HEPATITIS – AN OVERVIEW

Dr. JAYALAKSHMI
Hepatitis – inflammation of the liver –
causes
Viral hepatitis - most common
hepatitis viruses A, B, C, D, and E
Alcoholic hepatitis
caused by heavy alcohol use
Toxic hepatitis
caused by certain poisons, chemicals,
medicines, or supplements
Autoimmune hepatitis
chronic type in which your body's
immune system attacks your liver
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 History

▰ 500 B.C. written accounts of jaundice in Babylonia

▰ 400 B.C. Hippocrates describes “epidemic jaundice”
▰ 1883 jaundice noted to occur after inoculation of human sera
▰ 1941 post-vaccination jaundice occurs in >28,000 U.S. soldiers
▰ 1947 infectious hepatitis designated Hepatitis A; serum hepatitis
designated Hepatitis B
▰ 1963 Hepatitis B Surface Antigen identified
▰ 1973 Hepatitis A identified by electron microscopy
▰ Mid-1970’s Hepatitis D recognized
▰ Mid-1970’s Non-A, Non-B hepatitis described
▰ Mid-1980’s epidemics of “non-hepatitis A” enteric hepatitis
▰ 1989 Hepatitis C cloned and serological tests developed
▰ 1990 Hepatitis E cloned and characterized
Viral Hepatitis

Viral hepatitis refers to liver inflammation caused by one

of several types of viruses that attack the liver

 Hepatitis A Virus
 Hepatitis B Virus
 Hepatitis C Virus
 Hepatitis D Virus
 Hepatitis E Virus
Viral Hepatitis
 Viral Hepatitis - overview

A B C D E
Blood / Blood Blood / Blood Blood / Blood
Source of Virus Feces Derived Body Derived Body Derived Body Feces
Fluids Fluids Fluids
Routes of Percutaneous Percutaneous Percutaneous
Fecal-Oral Fecal-Oral
Transmission Permucosal Permucosal Permucosal
Chronic
No Yes Yes Yes No
Infection
Pre- / Post-
Blood Donor Exposure
Pre- / Post- Pre- / Post- Ensure Safe
Screening / immunization
Prevention Exposure Exposure Drinking
Risk Behavior
immunization immunization Water
Modification Risk Behavior
Modification
 Viral Hepatitis - Differential
Features
Features Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Genome type Ss RNA Ds DNA Ss RNA Ss RNA Ss RNA
Genome size 7.5 kB 3.2 kB 9.4 kB 1.7 kB 7.5 kB
Incubation 15-49 28-160 15-160 21-140 15-65
period, days
Fecal-oral yes no no no yes
transmission
Parenteral rare yes yes yes no
transmission
Sexual no yes, common yes, uncommon yes, uncommon no
transmission
Fulminant <1% <1% rare 2-7.5% ~1%, 30% in
hepatitis pregnancy
Chronic no 10% 85% 90% with no 7
hepatitis superinfection
 Incidence

 Viral hepatitis is a major public health concern, 10 millions cases

occur worldwide.
 It is nearly universal during childhood in developing countries.
 India is a hyperendemic for hepatitis A virus infection.
 Annually over 1 to 2 lakh Indians die due to illness related to HBV
infection.
 Worldwide 170 million people are infected with Hepatitis C virus (HCV).
Global epidemiology of viral hepatitis
Number of reported hepatitis outbreaks -
India
Stages of liver damage in
hepatitis
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 Hepatitis A

▰ Belongs to Picornaviridae ( Enterovirus 72)

▰ Genus – Hepatovirus
▰ Icosahedral particle – 27 – 32nm
▰ Capsid has three polypeptides – VP1, VP2 & VP3
▰ Linear ssRNA genome 7.5 kb
▰ Only one single serotype

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Hepatitis A Virus - HAV

• Hepatitis A (HAV):
– Non-enveloped RNA virus.
• Family:
– Picornaviridae.
• Mode of Transmission:
– Person-to-person through fecal-oral contamination.
• Incubation period:
– 4 weeks.

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Hepatitis A Virus - HAV

• Clinical features:
– Asymptomatic and anicteric to several weeks of malaise,
anorexia, nausea, vomiting, and elevated transaminases with or
without jaundice.
• Prognosis:
– No chronic state;10-15% may have a prolonged course.
– Isolated HAV infection has excellent prognosis of almost 100%
recovery (PALF data).

