Viral hepatitis

Getnet Worku (PhD)

 Viral hepatitis

• Viral hepatitis is a disease of the liver by a group of diverse

viruses that share a common ability to cause inflammation
and necrosis of the liver
• At least five different viruses cause hepatitis, and probably
more remain to be discovered or become better known
1) Hepatitis A virus (HAV)
2) Hepatitis B virus (HBV)
3) Hepatitis C virus (HCV)
4) Hepatitis D virus (HDV)
5) Hepatitis E virus (HEV)
 Viral hepatitis…

• One additional hepatitis virus, hepatitis G virus (HGV), has

been identified that is not associated with any clinical
disease so far
• Other viruses, such as Epstein-Barr virus and
cytomegalovirus, can cause inflammation of the liver, but
hepatitis is not the primary disease caused by them
• Drug and chemical toxicity can also cause acute hepatitis
that is clinically identical to viral hepatitis.
 Viral hepatitis…

• Viral hepatitis can be a sudden illness with a mild to

severe course followed by complete resolution. This is
called acute viral hepatitis and can be caused by all
of these viruses.
• Hepatitis can also have a prolonged course of active
disease or silent asymptomatic infection termed chronic
viral hepatitis.
• The parenterally (blood-to-blood) transmitted HBV, HCV,
and HDV can cause chronic hepatitis.
 Viral hepatitis…

• Acute viral hepatitis has a variable incubation period,

depending on the virus type (a few weeks to as long as 6 months)
• The earliest symptoms are nonspecific systemic symptoms
much like the flu, with fatigue, anorexia, nausea, vomiting,
low-grade fever, myalgia, cough, runny nose, pharyngitis,
and abdominal or right upper quadrant discomfort
• One to two weeks later the patient may develop jaundice as
the level of bilirubin, which is normally cleared by the
liver, rises
 Viral hepatitis…

• As the virus grows in the hepatocytes, these liver cells necrose

• The hepatocytes produce enzymes that are released during cell
death
• These are the liver-function enzymes aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
gamma-glutamyl transpeptidase (GGT), and alkaline
phosphatase.
• Elevated blood levels of these liver enzymes help establish the
diagnosis of hepatitis.
• So about 2 weeks into the illness, the patient is often
jaundiced, has a painful enlarged liver and high blood levels of
liver-function enzymes
 Chronic viral hepatitis

• Chronic viral hepatitis is more difficult to diagnose

because the patient is often asymptomatic with only an
enlarged tender liver and mildly elevated liver function
enzyme levels
 Hepatitis A virus
• Hepatitis A virus (HAV) belongs to the Picornaviridae
(picornaviruses) family and Hepatovirus genus.
• It is an unenveloped (naked capsid), with a cubic
(icosahedral) symmetry and a diameter of 27 nm
• The genome of HAV is a 7.4 kb positive-sense, single-
stranded RNA
• Multiple genotypes have been defined on the basis of
sequence comparisons
 HAV…

• Human HAV strains have been divided into six (formerly

seven) genotypes, three human genotypes (I, II, and III )
and three simian strains (IV, V, and VI)
• Phenotypic differences such as disease severity among the
genotypes have not been recognized
• there is only one recognized serotype of HAV based on
cross-neutralization studies
 HAV…

• HAV is a relatively stable virus under a variety of

environmental conditions
• HAV is more resistant to heat and may not be completely
inactivated by exposure to 60° C for 10 to 12 hours
• Complete inactivation in food requires heating to higher
than 85° C for at least 1 minute
• However, HAV can be reliably inactivated by autoclaving
(121° C for 30 minutes)
 HAV…

• The virus is resistant to most organic solvents and

detergents and to a pH as low as 3
• HAV can be inactivated by many common disinfecting
chemicals including hypochlorite (bleach), and quaternary
ammonium formulation containing 23% HCl
 HAV…
pathogenesis
• After a typical entrance via the oral route, HAV multiplies
in the epithelial lining of the intestinal tract.
• Viremia eventually occurs, and the virus spreads to the
liver
• Replicates in hepatocytes (little damage to cells) released
via bile to intestines
 HAV…
pathogenesis
• The amount of virus excreted is greatest before symptoms
appear and then declines rapidly
• There is a 15-40 day incubation period (about 1 month)
before the patient develops acute hepatitis
• Liver damage and clinical syndrome result of immune
response (CMI-CD8+ T cells) and not direct effect of virus
• Always cause acute disease - never chronic and not
oncogenic
 HAV…

