VIRAL HEPATITIS

A,B,C,D,E G .. ,B,C,
Dr.T.V.Rao MD

What Is Hepatitis?
 The word "hepatitis" means inflammation of the "hepatitis"
liver. liver. Toxins, certain drugs, some diseases, heavy alcohol use, bacterial and viral infections can all cause hepatitis. Hepatitis is also the name of a family of viral infections that affect the liver; the most common types in the United States are hepatitis A, hepatitis B, and hepatitis C.

Hepatitis
 Hepatitis (plural hepatitides) implies hepatitides)
injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar or hepato, meaning hepato, liver, liver, and suffix -itis, meaning itis, "inflammation" (c. 1727)

Viral Hepatitis
viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections.  Common viruses cause hepatitis include A,B,C,D,E. G .  Acute hepatitis  Viral Hepatitis: Hepatitis A through E (more than simplex, 95% of viral cause), Herpes simplex, Cytomegalovirus, Epstein-Barr, Cytomegalovirus, Epstein-Barr, yellow fever virus, adenoviruses. virus, adenoviruses.

 A group of viruses known as the hepatitis

Viral Hepatitis - Historical Perspectives

Infectious Viral hepatitis

A
NANB

Enterically E transmitted

Serum

B D

Parenteraly C transmitted F, G, TTV ? other

Type of Hepatitis
A
Source of virus feces

E
feces

blood/ blood/ blood/ blood-derived blood-derived blood-derived body fluids body fluids body fluids percutaneous percutaneous percutaneous permucosal permucosal permucosal yes yes yes

Route of transmission Chronic infection Prevention

fecal-oral

fecal-oral

no

no

pre/postexposure immunization

pre/postblood donor pre/postexposure screening; exposure immunization risk behavior immunization; modification risk behavior modification

ensure safe drinking water

Hepatitis A
 Hepatitis A is an acute liver disease
caused by the hepatitis A virus (HAV), lasting from a few weeks to several months. It does not lead to chronic infection.

Hepatitis A Virus

Hepatitis A Virus
 Naked RNA virus  Related to enteroviruses, formerly known as
enterovirus 72, now put in its own family: 72, family: heptovirus  One stable serotype only  Difficult to grow in cell culture: primary culture: marmoset cell culture and also in vivo in chimpanzees and marmosets  4 genotypes exist, but in practice most of them are group 1

Nature of HAV virus

 HAV is a 27 30 nm
spherical particle with cubic symmetry  Contain linear single stranded RNA genome with size of 7.5 kb.  Only one serotype

HAV characters
 HAV are stable to treatment with 20% ether,acid
and heat at 600c for 1 hour.  The virus are destroyed by autoclaving at 1210c for 20 minutes, boiling in water for 5 minutes  Treatment with chlorine 1 ppm for 30 minutes  Heating food > 850c for 1 minute destroys

Culturing HAV virus

 Various primate cell lines will support

grwoth of HAV,though fresh isolates of virus are difficult to adapt and grow.  Usually to cytopathic effects are apparent

Pathology in Viral Hepatitis

 Indicates inflamation of liver.  Microscopically there is spotty parenchymal cell
degeneration, with necrosis of Hepatocytes, with disruption of liver cell cords  The parenchymal changes are accompanied by Reticuloendothelial ( KUFFER) cell hyperplasia,periportal infiltration by monoculear cells and cell degeneration.

Causes liver damage

 Localised areas of necrosis are frequently
observed

 Later accumulation of macrophages near

degenerating Hepatocytes

Transmission Of Hepatitis A
: Ingestion of food or water contaminated with faecal matter, Even in microscopic amounts, From close person-toperson-to-person

Hepatitis A Virus Transmission

 Close personal contact
(e.g., household contact, child day care centers)

 Contaminated food, water

(e.g., infected food handlers, raw shellfish)

 Blood exposure (rare)

(e.g., injecting drug use, transfusion) Not transmitted by Transplacental route

Global Patterns of Hepatitis A Virus Transmission

Disease Peak Age Endemicity Rate of Infection High Moderate Low to High High Early childhood Late childhood/ young adults Young adults Transmission Patterns Person to person; outbreaks uncommon Person to person; food and waterborne outbreaks Person to person; food and waterborne outbreaks Travelers; outbreaks uncommon

Low

Low

Very low

Very low

Adults

Clinical Manifestations
 Incubation period 2 6 weeks  May be asymptomatic  Overt illness in 5%  Present as two stages,
1 Preicteric 2 Icteric

Clinical features
 Malaise  Anorexia  Nausea, omitting liver tenderness  Onset of Jaundice  Recovery in 4-6 weeks 4 Mortality 0.1 1 %

Hepatitis A - Clinical Complications



Complications:

Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis None

Chronic sequelae:

Laboratory Diagnosis
 Acute infection is diagnosed by the detection of HAV-IgM HAVin serum by EIA. EIA.

