Hepatotrophic Viruses – Dra.

Fe Bartolome
Goku Notes

Summary of Infections Produced

Introduction
Acute Chronic Fulminant Coinfection
Majority of the Hepatitis viruses are RNA viruses. with HIV
The only exception is Hepatitis B because it is a HAV HBV HAV HBV
DNA VIRUS. HBV HCV HBV HCV (has the
HBV comes from the family of Hepadna viridae. highest
One mode of transmission of hepatitis is fecal oral predilection)
route. HCV HDV HDV HGV
Hepatitis viruses A and E are transmitted through HDV HGV HEV
fecal oral route. (especially
in pregnant
Another mode of transmission is through parenteral,
women)
blood and blood products and Hepatitis, A, C, D, B
HEV
and G exhibit this mode of transmission.
HGV
Another is through sexual transmission.
Hepatitis can be transmitted sexually especially Chronic infection leads to cirrhosis and
through oro-anal sexual practices. hepatocellular carcinoma.
Hepatitis A infection can stem from oro-anal sexual HCV has the highest predilection to develop into
practices. hepatocellular carcinoma due to it being
Hepatitis B, C and D can also be transmitted predominantly chronic.
sexually.
Another is through perinatal transmission.
Hepatitis A Virus
Perinatal transmission is usually for Hepatitis B.

Most of the time, children do not develop jaundice.

Types of Infection Produced
In adults, only a small percentage develops
jaundice.
All of them will go through acute infection.
All hepatitis infections whatever is the cause will
There are some that will progress to chronic
develop the same symptoms initially.
infection ( Hepatitis B, C, D and G).
The thing that will point out the occurrence of liver
Chronic infection can lead to cirrhosis and
problem is the development of jaundice.
hepatocellular carcinoma.
Shellfish is known to be a source of infection for
Hepatitis C has the highest predilection to develop
Hepatitis A, especially those that come from
liver cirrhosis and hepatocellular carcinoma because
contaminated water.
it is the only one which is a predominantly chronic
Hepatitis A is transmitted through fecal oral route.
hepatitis.
Shellfish that comes from the contaminated water
Hepatitis A will undergo fulminant infection.
will be able to acquire the infective agent (HAV).
Hepatitis B can also undergo fulminant infection.
Hepatitis D can also develop into fulminant infection.
Characteristics, Morphology and Mode of
Hepatitis E can also develop into fulminant infection
Transmission
especially in pregnant women.
Hepatitis B, C and G can occur as coinfection with
HAV is previously known as Enterovirus 72 and it
HIV because they are transmitted almost in the
belongs to the Picornavirus family.
same manner.
HAV is a small RNA virus.
The highest coinfection rate with HIV among the 3 is
Before, the genus of HAV is called Heparna virus
Hepatitis C.
(because it is an RNA virus).
Now, it is called Hepatovirus.
The incubation period is about 1 month (2-6 weeks).
HAV symptoms are abrupt.
HAV causes acute infection.

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Goku Notes

In HBV, there is a longer incubation period so the Large viral shedding is seen in about 10 days before
onset of symptoms is more insidious. symptoms of jaundice appear or antibody can be
The receptor for HAV is known as T-cell detected.
immunoglobulin and mucin domain 1 (TIM-1) and it The virus does not cause cytopathic effects in the
is also known as HAVcr-1 or Hepatitis A cellular liver.
receptor 1. The virus has a slow replication.
This receptor is expressed not only on the Interferon limits the viral replication.
hepatocytes but also on T cells.
The virus has an icosahedral capsid. Clinical Presentation
It is not enveloped and it is a single stranded
positive sense RNA virus. Even during the incubation period, once the patient
The virus is highly resistant to anti-infection is already infected, the patient is already infectious
procedures enabling it to be easily spread. even without the signs and symptoms.
Transmission is fecal oral. The infection is milder in children as compared to
People who practice oro-anal sex can also get the adults.
infection. HAV can progress to a fulminant infection.
It is also transmitted through eating of contaminated The patient may die after fulminant infection has
shellfish and clams. developed.
There is only 1 serotype of HAV. In fulminant hepatitis, there is massive liver necrosis.
If an individual develops infection from HAV, the The symptoms of a patient with hepatitis regardless
immunity is lifelong. of the etiologic agent, is secondary to an immune
The person will develop the antibody and the response.
antibody is already protective. Hepatitis is an immune mediated infection.
Symptoms occur abruptly (5-15 days after exposure
Hepatitis A virus is stable to treatment of 20% and intensify 4-6 days before the appearance of
ether, acid (pH of 1.0 for 2 hours), and heat (60º jaundice).
for 1 hour).
Infectivity is preserved for at least 1 month after Initial Symptoms
the virus is dried and stored at 25ºC, and even
for a year if it is stored at -20ºC. Fever
The virus can be destroyed by autoclaving Fatigue
(121ºC for 20 mins), boiling for 5 mins, dry heat Loss of appetite
(180ºC for 1 hour), ultraviolet radiation, formalin Nausea
and chlorine. Abdominal pain
Dark urine (B2 which is conjugated bilirubin
goes to the urine. Dark urine is secondary to the
Pathogenesis hyperbilirubinemia.)
Pale stool (acholic, gray stools)
It is transmitted through fecal oral route. Jaundice which can be accompanied by
The virus enters the bloodstream through the abdominal pain and pruritus
epithelial lining of the oropharynx and the intestines.
The virus will then go to its target organ, which is the
liver. Children with HAV infection do not usually present
The virus has a tropism for the parenchyma of the with jaundice.
liver. During the appearance of jaundice, antibodies to the
The virus will not be destroyed by the Kupffer cells. virus are already being produced.
The virus will replicate in the hepatocytes and
Kupffer cells. Diagnosis
The virus is produced in the Kupffer cells before it
will be released in the bile and stool. Antibodies in hepatitis do not serve for protection.