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Hepatitis A Virus – Diagnosis

• IgM (immunoglobulin M) antibodies

Your body makes these when you’re first exposed to hepatitis A.
They stay in your blood for about 3 to 6 months.
• IgG (immunoglobulin G) antibodies
These show up after the virus has been in your body for a while.
You may have them all your life. They protect you against hepatitis A.
If you test positive for them but not for IgM antibodies, it means you
had a hepatitis A infection in the past or had vaccinations to protect
against it.

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Hepatitis A Virus - Management

• Treatment:
– Supportive management

• Prevention:
– Hand hygiene.

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Hepatitis A Virus - Management

• Post-exposure prophylaxis:
– Active immunization with an inactivated Hepatitis A vaccine is
recommended for all children in the United States beginning at one
year of age; consists of two doses six months apart.
– Other indications: unimmunized children travelling to endemic
areas (one month before travel), chronic liver disease, receiving
clotting factor concentrates, homosexual males and IV drug users.
– Passive immunization: HAV-Immunoglobulin is recommended for
contacts at day care centers or unimmunized household contacts
within two weeks as a single dose.

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 Hepatitis B Virus - HBV

• Hepatitis B (HBV):
– Enveloped DNA virus.

• Family:
– Hepadnaviridae.

• Mode of Transmission:
– Parenteral, sexual, and perinatal exposure.

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 Hepatitis B Virus - HBV

• 8 HBV genotypes (A through H), differ in geographic

distribution and outcome.
– Genotypes A and D: Most common in North America;
– B and C are most common in Asia.
– Genotype A has most favorable response to treatment
compared to other genotypes.
– Genotype B when compared with genotype C is more
commonly associated with the development of childhood
hepatocellular carcinoma (HCC).

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 Clinical Features of HBV

• Acute HBV infection:

– Incubation period: 40-150 days (average 12 weeks).
– Prodrome of fever, anorexia, fatigue, malaise and nausea.
– 1-2 weeks later, develop jaundice, hepatosplenomegaly,
pruritus and intense fatigue that lasts for 1-2 months.
– Acute liver failure is rare, occurring in 0.1 - 0.5% of cases.

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Transmission

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 Clinical Features of HBV

• Chronic HBV: ranges from asymptomatic to symptomatic hepatitis in

clinically related phases (see diagram) with progression to cirrhosis
with end-stage liver disease in 15-30% and HCC.
– Perinatally - acquired infection:
• Maternal HB eAg positive – 90% risk.
• Maternal HB eAg negative – 20% risk.
• Immune tolerant phase is characterized by no signs of
significant clinical liver disease.
• HB eAg clearance (seroconversion) occurs in approximately
15% by 21 years of age.*

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 Clinical Features of HBV

▰ Risk of developing chronic infection decreases with age.

▻ 25% to 30% of infants and children under 5 years of age.
▻ Less than 5% of older children and adults.
▰ Extra hepatic manifestations:
▻ Migratory arthritis, angioedema or maculopapular/urticarial rash,
glomerulonephritis, papular acrodermatitis of childhood
(Gianotti-Crosti syndrome).
▰ Confirmation of HBV infection is based on serological assays of the
specific viral antigens and antibodies.

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Natural History of HBV Infection

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 Acute HBV vs. Chronic HBV

  Replicative
Early/Acut Precore/core
Recovery phase phase Chronic
e phase HBV mutants
HBV
HBs Ag + - + +
HBe Ag + - + -
HB core Ig
+ - - -
M
HB core IgG - + + +
HBs Ab - + - -
HB e Ab - + - +
HBV DNA - +/- + +
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Chronic HBV Infection: Phases

• Immune tolerance phase:

– HB eAg positive, HB eAb negative.

– HBV DNA titers high.
– Normal LFTs.
– Liver biopsy showing minimal or non-specific hepatitis.

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Chronic HBV Infection: Phases

• Immune clearance phase:

– HB eAg positive, HB eAb negative.

– HBV DNA titers high.
– Elevated LFTs.
– Liver biopsy showing chronic hepatitis with moderate or
severe chronic necro-inflammation.

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Chronic HBV Infection: Phases

• Inactive carrier phase:

– HB eAg negative, HB eAb positive.

