ACUTE VIRAL HEPATITIS
Jonathan Wala
Definition
• Systemic infection affecting the liver
predominantly
• Almost all caused by 5 viral agents:
– Hepatitis A virus (HAV)
– Hepatitis B virus (HBV)
– Hepatitis C virus (HCV)
– Hepatitis D virus (HDV)
– Hepatitis E virus (HEV)
• All are RNA viruses except HBV (a DNA
virus)
• All produce clinically similar illness
ranging from:
– Acute infections: asymptomatic inapparent
to fulminant fatal
– Chronic infections: subclinical persistent to
rapidly progressive liver disease to cirrhosis
to hepatocellular carcinoma
ACUTE HEPATITIS A
Virology of hepatitis A
• Non-enveloped 27nm RNA virus
• Hepatovirus genus of picornavirus family
• Virion contains 4 capsid polypeptides VP1 to VP4
• 1 serotype
• Incubation period 4 weeks
• Viral replication in liver
• Virus present in liver, bile, stools and blood
• Anti-HAV IgM detected in acute illness, persists for several months
• Anti-HAV IgG appears during convalescence, persists indefinitely
• Patients with anti-HAV IgG are immune to re-infection
Epidemiology
• Most cases are sporadic
Reported risk factors for HAV infection
• Outbreaks can occur
• Transmission: faecal-oral
route:
– Person-to-person
– Contaminated food or water
• Persons excreting HAV in
stool for 2-3 weeks before
and up to 8days after
jaundice
• No carrier state
Pathogenesis
• No hepatitis virus
directly cytopathic to
hepatocytes
• Clinical manifestations
and outcome
determined by
immunological
responses of host
Pathology
• Similar in all viral hepatitis
• Panlobular infiltration with
mononuclear cells
• Liver cell damage:
– Hepatic cell necrosis
– Hepatic cell degeneration
– Cell dropout
– Ballooning of cells
– Acidophilic degeneration of
hepatocytes forming Councilman
(apoptotic) bodies
• Hyperplasia of Kupffer cells
• Variable degrees of cholestasis
• Hepatic cell regeneration
Clinical presentation
• Incubation period: • Ictal phase:
– 15-45 days (mean 4 weeks) – Clinical jaundice
– Prodromal symptoms diminish
• Pre-ictal phase: – Enlarged tender liver
– Prodromal symptoms – Splenomegaly and cervical
– Precede jaundice by 1-2 lymphadenopathy in 10-20%
weeks • Post-ictal phase:
– Constitutional symptoms: – Recovery phase
• Anorexia, nausea, vomiting – Duration 2-12 weeks
• Fatigue, malaise – Complete clinical and biochemical
• Arthralgias, myalgias recovery in 1-2 months after all
• Headache, photophobia cases of HAV
• Pharyngitis, cough, coryza • Substantial portion of patients
• Low-grade fever (38-39°C) never become icteric
Laboratory features
• Serum AST and ALT: • Serum bilirubin:
– Visible jaundice if bilirubin
– Variable ↑ during
>43umol/L (2.5mg/dL)
prodromal phase – Typical levels 85-340umol/L (5-
– Precede ↑ in bilirubin 20mg/dL)
– Peak levels 400- – Usually approx. equal amounts
of conjugated and
4000U/L:
unconjugated
• Reached in icteric phase
• Others:
• No correlation with
severity – Neutropenia and lymphopaenia
– Prolonged INR
– Hypoglycaemia
– Diffuse mild ↑ gamma globulin
Diagnosis
• Clinical features
• ↑AST/ALT and bilirubin (if only ↑AST?ALT:
anicteric hepatitis)
• Serology:
– IgM anti-HAV during acute illness
– No tests for faecal or serum HAV
Prognosis
• Virtually all previously healthy pts • Poor prognosis:
with HAV infection recover
• More complicated or protracted
– Initial clinical
course: presentation :
– Advanced age • Ascites
– Serious underlying medical disorders • Peripheral oedema
• Case fatality rate: 0.1% • Hepatic encephalopathy
• Complications: – Biochemical features:
– Relapsing hepatitis:
• Weeks to months after apparent
• Prolonged INR
recovery • Low serum albumin
– Cholestatic hepatitis: • Hypoglycaemia
• Protracted cholestatic jaundice and
pruritus • Very high serum bilirubin
Treatment
• Specific treatment:
– None
• Supportive treatment:
– Restrict physical activity
– Nutrition:
• High calories esp. in morning
• Parenteral feeding if necessary
– Avoid hepatotoxic drugs
– Cholestyramine for pruritus
Prevention
• Passive immunization with immunoglobulin
(anti-HAV) 0.02mL/kg:
– Given before exposure or early prodromal period
to:
– Intimate contacts (household, sexual, institutional)
– Travellers to endemic areas
• Active immunization with formalin-
inactivated HAV strains
Hepatitis A vaccines
ACUTE HEPATITIS B
Virology
• DNA virus of family
hepadnavirus
• 4 sets of viral products from
4 overlapping genes: S, C, P,
X
• Viral particles:
– 22nm particles:
• Spherical or long filamentous
• From excess viral envelope
protein
– 42nm particles:
• Double-shelled spherical
• Intact hepatitis B virion
Virology
Viral proteins: • DNA polymerase:
• Hepatitis B surface antigen (HBsAg): – From P gene
– From S gene
– On outer surface of virion and on – Has both DNA-dependent DNA
spherical/filamentous particles polymerase and RNA-
• Hepatitis B core antigen (HBcAg): dependent reverse
– From C gene transcriptase activity
– On surface of nucleocaspid core