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The purpose of antibodies in hepatitis is for Darkened urine due to hyperbilirubinemia and
diagnosis of the disease. pale stools are a probable sign that the patient
Serology is the best diagnostic procedure for has a liver pathology.
hepatitis infection in order to determine the level of HCV is common among IV drug abusers.
antibodies present. Before, it is HBV but it has been replaced by
During serology, it is important to take note what HCV.
kind of antibody the patient has. Infants born to HBV infected mothers can
If it is an IgM type of antibody, it means the patient become carriers for life even if they do not
has acute infection. manifest with symptoms.
IgM antibodies is followed by the appearance of IgG
anti HAV and this type of antibody confers lifelong
immunity to the patient from all strains of HAV. Summary of the Mode of Transmission of the
Viruses
Prevention and Treatment
Virus Mode of
Immune serum globulin prophylaxis is given before Transmission
or in early exposure. HAV Fecal oral route
For it to become effective in disease prevention, it Oro-anal sexual
should be given within or before the incubation practices
period (less than 2 weeks after the exposure). Parenteral
Blood and blood
Immunization of killed HAV is a best way to prevent
products
infection in children and high risk adults.
HBV Parenteral
HAV and HBV are the only hepatitis viruses which Blood and blood
have an available vaccine. products
They have a vaccine available for them due to them Perinatal
only having a single serotype. Sexual
Once a person is protected against HBV, that Secretions (semen,
person is also automatically protected against HDV. vaginal fluid, saliva,
breastmilk)
HAV vaccine is given for 2 doses, as opposed to
HCV Parenteral
HBV vaccine which is given in 3 doses.
Blood and blood
Booster dose is given 6-12 months after the initial products
dose. sexual
HAV vaccine is recommended to be given to infants, HDV Parenteral
as well as to ages 2-18 years old. Blood and blood
HAV vaccine can be given together with the HBV products
vaccine. Sexual
HEV Fecal oral route
Oro-anal sexual
Who should receive the vaccine? practices
HGV Parenteral
Children Blood and blood
Ages 2-18 years old products
Those who engage in oro-anal sex
Travelers to regions where HAV infection is Hepatitis B Virus
endemic
It is the only DNA virus among the hepatitis viruses.
The disease produced is called serum hepatitis.

Characteristics and Morphology

HBV is a DNA virus known as Hepadna virus.

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It is now known as Orthohepadna virus. Antigens and Antibodies