 Past Infection i.e. immunity is determined by the detection

of HAV-IgG by EIA. HAVEIA. routinely performed

 Cell culture difficult and take up to 4 weeks, not  Direct Detection EM, RT-PCR of faeces. Can RTfaeces. detect illness earlier than serology but rarely performed. performed.

Hepatitis A Infection
Typical Serological Course
Symptoms

Total antiHAV

Titer

ALT

Fecal HAV

IgM anti-HAV

Months after exposure

1 2

2 4

Treatment
 No specific antiviral drug is available  Treatment is symptomatic  Specific passive prophylaxis by pooled

normal human immunoglobulin given before exposure or in early incubation period can prevent or attenuate clinical illness.

Hepatitis A Vaccination Strategies Epidemiologic Considerations

 Many cases occur in community-wide community-

outbreaks  no risk factor identified for most cases  highest attack rates in 5-14 year olds 5 children serve as reservoir of infection
 travelers  homosexual men  injecting drug users

 Persons at increased risk of infection

Vaccination for HAV

children starting at age 1 year, travellers to certain countries, and others at risk.  A safe and effective formalin inactivated alum conjugated vaccine containing HAV grown in human diploid cell culture is available  A full course containing two intramuscular injections of the vaccine  Protection starts after 4 weeks after injection and lasts for 10 20 years

 Hepatitis A vaccination is recommended for all

Hepatitis A Vaccination Strategies Epidemiologic Considerations

 Many cases occur in community-wide community-

outbreaks  no risk factor identified for most cases  highest attack rates in 5-14 year olds 5 children serve as reservoir of infection
 travelers  homosexual men  injecting drug users

 Persons at increased risk of infection

Epidemiology
 A major communicable disease in the
Devloping world. world.  Well cooked food and sanitary water supply will protect the individual living  Community hygiene is important in schools, hostels and jails, as overcrowding and poor sanitation favour the spread

Prevention of Hepatitis A Infection

 Pre-exposure Pre travelers to intermediate HAVHAV-endemic regions and high

 Post-exposure (within 14 days) PostRoutine  household and other intimate contacts Selected situations  institutions (e.g., day care centers)  common source exposure (e.g., food prepared by infected food handler)

Hepatitis B Infection

Most Important Infectious Disease

 There are more than 350 million carriers  25% of them will develop chronic active

hepatitis.  World wide 1 million deaths a years are attributed to HBV related liver disease and Hepatocellular Carcinoma

Hepatitis B
 Hepatitis B is a liver disease caused by the
hepatitis B virus (HBV). It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term long(chronic) illness that can lead to liver disease or liver cancer.

Hepatitis B Virus
 Blumberg in 1965
discovers, names as Australia antigen.  1968 identified with association in serum hepatitis.  Surface component of HBV called as surface antigen.

HBV Viruses Under Electron Microscope

diameter  Filamentous or tubular 22 nm with varying length  Called as HBs Ag surface components which are produced in excess.  Third type double walled spherical structure 42 nm diameter called HBV

 Spherical particles 22 nm in

 Called as Dane
particle

HBV Surface antigens

 Enveloped proteins on
surface of virions and surplus 22 nm diameter spherical and filamentous particles constitute the B surface antigens  HBs Ag consists two major polypeptides and is glycolated

Structure 0f Hepatitis B virus

HBV shows antigenic diversity

 HBV shows antigenic diversity, two different
antigenic components and common group reactive antigen a  Two contain specific antigens dy wr Only one member of each pair being present at a time Divided into four Major antigenic subtypes adw, adr, ayw, and ayr

Geographic distribution
 ayw common in Europe,Australia,and     
America. adr - Prevalent in south, East India and Far east, ayr - very rare Core antigen HB c ag Be HBe is a soluble non particle nucelocapsid protein Both Hbc and Hbe are coded by same genes

Replication
 The RNA dependent DNA synthesis takes
place within the newly assembled Virion core in the cytoplasam.  Hepadnaviruses the only virus that produce genome DNA by reverse transcription with mRNA as the template

