Acute viral hepatitis prepared for medical students

Acute Viral Hepatitis
-Acute viral hepatitis is a systemic infection affecting the
liver predominantly.
-Almost all cases are due to one of the 5 major agents
namely
-Infrequent causes of viral hepatitis include
1. HAV,
2. HBV,
3. HCV,
4. HBV associated delta agent HDV and
5. HEV
1. adenoviruses,
2. CMV,
3. EBV and
4. rarely HSV.

Epidemiology of Viral Hepatitis
 The 5 agents account for more than 95 % of acute
viral hepatitis in the US.
 HAV is the most common cause of acute hepatitis
and HCV is the most common cause of chronic
hepatitis.
 Typical pattern of viral transmission is as follows,
Feco-oral Percutaneous Sexual Perinatal Unknown
HAV ||| - - - -
HBV - ||| ||| ||| |
HCV - ||| || | |
HDV - ||| ||| | -
HEV ||| - - - -

Natural history of Acute viral Hepatitis
 Clinical presentation can range from an
asymptomatic subclinical disease to self limited
symptomatic illness or fulminant hepatic failure.
 A and B are usually symptomatic while C is either
mildly symptomatic or subclinical.
 Acute Fulminant hepatitis with encephalopathy
 can occur in less than 1 % of pts with HAV or HBV.
 Not common with HCV and
 much higher with D and E.

Clinical Manifestations of Acute Viral
hepatitis
 IP varies according to the responsible agent.
 Constitutional symptoms precede jaundice by 1-2
weeks.
 The nausea ,anorexia or vomiting are due to
change in olfaction – aversion to food.
 Mild grade fever accompanies the prodrome.

 Dark urine and clay colored stools precede jaundice by
1-5 days
 Liver may become enlarged and tender with RUQ
discomfort.
 Transaminases increase during the prodrome and
precede the rise of bilirubin level & may reach up to
4000 u/l
 Jaundice will become evident when the total bilirubin is
> 2.5 mg/dl ( equally divided b/n direct and indirect )
hepatitis

 Relative lymphocytosis is common.
 PT may be prolonged in case of severe disease
signifying extensive necrosis with synthetic defect.
 Prolonged nausea, vomiting, poor intake and poor
hepatic glycogen reserve can lead to hypoglycemia
 Globulins may be diffusely increased
 Complete clinical and biochemical recovery is
expected within 3-4 months in hepatitis B and C in
cases which do not progress to chronic hepatitis.
hepatitis

 Initial presenting features like ascites, peripheral
edema ,and encephalopathy carry poor prognosis.
 A prolonged PT, low serum albumin level,
hypoglycemia and very high bilirubin level all show
severe hepatocellular necrosis.
 In hospitalized pts, case fatality rate of
 Acute hepatitis B is <0.1%.
 1-2 % in HEV reaching about 10-20% in
pregnant women.
 In acute B plus D is about 5%.
hepatitis

Diagnosis of Acute Viral Hepatitis

HAV
History- Historically known as infectious hepatitis
Virology
-It is an RNA virus of the picornaviridae family
Epidemiology of HAV
-Transmission is basically through feco-oral route.
-Very common in the underdeveloped world
-Occur as epidemic in these areas due to person
to person contact or sharing of common source.

HAV
Natural History of HAV
 IP is 15-45 days average being 4 weeks.
 Fecal shedding of the virus precedes onset of
symptoms by few weeks.
 Less than 1% of pts may develop acute fulminant
hepatitis.
 Doesn’t at all persist and never causes chronic
illness.

HAV
Clinical Picture of Acute HAV infection.
 Similar to other viral hepatitis.
Diagnosis of acute HAV infection
 Acute infection is documented by appearance of Ig M
anti-HAV which disappears several months later.
 Ig G anti-HAV appears after Ig M class and persists
indefinitely protecting the individual for life.

HAV
Treatment of HAV
 Is supportive
e.g. admission ,hydration ,glucose supplementation
 No antiviral therapy is available so far.
Prevention of HAV infection.
 For post-exposure prophylaxis –HAIG
 For pre exposure prophylaxis –
 Inactivated HAV or
 Recombinant vaccines are available.

