HEPATITIS
Dr. Adil Khazindar
Consultant Medicine & Infectious
Diseases
KAAUH
Types of Viral Hepatitis
HepatitisA
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.
Transmission: Ingestion of fecal matter, even in microscopic amounts, from
close person-to-person contact or ingestion of contaminated food or drinks.
Vaccination: Hepatitis A vaccination is recommended for all children starting at
age 1 year, travelers to certain countries, and others at risk
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 (chronic)
illness that can lead to liver disease or liver cancer.
Transmission: 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.
Vaccination: Hepatitis B vaccination is recommended for all infants, older
children and adolescents who were not vaccinated previously, and adults at risk
for HBV infection.
Hepatitis C
is a liver disease caused by the hepatitis C virus (HCV). HCV infection
sometimes results in an acute illness, but most often becomes a chronic
condition that can lead to cirrhosis of the liver and liver cancer.
Transmission: Contact with the blood of an infected person, primarily through
sharing contaminated needles to inject drugs.
Vaccination: There is no vaccine for hepatitis C.
Types of Viral Hepatitis
Hepatitis D
Is a serious liver disease caused by the hepatitis D virus (HDV)
and relies on HBV to replicate.
Transmission: Contact with infectious blood, similar to how HBV
is spread.
Vaccination: There is no vaccine for hepatitis D.
Hepatitis E
Is a serious liver disease caused by the hepatitis E virus (HEV)
that usually results in an acute infection. It does not lead to a
chronic infection. While rare in the United States, hepatitis E is
common in many parts of the world.
Transmission: Ingestion of fecal matter, even in microscopic
amounts; outbreaks are usually associated with contaminated
water supply in countries with poor sanitation.
Vaccination: There is currently no FDA-approved vaccine for
hepatitis E.
Hepatitis A
Hepatitis A, caused by infection with the hepatitis A virus
(HAV).
has an incubation period of approximately 28 days (range:
15–50 days).
HAV replicates in the liver and is shed in high concentrations
in feces from 2 weeks before to 1 week after the onset of
clinical illness.
HAV infection produces a self-limited disease that does not
result in chronic infection or chronic liver disease.
However, 10%–15% of patients might experience a relapse of
symptoms during the 6 months after acute illness.
Acute liver failure from hepatitis A is rare (overall case-fatality
rate: 0.5%).
The risk for symptomatic infection is directly related to age,
with >80% of adults having symptoms compatible with acute
viral hepatitis and the majority of children having either
asymptomatic or unrecognized infection.
Antibody produced in response to HAV infection persists for
life and confers protection against reinfection.
Incidence
There were 30,000 cases of Hepatitis A reported
to the CDC in the U.S. in 1997.
The agency estimates that there were as many as
270,000 cases each year from 1980 through
2000.
there were an estimated 32,000 new hepatitis A
virus infections in 2006. (However, the official
number of reported hepatitis A cases is much
lower since many people who are infected never
have symptoms and are never reported to public
health officials.
How is HAV transmitted?
Person-to-person transmission through the fecal-oral
route (i.e., ingestion of something that has been
contaminated with the feces of an infected person) is the
primary means of HAV transmission in the United States. Most
infections result from close personal contact with an infected
household member or sex partner.
Common-source outbreaks and sporadic cases also can occur
from exposure to fecally contaminated food or water.
Uncooked HAV-contaminated foods have been recognized as
a source of outbreaks.
Cooked foods also can transmit HAV if the temperature during
food preparation is inadequate to kill the virus or if food is
contaminated after cooking, as occurs in outbreaks associated
with infected food handlers.
Waterborne outbreaks are infrequent in developed countries
with well-maintained sanitation and water supplies.
Who is at increased risk for
acquiring HAV infection?
Travelers to countries with high or
intermediate endemicity of HAV
infection
Users of injection and non-injection
illegal drugs
Persons with clotting factor disorders
Persons working with nonhuman
primates susceptible to HAV infection
Signs & Symptoms
Some persons, particularly young children, are asymptomatic.
When symptoms are present, they usually occur abruptly and can
include the following:
Fever
Fatigue
Loss of appetite
Nausea
Vomiting
Abdominal pain
Dark urine
Clay-colored bowel movements
Joint pain
Jaundice .
When symptoms occur, how long do they usually last?
Symptoms usually last less than 2 months, although 10%–15%
of symptomatic persons have prolonged or relapsing disease for
up to 6 months.
How long does HAV survive outside the body?
How can the virus be killed?
HAV can live outside the body for months,
depending on the environmental
conditions.
The virus is killed by heating to 185
degrees F (85 degrees C) for one minute.
However, the virus can still be spread
from cooked food if it is contaminated
after cooking.
Adequate chlorination of water, as
recommended in the United States, kills
HAV that enters the water supply.
Cont.
Can hepatitis A become chronic?
No. Hepatitis A does not become chronic.
Can persons become reinfected with
HAV after recovering from hepatitis
A?
No. IgG antibodies to HAV, which appear
early in the course of infection, provide
lifelong protection against the disease.
How is HAV infection prevented?
Vaccination with the full, two-dose series of hepatitis A
vaccine is the best way to prevent HAV infection.
Hepatitis A vaccine has been licensed in the United States
for use in persons 12 months of age and older.
The vaccine is recommended for persons who are more
likely to get HAV infection or are more likely to get
seriously ill if they get hepatitis A
Immune globulin is available for short-term protection
(approximately 3 months) against hepatitis A, both pre-
and post-exposure. Immune globulin must be administered
within 2 weeks after exposure for maximum protection.
Good hygiene — including handwashing or use of hand
sanitizer after using the bathroom, changing diapers, and
before preparing or eating food — is also integral to
hepatitis A prevention, given that the virus is transmitted
through the fecal–oral route.
Who should be vaccinated
against hepatitis A?
All children at age 1 year (i.e., 12–23
months). Children who have not been vaccinated by age
2 can be vaccinated at subsequent visits.
