Hepatitis A-E Viruses

An Overview

Hepatitis
Hepatitis (plural hepatitides) is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The condition can be self-limiting (healing on its own) or can progress to fibrosis.

 Hepatitis are some time caused by viruses. The viruses involved, five of which have been reasonably well characterized, come from a wide range of virus families. Hepatitis A virus is a picornavirus, a small single strand RNA virus; hepatitis B virus belongs to the hepadnavirus family of double stranded DNA viruses; hepatitis C virus is a flavivirus, a single stand RNA virus; hepatitis E, also an RNA virus, is similar to a calicivirus.

Symptoms
Hepatitis may occur with limited or no symptoms, but often leads to jaundice, anorexia (poor appetite) and malaise. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort.

Diagnosis
Diagnosis can be made using various biochemical markers of hepatitis in conjunction with an assessment of the patient's medical history and a physical examination.

Viral Hepatitis - Historical Perspectives

Infectious

A
NANB

Enterically E transmitted

Viral hepatitis

Serum

B D

Parenterally C transmitted

parenterally
Not through the alimentary canal but rather by injection through some other route, as subcutaneous,intramuscular, intraorbital, in tracapsular, intraspinal, intrasternal, intravenous, etc. Origin: Gr. Enteron = intestine

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

Route of transmission

fecal-oral

fecal-oral

Chronic infection
Prevention

no

yes

yes

yes

no

pre/postexposure immunization

pre/postexposure immunization

blood donor pre/postscreening; exposure risk behavior immunization; modification risk behavior modification

ensure safe drinking water

Hepatitis A Virus

HEPATITIS A VIRUS
Hepatitis A virus belongs to picornavirus group. Picornaviruses have a single strand, 3polyadenylated, positive sense RNA genome surrounded by a naked (unenveloped) icosahedral capsid that is around 28 nm in diameter. There is only one serotype of HAV.

Replication

The virus binds to a receptor that is found on the surface of hepatocytes and a few other cells. The virus spends its entire life in the cytoplasm where it replicates using a virusencoded RNA-dependent RNA polymerase.

Hepatitis A - Clinical Features

Incubation period:
Complications: Chronic stage:

Average 30 days
Relapsing hepatitis None

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)

Global Patterns of Hepatitis A Virus Transmission

Disease Peak Age Endemicity Rate of Infection
High Low to High Early childhood Transmission Patterns Person to person; outbreaks uncommon

Moderate

High

Late childhood/ young adults

Young adults

Person to person; food and waterborne outbreaks

Person to person; food and waterborne outbreaks Travelers; outbreaks uncommon

Low

Low

Very low

Very low

Adults

Laboratory Diagnosis
Acute infection is diagnosed by the detection of HAV-IgM in serum by ELISA.

Past Infection i.e. immunity is determined by the detection of HAV-IgG by ELISA.

Prevention and Treatment of Hepatitis A virus

Hepatitis A can be prevented by vaccination, good hygiene and sanitation There are two types of vaccines: one type contains inactivated Hepatitis A virus, the other contains a live but attenuated virus. Both types stimulate active immunity against a future infection.

 There is a combined anti-HAV/HBV vaccine approved in the United States for recipients of 18 years and older. It contains Hepatitis A antigen and HBsAg. In other countries, this vaccine is available for children.

Hepatitis B Virus

HEPATITIS B VIRUS
Human hepatitis B virus is the prototype virus of the hepadnavirus family and causes serum hepatitis. HBV has a diameter of about 40nm. It infects humans and chimpanzees but there are closely related members of this family that infect other mammals and birds. HBV is a DNA virus and is enveloped. The DNA is only partly double stranded and forms a circle of around 3,200 bases.

Replication

HBV has a very curious way of replicating itself since , although it is a DNA virus, it uses a RNA proviral intermediate that has to be copied back to DNA.

Hepatitis B - Clinical Features

Incubation period:
Clinical illness (jaundice):

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%

Acute case-fatality rate: Chronic infection:

Premature mortality from chronic liver disease:

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

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. HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV infection.

Treatment
Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%.
Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.

Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

 Supportive care is the major treatment. AntiHBV immune globulin is effective soon after exposure. It can also be given neonatally to children of HBsAg-positive mothers. Ideally, the immune globulin should be administered within 24 hours of birth or exposure and is probably not effective after one week from exposure.

Prevention
Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.
There are normally three vaccinations for children (birth, 1 and 6 months) or adults to provide protective immunity. The vaccine is recommended for children up to 18 years and for adults at high risk. Other measures - screening of blood donors, blood and body fluid precautions.

Carcinogenesis
Individuals who are HBsAg positive are at a much higher risk of hepatocellular carcinoma than those who are negative. In patients with chronic hepatitis, there is destruction of hepatocytes as a result of the immune response to the virus. This results in regeneration (by cell division) of liver cells that may ultimately cause the cancer.

 Hepatitis C is a flavivirus (of which yellow fever is the prototype) that causes non-A, non-B hepatitis. Flaviviruses are icosahedral, positive strand RNA viruses and gain an envelope from their host cell. The virus particle is about 30 to 60nm across. The genome of 9,600 bases codes for ten proteins. In many ways, the flaviviruses are similar to picornaviruses with the prominent exception that they are enveloped.

Hepatitis C Virus
capsid envelop e protein c22 protease/helica se 33c c-100 RNA- RNA polymerase dependent

5
cor E1 e E2 NS 2 NS 3 NS 4 NS 5

hypervariable region

 There is one protein product from one open reading frame. The hepatitis C virus polyprotein is cleaved by both a virallyencoded protease activity and a cellular protease.

Hepatitis C - Clinical Features

Incubation period:
Clinical illness (jaundice):

Average 6-7 wks Range 2-26 wks 30-40% (20-30%) 70%

85-100% No protective antibody response identified

Chronic hepatitis:
Persistent infection: Immunity:

Chronic Hepatitis C Infection

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

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

Birth to HCV-infected mother

Laboratory Diagnosis
HCV antibody - generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears. HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy.

HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

Treatment
Interferon - may be considered for patients with chronic active hepatitis. The response rate is around 50% but 50% of responders will relapse upon withdrawal of treatment. Ribavirin - there is less experience with ribavirin than interferon. However, recent studies suggest that a combination of interferon and ribavirin is more effective than interferon alone.

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

Hepatitis D (Delta) Virus

antigen HBsAg

RNA

 Hepatitis D is a highly defective virus since it cannot produce infective virions without the help of a co-infecting helper virus. This helper virus is hepatitis B virus that supplies the HBsAg surface protein. In budding out of the cell, HDV acquires a membrane containing HBsAg.

 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 HBsAg which is required for reinfection of another cell. The HBsAg of HDV binds to the same surface receptor as HBV and the virus fuses with the cell membrane.

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

Diagnosis
There are commercially available tests that detect anti-HDV IgG

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

Hepatitis D Prevention

Treatment and Prevention

Since HDV depends on HBV for a productive infection, HBV/HDV co-infection can be prevented by HBV prophylaxis using the very effective HBV vaccine. There is no prophylaxis for HDV super-infection which can be diminished by education of HBV-infected patients such as counseling against intravenous drug use.

Hepatitis E Virus

 HEV is a small (approximately 34nm), round, icosahedral, positive strand RNA virus that does not have an envelope. It has a rather smooth surface but not as smooth a HAV. Diagnosis There are no commercially available tests for routine diagnosis

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

Prevention and Treatment

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.

No Vaccine