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04.

02-02
February 6, 2014
M ald o , M . D.
Things arent always going to be fair in the real world. Thats just the way it is. But for the most
part, you get what you give. Rest of your life is being shaped right now. With the dreams you Hepatitis Viruses
chase, the choices you make, and the person you decide to be. The rest of your life is a long time.
And the rest of your life starts right now. Haley, OTH

OUTLINE Hepatitis viruses produce acute inflammation of the liver,
Hepatitis Viruses 1 resulting in a clinical illness characterized by:
Hepatitis A 1 o Fever
Hepatitis B 3 o GI symptoms (nausea and vomiting, & jaundice)
Hepatitis C 7
Hepatitis D 9
Hepatitis E 9
Additional Information/Tables 10

LAST WEEKS AS 2nd YEAR STUDENTS! PUSH! J


GOODLUCK, EVERYONE!

HEPATITIS VIRUSES
VIRAL HEPATITIS - systemic disease primarily involving
the liver (figure 1)
o Hepatitis A virus (HAV) - infectious hepatitis
o Hepatitis B virus (HBV) - serum hepatitis
o Hepatitis C virus (HCV) - posttransfusion hepatitis
o Hepatitis E virus (HEV) - enterically transmitted Figure 1. Hepatitis virus
hepatitis

Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E


Family Picornaviridae Hepadnaviridae Flaviviridae Unclassified Hepeviridae
Genus Hepatovirus Orthohepadnavirus Hepacivirus Deltavirus Hepevirus
Virion 27 nm, icosahedral 42 nm, spherical 60 nm, spherical 35 nm, spherical 30-32 nm,
icosahedral
Envelope No Yes (HBsAg) Yes Yes (HBsAg) No
Genome ssRNA dsDNA ssRNA ssRNA ssRNA
Genome size 7.5 3.2 9.4 1.7 7.2
(kb)
Stability Heat- and acid- Acid-sensitive Ether-sensitive, Acid-sensitive Heat-stable
stable acid-sensitive
Transmission Fecal-oral Parenteral Parenteral Parenteral Fecal-oral
Prevalence High High Moderate Low, regional Regional
Fulminant Rare Rare Rare Frequent In pregnancy
disease
Chronic disease Never Often Often Often Never
Oncogenic No Yes Yes ? No
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Feces Blood/blood- Blood/blood- Blood/blood- Feces
Source of virus
derived body fluids derived body fluids derived body fluids
Route of Fecal-oral Percutaneous Percutaneous Percutaneous Fecal-oral
transmission Permucosal Permucosal Permucosal
Chronic infection No Yes Yes Yes No
Pre/post-exposure Pre/post-exposure Blood donor Pre/post-exposure Ensure safe
ummunization ummunization screening; risk immunization; rish drinking water
Prevention
behavior behavior
modification modification

DIAGNOSIS OF HEPATITIS Infectivity can be preserved for:


Liver biopsy tissue diagnosis of hepatitis o At least 1 month after being dried and stored at 25C
Tests for abnormal liver function, such as serum and 42% relative humidity or for years at 20C
alanine aminotransferase (ALT) and bilirubin Stable in:
o Supplement the clinical, pathologic, and epidemiologic o 20% ether
findings. o Acid (pH 1.0 for 2 hours)
o Heat (60C for 1 hour)
HEPATITIS A VIRUS
Destroyed by
First provisionally classified as Enterovirus 72
o Autoclaving (121C for 20 minutes)
Only one serotype is known.
o Boiling in water for 5 minutes
No antigenic cross-reactivity with other hepatitis viruses.
o Dry heat (180C for 1 hour)
Genomic sequence analysis of a variable region involving
o Ultraviolet irradiation (1 minute at 1.1 watts)
the junction of the 1D and 2A genes divided HAV isolates
o Formalin (1:4000 for 3 days at 37C)
into seven genotypes.
o Chlorine (10-15 ppm for 30 minutes).

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Hepatitis Viruses


Necessary to inactivate HAV Person to person;
o Heating food to >85C (185F) for 1 minute Low food &waterborne Low Young adults
o Disinfecting surfaces with sodium hypochlorite (1:100 outbreaks
dilution of chlorine bleach) Travelers; outbreaks
Very Low Very low Adults
Sensitive serologic assays and polymerase chain uncommon
reaction (PCR) detect HAV in stools and to measure In places where there is low endemicity, usually adults
specific antibody in serum. are infected.
Various primate cell lines will support growth of HAV, ANTI-HAV PREVALENCE in the Philippines: HIGH
though fresh isolates of virus are difficult to adapt and grow.
No cytopathic effects are apparent. LABORATORY DIAGNOSIS
ACUTE Diagnosed by the detection of HAV-IgM in
CLINICAL FEATURES
INFECTION serum by Enzyme Immunoassay (EIA)
INCUBATION Average 30 days PAST Immunity is determined by the detection of
PERIOD Range 15-50 days INFECTION HAV-IgG by EIA
<6 yrs: 10%
JAUNDICE BY AGE
6-14 yrs: 40%-50% CDC
GROUP
>14 years: 70-80%
Fulminant hepatitis
COMPLICATIONS Cholestatic hepatitis
Relapsing hepatitis
CHRONIC SEQUELAE None
*Infection in 6-10 is usually subclinical

OUTCOMES OF INFECTION
Onset of disease tends to occur abruptly with HAV (w/in 24
hours), in contrast to a more insidious onset with HBV &
HCV.
Complete recovery occurs9\ in most hepaA cases J
No chronicity
Disease is more severe in adults than in children, in
whom it often goes unnoticed
Relapses of HAV infection can occur 14 months after JAWETZ22
initial symptoms have resolved.