• Young children are the most frequently infected, and

they have a milder course than do adults, often without
developing jaundice or even symptoms
• At the other end of the spectrum, a small percentage ( 1-
4%), usually adults, will develop fulminant (severe)
hepatitis
• However, death from HAV is very rare ( 1%).
 HAV…

• The HAV capsid is antigenic, resulting in the host

production of anti-HAV lgM and later, the anti-HAV
IgG.
• Acute disease is diagnosed by the detection of IgM anti-
HAV because these antibodies appear about 4 weeks after
infection and disappear about 3 to 4 months after infection
• Anti-HAV IgG indicates old infection and no active
disease.
• This antibody lasts indefinitely and is protective, which
means that it will protect against future infection with HAV
 HAV…
Treatment
• No specific treatment for the disease exists, but people at
risk of exposure or who have been exposed to HAV can
be given immune globulin, which provides protection for
several months.
Prevention:
• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Inactivated vaccines are recommended for travelers to areas of
endemic disease
 Hepatitis B virus

• Hepatitis B virus (HBV) infects more than 500 million

people worldwide.
• It is the leading cause of chronic hepatitis, cirrhosis, and
hepatocellular carcinoma (HCC)
• Hepatitis B virus (HBV) is an enveloped DNA virus
belonging to the family Hepadnaviridae
• The complete virion is a 42 nm spherical particle that
consists of an envelope around a 27 nm core
• The core comprises a nucleocapsid that contains the DNA
genome
• The intact virus is called the Dane particle
 HBV…

• HBV is a small DNA virus, whose 3200 kilobases (kb)

partially double stranded DNA genome is maintained in a
circular conformation
• One of the unique features of HBV infection is the
production of large quantities of subviral spherical and
filamentous HBsAg particles in addition to complete
virus particles.
• These particles are devoid of HBV DNA genome and
hence are noninfectious.
• Because of their high immunogenicity, purified HBsAg
particles can be used as an HBV vaccine
A. the 42 nm particle is the “Dane particle” or the hepatitis B virus.
B. the 22 nm particles are the filamentous and circular forms of hepatitis
B surface antigen (HBsAg) some capsid proteins that have disassociated
from the intact virion.
 HBV…

• Hepatitis B surface antigen (HBsAg) and is of critical

importance because antibodies against this component
(antiHBsAg) are protective
• Removing HBsAg leaves the viral core, which is called
hepatitis B core antigen (HBcAg) and is also antigenic
• However, antibodies against the core (anti-HBcAg) are not
protective
• During active infection and viral growth, a soluble
component of the core is released.
• This is called HBeAg
 HBV…

• HBeAg antigen is a cleavage product of the viral core

structural polypeptide
• HBeAg is found dissolved in the serum, and is a marker
for active disease and a highly infectious state
• Pregnant mothers with HBeAg in their blood will almost
always transmit HBV to their offspring (90% transmission
rate), whereas mothers who have no HBeAg will rarely
infect the neonate ( 10% transmission rate)
 HBV…

• The viral genome consists of partially double-stranded

DNA with a short, single stranded piece
• It comprises 3200 nucleotides
• It has not yet been possible to propagate the virus in cell
culture.
 HBV…

• There are four major serotypes of HBV (adr, adw, ayr,

ayw) based on HBsAg antigenic epitopes.
• There are eight hepatitis B genotypes (A-H) based on
nucleotide sequence variation of HBV genome, which may
be associated with different clinical outcomes.
• These genotypes vary in geographic distribution
• Genotypes A and C predominate in the US. However, genotypes B and D are also present in the US.
Genotype F predominates in South America and in Alaska, while A, D and E predominate in Africa.
Genotype D predominates in Russia and in all its prior dominions, while in Asia, genotypes B and C
predominate.
• Available data suggests that genotype produces a milder disease, respond better to IFN therapy, and is
less likely to develop hepatocellular carcinoma.
 HBV…
Replication
 HBV…

• The replication of HBV involves a reverse transcription

step, and, as such, is unique among DNA viruses
• HBV has a specific tropism for the liver
• However, the receptor for HBV and the mechanism of viral
entry are not known
• After viral entry, the DNA is translocated to the nucleus,
the partially double-stranded DNA repair of the gapped (+)
DNA strand is accomplished by as yet unidentified
enzymes.
• found in a covalently closed circular form called CCC
DNA
 HBV…

