HEPATITIS VIRUS

COMPILED BY
DWI WAHYU INDRIATI
D3 ANALIS MEDIS
FAKULTAS VOKASI
UNIVERSITAS AIRLANGGA
 WHAT IS VIRAL HEPATITIS ?

• VIRAL HEPATITIS IS A SYSTEMIC

DISEASE WITH PRIMARY
INFLAMMATION OF THE LIVER BY
ANY ONE OF A HETEROGENOUS
GROUP OF HEPATOTROPIC
VIRUSES
2
 HEPATITIS
• HEPATITIS IS A GENERAL TERM REFERRING TO INFLAMMATION OF
THE LIVER
• CAUSES:
• INFECTIOUS
• VIRAL
• BACTERIAL
• FUNGAL
• PARASITIC
• NON INFECTIOUS
• ALCOHOL
• DRUGS
• AUTOIMMUNE
• METABOLIC DISEASES
 WHAT IS VIRAL HEPATITIS?
• HEPATO-TROPIC VIRUSES • OTHER VIRUSES
• HEPATITIS A VIRUS (HAV) • ADENOVIRUS
• HEPATITIS B VIRUS (HBV) • CYTOMEGALOVIRUS (CMV)
• HEPATITIS C VIRUS (HCV) • EPSTEIN BARR VIRUS (EBV)
• HEPATITIS D VIRUS (HDV) • HERPES SIMPLEX VIRUS
• HEPATITIS E VIRUS (HEV) (HSV)
• YELLOW FEVER VIRUS (YFV)
 HEPATITIS VIRUSES
• HEPATITIS A (HAV) PICORNAVIRIDAE (1973)

• HEPATITIS B (HBV) HEPADNAVIRIDAE (1970)

• HEPATITIS C (HCV) FLAVIVIRIDAE (1988)

• HEPATITIS D (HDV) ? (1977)

• HEPATITIS E (HEV) (CALICIVIRIDAE) (1983),

HEPEVIRIDAE

• HEPATITIS F – NOT SEPARATE ENTITY –

MUTANT OF B VIRUS.

• HEPATITIS G (HGV) FLAVIVIRIDAE (1995) 5

  CLINICAL TERMS
• HEPATITIS: INFLAMMATION OF LIVER;
• ACUTE VIRAL HEPATITIS: SYMPTOMS LAST LESS THAN 6 MONTHS
• ACUTE HEPATIC FAILURE:IS THE APPEARANCE OF SEVERE COMPLICATIONS RAPIDLY
AFTER THE FIRST SIGNS OF LIVER DISEASE (SUCH AS JAUNDICE), AND INDICATES THAT
THE LIVER HAS SUSTAINED SEVERE DAMAGE (LOSS OF FUNCTION OF 80-90% OF LIVER
CELLS).MASSIVE HEPATIC NECROSIS WITH IMPAIRED CONSCIOUSNESS WITHIN 8
WEEKS OF ONSET OF ILLNESS.
• CHRONIC HEPATITIS: INFLAMMATION OF LIVER FOR AT LEAST 6 MONTHS
• CIRRHOSIS: REPLACEMENT OF LIVER TISSUE FIBROSIS(SCAR TISSUE).THESE CHANGES
LEAD TO LOSS OF LIVER FUNCTION.
• FULMINANT HEPATITIS: SEVERE IMPAIRMENT OF HEPATIC FUNCTIONS OR SEVERE
NECROSIS OF HEPATOCYTES IN THE ABSENCE OF PREEXISTING LIVER DISEASE.
 Viral Hepatitis - Historical Perspectives

“Infectious” A Enterically
E
transmitted

Viral hepatitis NANB

Parenterall
“Serum” B D C y
transmitted
F, G, TTV
? other
  TYPES OF VIRAL HEPATITIS
Viral Hepatitis A Viral Hepatitis B Viral Hepatitis C Viral Hepatitis D Viral Hepatitis E

