Hepatitis is inflammation of the liver that can be caused by several different viruses. This document discusses hepatitis A, B, C, D and E viruses. It provides details on the transmission, symptoms, treatment and prevention of each viral type. It notes that hepatitis B and C pose more significant health risks as they can lead to chronic liver disease and liver cancer if not properly treated. Vaccines exist to prevent hepatitis A and B infections.

1. Viral Hepatitis
Dr. Aloo

2. Introduction
Hepatitis
• First, “hepatitis” is the name of each of the hepatotropic viruses (hepatitis
A, B, C, D, and E) that have a specific affinity for the liver.
• Second, “hepatitis” stands for the histologic patterns of hepatitic injury,
both acute and chronic (depending on the specific virus), that are seen in
the livers infected by hepatotropic viruses (and in autoimmune and drug or
toxin induced hepatitis, as well).
• Third, to a more minor degree, it is any form of hepatocellular injury due to
infection by other, usually systemic viruses, such as (1) mild Epstein-Barr
virus hepatitis sometimes seen in infectious mononucleosis; (2)
cytomegalovirus, herpes virus, and adenovirus infections, particularly in
the newborn or immunosuppressed patient; and (3) yellow fever (yellow
fever virus), a major and serious cause of hepatitis in tropical countries.

3. Hepatitis A Virus
• Hepatitis A virus (HAV) is a usually benign, self-limited disease with an
incubation period of 2 to 6 weeks.
• HAV does not cause chronic hepatitis or a carrier state and only
uncommonly causes acute hepatic failure, so the fatality rate associated
with HAV is only about 0.1-0.3%.
• HAV occurs throughout the world and is endemic in countries with poor
hygiene and sanitation.
• Many individuals in these countries have detectable anti-HAV antibodies by
the time they are 10 years old.
• Clinical disease tends to be mild or asymptomatic and is rare after
childhood.

4. Cont.
• Discovered in 1973, HAV is a small, nonenveloped, positive-strand RNA
picornavirus that occupies its own genus, Hepatovirus.
• Ultra structurally, HAV is an icosahedral capsid 27 nm in diameter.
• The receptor for HAV is HAVcr-1, a 451–amino acid class I integral-membrane
mucin-like glycoprotein.
• HAV is spread by ingestion of contaminated water and foods and is shed in the
stool for 2 to 3 weeks before and 1 week after the onset of jaundice.
• Thus, close personal contact with an infected individual or fecal-oral
contamination during this period accounts for most cases and explains the
outbreaks in institutional settings such as schools and nurseries, and the water-
borne epidemics in places where people live in overcrowded, unsanitary
conditions.
• HAV vaccine, available since 1992, is effective in preventing infection.

5. Cont.
• HAV can also be detected in serum and saliva.
• Because HAV viremia is transient, blood-borne transmission of HAV occurs only
rarely; therefore, donated blood is not specifically screened for this virus.
• Specific IgM antibody against HAV appears with the onset of symptoms,
constituting a reliable marker of acute infection.
• Fecal shedding of the virus ends as the IgM titer rises.
• The IgM response usually begins to decline in a few months and is followed by
the appearance of IgG anti-HAV.
• The latter persists for years, perhaps conferring lifelong immunity against
reinfection by all strains of HAV.
• Since there are no routinely available tests for IgG anti-HAV, the presence of IgG
anti-HAV is inferred from the difference between total and IgM anti-HAV.

6. Hepatitis B Virus
• Hepatitis B virus (HBV) can produce
• acute hepatitis followed by recovery and clearance of the virus,
• Non-progressive chronic hepatitis
• progressive chronic disease ending in cirrhosis
• acute hepatic failure with massive liver necrosis
• an asymptomatic, “healthy” carrier state.
• HBV-induced chronic liver disease is also an important precursor for
the development of hepatocellular carcinoma even in the absence of
cirrhosis.

