HEPATITIS VIRUSES AND THEIR DISEASES

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HEPATITIS VIRUSES AND THEIR DISEASES
Jeremy Garson j.garson_at_ucl.ac.uk Paul
Griffiths pgriffiths_at_rfc.ucl.ac.uk Richard
Tedder r.tedder_at_ucl.ac.uk Department of Virology,
RFUCMS
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What is viral hepatitis?

• principally inflammation of the liver
• dominant symptom is jaundice
• associated with liver enzymes in the plasma
• loss of liver excretory and synthetic functions
• usually self limiting but may be chronic

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Viral causes of hepatitis
As a manifestation of a general infection for
example Glandular fever (EBV),Varicella and
CMV, Yellow fever,
viral haemorrhagic fevers As a
manifestation of infection by one of the
hepatotropic viruses for example hepatitis
type B (HBV), hepatitis C (HCV)
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The MAJOR hepatotropic viruses
Type Virus Genome Route Illness_at_
Carriers Anti-virals A HAV RNA
enteric mild NO Vac/Ig no B HBV
DNA parenteral moderate
YES Vac/Ig yes C HCV RNA parenteral
mild YES nil yes D HDV RNA
parenteral moderate YES nil no E HEV
RNA enteric mild NO ?
Ig no
Immun- isation
_at_ i.e. Acute illness Controlled by preventing
hepatitis B unless pregnant
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Acute hepatitis
Ballooning degeneration, note vaculoated, pale
appearance of the hepatocytes Note also
Councilman bodies (acidophilic bodies) and
inflammatory cells
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Hepatitis carriers

• They represent a major adaptation by the viruses
  for viral survival. They are common for HCV and
  HBV.
• Carriers
• evolve from acute infections which are mild and
  anicteric (HBV more so than HCV)
• may be asymptomatic but detectable by blood
  testing
• are frequently the source of infection for
  others
• suffer long term sequelae of persistent
  infection

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Cirrhosis with massive fibrosis
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Primary Liver Cancer (hepatoma)

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EM of hepatitis A virus (member of picornavirus
family - enterovirus 72)
10

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Hepatitis A Virus Transmission

• Close personal contact (e.g., household contact,
  sexual contact, child day care centers)
• Homeless persons poor hygiene
• Contaminated food, water (e.g., infected food
  handlers, raw shellfish)
• Blood exposure (rare, e.g. haemophiliacs,
  injecting drug use, transfusion)

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Hepatitis A - Risk Groups

• Many cases occur in community-wide outbreaks
• no risk factor identified for most cases
• highest attack rates in 5-14 year olds
• children serve as reservoir of infections
• Persons at increased risk of infection
• travellers
• homosexual men
• injecting drug users
• sanitation workers

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Hepatitis A - Clinical Features

• Incubation period average 40 days, range 15-50
  days
• Proportion jaundiced under 6 yrs, lt10 6-14
  yrs, 40-50, over 14 yrs, 70-80
• Case fatality rate less than 0.1, higher in
  elder age groups
• Chronic sequelae no carriers, relapsing slow
  recovery occasionally

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Laboratory Diagnosis of acute HAV infection

• Acute infection is routinely diagnosed by the
  detection of IgM anti-HAV by Elisa
• Genome or antigen detection in stool may be used
• Immunity to HAV is confirmed by the detection of
  Total anti-HAV in serum
• Beware false-positive low level reactions for
  IgM and post-vaccine IgM anti-HAV

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Hepatitis A Infection
Total anti-HAV
Jaundice
Transaminases
Titre
Faecal HAV
IgM anti-HAV
4
5
6
12
24
0
1
2
3
Months after exposure
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Hepatitis A Prevention

• Pre-exposure Vaccine (killed whole virus)
• Travellers to intermediate and high
  HAV-endemicity regions Active within 14 days of
  first dose
• Post exposure Vaccine and immunoglobulin HNIG
  (within 14 days)
• Household and other intimate contacts.
  Institutions (e.g. day care centers) and other
  common source exposures