Agent Hepatitis A virus Hepatitis B virus Hepatitis C virus Hepatitis D virus Hepatitis E virus
(HAV); ssRNA; No (HBV); dsDNA; (HCV); ssRNA; (HDV); ssRNA; (HEV); ssRNA; no
envelope envelope envelope envelope from envelope
HBV
Route of Fecal-oral Parenteral, Parenteral Parenteral Fecal-oral
Transmission Vertical, Sexual.
Age affected Children Any age Adults Any age Young adults

Carrier state Nil Common Present Nil (only with Nil

HBV)
Incubation period 10-50 days (avg. 50-180 days 40-120 days 2-12 weeks 2-9 weeks
25-30) (avg. 60-90)
Chronic infection No Yes Yes Yes No

Specific Prophylaxis Ig and Vaccine Ig and Vaccine Nil HBV vaccine Nil
 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 Feco-oral Percutaneous Percutaneous Percutaneous Feco-

Transmission Permucosal Permucosal Permucosal oral
Chronic No Yes Yes Yes No
Infection
Prevention Pre Post Pre Post Blood donor Pre Post Ensure
Exposure Exposure screening Exposure Safe
Immunization Immunization Immunization Drinking
Blood donor water
screening

9
HAV
HAV

11

EXAMINED BY ELECTRON MICROSCOPE

 HEPATITIS A

 HEPATITIS A (FORMERLY KNOWN AS “INFECTIOUS” HEPATITIS

OR EPIDEMIC JAUNDICE) IS AN ACUTE INFECTIOUS DISEASE
CAUSED BY HEPATITIS A VIRUS (HAV).
 HAV

• PICORNAVIRUS FAMILY
• SS RNA VIRAL GENOME
OF 7.5 KB
• THE CAPSID IS
COMPOSED OF 3
STRUCTURAL PROTEINS;
VP1, VP2 AND VP3
• A SINGLE SEROTYPE
GENOME ORGANISATION OF HAV

Costa-Mattioli M et al. J Gen Virol 84 (2003), 3191-3201

 HAV GENOTYPES
FH3 LY6
AH3
LU38 AH2
FH1GBM
Genotype IA
FH2
AH1 F.G.
NCACG
HM-175
HAF-203 1000
Genotype IB
L-A-1 1000 PA21 GA76
MBB
P27 Genotype IIIA
1000
1000 NOR21
1000 989 612

Genotype IIA CF53

Genotype IIB SLF88 Genotype IV

simian strain
CY-145
Genotype V
simian strain
AGM27

0.1
 GENOTYPING

• HAV RNA ISOLATION FROM SERUM

• REVERSE TRANSCRIPTASE (RT)
• PCR
• SEQUENCING
 MOLECULAR EPIDEMIOLOGY OF HAV
• BY SEQUENCING 350-450 BP IN THE
VP1-2PA REGION WE CAN DISTINGUISH
BETWEEN OUTBREAK STRAIN
• WITHIN OUTBREAKS HAV SEQUENCES ARE
IDENTICAL OR VERY CLOSELY RELATED SO
THAT EPIDEMIOLOGICAL DEFINED CASES
ARE CONFIRMED OR PRECLUDED
 HEPATITIS A VIRUS
NAKED RNA VIRUS
RNA

-HAV WAS ISOLATED BY PURCELL IN 1973

-MEMBER OF FAMILY: PICRONAVIRIDAE PREVIOUSLY WAS CLASSIFIED IN THE GENUS

ENTEROVIRUS AS ENTEROVIRUS 72 IN 1983

-IT MULTIPLIES ONLY IN HEPATOCYTES

-ONE STABLE SEROTYPE ONLY

-3 GENOTYPES EXIST, AND DIVIDED INTO SUBTYPES A AND B, WHILE
GENOTYPE I IS THE MOST FREQUENTLY REPORTED BUT GENOTYPE II IS HARDLY
ISOLATED
18
-DIFFICULT TO GROW IN CELL CULTURE: PRIMARY MARMOSET CELL CULTURE AND
ALSO IN VIVO IN CHIMPANZEES AND MARMOSETS
 RESISTANCE ( HAV)
• RESISTANT TO INACTIVATION BY HEAT AT 600 C
FOR ONE HOUR, ETHER & ACID AT PH 3.

