MEDICAL MICROBIOLOGY

HEPATOTROPHIC VIRUSES – MAY 3, 2017

ARNEL G. BAYOTAS, M.D.
PATHOGENESIS
 Hepatitis A- Etiologic agent of viral hepatitis type A
(infectious hepatitis)
 Hepatitis B- Associated with viral hepatitis B (serum
hepatitis)
 Hepatitis C- Agent of hepatitis C (common cause of
posttransfusion hepatitis)
 Hepatitis D- Defective virus; requires the presence
of Hepatitis B surface antigen
 Hepatitis E- Fecal oral route; Agent of enterically
transmitted hepatitis
 Hepatitis G- Similar to Hepatitis C

HEPATITIS A
 Viral shedding is approx. 10 days before the symptoms  Period
 Infectious Hepatitis of communicability
 Formerly Enterovirus 72 in the Picornavirus family  Liver pathology is indistinguishable histology from HBV
 A picornavirus, the prototype of genus Hepatovirus  Does not cause chronic liver disease
 New genus: Heparnavirus  Not associated with hepatic CA
 Spread by fecal-oral route
 Incubation period:15-50 days EPIDEMIOLOGY
 Period of communicability: before to after symptoms appear  Agent of acute hepatitis – approx. 40% of cases
 Does not progress to chronic infection  Period of communicability: 10-14 days before symptoms appear
 Self-limiting infection
TRANSMISSION
 Old age patient  Susceptible to “Massive hepatic necrosis”
 Virus can be transmitted via fecal-oral route
STRUCTURE  Ingestion of contaminated food and water
 Shellfish - important sources of the virus
 Virus can be transmitted by food handlers, day-care workers,
and children

CLINICAL SYNDROME

 Naked, icosahedral capsid

 (+) VPg protein (VP1to VP4)
 Single-stranded RNA, linear, positive-sense
 Only one serotype

REPLICATION
 Replicates in the cytoplasm
 Interacts with HAVCR-1 expressed on liver and T cells
o Specificity of HAVCR-1 correlates to the severity of the
disease cause by HAV
 Flu-like symptoms or Jaundice
 HAV is not cytolytic and released by exocytosis
 Elevation of transaminases (ALT)  Liver damage application to
o Massive necrosis related to HAV infection is not due
immune response against viral infected hepatocytes
to HAV itself but due to Immune Mediated Response
 Dark urine  Bilirubinuria
of the host against to hepatocytes infected with HAV
 Symptoms are very similar to HBV
 Symptoms occur 15-50 days after exposure
 Symptoms wane during jaundice period

TREATMENT AND PREVENTION

 Prophylaxis with immune serum globulin given before or early in
the incubation period (i.e. < 2 weeks after exposure)  80% to
90% effective in preventing clinical illness

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
o Active immunization with killed HAV for two doses THREE MORPHOLOGIC FORMS OF HBsAg (Using Electron microscopy)
(initial dose + booster 6-12 months later)
 Active immunization recommended for:
o Travelers to developing countries
o Children 2 – 18 years’ old
o Men who have sex with men

LABORATORY DIAGNOSIS
 Basis for diagnosis:
o Time course of the clinical symptoms
o Identification of a known infected source
 Serologic tests
o Anti-HAV IgM – ELISA or RIA
o Viral isolation is not performed
A. Small, spherical particles – most numerous; made up exclusively
HEPATITIS B of HBsAg
B. Tubular or filamentous forms – result from overproduction of
 HBV is the major member of the hepadnaviruses HBsAg
 Establishes chronic infections → liver disease and HCC C. Large, spherical virions – originally referred to as Dane particles
 Infects the liver, lesser extent, the kidneys and pancreas
 Only Hepatic viruses that has DNA genetic material
 Partially double stranded DNA  The positive strand is partially STRUCTURE
complete strand and negative strand is totally complete

