C

I S
T IT
P A
HE
 Hepatitis C infection is an infection of the liver
caused by the hepatitis C virus (HCV).
 The hepatitis C virus belongs to the genus
Hepacivirus a member of the family
Flaviviridae.
 Viruses belonging to this family all
have a plus sense RNA as their genetic
material.
 All hepatitis C viruses are made up of
an outer coat (envelope) and contain
enzymes and proteins that allow the
virus to reproduce within the cells of
the body, in particular, the cells of the
liver.
Although this basic structure is
common to all hepatitis C viruses,
there are at least six distinctly
different strains of the virus which
have different genetic profiles
(genotypes).
 Even within a single genotype there
may be some variations (genotype 1a
and 1b, for example).
 Genotyping is important to guide
treatment because some viral
genotypes respond better to therapy
than others.
 The genetic diversity of HCV is
one reason that it has been difficult
to develop an effective vaccine
since the vaccine must protect
against all genotypes.
Transmission
Although HCV, like HBV, can cause
chronic persistent hepatitis, deaths
from acute liver failure are rare. HCV
infection usually results from:
 Use of intravenous drugs. This a highly
efficient route of infection. Among needle-
sharing drug users, there is a 30%
prevalence of HCV infection within three
years of initiation and greater than 50%
after five years. Most (50-90%) HIV infected
intravenous drug users are also HCV-
infected.
 Blood transfusion or tissue
transplantation. Since the introduction
of blood screening, the incidence of
transfusion-associated HCV infections
has fallen.
 Occupational exposure to blood and other
fluids:
This is rather inefficient with a 1.8%
incidence of infection after a needle stick from
an HCV-positive person. Splashes of blood or
contact with a wound may also result in rare
transmission.
 Inadvertent (iatrogenic/nosocomial)
transmission as a result of inoculations
 An HCV-infected mother at the time of
delivery: About 6% of babies born to
infected mothers become HCV-infected
but this rises to 17% if the mother is also
HIV-infected. It does not appear that HCV
can be transmitted by breastfeeding.
Infected infants do well and severe HCV-
hepatitis is rare.
 Sexual intercourse with an infected
person: The risk is increased with
multiple sex partners but the efficiency
of spread is low and what influences
transmission is unknown.
Pathogenesis
 HCV enters the bloodstream and infects
hepatocytes.
 The virus usually does not kill the host cell
and thus can set up a persistent infection
leading to chronic disease.
 Symptoms, similar to HBV, again do not
result from the virus but from the effect of
the immune system on infected hepatocytes,
the cytotoxic T cell response being the most
important factor.
Viremia is detected one to three weeks after
infection.
After a prodromal phase of six to seven weeks
(although ranging from two to twenty six
weeks), symptoms appear (jaundice,
abdominal pain, nausea, appetite-loss and
dark urine).
These are usually milder than with HBV and
in more than 80% of patients the acute phase
of viremia is asymptomatic.
 In the acute phase of infection, virus
particles can be detected for several months.
 In 15-25% of patients, the virus is cleared
ending the infection but, in the majority of
infected people, HCV sets up a persistent
liver infection that may last for many years
leading to chronic active hepatitis.
 Many of these patients develop cirrhosis of
the liver and some experience liver failure.
 During the chronic infection period, HCV
can give rise to extra-hepatic
manifestations; these include essential
mixed cryoglobulinemia (resulting in rash,
vasculitis etc.), porphyria cutanea retarda,
membranoproliferative glomerulonephritis
and possibly diabetes mellitus and
lymphoma.
 These symptoms may be due to immune
complexes that are formed and also to
autoimmune disease.
 Pathogenicity of HCV infections is
promoted under a variety of conditions
including increased consumption of alcohol
and co-infection with HIV or chronic HBV.
 It is also greater in older people (more than
40 years) and in males.
Carcinogenesis:
After many years (up to thirty), a
small proportion (5%) of HCV
chronically-infected patients develop
hepatocellular carcinoma.
Immunology
 Symptoms, when they occur, extend from one
to more than five months after infection;
virus is detectable in the bloodstream during
this period.
 Also during this period, liver enzymes, such
as alanine aminotransferase, are elevated .
 Anti-HCV antibodies rise after two
months and are detectable for several
years if the patient is chronically infected
(figure 29).
 There are six serotypes of HCV that
circulate worldwide with multiple
subtypes.
Diagnosis
 Symptoms are the first aspect of
diagnosis.
 These include jaundice, nausea and
fatigue accompanied by elevated (at
least ten fold) alanine
aminotransferase.
 Antibodies against HCV are also
clearly indicative.
 There is a highly specific ELIZA test
that detects HCV antibodies; however,
these do not appear until eight to
twenty weeks after infection which is
after the end of the prodromal phase.
 Thus, antibody is not a reliable
indicator of acute infection.
 PCR can be used to detect viral
RNA within a week or two of
infection in seronegative patients.
 There is also a recombinant
immunoblot assay(RIBA), that
detects two or more HCV
antibodies.
 People who have been
occupationally exposed to HCV-
infected blood or children of
infected mothers should be
tested .
 Chronic infection can be diagnosed from
the presence of antibodies and long term
elevation of serum aminotransferases.
 This can be confirmed by PCR since in a
chronic infection, viral RNA should be
present in the blood stream.
In immuno-suppressed patients, PCR testing
is necessary and this is also the case when
other liver-damaging behavior, such as
alcoholism, is suspected.
Other problems that may be confused with
HCV hepatitis are autoimmune hepatitis,
chronic hepatitis B and D, alcoholic
hepatitis, fatty liver, and sclerosing
cholangitis.
 The table below provides guidelines for interpreting the results of testing for HCV antibodies
by EIA and RIBA and for hepatitis C virus RNA:

Anti-HCV
Anti-HCV (RIBA) HCV RNA Interpretation
(ELISA/EIA)

Negative Negative Negative No infection

Positive Positive Positive Ongoing infection

Past or current infection. Additional or

Positive Positive Negative repeat testing should be done to exclude
fluctuating or low levels of viremia.

Positive Negative Negative False positive ELISA; no infection

Positive Indeterminate Negative Situation unclear, consider additional testing

New (acute) HCV infection or chronic HCV

Negative Negative Positive infection in an immunocompromised person
unable to make adequate antibodies
Treatment
 The patient should be assessed for chronic
liver disease and counseled to avoid behavior,
such as alcohol consumption, that may
exacerbate liver damage.
 Two drugs in combination are recommended
in a 24-48 week regimen.
 These are ribavirin and pegylated
interferon alpha-2a and 2b
(Peginterferon which has the trade
names Pegintron)
(the interferon is processed by attaching
ethylene glycol to it. This process is called
pegylation and it slows the elimination of
interferon from the body so that its effects are
more prolonged).
HEPATITIS D
In 1977, an Italian doctor named Mario
Rizzetto discovered a new nuclear antigen in
the liver cells of patients infected with
Hepatitis B Virus (HBV).
The antigen was thought to be a new protein
encoded by HBV, and it was labeled as the
delta antigen. Subsequent research on
chimpanzees, however, indicated that this
antigen was derived from a new virus,
named the Hepatitis Delta Virus (HDV).
HDV is not classified into a viral family
because it is a unique virus dependent on
HBV.
HDV is a co-infection of HBV. The envelope
of HDV particles contains the Hepatitis B
surface antigen (HBsAg).
The production and transmission of HDV is
entirely dependent on HBV to provide
HBsAg.
Thus, HDV is considered a satellite virus of
HBV.
Unlike a classical satellite virus, however,
HDV does not share sequence similarity with
HBV, and it can replicate independently of
HBV.
There are at least three HDV genotypes: I, II,
and III.
 HDV isolates of Genotype I have been
reported in every part of the world, and the
pathogenesis of Genotype I infections
varies from fulminant hepatitis to
asymptomatic chronic liver disease.
 The milder HDV II genotype is found
primarily in Asia, including Japan,
Taiwan, and Russia. Some sequences
from Taiwan and the Okinawa islands
have been assigned to a subtype of
Genotype II, called Genotype IIB.
 HDV genotype III has been isolated only
in northern South America (Peru,
Venezuela, and Columbia) and is
associated with severe acute hepatitis.
 Furthermore, HDV genotype I is the only
genotype found in some locations,
including Europe and North America.
 Multiple genotypes have been detected in
Africa and in Asia.
 Mixed infections of genotypes I and II or
II and IIb have been reported in Taiwan.
HDV consists of a single stranded, negative
sense, circular RNA virus, with an envelope
made up of HBAg.
Virions are 35-43 nm and are roughly
spherical, with no distinct nucleocapsid
structure.
The nucleocapsid is made up of 60 large and
small delta antigens. These are the only
proteins encoded by HDV.
Viral replication occurs in the nucleus of
primary hepatocytes.
New virions can be assembled only in the
presence of hepatitis B virus.
Transmission:
HDV can be transmitted via blood
exchange, sexual contact, sharing
needles, and from mother-to-child.
Clinical Features
Although clinical features are variable, the clinical
course of HDV is typically more severe than that of the
other hepatitis viruses.
After an incubation period of 3-7 weeks, nonspecific
clinical symptoms, including fatigue, lethargy, nausea,
and anorexia, begin and last for about 3-7 days.
Viral replication is usually diminished during
this phase.
Jaundice occurs in the next phase of
symptoms.
Fatigue and nausea usually continue, and the
serum bilirubin level becomes abnormal.