• INACTIVATED BY BOILING FOR ONE MINUTE, 1:

4,000 FORMALDEHYDE AT 370 C FOR 72 HOURS
& CHLORINE 1 PPM FOR 30 MINUTES.

• NOT AFFECTED BY ANIONIC DETERGENTS.

• SURVIVES PROLONGED STORAGE AT 40 C OR

BELOW. 19
 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, RAW
SHELLFISH)

• BLOOD EXPOSURE (RARE)

(E.G., INJECTING DRUG USE, TRANSFUSION) 20
-Prodromal or Preicteric phase : (symptoms:
fatigue, joint- and abdominal pain, malaise,
vomiting, lack of appetite, hepatomegaly)

-Icteric phase: Icterus: jaundice (skin, sclera,

mucous membranes,
cause: elevated bilirubin level, bilirubinuria: dark
urine, pale stool)

21
 PATHOGENESIS - HAV
CAUSE SUBACUTE DISEASE IN CHILDREN & YOUNG ADULTS.
HAV INVADE INTO HUMAN BODY BY FECAL-ORAL ROUTE,
MULTIPLIES IN THE INTESTINAL EPITHELIUM & REACHES THE
LIVER BY HEMATOGENOUS SPREAD.
AFTER ONE WEEK, THE HAV REACH LIVER CELLS REPLICATE
WITHIN.THEN ENTER INTESTINE WITH BILE AND APPEAR IN
FECES.
INCUBATION PERIOD : 2 TO 6 WEEKS.
23
 Hepatitis A Infection
Typical Serological Course
Symptoms IgG anti-HAV

Titre ALT

Fecal
HAV
IgM anti-HAV

24
0 1 2 3 4 5 6 1 2
2 4
Months after exposure
 PATHOGENESIS – HAV CONTD--

• AFTER HAV REPLICATING AND DISCHARGING,LIVER CELLS

DAMAGE BEGIN

• ANIMAL EXPERIMENT PROVED THAT IMMUNE COMPLEX MAY

ATTEND THE PATHOGENESIS OF HAV

• COMPLEMENT LEVEL REDUCE THE PATHOGENESIS MAYBE

FOLLOWING:
• ACTIVATED T CELL SECRETE Γ-INF THAT PROMOTE THE
REPRESENTATION OF HLA ON THE LIVER CELLS,CTL MAY KILL
THE TARGET CELL INFECTED WITH HAV
25
 LAB.DIAGNOSIS
1. DEMONSTRATION OF VIRUS IN FECES:
BY: IMMUNOELECTRON MICROSCOPY

2. VIRUS ISOLATION:
3. DETECTION OF ANTIBODY :BY ELISA
4. BIOCHEMICAL TESTS:
I) ALANINE AMINOTRANSFERASE (ALT)
II) BILIRUBIN
III) PROTEIN
5. MOLECULAR DIAGNOSIS : RT PCR OF FECES
26
Prevention:-
-hygienic measures and sanitation
-passive immunization(Human Immunoglobulin
Gamma globulin given before exposure to virus
or early during the incubation period, will
prevent or attenuate a clinical illness.
-active immunization
Several inactivated or live attenuated vaccines
against hepatitis A have been developed.

Treatment:
-nospecific, dietary food and long rest
 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 28
Hepatitis B
Hepatitis B (formerly known as “serum” hepatitis)
is an acute systemic infection with major pathology
in the liver, caused by hepatitis B virus.
Transmitted by the Parenteral route.
The acute illness causes liver inflammation, vomiting,
jaundice, and, rarely, death. Chronic hepatitis B may
eventually cause cirrhosis and liver cancer.
Hepatitis B is endemic throughout the world,
especially in tropical & developing countries.
 Epidemiology Determinants
Agent factor

a)AGENT: Hepatitis B Virus (HBV)

-It is a complex, 42 nm double-shelled DNA virus originally known

as “Dane Particle”.
-It replicates in liver cell.