Children and adolescents ages 2–18 who live in
states or communities where routine hepatitis A
vaccination has been implemented because of high
disease incidence.
Persons traveling to or working in countries that
have high or intermediate rates of hepatitis A.
Persons traveling to or working in countries that
have high or intermediate rates of hepatitis A.
Persons who have occupational risk for infection
Persons who have chronic liver disease.
Persons who have clotting-factor disorders
Hepatitis A Vaccine
How long does protection from hepatitis A vaccine last?
A recent review by an expert panel, which evaluated the projected
duration of immunity from vaccination, concluded that protective
levels of antibody to HAV could be present for at least 25 years in
adults and at least 14–20 years in children.
Can hepatitis A vaccine be administered concurrently with other
vaccines?
Yes. Hepatitis B, diphtheria, poliovirus (oral and inactivated), tetanus,
oral typhoid, cholera, Japanese encephalitis, rabies, and yellow fever
vaccines and immune globulin can be given at the same time that
hepatitis A vaccine is given, but at a different injection site.
Can hepatitis A vaccine be given during pregnancy?
The safety of hepatitis A vaccination during pregnancy has not been
determined; however, because the vaccine is produced from
inactivated HAV, the theoretical risk to the developing fetus is
expected to be low. The risk associated with vaccination, however,
should be weighed against the risk for hepatitis A in women who
might be at high risk for exposure to HAV.
Can hepatitis A vaccine be given to immunocompromised persons
(e.g., persons on hemodialysis or persons with AIDS)?
Yes. Because hepatitis A vaccine is inactivated, no special
precautions need to be taken when vaccinating immunocompromised
persons.
Hepatitis B
Hepatitis B is a disease caused by hepatitis B virus which infects the liver of
hominoidae, including humans, and causes an inflammation called hepatitis. Originally
known as "serum hepatitis",
The disease has caused epidemics in parts of Asia and Africa, and it is endemic in
China.
About a third of the world's population, more than 2 billion people, have been
infected with the hepatitis B virus.
This includes 350 million chronic carriers of the virus.
Transmission of hepatitis B virus results from exposure to infectious blood or body
fluids containing blood.
The acute illness causes liver inflammation, vomiting, jaundice and—rarely—death.
Chronic hepatitis B may eventually cause liver cirrhosis and liver cancer—a fatal
disease with very poor response to current chemotherapy.
The infection is preventable by vaccination.
Hepatitis B virus is an hepadnavirus—hepa from hepatotrophic and dna because it is a
DNA virus—and it has a circular genome composed of partially double-stranded DNA.
The viruses replicate through an RNA intermediate form by reverse transcription, and
in this respect they are similar to retroviruses.
Although replication takes place in the liver, the virus spreads to the blood where
virus-specific proteins and their corresponding antibodies are found in infected people.
Bloods test for these proteins and antibodies are used to diagnose the infection.
History
The earliest record of an epidemic caused by Hepatitis B virus was made
by Lurman in 1885.
An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard
employees were vaccinated with lymph from other people. After several
weeks, and up to eight months later, 191 of the vaccinated workers
became ill with jaundice and were diagnosed as suffering from serum
hepatitis.
Other employees who had been inoculated with different batches of
lymph remained healthy.
Lurman's paper, now regarded as a classical example of an
epidemiological study, proved that contaminated lymph was the source of
the outbreak.
Later, numerous similar outbreaks were reported following the
introduction, in 1909, of hypodermic needles that were used, and more
importantly reused, for administering Salvarsan for the treatment of
syphilis.
The virus was not discovered until 1965 when Baruch Blumberg, then
working at the National Institutes of Health (NIH), discovered the Australia
antigen (later known to be Hepatitis B surface antigen, or HBsAg) in the
blood of Australian aboriginal people.
Although a virus had been suspected since the research published by
MacCallum in 1947, D.S. Dane and others discovered the virus particle in
1970 by electron microscopy.
By the early 1980s the genome of the virus had been sequenced, and the
first vaccines were being tested.
HBV
Hepatitis B virus (HBV) is a member of the Hepadnavirus
family.
The virus particle, (virion) consists of an outer lipid
envelope and an icosahedral nucleocapsid core composed of
protein.
The nucleocapsid encloses the viral DNA and a DNA
polymerase that has reverse transcriptase activity.
The outer envelope contains embedded proteins which are
involved in viral binding of, and entry into, susceptible cells.
The virus is one of the smallest enveloped animal viruses
with a virion diameter of 42nm, but pleomorphic forms
exist, including filamentous and spherical bodies lacking a
core.
These particles are not infectious and are composed of the
lipid and protein that forms part of the surface of the virion,
which is called the surface antigen (HBsAg), and is
produced in excess during the life cycle of the virus.
HBV Genome
The genome of HBV is made of circular DNA, but it is unusual because the DNA is not
fully double-stranded.
One end of the full length strand is linked to the viral DNA polymerase.
The genome is 3020-3320 nucleotides long (for the full length strand) and 1700-
2800 nucleotides long (for the short length strand).
The negative-sense, (non-coding), is complementary to the viral mRNA.
The viral DNA is found in the nucleus soon after infection of the cell.
The partially double-stranded DNA is rendered fully double-stranded by completion
of the (+) sense strand and removal of a protein molecule from the (-) sense strand
and a short sequence of RNA from the (+) sense strand.
Non-coding bases are removed from the ends of the (-)sense strand and the ends
are rejoined.
There are four known genes encoded by the genome called C, X, P, and S. The core
protein is coded for by gene C (HBcAg), and its start codon is preceded by an
upstream in-frame AUG start codon from which the pre-core protein is produced.
HBeAg is produced by proteolytic processing of the pre-core protein. The DNA
polymerase is encoded by gene P. Gene S is the gene that codes for the surface
antigen (HBsAg).
