Transcript viral hepatitis

VIRAL HEPATITIS
Table 1. Characteristics of hepatitis viruses
Property
HAV
HEV
HBV
HCV
Family
Nucleic acid type
Transmission
Maximum titer
Fulminant disease
Chronicity
Malignancy
Serologic tests
Antigen
Antibody
Picornaviridae
RNA
Fecal-oral
109/ml
Rare
No
No
?
Hepadnaviridae
Flaviviridae
RNA
DNA
RNA
Fecal-oral
Parenteralsexual
Parenteral
Pregnant
women
109-10/ml
Rare
Rare
50-90%
No
1-10%
Yes
No
Yes
Genotypes
7
Vaccination
Yes
Yes
Yes
?
106/ml
No
Yes
Yes
Yes
Yes
Yes
>6weeks
3
5
Types 1-6 with
subtypes a, b, c
No
Yes
No
HEPATITIS A

Hepatitis A virus (HAV) is a member of picornaviridae family (which
includes poliovirus and rhinoviruses, agents of the common cold).

The virus particle
- is of 27nm in diameter
- is not enveloped
- has an outer capsid which surrounds a single-stranded RNA
Risk factors for acquisition:
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contact with acutely ill individuals
travel to endemic areas
homosexual activity
contact with children attending day care centers
illicit drug use
Among the persons under 18 years old, 50% in
France, 90% in Portugal and >95% in Romania
present antibodies against HAV.
Pathogenesis
 During acute HAV infection, there is an initial
viremia and fecal shedding of viruses; viremia
persists for up to 3 weeks.
Histopathological aspects include the existence
of:
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hepatocellular necrosis
centrilobular cholestasis
periportal infiltration of the liver with mononuclear inflammatory
cells
Clinical manifestations

Only 10% of A-hepatitis are clinically
manifested.

The incubation period: the symptoms of HA
usually appear about 4 weeks after exposure,
but the interval may range from 2-6wks.

The clinical manifestations are different in
adults and young children (children of less than
2 years old experience asymptomatic infection or
develop other symptoms than those suggestive
for hepatic inflammation.
A.
Prodromal (preicteric) phase lasts for 4-10 days