• Host RNA polymerase directs the transcription of viral

mRNAs to encode early proteins, including HBcAg,
HBeAg, and viral DNA polymerase as well as full-length
RNA (pregenomic RNA)
• HBsAg is encoded later and associates with the membranes
of endoplasmic reticulum or Golgi apparatus
• The pregenome RNA is translated to produce polymerase
protein, P, which possesses reverse transcriptase activity
and capsid
 HBV…

• Using pregenome RNA as a template reverse transcription

begins with synthesis of (-) strand DNA followed by (+)
strand DNA synthesis.
• Before the completion of + strand synthesis, core particles
mature and these structures acquire envelopes by budding
into the ER, where viral morphogenesis is completed.
• Progeny-enveloped virions are released from the cell by
exocytosis or are recycled to the nucleus, where the
process is repeated.
 HBV…
Pathogenesis
• Transmission is via exposure to blood and blood products
containing the virus, by sexual intercourse and vertically at
birth (this is the main route of transmission in Asia and
Africa)
• Incubation period of 6 weeks–6 months
• Viral replication in liver results in lysis of hepatocytes by
CTL in those who mount an effective immune response
 HBV…
Pathogenesis
• Hepatic damage is reversed in 8–12 weeks in >90% cases
• 2–10% become chronic carriers (persistence of HBsAg for
>6 months)
• 95% of newborns of carrier mothers become carriers if
untreated
 HBV…
Acute Hepatitis B
• Many cases of acute hepatitis B are subclinical
• The infected person is often entirely unaware
• In about a third of the cases, the patient exhibits symptoms
of disease—the person feels unwell and often suffers from
low-grade fever, nausea, and abdominal pain.
• Eventually, jaundice, dark urine, and other evidence of
liver damage appears
• However, in a few cases (less than 1%), the patient
develops fulminant hepatitis, causing sudden, massive
liver damage; survival without a liver transplant is
uncommon.
Jaundice
Acute Hepatitis B

Weeks after Exposure

 HBV…
Chronic Hepatitis B
• Chronic infection
• Immune tolerance (usually infections acquired at birth)-
there is circulating HBsAg, HBeAg, and high levels of
HBV DNA
• Immune clearance (many patients clear Hbe antigen and
HBe antibody positivity)
• Inactive carrier (HBe antibody positive with low levels of
virus present in blood)
• HBeAg-negative chronic hepatitis B (HBe antigen
negative, HBe antibody positive & HBV DNA detected).
Chronic Hepatitis B
 HBV…

• Chronic hepatitis B (CHB) has a variable natural history,

ranging from an inactive carrier state with an excellent
long-term prognosis, to progressive liver fibrosis which
may lead to the development of cirrhosis and
hepatocellular carcinoma (HCC)
• Of adults with CHB, approximately 20–30% will develop
these complications, and an estimated 686,000 people die
prematurely due to HBV every year.
 HBV…
Diagnosis
• Serological tests are made by immunoassays detecting HBsAg,
HBeAg and antibodies to HBcAg (IgM and IgG), anti-HBeAg
and anti-HBsAg
• HBsAg - used as a general marker of infection.
• HBsAb - used to document recovery and/or immunity to HBV
infection.
• anti-HBc IgM - marker of acute infection.
• anti-HBcIgG - past or chronic infection.
• HBeAg - indicates active replication of virus and therefore
infectiveness.
• Anti-Hbe - virus no longer replicating. However, the patient can
still be positive for HBsAg which is made by integrated HBV.
 HBV…
Diagnosis
• HBV-DNA for quantitative nucleic acid detection to
determine viral load (RT-PCR) and genotype assessment.
• indicates active replication of virus, more accurate than
HBeAg especially in cases of escape mutants. Used mainly
for monitoring response to therapy
Interpretation of Serologic Tests in Hepatitis B
 HBV…
Treatment
• Antiviral agents active against HBV have been shown to
suppress HBV replication, prevent progression to cirrhosis,
and reduce the risk of HCC and liver-related death
• Available antivirals include
• Interferons (either interferon alfa or pegylatedinterferon
alfa) suppress HBV DNA levels and lead to seroconversion
of HBeAg in around 35% of patients with chronic
Hepatitis B infection
 HBV…
Treatment
• Nucleoside analogs lamivudine, adefovir, entecavir, and
telbivudine) or a nucleotide analog (tenofovir)
• Seroconversion of HBeAg is similar to the interferons (-
30-35%).
• Drawbacks include the development of drug resistance
(particularly with lamivudine), the need for long term or
indefinite treatment, and expense
• Combinations of at least two drugs are recommended to
minimize development of resistance
• These antivirals inhibit viral replication and may reduce
viral load but do not cure HBV infection
 HBV…
Prevention
• Vaccination - highly effective recombinant vaccines are now
available. Vaccine can be given to those who are at increased
risk of HBV infection such as health care workers. It is also
given routinely to neonates as universal vaccination in many
countries.
• Hepatitis B Immunoglobulin - HBIG may be used to protect
persons who are exposed to hepatitis B. It is particular
efficacious within 48 hours of the incident. It may also be given
to neonates who are at increased risk of contracting hepatitis B
i.e. whose mothers are HBsAg and HBeAg positive.
• Other measures - screening of blood donors, blood and body
fluid precautions
 Hepatitis D (Delta Hepatitis)
• HDV is small (36 nm in diameter) virus requires the presence of
HBsAg (HBV surface antigen) on its envelope for its transmission,
and is thus found only in persons with acute or chronic HBV infection