The HBsAg gene is one long open reading frame but contains three in frame "start"
(ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S.
Because of the multiple start codons, polypeptides of three different sizes called
large, middle, and small (pre-S1 + pre-S2 + S, pre-S2 + S, or S) are produced.
The function of the protein coded for by gene X is not fully understood.
Replication
The life cycle of Hepatitis B virus is complex.
Hepatitis B is one of a few known non-retroviral viruses which use reverse
transcription as a part of its replication process.
The virus gains entry into the cell by binding to a receptor on the surface
of the cell and enters it by endocytosis.
Because the virus multiplies via RNA made by a host enzyme, the viral
genomic DNA has to be transferred to the cell nucleus by host proteins
called chaperones.
The partially double stranded viral DNA is then made fully double stranded
and transformed into covalently closed circular DNA (cccDNA) that serves
as a template for transcription of four viral mRNAs.
The largest mRNA, (which is longer than the viral genome), is used to
make the new copies of the genome and to make the capsid core protein
and the viral DNA polymerase.
These four viral transcripts undergo additional processing and go on to
form progeny virions which are released from the cell or returned to the
nucleus and re-cycled to produce even more copies.
The long mRNA is then transported back to the cytoplasm where the virion
P protein synthesizes DNA via its reverse transcriptase activity.
Prevalence
The primary method of transmission reflects the prevalence
of chronic HBV infection in a given area.
In low prevalence areas such as the continental United
States and Western Europe, where less than 2% of the
population is chronically infected, injection drug abuse and
unprotected sex are the primary methods, although other
factors may be important.
In moderate prevalence areas, which include Eastern
Europe, Russia, and Japan, where 2-7% of the population is
chronically infected, the disease is predominantly spread
among children.
In high prevalence areas such as China and South East
Asia, transmission during childbirth is most common,
although in other areas of high endemicity such as Africa,
transmission during childhood is a significant factor.
The prevalence of chronic HBV infection in areas of high
endemicity is at least 8%.
Transmission
Transmission of hepatitis B virus results from exposure to
infectious blood or body fluids containing blood.
Possible forms of transmission include (but are not limited
to) unprotected sexual contact, blood transfusions, re-use
of contaminated needles & syringes, and vertical
transmission from mother to child during childbirth.
Without intervention, a mother who is positive for HBsAg
confers a 20% risk of passing the infection to her offspring
at the time of birth. This risk is as high as 90% if the
mother is also positive for HBeAg.
HBV can be transmitted between family members within
households, possibly by contact of nonintact skin or mucous
membrane with secretions or saliva containing HBV.
However, at least 30% of reported hepatitis B among
adults cannot be associated with an identifiable risk factor.
Symptoms
Acute infection with hepatitis B virus
Is associated with acute viral hepatitis – an illness that begins with
general ill-health, loss of appetite, nausea, vomiting, body aches, mild
fever, dark urine, and then progresses to development of jaundice.
It has been noted that itchy skin has been an indication as a possible
symptom of all hepatitis virus types.
The illness lasts for a few weeks and then gradually improves in most
affected people.
A few patients may have more severe liver disease (fulminant hepatic
failure), and may die as a result of it.
The infection may be entirely asymptomatic and may go unrecognized.
Chronic infection with Hepatitis B virus
May be either asymptomatic or may be associated with a chronic
inflammation of the liver (chronic hepatitis), leading to cirrhosis over a
period of several years.
This type of infection dramatically increases the incidence of hepatocellular
carcinoma (liver cancer).
Chronic carriers are encouraged to avoid consuming alcohol as it
increases their risk for cirrhosis and liver cancer.
Hepatitis B virus has been linked to the development of Membranous
glomerulonephritis (MGN).
Diagnosis
Treatment
Acute hepatitis B infection does not usually require treatment because most adults clear
the infection spontaneously.
Early antiviral treatment may only be required in fewer than 1% of patients, whose
infection takes a very aggressive course ("fulminant hepatitis") or who are
immunocompromised.
On the other hand, treatment of chronic infection may be necessary to reduce the risk of
cirrhosis and liver cancer.
Chronically infected individuals with persistently elevated serum alanine
aminotransferase, a marker of liver damage, and HBV DNA levels are candidates for
therapy.
Although none of the available drugs can clear the infection, they can stop the virus from
replicating, and minimize liver damage such as cirrhosis and liver cancer.
Currently, there are seven medications licensed for treatment of hepatitis B infection in
the United States. These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera),
tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude) and the two immune
system modulators interferon alpha-2a and alfa-2a (Pegasys).
The use of interferon, which requires injections daily or thrice weekly, has been
supplanted by long-acting pegylated interferon, which is injected only once weekly.
However, some individuals are much more likely to respond than others and this might
be because of the genotype of the infecting virus or the patient's heredity.
The treatment works by reducing the viral load, (the amount of virus particles as
measured in the blood), which in turn reduces viral replication in the liver.
Infants born to mothers known to carry hepatitis B can be treated with antibodies to the
hepatitis B virus (hepatitis B immune globulin or HBIg). When given with the vaccine
within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This
treatment allows a mother to safely breastfeed her child.
Reactivation
Hepatitis B virus DNA persists in the body after infection
and in some people the disease re-occurs.
Although rare, reactivation is seen most often in people
with impaired immunity.
Hepatitis B goes through cycles of replication and non-
replication.
Approximately 50% of patients experience acute
reactivation.
Male patients with baseline ALT of 200 UL/L are three
times more likely to develop a reactivation than patients
with lower levels.
Patients who undergo chemotherapy are at risk for HBV
reactivation.
The current view are that immunosuppressive drugs favor
increased HBV replication while inhibiting cytotoxic T cell
function in the liver.
Prognosis
Hepatitis B virus infection may either be acute (self-limiting) or
chronic (long-standing). Persons with self-limiting infection clear
the infection spontaneously within weeks to months.
