Download Hepatitis Viruses

Hepatitis Viruses
Dr. Alvaro Barboza Quintana.
Profesor de Patología.
Fac. Medicina UANL.
Escuela de Medicina ITESM.
Causes of hepatitis
Hepatitis can be caused by
some viruses, bacteria,
parasites, fungi and
chemicals as part of the
clinical features that
characterizes each disease.
But the hepatitis viruses, a
heterogeneous group of
viruses with an special
affinity for the liver, are the
mayor cause of viral
hepatitis.

Liver is often affected by:
– Citomegalovirus.
– Mononucleosis.
– Yellow fever.

Virus with high affinity for
liver:
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Hepatitis
Hepatitis
Hepatitis
Hepatitis
Hepatitis
Hepatitis
Hepatitis
virus
virus
virus
virus
virus
virus
virus
A.
B.
C.
D.
E.
F.
G.
agent
transmission
hepatitis
HAV
HBV
HCV
HDV
HEV
HGV
icosahedral capsid,
RNA
enveloped
of acute DNA
enveloped
RNA
enveloped
coinfection, RN
unenveloped RNA
fecal-oral
incubation
period
chronic
2-6 wk
none
parenteral;
close contact
4-26 wk
5-10%
parenteral;
close contact
parenteral;
close contact
water-borne
2-26 wk
>50%
RNA virus parenteral
4-7 wk
<5%
80%superinfect.
2-8 wk
none
unknown
none
Hepatitis A (HAV)
A benign, selflimited disease,
known as infectious
hepatitis. Accounts
for about 25% of
clinically evident
acute hepatitis.
Epidemiology
Transmission
Fecal-oral route. Excreted in the stool of patients
2-3 weeks before, and 8-10 days after, the onset
of jaundice. The virus particle is resistant to
degradation, remaining infectious in the
environment for weeks.
  Person-to-person transmission.- cause
outbreaks in places like institutions.
  Fecal contamination of a single source.- can
lead to sudden epidemies.
Hepatitis A virus
Distribution and
incidence.
Worldwide
infection,
especially in
areas with
substandar
hygiene and
sanitation.
Clinical disease
HAV causes
an acute,
highly
contagious
form of
hepatitis:
Clinical infection
 The pre-icteric stage is characterized by
nonspecific, flu-like symptoms of anorexia,
nausea, vomiting, and malaise.
 The icteric stage is characterized by
hyperbilirubinemia, jaundice, hepatomegaly, right
upper quadrant tenderness, and raised serum
levels of liver enzymes such as alanine
aminotransferase (ALT) and aspartate
aminotransferase (AST).
Morphologic features in
acute hepatitis:
Morfologic changes in
acute viral hepatitis are
shared among
hepatotropic virus

inflammatory infiltrate,
bile duct reaction,
balloning degeneration
(were the hepatocite
cytoplasm looks
empty), macrophage
aggregates, cholestasis
and apoptosis.
Portal tract inflammation, Kupffer's cell
hypertrophy and spotty acidophilic
necrosis of hepatocytes.
Diagnosis


Clinical data
Serologic tests that
detect antibodies to
HAV. The finding of IgM
anti-HAV antibodies
indicates current or
recent infection, while
the finding of IgG antiHAV antibodies (without
IgM antibodies)
indicates past exposure
to the virus.
Treatment
Supportive therapy.
Immunity after HAV infection is usually
lifelong, infrequently waning in the elderly.
Relapses occur, but chronic carriers of HAV
have not been detected. In developing
countries, with inadequate sanitation,
infection occurs more in childhood.
Prevention with killed virus vaccine.
Hepatitis B virus (HBV)
Epidemiology
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300,000 people are afected (USA)
Endemic in Italy, Grece, Africa and the
southeast of Asia
The hepatocellular carcinoma is
endemic in those countries
Asymptomatic patients may have the
virus in blood and other body fluids
this is why it’s easily transmited
Incubation period: 6 weeks-6 months
Transmission
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Blood
Sexual contact
Perinatal
Risk group
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Drug users that share needles
Sexually active people (especially those who
are promiscuous)
Patients that have dialysis
Infants born to infected mothers
Healthcare workers
Clinical manifestations
Acute
 Subclinical infections
– Are more common than
clinical infections
– Liver enzymes are elevated
– The severity of the disease
is related to the viral dose
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Jaundice
Fatigue
Abdominal pain
Anorexia
Nausea
Vomiting
Clinical manifestations
Chronic
 Carriers: individuals who have
detectable HBsAg (hepatitis B
superficial antigen) for at least 6
months
 Of patients that become chronic
carriers, the majority (90%) develop
chronic persistent hepatitis and rest
will develop chronic active hepatitis
Serologic markers for hepatitis B
Serologic markers in chronic HBV
Persistent hepatitis B

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They remain clinically well, but they
are able to infect other people
The liver enzymes may be slightly
elevated
It can lead to terminal liver failure
Chronic active hepatitis

Patients are more likely to be
symptomatic and to have a more
severe manifestations
Complications of chronic hepatitis

