OBJECTIVES
1. To identify the most common causes of viral hepatitis.
2. To differentiate between hepatitis A, B, C, D and E viruses.
3. To recognize similarities between the hepatitis viruses.
Hepatitis
is a liver disease characterized by weakness and fatigue, anorexia,
nausea, low-grade fever, abdominal pain or discomfort and jaundice.
This disease is often caused by viral infection. While many viruses
-- including yellow fever, rubella and cytomegalovirus -- can cause
hepatitis, the most common causes of viral hepatitis are hepatitis A
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis
delta virus (HDV) and hepatitis E virus (HEV). Hepatitis F virus (HFV)
and hepatitis G virus (HGV) have also been reported. The study with
HFV, however, could not be confirmed and this virus is not believed
to exist. HGV is also called GB virus type-C (GBV-C). This virus does
not appear to be associated with hepatitis and is no longer considered
to be a major causative factor for viral hepatitis.
HAV
HAV is
transmitted by the fecal-oral route. Individuals can be infected by
this virus when they eat contaminated food or drink contaminated water.
The virus will first infect the epithelial cells of the gastrointestinal
tract and spread to the underlining lymphatic system. It is from the
lymphatic system that the virus enters the circulation system to infect
the liver and cause hepatitis. The incubation period of this virus is
between two and three weeks before the onset of symptoms. HAV usually
causes a self-limited acute infection. People exposed to this virus
will most likely recover from the infection and develop a long-term
immunity to it.
Due to
the poor health environment in many developing countries, more than
90 percent of the adult population in those countries has been exposed
to this virus. In the United States, HAV is not as common. Every year,
however, there are about 25,000 cases of hepatitis A reported. Taking
into consideration under-reporting and asymptomatic infections, the
total number of HAV infections in the United States is estimated to
be about 125,000 to 200,000 cases per year. A recent outbreak of hepatitis
A in Michigan was caused by a contaminated strawberry dessert that was
distributed to school children.
An HAV vaccine that has been approved by the Food and Drug Administration
(FDA) and is available to the general public is prepared from inactivated
HAV particles and has little side effects. People traveling to high-risk
areas such as Africa, Asia or South America should consider taking this
vaccine to prevent contracting HAV. It takes four weeks for immunity
to be activated by the HAV vaccine and those planning an immediate trip
should take immune globulin for passive protection.
HBV
HBV can
cause acute and chronic hepatitis. People who fail to clear the virus
after the initial infection will become chronic carriers. It is estimated
that more than 300 million people in the world are HBV carriers. In
many parts of the world, the HBV carrier population is at least 10 percent
of the total population, and in the United States, there are approximately
1 million HBV carriers. Chronic infection by HBV can lead to liver cirrhosis
and hepatocellular carcinoma, which can be lethal.
Due to the high prevalence of HBV, hepatocellular carcinoma has become
one of the most common cancers in the world. In contrast to HAV, HBV
cannot be transmitted by food or casual contact. In the endemic areas
such as sub-Saharan Africa and China, the major transmission route is
vertical transmission: the virus is transmitted from mother to child
during delivery. Neonatal infection frequently leads to chronic infection,
likely due to the immature immune system of the newborn. Vertical transmission
passes the virus from one generation to another, which explains why
the percentage of the carrier population in endemic areas does not change
significantly.
HBV can be transmitted by sex, thus, individuals with multiple sex partners
are at risk for contracting HBV. Besides sex, the virus can be transmitted
between intravenous (IV) drug users when they share contaminated syringe
needles. HBV infection is common among hemophiliacs -- who must rely
on blood-derived coagulation factors to maintain their health -- and
kidney dialysis patients.
HBV vaccines
derived from inactivated virus and recombinant DNA technology are prepared
by inactivating the virus isolated from the blood of HBV carriers. Due
to the large number of HBV carriers in the endemic areas, this vaccine
is relatively cheap and easy to prepare. It was used frequently in HBV
endemic areas in the United States before 1990. It is prepared by expressing
the surface antigen gene of HBV in a heterologous host such as yeast.
The HBV surface antigen is then purified from the yeast and used as
the vaccine. This vaccine is safe and generates only mild, if any, side
effects. It is highly efficacious and generates protection for more
than 90 percent of the people who received the vaccine.