7. Mode of transmission of Hepatitis B:
• Hepatitis B is transmitted by the exchange of body fluids-blood,
serum, semen, breast milk, and in some circumstances saliva.
• Concentration of HBV in various body fluids:
• High: blood, serum, wound exudates
• Moderate: semen, vaginal fluids, saliva
• Low: urine, feces, sweat, tears, breast milk
• Routes of Transmission:
• From infected mother to child
• Transfusion of HBV-infected blood or blood products
• Sexual contact with an infected person.

8. Cont.
• Incubation period (2 to 26 weeks).
• HBV remains in the blood until and during active episodes of acute and
chronic hepatitis.
• Approximately 65% of adults newly acquiring HBV have mild or no
symptoms and do not develop jaundice.
• The remaining 25% have nonspecific constitutional symptoms such as
anorexia, fever, jaundice, and upper right quadrant pain.
• In almost all cases the infection is self-limited and resolves without
treatment.
• Chronic disease occurs in 5%-10% of infected individuals. Fulminant
hepatitis (acute hepatic failure) is rare, occurring in approximately 0.1%
to 0.5% of acutely infected individuals.

9. Cont.
• HBV was first linked to hepatitis in the 1960s when the Australian
antigen (later known as HBV surface antigen) was identified.
• The virus is a member of the Hepadnaviridae, a family of DNA viruses
that cause hepatitis in multiple animal species.
• The mature HBV virion is a 42-nm, spherical double-layered “Dane
particle” that has an outer surface envelope of protein, lipid, and
carbohydrate enclosing an electron-dense, 28-nm, slightly hexagonal
core.
• The genome of HBV is a partially double-stranded circular DNA
molecule having 3200 nucleotides with four open reading frames
coding for:

10. 1. A nucleocapsid “core” protein (HBcAg, hepatitis B core antigen) and
a longer polypeptide transcript with a pre-core and core region,
designated HBeAg (hepatitis B e antigen).
The precore region directs the secretion of the HBeAg polypeptide,
whereas HBcAg remains in hepatocytes, where it participates in the
assembly of complete virions.
2. Envelope glycoproteins (HBsAg, hepatitis B surface antigen), which
consist of three related proteins: large, middle, and small HBsAg.
Infected hepatocytes are capable of synthesizing and secreting
massive quantities of noninfective surface protein (mainly small
HBsAg).

11. 3. A polymerase (Pol) that exhibits both DNA polymerase activity and
reverse transcriptase activity.
Replication of the viral genome occurs via an intermediate RNA
template, through a unique replication cycle: DNA → RNA → DNA
4. HBx protein, which is necessary for virus replication and may act as a
transcriptional transactivator of both viral genes and a subset of host
genes. It has been implicated in the pathogenesis of hepatocellular
carcinoma in HBV infection.

13. Hepatitis B Antigens
• The natural course of the disease can be followed by serum markers:
• HBsAg appears before the onset of symptoms, peaks during overt disease,
and then often declines to undetectable levels in 12 weeks, although it may
persist in some individuals for as long as 24 weeks.
• Anti-HBs antibody does not rise until the acute disease is over, concomitant
with the disappearance of HBsAg In some cases, however, Anti-HBs
antibody is not detectable for a few weeks to several months after the
disappearance of HBsAg.
• During this window period, serologic diagnosis can be made by detection
of IgM anti-HBc antibody. Anti-HBs may persist for life, conferring
protection; this is the basis for current vaccination strategies using
noninfectious HBsAg

14. Cont.
• HBeAg, HBV-DNA, and DNA polymerase appear in serum soon after HBsAg, and
all signify active viral replication.
• Persistence of HBeAg is an important indicator of continued viral replication,
infectivity, and probable progression to chronic hepatitis.
• The appearance of anti-HBe antibodies implies that an acute infection has peaked
and is on the wane.
• IgM anti-HBc antibody becomes detectable in serum shortly before the onset of
symptoms, concurrent with the onset of elevated serum aminotransferase levels
(indicative of hepatocyte destruction).
Over a period of months the IgM anti-HBc antibody is replaced by IgG anti-HBc.
As in the case of anti-HAV, there is no direct assay for IgG anti-HBc; its presence is
inferred from decline of IgM anti-HBc in the face of rising total anti-HBc.

