Hepatit is

▪ Inflammation of the liver can be caused by a

variety of organisms and toxins.
▪ Infectious mononucleosis (EBV), leptospirosis,
syphillis, amebiasis, TB, toxoplasmosis
▪ Drugs, Alcohol
▪ Microscopically:
� spotty parenchymal cell degeneration
� Necrosis of hepatocytes
� Diffuse lobular inflammatory reaction
� Disruption of liver cell cords.
Hepatitis

▪ Parenchymal changeS:
� Reticuloendothelial (Kupffer) cell hyperplasia
� Periportal infiltration by mononuclear cells
� Cell degeneration
▪ Later stages:
� Accumulation of macrophages near degenerating
hepatocytes
▪ Preservation of reticulum framework allows
hepatocyte regeneration.
 Hepatitis Viruses
▪ Pathogenesis specifically involves replication IN
and destruction of hepatocytes.
▪ HAV- Infectious hepatitis
▪ HBV- Serum hepatitis
▪ HCV- Posttransfusion hepatitis
▪ HDV- defective virus dependent on coinfection
with HBV
▪ HEV- Enterically transmitted hepatitis.
 Clinical Findings

▪ Jaundice
� May appear within few days of the prodromal
period
� Anicteric hepatitis is more common
▪ Gastrointestinal symptoms:
� nausea, vomiting, anorexia, mild fever
Extrahepatic manifestations

▪ Transient serum sickness-like

prodrome:
▪ Fever, skin rash
▪ Polyarthritis
▪ Necrotizing vasculitis (PAN)
▪ Glomerulonephritis (HCV)
WHICH IS WHICH?
Onset of disease
▪ HAV- Abruptly (within 24 hours)
▪ HBV, HCV- more insidious onset
HEPADNAVIRIDAE (Hepatotropic DNA
Viruses)

▪ Consists of Hepatitis-causing viruses with DNA

genomes.
▪ HUMANS Only
▪ Unique:
� replication of DNA genome proceeds via an RNA
intermediate, which in turn is “reverse transcribed” by a
viral enzyme homologous to the retrovirus REVERSE
TRANSCRIPTASE.
▪ Package DNA genome
 Hepatitis B (HBV)

▪ Leading cause of
�chronic hepatitis,
�Cirrhosis
�Hepatocellular carcinoma
▪ Accounts for 1 million deaths
annually.
 Structure of HBV
▪ Dane particle (42nm)
▪ Spherical particles/
▪ Icosahedral
nucleocapsid (contains
HBcAg) enclosed in an
envelope (contains
HBsAg)
▪ Tubular or filamentous
forms
Organization of the HBV Genome

▪ Short, partly single-stranded, partly double-stranded,

noncovalently closed, circular DNA
▪ Circular structure: base-pairing the strands at one end.
Viral Genome

▪ One molecule of
DS DNA, circular.
▪ In virion
� Negative DNA
strand- full length
� Positive DNA
strand- partially
complete
 HBV Viral proteins
▪ Four proteins encoded by viral DNA:
1. Core protein (Hepatitis B Nucleocapsid Core
antigen HBcAg).
2. Envelope protein (glycoprotein, Hepatitis B
Surface Antigen, HBsAg).
3. Multifunctional reverse transcriptase/DNA
polymerase, complexed with the DNA genome
within the capsid.
4. Nonstructural regulatory protein designated
the “X protein”
 What about the HBeAg?

▪ Produced from an alternate start site upstream of

the start of HBcAg, followed by proteolytic
processing of the pre-core protein.
Replication
Transmission

▪ Infectious HBV is present in ALL BODY FLUIDS

of an infected individual.
▪ BLOOD, Semen, saliva, breastmilk
▪ Titer of infectious virus in blood: 10^8 particles
per ml.
▪ Endemic: SE, Africa, ME.
� From chronically infected mother or from infected
siblings.
Pathogenesis
▪ Fully differentiated hepatocytes:
� primary cell type infected by HBV.
▪ Primary cause of hepatic cell destruction:
� Cell-mediated immune response, which results in
INFLAMMATION and NECROSIS.
▪ Cells involved:
� Cytotoxic T cells, which react specifically with the
fragments of Nucleocapsid proteins (HBcAg and HBeAg),
expressed on the surface of infected hepatoctyes.
 Pathogenesis

▪ Enhanced natural killer cell activity +production

of Interferon γ = contributes to limiting the extent
of infection.
▪ Anti-HBsAg antibody- does not appear until well
into the convalescence period, when it may aid in
clearing any remaining circulating free virus.
� Provides protection against reinfection.
Anti-HBsAg antibody

