HEPATITIS VIRUSES

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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), Hepevirus

Hepatitis G (HGV) Flaviviridae (1995)

SEN (1997)

TT Anelloviridae, Anellovirus (2000)

http://mikrobiologia.sote.hu

HEPATITIS VIRUSES

Prof. Dr. Éva Ádám D.Sc.


Hepatitis: infectious liver disease of

various viral origin (symptoms: fatigue,

joint- and abdominal pain, malaise,

vomiting, lack of appetite, hepatomegaly)

Icterus: jaundice (skin, sclera, mucous membranes,

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

Prof. Dr. Éva Ádám D.Sc.

stool


HEPATITIS VIRUSES TRANSMITTED

FECAL ORAL ROUTE

Hepatitis A virus

Hepatitis E virus

Prof. Dr. Éva Ádám D.Sc.


CLASSIFICATION OF PICORNAVIRUSES

ENTEROVIRUS GENUS

POLIOVIRUS 1-3 1

Coxsackie viruses A1-A24 A1 A24 (type ( type 23: no)

B1-B6 B1 B6

Echoviruses 1-34 34 (types ( types 10 and 28: no)

Enteroviruses 68-71 68 71

Rhinoviruses 1-110 110

HEPATOVIRUS GENUS

HEPATITIS A VIRUS

APHTHOVIRUS GENUS

Prof. Dr. Éva Ádám D.Sc.

pH stable

pH sensitive


Prof. Dr. Éva Ádám D.Sc.


• faecal-oral transmission( hands, foods, water,

„frutta di mare”)

• Replication: hepatocytes (focal necrosis)

• Latency: rather short (10- 45 days)

• Asymptomatic, symptoms with or without icterus

• Icterus: > 6 years 10 %, < 14 years 70%, fever, malaise, vomiting,

• Hepatocyte lesion (low) → regeneration→ regeneration complete recovery

• Complications: rare

Prof. Dr. Éva Ádám D.Sc.


PREVALENCE OF HEPATITIS A VIRUS

(ANTIBODIES)

Prof. Dr. Éva Ádám D.Sc.


Diagnosis: HAV specific IgM, or antigen detection, IEM (virus in

stool)

Prof. Dr. Éva Ádám D.Sc.


PREVENTION and CONTROL

• Endemic areas: boiled drinking water, avoid raw

shellfish, vegetables

• Hand disinfection

• Vaccination of seronegative persons (suggested for

people traveling to infected areas, after disasters

/flood disaster/ inactivated virus i.m.)

• Passive immunization (HAIG):

contacts of sick patients

Prof. Dr. Éva Ádám D.Sc.


Hepeviridae,

Hepevirus genus

33 nm, icosahedral,

(ss + RNA, genome:

similar to rubella virus

(Togaviridae)

Hepatitis E virus

• Fecal-oral transmission (water!) great epidemics (China, India),

heat and acid stable, zoonosis! (pig 1997, dog, chicken, rat), very

rarely: transfusion

• Latency: 15-60 days

• Symptoms as in the case of HAV (mild disease, no chronic

disease or chronic carrier state) self-limiting

• Europe: sporadic only

• Complications: in pregnant woman 25% with high mortality!!!

(DIC)

Prof. Dr. Éva Ádám D.Sc.


HEPATITIS E VIRUS INFECTION: DIAGNOSIS

• anti-HEV Ig ELISA

Control: for pregnant woman HEIG (antibody) in the endemic areas,

vaccine (recombinant Baculovirus, clinical phase 2, USA, Nepal)

Prof. Dr. Éva Ádám D.Sc.


PREVALENCE OF HEPATITIS E VIRUS

Prof. Dr. Éva Ádám D.Sc.


PARENTERALLY TRANSMITTED

HEPATITIS VIRUSES

Hepatitis B virus

Hepatitis C virus

Hepatitis D virus

Hepatitis G virus

Prof. Dr. Éva Ádám D.Sc.


HEPATITIS B VIRUS (HBV)

HEPADNA VIRIDAE

ORTHOHEPADNAVIRUS

AVIHEPADNAVIRUS

Prof. Dr. Éva Ádám D.Sc.