16. Cont.

17. Pathogenesis of hepatitis B virus
• The host’s immune response to the virus is the main determinant of the outcome of the infection.
Is an immune-pathologic disease
• HBV after entering the blood infects hepatocytes with the expression of viral antigen on the
surface of infected cells. Copies the of HBV genome integrate into hepatocyte chromosomes and
remain latent.
• Viral DNA and HBc Ag can be detected the in the nucleus while HBs Ag the in the cytoplasm and
the at hepatocyte membrane.
• The intracellular accumulation of filamentous form of HBs Ag produces the ground glass
appearance of affected hepatocyte which is the characteristic feature of HBV infection.
• Adaptive immunity is more involved the innate immunity in causing tissue destruction. In fact
both tissue destruction and virus clearance from the host cell are attributed to cellular immunity
(CMI)
• MHC I activated CD8 T-cell and MII-activated CD4 T-cells are involved in pathology of disease.
However most of the destruction is due to CD8 T cells.
• CD8 T cells also induce TNF-α and other cytokines including interferon-Ƴ which further compound
the non-specific liver destruction.

18. Treatment and Vaccine
• Age at the time of infection is the best predictor of chronicity.
• The younger the age at the time of HBV infection, the higher the
probability of chronicity.
• Despite progress in the treatment of chronic HBV infection, complete cure
is extremely difficult to achieve even when treated with highly effective
antiviral agents.
• The difficulty in achieving cure has been attributed to the ability of the
virus to insert itself in the host DNA, thus limiting the development of an
effective immune response (HBsAb development).
• This allows the virus to persist in the face of drugs that impair its
replication. Hence, the goal of the treatment of chronic hepatitis B is to
slow disease progression, reduce liver damage, and prevent liver cirrhosis
or liver cancer.

19. Cont.
• Treatment of patients with hepatitis is supportive and directed at allowing hepatocellular
damage to resolve and repair itself.
• Recombinant interferon-α and pegylated interferon-α are currently used in HBV
treatment.
• Antiviral drugs: Nucleotide analogs (Lamivudine)
• Orthotopic liver transplant: It is the treatment for chronic hepatitis end stage liver
damage
• Vaccine for HBV is available since 1982. Initially vaccine was prepared by purifying HBs
Ag associated with 22 nm particle and inactivating through formalin treatment.
• Recombinant HBs Ag produced by recombinant DNA technology using yeast cell or
mammalian cell line culture is used as first recombinant vaccine.
• Passive immunization using specific hepatitis B immune globulin (HBIG) have shown
effective protection. However it is not recommended for pre-exposure prophylaxis.

20. Hepatitis C Virus
• Hepatitis C Virus (HCV) is a major cause of liver disease worldwide,
with approximately 170 million people affected.
• common risk factors for HCV infection are:
• Intravenous drug abuse
• Multiple sex partners
• Having had surgery within the last 6 months
• Needle stick injury
• Multiple contacts with an HCV-infected person
• Employment in medical or dental fields
• Unknown

21. HCV
• HCV, discovered in 1989, is a member of the Flaviviridae family.
• It is a small, enveloped, single-stranded RNA virus with a 9.6-kilobase
(kb) genome that codes for a single polyprotein with one open
reading frame, which is subsequently processed into functional
proteins.
• Because of the low fidelity of the HCV RNA polymerase, the virus is
inherently unstable, giving rise to multiple genotypes and subtypes.

22. HCV
• This genomic instability and antigenic variability have seriously
hampered efforts to develop an HCV vaccine.
• In particular, elevated titers of anti-HCV IgG occurring after an active
infection do not confer effective immunity.
• A characteristic feature of HCV infection, therefore, is repeated bouts
of hepatic damage, the result of reactivation of a preexisting infection
or emergence of an endogenous, newly mutated strain.