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The original Dane photomicrograph
42nm Dane particles 22nm HBsAg spheres and
filaments
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Global Patterns of Chronic HBV Infection

• High (gt8) 45 of global population, lifetime
  risk of infection gt60, early childhood
  infections common which regenerates carriers
• Intermediate (2-7) 43 of global population,
  lifetime risk of infection 20-60, infections
  occur in all age groups
• Low (lt2) 12 of global population, lifetime
  risk of infection lt20, most infections occur in
  adult risk groups

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Modes of Transmission of Hepatitis B Virus

• Sexual - Sex workers and homosexuals are
  particular at risk
• Parenteral - IVDA, Health Workers are at
  increased risk
• Perinatal - Mothers who are HBeAg positive are
  much more likely to transmit to their
  offspring than those who are not. Perinatal
  transmission is the main means of transmission
  in high prevalence populations and the origin
  of carriers
• Transfusion- Screening and viral inactivation
  have all but eliminated this in Europe

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Nature of hepatitis B infections

• Acute infections, self limiting
• often mild
• only some 10 are symptomatic
• incubation period is around 3 months

• Chronic infections, these are termed carriers
• associated with chronic liver disease sequelae
• two major states depending upon presence in
  serum of e antigen (HBeAg) or its antibody
  (anti-HBe)
• a late stage dynamic interaction and selection
  of various viral mutations which may lead to
  escape variants

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Hepatitis B - Clinical features of acute infection

• Incubation period average 60-90 days, range
  45-180 days
• Proportion jaundiced under 5 yrs, lt10 over 5
  yrs, 30-50
• Acute case-fatality rate 0.5-1
• Incidence of carriers under 5 yrs, 30-90
  over 5 yrs, 2-10
• Carriage associated with increased mortality

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Hepatitis carriers

• The HBeAg sero-positive carrier represents a
  potent source of HBV
• HBV DNA levels of 109 copies or more per ml
• Low grade persisting liver inflammation
• Infectious sexually and during childbirth
• Are sometimes called Super-carriers
• Will lose serum HBeAg at some stage and then
  become lower infectivity Simple-carriers
  seropositive for anti-HBe
• Will select for s (codon 145) and c (codon 28)
  escape mutants

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Diagnosis of HBV infection

• A battery of serological tests are used for the
  diagnosis of acute and chronic hepatitis B
  infection
• HBsAg used as a general marker of infection
• anti-HBs used to document recovery and/or
  immunity to HBV infection
• anti-HBc IgM marker of acute infection
• anti-HBc current or past infection
• HBeAg active replication of virus and marks
  high infectivity
• Anti-HBe coincides with significant reduction
  in replication
• HBV-DNA measures viral load and indicates level
  of replication of virus, more accurate than
  HBeAg. Used mainly for monitoring response to
  therapy

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Acute Hepatitis B Virus Infection with Recovery
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titre
anti-HBs
IgM anti-HBc
HBsAg
0
4
8
12
16
24
28
32
52
100
20
36
Weeks after Exposure
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Acute Hepatitis B Virus Infection progressing to
carrier
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titre
IgM anti-HBc
Years
0
4
8
12
16
20
24
28
32
36
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Weeks after Exposure
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Treatment of HBV persistent infection

• Interferon - for HBeAg ve carriers with chronic
  active hepatitis. Response rate (loss of HBeAg)
  is claimed to be 30 to 40.
• Lamivudine - a nucleoside analogue reverse
  transcriptase inhibitor. Well tolerated, most
  patients will respond favorably. However,
  tendency to relapse on cessation of treatment.
  Another problem is the rapid emergence of drug
  resistance, in up to 50 in two years. The
  mutation YMDD to YVDD is similar to that seen in
  HIV.
• Adefovir a nucleotide analogue reverse
  transcriptase inhibitor. Used alone or in
  combination with lamivudine.
• Successful response to treatment will result in
  the disappearance of HBsAg, HBV-DNA, and
  seroconversion to anti-HBs (and to anti-HBe).