Taiwan
is a hyperendemic area where 15 percent to 20 percent of the adult population
carries HBV. A massive vaccination program was initiated in Taiwan in
1984 to immunize the children. A study conducted in 1999 revealed the
prevalence rate of HBV in Taiwan was 0.7 percent among those younger
than age 15, and 7 percent among people ages 15 to 20. This study indicates
that the HBV vaccination is an effective way to stop the spread of the
virus. The reduction of the HBV carrier population in Taiwanese children
is coupled with a significant reduction of hepatocellular carcinoma
cases in children, making the HBV vaccine an effective cancer vaccine.
Infants
typically should receive HBV vaccines at 2, 4 and 9 months of age. Infants
born to HBV-carrier mothers should receive the immune globulin at birth
for passive protection against virus exposure during birth.
The vaccines
are ineffective for HBV carriers, and there are no other effective therapies
for HBV patients at present. While interferon-a and lamivudine have
been used to treat HBV patients, they generate sustained response to
only a small fraction of patients. Due to the high mortality rate of
hepatocellular carcinoma and the increased risk of HBV carriers for
this cancer, HBV carriers should be monitored at least once a year for
people younger than 40 and once every six months for people older than
40. The most effective treatment at present is to surgically remove
the tumor. However, this will require early detection of the cancer.
HCV
HCV was
responsible for more than 90 percent of the post-transfusion viral hepatitis
in the United States before 1990 and was called the "post-transfusion
non-A, non-B virus." Before 1980, approximately one-third of the
people who received blood transfusions would contract viral hepatitis;
between 1980 and 1990, approximately one-tenth of the people who received
blood transfusions would develop post-transfusion viral hepatitis. In
1989, Michael Houghton, M.D., and his colleagues at Chiron Corp., in
the San Francisco area used a recombinant DNA technology to successfully
isolate the virus. Diagnostic tests were developed immediately after
and used extensively by the blood banks and hospitals to screen HCV-contaminated
blood. Currently, the risk for contracting HCV during blood transfusion
is 1-in-100,000 units of blood. Similar to HBV, HCV can cause acute
and chronic hepatitis. Chronic HCV infection can lead to liver cirrhosis
and hepatocellular carcinoma.
More than 85 percent of people infected by HCV will become chronic carriers.
This is in sharp contrast to HBV infection, which causes chronic infection
in only 5 percent of the adult population. About 20 percent of HCV carriers
will develop severe liver cirrhosis within 20 years and will require
liver transplantation to survive. It is estimated there are 170 million
HCV carriers in the world with nearly 4 million residing in the United
States. Due to its large carrier population, HCV is the No. 1 cause
of liver transplants in the nation. Besides blood transfusion, HCV can
be transmitted by IV drug abuse and nasal use of cocaine, and is common
among hemophiliacs and kidney dialysis patients. Its transmission by
sex is possible although rare. The transmission route for a large number
of HCV patients is not clear, as these patients did not have blood transfusions
and do not belong to any of the high-risk groups. It is suspected that
manicures, tattoos and acupuncture can cause transmission of HCV.
Unlike
HBV, there is no vaccine available for HCV due in part to the high mutation
rate of the virus. Based on the relatedness of genetic codes, HCV is
divided into six major genotypes with minor subtypes. Genotypes 1a and
1b are two prevalent genotypes in the United States. Interferon-a has
been found to generate sustained response in approximately 15 percent
of HCV patients. While not effective by itself, the nucleoside analog
ribavirin would increase the efficacy of interferon-a therapy to generate
a 40 percent to 50 percent sustained response in HCV patients. The efficacy
of the anti-HCV therapy is dictated by HCV genotypes and viral load.
Genotype 1b is most resistant to the combination therapy of interferon
and ribavirin. High viral load in the patient reduces the efficacy of
anti-HCV therapy. Interferon and ribavirin generate severe side effects
including flu-like symptoms and anemia, and thus many patients are unable
to tolerate these two drugs. The interferon therapy requires three injections
every week. A modified interferon called pegylated interferon increases
the half-life of interferon in the body and reduces the injection frequency
to once per week. This pegylated interferon is undergoing clinical trials.
Scientists are exploring new anti-HCV treatments in the laboratories.
It is conceivable that better anti-HCV drugs will be developed in the
near future.