OUTCOMES OF INFECTION WITH HEPATITIS A VIRUS


OUTCOME CHILDREN ADULTS
Inapparent
(subclinical) 8095% 1025%
infection
Icteric disease 520% 7590%
Complete
> 98% > 98%
recovery
Chronic disease None None
Mortality rate 0.1% 0.32.1%

TRANSMISSION
Close personal contact household contact, sex contact,
child day care centers)
Contaminated food, water (e.g. infected food handlers,
raw shellfish) Figure 2. Immunologic and biologic events associated with
Blood exposure (rare) (e.g. injecting drug use, human infection with hepatitis A virus
transfusion)
o Incidence of getting it from transfusion is low since viral HEPA A VIRUS (HAV):
shedding coincides with prodrome meaning patients Detected by immune electron microscopy in fecal extracts
already exhibit signs, e syempre kung naninilaw na yung Appears early in the disease & disappears w/in 2 wks
patient they will not be allowed to donate blood following onset of jaundice.
GLOBAL PATTERNS OF INFECTION Can be detected in liver, stool, bile, & blood by
ENDEMI- DISEASE PEAK AGE OF TRANSMISSION immunoassays, nucleic acid hybridization assays, or PCR
CITY RATE INFECTION PATTERNS Detected in stool from about 2 wks prior to onset of
Person to person; jaundice up to 2 wks after
Low to Early
High outbreaks
High childhood ANTIBODIES(ABS):
uncommon
Late Person to person; Anti-HAV IgM: acute phase
Moderate High childhood/ food & waterborne o Peaks ~ 2 wks after elevation of liver enzyme
young adults outbreaks o Declines to nondetectable levels within 36 mos

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Hepatitis Viruses


Anti-HAV IgG: Two major polypeptides (one glycosylated)
o Appears soon after the onset of disease PROTEINS Present in HBsAg
o Persists for decades Present in HBcAg
Thus, detection of IgM-specific anti-HAV in the blood of an ENVELOPE Contains HBsAg and lipid.
acutely infected patient confirms the diagnosis of hepatitis By means of an intermediate RNA copy of the
A. DNA genome (HBcAg in nucleus; HBsAg in
ELISA - method of choice for measuring HAV Abs REPLICATI
cytoplasm). Both mature virus and 22-nm
ON
spherical particles consist of HBsAg secreted
EPIDEMIOLOGY from the cell surface.
Many cases occur in community-wide outbreaks Family is made up of many types that infect
o No risk factor identified for most cases humans & lower animals (eg, woodchucks,
o Highest attack rates in 5-14 years CHARAC- squirrels, ducks)
o Children serve as reservoir of infection (since they TERISTICS Cause acute & chronic hepatitis, often
experience subclinical infection) progressing to permanent carrier states
& hepatocellular carcinoma
Persons at increased risk of infection
o Travelers STRUCTURE AND COMPOSITION
o Homosexual men Note: Nice to know lang ata to. Pero daanan, baka kasi magtanong pa rin sila
o Injecting drug users galling ditto. J Push! :D
Electron microscopy of HBsAg-positive serum reveals three
PREVENTION morphologic forms:
1. SPHERICAL PARTICLES (Most common)
Immune Globulin
2. TUBULAR FORM
o Pre-exposure (Persons at increased risk for infection)
3. FILAMENTOUS FORM
Travelers to intermediate & high HAV-endemic
countries
Homosexual men
Injecting drug users
o Post-exposure (Immunoglobulin (IG))
Routine
Household and other intimate contacts
Selected situations
Institutions (e.g. day care centers)
Common source exposure (e.g. food prepared by
infected food handler)
* When administered within 2 weeks after an exposure to
hepatitis A virus, IG is 80-90% effective in preventing
hepatitis A.
Wash hands
Use gloves when appropriate
Risk reduction if involved in oral/anal sexual practices
Risk reduction if involved in intravenous drug use
Hepatitis A Vaccine
o Used for pre-exposure prophylaxis
o Given as 2-dose series
o Licensed for use for persons >2 years old
o Duration of protection is at least 20 years possibly
All forms are made exclusively of HBsAg, however,
lifelong
tubular and filamentous form result from
o Unresolved issues:
overproduction of HBsAg.
Use for post-exposure prophylaxis
The outer surface, or envelope, contains HBsAg and
Use in community-wide outbreaks
surrounds a 27-nm inner nucleocapsid core that contains
HBcAg.
HEPATITIS B VIRUS
Different HBV isolates share 90-98% nucleotide sequence
HBV establishes chronic infections, especially in those homology.
infected as infants o Full-length DNA negative strand (L or long strand)
It is a major factor in the eventual development of liver complementary to all HBV mRNAs
disease and hepatocellular carcinoma in those o Positive strand (S or short strand) variable and
individuals. between 50% and 80% of unit length
S gene has three in-frame initiation codons and encodes
IMPORTANT PROPERTIES OF HEPADNAVIRUSES the major HBsAg, as well as polypeptides containing in
About 42 nm in diameter overall addition pre-S2 or pre-S1 and pre-S2 sequences.
VIRION
(nucleocapsids, 18 nm) C gene has two in-frame initiation codons and encodes
One molecule of double-stranded DNA, HBcAg plus the HBe protein, which is processed to produce
circular, 3.2 kbp. In virion, negative DNA soluble HBeAg.
GENOME strand is full length and positive DNA strand The particles containing HBsAg are antigenically complex
is partially complete. The gap must be HBsAg staibility does not always coincide with that of the
completed at beginning of replication cycle infectious agent:

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Hepatitis Viruses


Hepa B s Antigen (HBsAg) Hepa B Virus (HBV) the disease (i.e. jaundiced), compared to adults. However,
Both are stable at -20 C for over 20 years & stable to people infected at an earlier age will usually proceed to a
repeated freezing and thawing chronic infection L
HBsAg is stable at pH 2.4 for Stable at 37 C for 60 min **Incubation Period appears to vary w/ dose of HBV
up to 6hrs, but HBV & remains viable after administered & route of administration, being prolonged
infectivity is lost. being dried & stored at 25 in those who receive a low dose of virus or who are infected
C for at least 1 week by a nonpercutaneous route.
Antigenicity is destroyed by HBV (but not HBsAg) is
sodium hypochlorite 0.5% sensitive to higher temp SPECTRUM OF CHRONIC HEPATITIS B DISEASES
(eg, 1:10 chlorine bleach) (100 C for 1 minute) or to Chronic Persistent Hepatitis asymptomatic
w/in 3 min at low protein longer incubation pd (60 Chronic Active Hepatitis symptomatic exacerbations of
concentrations but undiluted C for 10 hours) hepatitis
serum specimens require Cirrhosis of Liver
higher conc (5%) Hepatocellular Carcinoma
HBsAg is not destroyed by ultraviolet irradiation of plasma TRANSMISSION OF HEPATITIS B VIRUS AND
or other blood products, and viral infectivity may also SPECTRUM OF OUTCOMES OF INFECTION
resist such treatment. TRANSMISSION1
VERTICAL CONTACT PARENTERAL,
REPLICATION OF HEPATITIS B VIRUS
(ASIA) (AFRICA) SEXUAL
Age at Newborns, Young Teenagers,
infection infants children adults
Recovery
from acute 5% 20% 90-95%
infection
Progression
to chronic 95% 80% 5-10%
infection
Chronic
carriers2
10-20% 10-20% 0.5%
(% of total
population)
1
Vertical & contact-associated transmission occurs in
The infectious virion attaches to cells and becomes endemic regions; parenteral & sexual transmission are
uncoated the main modes of transmission in nonendemic regions.
2
In the nucleus, the partially double-stranded viral At high risk of developing hepatocellular carcinoma.
genome is converted to covalently closed circular double-
stranded DNA (cccDNA). OUTCOMES HBV INFECTION
cccDNA serves as template for all viral transcripts, Varies ranging from complete recovery to progression to
including a 3.5-kb pregenome RNA. chronic hepatitis &, rarely, death due to fulminant disease.
The pregenome RNA becomes encapsidated with newly 6580% are inapparent, with 9095% of
ADULTS
synthesized HBcAg. all patients recovering completely.
Within the cores, the viral polymerase synthesizes by INFANTS &
8095% become chronic carriers and
reverse transcription a negative-strand DNA copy. YOUNG
their serum remains positive for HBsAg
The polymerase starts to synthesize the positive DNA CHILDREN
strand, but the process is not completed. INDIVIDUALS
Majority are symptomatic for many years;
Cores bud from the pre-Golgi membranes, acquiring WITH
there may or may not be biochemical and
HBsAg-containing envelopes, and may exit the cell. CHRONIC
histologic evidence of liver disease
Alternatively, cores may be reimported into the nucleus and HBV
initiate another round of replication in the same cell. CHRONIC High risk of developing hepatocellular
CARRIERS carcinoma
CLINICAL FEATURES Rarely occurs with HAV or HCV infections
Occasionally develops during acute viral
INCUBATION **Average 60-90 days
hepatitis
PERIOD (IP) Range 45-180 days
Defined as hepatic encephalopathy
CLINICAL ILLNESS <5 yrs. <10% w/in the first 8 weeks of disease in
(JAUNDICE) >5 yrs. 30%-50% patients without preexisting liver
ACUTE CASE- disease
0.5%-1% FULMINANT
FATALITY RATE Fetal in 7090% of cases, with survival
HEPATITIS
CHRONIC <5 yrs. 30%-90% uncommon over the age of 40 years
INFECTION >5 yrs. 2%-10% Fulminant HBV disease is assoc w/
PREMATURE superinfection by other agents, including
MORTALITY FROM HDV.
15%-25% In most patients who survive, complete
CHRONIC LIVER
DISEASE restoration of the hepatic parenchyma and
normal liver function is the rule.
*Most of cases under 5 years are acquired through
perinatal transmission. Among these only a few manifest