 A small, circular, enveloped partly ds DNA virus

 Encodes a reverse transcriptase and replicates through an RNA
intermediate
 Virion – Dane particle
 HBsAg – Australian antigen
o 3 glycoproteins found in the Virion
 L – gp42
 M – gp36
 S – gp27 → major component of HBsAg
particles
 HBsAg contains:
o Group specific (termed a)
o Type-specific determinants (termed d or y and w or r)
 Structure: enveloped, with icosahedral nucleocapsid core;
partially double stranded circular DNA genome
o Large polymerase P protein with reverse transcriptase
& ribonuclease H activity
o HBcAg
o HBeAg
o HBsAg
o HBx protein- for virus replication; transcriptional
transactivator uncontrolled proliferation 
Hepatocellular CA

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
REPLICATION

 Replication – unique features: SYMPTOMS OF TYPICAL ACUTE HBV INFECTION

o With distinctly defined tropism for the liver
o Small genome  necessitates economy
o Replicates through an RNA intermediate
o Produces and releases antigenic decoy particles -
HBsAg
o Binds to polymerized human serum albumin other
serum proteins
o Partial DNA strand completed by being formed into a
complete ds DNA circle  delivered to nucleus

PATHOGENESIS
 Major source of infection: blood
 Other sources: semen, saliva, milk, vaginal & menstrual
secretions, and amniotic fluid
 Most efficient way to acquire virus: injection of virus into the
blood stream
 Common but less efficient routes: sexual contact and birth
 Mother-to-child infection:
o Can be transmitted from a chronically-infected
mother to her child during the birthing process
o One of the most common modes of transmission for
Asians
 Blood-borne infection:
o Wound-to-wound contact
o Blood transfusion
o Reusing syringes or medical services
o Sharing razors or toothbrushes contaminated by
blood
o Reusing or sharing needles for tattoos, piercings,
acupuncture, or injection drugs
 HBV is NOT spread through:
o Sharing of food or water
o Sharing eating utensils or drinking glasses
o Tears, sweat, urine, or stool
o Coughing or sneezing
o Hugging or kissing  ALT (transaminase)- signifies on-going liver damage
o Breastfeeding  HBsAg- First marker, infected with HBV; denied for blood
o Mosquitoes donation. Appear before the onset of the symptoms; During the
disease, detectable 2-6 weeks in advance in clinical or
biochemical evidence of HBV
 HBeAg- it is not the envelope, signifies active viral replication;
Highly infectious  Viral Load increase
 HBV DNA- found in the serum infected with HBV
 Anti HBs- signifies immunity, recovery and vaccination;
sometimes it remains negative  4 to 6 months there is
possibilities that Anti HBs will gone

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
 IgM-anti HBc- marker requested during recent infection/ acute What are the tests which you have to take?
infection/ window period, onset of the symptoms • ALT blood test – to determine whether treatment against HBV is
 Anti HBe- occurs after several weeks after the appearance of IgM needed; monitor HBV disease progression
anti-HBc; appears after decrease of HBeAg. Decrease Anti HBe • HBV DNA level – direct measure of HBV viral load; helps evaluate
means viral replication is ceased treatment response
 Over a period of months, IgM anti HBc is replaced by IgG anti • HBeAg and anti-HBe tests
HBc o HBeAg seroconversion (loss of HBeAg) and
 Persistent elevation HBsAg and HBeAg is considered a chronic development of anti-HBe is a sign that the treatment
state of HBV is working
 Differentiate between acute and chronic  IgM anti HBc (4-6
months) Serologic Markers of HBV Exposure
 IgG anti HBc  usually occur during recovery or chronic stage of  HBV core antigen (HBcAg)
infection or persis for life o Not detected in serum
 Anti HBs  develop immunity from disease, vaccination only o CTL epitopes expressed on hepatocyte surface in
 Anti HBs + IgG anti HBc- natural infection, previous infection association with HLA-A2 molecules
 Anti-HBc
Inactive HBsAg carrier state o Presence of high titers of anti-HBc IgM indicates early
• HBsAg (+) > 6 months acute infection
• HBeAg (-), anti-HBe (+) o Anti-HBc IgG can be detected in both acute & chronic
• Serum HBV DNA < 2,000 IU/ml HBV infection (remains for lifetime)
• Persistently normal ALT/AST levels  HBeAg
• Liver biopsy confirms absence of significant hepatitis o “Early” appearance during acute infection
o Marker of high degree of infectivity
Chronic Hepatitis B o Correlates with high level of HBV replication
• HBsAg (+) > 6 months  Anti-HBe
• Serum HBV DNA > 20,000 IU/ml (Lower values 2,000 – 20,000 o
IU/ml often seen in HBeAg (-) chronic hepatitis B end of replicative phase of disease
• Persistent or intermittent elevation in AST/ALT levels  HBsAg
• Liver biopsy showing chronic hepatitis with moderate or severe o Marker of infectivity
necroinflammation o Presence in serum for at least 6 mos. Indicates chronic
infection
Resolved Hepatitis B  Anti-HBs
• Previous known history of acute or chronic hepatitis B or the o Indicates an immune response to HBV infection or
presence of anti-HBc + anti-HBs vaccination, or the presence of passively acquired
• HBsAg (-) antibody (HBIG)
• Undetectable serum level of HBV DNA
• Normal ALT levels