Children are less likely than adults to clear the infection. More
than 95% of people who become infected as adults or older
children will stage a full recovery and develop protective immunity
to the virus.
However, only 5% of newborns that acquire the infection from
their mother at birth will clear the infection.
This population has a 40% lifetime risk of death from cirrhosis or
hepatocellular carcinoma.
Of those infected between the age of one to six, 70% will clear
the infection.
Hepatitis D infection can only occur with a concomitant infection
with Hepatitis B virus because the Hepatitis D virus uses the
Hepatitis B virus surface antigen to form a capsid.
Co-infection with hepatitis D increases the risk of liver cirrhosis
and liver cancer.
Polyarteritis nodosa is more common in people with hepatitis B
infection.
Prevention
Several vaccines have been developed for the prevention of hepatitis B virus
infection.
These rely on the use of one of the viral envelope proteins (hepatitis B
surface antigen or HBsAg).
The vaccine was originally prepared from plasma obtained from patients who
had long-standing hepatitis B virus infection.
However, currently, these are more often made using recombinant DNA
technology, though plasma-derived vaccines continue to be used; the two
types of vaccines are equally effective and safe.
Following vaccination Hepatitis B Surface antigen may be detected in serum
for several days; this is known as vaccine antigenaemia.
Vaccine is generally administered in either a two, three, or four dose
schedules; and can be received by infants to adults.
It provides protection for 85-90% of individuals, and lasts for 23 years.
Unlike Hepatitis A, Hepatitis B does not generally spread through water and
food.
Instead, it is transmitted through body fluids, from which prevention is
taken to avoid: unprotected sexual contact, blood transfusions, re-use of
contaminated needles and syringes, and vertical transmission during child
birth.
Infants may be vaccinated at birth.
HCV
Hepatitis C is an infectious disease affecting the liver, caused by the
hepatitis C virus (HCV).
The infection is often asymptomatic, but once established, chronic infection
can progress to scarring of the liver (fibrosis), and advanced scarring
(cirrhosis).
In some cases, those with cirrhosis will go on to develop liver failure or
other complications of cirrhosis, including liver cancer.
The hepatitis C virus (HCV) is spread by blood-to-blood contact.
Most people have few symptoms after the initial infection, yet the virus
persists in the liver in about 80% of those infected.
Persistent infection can be treated with medication, such as interferon and
ribavirin, but only a minority is cured.
Those who develop cirrhosis or liver cancer may require a liver transplant,
although the virus may recur after transplantion.
An estimated 150-200 million people worldwide are infected with hepatitis
C. Apart from humans, it only infects chimpanzees.
No vaccine against hepatitis C is available. The existence of hepatitis C
(originally "non-A non-B hepatitis") was postulated in the 1970s and proved
conclusively in 1988.
It is one of five known hepatitis viruses: A, B, C, D, and E.
History
In the mid 1970s, Harvey J. Alter, Chief of the Infectious Disease Section in the
Department of Transfusion Medicine at the National Institutes of Health, and his research
team demonstrated that most post-transfusion hepatitis cases were not due to hepatitis A
or B viruses.
Despite this discovery, international research efforts to identify the virus, initially called
non-A, non-B hepatitis (NANBH), failed for the next decade.
In 1987, Michael Houghton, Qui-Lim Choo, and George Kuo at Chiron Corporation,
collaborating with Dr. D.W. Bradley from CDC, utilized a novel molecular cloning approach
to identify the unknown organism.
In 1988, the virus was confirmed by Alter by verifying its presence in a panel of NANBH
specimens.
In April of 1989, the discovery of the virus, re-named hepatitis C virus (HCV), was
published in two articles in the journal Science. Chiron filed for several patents on the
virus and its diagnosis.
A competing patent application by the CDC was dropped in 1990 after Chiron paid $1.9
million to the CDC and $337,500 to Bradley.
In 1994 Bradley sued Chiron, seeking to invalidate the patent, have himself included as a
co-inventor, and receive damages and royalty income. He dropped the suit in 1998 after
losing before an appeals court.
In 2000, Drs. Alter and Houghton were honored with the Lasker Award for Clinical Medical
Research for "pioneering work leading to the discovery of the virus that causes hepatitis C
and the development of screening methods that reduced the risk of blood transfusion-
associated hepatitis in the U.S. from 30% in 1970 to virtually zero in 2000."
In 2004 Chiron held 100 patents in 20 countries related to hepatitis C and had successfully
sued many companies for infringement.
Scientists and competitors have complained that the company hinders the fight against
hepatitis C by demanding too much money for its technology
Virology
The Hepatitis C virus (HCV) is a small (50 nm in size), enveloped, single-
stranded, positive sense RNA virus.
It is the only known member of the hepacivirus genus in the family
Flaviviridae. There are six major genotypes of the hepatitis C virus, which
are indicated numerically (e.g., genotype 1, genotype 2, etc.).
The hepatitis C virus (HCV) is transmitted by blood-to-blood contact.
In developed countries, it is estimated that 90% of persons with chronic HCV
infection were infected through transfusion of unscreened blood or blood
products or via injecting drug use or, rarely, by inhalational drug use.
In developing countries, the primary sources of HCV infection are
unsterilized injection equipment and infusion of inadequately screened blood
and blood products.
Although injection drug use and receipt of infected blood/blood products are
the most common routes of HCV infection, any practice, activity, or situation
that involves blood-to-blood exposure can potentially be a source of HCV
infection.
The virus may be sexually transmitted, although this is rare, and usually
only occurs when an STD (like HIV) is also present and makes blood contact
more likely.
Epidemiology
Hepatitis C infects nearly 200 million people worldwide and 4 million in the
United States.
There are about 35,000 to 185,000 new cases a year in the United States,
and hepatitis C is the leading cause of liver transplant in the USA.
Co-infection with HIV is common and rates among HIV positive populations
are higher.