 Historically known as serum hepatitis
 Enveloped partially dsDNA virus
 Member of the Hepadnaviridae family
 Found in blood and all body fluids
 100 times more infectious than HIV
 Able to survive in dried blood for longer than 1 week
HBV

 Enveloped partially dsDNA virus
(42nm)
 Compact genomic structure
 4 overlapping open reading frames
 Reverse transcriptase/ DNA
polymerase domain overlaps with
surface gene
 Encodes 4 sets of viral proteins
3213 157
2856
2
4
5
8
preS1 preS2
S
8
3
4
Y
M
D
D
1376
X
1837
1816
1622
1903
2
3
0
9
DR1 DR2 RNA
prim
er
EcoRI
3221, 1
c
o
r
e
precore
(+)
(-)
polymerase
1. HBsAg,
2. HB core Ag,
3. viral polymerase and
4. HBx protein

 Its S gene codes for the envelope protein expressed
on the surface of the virion called HBsAg.
 Its C gene codes for HBcAg, a nucleocapsid protein
called core antigen.
 C gene also codes for HbeAg that is a qualitative
indicator of replication and infectivity.
 P gene codes for DNA polymerase
 x-genes- codes for HBxAg, clinically unimportant but it
may contribute to carcinogenesis by binding to p53 .
HBV

1. HBV virions bind to the
hepatocyte receptor –
sodium taurocholate co-
transporting polypeptide –
and are internalized
2. In nucleus genome
repaired to form cccDNA
3. Translation of viral mRNA
to proteins in cytoplasm
HBV Replication Cycle

HBV Replication Cycle (continued)
4. Incorporation into ER and
reverse transcription of
RNA
5. Budding and secretion of
of viral cores to ER, and
packaging in Golgi
apparatus or
6. Recycling of genome to
nucleus with repletion of
intranuclear cccDNA

HBV Serologic Markers
HBsAg
 General infection marker
 First serologic marker to appear
 Infection considered chronic if persistent for > 6 months
 Indicative of number of infected hepatocytes

HBeAg
Nucleocapsid antigen
Indicates active replication of virus – high infectivity
E.g. HBsAg carrier mother who are HBeAg positive almost
invariably(>90%) transmit HBV to their offspring than
HBsAg carrier mothers who are HBeAg negative(10-15 %)
 Thus, HBeAg positivity signifies that there is ongoing
 Absent in precore or basal core promoter mutations
HBV Serologic Markers (continued)
viral replication,
infectivity and
liver injury.

Anti-HBs (HBsAb)
 Recovery and/or immunity to HBV
 Detectable after immunity conferred by HBV
vaccination
Anti-HBe (HBeAb)
 Generally indicates virus is no longer replicating
 Present in HBeAg negative disease

Anti-HBc total (HBcAb total)
IgG core Ab
 Past exposure to HBV
IgM Core Ab
 Acute infection or reactivation
HbcAg
 HbcAg is coated by HBsAg and can’t be picked
from serum

Spectrum of Disease
Acute
HBV
infection
Chronic
HBV
infection
Fatal
progressive
liver failure
Cirrhosis HCC
Death
Decompensated
cirrhosis
Fulminant
hepatic failure
0.5-1%
20-50% childhood infection
<5% adult infection
20%/yr <1 – 5%/yr
90-95 % of neonates

HBV
Molecular Variants of HBV ( Mutants )
 Genetic mutations in the precore region of the HBV
genome produces HBV that doesn’t express the
HBeAg.
 Pts infected by such mutant strains
 These mutant viruses cause an acute hepatitis that
tends to progress to
are negative for HBeAg
Positive for anti-HBe and
Have detectable HBV DNA.
 fulminant hepatitis ,
 severe chronic hepatitis or
 cirrhosis.

HBV
Mechanism of Liver Injury
 Immune mediated cytotoxicity plays the major role than direct
cytopathic effect of the virus.
 CD8 cytotoxic T lymphocytes recognize the HBcAg and
HBeAg on infected hepatocytes and kill them.
 But there is also place for viral factor as cause of cytotoxicity.
Epidemiology of HBV
 Infection with HBV is defined by the presence of HBsAg.
 ~90-95 % of neonates and about 5 % of adults with acute
infection progress to chronic HBV infection.

HBV
 About 5% of the world population and 10 % of
sub Saharan African and Asian pop are chronically
infected with HBV.
 This high carriage in the area is due to perinatal
transmission and failure of neonates to clear the
virus (immune tolerance)
 Of patients with chronic HB , about 20 % progress
to liver cirrhosis and then HCC.