The virus also causes infection to chimpanzees.
It has a small, circular and partially double stranded The virus itself is antigen like as it enters the body.
genome. The surface antigens are the ones that establish
The double strand of the genome becomes infections.
complete inside the infected cell. The virus has an HBe or Envelope Antigen
HBV has a polymerase that has a reverse incorporated in the nucleocapsid.
transcriptase activity. HBe antigen is the marker for infectivity.
Reverse transcriptase enables the production of If surface antigen and HBE antigen are reactive, it
DNA RNA hybrid and it has also a ribonuclease means that the patient is infected and highly
activity. infectious.
This ribonuclease cleaves the hybrid enabling the HBe reactivity also signifies active viral replication.
genome to be incorporated in the DNA of the host HBc is the Core antigen.
cell. The core antigen is only found inside the
The RNA is used as a template to produce the RNA hepatocyte.
genome of the virus. It cannot be seen in serology.
This is a characteristic unique to HBV. Only the antibody to the core antigen can be
HBV also produces antigens to decoy particles detected in serology.
enabling the virus to evade the host immune Anti HBc is only seen during the window period
defense and making it able to enter the phagocytes. together with anti-HBe.
There are 3 morphologic forms of HBV. Mostly, the anti-HBc alone will be seen in the
The small, spherical particles are the most window period.
numerous and are made up mostly of surface The core antigen remains in the phagocytes
antigens. because it is necessary for viral replication.
Surface antigens are the first to enter and establish The genome of the virus codes for another protein
infection. which is called the HBx protein.
Reactive surface antigen detected in serology HBx protein is a transcriptional transactivator.
denotes that the person has developed a new It has the ability to stimulate cell proliferation.
infection. The HBV genome is integrated into the host genome
The large and spherical virion is called the Dane (insertional mutagenesis).
Particle. The host cell DNA will undergo mutation because
The tubular or the filamentous forms are the decoy the genome of the virus is inserted in it.
particles. It will predispose to mutation of the host gene.
These decoy particles outnumber the virion itself Neoplasia can develop.
and they result from massive release of surface The virus can induce chronic inflammation.
antigens. If the surface antigen is persistently reactive even 6
The immune system of the host will attack them, months after the initial infection, it is a chronic HBV
enabling now the virion to be able to go and infection.
replicate in the phagocytes. If it is an acute infection, if anti-HBs is already
HBV enters the hepatocytes by binding to detected, there should be no more surface antigen
polymerized human serum albumin and other serum reactivity.
proteins. Chronic inflammation is a predisposing factor to
This binding will facilitate the viral entry to the liver. neoplasia.
As it enters, it still has a partially double stranded HBx protein stimulates cell proliferation.
DNA. The presence of chronic inflammation and the HBx
HBV can also infect the kidneys. protein are the predisposing factors for
HBV is designated as Orthohepadna virus to tell that hepatocellular carcinoma development.
it is human infection.
HBV infects not only the liver, but also the kidneys
and the pancreas of the infected individual.

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 Hepatotrophic Viruses – Dra. Fe Bartolome
Goku Notes

Clinical Symptoms Window period is the time of disappearance of the

surface antigen and appearance of anti HBsAg.
Fulminant HBV
Cirrhosis which eventually leads to liver failure Receptors in the Liver
An evidence of chronic inflammation is the presence
of cirrhosis. Transferrin receptor
Asialoglycoprotein receptor
Anti HBs Human Liver annexin V receptor

If it is reactive, it has 3 possible interpretations. The most efficient way to transmit the virus is
One interpretation is that the patient already has a through the secretions.
previous infection and therefore, is already immune Common but less efficient modes of
to HBV infection. transmission are sexual contact and birth.
IgG antibodies can be seen in the patient because it Sexual contact is the most common mode of
is already a previous infection. transmission in endemic areas.
If it is a resolution of infection, IgM antibodies can be Blood products and use of syringes can also
seen on the patient. be a mode of transmission.
Second interpretation is that the patient has Sharing of toothbrushes can also be a mode of
prophylaxis to HBV because he had an exposure to transmission.
the virus. HBV is a blood borne infection.
The patient had already been given hepatitis HBV can be seen in breast milk but it cannot be
immune gamma globulin. transferred through breastfeeding.
The patient will have reactive anti HBs. HCV cannot be transmitted through
The third interpretation is the patient had an breastfeeding.
immunization for HBV. HBV cannot be transmitted through kissing.
If the immunization is effective, anti-HBs titers will HBV cannot be transmitted by vectors.
rise.
In immunized patients, only anti-HBs is reactive, all
the others will be non-reactive. Pathogenesis

Anti HBe Once the virus enters the bloodstream, there is

already antibody production.
If it is present in the serum of the surface antigen The virus spreads to the liver where it replicates
carrier, it means the level of the virus is low. within 3 days of its acquisition.
It can be seen during the window period together Symptoms may not be noted for 45 days or longer
with the anti HBc. depending on the person, the infectious dose and
the route of infection.
Anti HBc The virus will then establish infection, accounting to
the production of anti HBs.
Anti HBc indicates infection with HBV. There will be further production of antibody.
It can be IgM or IgG. Hypersensitivity will follow.
If it is an IgM anti HBc, it is a recent infection and it Immune complexes formed between HBsAg and anti
will remain positive even 4-6 months after. HBs are responsible for the development of
IgG type of anti HBc will mean previous infection. hypersensitivity reaction.
If anti HBc is present alone, it means that it is the It is a Type III hypersensitivity reaction.
window period. HBV induces Type III hypersensitivity as opposed to
If the patient is reactive to surface antigen and also HAV which can induce Type II hypersensitivity
reactive to anti HBc, the surface antigen levels will reaction.
go down and the appearance of anti HBsAg will Dengue and HBV both induces Type III
follow. hypersensitivity.