Pathogenesis of HBV infection

    
Disease is Immune mediated Hepatocytes carry viral antigen Immune response subject to antibody dependent. N K cell and cytotoxic T cell attack In the absence of adequate immune response HBV infection may not cause hepatitis.  But lead to carrier state.  Infection Immunodeficient person are likely to because asymptomatic carrier followed infection

Hepatitis B - Clinical Features

 Incubation period:  Clinical illness (jaundice):  Acute case-fatality rate:  Chronic infection:  Premature mortality from chronic liver disease: Average 60-90 days Range 45-180 days <5 yrs, <10% 5 yrs, 30%-50% 0.5%-1% <5 yrs, 30%-90% 5 yrs, 2%-10% 15%-25%

What are the clinical symptoms of Hepatitis B??

Spectrum of Chronic Hepatitis B Diseases

1 Chronic Persistent asymptomatic Hepatitis -

2. Chronic Active Hepatitis symptomatic exacerbations of hepatitis 3. Cirrhosis of Liver 4. Hepatocellular Carcinoma

Acute Hepatitis B Virus Infection with Recovery

Typical Serologic Course

Symptoms HBeAg anti-HBe

Total anti-HBc

Titre
HBsAg IgM anti-HBc anti-HBs

12 16 20 24 28 32 36

52

100

Weeks after Exposure

Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course

Acute (6 months) HBeAg HBsAg Total anti-HBc Chronic (Years) anti-HBe

Titre

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Years

Weeks after Exposure

Global Patterns of Chronic HBV Infection

 High (>8%): 45% of global population
 lifetime risk of infection >60%  early childhood infections common

 Intermediate (2%-7%): 43% of global population (2% lifetime risk of infection 20%-60% 20% infections occur in all age groups

 Low (<2%): 12% of global population

 lifetime risk of infection <20%  most infections occur in adult risk groups

Concentration of Hepatitis B Virus in Various Body Fluids

High blood serum wound exudates Moderate semen vaginal fluid saliva Low/Not Detectable urine feces sweat tears breastmilk

How Hepatitis B is transmitted

Contact with infectious blood, semen, and other body fluids from having sex with an infected person, sharing contaminated needles to inject drugs, or from an infected mother to her newborn.

Hepatitis B Virus Modes of Transmission

 Sexual - sex workers and homosexuals are particular at risk.  Parenteral - IVDA, Health Workers are at increased risk.  Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations.

Diagnosis
 A battery of serological tests are used for the diagnosis of       
acute and chronic hepatitis B infection. infection. HBsAg - used as a general marker of infection. infection. HBsAb - used to document recovery and/or immunity to HBV infection. infection. antianti-HBc IgM - marker of acute infection. infection. antianti-HBcIgG - past or chronic infection. infection. HBeAg - indicates active replication of virus and therefore infectiveness. infectiveness. AntiAnti-Hbe - virus no longer replicating. However, the replicating. patient can still be positive for HBsAg which is made by integrated HBV. HBV. HBVHBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. mutants. Used mainly for monitoring response to therapy. therapy.

Treatment
 Patients with Hepatitis needs supportive
treatment  Recombinant Interferon alfa therpay is beneficial in HBV and HCV

Treatment
hepatitis.  Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. 40%  alpha-interferon 2b (original) alpha alpha-interferon 2a (newer, claims to be more efficacious and alphaefficient)

 Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. inhibitor.

Well tolerated, most patients will respond favorably. However, favorably. tendency to relapse on cessation of treatment. Another problem is the treatment. rapid emergence of drug resistance. resistance.

 Adefovir less likely to develop resistance than Lamivudine and may

be used to treat Lamivudine resistance HBV. However more expensive HBV. and toxic

 Entecavir most powerful antiviral known, similar to Adefovir  Successful response to treatment will result in the disappearance of
HBsAg, HBV-DNA, and seroconversion to HBeAg. HBVHBeAg.

High Risk Individuals

 Medical and Dental surgeons  Pathologists  Physicians  Laboratory technicians  Blood bank personnel

HBV is common in
 Patients undergoing Dialysis  Staff of Hem dialysis Units

Vaccination Genetically Engineered

 Vaccination
highly effective recombinant vaccines are now available. available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given workers. routinely to neonates as universal vaccination in many countries. countries.

Hepatitis B Immunoglobulin
 Hepatitis B Immunoglobulin - HBIG may be
used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive

Blood screening is Mandatory

 Other measures screening of blood donors, blood and body fluid precautions is mandatory in majority of Countreis

Universal Precautions
 Universal precautions," as defined by
CDC, are a set of precautions designed to prevent transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and other blood borne pathogens when providing first aid or health care.