– HBV DNA titers low (< 2,000 IU/mL).
– Normal LFTs.
– Liver biopsy absence of significant hepatitis.

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Chronic HBV Infection: Phases

▰ Reactivation phase:

▻ Often associated with precore or core mutations

▻ HB eAg negative, HB eAb positive.
▻ HBV DNA titers moderately high.
▻ Elevated LFTs.
▻ Liver biopsy showing chronic hepatitis.

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Chronic HBV Infection: Phases

▰ Resolved hepatitis B:

▻ Previous known history of acute or chronic hepatitis B

or presence of HB core IgM negative, IgG positive and
HBsAb negative.
▻ HBsAg negative.
▻ Undetectable HBV DNA titers.
▻ Normal ALT levels.

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Chronic HBV Infection: Phases

▰ Resolved hepatitis B:

▻ Previous known history of acute or chronic hepatitis B

or presence of HB core IgM negative, IgG positive and
HBsAb negative.
▻ HBsAg negative.
▻ Undetectable HBV DNA titers.
▻ Normal ALT levels.

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HBV – Diagnosis

▰ Blood tests. Blood tests can detect signs of the hepatitis B

virus in your body and tell your doctor whether it's acute
or chronic. A simple blood test can also determine if
you're immune to the condition.
▰ Liver ultrasound. A special ultrasound called transient
elastography can show the amount of liver damage.
▰ Liver biopsy. Your doctor might remove a small sample
of your liver for testing (liver biopsy) to check for liver
damage. During this test, your doctor inserts a thin needle
through your skin and into your liver and removes a tissue
sample for laboratory analysis.

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HBV – Diagnosis

▰ The laboratory can test for a wide range of HBV antigens

and antibodies, using immnoassays based on enzyme
reactivity (EIA) or chemiluminesence (CLIA) and ELISA.
▰ HBV DNA can be quantified in serum or plasma using
real time polymerase chain reaction (PCR) assays.
▰ Focuses on the detection of the hepatitis B surface antigen
HBsAg.
▰ Acute HBV infection is characterized by the presence of
HBsAg and immunoglobulin M (IgM) antibody to the core
antigen, HBcAg.

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HBV – Diagnosis

▰ During the initial phase of infection, patients are also

seropositive for hepatitis B e antigen (HBeAg). HBeAg is
usually a marker of high levels of replication of the virus.
The presence of HBeAg indicates that the blood and body
fluids of the infected individual are highly contagious.
▰ Chronic infection is characterized by the persistence of
HBsAg for at least 6 months (with or without concurrent
HBeAg). Persistence of HBsAg is the principal marker of
risk for developing chronic liver disease and liver cancer
(hepatocellular carcinoma) later in life.

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Antigenic diversity

 Hepatitis B surface antigen (HBsAg)

common group reactive antigen : a
type specific antigens : d-y and w-r
Antigenic subtypes : adw, adr,ayw,ayr

 Hepatitis B core antigen (HBcAg) antigen on

nucleocapsid core
 HBeAg : nucleocapsid protein

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Hepatitis B Virus Serological and Virological
Markers
HBsAg HBV infection, both acute and chronic
HBeAg High-level HBV replication and infectivity; marker for
treatment response
HBV DNA Level of HBV replication; primary virologic marker for
treatment response
Anti-HBc (IgM) Acute HBV infection; could be seen in flare of chronic
hepatitis B
Anti-HBc (IgG) Recovered or chronic HBV infection
Anti-HBs Recovered HBV infection or marker of HBV vaccination;
immunity to HBV infection (titer can be measured to
assess vaccine efficacy)
Anti-HBe Low-level HBV replication and infectivity; marker for
treatment response
Anti-HBc (IgG) and anti-HBs Past HBV infection; could lose anti-HBs
Anti-HBc (IgG) and HBsAg Chronic HBV infection 39

Anti-HBc (IgG) and/or anti-HBs and Latent or occult HBV infection

 Primary markers for the diagnosis of
acute hepatitis B infection

Diagnosis HBV Antigens HBV DNA Anti-HBV Antibodies

HBsAg HBeAg Anti-HBc Anti-HBe Anti-HBs
IgM Total Ig
Acute HBV ++ + + ++ + - -
Resolving
early - ± + ± ± ± ±
late - - - - + + +
Immune
vaccination - - - - - - +
past - - - - + - +
infection