It’s associated with cirrohosis and
hepatocellular carcinoma
Liver architecture is
usually well preserved
With lymphoid
aggregates in portal
tract.
Limitant plate
damage or
interface necrosis.
Cirrhosis

Chronic carriers especially those
with chronic active hepatitis, may
develop cirrhosis
HBV as oncogenic factor
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Causes between 250,000-1,000,000
deaths worldwide in a year
Approximately 80% of the cases of HC
are owed to HBV
The period between the infection with
HB until the development of HC could
be from 9-35 years
Hepatocellular carcinoma. Such liver cancers arise of cirrhosis
Hepatocellular carcinoma.
There is no discernable normal lobular architecture, though vascular structures
are present
Prevention

Hepatitis B vaccine (available since
1982)
– Routine vaccination of 0-18 year olds

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Screening pregnant women and
treatment of infants born to infected
women
Screening of blood/organ/tissue
donors
Hepatitis C

90% of the cases
are associated to
transfusions
Transmission
 Blood
 Needles
 Sexual intercourse
Hepatitis C virus
Epidemiology

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5-10% of the cases are posttransfusions
It produces cronic hepatitis
– Cirrosis  in 20% of the cases
– Hepatocellular carcinoma  in 50% of
the cases
Clinical manifestations

It has 2 types:
– Acute:
It could last 4/6 months
 Similar to manifestations seen in hepatitis A
or B, but with less inflamation

– Chronic:
More then 10 years
 Leads frecuently to hepatocelluar carcinoma
and cirrosis

Hepatitis C.
Diagnosis and treatment
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ELISA
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Interferon alfa
Hepatitis D virus. Delta agent.
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HDV is a defective
RNA virus. Needs to
be encapsulated by
HBsAg.
Superinfection of a
chronic carrier of
HBV
Progression to
cirrhosis in 80%
Hepatitis E virus.
High mortality range among
pregnant women 20%
Drug and toxin
Induced liver Disease
hepatotoxicity from
chemicals
Drug Induced liver
Disease
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Liver is the mayor detoxifying organ in the
body.
Liver is subjet to potential damage from
pharamceutical and environmental
chemicals.
Injury may result from:
– Direct toxicity
– Hepatic conversion of chemical.
– Immune mechanisms.
Drug Induced liver
Disease
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Liver damage from chemicals may be
immediate or take months.
Forms of liver injury:
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Hepatocyte necrosis
Cholestasis
Insidious onset of dysfunction.
Drug induced chronic hepatitis is
indistinguishable from chrinc viral hepatitis
Drug Induced liver Disease
Hepatocelular
damage
Chemicals
Microvesicular fatty change
Tetracycline, salicylates.
Macrovesicular fatty change Ethanol, methrotexate.
Massive necrosis
Acetaminophen,
insoniazid.
Hepatitis, acute and chronic Methyldopa, phenytoin.
Cholestasis
Anabolic steroids, oral
contraceptives.
Drug Induced liver
Disease
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Reye syndrome
– Mitochonrdial dysfuntion in liver and
some other organs.
– Predminantly in children given
acetylsalicylic acid cause of fever.
– Produces microvesicular steatosis with
severe liver dysfuntion.
Alcholic liver disease
(Ethanol Metabolism)
Epidemiology
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It develop only after a "threshold" dose
600 kg for men and 150 to 300 kg for
women.
one must consume eight 12-oz beers, 1 L of
wine, daily for a period of 20 years
Almost all people who exceed this threshold
dose of ethanol exhibit some biochemical or
histologic abnormality suggestive of liver
injury
Epidemiology
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fewer than 50% of people who ingest
the calculated threshold dose of
ethanol eventually develop serious
alcoholic liver disease (e.g., alcoholic
hepatitis or fibrosis).
This suggest that the pathogenesis
involves hereditary and enviromental
disorders.
Metabolism
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Liver. 3 enzyme systems: ADH, MEOS
and catalase.
There exist several isoforms of the
ADH enzyme (alfa, beta and gamma)
and variation in this changes the
metabolic rate of ethanol. Asians
(beta2) 20% faster.
ADH acts alone when tissue levels do
not exceed 10 mmol/L
MEOS
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Cytochrome P-450 2E1 (CYP2E1)
also the metabolism of other drugs such as
acetaminophen, haloalkanes, and
nitrosamines
Chronic ethanol consumption up-regulates
CYP2E1
CYP2E1-mediated ethanol oxidation yields
reactive oxygen intermediates
These are capable of provoking
hepatocellular damage
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Acetaldehyde is a highly reactive and
potentially toxic compound. It is
metabolized by the ALDH .
Half of Chinese people are deficient of
this enzyme.
Gastric metabolism
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Gastric ADH is implicated in first-pass
metabolism of ethanol
This limit the ethanol delivery to the
portal circulation
This enzyme is lower in Women.
Oxidant Stress
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DNA is sensitive to oxidant stress.
Mitochondrial DNA is more susceptible
than nuclear DNA to oxidative damage
because of reduced protection by
histone and nonhistone proteins and
because of a decreased capacity for
repair
This causes deletion and mutations in
DNA
Oxidant Stress
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Chronic alcohol consumption indeed leads to
depletion of several antioxidants in the liver
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Vitamin A depletion causes lysosomal
damage
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Vitamin E depletion enhaces lipid
peroxidation
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Glutation depletion impairs mitochondrial
function.
Alcoholic liver disease
Traditional spectrum of injury
* Fatty change
* Alcoholic hepatitis
* Alcoholic cirrhosis
Alcoholic hepatitis
Hepatocyte necrosis
Infiltrate of neutrophil
polymorphs
+/- fatty change
+/- Mallory bodies
+/- bile stasis
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MECHANISMS OF TISSUE DAMAGE
2 ways of damage: Indirect
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Ingestion of Ethanol
Increases the release of endotoxins, from the gram
negative bacteria in the natural flora of the intestinal
tract
Kupffer cells release toxic mediators:Reactive Oxygen
Intermediates (ROIs) and Tumor Necrosis Factor
(TNF)
Synergize to cause oxidative damage to hepatocytes.
the inflammatory response.
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Direct Damage
Alcohol
metabolism