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Prevention of HBV infection

• The essential two components of this are policies
  for PREVENTION OF EXPOSURE, and policies for
  PROPHYLAXIS once exposure is predicted or has
  occurred.
• Prevention. This includes identification of
  infected individuals and containment of the
  infection risk. Good examples are UK ante-natal
  screening, Renal unit policy, Exposure-prone
  procedures for HBV Infected Health care workers
  and the Global Eradication Programme.
• Prophylaxis. Pre-exposure is active immunisation
  with Vaccine. Post-exposure is accelerated active
  immunisation, together with HBIG in some
  circumstances depending upon perceived risks.

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HCV genome genotypes
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Risk Factors Associated with Transmission of HCV

• Transfusion or transplant from infected donor
• Injecting drug use
• Haemodialysis (duration of treatment)
• Accidental injuries with needles/sharps
• Sexual/household exposure to HCV-infected contact
• Multiple sex partners
• Birth to HCV-infected mother

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Hepatitis C - Clinical features of acute infection

• Incubation period average 6-7 wks, range 2-26
  wks
• Proportion jaundiced less than 10 ,
  transaminitis
• Acute case fatality rate less than 0.1
• Incidence of carriers 70 or more
• Carriage associated with increased mortality

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Chronic Hepatitis C Infection

• All the manifestations of chronic hepatitis B
  infection may be seen, chronic persistent
  hepatitis, chronic active hepatitis, cirrhosis,
  and hepatocellular carcinoma.
• Extrahepatic diseases mixed essential
  cryoglobulinaemia, glomerulonephritis, sporadic
  porphyria cutanea tarda, depression.

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Diagnosis of HCV infection

• HCV antibody - generally used to diagnose
  hepatitis C infection in chronic disease.
  Requires confirmation. Not useful in the acute
  phase as it takes at least 4 weeks after
  infection before antibody appears. NB Most but
  not all seropositive people are viraemic.
• HCV-RNA - various techniques are available e.g.
  RT-PCR and branched DNA. May be used to diagnose
  HCV infection in the acute window phase. However,
  its main use is in quantitative monitoring of the
  response to antiviral therapy.
• HCV-antigen - an EIA for HCV antigen is
  available. It is used in the same capacity as
  HCV-RNA tests and is much easier to carry out but
  is less sensitive.

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Hepatitis C Virus Infection
anti-HCV
Symptoms
Antigen/RNA RNA
Titre
ALT
Normal
6
1
2
3
4
0
1
2
3
4
5
Months
Years

Time after Exposure
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Treatment of chronic HCV infection

• Interferon - may be considered for patients with
  chronic active hepatitis. The initial response
  rate is around 50 but 50 of responders will
  relapse upon withdrawal of treatment, i.e. giving
  a long term response of 25.
• Ribavirin - recent studies show that a
  combination of interferon and ribavirin is most
  effective. PEG-interferon /- ribavirin has
  improved results.
• The genotype of the infection influences long
  term responses. Overall some 50 of patients will
  clear virus permanently on combined therapy but
  for genotype 1 the figure is around 15 to 20.
• Very early treatment may offer much greater
  success rates.