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 Primary markers for the diagnosis of
Chronic hepatitis B infection

Diagnosis HBV Antigens HBV DNA Anti-HBV Antibodies

HBsAg HBeAg Anti-HBc Anti-HBe Anti-HBs
IgM Total Ig
HBeAg
positive
chronic + + ++ ++ - -
hepatitis B
HBeAg + - +/++ ++ ± -
negative
chronic
hepatitis B

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Clinical course and serologic profiles of
(A) acute and (B) chronic hepatitis B

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Clinical course and serologic profiles of
(A) acute and (B) chronic hepatitis B

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HBV Treatment Algorithm

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HBV - Treatment

• Acute HBV:
– Supportive care.

• Chronic HBV:
– Consider therapy if persistently elevated
transaminases and liver biopsy-proven significant
fibrosis.
– Therapeutic options: pegylated-interferon alpha,
lamivudine, adefovir dipivoxil, tenofovir, entecavir.

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 HBV - Treatment

• Post-liver transplant:
– Long-term HBIG and a nucleoside analog (lamivudine, entecavir,
or tenofovir).
– YMDD mutation is significant for the development of nucleoside
analog resistance.
• Immunoprophylaxis:
– Prevention of perinatal transmission by active and passive
immunization is highly effective.
– Infants born to HB sAg positive mothers should receive HBV
vaccine and HBIG within 12hrs of birth.

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 HBV - Immunoprophylaxis

▰ HBV vaccine:
▻ Three dose administration for all infants and children under 11
years of age, unimmunized adolescents and adults, high-risk
groups such as multiple sexual partners, homosexual males.

▰ Routine post-vaccination HBV serologic testing after the third dose of

vaccine (between 9 and 18 months of age at a well baby visit) is
advised for infants born to HBs Ag-positive women.

▰ HBV surface antibody testing should not be performed before nine

months of age to avoid confusion with HBIG administered during
infancy.
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 Hepatitis B Vaccine Recommendations

The hepatitis B vaccine is recommended for all infants and children up to age
18 years by the World Health Organization (WHO)
▰ All infants, beginning at birth
▰ All children aged <19 years who have not been vaccinated previously
▰ Susceptible sexual partners of hepatitis B-positive persons
▰ Sexually active persons who are not in a long-term, mutually
monogamous relationship (e.g., >one sex partner during the previous six
months)
▰ Persons seeking evaluation or treatment for a sexually transmitted
disease
▰ Men who have sex with men
▰ Injection drug users
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▰ Susceptible household contacts of hepatitis B-positive persons
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Hepatitis C virus- HCV

• HCV:
– Enveloped single-stranded RNA virus.

• Family:
– Flaviviridae.

• Six genotypes (1-6) with subtypes identified differing in

treatment response and prognosis.

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Hepatitis C virus- HCV

• Genotype 1:
– Most common in North America and is associated
with less favorable response to treatment (30-50%).

• HCV:
– Highly prevalent and the most important cause of
chronic viral hepatitis in the US.
– Most common cause of liver transplantation in
adults in US.ro

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HCV-Clinical Features

• Modes of transmission:
– a) Percutaneous: IV drug use, blood trans-
fusions, accidental needle stick injury, skin
tattooing,
– b) Non-percutaneous: intra-familial and sexual
routes, risk of vertical transmission is
approximately 3-5% (2-3 times higher in
HIV/HCV co-infection).

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 HCV-Clinical Features

• Incubation Period:
– 15-50 days with symptoms developing 5-12
weeks after exposure.

• Acute HCV infection:

– Mostly asymptomatic.

• Acute liver failure is rare; however, co-infection

with other hepatotropic viruses such as HBV may
cause rapid progression of disease.
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 HCV-Clinical Features

▰ Chronic HCV infection:

▻ Spectrum of minimal clinical symptoms to fatigue,

jaundice, elevated transaminases.

▰ Extra hepatic manifestations:

▻ Essential mixed cryoglobulinemia, focal lymphocytic

sialadenitis, autoimmune thyroiditis, porphyria cutanea
tarda, lichen planus and non-Hodgkin lymphoma. 55
 HCV-Clinical Features

▰ Natural history:

▻ Acute hepatitis C infection  chronic hepatitis (85%) 

cirrhosis (20% over 20 years)  HCC (4%)  death due to
decompensated liver disease (3.6%).