consumption

Relative
deficiency.
NADH
NADH
NADH deficiency  Slow / incomplete
fat metabolism  Accumulation of fat
in liver.
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Injury on structures of the liver
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A. Mitochondria
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Know as “megamitochondria”
25% of the patient with AAH.
Characterized by: Oxidative fosforilation and Krebs
Cycle inhibited (40%)
Reduction of the B-oxidation of the fatty acids
leading to a “microvesicular esteatosis”
B. citokines.
Elevated plasma levels of: Il,1,6,8, and TNF-alpha.
(the last 2 related to worst prognosis) (seen in 75%
of the patients)
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C. Kupfer Cells
Secretes high levels of:
TNF-alpha. This is a strong factor for
adherence and activation of the leucocytes.
IL-8- main mediator for neutrophils atraction
D. Alterations of the hepatocelular protein
Aldehide and ethanol change conformation of
the surface proteins. In such way the immune
system recognizes them as “Neoantigens”
E. Fibrosis
Irreversible
Occurs at only 10 – 15% of the alcoholics
Due to activation of the Ito Cells (Fat store cells or
perisinusoids cells) that are at Disse Spece.
Function: normally stores vitamyn A, But en presence of
Ethanol  miofibrobñastic cells and Hipersecretes
collagen fibrosis
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F. Hipoxia
Hipermetabolic state induces aumented O2 usage,
leaving the pericentral zone lackting O2. This is
because the flow is from the periportal zone to the
pericentral zone.
Though it leads to damage of the pericentral zone.
Other cause of perocentral hipoxia is that CYP2E1 is
most abundant at the pericentral zone. (main site of
metabolism)
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Other factors contributing to the lipid
accumulation are:
The oversupply of free fatty acids to the liver.
Interference with the triglyceride cycle.
The increased synthesis or esterification of
fatty acids
Decreased fatty acid oxidation.
Decreased apoprotein synthesis.
Decreased synthesis or secretion of very low
density lipoproteins.
This liver is slightly enlarged and has a pale yellow
appearance, seen
both on the capsule and cut surface. This uniform change is
consistent with fatty metamorphosis (fatty change).
Massive hepatomegaly in an elderly alcoholic; the
liver weighed 2010 grams. Note the tinge of
yellow.
Micro
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ballooning degeneration of hepatocytes,
inflammation with neutrophils near mallory bodies
Mallory bodies (abnormal perinuclear aggregations of
cellular intermediate filament proteins “citokeratin”).
.
Mallory's hyaline is seen here, but there are also neutrophils, necrosis of
hepatocytes, collagen deposition, and fatty change. These findings are
typical for acute alcoholic hepatitis. Such inflammation can occur in a
person with a history of alcoholism who goes on a drinking "binge" and
consumes large quantities of alcohol over a short time.
Hyaline Mallory´s Bodies
In globoid hepatocyte. There
Is an interstitial infiltrate of
Neutrophils.
Mallory´s bodies are positive
For CK immunoperoxidase.
Clinical manifestations
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Vomiting
Diarrhea
Jaundice
Psychological disturbances.
Hepatic encephalopathy
Ascites
Bleeding esophageal
Varices (varicose veins in the esophagus), abnormal
blood clotting and coma.
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Main Reason for consulting:
Pathologically, it results in an enlarged liver
Painful to palpation.
Enlargement is due to the accumulation of
fat and the swelling of liver cells, and to the
accumulation of proteins that are normally
secreted.
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Lab
AST to ALT ratio = 2:1
Alkaline Phosphatase elevated
Gamma glutamyl transferase (GGT)
Hypoalbuminemia
Management
Alcohol Cessation
Increased caloric and protein intake
Vitamin supplementation (Thiamine)
Corticosteroids
Prognosis
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Mortality 10-15% from acute hepatitis
Cirrhosis develops in 50% of alcoholic
hepatitis
Alcoholic liver disease
Immediate causes of death:
* massive gastrointestinal
* variceal haemorrhage
* hepatic coma
* infection
* hepatorenal syndrome
Alcoholic Liver Disease.
The End.