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Hepatitis Viruses


LABORATORY DIAGNOSIS Used mainly for monitoring response to
therapy
JAWETZ:
WINDOW IgM anti-HBc and total anti-HBc are the
DNA polymerase activity, HBV DNA, and HbeAg
PERIOD only serologic markers that are present
o Representative of the viremic stage of hepatitis B
o Occur early in the incubation period, concurrently or
shortly after the first appearance of HBsAg ACUTE INFECTION
PERIOD OF HIGHEST COMMUNICABILITY: Note: Same lang ung dalawang graph. May ALT level and
o High concentrations of HBV particles may be present in kailan lumalabas ung symptoms ung sa Jawetz kaya sinama
the blood (up to 1010 particles/mL) during the initial na rin namin. J
phase of infection CDC Graph:
HbsAg
o detectable 2-6 weeks in advance of clinical and
biochemical evidence of hepatitis
o persists throughout the clinical course of the disease
o disappears by the sixth month after exposure.
HBsAg can be detected in saliva, nasopharyngeal washings,
semen, menstrual fluid, and vaginal secretions as well as in
blood.
It should be assumed that all bodily fluids from HBV-
infected patients may be infectious
Hepa B surface antigen
HbsAg General marker of infection
(red line) First serologic marker to appear
Presence indicates either acute or chronic
Antibody to hepatitis B surface antigen
marker of immunity.
Detectable during convalescence after the Jawetz Graph:
anti-HBs
disappearance of HBsAg
(orange
Its presence indicates an immune response
line)
to HBV infection, an immune response to
vaccination, or the presence of passively
acquired antibody.
Antibody to hepatitis B core antigen
Nonspecific marker of acute, chronic or
Total anti-
resolved HBV infection.
HBc
Not a marker of vaccine-induced immunity
(blue line)
It may be used in prevaccination testing to
determine previous exposure to HBV infection
IgM anti- IgM antibody subclass of anti-HBc
HBc Positivity indicates recent infection with HBV
(yellow (< or = to 6 mos; CDC: 6-8 months)
line) Presence indicates acute infection
IgG anti- IgG antibody subclass of anti-HBc
HBc Presence indicates chronic infection
Hepatitis B e antigen
Marker of a high degree of HBV infectivity, Summary of serologic events as transcribed from the
and it correlates with a high level of HBV Animated Graph Tutorial from CDC. J
HbeAg replication In acute hepatitis B, the first serologic marker to appear
(pink bar) Detectable in patients with acute disease following Hepatitis B virus is HBsAg (red line).
Primarily used to help determine the clinical On average HBsAg can be detected one month after
management of patients with chronic HBV exposure to the virus. But, it can range from about one
infection week to nine weeks.
May be present in an infected or immune When HBsAg is positive, HBV DNA can usually be
person. detected in the patients blood.
anti-Hbe Virus no longer replicating The duration of HBsAg enhance HBV DNAs variable.
(yellow Patient can still be positive for HbsAg which is o About 50% of the patients will be HBsAg and HBV DNA
bar) made by integrated HBV negative by 7 weeks after symptoms appear
In persons with chronic HBV infection, its o All patients who recover will be HBsAg and HBV DNA by
presence suggests a low viral titer an a low 15 weeks after the appearance of symptoms.
degree of infectivity Hepatitis B antigen termed HBeAg (pink bar) is generally
Indicates active replication of virus detectable in patients with acute disease. The presence of
More accurate than HbeAg, especially in HBeAg in serum correlate with higher titer of virus and
HBV-DNA
cases of escape mutants greater infectivity.
(orange The presence of anti-HBe denotes lower level of virus
Correlates well with infectivity
bar)
When HbsAg is positive, this can be detected therefore less infectivity.
in patients blood Symptoms when present occur at the average of 12 weeks

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after exposure with a range of 9 weeks to 21 weeks. serum as long as HbsAg is present.
A diagnosis of acute hepatitis B can be made in the Most useful detection methods:
detection of IgM class antibody to HBcAg. IgM anti-HBc is o ELISA HBV antigens and antibodies
generally detectable at the time of onset of symptoms and o PCR viral DNA.
decline to subdetectable levels within 6 to 8 months.
Total antibody to the anti-HBc persists indefinitely as a INTERPRETATION OF HBV SEROLOGIC MARKERS IN
marker of past infection. PATIENTS WITH HEPATITIS.
Anti-HBs becomes detectable during convalescence and Assay Results
after the disappearance of HBsAg and generally indicates HbsAg Anti- Anti-
recovery and immunity from reinfection. INTERPRETATION
HBs HBc
There is a period of time called the WINDOW PERIOD Early acute HBV infection.
which occurs after the disappearance of HBsAg and (+) (-) (-) Confirmation is required to
before the appearance of anti-HBs. exclude nonspecific reactivity
HBV infection, either acute or
CHRONIC INFECTION
chronic. Differentiate with IgM
(+) () (+) anti-HBc. Determine level of
replicative activity (infectivity)
with HbeAg or HBV DNA.
Indicates previous HBV
(-) (+) (+) infection & immunity to
hepatitis B.
Possibilities include:
HBV infection in remote past
low-level HBV carrier
window between
disappearance of HbsAg and
(-) (-) (+) appearance of anti-HBs
False-positive or nonspecific
Summary of serologic events as transcribed from the reaction
Animated Graph Tutorial from CDC. J Investigate with IgM anti-HBc.
The diagnosis of chronic hepatitis B virus infection is made When present, anti-Hbe helps
when both HBsAg (red) and total anti-HBc (blue) remain validate the anti-HBc reactivity.
persistently detectable for life, generally for life. Never infected with HBV.
People with chronic hepatitis B infection will usually have Possibilities include another
detectable HBV DNA in serum as well. infectious agent, toxic injury to
(-) (-) (-)
Chronic hepatitis B infection is diagnosed: liver, disorder of immunity,
o Both HBsAg and total anti-HBc positive on at least 2 hereditary disease of the liver, or
separate sample 6 months apart disease of the biliary tract.
o When a person is HBsAg and total anti-HBc positive and (-) (+) (-) Vaccine-type response.
IgM Anti-HBc negative in a single sample
HBeAg indicates NOTES FROM DR. MALDOS LECTURE
o Greater infectivity IgM IgG
o Higher levels of HBV DNA Anti-
HbsAg Anti- Anti- HbeAg Interpretation
o Leads to a major clinical course. HBs
HBc HBc
o Anti-HBe conveys just the opposite scenario. (+) (-) (+) (+) Acute infection
Jawetz: (-) (-) (+) (+) Recent infection
High levels of IgM-specific anti-HBc are frequently (-) (+) (-) (-) (-) Vaccine
detected at the onset of clinical illness.
o Because this antibody is directed against the 27-nm
internal core component of HBV, its appearance in the
serum is indicative of viral replication.
Antibody to HBsAg is first detected at a variable period
after the disappearance of HBsAg. It is present in low
concentrations.
Before HBsAg disappears, HBeAg is replaced by anti-HBe,
signaling the start of resolution of the disease.
Anti-HBe levels often are no longer detectable after 6
months.
HBV CHRONIC CARRIERS
o Those in whom HBsAg persists for more than 6 months
in the presence of HBeAg or anti-HBe. HBsAg may
persist for years after loss of HbeAg.
In contrast to the high titers of IgM-specific anti-HBc Note: Chronic infection is higher among those infected
observed in acute disease, low titers of IgM anti-HBc are
in early age and declines with increasing age while
found in the sera of most chronic HbsAg carriers.
Small amounts of HBV DNA are usually detectable in the symptomatic infection is higher among the adults.