▰ Neonatally acquired infection is associated with a 25%

spontaneous clearance rate by 7.3 years.

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 HCV-Diagnosis

▰ Initial test:
▻ Serum HCV antibody
▻ HCV RNA by RT-PCR.

▰ Infants born to HCV infected mothers,

▻ HCV antibody testing performed at 18 months of age or older.
▻ If earlier diagnosis is desired, HCV RNA testing may be
considered at 1-2 months of age.

▰ HCV genotyping should be performed prior to treatment to

determine prognosis and the duration of therapy.

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 HCV-Clinical Management

▰ Liver biopsy:
▻ Consider for staging and treatment assessment.

▰ Initiating therapy:
▻ Based on the presence of signs and/or symptoms of clinical
liver disease, liver biopsy showing severity of liver damage
and in some cases parental or patient’s request for therapy.

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 HCV-Clinical Management

▰ Cirrhotic patients:
▻ screened for HCC by liver ultrasonography and AFP every 6
months.
▻ Serial Hepatic MR imaging may be used to identify early
lesions.

▰ Recurrent HCV infection in patients transplanted for HCV

cirrhosis is almost universal.

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Treatment Algorithm for HCV Genotype 1

▰ Acute HCV:
▻ PEG-IFN Monotherapy:
▻ May prevent chronic infection if initiated
within 3 months of exposure.

▰ Chronic HCV:
▻ Combination therapy: PEG-IFN + ribavirin.

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Treatment Algorithm for HCV Genotype 1

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 Virologic Response during Therapy

• Rapid Virologic Response (RVR):

– HCV RNA negative by week 4 of treatment by PCR.
• Allows shortening of course for genotypes 2 & 3, and low
viral load genotype 1.

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 Virologic Response during Therapy

• Early Virologic Response (EVR):

– >2 log reduction in HCV RNA compared to
baseline[partial EVR] or HCV RNA negative at week 12 of
treatment.
• Predicts lack of Sustained Virologic Response (SVR).

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 Virologic Response during Therapy

• Sustained Virologic Response (SVR):

– HCV RNA negative 24 weeks after cessation of
treatment.
• Best predictor of long term response to treatment

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Hepatitis D virus

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Hepatitis D Virus- HDV

• Small defective RNA virus, incubation period 35 days.

• Dependent on active HBV infection and is associated with more
severe clinical liver disease.
• Co-infection (simultaneous) or super-infection (pre-existing HBV
infection).

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 Hepatitis D Virus- HDV

• Diagnosis:
– Acute: HDV antigen + ; either
• Co-infection HBV core IgM +
• Super-infection: HBV core IgM -
– Chronic: HDV antigen - ; HBV core IgM -; HDV RNA+
• More than double the rate of progression to cirrhosis than HBV
alone.
• Treatment:
– No treatment recommendations for chronic HDV in
children, rarely interferon-alpha may used.
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Hepatitis E virus

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Hepatitis E Virus- HEV

• Family:
– Calicivirus.

• Mode of transmission:
– Fecal-oral route.

• Incubation period :
– 2-9 weeks.

• Affects mainly adolescents and adults.

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Hepatitis E Virus- HEV

• Clinical Course:
– Acute self-limited infection with clinical
features similar to HAV;
– May be severe in those with preexisting
chronic liver disease.

• High mortality for pregnant women

particularly in the third trimester.

• No chronic state.

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Alcoholic hepatitis

⚫ Alcoholic hepatitis is a diseased, inflammatory

condition of the liver caused by heavy alcohol
consumption over an extended period of time.
⚫ Diagnosis are CBC, Liver function tests,
Ultrasound, CT scan, blood clotting tests, liver
biopsy.
⚫ Patients needs to stop receive drinking.

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 Autoimmune Hepatitis

 It is a chronic inflammation of liver of unknown cause.

 It is characterized by the presence of autoantibodies, serum IG.

 Majority of patients are women.

 There is an autoimmune reaction against normal hepatocytes.

 In Diagnosis serological markers are useful such as antinuclear

antibodies , anti-DNA antibodies.

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