At the same time, the infected person may
have clay-colored stool and dark urine. This
is evidence of the liver's diminished ability
to excrete bilirubin.
Diagnosis
Type D hepatitis should be
considered in individuals who are
HBsAg positive or who have
evidence of recent HBV infection.
The diagnosis for Hepatitis D infection is
made following serologic tests for the
virus:
 Total anti-HDV antibodies are
detected by radioimmunoassay (RIA)
or enzyme immunoassay (EIA) kits.
 To monitor ongoing HDV infection,
reverse transcriptase-polymerase
chain reaction (RT-PCR) should be
used. RT-PCR can detect 10 to 100
copies of the HDV genome in infected
blood serum.
Each of the markers of HDV infection,
including IgM and IgG antibodies,
disappears within months after
recovery.
In chronic Hepatitis D infection, on the
other hand, HDV RNA, HDAg, IgM anti-
HD antibodies, and IgG anti-HD
antibodies persist.
Outcomes
The outcome of disease depends on
whether HDV is contracted as a co-
infection or a superinfection:
Co-infection:
Co-infection occurs when both HDV and
HBV are contracted simultaneously.
This results in acute HDV and HBV
infection.
Depending on the relative amounts of
HBV and HDV, one or two episodes of
hepatitis occurs.
Co-infections of HDV and HBV are usually
acute and self-limiting infections.
HBV/HDV co-infections cause chronic
HDV infections in less than 5% of co-
infected patients. Although clinical
symptoms disappear, fatigue and
lethargy may persist for weeks or
months.
Superinfection:
Superinfection occurs when chronic HBV
carriers are infected with HDV.
This leads to severe acute hepatitis and
chronic Hepatitis D infection in 80% of
the cases. Superinfection is associated
with the fulminant form of viral hepatitis.
Fulminant viral hepatitis, the most
severe form of acute disease, is about
ten times more common in HDV
infections than in the other types.
It is characterized by hepatic
encephalopathy that is manifested by
changes in personality, disturbances in
sleep, confusion, difficulty concentrating,
and sometimes abnormal behavior and
coma.
The mortality rate of fulminant hepatitis
is about 80%.
Chronic hepatitis D infection progresses
to liver cirrhosis in about 60-70% of
patients. Cirrhosis takes about 5-10 years
to develop, but can appear two years after
the onset of infection.
Hepatocellular carcinoma occurs in
chronically infected HDV patients with
the same frequency as in patients with
ordinary HBV. Overall, the mortality rate
for HDV infections lies between 2% and
20%, values ten times greater than the
mortality rates for HBV.
Prevention and Treatment
Prevention of Hepatitis Delta Virus
infection is based on prevention of HBV, as
HDV requires the surface antigen of HBV
to cause infection.
There is no vaccine for HDV, but there is
an effective vaccine for HBV.
In order to prevent HDV-HBV co-infection,
the HBV vaccine or post exposure
prophylaxis (Hepatitis B Immune
Globulin) can be used to prevent infection.
There is no specific treatment for HDV
infections. Immunosuppressive therapy
has no positive clinical effect. Antiviral
drugs, including Acyclovir, Ribavirin,
Lamivudine, and synthetic analogs of
thymosin have all proved ineffective.
The only way to prevent HBV-HDV
superinfection is to educate chronic HBV
carriers about transmission and risky
behaviors.
Hepatitis E
 Hepatitis E virus (HEV) is an
enterically-transmitted acute viral
hepatitis.
 Infection with this virus was first
documented in 1955 during an
outbreak in New Delhi, India
Hepatitis E virus (HEV) is an icosahedral,
non- enveloped single stranded RNA
virus that is approximately 27 to 34 nm
in diameter .
It has been classified as the single
member of the genus hepevirus in the
family Hepeviridae
Transmission and Exposure
Hepatitis E virus is usually spread by the
fecal-oral route. The most common
source of infection is fecally
contaminated drinking water.
In developed countries sporadic