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GLOBAL PATTERNS OF INFECTION o Particularly efficacious w/in 48hrs of the incident
High: 45% of global population o May also be given to neonates who are at increased risk
o Lifetime risk if infection >60% of contracting hepatitis B (i.e. whose mothers are Hbsag
o Early childhood infections common and HbeAg positive)
Intermediate: 43% of global population Other measures
o Lifetime risk if infection 20%-60% o Screening of blood donors, blood and body fluid
o Infections occur in all age groups precautions
Low: 12% of global population Twinrix
o Lifetime risk of infection <20% o Combination hepatitis A & B vaccine made by
o Most infections occur in adult risk groups GlaxoSmithKline and approved for persons aged 18
HbsAg PREVALENCE in the Philippines: High years and older
o Indicated for persons at risk for both eap A & B
CONCENTRATION OF HBV IN VARIOUS BODY FLUIDS o Administered in a 3 dose series at 0, 1, & 6 months
High Moderate Low/Not Detectable
Blood Semen Urine HEPATITIS C VIRUS
Serum Vaginal fluid Feces Positive-stranded RNA virus
Wound Saliva Sweat Family Flaviviridae, genus Hepacivirus
exudates Tears Differentiated by RNA sequence analysis into at least six
Breastmilk major genotypes (clades) and more than 100 subtypes.
The genome is 9.4 kb in size and encodes a core protein,
MODES OF TRANSMISSION two envelope glycoproteins, and several nonstructural
SEXUAL proteins
o Sex workers & homosexuals are particular at risk Most cases of posttransfusion NANB (non-A, non-B)
PARENTERAL hepatitis were caused by HCV.
o IV drug users, health workers Most new infections with HCV are subclinical.
PERINATAL 70-90% of HCV patients develop chronic hepatitis
o Mothers who are HbeAg positive are much more likely to 10-20% at risk of progressing to chronic active hepatitis
transmit to their offspring than those who are not and cirrhosis
o main means of transmission in high prevalence In some countries, as in Japan, HCV infection often leads to
population hepatocellular carcinoma.
No documented fecal-oral transmission o From lecture: Higher chances to develop hepaticoellular
carcinoma with HCV
TREATMENT HCV displays genomic diversity, with different genotypes
INTERFERON (clades) predominating in different parts of the world.
The virus undergoes sequence variation during chronic
o For HbeAg positive carriers w/ chronic active
hepatitis infections.
Quasi-species - complex viral population in a host
o Response rate is 30 to 40%
o 5,000,000 units daily, administered by subcutaneous or This genetic diversity is not correlated with differences in
clinical disease, although differences do exist in
intramuscular injection, for a total of 16 weeks
LAMIVUDINE response to antiviral therapy according to viral
genotype.
o Nucleoside analogue reverse transcriptase inhibitor
o Well tolerated, most patients will respond favorably
o However, tendency to relapse on cessation of treatment CLINICAL FEATURES
L
Average 6-7 weeks
o Another problem is the rapid emergence of drug Incubation period
Range 2-26 weeks
resistance
Clinical illness
Successful response to treatment will result in the 30-40% (20-30%)
(jaundice)
disappearance of HbsAg, HBV-DNA & seroconversion to
Chronic hepatitis 70-90%
HbeAg.
Persistent infection 85-100%
Immunity No protective Ab response identified
NOTES FROM LECTURE RE: TREATMENT
Acute Infection No need for treatment
Hepatitis C is usually clinically mild, with only minimal
Reactive after 6 months Establish if chronic or carrier
to moderate elevation of liver enzymes.
Chronic Treat
Most patients are asymptomatic, but histologic
Carrier Reassurance
evaluation often reveals evidence of chronic active hepatitis
20-50% - develop cirrhosis and are at high risk for
PREVENTION hepatocellular carcinoma (5-25%) decades later.
Vaccination End-stage liver disease associated with HCV is the most
o Highly effective recombinant vaccines are now available frequent indication for adult liver transplants.
o Given to those who are at increased risk of hbv infection
such as health care workers
MODES OF TRANSMISSION
o Given routinely to neonates as universal vaccination in
RISK FACTORS
many countries
Transfusion or transplant from infected donor
Hepatitis B Immunoglobulin
Injecting drug use (80%)
o May be used to protect persons who are exposed to
Hemophiliacs treated w/ clotting factor products before
hepatitis B
1987