Universal Precautions
 Under universal precautions, blood and
certain body fluids of all patients are considered potentially infectious for HIV, HBV and other blood borne pathogens.

Hand washing Minimal health precaution to Medical and Paramedical staff

Hepatitis C Infection
Hepatitis C Virus
Non A, non B Hepaci virus

What is Hepatitis C Virus

 Hepatitis C virus also known as Non A or
Non B virus found while doing experiments on Chimpanzees.  HCV infections are seen only in humans  The epidemiology is like HBV infection.

HCV Virology
 The virus is not been
grown in culture  The virus is 50- 60 nm 50with linear single stranded RNA genome surrounded by an enveloped carrying glycoprotein spikes  Now classified as Hepacivirus in the family of Flaviviridae  Six genotypes are identified, with high mutability

Hepatitis C Virus
capsid envelop e protein c22 5 cor E1 e E2 NS 2 NS 3 NS 4 NS 5 protease/helica se 33c c-100 3 RNA- RNA polymerase dependent

hypervariable region

Hepatitis C Virus
Genome resembled that of a flavivirus
positive stranded RNA genome of around 10, 10,000 bases

1 single reading frame, structural genes at

the 5' end, the non-structural genes at the 3' nonend. end. enveloped virus, virion thought to 30-60nm 30-60nm in diameter

 Morphological structure remains unknown

Hepatitis C virus
Genotype 1 and 4 has a poorer
prognosis and response to interferon therapy,

In Hong Kong, genotype 1 accounts

for around 67% of cases and genotype 67% 6 around 25%. 25% Now 6 genotypes are identified. identified.

Terminology
Family Genus Species Genotype Subtype Quasispecies

Term

Definition

% Nucleotide Similarity 65.7-68.9

Genotype

Genetic heterogeneity among different HCV isolates Closely related isolates within each of the major genotypes Complex of genetic variants within individual isolates

Subtype

76.9-80.1

Quasispecies

90.8-99

Pathogenesis

Hepatitis C - Clinical Features

Incubation period: Clinical illness (jaundice): Chronic hepatitis: Persistent infection: Immunity: Average 6-7 wks Range 2-26 wks 30-40% (20-30%) 70% 85-100% No protective antibody response identified

How HCV transmitted

 Blood transfusions  Transplantation of organs  Injectable drug abusers  Immunocompromised  Sexual transmission ?  Less important  Vertical transmission is possible

Clinical features
 Overt Jaundice is seen in 5% of patients  About 50 80% patients progress to
chronic hepatitis  May progress to Cirrhosis, or Hepatocellular carcinoma

Chronic Hepatitis C Infection

 The spectrum of chronic hepatitis C infection is
essentially the same as chronic hepatitis B infection. infection.

 All the manifestations of chronic hepatitis B

infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma.

Transmission of HCV
 Percutaneous
 IV drugs  Clotting factors before viral inactivation  Transfusion, transplant from infected donor  Therapeutic (contaminated equipment, unsafe injection practices)  Occupational (needle stick)  Per mucosal  Perinatal  Sexual

HCV - Occupational Transmission

 Inefficiently transmitted  Average incidence 1.8% following      

needle stick from HCV-positive source HCV10 times lower than HBV infection HollowHollow-bore needles Case reports from blood splash to eye No reports from skin exposures to blood Prevalence 1-2% among health care 1workers Lower than in the general population

Risk Factors Associated with Transmission of HCV

 Transfusion or transplant from infected donor  Injecting drug use  Hemodialysis (yrs on treatment)  Accidental injuries with needles/sharps  Sexual/household exposure to anti-HCV-positive contact  Multiple sex partners

Hepatitis C Virus Infection

Typical Serologic Course
Symptoms

antiHCV

Titre

ALT

Normal 0 1 2 3 4 5 6 Month s Time after 1 2 3 Years 4

Exposure

Laboratory Diagnosis
 HCV antibody - generally used to diagnose
hepatitis C infection. Not useful in the acute infection. phase as it takes at least 4 weeks after infection before antibody appears. appears.

 ELISA test results to be confirmed with

Immunoblotting assay

Molecular Methods in Diagnosis

 HCV-RNA - various techniques are available e.g. HCVPCR and branched DNA. May be used to diagnose DNA. HCV infection in the acute phase. However, its main phase. use is in monitoring the response to antiviral therapy. therapy.

 HCV-antigen - an EIA for HCV antigen is available. HCVavailable.