10,000-20,000 deaths a year in the United States are from HCV;
expectations are that this mortality rate will increase, as those who were
infected by transfusion before HCV testing become apparent.
A survey conducted in California showed prevalence of up to 34% among
prison inmates; 82% of subjects diagnosed with hepatitis C have previously
been in jail, and transmission while in prison is well described.
Prevalence is higher in some countries in Africa and Asia.
Egypt has the highest seroprevalence for HCV, up to 20% in some areas.
There is a hypothesis that the high prevalence is linked to a now-discontinued
mass-treatment campaign for schistosomiasis, which is endemic in that
country.
Regardless of how the epidemic started, a high rate of HCV transmission
continues in Egypt, both iatrogenically and within the community and
household.
Co-Infection with HIV
Approximately 350,000, or 35% of patients in the
USA infected with HIV are also infected with the
hepatitis C virus, mainly because both viruses are
blood-borne and present in similar populations.
In other countries co-infection is less common,
and this is possibly related to differing drug
policies.
HCV is the leading cause of chronic liver disease
in the USA.
It has been demonstrated in clinical studies that
HIV infection causes a more rapid progression of
chronic hepatitis C to cirrhosis and liver failure.
This is not to say treatment is not an option for
those living with co-infection.
Transmission
Several activities and practices have been identified as potential
sources of exposure to the hepatitis C virus. Anyone who may have
been exposed to HCV through one or more of these routes should be
screened for hepatitis C.
Injection drug use
Those who currently use or have used drug injection as their delivery
route for illicit drugs are at increased risk for getting hepatitis C
because they may be sharing needles or other drug paraphernalia
(includes cookers, cotton, spoons, water, etc.), which may be
contaminated with HCV-infected blood.
An estimated 60% to 80% of all IV drug users in the United States
have been infected with HCV.
Drug use by nasal inhalation (Drugs that are "snorted")
Researchers have suggested that the transmission of HCV may be
possible through the nasal inhalation (insuffulation) of illegal drugs
such as cocaine and crystal methamphetamine when straws
(containing even trace amounts of mucus and blood) are shared
among users.
Blood products
Blood transfusion, blood products, or organ transplantation prior to
implementation of HCV screening (in the U.S., this would refer to
procedures prior to 1992) is a decreasing risk factor for hepatitis C.
Transmission Cont.
The virus was first isolated in 1989 and reliable tests to screen for the virus were not
available until 1992. Therefore, those who received blood or blood products prior to
the implementation of screening the blood supply for HCV may have been exposed to
the virus. Blood products include clotting factors (taken by hemophiliacs),
immunoglobulin, Rhogam, platelets, and plasma.
In 2001, the Centers for Disease Control and Prevention reported that the risk of HCV
infection from a unit of transfused blood in the United States is less than one per
million transfused units.
Iatrogenic medical or dental exposure
People can be exposed to HCV via inadequately or improperly sterilized medical or
dental equipment.
Equipment that may harbor contaminated blood if improperly sterilized includes
needles or syringes, hemodialysis equipment, oral hygiene instruments, and jet air
guns, etc.
Scrupulous use of appropriate sterilization techniques and proper disposal of used
equipment can reduce the risk of iatrogenic exposure to HCV to virtually zero.
Occupational exposure to blood
Medical and dental personnel, first responders (e.g., firefighters, paramedics,
emergency medical technicians, law enforcement officers), and military combat
personnel can be exposed to HCV through accidental exposure to blood through
accidental needlesticks or blood spatter to the eyes or open wounds.
Recreational exposure to blood
Contact sports and other activities, such as "slam dancing" that may result in
accidental blood-to-blood exposure are potential sources of exposure to HCV.[12]
Transmission Cont.
Sexual transmission of HCV is considered to be rare.
Studies show the risk of sexual transmission in heterosexual, monogamous relationships is
extremely rare or even null.
The CDC does not recommend the use of condoms between long-term monogamous discordant
couples (where one partner is positive and the other is negative). However, because of the high
prevalence of hepatitis C, this small risk may translate into a non-trivial number of cases
transmitted by sexual routes. Vaginal penetrative sex is believed to have a lower risk of
transmission than sexual practices that involve higher levels of trauma to anogenital mucosa
Body piercings and tattoos
Tattooing dyes, ink pots, stylets and piercing implements can transmit HCV-infected blood from one
person to another if proper sterilization techniques are not followed. Tattoos or piercings performed
before the mid 1980s, "underground," or non-professionally are of particular concern since sterile
techniques in such settings may have been or be insufficient to prevent disease. Despite these
risks, it is rare for tattoos to be directly associated with HCV infection and the U.S.
Shared personal care items
Personal care items such as razors, toothbrushes, cuticle scissors, and other manicuring or
pedicuring equipment can easily be contaminated with blood. Sharing such items can potentially
lead to exposure to HCV. Appropriate caution should be taken regarding any medical condition
which results in bleeding such as canker sores, cold sores, and immediately after flossing.
HCV is not spread through casual contact such as hugging, kissing, or sharing eating or cooking
utensils.
Vertical transmission
Vertical transmission refers to the transmission of a communicable disease from an infected mother
to her child during the birth process.
Mother-to-child transmission of hepatitis C has been well described, but occurs relatively
infrequently. Transmission occurs only among women who are HCV RNA positive at the time of
delivery; the risk of transmission in this setting is approximately 6 out of 100.
Among women who are both HCV and HIV positive at the time of delivery, the risk of transmitting
HCV is increased to approximately 25 out of 100.
The risk of vertical transmission of HCV does not appear to be associated with method of delivery
or breastfeeding.
Signs &Symptoms
Acute
Acute hepatitis C refers to the first 6 months after infection with HCV.
Between 60% to 70% of people infected develop no symptoms during the
acute phase.
In the minority of patients who experience acute phase symptoms, they
are generally mild and nonspecific, and rarely lead to a specific diagnosis
of hepatitis C.