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Hepatitis Viruses


Hemodialysis (years on treatment) (10%) Summary of serologic events as transcribed from the
Multiple sex partners Animated Graph Tutorial from CDC. J
Accidental injuries with needle sharps (health care In a recently acquired infection, liver enzymes ALT
workers-1%) (yellow line) are elevated often at least 7 times the
Sexual household exposure to anti-HCV-positive contact upper limit of normal.
Birth to HCV-infected mother (not as frequent as HBV) 8 out of 10 infections have no symptoms with recently
Not passed through breastmilk acquired HCV infection.
Transmission is primarily through direct percutaneous Symptoms (green bar) occur about 6 weeks after
exposures to blood, though in 1050% of cases the source exposure and persist during the time of enzyme elevation.
of HCV cannot be identified. On the average, anti-HCV (red line) becomes positive
HCV was found in saliva from more than a third of patients about 7 weeks after exposure and remains positive
with HCV and HIV coinfections. generally for life. Rarely, anti-body seroconversion can be
Infection can be associated with tattooing &, in some delayed for month.
countries, with folk medicine practices. HCV RNA
The average time from exposure to seroconversion is 89 o Found in blood as early as 1-2 weeks after exposure
weeks, and about 90% of patients are anti-HCV-positive o Transiently undetectable when anti-HCV starts to rise.
within 5 months. In patients who recently acquire HCV infection who
recover
ANTI-HCV PREVALENCE in Philippines: Unknown o Liver ezyme levels return to normal
o Anti-HCV remains positive
LABORATORY DIAGNOSIS Chronic infection (55-85%)
o Persistent presence of HCV RNA
Generally used to diagnose hepatitis C
o Fluctuating ALT level indicating continuing liver
infection
HCV inflammation
Not useful in the acute phase as it takes at
antibody o ALT seen in patients with chronic infection is elevated
least 4 weeks after infection before antibody
but tend to be lower than patients with recently
appears
acquired infection.
Various techniques are available e.g. PCR and o ALT level can be normal with chronic infection and can
branched DNA have periods where HCV RNA is negative.
HCV-RNA May be used to diagnose HCV infection in the This is why single HCV RNA result does not
acute phase determine that a person is no longer infected
However, its main use is in monitoring the with HCV.
response to antiviral therapy
An EIA for HCV antigen is available Jawetz:
HCV Most primary infections are asymptomatic or clinically
It is used in the same capacity as HCV-RNA
antigen mild
tests but is much easier to carry out
CDC: o 2030% have jaundice
o 1020% have only nonspecific symptoms such as
anorexia, malaise, and abdominal pain
ENZYME IMMUNOASSAYS (EIA) detect antibodies to HCV
but do not distinguish between acute, chronic, or resolved
infection.
o Anti-HCV antibodies can be detected in 5070% of
patients at onset of symptoms, whereas in others
antibody appearance is delayed 36 weeks.
o Antibodies are directed against core, envelope, and
NS3 and NS4 proteins and tend to be relatively low in
titer.
NUCLEIC ACID-BASED ASSAYS (eg, RT-PCR)
o Detect the presence of circulating HCV RNA and are
useful for monitoring patients on antiviral therapy.
o Used to genotype HCV isolates.
JAWETZ: Occult HBV infections
o Occur frequently (about 33%) in patients with chronic
HCV liver disease
o Those in which the patients lack detectable HBsAg but
HBV DNA can be identified in liver or serum samples
o Unrecognized HBV infections may be clinically
significant.

TREATMENT
INTERFERON
o May be considered for patients with chronic active
hepatitis
o Response rate is around 50% but 50% of responders will
relapse upon withdrawal of treatment

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Hepatitis Viruses


RIBAVIRIN
o There is less experience with ribavirin than interferon
Recent studies suggest that a combination of interferon
& ribavirin is more effective than interferon alone

PREVENTION
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions
No vaccine
Virus inactivation of plasma derived products
Professional and public education

HEPATITIS D (DELTA VIRUS)


An antigen-antibody system termed the delta antigen
(delta-Ag) and antibody (anti-delta) is detected in
some HBV infections.
The antigen is found within certain HBsAg particles.
In blood, HDV (delta agent) contains delta-Ag (HDAg)
surrounded by an HBsAg envelope.
It has a particle size of 35-37 nm and a buoyant density of
1.24-1.25 g/mL in CsCl.
The genome of HDV consists of single-stranded, circular,
negative-sense RNA, 1.7 kb in size.
It is the smallest of known human pathogens and
resembles subviral plant pathogens, ie, viroids.
No homology exists with the HBV genome.
HDAg is the only protein coded for by HDV RNA and is
distinct from the antigenic determinants of HBV.
HDV is a defective virus that acquires an HBsAg coat for
transmission.
It is often associated with the most severe forms of
hepatitis in HBsAg-positive patients.

CLINICAL FEATURES MODES OF TRANSMISSION


COINFECTION Percutaneous exposures (injecting drug use)
o Severe acute disease Permucosal exposures (sex contact)
o Low risk of chronic infection The primary routes of transmission are believed to be
SUPERINFECTION similar to those of HBV, though HDV does not appear to be
o May present as an acute hepatitis a sexually transmitted disease.
o Usually develop chronic HDV infection Persons who have received multiple transfusions,
o High risk of severe chronic liver disease intravenous drug abusers, and their close contacts are at
high risk.
LABORATORY DIAGNOSIS HDV has been transmitted perinatally, but fortunately it is
not prevalent in regions of the world (such as Asia) where
Serologic patterns following HDV infection perinatal transmission of HBV occurs frequently.
o Because HDV is dependent on a COEXISTENT HBV
INFECTION, acute type D infection will occur either as: HDV PREVALENCE in the Philippines: Very low
Simultaneous infection (coinfection) with HBV
Person chronically infected with HBV PREVENTION
(superinfection)
HBV-HDV Coinfection
COINFECTION SUPERINFECTION o Pre or postexposure prophylaxis to prevent HBV infection
Ab to HDAg develops late Results in persistent HDV HBV-HDV Superinfection
in the acute phase & infection (over 70%) o Education to reduce risk behaviors among persons with
may be of low titer. High levels of both IgM chronic HBV infection
Assays for HDAg or HDV and IgG anti-HD persist, o Vaccination does not protect hepatitis B carriers from
RNA in the serum or for as do levels of HDV RNA superinfection by HDV.
IgM-specific anti-HDV are and HDAg
preferable. May be associated with HEPATITIS E
All markers of HDV FULMINANT HEPATITIS
replication (ie HDV RNA) *In short, ALL markers are Transmitted enterically
disappear during persistently HIGH unlike Occurs in epidemic form in developing countries, where
convalescence; even the that of coinfection. In water or food supplies are sometimes fecally contaminated
HDV antibodies may addition, superinfection has First documented in samples collected during the New
disappear within months worse prognosis. Delhi outbreak
to years. Pregnant women may have a high (20%) mortality rate if
fulminant hepatitis develops