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The patient can develop polyarteritis nodosa or ALT will tell that there is damage to the liver.
glomerulonephritis. A patient diagnosed with hepatitis must be asked to
If there is already activation of cell mediated have ALT levels screened because it is a way of
immunity, the symptoms will appear because the monitoring the disease progression.
manifestations of the patient are consequences of Upon resolution ALT levels are expected to go back
the immune response to the virus. to normal.
The purpose of the cell mediated immunity is to clear Persistently elevated ALT signifies that the patient
the body of the virus. has a chronic infection.
Epitopes from the HBc antigen are prominent T cell To measure the viral load, DNA level may be
antigens. measured.
Insufficient T cell response can result to occurrence DNA levels can be used to assess if treatment is
of mild symptoms and inability to resolve the effective.
infection. If the treatment is effective, the viral load should go
This will predispose to chronic inflammation. down.
The most common symptoms of HBV are HBeAg and anti Hbe antigen should also be
nonspecific (malaise, nausea). requested.
Eventually, there will be jaundice and dark urine. HBeAg antigen signifies infectivity.
Some patients manifest with pruritus because the If treatment is effective, HBeAg should be non-
bile salts have deposited in the skin. reactive and anti HBe will appear.

Clinical Outcomes of HBV Infection Serologic Markers

90% will undergo resolution. Anti Hbc which can be IgM or IgG
1% will develop fulminant hepatitis. HBeAg which is the marker of high infectivity which
9% progress to chronic hepatitis. means the virus is actively replicating and patient is
50% of chronic hepatitis patients may still undergo highly infectious
resolution. Anti HBe is associated with decreasing levels of the
The other 50% of chronic hepatitis may either DNA
develop an asymptomatic or carrier state. HBsAg which is also a marker of infectivity in the
There are no symptoms but the patient is actively sense that the patient is known to be infected with
releasing the virus so HBeAg is reactive. the virus
HBsAg is also positive but the virus load is low. Anti HBs
These patients can also develop a chronic persistent
or a chronic active hepatitis. Diagnostic Criteria
There is already necrosis in chronic active hepatitis.
Only 1/3 of patients develop chronic active hepatitis. Chronic HBV infection Persistent elevation
2/3 will develop chronic passive or chronic persistent of HbsAg for more
hepatitis. than 6 months
DNA load is high
Abnormal liver
Sequelae of Chronic Persistent and Chronic Active
profile test due to
HBV ongoing liver
damage
Type III Hypersensitivity Bridging fibrosis,
Cirrhosis lobular disarray and
Hepatocellular carcinoma ballooning
degeneration upon
fine needle biopsy of
Laboratory Diagnosis
the liver
Carrier State HBsAg is positive
ALT will not tell that the infection is a hepatitis HBeAg ang anti HBe
infection.

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may both be positive When requesting for a serologic profile, all

Viral load is low hepatitis viruses must be screened.
AST/ALT levels are
normal
There is no evidence
Prevention and Treatment
of hepatitis on liver
biopsy
It is an acute HBV immune globulin administered within a week of
infection that exposure as well as to newborn infants of HBsAg
resolved but there positive mothers
are still some virus HIV drugs which act on the reverse transcriptase
left which are can be used for HBV infections (Lamivudine).
actively replicating
but these remaining Nucleoside analogs can be used (Adefovir, Dipivoxil,
viruses are not Famcyclovir).
enough to produce Pegylated interferon alpha for at least 4 months
symptoms on the Chronic HBV infection requires long term treatment.
patient. Vaccination for infants, children and people in high
risk groups
Resolved infection Reactive anti HBc Immune globulin for probable exposure
Reactive anti HBs
HBV is given at 3 doses
Negative HBsAg nd
ALT levels are 2 dose is 1 month after the first dose
normal 3rd dose is 6 months after the first dose
Virus levels are
nondetectable Hepatitis C Virus

Predominant cause of non A and non B hepatitis

IgM anti HBc is the best way to diagnose recent worldwide
infection. It comes from the same family as Dengue virus
If only anti HBc is reactive, it means the patient is on (Flaviviruses).
the window period. Enveloped and positive sense RNA
During this period, it is expected that anti HBs levels It has the same mode of transmission as HBV
of the patient will start to elevate. (parenteral and sexual).
It is not transmitted perinatally.
It is not associated with fulminant hepatitis
Patients infected with HCV will have chronic and
persistent hepatitis
Can occur as a co-infection with HIV
Highest predilection to co-infect with HIV
HCV can undergo mutation.
No vaccine is developed against it.