Symptoms of acute hepatitis C infection include decreased appetite,
fatigue, abdominal pain, jaundice, itching, and flu-like symptoms.
The hepatitis C virus is usually detectable in the blood within one to three
weeks after infection, and antibodies to the virus are generally detectable
within 3 to 12 weeks.
Approximately 15-40% of persons infected with HCV clear the virus from
their bodies during the acute phase as shown by normalization in liver
function tests (LFTs) such as alanine transaminase (ALT) & aspartate
transaminase (AST) normalization, as well as plasma HCV-RNA clearance
(this is known as spontaneous viral clearance).
The remaining 60-85% of patients infected with HCV develop chronic
hepatitis C, i.e., infection lasting more than 6 months.
Previous practice was to not treat acute infections to see if the person
would spontaneously clear; recent studies have shown that treatment
during the acute phase of genotype 1 infections has a greater than 90%
success rate with half the treatment time required for chronic infections.
Chronic HCV
Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for
more than six months.
Clinically, it is often asymptomatic (without symptoms) and it is mostly discovered
accidentally.
The natural course of chronic hepatitis C varies considerably from one person to
another.
Virtually all people infected with HCV have evidence of inflammation on liver
biopsy, however, the rate of progression of liver scarring (fibrosis) shows
significant variability among individuals.
Recent data suggest that among untreated patients, roughly one-third progress to
liver cirrhosis in less than 20 years. Another third progress to cirrhosis within 30
years. The remainder of patients appear to progress so slowly that they are
unlikely to develop cirrhosis within their lifetimes.
Factors that have been reported to influence the rate of HCV disease progression
include age (increasing age associated with more rapid progression), gender
(males have more rapid disease progression than females), alcohol consumption
(associated with an increased rate of disease progression), HIV coinfection
(associated with a markedly increased rate of disease progression), and fatty liver
(the presence of fat in liver cells has been associated with an increased rate of
disease progression).
Symptoms specifically suggestive of liver disease are typically absent until
substantial scarring of the liver has occurred.
However, hepatitis C is a systemic disease and patients may experience a wide
spectrum of clinical manifestations ranging from an absence of symptoms to a
more symptomatic illness prior to the development of advanced liver disease.
Generalized signs and symptoms associated with chronic hepatitis C include
fatigue, marked weight loss, flu-like symptoms, muscle pain, joint pain,
intermittent low-grade fevers, itching, sleep disturbances, abdominal pain
(especially in the right upper quadrant), appetite changes, nausea, diarrhea,
dyspepsia, cognitive changes, depression, headaches, and mood swings.
Cont.
Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms
may appear that are generally caused by either decreased liver function or
increased pressure in the liver circulation, a condition known as portal
hypertension.
Possible signs and symptoms of liver cirrhosis include ascites, bruising and
bleeding tendency, bone pain, varices, fatty stools (steatorrhea), jaundice,
and a syndrome of cognitive impairment known as hepatic encephalopathy.
Liver function tests show variable elevation of ALAT, AST and GGTP and
periodically they might show normal results. Usually prothrombin and
albumin results are normal. The level of elevation of liver tests do not
correlate well with the amount of liver injury on biopsy.
Viral genotype and viral load also do not correlate with the amount of liver
injury. Liver biopsy is the best test to determine the amount of scarring and
inflammation.
Radiographic studies such as ultrasound or CT scan do not show liver injury
until it is fairly advanced.
Chronic hepatitis C, more than other forms of hepatitis, is diagnosed
because of extrahepatic manifestations associated with the presence of HCV
such as thyroiditis with hyperthyreosis or hypothyreosis, porphyria cutanea
tarda, cryoglobulinemia (a form of small-vessel vasculitis) and
glomerulonephritis, specifically membranoproliferative glomerulonephritis
(MPGN).
Hepatitis C is also associated with sicca syndrome (an autoimmune
disorder), thrombocytopenia, lichen planus, diabetes mellitus and with B-cell
lymphoproliferative disorders.
Diagnosis
The diagnosis of "hepatitis C" is rarely made during the acute phase of the
disease because the majority of people infected experience no symptoms during
this phase of the disease.
Those who do experience acute phase symptoms are rarely ill enough to seek
medical attention. The diagnosis of chronic phase hepatitis C is also challenging
due to the absence or lack of specificity of symptoms until advanced liver disease
develops, which may not occur until decades into the disease.
Chronic hepatitis C may be suspected on the basis of the medical history
(particularly if there is any history of IV drug abuse or inhaled substance usage
such as cocaine), a history of piercings or tattoos, unexplained symptoms, or
abnormal liver enzymes or liver function tests found during routine blood testing.
Occasionally, hepatitis C is diagnosed as a result of targeted screening such as
blood donation (blood donors are screened for numerous blood-borne diseases
including hepatitis C) or contact tracing.
Hepatitis C testing begins with serological blood tests used to detect antibodies
to HCV. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks
after exposure, in >90% within 5 months after exposure, and in >97% by 6
months after exposure. Overall, HCV antibody tests have a strong positive
predictive value for exposure to the hepatitis C virus, but may miss patients who
have not yet developed antibodies (seroconversion), or have an insufficient level
of antibodies to detect. Rarely, people infected with HCV never develop
antibodies to the virus and therefore, never test positive using HCV antibody
screening.
Because of this possibility, RNA testing (see nucleic acid testing methods below)
should be considered when antibody testing is negative but suspicion of hepatitis
C is high (e.g. because of elevated transaminases in someone with risk factors
for hepatitis C).
Diagnosis cont.
Anti-HCV antibodies indicate exposure to the virus, but cannot
determine if ongoing infection is present. All persons with positive
anti-HCV antibody tests must undergo additional testing for the
presence of the hepatitis C virus itself to determine whether
current infection is present. The presence of the virus is tested for
using molecular nucleic acid testing methods such as polymerase
chain reaction (PCR), transcription mediated amplification (TMA),
or branched DNA (b-DNA).