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Hepatitis Viruses


The viral genome has been cloned and is a positive-sense,
single-stranded RNA 7.6 kb in size
Animal strains of HEV are common Additional Information from Jawetz J
o There is evidence of HEV or HEV-like infections in HEPATITIS VIRUS INFECTIONS IN HUMANS
rodents, pigs, sheep, and cattle in the United States. PATHOLOGY
o There is the possibility of spread of virus from animals to Hepatitis is a general term meaning inflammation of the
humans. liver.
Microscopically
CLINICAL FEATURES o Spotty parenchymal cell degeneration, necrosis of
hepatocytes, diffuse lobular inflammatory reaction,
Average: 40 days
Incubation period disruption of liver cell cords
Range 15-60 days
o accompanied by reticuloendothelial (Kupffer) cell
Overall 1-3%
Case-fatality rate hyperplasia, periportal infiltration by mononuclear cells,
Pregnant women 15-25% and cell degeneration
Illness severity Increased with age o Localized areas of necrosis are frequently observed.
Chronic sequelae None identified o Later in the course of the disease, there is an
accumulation of macrophages near degenerating
LABORATORY DIAGNOSIS hepatocytes.
o Preservation of the reticulum framework allows
hepatocyte regeneration so architecture of the liver
lobule can be regained.
o The damaged hepatic tissue is usually restored in 8-12
weeks.
Chronic carriers of HBsAg may or may not have
demonstrable evidence of liver disease.
Persistent (unresolved) viral hepatitis
o Characterized by sporadically abnormal
aminotransferase values and hepatomegaly
o Histologically, the lobular architecture is preserved,
with portal inflammation, swollen and pale hepatocytes
(cobblestone arrangement), and slight to absent fibrosis.
o This lesion is frequently observed in asymptomatic
carriers, usually does not progress toward cirrhosis, and
has a favorable prognosis.
Chronic active hepatitis
EPIDEMIOLOGIC FEATURES o Wide spectrum of histologic changes
Most outbreaks associated with fecally contaminated o Inflammation and necrosis
drinking water. o Collapse of the normal reticulum framework with
Several other large epidemics have occurred since in the bridging between the portal triads or terminal hepatic
Indian subcontinent and the USSR, China, Africa and veins
Mexico. Acute viral hepatitis
In the United States and other nonendemic areas, where o More extensive damage may occur that prevents
outbreaks of hepatitis E have not been documented to orderly liver cell regeneration
occur, a low prevalence of anti-HEV (<2%) has been found o Such fulminant or massive hepatocellular necrosis
in healthy populations. The source of infection for these 1-2% of jaundiced patients with hepatitis B.
persons is unknown. Coinfected with HDV than in the absence of HDV.
Minimal person-to-person transmission. None of the hepatitis viruses are typically
cytopathogenic, and it is believed that the cellular damage
PREVENTION AND CONTROL MEASURES FOR seen in hepatitis is immune-mediated.
TRAVELLERS TO HEV-ENDEMIC REGIONS Both HBV and HCV have significant roles in the
Avoid drinking water (and beverages with ice) of unknown development of hepatocellular carcinoma that may
purity, uncooked shellfish, and uncooked fruit/vegetables appear many (15-60) years after establishment of chronic
not peeled or prepared by traveller. infection.
IG prepared from donors in Western countries does not
prevent infection.
Unknown efficacy of IG prepared

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Hepatitis Viruses

CLINICAL FINDINGS
EPIDEMIOLOGIC AND CLINICAL FEATURES OF VIRAL HEPATITIS TYPES A, B, AND C
Feature VIRAL HEPATITIS A VIRAL HEPATITIS B VIRAL HEPATITIS C
Incubation Period 10-50 days (ave: 25-30 days) 50-180 days (ave: 60-90 days) 15-160 days (ave: 50)
Principal age distribution Childrena, young adults 15-29 yearsb, babies Adultsb
Seasonal incidence Throughout the year but tends Throughout the year Throughout the year
to peak in autumn
Route of infection Predominantly fecal-oral Predominantly parenteral Predominantly parenteral
Occurrence of virus
Blood 2 weeks before to 1 week after Months to years Months to years
jaundice
Stool 2 weeks before to 2 weeks Absent Probably absent
after jaundice
Urine Rare Absent Probably absent
Saliva, semen Rare (saliva) Frequently present Present (saliva)
Clinical and laboratory
features
Onset Abrupt Insidious Insidious
Fever >38 C Common Less common Less common
Duration of 1-3 weeks 1-6+ months 1-6+ months
aminotransferase elevation
Immunoglobulins (IgM Elevated Normal to slightly elevated Normal to slightly elevated
levels)
Complications Uncommon, no chronicity Chronicity in 10% (95% in Chronicity in 70-90%
neonates)
Mortality rate (icteric <0.5% <1-2% 0.5-1%
cases)
HbsAg Absent Present Absent
Immunity
Homologous Yes Yes Probably no
Heterologous No No No
Duration Probably lifetime Probably lifetime ?
Immune globulin Regularly prevents jaundice Prevents jaundice only if ?
intramuscular (IG, gamma- immune globulin is of sufficient
globulin, ISG) potency against HBV
a
Nonicteric hepatitis is common in children.
b
Among the age group 1529 years, hepatitis B and C are often associated with drug abuse or promiscuous sexual behavior.
Patients with transfusion-associated HBV or HCV are generally over age 29.