23. Pathogenesis
• The incubation period for HCV hepatitis ranges from 4 to 26 weeks, with a mean
of 9 weeks.
• In about 85% of individuals, the clinical course of the acute infection is
asymptomatic and typically missed.
• HCV RNA is detectable in blood for 1 to 3 weeks, coincident with elevations in
serum transaminases.
• In symptomatic acute HCV infection, anti-HCV antibodies are detected in only
50% to 70% of patients; in the remaining patients, the anti-HCV antibodies
emerge after 3 to 6 weeks.
• The clinical course of acute HCV hepatitis is milder than that of HBV; rare cases
may be severe and indistinguishable from HAV or HBV hepatitis.
• It is not known why only a small minority of individuals are capable of clearing
HCV infection.

24. • Persistent infection and chronic hepatitis are the hallmarks of HCV
infection, despite the generally asymptomatic nature of the acute
illness.
• In contrast to HBV, chronic disease occurs in the majority of HCV-
infected individuals (80% to 90%) and cirrhosis eventually occurs in as
many as a 20% of individuals with chronic HCV infection.
• The mechanisms that lead to the chronicity of HCV infection are not
well understood, but it is clear that the virus has developed multiple
strategies to evade host antiviral immunity.

25. • In more than 90% of individuals with chronic HCV infection,
circulating HCV RNA persists despite the presence of antibodies.
• Hence, in persons with chronic hepatitis, HCV RNA testing must be
performed to assess viral replication and to confirm the diagnosis of
HCV infection.
• A clinical feature that is quite characteristic of chronic HCV infection
is persistent elevations in serum aminotransferases.
• Their levels wax and wane but almost never become normal.
• Therefore, any individual with detectable HCV RNA in the serum
needs close clinical follow-up.

26. Treatment
• HCV infection is potentially curable.
• based on the combination of pegylated IFN-α and ribavirin and cure
rates depended on the viral genotype; patients with genotype 2 or 3
infection generally have had the best responses.
• Host genotype also influences the response.
• New drugs targeting viral protease and polymerase have now been
approved or are in development.
• With currently available drugs sustained virologic response (defined
as undetectable HCV RNA in the patient’s blood 24 weeks after the
end of treatment) can be achieved in 50% to 80% of patients.

27. Phases of Hepatitis C virus
Phase I: Infection
• HCV virus enters the bloodstream, attaches to liver cells, and begins to reproduce.
• New virus, made in infected liver cells, invades more liver cells and infects them
Phase II: Inflammation
• Infected liver cells become inflamed.
• The inflammation causes liver cells to die
Phase III: Fibrosis
• Over time, hepatitis C commonly progresses to fibrosis.
• Among the healthy and inflamed liver cells strands of scar tissue develop. If your liver biopsy
shows significant fibrosis, it usually means you've been infected with HCV for 10 years or more
Phase IV: Cirrhosis
• When fibrosis increases, cirrhosis begins to appear.
• Cirrhosis affects how blood flows in and out of the liver. This impairs normal liver functions

28. Hepatitis D Virus
• Also called “the delta agent,” hepatitis D virus (HDV) is a unique RNA
virus that is dependent for its life cycle on HBV.

29. • Infection with HDV arises in the following settings.
• • Co-infection occurs following exposure to serum containing both HDV and HBV. The HBV must become
established first to provide the HBsAg necessary for development of complete HDV virions. Co-infection of
HBV and HDV results in acute hepatitis that is indistinguishable from acute hepatitis B.
• It is self -limited and is usually followed by clearance of both viruses.
• However, there is a higher rate of acute hepatic failure, in intravenous drug users.
• • Superinfection occurs when a chronic carrier of HBV is exposed to a new inoculum of HDV.
• This results in disease 30 to 50 days later presenting either as severe acute hepatitis in a previously
unrecognized HBV carrier or as an exacerbation of preexisting chronic hepatitis B infection.
• Chronic HDV infection occurs in almost all of such patients.
• The superinfection may have two phases: an acute phase with active HDV replication and suppression of
HBV with high transaminase levels, and a chronic phase in which HDV replication decreases, HBV replication
increases, transferase levels fluctuate, and the disease progresses to cirrhosis and sometimes hepatocellular
carcinoma