VIRION: cubical, peplon

Dane particle, 42 nm infectious

Au-antigen (HBsAg),

antigen determinants:

a: group specific,

subdeterminants: d/y and w/r:

(adw, ayw, adr, ayr fenotypes)

22 nm HBc and HBe antigens

(core)

NUCLEIC ACID: partially ds DNA,

circular (longer chain +, shorter

chain -), special polymerase

B. Blumberg

(1976. Nobel Prize)

Prof. Dr. Éva Ádám D.Sc.


TRANSMISSION OF HBV

• Parenteral: i.v. drug users, accidental pricking, health-care workers

• Hemodialysis

• Perinatal (HBeAg positive mothers)

• Sexual: sex workers

• High virus concentration: blood, serum, wounds exudate

• Moderate virus concentration: semen, vaginal fluid, saliva

• HBV survives on surfaces min. 1 week

****

Latency: 45-180 days

Icterus (jaundice): < 5 years 30-50

Acute death (fulminant hepatitis): 0,5- 1 %

Chronic infection: > 5 years 30-90% , < 5 years 2-10%

Chronic persistant hepatitis: asymptomatic

Chronic active hepatitis: symptomatic

Prof. Dr. Éva Ádám D.Sc.


Adults and elderly children: 90-99%

Newborn babies and children: 5-20%

POSSIBLE OUTCOMES

Adults and elderly children : 1-10% 1 10%

Newborn babies and children: : 80-95 80 95 %

ACUTE INFECTION CHRONIC INFECTION

Subclinical

Fulminant

hepatitis

Hepatitis with icterus (adults)

Cirrhosis

Extrahepatic: arthritis,

polyarthritis, glomerulonephritis

Asymptomatic Chronic persistent

hepatitis

Chronic active hepatitis

Hepatocellular

carcinoma

Prof. Dr. Éva Ádám D.Sc.

ascites in the abdomen


Outcome of HBV

infection:

dependent on the

immune function

Newborn babies:

immatured immune system

(T cytotoxic system),

antibodies from the mother

induce ADCC (Antibody

Dependent Cellular

Cytotoxicity) reaction

Adults: steroid treatment

(decrease of T cytotoxic

activity), AIDS: no T-helper

cells

Prof. Dr. Éva Ádám D.Sc.


ACUTE HEPATITIS B VIRUS

INFECTION

Jaundice

HBsAg

HBeAg

ALT

Anti-HBc

0 1 2 3 4 5 6 12 24 month

Markers: antigens (HBsAg, HBeAg),

antibodies (anti-HBs, -HBc, -HBe)

Prof. Dr. Éva Ádám D.Sc.

Anti -HBs

Anti-HBe


CHRONIC HEPATITIS B VIRUS

INFECTION

symptoms

HBeAg

HBsAg

1 2 3 4 5 6 months 2 4 6 8 10 years

Chronic hepatitis B virus infection: HBsAg, anti-HBc

Prof. Dr. Éva Ádám D.Sc.

Anti-HBc

Anti-HBe

Chronic active hepatitis B: HBeAg, HBV polymerase, Dane particle,

anti-HBe


SURVIVAL IN CHRONIC HEPATITIS B

VIRUS INFECTION

80

60

40

20

Rate of survival %100

Outcome is dependent on

period of virus replication,

severity of liver cell destruction

(alcohol, drugs), HDV infection

5 10 15 20 years

Prof. Dr. Éva Ádám D.Sc.

Chronic persistant

hepatitis

Chronic active

hepatitis

Chronic active

hepatitis with

cirrhosis

HBV carriers: about 300 millions (40 %

cirrhosis, carcinoma), 6 millions death/year,

120 millions babies/year (chronic carrier

state)


PREVALENCE OF HBV SURFACE ANTIGEN (HBsAg)

Prof. Dr. Éva Ádám D.Sc.


CONTROL

HBsAg produced by recombinant DNA technology

Obligatory in age group 14 and for newborn

babies of HBsAg positive mothers (Hungary)

Preexposure/postexposure vaccination

Priority candidates for Hepatitis B Vaccine

newborn babies of HBsAg positive mothers

sexual and close household contacts of HBV carriers

needle-stick injuries from HBV carriers

parenteral drug abusers

homosexually active men

heterosexually promiscuous persons (prostitutes)

hemophiliacs, hemodialysis patients

health care and public safety workers potentially

exposed to human blood

immuno-suppressed or cancer patients

Combined vaccine: TWINRIX (HAV+HBV)

Prof. Dr. Éva Ádám D.Sc.