In viral hepatitis, onset of jaundice is often preceded by Lamivudine (Virus is rarely eliminated and viral replication
gastrointestinal symptoms such as nausea, vomiting, resumes in the majority of patients when treatment is
anorexia, and mild fever. Jaundice may appear within a few stopped)
days of the prodromal period, but anicteric hepatitis is Combination therapy of interferon- and ribavirin agains
more common. chronic hepatitis C (sustained response rate of up to 50%)
Extrahepatic manifestations: Orthotopic liver transplantation is a treatment for chronic
HEPATITIS A Unusual Hepa B and C end- stage liver damage.
Transient serum sickness-like prodrome
consisting of fever, skin rash, and Interpretation of HAV, HCV, and HDV Serologic
HEPATITIS B polyarthritis; necrotizing vasculitis Markers in Patients with Hepatitis.
(polyarteritis nodosa); and
glomerulonephritis Assay Results Interpretation
CHRONIC Cryoglobulinemia and Glomerulonephritis Anti-HAV IgM-positive Acute infection with HAV
HEPATITIS C
Anti-HAV IgG-positive Past infection with HAV
TREATMENT Anti-HCV-positive Current or past infection with HCV
Supportive and directed at allowing hepatocellular damage
to resolve and repair itself. Anti-HDV-positive, Infection with HDV
Only HBV and HCV have specific treatments, and those are HBsAg-positive
partially effective.
Anti-HDV-positive, Coinfection with HDV and HBV
Recombinant interferon- and pegylated interferon- are
anti-HBc IgM-positive
currently the therapy of proven benefit in the treatment of
patients chronically infected with HBV or HCV. Anti-HDV-positive, Superinfection of chronic HBV
anti-HBc IgM-negative infection with HDV

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Hepatitis Viruses

Nomenclature and Definitions of Hepatitis Viruses, Antigens, and Antibodies

COMPONENT
DISEASE DEFINITION
OF SYSTEM
HAV Hepatitis A virus. Etiologic agent of infectious hepatitis. A picornavirus, the prototype of a new genus, Hepatovirus.
Hepatitis
Anti-HAV Antibody to HAV. Detectable at onset of symptoms; lifetime persistence.
A
IgM anti-HAV IgM class antibody to HAV. Indicates recent infection with hepatitis A; positive up to 46 months after infection.

HBV Hepatitis B virus. Etiologic agent of serum hepatitis. A hepadnavirus.

Hepatitis B surface antigen. Surface antigen(s) of HBV detectable in large quantity in serum; several subtypes
HBsAg identified.

Hepatitis B e antigen. Associated with HBV nucleocapsid; indicates viral replication; circulates as soluble antigen in
HBeAg serum.

Hepatitis HBcAg Hepatitis B core antigen.


B
Antibody to HBsAg. Indicates past infection with and immunity to HBV, presence of passive antibody from HBIG, or
Anti-HBs immune response from HBV vaccine.

Anti-HBe Antibody to HBeAg. Presence in serum of HBsAg carrier suggests lower titer of HBV.

Anti-HBc Antibody to HBcAg. Indicates infection with HBV at some undefined time in the past.

IgM anti-HBc IgM class antibody to HBcAg. Indicates recent infection with HBV; positive for 46 months after infection.

Hepatitis HCV Hepatitis C virus, a common etiologic agent of posttransfusion hepatitis. A flavivirus, genus Hepacivirus.
C Anti-HCV Antibody to HCV.

HDV Hepatitis D virus. Etiologic agent of delta hepatitis; causes infection only in presence of HBV.
Hepatitis
HDAg Delta antigen (delta-Ag). Detectable in early acute HDV infection.
D
Anti-HDV Antibody to delta-Ag (anti-delta). Indicates past or present infection with HDV.

Hepatitis Hepatitis E virus. Enterically transmitted hepatitis virus. Causes large epidemics in Asia, North and West Africa, and
HEV Mexico; fecal-oral or waterborne transmission. Unclassified.
E
Immune globulin USP. Contains antibodies to HAV; no antibodies to HBsAg, HCV, or human immunodeficiency virus
Immune IG (HIV).
globulins
HBIG Hepatitis B immune globulin. Contains high titers of antibodies to HBV.

HEPATITIS A HEPATITIS B HEPATITIS C HEPATITIS D HEPATITIS E

Hello there. Hey, Hepatitis B Virus here. Hiho! Hey folks. Hello, My name is Hepatitis
My name is Hepatitis A I'm from I am Hepatitis C Virus. My name is Hepatitis D virus. E Virus.
virus. the Hepadnaviridaefamily. I'm from the I'm also called Hepatitis Delta. I am a Hepevirus.
Picornaviridae is my family. familyFlaviviridae.
I'm pass to you through the I visit many babies through I can't get you on my own, I I'm like cousin Hepatitis A.
mouth, in things like milk their mums. I get to you in blood. need my friend HBV. I move around in your
and seafood. I'm often sexually I use needles, piercings, We have a "co-infection". water.
I also like poor hygiene and transitted. tattoos and blood I can get into you at the same I get into seafood, but I
lots of people close I get into your liver. transfusions. time as my cousin. also
together. There I get to work, giving I often hang around for Or I can visit people who hang out in farm animals
already have him.
I love school camps. you pain, nausea, fever and years and can give you like
I get into your liver. jaundice. cirrhosis. pigs and cows.
My job is to make your liver
I give you nausea, side I can hang around for even worse.
pain, vomiting and fever. years. There are vaccines for my I'm most fond of places
You can vaccinate against I make you more likely to cousins Hep A and Hep B, with unclean water.
me though. get liver cancer. but not for me.
Plus I don't hang around as
long some of my cousins.

DIONISIO Page 12 of 12