It is used in the same capacity as HCV-RNA tests but HCVis much easier to carry out. out.

Prognostic Tests
 Genotyping genotype 1 and 4 have a worse prognosis overall and
respond poorly to interferon therapy. A number of commercial and therapy. in-house assays are available. inavailable.
 Genotypic methods DNA sequencing, PCR-hybridization e.g. INNOPCRINNOLIPA. LIPA.  Serotyping particularly useful when the patient does not have detectable RNA. RNA.

 Viral Load patients with high viral load are thought to have a
poorer prognosis. Viral load is also used for monitoring response to prognosis. IFN therapy. A number of commercial and in-house tests are therapy. inavailable. available.

HCV Treatment

 -Interferon  Ribavirin  Effective in about 50% of cases  No vaccine

Treatment
 Interferon - may be considered for patients
with chronic active hepatitis. The response hepatitis. rate is around 50% but 50% of responders 50% 50% will relapse upon withdrawal of treatment. treatment.

 Ribavirin - there is less experience with

ribavirin than interferon. However, recent interferon. studies suggest that a combination of interferon and ribavirin is more effective than interferon alone. alone.

Prevention of Hepatitis C
 Screening of blood, organ, tissue donors  High-risk behavior modification  Blood and body fluid precautions

Hepatitis D
Delta agent

Hepatitis D Virus
 The delta agent is a defective virus which
shows similarities with the viroids in plants.  The agent consists of a particle 35 nm in diameter consisting of the delta antigen surrounded by an outer coat of HBsAg.  The genome of the virus is very small and consists of a single-stranded RNA single-

Hepatitis D - Clinical Features

 Coinfection severe acute disease. low risk of chronic infection.  Superinfection usually develop chronic HDV infection. high risk of severe chronic liver disease. may present as an acute hepatitis.

Hepatitis D Virus Modes of Transmission

 Percutanous exposures  injecting drug use  Permucosal exposures  sex contact

HBV - HDV Coinfection

Typical Serologic Course
Symptoms ALT Elevated

Titre
IgM anti-HDV

anti-HBs

HDV RNA HBsAg Total anti-HDV

Time after Exposure

HBV - HDV Coinfection

Typical Serologic Course
Symptoms ALT Elevated

Titre
IgM anti-HDV

anti-HBs

HDV RNA HBsAg Total anti-HDV

Time after Exposure

HBV - HDV Superinfection

Typical Serologic Course
Jaundice Symptoms ALT Total anti-HDV

Titre

HDV RNA HBsAg IgM anti-HDV

Time after Exposure

Hepatitis D - Prevention


HBV-HDV Coinfection Pre or postexposure prophylaxis to prevent HBV infection.

HBV-HDV Superinfection Education to reduce risk behaviors among persons with chronic HBV infection.

Hepatitis E infection
NANB

Hepatitis E Virus
 Calicivirus-like viruses Calicivirus unenveloped RNA virus, 32-34 nm in 32diameter  +ve stranded RNA genome, 7.6 kb in size.  very labile and sensitive  Can only be cultured recently

Hepatitis E Virus

Hepatitis E - Clinical Features



Incubation period: Case-fatality rate:

 

Illness severity: Chronic sequelae:

Average 40 days Range 15-60 days Overall, 1%-3% Pregnant women, 15%-25% Increased with age None identified

Hepatitis E Virus Infection

Typical Serologic Course Symptoms
ALT IgG anti-HEV

Titer
Virus in stool

IgM anti-HEV

1 0

1 1

1 2

1 3

Weeks after Exposure

Hepatitis E Epidemiologic Features



Most outbreaks associated with faecally contaminated drinking water. Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico. In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown. Minimal person-to-person transmission.

Prevention and Control Measures for Travelers to HEV-Endemic Regions



Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler. IG prepared from donors in Western countries does not prevent infection. Unknown efficacy of IG prepared from donors in endemic areas. Vaccine?

Hepatitis G virus
    
A new virus recently identified in Humans. Not grown in culture lines RNA genome is cloned Its role still for debate HGV RNA was found in acute, chronic, fulminant hepatitis , hemophiliacs, patients with multiple transfusions  It resembles HCV In all other aspects

Protect yourself
Medical and Paramedical staff can reduce, avoid the incidences of accidental infection with HBV,HCV,HDV,and Hepatitis G infections with, safe handling of needles

Prevent needle stick injuries

Report your needle stick injuries to higher authorities

Created for benefit of Medical and Paramedical Students in Developing World

Dr.T.V.Rao MD Email [email protected]