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
QUICK TEST RESULT

RESULT INTERPRETATION
HBsAg (+) Chronic HBV infection if HBsAg remains (+)
Anti-HBs (-) for six months
HBsAg (-) Immune to HBV
Anti-HBs (+)
HBsAg (-) Unprotected; need vaccination
Anti-HBs (-)
HBsAg (+) Chronic HBV infection
Anti-HBs (+)
(rare)

SIMPLIFIED DIAGNOSTIC APPROACH IN PATIENTS PRESENTING WITH

ACUTE HEPATITIS

Serologic Tests of Patient’s Diagnostic Interpretation TEMPORAL CHANGES IN SEROLOGIC MARKERS IN HEPATITS C VIRAL
Serum INFECTION
HBsAg IgM IgM
Anti- anti-
HAV HBc
+ - + Acute hepatitis B
+ - - Chronic hepatitis B
+ + - Acute Hepatitis A superimposed on chronic
HBV
+ + + Acute hepatitis A and B
- + - Acute hepatitis A
- + + Acute hepatitis A and hepatitis B (HBsAg
below detection level)
- - + Acute hepatitis B (HBsAg below detection
level)
- - - Test for acute hepatitis C (anti-HCV)

HEPATITIS C

 NANB Post-Transfusion Hepatitis

 Predominant cause of NANBH and major cause of post-
transfusion hepatitis
 Member of Hepaciviridae in the Flaviviridae family
 Enveloped, positive-sense RNA virus; labile to drying
 Genome encodes two glycoproteins (E1, E2) that undergo
variation due to hypervariable regions within their genes

PATHOGENESIS
 Binds to cells using CD81 surface receptors OR coats itself with
LDL or VLDL  uptake into hepatocytes  remain in the ER and
is cell-associated
 Bind to:
o TNFR  inhibit apoptosis LABORATORY DIAGNOSIS
o Protein kinase R (PKR)  inhibit interferon α  Diagnosis and detection of HCV infection are based on ELISA
recognition of antibody.
CLINICAL SYNDROME o Seroconversion occurs within 7 to 31 weeks of
 Acute disease similar to HAV and HBV infection but with less infection
intense inflammatory response and milder symptoms  Recombinant interferon- α alone or with ribavirin is the only
 Chronic and persistent hepatitis is the hallmark of infection known treatment

TRANSMISSION
 Primarily in infected blood and sexually
 Others: semen, vaginal secretions, transfusion, needle stick
injury, shared drug paraphernalia, and breast-feeding
 Almost all (>90%) HIV-infected individuals who are or were IV
drug users are infected with HCV
HEPATITIS D
 Responsible for causing 40% of the fulminant hepatitis infections
 Unique feature: uses HBV and target cell proteins to replicate
and produce its one protein → HBsAg essential for packaging the
virus