• The HDV genome is a small single-stranded, circular (–) RNA (1.7

kb) genome that is enclosed by hepatitis delta antigen, which
functions as a nucleocapsid for the viral genome

• Replication of HDV is complex and unique

• Transcription and replication of HDV occurs in the nucleus using host

cell RNA polymerase
 HDV…
Epidemiology
• Worldwide distribution; high prevalence in the
Mediterranean area, Africa, South America, Japan
and the Middle East.
Ethiopia

• Like hepatitis B virus, hepatitis D virus is spread in bodily

fluids via sexual activity and the use of contaminated
needles.
• Affects the same risk groups to HBV.
 HDV disease

• HDV can occur as either acute (coinfection form) or

chronic (superinfection form) hepatitis.
• In people with a case of self-limiting acute hepatitis B,
coinfection with HDV disappears as the HBV is cleared
from the system
• However, if the HBV infection progressed to the chronic
stage, superinfection with HDV is often accompanied by
progressive liver damage and a fatality rate several times
that of people infected with HBV alone
• Most simultaneous acute infections in adults are cleared
along with hepatitis B.
• Of acute coinfections, 1% to 3% become chronic, and 70%
to 80% of superinfections develop into chronic hepatitis D
• Once chronic infection is established, the clinical course of
hepatitis is accelerated
• Cirrhosis occurs in 60% to 80% of chronic hepatitis D
patients, and the risk of HCC is about threefold
 Diagnosis

• Serology (EIA) can be used to detect HDV antibody and HDV

antigen;
• The IgM antibodies appear within 3 weeks of infection and persist
for several weeks, whereas IgG antibodies persist for years

• Nucleic acid detection methods (PCR)

• Prevention
• HBV vaccination and subsequent immunity to HBV reduces the
risk of acquiring the delta agent
 Hepatitis C virus

• HCV is a roughly spherical, enveloped, positive-strand

RNA virus approximately 55 nm in diameter
• Member of Flaviviridae family and Hepacivirus genus
• Positive-sense RNA genome encodes three structural (C,
core; E1 and E2, envelope) and five nonstructural (NS2-
NS5) proteins
HCV…
 HCV…

• HCV is highly heterogeneous because the genome of HCV

is highly mutable, because its RNA-dependent RNA
polymerase lacks proofreading ability.
• Mutations give rise to HCV quasispecies (variants) and
antigenic variation, most noticeably in the E2 glycoprotein
hypervariable regions (HVR1 and HVR2), which may
allow the virus to escape immune response and cause
chronic or persistent infection in infected persons.
 HCV…