HDV
HDV was
originally identified as an antigen associated with HBV infection antigen
called delta antigen. It was found that the antigen was a distinct virus,
which was named hepatitis delta virus or HDV. HDV is a defective virus
and needs the surface antigen of HBV to mature, which explains why HDV
is always associated with HBV infection. HDV can only be co-transmitted
with HBV to patients or superinfect HBV patients. HDV transmission is
mainly by IV drug abuse. Hemophiliacs receiving blood-clotting factors
are at risk for contracting this virus, and it can be transmitted by
sex. Vertical transmission is rare. Co-infection of HBV and HDV can
cause a more severe acute disease than by HBV alone; however, this co-infection
less frequently leads to chronic infection by HBV. The superinfection
of HBV carriers by HDV can cause rapid progression to fulminant hepatitis
with a high mortality rate of about 20 percent. HDV is more prevalent
in the Mediterranean basin, Middle East, South America, West Africa
and South Pacific Islands. Approximately 5 percent of chronic HBV carriers
are infected with HDV. There is no vaccine available to this virus,
but the prevention of HBV infection with HBV vaccines will prevent infection
by HDV. For chronic HBV carriers, preventing HDV superinfection depends
primarily on education to reduce risk behaviors.
HEV
HEV is
transmitted by the fecal-oral route, with fecally contaminated water
as the most common cause of transmission. Unlike HAV, person-to-person
transmission of HEV is rare. Outbreaks of HEV have been reported worldwide
and it is endemic in developing countries with poor environmental sanitation.
Virtually all HEV cases in the United States are travelers returning
from endemic areas. Nevertheless, in the United States, about 1 percent
of the population is seropositive for anti-HEV reactive antibodies.
Animal reservoirs including rats and domesticated pigs are suggested
causes of the high prevalence of anti-HEV antibodies in the U.S. population.
The incubation period for this virus before the onset of symptoms is
between 15 and 60 days, with a mean incubation period of 40 days. The
symptoms of acute hepatitis E include abdominal pain, anorexia, dark
urine, mild fever, jaundice, malaise and nausea. This virus causes only
self-limited acute infection and no evidence of chronic infection has
been found in the long-term follow-up studies of HEV patients.
Clean water
supplies and prudent hygienic practices can reduce the risk for hepatitis
E. Travelers to developing countries should avoid drinking water of
unknown purity and eating uncooked shellfish or vegetables that are
not prepared by themselves. There are no vaccines available to prevent
HEV infection, and immune globulin prepared from plasma collected in
non-HEV-endemic areas is not effective in providing passive immunization
against HEV. The efficacy of immune globulin prepared from plasma collected
in HEV-endemic areas is unclear.
Conclusion
There are
five major hepatitis viruses. HAV and HEV are transmitted by the fecal-oral
route and cause only self-limited acute infection. In contrast, HBV,
HCV and HDV are transmitted by the parenteral route and can cause acute
and chronic hepatitis. An HAV vaccine is available and people planning
trips to HAV-endemic areas should receive this vaccine for protection.
Since the HEV vaccine is not yet available, prudent hygienic practices
and eating only cooked food will reduce the risk for hepatitis E for
people traveling in endemic areas. HBV vaccines are available. Due to
the large number of HBV carriers in the world, it will be wise to get
vaccinated against hepatitis B. In many states in the U.S., school children
are required to get vaccinated against hepatitis B. Vaccines for HCV
and HDV are not available, therefore, the prevention of infection against
these two viruses relies on education to reduce risk behaviors.
Chronic
infection by HBV and HCV can lead to liver cirrhosis and hepatocellular
carcinoma. Liver cirrhosis caused by HBV and HCV can be exacerbated
by alcohol, and the development of hepatocellular carcinoma in chronic
hepatitis patients can be facilitated by environmental factors such
as aflatoxin. Patients chronically infected by HBV or HCV should be
monitored for hepatocellular carcinoma on a regular basis. If untreated,
hepatocellular carcinoma will be fatal. Surgical removal of the tumor
remains to be the most effective way for treating this disease. However,
the prognosis for this surgical operation depends heavily on the size
of the tumor. Therefore, the early detection of hepatocellular carcinoma
is critical. Finally, the combined therapy using interferon and ribavirin
generates sustained response in 40 percent to 50 percent of HCV patients.
Therefore, this therapy should be considered for HCV patients with advanced
liver diseases.
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