IG:0.02ml/kg
+ Hepatitis A vaccine
– Larger, 42nm spherical virions (originally referred to as 
Dane particle)
>2 wks No All ages No prophylaxis • Envelope contains HBsAg and surrounds the 
nucleocapsid core containing HBcAg.
Hepatitis A vaccine
Yes >/=1yo • Humans: only reservoir

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Hepatitis B - Clinical Features Clinical manifestations
Anicteric‐majority of cases including children
 Incubation period: Average 60‐90 days Icteric Phase‐similar to hepatitis A or C, maybe more severe
Range 45‐180 days Extrahepatic manifestations‐occur early; may precede jaundice 
 Clinical illness (jaundice): <5 yrs, <10% as arthralgia, arthritis, macular rashes, thrombocytopenia, 
5 yrs, 30%‐50% papular acrodermatitis,(Gianotti‐Crosti syndrome), 
 Acute case‐fatality rate: 0.5%‐1% glomerulonephritis, aplastic anemia
 Chronic infection: <5 yrs, 30%‐90% Chronic infection‐
5 yrs, 2%‐10%  perinatal transmission‐ >90% risk of chronic infection
 Premature mortality from
1‐5 years old‐ 25‐50%
chronic liver disease: 15%‐25% older children/adult‐ 6‐10%
* ~25% on infants and children with chronic hepatitis B will 
eventually develop HBV related hepatocellular Ca or cirrhosis

Acute Hepatitis B Virus Infection with Recovery


Spectrum of Chronic Hepatitis B Diseases Typical Serologic Course

Symptoms
1. Chronic Persistent Hepatitis ‐ asymptomatic
HBeAg anti-HBe

2. Chronic Active Hepatitis ‐ symptomatic 
Total anti-HBc
exacerbations of hepatitis
Titre
3.  Cirrhosis of Liver
HBsAg IgM anti-HBc anti-HBs
4.  Hepatocellular Carcinoma

0 4 8 12 16 20 24 28 32 36 52 100

Weeks after Exposure

Progression to Chronic Hepatitis B Virus Infection Outcome of Hepatitis B Virus Infection


Typical Serologic Course by Age at Infection
100 100
Acute Chronic
(6 months) (Years) 80
Chronic Infection (%)

80 Symptomatic Infection (%)


HBeAg anti-HBe
HBsAg
60 60
Total anti-HBc Chronic Infection
Titre
40 Chronic Infection (%) 40

IgM anti-HBc 20 20

Symptomatic Infection
0 0
Birth 1-6 months 7-12 months 1-4 years Older Children
0 4 8 12 16 20 24 28 32 36 52 Years and Adults

Weeks after Exposure Age at Infection

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Concentration of Hepatitis B Virus in  Hepatitis B Virus 
Various Body Fluids Modes of Transmission

Low/Not  Sexual ‐ sex workers and homosexuals are 


High Moderate Detectable particular at risk.
blood semen urine  Parenteral ‐ IVDU,  Health  Workers  are  at 
serum vaginal fluid feces increased risk.
wound exudates saliva sweat  Perinatal ‐HBeAg +  mothers;  main  means 
tears of  transmission  in  high  prevalence 
breastmilk populations.

Diagnosis Treatment
• HBsAg ‐ general marker of infection. • Interferon  ‐ for  HBeAg (+)  carriers  with  chronic 
• HBsAb ‐ recovery &/or immunity to HBV infection.  active hepatitis. Response rate is 30 to 40%.
• anti‐HBc IgM ‐ marker of acute infection.
• Lamivudine ‐ a  nucleoside  analogue  reverse 
• anti‐HBc IgG ‐ past or chronic infection. transcriptase  inhibitor.  Well  tolerated,  most 
• HBeAg ‐ active replication of virus ; infectiveness. patients  will  respond  favorably;  tendency  to 
• Anti‐Hbe ‐ virus  no  longer  replicating;  the  patient  can  relapse  on  cessation  of  Tx;  rapid  emergence  of 
still be (+) for HBsAg made by integrated HBV. drug resistance.
• HBV‐DNA  ‐ active  replication  ,  more  accurate  than 
HBeAg especially  in  escape  mutants;  for  monitoring 
• Successful  response  to  Tx:  disappearance  of 
response to therapy. HBsAg, HBV‐DNA, and seroconversion

Indications and dosing schedule for Hepatitis B Vaccine and


hepatitis B Immune Globulin
Groups Vaccine schedule HBIG HBIG Schedule Hepatitis C Virus
Dose
(u/L)
Neonates
Infants HBsAg – (+) women Birth, 1, 6mo 0.5 Within 12 hr of birth
Inants HBsAg – (-) women Birth, 1-2,6-18 mo None capsid envelope protease/helicase RNA-dependentRNA polymerase
protein
Children & Adolescents 0,1, and 6 mo None
(11-19yr) c22 33c c-100
Contact w/ acute HBv
Intimate 0-19 y/o Exposure, 1 and 6 mo 0.06/kg At exposure 5’ 3’
> 19y/o Exposure, 1 and 6 mo 0.06/kg At exposure
Household None None core E1 E2 NS NS NS NS
Casual none None 2 3 4 5

Contact w/ chronic HBv


Intimate and Household
0 -19 y/o Exposure, 1 and 6 mo None hypervariable
> 19 y/o Exposure, 1 and 6 mo None region
Casual None