HBV occurs in 3 morphology form in serum:

i. Small spherical particles with an average Diameter of 22nm.
ii. Filamentous or Tubules of varying length & of 22 nm diameter.
iii. Dane particle.
Out of 3 morphology forms, only the Dane particle is considered infectious, othe
circulating morphology forms are not infectious.
HBV : Structure
 HBV STRUCTURE & ANTIGENS
Dane particle

HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype) 33

HBeAg = secreted protein; function unknown

GENOME

34
 HBV Genome
4 Overlapping – Open Reading Frames which encode structural and non structural viral proteins.
• S gene encodes 3 Surface Proteins
[ Small(S),Middle(M),Large(L) ]
• C gene encodes Core Proteins Hepatitis B core Antigen( HBcAg)
& Hepatitis B e (Hbe) Protein (Non structural protein)
• P gene encodes HBV Polymerase (has 2 motifs- Reverse transcriptase motif
RNAse H Motif)
[ Code for 2 enzymes involved in HBV replication ]
• X gene encodes X Protein (Transcriptor involved in HBV replication)
Replication of HBV

36
 HBV: Modes of Transmission

 Parenteral - IV drug abusers, health workers are

at increased risk.

 Sexual - sex workers and homosexuals are

particular at risk.

 Perinatal (Vertical) – mother (HBeAg+) →infant.

37
 EPIDEMIOLOGY
• 350,000,000 CARRIERS WORLDWIDE
• 120,000,000 CARRIERS IN CHINA
- THE CARRIER RATE CAN EXCEED 10%
-15 TO 25% OF CHRONICALLY INFECTED PATIENTS WILL
DIE FROM CHRONIC LIVER DISEASE
• 500,000 DEATHS/YEAR IN CHINA
• 982,297 LIVER DISEASE IN CHINA 2005
• 50% OF CHILDREN BORN TO MOTHERS WITH CHRONIC 38

HBV IN THE US ARE ASIAN AMERICAN

 Concentration of Hepatitis B Virus
in Various Body Fluids
Low/Not
High Moderate Detectable

blood semen urine

serum vaginal fluid faeces
wound exudates saliva sweat
tears
Breast milk
39
b) High Risk Group:

 PEOPLE FROM ENDEMIC REGIONS

 BABIES OF MOTHERS WITH CHRONIC HBV
 INTRAVENOUS DRUG ABUSERS
 PEOPLE WITH MULTIPLE SEX PARTNERS
 HEMOPHILIACS AND OTHER PATIENTS REQUITING BLOOD
AND BLOOD PRODUCT TREATMENTS
 HEALTH CARE PERSONNEL WHO HAVE CONTACT WITH
BLOOD
 PATIENTS WHO ARE IMMUNOCOMPROMISED.
 Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBe Ag anti- HBe

Total anti- HBc

Titre

HBs Ag IgM anti- HBc anti- HBs

0 4 8 12 16 20 24 28 32 36 52 100 41

Weeks after Exposure

 PATHOGENESIS & IMMUNITY
• VIRUS ENTERS HEPATOCYTES VIA BLOOD
• IMMUNE RESPONSE (CYTOTOXIC T CELL) TO VIRAL ANTIGENS
EXPRESSED ON HEPATOCYTE CELL SURFACE RESPONSIBLE
FOR CLINICAL SYNDROME
• 5 % BECOME CHRONIC CARRIERS (HBSAG> 6 MONTHS)
• HIGHER RATE OF HEPATOCELLULAR CA IN CHRONIC
CARRIERS, ESPECIALLY THOSE WHO ARE “E” ANTIGEN
POSITIVE
• HEPATITIS B SURFACE ANTIBODY LIKELY CONFERS LIFELONG
IMMUNITY (IGG ANTI-HBS)
• HEPATITIS B E AB INDICATES LOW TRANSMISSIBILITY 42
 HBV – SEROLOGY INTERPRETATION