• Hepatitis B x antigen
– Do not circulate in serum
• Hepatitis B e antigen (HBeAg): (HBxAg):
– From C gene – From X gene
– Soluble, non-particulate nucleocaspid – Small non-particulate protein
core protein
capable of transactivating
– Has signal peptide that binds it to
endoplasmic reticulum → secretion into transcription of both viral and
circulation cellular genes
Hepatitis B virion
Pathogenesis
Epidemiology
Blood transmission
Epidemiology
Clinical features
• Acute hepatitis B same as acute hepatitis A
except:
– Incubation period 30-180 days (mean 4-12 weeks)
– Can occur in background of chronic hepatitis B:
• Superinfection with HDV
• Spontaneous reactivation: from non-replicative to
replicative infection
– With spontaneous HBeAg to anti-Hbe seroconversion
– With emergence of a precore mutant
Complications
• Serum-sickness-like illness:
– Mortality: >80% if deep
– During prodromal phase
coma
– Arthralgias, arthritis, rash,
angioedema, rarely haematuria – Terminal events:
• Cerebral oedema with
• Fulminant hepatitis (massive
brainstem compression
hepatic necrosis): • GI bleeding
– Seen with HBV, HDV, HEV, rarely • Sepsis
HAV
• Respiratory failure
– Present with hepatic
• Renal failure
encephalopathy
• Cardiovascular collapse
– Warning signs:
• Rapidly shrinking liver – Survivors: complete
• Rapidly rising bilirubin biochemical and
• Markedly prolonged PT (INR) histological recovery
• Falling AST/ALT
• Clinical signs of encephalopathy
Complications
• Chronic hepatitis B:
• Bridging or multilobular
– ↑Risk in: hepatic necrosis on liver
• Neonates biopsy
• Down’s syndrome • Failure of AST/ALT,
• Chronic haemodialysis bilirubin and globulin
patients levels to return to normal
• Immunosuppressed within 6-12 months
patients • Persistence of HBeAg
– Diagnosis: beyond 3 months
• Persistence of HBsAg
• Lack of complete
beyond 6 months
resolution of anorexia,
weight loss and fatigue
and persistence of
hepatomegaly
Complications
• Rare complications: – Peripheral neuropathy
– Pancreatitis – In children: anicteric
– Myocarditis hepatitis, non-pruritic
papular rash of face,
– Atypical pneumonia
buttocks, limbs, and
– Aplastic anaemia lymphadenopathy
– Transverse myelitis (papular acrodermatitis
of childhood or Gianotti-
Crosti syndrome)
Laboratory evaluation
• LFTs abnormalities similar to acute hepatitis A
• Specific serological and virological markers of
HBV
Serological markers
• HBsAg: • IgM anti-HBc
– 1st serologic marker to appear – For diagnosis of acute HBV
following acute infection infection
– Can be detected as early as 1 or 2 – Detectable at time of clinical onset
weeks and as late as 11 or 12 weeks and declines to sub-detectable
(mode 30-60 days) after exposure to
levels within 6 months
HBV
– No longer detectable in serum after • IgG anti-HBc
about 3 months in persons who have – Persists indefinitely as a marker of
recovered past infection
• HBeAg: • HBsAb (or Anti-HBs):
– Detectable in patients with active – Becomes detectable during
infection convalescence after the
– Correlates with higher titers of HBV disappearance of HBsAg in patients
and greater infectivity who do not progress to chronic
– Marker of replication infection
– Presence following acute infection
indicates recovery and immunity
from re-infection
Diagnosis
Treatment
• In previously healthy adults with acute
hepatitis B:
– Recovery in approx. 99%
– Hence, specific therapy not necessary
• Rarely in severe acute hepatitis B:
– Nucleoside analogue e.g. lamivudine
Prevention
Prevention
• Post-exposure – Dose of HBIG:
prophylaxis: • Neonates: 0.5mL IM in
thigh immediately after
– For unvaccinated persons
birth
sustaining exposure to • Adults: 0.06mL/kg
HBV:
– Combination of:
• Hepatitis B immune
globulin (HBIG): for rapid
achievement of high-titre
circulating anti-HBs
• Hepatitis B vaccine: for
achievement of long-lasting
immunity
ACUTE HEPATITIS D
ACUTE HEPATITIS C
Virology
• Linear single-stranded • 6 genotypes:
RNA virus – Differ in sequence
• Only member of genus homology by >30%
Hepacivirus, family – Several subtypes within
genotypes
Flaviviridae
– Result from HCV high
• Does not integrate into mutation rate →
host genome interferes with effective
• Circulates in low titres humoral immunity
• Particles: 40-60nm
Virology
Hepatitis C virus and
genome
Virology
Hepatitis C lifecycle
Clinical features
Treatment
Drugs used: • Small-molecule
• Interferon alfa:
inhibitors of HCV
– Potent inhibitor of HCV replication
– Acts by inducing interferon- infection
stimulated host genes that have – Initial effort focused on
antiviral functions
two viral-encoded
– Pegylated form: longer acting
enzymes:
• Ribavirin:
• NS3/4A serine protease:
– Acts synergistically with and is
– cleaves HCV polyprotein
used in combination with
interferon alfa – inhibitors: telaprevir
and boceprevir
– Probably has multiple
mechanisms of action • NS5B RNA-dependent
RNA polymerase