outbreaks have occurred following
consumption of uncooked/undercooked
pork or deer meat. Consumption of
shellfish was a risk factor in a recently
described outbreak.
There is a possibility of zoonotic spread
of the virus. HEV RNA had been
extracted from meat and organ of some
animal species including pigs, boar, and
deer. Foodborne infection could occur
from consumption of
uncooked/undercooked products from
infected animals.
 Little information regarding the
vertical transmission of HEV
but it can occur.
 One report evaluated eight babies
born to mothers infected with
hepatitis E in the third trimester.
Six infants had clinical, serologic,
or virologic evidence of HEV
infection.
 Two infants died within 24 hours
of birth, one of whom had
massive hepatic necrosis at
autopsy. 
signs and symptoms of Hepatitis E:
When they occur, the signs and symptoms of
Hepatitis E are similar to those of other types
of acute viral hepatitis and can include:
•Fever
•Fatigue
•Loss of appetite
•Nausea
•Vomiting
•Abdominal pain
•Jaundice
•Dark urine
•Clay-colored stool
•Joint pain
Symptomatic illness following HEV
infection acquired sporadically or during
outbreak in developing countries
commonly occur among older
adolescents and young adults (aged 15–
44 years).
Children infected with HEV usually have
mild or no symptoms.
Pregnant women are more likely to
experience severe illness including
fulminant hepatitis, and death.
When symptoms occur, they usually
develop 15 to 60 days (mean: 40 days)
after exposure.
The period of communicability has not
been clearly determined, but virus
excretion in stool has been
demonstrated up to 14 days after the
onset of jaundice.
Most people with Hepatitis E recover
completely. The overall case-fatality rate
is about 1%.
However, for pregnant women, Hepatitis
E can be a serious illness with mortality
reaching 10%–30% among pregnant
women in their third trimester of
pregnancy.
Hepatitis E could also be serious among
persons with preexisting chronic liver
disease resulting in decompensation
and mortality.
To date, there is no report of progression
of acute hepatitis E to chronic Hepatitis E
in developing countries. However, more
and more cases of Hepatitis E with
progression to chronic hepatitis and
chronic liver disease are being reported
among cases acquired in the developed
countries.
These chronic cases are exclusively
among persons who are on
immunosuppressive treatment for solid
organ transplant.
Diagnosis
Hepatitis E should be suspected in
outbreaks of waterborne hepatitis
occurring in developing countries,
especially if the disease is more severe in
pregnant women, or if hepatitis A has
been excluded.
If laboratory tests are not available,
epidemiologic evidence can help in
establishing a diagnosis
Laboratory Criteria for Diagnosis
• IgM anti-HAV negative and
• IgM anti-HBc negative (if done) or
HBsAg negative and
• Antibody to hepatitis C virus (anti-
HCV) negative (if done) and
• IgM anti-HEV positive.
HEV RNA can be detected in acute phase
feces by PCR in approximately 50% of
cases.
Immune electron microscopy is positive
in only about 10% of cases.
Diagnostic tests available in research
laboratories include: enzyme
immunoassays (EIAs) and Western blot
assays to detect IgM and IgG anti-HEV in
serum, polymerase chain reaction (PCR)
tests to detect HEV RNA in serum and
stool, immunofluorescent antibody
blocking assays to detect antibody to
HEV antigen in serum and liver and
immune electron microscopy to visualize
viral particles in feces.
Treatment
No therapeutic measures have been
proven effective following the onset of
disease.
Prevention and Control
Prevention of hepatitis E relies primarily
upon the provision of clean water
supplies. Educational programs should
be designed to stress sanitary disposal
of feces and careful hand washing after
defecation and before handling food.
Travelers to endemic areas should take
precautions to avoid contaminated food
and water,