▪ Responsible for the extrahepatic damage seen in 10-20

% of patients,
▪ There is formation and deposition of HBsAg/Anti-
HBsAg antibody immune complex and the consequent
activation of complement.
Clinical Significance: Acute
Disease
▪ Phases in acute Hepatitis B Virus infections:
� Incubation period: 45- 120 days
▪ Pre-icteric (prejaundice) phase:
� Several days to week.
� Mild fever, malaise, anorexia, myalgia, nausea
▪ Acute, icteric phase:
� 1-2 months
� Dark urine (bilirubinuria), jaundice, enlarged and tender liver.
▪ Convalescent period:
� several more months
 Course of Acute HBV Infection

▪ Appearance of viral antigens:

� HBsAg and HBeAg- first indicators of HBV infection to appear
in the blood during incubation period.
� Indicates active infection, but does not distinguish between
acute and chronic infections.
 Fulminant Hepatitis

▪ 1-2% of acute symptomatic cases,

▪ Rare syndrome, more extensive necrosis of the liver occurs during the first 8
weeks of the acute illness.
▪ Accompanied by FEVER, ABDOMINAL PAIN, RENAL DYSFUNCTION, COMA,
SEIZURES.
▪ Fatal in 8% cases.
▪ HBV +HDV or another hepatitis virus.
▪ Tx: LIVER TRANSPLANT
 Course of Acute Hepatitis B
Virus Infection
▪ Appearance of antiviral antibodies d
▪ Antibodies to HBcAg rise concurrently with liver
enzymes
▪ Anti-HBsAg antibodies do not appear until the
beginning of convalescence period.
▪ Resolved infection:
� Anti-HBcAg and anti-HBsAg remain present for life,
providing immunity to reinfection.
▪ Continued presence of HBsAg beyond 6 months and
absence of Anti-HBsAg indicates:
▪ CHRONIC infection.
Clinical Significance:
Chronic Disease

▪ High rate among infants born to HBV

infected mothers
▪ Less competent immune status of newborns.
▪ Adults with immune deficiencies
 Types of Chronic Carriers

▪ Asymptomatic carriers of HBsAg- most common

type of persistently infected individuals.
� Have Anti-HBeAg antibodies and little or no infectious
virus in their blood.
▪ Chronic Persistent Hepatitis- minimal chronic
hepatitis
� Asymptomatic most of the time
� Higher risk of reactivation of disease
� Small fraction leads to cirrhosis.
 Types of Chronic Carriers

▪ Severe chronic hepatitis (Chronic active

hepatitis)- results in more frequent exacerbations
of acute symptoms:
� liver damage leading to cirrhosis- highest risk
� Hepatocellular carcinoma
� Chronic fatigue
� Anorexia
� Malaise, anxiety
� Serum levels of liver enzymes and bilirubin:
INCREASED, reflecting the extent of necrosis.
 Development of Hepatocellular
carcinoma (hepatoma)

▪ 10-1oo times more frequent in areas with

high HBV endemicity
▪ Males- higher rate of chronic HBV infecitons
▪ Higher rate of progression to cirrhosis
▪ Higher rate of HCC
▪ Male to female ratio- 6:1
 H C C

▪ Appears many years after the primary HBV infection.

▪ Tumor is slow growing and occasionally metastasizes.
▪ Clinically:
� weight loss, RUQ pain, fever, intestinal bleeding.
▪ Chronic HBV provides the opportunity for chromosomal rearrangements
and mutations.
 Laboratory Identification

▪ Purpose:
� Determine which hepatitis virus is the cause of the illness.
� Distinguish acute from chronic infections
▪ Elevated: Aminotransferases, bilirubin, prothrombin
time
▪ ELISA: HAV, HBV, HCV, HDV
 Treatment

▪ Acute hepatitis
� 95% of adults, the immune system controls the infection
� Eliminates the virus within about 6 months
▪ Chronic Hepatitis
� Reduce the risk of progressive chronic liver disease, cirrhosis,
and HCC
� Interferon alpha
� Pegylated Interferon alpha, entecavir, tenofovir
� Lamivudine- high rate of resistance, low cost
 Prevention
▪ Active:
�HBsAg- prepare vaccines conferring protection because
antibody to the virion component neutralizes infectivity
�Initiated at birth
▪ Passive:
�Hepatitis B Immunoglobulin (HBIG)
�Prepared from blood donors having a high titer of anti-
HBsAg antibody
�Initial step in preventing infection of individuals
accidentally exposed to HBV-contaminated blood by
needlestick
�Given to infants with HBV positive mothers