30. • Worldwide, 15 million people are estimated to be infected with HDV
(about 5% of 300 million of HBV infected persons).
• Prevalence varies, being high in the Amazon basin, and in central
Africa, the Middle East, and the Mediterranean basin, where 20% to
40% of HbsAg carriers may have anti-HDV antibody; the rate has been
declining in recent years.
• Surprisingly, HDV infection is uncommon in the large population of
HBsAg carriers in Southeast Asia and China.
• In western countries it is largely restricted to intravenous drug
abusers and those who have had multiple blood transfusions

31. • HDV, discovered in 1977, is a 35-nm, double-shelled particle. The external coat antigen of
HBsAg surrounds an internal polypeptide assembly, designated delta antigen (HDAg), the
only protein produced by the virus.
• Associated with HDAg is a small circular molecule of single-stranded RNA, whose length
is smaller than the genome of any known animal virus. Replication of the virus is through
RNA-directed RNA synthesis by host RNA polymerase.
• HDV RNA is detectable in the blood and liver just before and in the early days of acute
symptomatic disease.
• IgM anti-HDV antibody is the most reliable indicator of recent HDV exposure, although its
appearance is late and frequently short-lived.
• Nevertheless, acute co-infection by HDV and HBV is best indicated by detection of IgM
against both HDAg and HBcAg (denoting new infection with hepatitis B). With chronic
delta hepatitis arising from HDV superinfection, HBsAg is present in serum, and anti-HDV
antibodies (IgG and IgM) persist for months or longer.
• Vaccination for HBV also prevents HDV infection

32. Hepatitis E Virus
• Hepatitis E virus (HEV) is an enterically transmitted, water-borne infection that occurs primarily in
young to middle-aged adults.
• HEV is a zoonotic disease with animal reservoirs, such as monkeys, cats, pigs, and dogs.
• Epidemics have been reported in Asia and the Indian subcontinent, sub-Saharan Africa, Middle
East, China and Mexico, although sporadic cases are seen in industrialized nations, particularly in
regions where pig farming is common.
• Sporadic infection may also occur in travelers to these regions, but, most importantly, HEV
infection accounts for more than 30% to 60% of cases of sporadic acute hepatitis in India,
exceeding the frequency of HAV.
• A characteristic feature of HEV infection is the high mortality rate among pregnant women,
approaching 20%.
• In most cases the disease is self-limiting; HEV is not associated with chronic liver disease or
persistent viremia in immunocompetent patients.
• Chronic HEV infection does occur in patients with AIDS and immunosuppressed transplant
patients. The average incubation period following exposure is 4 to 5 weeks.

33. • Discovered in 1983, HEV is an unenveloped, positive stranded RNA virus in
the Hepevirus genus.
• Viral particles are 32 to 34 nm in diameter, and the RNA genome is
approximately 7.3 kb in size. Virions are shed in stool during the acute
illness.
• Before the onset of clinical illness, HEV RNA and HEV virions can be
detected by PCR in stool and serum.
• The onset of rising serum aminotransferases, clinical illness, and elevated
IgM anti-HEV titers are virtually simultaneous.
• Symptoms resolve in 2 to 4 weeks, during which time the IgM is replaced
with a persistent IgG anti-HEV antibodies.

34. Clinicopathologic Syndromes of Viral Hepatitis
• Several clinical syndromes may develop following exposure to
hepatitis viruses:
• (1) acute asymptomatic infection with recovery (serologic evidence
only),
• (2) acute symptomatic hepatitis with recovery, anicteric or icteric,
• (3) chronic hepatitis, with or without progression to cirrhosis, and
• (4) acute liver failure with massive to sub massive hepatic necrosis.