Immunosuppressed or Exposure, 1 qnd 6 mo none


hemodialysis patients

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Hepatitis C Hepatitis C ‐ Clinical Features
Degree of Seroprevalence • Transmission : blood or body fluid
exposure
• Parenteral exposure to HCV‐
Large,repeated 60=90%
infected blood: primary route;  Incubation period: Average 6‐7 wks
seroprevalence depend on 
exposure(IV drug
degree of exposure Range 2‐26 wks
users,hemophiliacs
before 1987 Clinical manifestations:
Frequent ,smaller 10-20%
exposure(hemodialy
sis pt)
Asymptomatic illness‐ majority of cases
Inapparent 1-10% Symptomatic illness: mimics hepatitis A or B
percutaneous
exposure(sex • Perinatal transmission is  Extrahepatic manifestations: essential mixed 
worker) uncommon(5‐6%)
Sporadic exposure 1% cryoglobulinemia,cutaneous vasculitis,peripheral neuropathy, 
glomerulonephritis,etc.

Risk Factors Associated with 
Chronic Hepatitis C Infection
Transmission of HCV
• HCV  most  likely  to  cause  chronic  infection;~85%  become 
chronic  Transfusion or transplant from infected donor
• After  ~20‐30  years,  about  25%  ultimately    progress  to   Injecting drug use
cirrhosis, liver failure & occasionally
primary hepatoCa
 Hemodialysis (yrs on treatment)
• Hepatocellular Ca associated with HCV, which is less effective   Accidental injuries with needles/sharps
than  HBV  in  causing  primary  hepatoCa almost  always  occurs 
 Sexual/household exposure to anti‐HCV‐positive 
with  cirrhosis;  results  from  chronic  inflammation  &  necrosis 
rather than oncogenic effect of virus contact
 Multiple sex partners
 Birth to HCV‐infected mother

Laboratory Diagnosis Treatment
• HCV antibody ‐ Not useful in the acute phase ;  • Interferon  ‐ considered  for  chronic  active 
at least 4 weeks after infection before (+) hepatitis;response rate  ~  50%  but  50%  of 
• HCV‐RNA ‐ PCR  and  branched  DNA;  useful  in  responders will relapse upon withdrawal of Tx.
the acute phase; used mainly  in monitoring   • Ribavirin ‐ recent  studies  suggest  that  a 
response to antiviral therapy.
combination  of  interferon  and  ribavirin is 
• HCV‐antigen ‐ by EIA , much easier procedure more effective than interferon alone.

5 | PEDIA-VIRO
Prevention of Hepatitis C Hepatitis D (Delta) Virus
 antigen HBsAg

 Screening of blood, organ, tissue donors

 High‐risk behavior modification

 Blood and body fluid precautions

RNA

Hepatitis D Hepatitis D Virus Modes of


• Is a highly defective virus 
Transmission
– it cannot produce infective virions without the help of a co‐infecting 
helper virus  HBV ‐‐ supplies the HBsAg surface protein.   Percutanous exposures
• In budding out of the cell, HDV acquires a membrane 
containing HBsAg.   injecting drug use
– HDV can only form an infectious particle if the cell in which it
replicates is co‐infected with HBV since the latter provides the surface   Permucosal exposures
HBsAg which is required for reinfection of another cell.
• HDV has a small circular RNA genome (1,700 bases) that   sex contact
encodes a protein called the delta antigen. This complexes 
with the RNA. 
• The RNA is single stranded negative sense and is a covalently 
closed circle. 

Hepatitis D - Clinical Features


Hepatitis D ‐ Prevention
 Coinfection
– severe acute disease.  HBV‐HDV Coinfection
– low risk of chronic infection. Pre  or  postexposure prophylaxis  to  prevent 
 Superinfection HBV infection.
acute illness is rare
 HBV‐HDV Superinfection
– chronic infection is common
risk of fulminant hepatitis is highest; suspect in  Education  to  reduce  risk  behaviors  among 
any child w/ acute liver failure persons with chronic HBV infection.

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Hepatitis E Virus
Hepatitis E ‐ Clinical Features
• enteric non‐A, non‐B hepatitis 
 Incubation period: Average 40 days
Range 15‐60 days
 Case‐fatality rate: Overall, 1%‐3%
Pregnant women, 
15%‐25%
 Illness severity: Increased with age
 Chronic sequelae: None identified

Hepatitis E Virus Infection


Typical Serologic Course Hepatitis F (HFV)
Symptoms
• ‐in 1994, french researchers isolated an enteric agent
ALT IgG anti-HEV responsible for sporadic non‐ A‐E hepatitis
‐not confirmed by others

Titer IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Weeks after Exposure

Hepatitis G (HGV)
‐RNA virus, flaviviridae family, 27% homology to HCV
‐reported in adults and children
‐seen in HIV pts and in 10‐20% of adults with chronic hepatitis B  
and hepatits C
‐primary source: transfusion; organ transplant, IV drug use, 
THE END
hemodialysis, sexual  transmission
‐ accounts for only small proportion of cases of non‐A‐E 

hepatitis
‐most infection not associated with hepatic inflammation 
;doesn’t seem to worsen coinfection with hepatitis B or C
‐diagnosis: HGV RNA PCR
‐prevention: none

Edited by KDE

7 | PEDIA-VIRO

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