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Hepatitis D (Delta) Virus, HDV
? antigen
HBsAg
RNA
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Geographic Distribution of HDV Infection
Taiwan
Pacific Islands
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
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HBV/HDV Co-infection
Symptoms
ALT Elevated
Titre
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV


Time after Exposure
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HBV - HDV Superinfection
Jaundice
Symptoms
Total anti-HDV
ALT
Titre
HDV RNA
HBsAg

IgM anti-HDV

Time after Exposure
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Hepatitis D - Clinical Features

• Co-infection
• severe acute disease
• low risk of chronic infection
• Super-infection
• usually develop chronic HDV infection
• high risk of severe chronic liver disease
• may present as an acute hepatitis

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EM Hepatitis E Virus

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Prevention and Control Measures for Travelers to
HEV-Endemic Regions

• Avoid drinking water (and beverages with ice) of
  unknown purity, uncooked shellfish, and uncooked
  fruit/vegetables not peeled or prepared by
  traveller
• IG prepared from donors in Western countries does
  not prevent infection
• Unknown efficacy of NHIG prepared from donors in
  endemic areas
• No vaccine

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Hepatitis E, HEV

• Most outbreaks associated with faecally-contaminat
  ed drinking water
• Minimal person-to-person transmission
• Large scale common-source outbreaks associated
  with sewage overflow into water reservoirs

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Hepatitis E - Clinical Features

• Incubation period average 40 days, range 15-60
  days
• Case-fatality rate overall 1-3, pregnant
  women 15-25
• Incidence of jaundice similar to HAV, increased
  with age
• Carriers none identified

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Hepatitis E Virus Infection
Symptoms
IgG anti-HEV
ALT
Titer
IgM anti-HEV
Virus in stool
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Weeks after Exposure
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Hepatitis Clinical Problems Case 1 A 21 year
old man who gave a history of having multiple
male sexual partners over the past year presented
with recent onset of jaundice. On further
questioning he admitted to having pale stools and
dark urine. He was admitted and a clinical
examination revealed a slightly enlarged liver
with some right hypochondrial tenderness. A
blood sample was sent for hepatitis serology. The
results for hepatitis B were as
follows HBsAg Positive HBeAg Positive anti-H
Bc Positive anti-HBc IgM Positive
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Case 1 continued Questions (i) How would you
interpret these results? (ii) How would you
manage a) this patient's admission? b) the
source of infection? c) sexual and close
household contacts? (iii) What are the general
indications for active immunisation with HBV
vaccine?
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Hepatitis Clinical Problems Case 2 A 24 year
old injecting drug user is noted to be mildly
jaundiced when attending his local needle
exchange clinic. On further questioning he
admitted to feeling generally unwell with mild
right hypochondrial pain and anorexia. A blood
sample was sent for "hepatitis serology". The
laboratory results obtained were as follows
Hepatitis A Total anti-HAV Positive anti-HA
V IgM Negative Hepatitis B HBsAg Negative
anti-HBc Positive anti-HBs Positive anti-H
Bc IgM Negative Hepatitis C anti-HCV
Negative
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Case 2 continued Questions (i) How would you
interpret these results? (ii) Do these results
exclude an acute HCV infection? Justify your
answer. (iii) How would you make the diagnosis of
an acute HCV infection? (iv) What is the most
likely route of infection in this
patient? (v) How else may this virus be
transmitted to others? (vi) Should you be
surprised at the patients HBV and HAV
serological results? Justify your answers.
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Hepatitis Clinical Problems Case 3 A newly
qualified houseman, working in the AE department
on Saturday night, accidentally stabbed himself
in the thumb while trying to re-sheath a needle.
He had been taking blood, with great difficulty
due to lack of suitable veins, from a young man
who was found unconscious in the gents toilet at
Oxford Circus underground station. The houseman
did nothing at the time because his thumb did not
bleed very much but he attended the Occupational
Health Department on Monday morning because he
was afraid that the thumb might, in his own
words, go septic.
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• Case 3 continued
• Questions
• Did the houseman act correctly?
• What should he have done?
• a) immediately b) subsequently
• (iii) Why might it be significant in this case
  that the houseman had great difficulty taking
  the blood sample?
• (iv) To which pathogens might the houseman have
  been exposed?
• (v) How should the houseman have avoided the
  needlestick injury?
• (vi) What should the occupational health
  physician do with the worried houseman on
  Monday morning?