HBV
Transmission of HBV
-Perinatal Transmission
.The most common mode world wide.
.Contact with maternal blood during delivery com-
moner than in utero infection.
-Percutaneous Transmission
.Blood transfusion , IV drug use, needle prick etc.
.Risk of acquiring HBV by needle prick from
infected pt is as high as 5% compared with
0.03 % for HIV.

HBV
-Sexual Transmission
.More common way of transmission
for HBV compared to HIV and HCV.
.Accounts for more than 50 % of the cases.
-Unknown Cause of Transmission
.27% of cases of HBV are acquired through
unknown means.

HBV
Natural History of HBV
 The incubation period of HBV is 30-180 days mean
being 12 weeks.
 Clinical acute hepatitis B ranges from mild self
limiting disease to acute fulminant hepatitis (< 1%)
 About 95% of adults and 5% of infants develop
anti-HBs and clear the virus
 while
about 5% of adults
95% of infants run the chronic course.

HBV
Diagnosis of Acute HBV infection
 HBsAg is the first serum marker of HBV infection and it signifies
presence of the virion in blood
 HBeAg, marker of active replication ,also appear shortly after
HBsAg.
 When viral replication slows ,
 The first Ab to appear is IgM Anti-HBc Ab.
 Weeks later , IgM disappears and IgG anti-HBc appears.
 HBeAg disappears and
 anti-Hbe appears and stays for years.

HBV
 IgM anti-HBc signifies an acute HBV infection
 IgG anti-HBc shows infection in the past or Chronic HBV
infection
 In patients who clear the HBV , HBsAg disappears in
about 4-6 months and anti-Hbs Ab appears shortly
after a brief window period and persist for life
 Anti-HBs Ab is a protective Ab against HBV reinfection.
 In the clinical window of acute hepatitis B, both HBsAg
and anti-HBs are negative but anti-HBc is positive.

HBV
Predictors of progression to Chronic Hepatitis B
-any of these clinical , immunological , histological or
biochemical findings may show that an acute infection has
progressed to a chronic HBV infection
1.lack of complete resolution of clinical symptoms
like anorexia, fatigue ,wt loss and hepatomegally.
2 .the presence of bridging or multilobular hepatic
necrosis on liver bx during protracted acute sev
ere viral hepatitis.

HBV
3 .Failure of the serum
aminotransferases ,bilirubin and globulin level to
return to normal in 6-12 months of the acute illness
4 .The persistence of HbeAg for more than 3 mon
ths and HBsAg for more than 6 months.

HBV
Extra Hepatic Manifestations of HBV.
 Believed to be due to accumulation of circulating
HBsAg-anti HBs immune complexes in tissues.
 Occurs in about 10-20 % of pts with HBV infection.
 The two most common manifestations are
 Immune complex deposition mediated glomerular
disease may give picture of
 Polyarthritis nodossa and
 glomerular disease
 membranous glomerullopathy or
 membranoproliferative GN---- NS

HBV
Pathologic findings in HBV infection
-inactive carriers have no or minimal findings on
liver bx.
-panlobular infiltrations with mononuclear cells , hep
atic cell necrosis , hepatic cell drop out .
-bridging hepatic necrosis with bridging b/n lobules
with collapse of reticulin network.
-in fulminant hepatitis (massive hepatic Necrosis ) ,a
small shrunken soft liver is the finding.

HBV
Treatment of Acute Hepatits B
 In previously healthy adults ,anti viral therapy isn’t
needed for acute HBV infection as recovery is the
rule in 95-99 % of the cases.
 In rare cases of severe acute diseases , antiviral
therapy may be necessary.
 Nucleoside analogues such as lamivudine , adefovir
or dipivoxil are the oral agents used.
 Lamivudine is given at 100mg/d for 48-52 weeks.

HBV
-supportive therapy like admission ,adequate
hydration , vitamin and glucose supplementation ,
high calorie and low protein diet should be
instituted.
-drugs that may cause cholestasis and drugs with
liver metabolism should be avoided.

HBV
HBV infection Prevention
-For post exposure prophylaxis , HBIG which has high
titer of anti-HBs can be used as passive
immunization.
-As pre-exposure prophylaxis for risky individuals
recombinant HBsAg vaccines can be administered

Hepatitis C Virus
Single-stranded, positive sense, RNA virus
 Flaviviridae family
No RNA polymerase proofreading ability
 Forms heterogeneous viral populations or quasispecies
 Half-life: 2.7 hours
 Daily production: 1012
virions
 3000-amino acid polyprotein
 Great genetic diversity
 Six genotypes: 1,2,3,4,5,6; >80 subtypes: a, b, c, etc.