All HCV nucleic acid molecular tests have the capacity to detect
not only whether the virus is present, but also to measure the
amount of virus present in the blood (the HCV viral load).
The HCV viral load is an important factor in determining the
probability of response to interferon-based therapy, but does not
indicate disease severity nor the likelihood of disease progression.
In people with confirmed HCV infection, genotype testing is
generally recommended. HCV genotype testing is used to
determine the required length and potential response to
interferon-based therapy
Treatment
There is a very small chance of clearing the virus spontaneously in chronic HCV carriers
(0.5 to 0.74% per year), however, the majority of patients with chronic hepatitis C will not
clear it without treatment.
Current treatment is a combination of pegylated interferon alpha (brand names Pegasys
and PEG-Intron) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending
on genotype.
Indications for treatment include patients with proven hepatitis C virus infection and
persistent abnormal liver function tests. Sustained cure rates (sustained viral response) of
75% or better occur in people with genotypes HCV 2 and 3 in 24 weeks of treatment,
about 50% in those with genotype 1 with 48 weeks of treatment and 65% for those with
genotype 4 in 48 weeks of treatment.
About 80% of hepatitis C patients in the United States have genotype 1. Genotype 4 is
more common in the Middle East and Africa.
Should treatment with pegylated ribivirin-interferon not return a 2-log viral reduction or
complete clearance of RNA (termed early virological response) after 12 weeks for
genotype 1, the chance of treatment success is less than 1%.
Early virological response is typically not tested for in non-genotype 1 patients, as the
chances of attaining it are greater than 90%.
The mechanism of action is not entirely clear, because even patients who appear to have
had a sustained virological response still have actively replicating virus in their liver and
peripheral blood mononuclear cells.
The evidence for treatment in genotype 6 disease is currently sparse, and the evidence
that exists is for 48 weeks of treatment at the same doses as are used for genotype 1
disease.
Physicians considering shorter durations of treatment (e.g., 24 weeks) should do so within
the context of a clinical trial.
Treatment during the acute infection phase has much higher success rates (greater than
90%) with a shorter duration of treatment; however, this must be balanced against the
15-40% chance of spontaneous clearance without treatment
Treatment Cont.
Those with low initial viral loads respond much better to treatment
than those with higher viral loads (greater than 2 million virions/ml).
Current combination therapy is usually supervised by physicians in
the fields of gastroenterology, hepatology or infectious disease.
The treatment may be physically demanding, particularly for those
with a prior history of drug or alcohol abuse. It can qualify for
temporary disability in some cases.
A substantial proportion of patients will experience a panoply of side
effects ranging from a 'flu-like' syndrome (the most common,
experienced for a few days after the weekly injection of interferon) to
severe adverse events including anemia, cardiovascular events and
psychiatric problems such as suicide or suicidal ideation. The latter
are exacerbated by the general physiological stress experienced by
the patient.
Current guidelines strongly recommend that hepatitis C patients be
vaccinated for hepatitis A and B if they have not yet been exposed to
these viruses, as this would radically worsen their liver disease.
Alcoholic beverage consumption accelerates HCV associated fibrosis
and cirrhosis, and makes liver cancer more likely; insulin resistance
and metabolic syndrome may similarly worsen the hepatic prognosis.
There is also evidence that smoking increases the fibrosis (scarring)
rate.
During Pregnancy & Breast
Feeding
If a pregnant woman has risk factors for hepatitis C, she should be tested for
antibodies against HCV.
About 4% infants born to HCV infected women become infected.
There is no treatment that can prevent this from happening.
There is a high chance of the baby ridding the HCV in the first 12 months.
In a mother that also has HIV, the rate of transmission can be as high as 19%.
There are currently no data to determine whether antiviral therapy reduces
perinatal transmission.
Ribavirin and interferons are contraindicated during pregnancy. However,
avoiding fetal scalp monitoring and prolonged labor after rupture of
membranes may reduce the risk of transmission to the infant.
HCV antibodies from the mother may persist in infants until 15 months of age.
If an early diagnosis is desired, testing for HCV RNA can be performed between
the ages of 2 and 6 months, with a repeat test done independent of the first
test result.
If a later diagnosis is preferred, an anti-HCV test can performed after 15
months of age.
Most infants infected with HCV at the time of birth have no symptoms and do
well during childhood.
There is no evidence that breast-feeding spreads HCV. To be cautious, an
infected mother should avoid breastfeeding if her nipples are cracked and
bleeding.
Alternative Therapy
Several alternative therapies purport to
maintain liver functionality, rather than
treat the virus itself, thereby slowing the
course of the disease to retain quality of
life.
As an example, extract of Silybum
marianum and Sho-saiko-to are sold for
their HCV related effects; the first is said
to provide some generic help to hepatic
functions, and the second claims to aid in
liver health and provide some antiviral
effects.[25]
Experimental Therapy
The drug viramidine, which is a prodrug of ribavirin that has better targeting for the liver,
and therefore may be more effective against hepatitis C for a given tolerated dose, is in
phase III experimental trials against hepatitis C. It will be used in conjunction with
interferons, in the same manner as ribavirin. However, this drug is not expected to be
active against ribavirin-resistant strains, and the use of the drug against infections which
have already failed ribavirin/interferon treatment, is unproven.
There are new drugs under development like the protease inhibitors (including VX 950)
and polymerase inhibitors (such as NM 283), but development of some of these is still in
the early phase. VX 950, also known as Telaprevir is currently in Phase 3 Trials.
One protease inhibitor, , had to be discontinued due to safety problems early in the
clinical testing. Some more modern new drugs that provide some support in treating HCV
are Albuferon, , and DAPY.[citation needed] Antisense phosphorothioate oligos have been
targeted to hepatitis C.
Antisense Morpholino oligos have shown promise in preclinical studies however, they were
found to cause a limited viral load reduction.