Clinical Presentations

Only a small percentage will present as acute

infection with resolution
Most patient will develop chronic hepatitis
Cirrhosis leading to liver failure and Hepatocellular
carcinoma can develop.

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Pathogenesis Hepatitis D Virus

Receptor is the CD81 (tetraspanin) receptors Considered as a defective virus

expressed on hepatocytes and B cells. It cannot cause infection without HBV.
It coats itself on LDL and VLDL and uses the It needs the surface antigen of HBV for it to establish
lipoprotein receptors to facilitate uptake into infection.
hepatocytes. It has the same mode of transmission as HBV.
The virus can inhibit Tumor Necrosis Factor receptor In terms of prevention, it is the same as HBV.
which is part of extrinsic apoptotic pathway. Mode of entry is the same as HBV.
The virus inhibits apoptosis so it can progress to
hepatocellular carcinoma. Replication
Chronic inflammation can also predispose the
patient to develop hepatoma. There is a formation of an RNA structure called
To aid the survival of the virus inside, it inhibits ribozyme.
Protein kinase 1 so they have the ability to inihibit This is needed to cleave the RNA of the virus in
Interferon Alpha. order to produce the messenger RNA.
Part of the management for HCV is giving Interferon
Alpha (because Interferon Alpha is inhibited). Types of Infection
The patient complains more of chronic fatigue rather
than jaundice during chronic hepatitis because in 1. Coinfection
chronic infection, jaundice is not pronounced.
Chronic persistent and chronic active hepatitis can a healthy patient with both HBV and HDV (acute
develop in the patient. HBV and acute HDV)
Alcohol can hasten the development of the disease. Serologic features of acute HBV infection
Presence of anti HDV IgM
Mode of Transmission 90% will recover
3-4 % will develop fulminant hepatitis.
Mode of transmission is through blood and sexual Only a small percentage can progress to chronic
transmission. infection.
It can be transmitted through breastfeeding. HBV is the one that caused the chronic infection.
Virus load in breastmilk is lower as compared to Serologic profile of chronic patients will have the
HBV. same serologic profile as chronic HBV infection and
anti HDV IgG.
Diagnosis Chronic infection will progress to cirrhosis
Has a higher chance of recovery
Serology through measuring Viral RNA and the anti
HCV 2. Superinfection
Viral RNA is measured for treatment purposes
(monitor the effectiveness of treatment). Patient already has HBV.
Genome detection and quantification of viral RNA by Patient is an asymptomatic HBV carrier.
RTA PCR are the gold standards. Progression of infection is faster because HBV is
already established.
Treatment and Prevention Acute liver disease recovery is low.
80% will develop chronic infection.
Pegylated Interferon Alpha Has the higher chance to develop a fulminant
Ribavirin infection
Viral RNA load should be quantified while the patient Has the higher chance of progressing to chronic
is on treatment. infection
Protease inhibitors (Bocepevir and Telaprevir)
No vaccine is available.

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Goku Notes

Hepatitis E Virus

Transmitted through fecal oral route

Belongs to Hepevirus genus
Belongs to Calici virus family
It has a milder course compared to HAV except in
pregnant women where they can develop a
fulminant hepatitis.

Hepatitis G Virus

Also known as GB virus C or GBV-C

Also a Flavivirus
Mode of transmission is similar to HIV and similar to
HCV
Transmission is mainly through blood.
It can also replicate inside monocytes.
Infection of the liver is quite rare.
If it infects the liver, it is more of a chronic hepatitis.
Can occur as a coinfection with HIV
The virus can inhibit the virus replication of HIV.
It can prevent the development of HIV disease.
If HGV is present, HIV will not replicate.
Detection is through RT-PCR

END

Sources:

Dra. Barts’ lecture (Recording by VNC)

Robbins 9th Ed.
Jawetz 26th Ed.
Murray 7th ed.

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