Risk Factors for HCV infection
 Injecting drug use
 Blood/blood products <1992 or
where blood safety is
inadequate
 Unsafe medical or dental
interventions
 Traditional practices
 Tattooing and body piercing
using unsterilized equipment
 Needle stick injuries
(healthcare workers)
 Perinatal/mother to child
 Haemodialysis
 Sexual transmission
(notably men who have
sex with men)

H
C
V
Li
fe
cy
cl
e
O
ve
rv
ie
w

Steps in the HCV life cycle:
1.HCV virus infects human - circulates in the blood as a lipoviral
particle.
2.It enters the hepatocytes by binding its envelope proteins (E1, E2) to
CD81, SR-B1, claudin and occludin co-receptors.
3.Cytoplasmic release and uncoating of RNA genome
4.IRES-mediated (internal ribosomal entry site) translation and
polyprotein processing by cellular and viral proteases ( into 10 viral
proteins)
5. RNA replication (creation of minus strand template followed by
production of plus strand RNA copies) occurs at an endoplasmic
reticulum membrane derived replication complex (the membranous
−
web), which includes the lipid droplet (LD) and nonstructural viral
proteins NS4A NS5B.
−
6. Packaging and assembly by the Golgi apparatus and
subsequently released by the cell.
7. Virion maturation
8.Release from host cell

Lifecycle: Viral Polyprotein
The viral
RNA
undergoes
translation
resulting in
a single
viral
polyprotein.

Viral Enzymes
 NS3/4A protease assists in the downstream cleavage of viral
peptides. It also has ability to cleave and inactivate host
proteins that aid in antiviral activity (IRF-3)
 NS5B RNA-dependent RNA polymerase (RdRp) facilitate viral
replication by copying a positive strand RNA into negative
strand intermediate ( a template for more viral RNA genomes)
 NS5B RdRp lacks proof reading capabilities and therefore
mutations of HCV genome occurs at a rate of 10-4
per
nucleotide
 NS5A “replicase” assists in viral replication and viral assembly.

HCV
-the most sensitive indicator of HCV infection is HCV
RNA.
Epidemiology of HCV.
-about 2% of the world pop harbor the infection.
-genotype 1 is the commonest worldwide.
-HCV accounts for 40% of chronic liver disease.
Transmission of HCV infection
-it can be transmitted through blood transfusion, IV
drug use ,and through occupational risk.

HCV
Natural History of Acute Hepatits C
 IP is 15-180 days mean being 8-12 weeks.
 Most acute HCV infection is asymptomatic and when
symptomatic ,tends to be mild with mild elevation in
transaminases compared to A and B.
 Acute fulminant hepatitis with HCV is not common.
Natural History of Chronic hepatits C.
 Only about 15% of pts will clear the virus after
an acute hepatitis C infection.

HCV
 About 85 % of acute infection will generally lead
to chronic HCV carriage.
 ~20 % of the 85 % will finally end up in liver
cirrhosis in 10-20 years time.
 pts with HCV induced cirrhosis are at risk of
developing HCC as is also the case with HBV
induced liver cirrhosis.

HCV
Extra Hepatic Manifestation of HCV Infection
.Hematologic -Essential Mixed Cryoglobulinemia
-B-cell NHL
.Renal -Membranous and membranoprolife
rative GN ---- Nephrotic Syndrome
.Autoimmune -ITP, Myesthenia Gravis, Autoimmune
thyroiditis.
.Dermatologic -Porphyria cutana tarda , Lichen planus
.Endocrine -DM
.HCV may be associated with myocarditis and cardi
omyopathy.

HCV
Pathologic Findings in HCV
-Similar to the findings in HBV discussed.
Diagnosis of Hepatitis C infection.
 The gold standard is determination of HCV RNA.
 Anti-HCV can be determined to diagnosis the
infection. It may never become detectable in 5-10%
of the cases.
 Episodic fluctuation in the aminotransferase level is
common with HCV infection.