• There are six main genotypes, which respond differently to

antiviral treatment.
• United States, 60% to 70% of isolates are either of
genotype 1a or 1b
• In contrast, genotype 4 infections are prevalent throughout
Africa and the Middle East.
 HCV…
replication
• HCV uses a series of cellular receptors, such as tetraspanin
CD81
• followed by virus entry into target cells probably via
receptor-mediated endocytosis.
• HCV replicates in the cytoplasm via negative-sense RNA
intermediates
• The RNA genome is encoded into a polyprotein, which is
processed into individual proteins by viral and host
proteases
 HCV…
Epidemiology
• Similar to HBV, HCV is spread parenterally.
• The transmission of HCV by blood well documented
• Sexual transmission likely but to a lower extent than HBV
• Worldwide 150 million people are chronically infected
 HCV…
pathogenesis
• Cell-mediated immune responses and elaboration by T
cells of antiviral cytokines contribute to the containment of
infection and pathogenesis of liver injury associated with
hepatitis C
 HCV…
disease
• The majority of infections with HCV are subclinical, but
about 25 percent of infected individuals present with acute
hepatitis, including jaundice
• More important, a significant proportion of infections
progress to a chronic hepatitis and cirrhosis.
• Some of these individuals go on to develop hepatocellular
carcinoma many years after the primary infection
HCV…
disease
 HCV…
Diagnosis
• Serology by EIA to detect HCV antibodies, antigens
• RT-PCR: for diagnosis and viral load
• Genotyping is important for therapy
Treatment
• Combination therapy with interferon-α and ribavirin can
benefit some persons with chronic infection
Prevention
• Routine testing of all blood and organ donors for HCV antibody has been
undertaken, to prevent transmission by transfusion or
transplantation
 Hepatitis E virus (HEV)

• Non-enveloped, positive-strand RNA virus, it represents

the only species in the Hepeviridae family.
• There are 4 known genotypes that infect certain mammals
including man.
 HEV…

• Endemic in Indian subcontinent, Southeast Asia, Middle

East, North Africa and Central America.
• Common source outbreaks caused by contaminated water
or food are common.
• In developed countries, sporadic cases are detected among
travellers returning from endemic areas.
• More recently strains (genotypes 3 and 4) of hepatitis E
have been detected in domestic animals in industrialized
countries and are implicated in zoonotic infections
 HEV…

• Transmission by the faecal-oral route and rarely by

blood transfusion in endemic countries
• Incubation period is up to 6 weeks. Specific IgG and IgM
antibodies are produced.
• Acute self-limiting hepatitis with no evidence of chronic
infection – indistinguishable from other acute hepatitis
infections
• High mortality rate (10–20%) in pregnant women has been
observed in India.
 Treatment

• No specific treatment
• Prevention
• Safe hygienic measures reduce risks of transmission
 Diagnosis

• Serology: (detection of IgG and IgM antibodies by EIA)

• PCR: nucleic acid detection in reference laboratories
Comparison of Hepatitis A, B, D (Delta), C, and E
 Hepatic Abscess

• A bacterial, fungal, or parasitic enclosed collection of pus

that involves the liver parenchyma
• Liver abscesses or cysts are most commonly the result of
direct extension to the liver or hematogenous extension to
the liver

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• Bacterial or Pyogenic Etiology
Gram-negative pathogens. Escherichia coli and Klebsiella spp are the
most common
• Other pathogens include:
Pseudomonas spp
Proteus spp
Enterobacter spp
Citrobacter spp
• Anaerobic bacteria Bacteroides spp
Gram-positive etiology
• Staphylococcus aureus
• Enterococcus and viridans streptococci (S. milleri)
• Beta-hemolytic streptococci
• miliary form of Mycobacterium tuberculosis
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• Fungal Etiology. (Patients are usually immunocompromised.)
• Most commonly include
• Candida spp
• Aspergillus spp

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• Parasitic causes.
Entameba histolytica
Echinococcus granulosus (hydatid cyst)
Fasciola hepatica

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 Hepatic abscess…
Lab dx
• LFTs. Almost always demonstrates elevated levels of
alkaline phosphatase and ALT

• Aspiration of abscess contents for Gram stain and culture

• Serology. Entameba histolytica, and Echinococcus spp
• Radiography studies - US or CT

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 Hepatic abscess…

• Treatment

• drainage of abscess contents (pericystectomy or formal

hepatic resection for Echinococcus)
• administration of parenteral antimicrobial agents,
• treatment of the underlying condition

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 Hepatobiliary Infections

• Cholecystitis
• An inflammatory condition of the gallbladder with a resultant
infection.
• Risks – gallstone, Trauma and resuscitation from hemorrhagic
shock
• Microbial Causes to Cholecystitis
- Gram-negative enteric bacilli (eg, Enterobacteriaceae)
- Enterococci
- Intestinal anaerobes (eg, Bacteroides spp, Clostridium spp)

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