• ACUTE INFECTION
• HBSAG POSITIVE AND ANTI-
HBCAG IGM
• RARELY, IGM ANTI-HBC ONLY
MARKER
• USUALLY SEEN IN ACUTE
FULMINATE HEP B
• CHRONIC INFECTION
• HBSAG POSITIVE AND ANTI-
HBCAG
• PREVIOUS INFECTION
• HBSAG NEGATIVE
• ANTI-HBS POSITIVE
• IGG ANTI-HBC POSITIVE
CLINICAL OUTCOMES OF HEPATITIS B INFECTIONS

. Clinical outcomes of acute hepatitis B infection. (Redrawn from White DO, Fenner F: Medical virology, ed
3, New York, 1986, Academic Press

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,
DETERMINANTS OR ACUTE AND CHRONIC HBV INFECTION

Figure 66-7
From Murray et. al., Medical
Microbiology 5th edition, 2005,
Chapter 66, published by Mosby
Philadelphia,,
Possible Outcomes of HBV Infection
Acute hepatitis B infection

3-5% of adult- 95% of infant-

acquired infections acquired infections
Chronic HBV infection

Chronic hepatitis

12-25% in 5 years
Cirrhosis
6-15% in 5 years 20-23% in 5 years

Hepatocellular Liver failure

carcinoma 46

Death Liver transplant Death

DIAGNOSIS
 Serology
 Liver Chemistry tests
AST, ALT, ALP, and total Bilirubin

 Histology--Immunoperoxidase staining
 HBV Viral DNA--Most accurate marker of viral DNA
and detected by PCR
 Liver Biopsy--to determine grade(Inflammation) and
stage(Fibrosis) in chronic Hepatitis
 Serologic Events
1) HBsAg :- It is the first marker to appear in blood after infection.
2) Anti-HBs(HBsAb) :-Disappearance of HBsAg and the appearance
of anti-HBs signals recovery from HBV infection, non-infectivity.
3) Anti-HBc :- IgM anti-HBc appears shortly after HBsAg is detect
(HBcAg alone dose not appear in serum)
IgM-HBc may also or can persist for 3-6 months or longer.
IgG-HBc also appear during acute hepatitis B but persist
indefinitely.
4) HBeAg :-
 HBeAg appear in blood concurrently with HBsAg, or soon
afterwards.
 HBeAg is a soluble protein found only in HBeAg positive serum.
 HBeAg indicate viral replication and infectivity.
 Persistence of HBeAg in serum beyond 3 month indicate an
increased like hood of chronic hepatitis B.
 Symptoms
ALT


concentration

Anti-HBc
HBsAg

Anti-HBs

Anti-HBc Anti-HBe
HBeAg IgM

8 12 16 20 24 28 32 36 40 44 52

Weeks post infection

Interpretation of common serological patterns in HBV infection

Virus/Antibody markers
Interpretation
HBsAg HBeAg Anti-HBc Anti-HBs Anti-HBe

Acute HBV infection; highly infectious

+ + IgM - -

Late/Chronic HBV infection or carrier state;

+ + IgG - - highly infectivity

Late/Chronic HBV infection or carrier state;

+ - IgG - +/- low infectivity

Seen rarely in early acute HBV infection;

- +/- IgM - +/- infectious

Remote HBV infection; infectivity nil or very

- - IgG +/- +/- low

Immunity following HBV vaccine

- - - + -
 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.
Prevention

 VACCINATION
- HIGHLY EFFECTIVE RECOMBINANT VACCINES
 HEPATITIS B IMMUNOGLOBULIN (HBIG)
-EXPOSED WITHIN 48 HOURS OF THE INCIDENT/
NEONATES WHOSE MOTHERS ARE HBSAG AND HBEAG
POSITIVE.
 OTHER MEASURES
-SCREENING OF BLOOD DONORS, BLOOD AND BODY
FLUID PRECAUTIONS.
Treatment

 INTERFERON ALFA (INTRON A)

RESPONSE RATE IS 30 TO 40%.
 LAMIVUDINE (EPIVIR HBV)
(RELAPSE ,DRUG RESISTANCE)
 ADEFOVIR DIPIVOXIL (HEPSERA)