Immunoglobulins against the hepatitis C virus exist and newer types are under
development. Thus far, their roles have been unclear as they have not been shown to help
in clearing chronic infection or in the prevention of infection with acute exposures (e.g.
needlesticks). They do have a limited role in transplant patients.
In addition to the standard treatment with interferon and ribavirin, some studies have
shown higher success rates when the antiviral drug amantadine (Symmetrel) is added to
the regimen. Sometimes called "triple therapy", it involves the addition of 100 mg of
amantadine twice a day.
Studies indicate that this may be especially helpful for "nonresponders" - patients who
have not been successful in previous treatments using interferon and ribavirin only.
Currently, amantadine is not approved for treatment of Hepatitis C, and studies are
ongoing to determine when it is most likely to benefit the patient.
Followup studies have shown no benefit to adding this drug and currently it is not
commonly used by experienced hepatologists.
Prevention
The following guidelines will prevent infection with the hepatitis C
virus, which is spread by blood:
Avoid sharing drug needles or any other drug paraphernalia
including works for injection or bills or straws
Avoid unsanitary tattoo methods
Avoid unsanitary body piercing methods
Avoid unsanitary acupuncture
Avoid needlestick injury
Avoid sharing personal items such as toothbrushes, razors, and
nail clippers.
Use latex condoms correctly and every time you have sex if not in
a long-term monogamous relationship
Proponents of harm reduction believe that strategies such as the
provision of new needles and syringes, and education about safer
drug injection procedures, greatly decreases the risk of hepatitis C
spreading between injecting drug users.
No vaccine protects against contracting hepatitis C, or helps to
treat it. Vaccines are under development and some have shown
encouraging results.
Autoimmune Hepatitis
Autoimmune hepatitis is a disease in which the
body’s own immune system attacks the liver and
causes it to become inflamed.
The disease is chronic, meaning it lasts many
years.
If untreated, it can lead to cirrhosis and liver
failure.
There are two forms of this disease.
Type 1, or classic, autoimmune hepatitis is the
more common form. This is the form that mostly
affects young women and is often associated with
other autoimmune diseases.
Type 2 autoimmune hepatitis is less common
and generally affects girls between the ages of 2
and 14.
What Is The Cause?
The immune system normally attacks bacteria,
viruses and other invading organisms.
It is not supposed to attack your own cells; if it
does, the response is called autoimmunity.
In autoimmune hepatitis, the immune system
attacks your liver cells, causing long-term
inflammation and liver damage.
Scientists don’t know why the body attacks itself
in this way, although heredity and prior infections
may play a role.
Who Is at Risk?
About 70 percent of people with
autoimmune hepatitis are women,
usually between the ages of 15 and
40.
Many people with this disease also
have other autoimmune diseases,
including type 1 diabetes, thyroiditis,
ulcerative colitis, vitiligo, or Sjogren’s
syndrome .
Symptoms
Often, the symptoms of autoimmune hepatitis
are minor.
When symptoms do occur, the most common are
fatigue, abdominal discomfort, aching joints,
itching, jaundice, enlarged liver, nausea and
spider angiomas (blood vessels) on the skin.
Other symptoms may include dark urine, loss of
appetite, pale stools and absence of
menstruation.
More severe complications can include ascites
and mental confusion.
Diagnosis
Blood tests. A routine blood test for liver enzymes can help
reveal a pattern typical of hepatitis, but further tests, especially
for autoantibodies, are needed to diagnose autoimmune hepatitis.
Antibodies are proteins made by the immune system to fight off
bacteria and viruses. Autoantibodies attack the body’s cells.
In autoimmune hepatitis, the immune system makes one or more
types of autoantibodies.
The most common are antinuclear antibodies (ANA), smooth
muscle antibodies (SMA), and antibodies to liver and kidney
microsomes (anti-LKM). People with type 1 have ANA, SMA, or
both, and people with type 2 have anti-LKM.
Blood tests also help distinguish autoimmune hepatitis from other
diseases that resemble it, such as viral hepatitis B or C or a
metabolic disease such as Wilson disease.
Liver biopsy. A tiny sample of liver tissue, examined with a
microscope, can help doctors accurately diagnose autoimmune
hepatitis and tell how serious it is.
Treatment
The primary treatment is medicine to suppress, or slow down, an overactive immune
system.
Both types of autoimmune hepatitis are treated with daily doses of a corticosteroid called
prednisone.
Treatment may begin with a high dose of 30 to 60 mg per day and be lowered to 10 to
20 mg per day as the disease is controlled. The goal is to find the lowest possible dose
that will control the disease.
Another medicine, azathioprine (Imuran) is also used to treat autoimmune hepatitis. Like
prednisone, azathioprine suppresses the immune system, but in a different way.
Treatment may begin with both azathioprine and prednisone, or azathioprine may be
added later, once the disease is under control. The use of azathioprine allows for a lower
dose of prednisone, which in turn reduces predisone’s side effects.
In about seven out of 10 people, the disease goes into remission within 3 years of
starting treatment. Remission occurs when symptoms disappear and lab tests show
improvement in liver function.
Some people can eventually stop treatment, although many will see the disease return.
People who stop treatment must carefully monitor their condition and promptly report
any new symptoms to their doctor.
Treatment with low doses of prednisone or azathioprine may be necessary on and off for
years, if not for life.
Some people with mild forms of the disease may not need to take medication. Doctors
assess each patient individually to determine whether those with mild autoimmune
hepatitis should undergo treatment.
Other Treatment
People who do not respond to standard
immune therapy or who have severe side
effects may benefit from other
immunosuppressive agents such as
mycophenylate mofetil, cyclosporine, or
tacrolimus.
People who progress to end-stage liver
disease—also called liver failure—or
cirrhosis may need a liver transplant.
Transplantation has a 1-year survival rate
of 90 percent and a 5-year survival rate of
70 to 80 percent.