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
STRUCTURE INTERPRETATION OF HDV SEROLOGIC MARKERS

ASSAY RESULT INTERPRETATION

Anti-HDV (+), Infection with HDV
HBsAg (+)
Anti-HDV (+), Co-infection with HDV and HBV
anti-HBc IgM (+)
Anti-HDV (+), Super-infection of chronic HBV infection with
anti-HBc IgM negative HDV

TREATMENT, PREVENTION AND CONTROL

 No known specific treatment
o Because the HDV depends on HBV for replication and
spreads the same routes
 Prevention:
o Immunization with HBV vaccine
o Avoidance of high-risk behavior
o Avoidance HDV-contaminated blood products
REPLICATION
 Circular, ssRNA genome with extensive base-pairing HEPATITIS E
 Binds to and internalized by hepatocytes in the same manner as
HBV • E-NANBH (the E stands for enteric or epidemic)
 Replication process unusual → forms an RNA structure called a • Spread by the fecal-oral route
ribozyme → cleaves the RNA circle to produce an mRNA • Resembles the caliciviruses
• Symptoms and course are similar to HAV disease
PATHOGENESIS • Causes only acute disease
 Transmission: Similar to HBV • Mortality rate: 1-2%; 20% in pregnant women
 Consequences of delta virus infection:
HEPATITIS G

• Flavivirus similar to HCV

• MOT:
o Contaminated blood or blood products
o Sexual contact
• 75% cleared from plasma; 25% chronic
• Commonly co-infects patients with HIV  protects against HIV
disease

IMPORTANT PROPERTIES OF HEPATITIS VIRUSES

Virus Genome Replication DNA HBsAg in Virus family

CONSEQUENCES OF DELTA VIRUS INFECTION defective polymerase envelope
in virion
HAV ssRNA NO NO NO PICORNAVIRUS
HBV dsDNA1 NO YES YES HEPADNAVRUS
HCV ssRNA NO NO NO FLAVIVIRUS
HDV ssRNA2 YES NO YES DELTAVIRUS
HEV ssRNA NO NO NO CALICIVIRUS

1 Interrupted, circular dsDNA

2 Circular, negative-sense ssRNA

Feature HAV HBV HCV HDV HEV

Common name infectious serum NANB Delta Enteric
posttransfusion agent NANBH
Virus Structure Picornavirus Hepadnavirus, Flavivirus; Viroid like; Hepevirus;
Capsid, RNA Envelope, DNA envelope, RNA envelope, capsid RNA
circular RNA
Transmission Fecal-oral; Parenteral; Parenteral; Parenteral; Fecal-oral
sexual sexual;
perinatal
Onset Abrupt Insidious Insidious Abrupt Abrupt
I.P. (days) 15 – 50 45 – 160 14 – 180 15 – 64 15 – 50
Severity Mild Occ. Severe Usually Superinfection Normal px,
sub-clinical; with HBV mild;
80% often severe pregnant
chronicity women,
severe
Mortality < 0.5% 1% - 2% ~ 4% High to Pregnant
very high women,
20%

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MEDICAL MICROBIOLOGY
HEPATOTROPHIC VIRUSES – MAY 3, 2017
ARNEL G. BAYOTAS, M.D.
Chronicity/ NO YES YES YES NO
Carrier state
Other dse Fulminant PHC, PHC, Cirrhosis, NONE
assn’s rare cirrhosis, cirrhosis fulminant
fulminant
Lab diagnosis Symptoms Symptoms Symptoms and Anti-HDV ELISA ---
+ anti- & serum levels anti- HCV ELISA
HAV IgM of HBsAg,
HBeAg, and
anti- HBc IgM

ajc2017ENDajc2017

ajc2017END OF MEDICAL MICROBIOLOGY Bajc2017

Protocambium, MD would like to thank these people for their generous contributions and
support

Ma. Carmela Concepcion

Elaine Jean Caluag -gokunotes
Juan Paolo de Guzman
Nikky Castro
Deanne Alison Catapang
Yham Hanafie
Kimsha Concepcion

And to all my batch 2019 friends, Thank you!

PROTOCAMBIUM, MD- Batch 2020

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