HCV
Treatment of acute HCV infection.
 Supportive treatment is important in acute setting.
 Unlike acute HBV infection , since chronicity is the
rule with most of acute HCV , anti viral therapy is
recommended in the acute phase.
Options

HCV
Prevention.
No active or passive immunization so far known.

HDV
History- known as HBV associated delta agent.
Virology
 Is a defective RNA virus that requires helper function of
HBV for replication and expression.
Epidemiology of HDV
 It is believed to infect about 5% of the worlds HbsAg
carriers.
 IV drug use is the most incriminated way of transmission.
 Sexual and perinatal transmission is also possible.

HDV
Natural History of HDV
 Co-infection with B and D causes same clinical
picture as B alone but could be severe one or even
fulminant hepatitis.
 Although acute hepatitis D co- infection doesn’t
increase the likelihood of chronicity of Hepatitis B, it
can contribute to the severity of chronic hepatitis B.

HDV
 Hepatitis D super infection can transform inactive or
mild hepatitis B into severe , progressive chronic
hepatitis or cirrhosis.
 Hepatitis D super infection in pts with chronic
hepatitis B can lead to fulminant hepatitis.
Pathologic Findings in HDV.
 Similar to that found in other viruses and HBV.

HDV
Clinical Pictures
 Similar to other hepatitis viruses and HBV
Diagnosis of HDV infection
 Detection of HDV RNA in serum
 Determination of anti-HDV. (IgM and IgG)
 Anti-HBc should be determined to know whether it is
a co-infection or super infection on hepatitis B.
 Co-infection- Anti-HBc will be of IgM class
 Super infection-Anti-Hbc will be of IgG class.

HDV
Treatment of HDV
 During the acute phase, supportive Rx as other viral
hepatitis.
 HBV and HDV co-infection is said to be less
responsive to interferon than HBV infection alone.
 Lamivudine appears to be effective against HBV
HDV co-infection.

HEV
History- has occurred as epidemics in history
Virology
-is an RNA virus , a calciviridae family.
Epidemiology of HEV
 Transmission is usually feco-oral
 Is endemic in some resource poor countries and can
occur as epidemic in these areas.
 Can occur sporadically in people visiting these areas

HEV
Natural course of HEV.
 Usually cause acute hepatitis less severe than B.
 Never cause a chronic hepatitis.
 Can be complicated by fulminant hepatitis esp in
pregnant women.
Diagnosis of HEV infection
 IgM and IgG anti-HEV signify spectrum of acute
infection.
 HEV RNA is also detectable

HEV
Treatment of acute HEV infection.
-treatment is supportive
-no antiviral treatment is there.

Complications
Common Complications
-Fulminant hepatitis
-Chronic hepatitis
-Cirrhosis and HCC.
Rare Complications
1. Pancreatitis,
2. Myocarditis,
3. Atypical Pneumonia,
4. Aplastic Anemia,
5. Transverse Myelitis And
6. Peripheral Neuropathy.

ALF
Evidence of
 coagulation abnormality, usually an INR >1.5, and
 any degree of mental alteration (encephalopathy)
in a patient without pre-existing cirrhosis and with
an illness of <26 weeks’ duration.
Definition

Acute Fulminant Hepatitis
 It is a severe form of acute liver disease
 Is associated with massive hepatic necrosis
 Comprises of
 a rapidly shrinking liver size
 rapidly rising bilirubin level
 marked prolongation of PT together with
clinical signs
 confusion ,
 disorientation,
 Somnolence
 ascites and edema indicating that the pt
has hepatic failure with encephalopathy.

 Cerebral edema,
 brainstem compression,
 GI bleeding
 Sepsis
 Respiratory failure
 Cardiovascular collapse and
 Renal failure are the terminal events.

-it carries mortality rate of > 80 %.
Viral causes of Acute Fulminant Hepatitis
HAV – 0.1%
HBV - 0.1-1%
HCV - 0.1%
HDV - Co-infection with HBV – 5%
- Super-infection on HBV- 20 %
HEV -1-2% in general population
10-20% in pregnant women.

Acute Fulminant Hepatitis.
Management of Acute Fulminant Hepatitis.
1. -maintainance of fluid balance.
2. -support of circulation and respiration.
3. -control of bleeding.
4. -correction of hypoglycemia.
5. -protein restriction.
6. -administration of neomycin and lactulose.
7. -prophylactic broad spectrum antibiotic.
8. -liver transplantation in case of ALF.

Acute viral hepatitis prepared for medical students

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