HEPATITIS D VIRUS

(HDV, DELTA AGENT)

VIRION: spherical, 36-38 nm,

HBV capsid, HDV nucleoprotein

NUCLEIC ACID: (-) ss RNA, circular

Satellite virus : replicates only

in the presence of HBV

Prof. Dr. Éva Ádám D.Sc.


Prof. Dr. Éva Ádám D.Sc.


COINFECTION or SUPERINFECTION

ALT

Anti-HBs

Anti-HDV IgG

Anti HDV IgM

HBsAg

HDV RNA

Prof. Dr. Éva Ádám D.Sc.

ALT

Anti-

HDV

IgG

Anti HDV IgM


HEPATITIS C VIRUS (HCV ( )

FLAVIVIRIDAE

Hepacivirus genus

Prof. Dr. Éva Ádám D.Sc.


VIRION: spherical, icosahedral,

NUCLEIC ACID: ss (+) RNA

Prof. Dr. Éva Ádám D.Sc.


• virus previously identified as NANB virus (50 % of isolates are

HCV (posttransfusional hepatitis)

• diseases are mainly subclinical, about in one half of the cases chronic

hepatitis develops ( cirrhosis)

• HCV infection is major risk factor for the development of hepatocellular

carcinoma /HCC/ (anti -HCV in the serum or HCV RNA is detectable)

• in southern Europe and Japan: 50-75 % of patients with HCC have

evidence for HCV infection

• precise mechanism is unknonw (inflammation, chronic hepatitis, cirrhosis)

Prof. Dr. Éva Ádám D.Sc.


Comparison of

HBV and HCV

transmission

Prof. Dr. Éva Ádám D.Sc.


OUTCOMES of HCV hepatitis

Prof. Dr. Éva Ádám D.Sc.


15-30%

recovery

Acute HCV infection

70-85 %

Prof. Dr. Éva Ádám D.Sc.

Chronic disease

chronic hepatitis C

mild moderate severe

Hepatocellular

carcinoma

DEATH

cirrhosis

Very severe liver disease

Liver transplantation


Serologic Pattern of Acute HCV Infection

with Recovery

Titer

Symptoms +/-

HCV RNA

Normal

ALT

0 1 2 3 4 5 6 1 2 3 4

Years

Months

Prof. Dr. Éva Ádám D.Sc.

anti-HCV


Serologic Pattern of Acute HCV Infection

with Progression to Chronic Infection

Titer

Symptoms +/-

HCV RNA

Normal

0 1 2 3 4 5 6 1 2 3 4

Years

Months

Prof. Dr. Éva Ádám D.Sc.

anti-HCV

ALT


Diagnosis

• anti-HCV Ig (ELISA, Western blot)

• HCV core ag (ELISA)

• HCV RNA detection (RT-PCR), in

acute phase and in monitoring the

response of therapy

• 4-6 weeks “Windows” period

Prof. Dr. Éva Ádám D.Sc.


HCV PREVALENCE IN BLOOD DONORS

Prof. Dr. Éva Ádám D.Sc.


THERAPY

• interferon

• ribavirin

• liver transplantation

PREVENTION

• donor screening

• change the behavior of risk groups

• safe handling of body fluids ( blood, serum)

• future: recombinant vaccine under development (human clinical

trial)

Prof. Dr. Éva Ádám D.Sc.


others

unknown

alcohol

Prof. Dr. Éva Ádám D.Sc.

HBV and alcohol

HCV and alcohol

Cause of severe destruction of liver cells (chronic

hepatitis)


HEPATITIS G VÍRUS

FLAVIRUS: similar morphology and genom

◊ in risk groups: acute, chronic and fulminant hepatis

◊ transmission: blood (mother- newborn babies)

◊ prevalence is higher in HCV infected people

Prof. Dr. Éva Ádám D.Sc.


TT VIRUS

- 1997. Japan (Torque Teno, TT virus, Torque Teno Minivirus,

TTMV)

- circular ss DNA, naked, from 40 genotypes 2 are causative

agents of hepatitis, supposed taxonomy: Anelloviridae,

genus Anellovirus)

- presence: serum, stool, liver cells replication (spreading:

enteral and parenteral

SEN VIRUS

- 2000 Italy (in hepatitis with unknown origin)

- the genom is similar to TT virus genom, 8 genotypes

Prof. Dr. Éva Ádám D.Sc.

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