Gastrointestinal symptoms: anorexia, nausea and vomiting, right
upper-quadrant pain,
diarrhea (in children –20% of cases ), distaste for cigarettes (in
smokers only);
Influenza-like - syndrome: fever /chills, muscle pain, headache;
Rheumatic syndrome: arthralgias (usually disappear after onset of
jaundice);
Eruptions: petechiae, measles/scarlet fever-like exanthema;
Fatigability;
Pruritus;
Jaundice
Acute abdomen (mimicking an appendicitis)
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could be very variable:
B. Icteric phase – is ushered by the appearance
of dark, golden-brown urine due to bilirubinuria,
followed one to several days later by pale stools
yellowish coloration of the mucous membranes,
conjunctivae, sclerae and skin.
The physical examination
2 special forms of evolution may be encountered:
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Cholestatic hepatitis A - >12 weeks of jaundice
Relapsing hepatitis A
Diagnostic
1. AST (Aspartate Aminotransferase) or SGOT (Serum GlutamicOxalacetic Transaminase) (N = 5 – 54 U/L).
2. ALT (Alanine Aminotransferase) or SGPT (Serum Glutamic-Piruvic
Transaminase): (N = 0 – 36 U/L).
3. Alkaline Phosphatase (N = 40 –120 U/L).
4. GGT (Gamma Glutamyltransferase) (N = 3 – 59 U/L).
5. LDH (Lactose DeHydrogenase) (N = 135 – 225 U/L)..
6. Total bilirubin
7. Direct bilirubin (conjugated) (N = 0 – 5 μmol/L).
8. Albumin (N = 35 – 50 g/L)9. PT (Prothrombin Coagulation Time) (N = 10 – 12 sec.) or QUICK
Index (N≥80%).
10. Urine tests: bilirubin appears in the urine in the prodromal phase
and may lead to the diagnosis
11. Peripheral blood:
12. Serological confirmation is always required, by the specific
detection of IgM anti HAV.
Complications
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Neurological complication: encephalitis,
meningoencephalitis, Guillain-Barre syndrome,
mononeuritis affecting cranial or peripheral nerves.
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Myocardial involvement: myocarditis and
electrocardiographic changes
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Pancreatitis
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Pleural effusions and ascites
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Aplastic anemia
Differential diagnosis of
jaundise
I Abnormalities of bilirubin metabolism
1. Increased bilirubin production (unconjugated bilirubinemia):
• Hemolysis
• Ineffective erythropoiesis: megaloblastic anemias, myeloproliferative
diseases, protoporphyria etc
• Blood transfusions
• Resorbtion of haematomas
2. Decreased hepatic clearence:
a.decreased uptake and/or conjugation of bilirubin
• Gilbert syndrome, Crigler Najjar syndrome
• Rifampin
• Physiologic jaundice of neonate
b.Decreased canalicular excretion of bilirubin: Dubin-Johnson and Rotor
syndromes
II. Hepatocellular jaundice
1.
Acute/subacute hepatocellular damage
• Acute hepatitis: viral (CMV, Epstein-Barr virus, herpes), bacterial
(leptospirosis, brucellosis, staphylococcal, gram-negative bacillary sepsis,
tuberculosis, salmonellosis), amoebiasis, giardiasis
• Hepato-toxines: alcohol, Amanita, acethaminophen;
• Drugs: isoniazide, macrolides, sulfonamides, metildopa, valproic acid,
paracetamol, non steroidal anti-inflammatory drugs, halothane and
derivatives, antidepressants, anti-HIV, ketoconazole
• Chemical agents: carbon tetrachloride, tetrachloroethylene
• Metabolic disorders: Wilson’s disease, Reye’s syndrome
• During pregnancy: acute liver steatosis
2.Chronic hepatocellular diseases
□Chronic active hepatitis
□ Cirrhosis
□ Neoplasia
□ Neonatal hepatitis
□ Autoimmune hepatitis
□ Alfa1-antitripsin deficiency
III. Biliary obstruction
Extrahepatic
•Gallstones
• Neoplasia
• Sclerosing colangitis
• Biliary stricture
• Pancreatitis
• Parasites
Intrahepatic
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Cholestatic viral hepatitis
Postoperative cholestasis
Benign recurrent cholestasis
Primary biliary cirrhosis
Chronic inflammatory bowel disease
Biliary atresia
Treatment
The aim of the treatment is to maintain comfort and
nutritional balance.
 Bed rest is indicated.
 A high-calorie, high-protein diet has been shown to
reduce the length of time in hospital.
 The adequate calories must be provide: 30-35 kcal/kg,
mostly from carbohydrates.
 Low-fat diet is frequently advised. Avoidance of alcohol
is recommended for some months after acute infection.
 Patients with severe anorexia, nausea or vomiting
occasionally need nutritional support.
 Meat can be introduced when urine exam for bilirubin
and urobilinogen are back to normal. In cholestatic
hepatitis hypertonic glucose is used.
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Prevention
 Now,
there is available a double vaccine
against A and B hepatitis viruses (Twinrix)
HEPATITIS B
The hepatitis B virus (HBV), discovered in
1966, infects more than 400 million people
world-wide.
Epidemiology
 Areas
with high prevalence  Areas with low level of endemicity The distribution of hepatitis B infection
varies greatly throughout the world.
Modes of trasmission

Contact transmission through body secretions:
semen, vaginal secretions, blood, saliva
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Maternal-neonatal transmission: 5 –10 % of
neonatal HBV infections result from in utero
infection
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Percutaneous transmission: drug abusers, health
care workers
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Blood transfusions.
Virologic characteristics
HBV belongs to Hepadnaviruses (DNA-woodchuck hepatitis virus,
the duck hepatitis virus and other avian and mammalian variants).
The hole VIRION – the Dane particle is a 42 nm sphere, which
contains:
□ the core enclosing the DNA and
□ an envelope material , which is found abundantly in the circulation,
shaped as small spheres and rods with an average width of 22 nm.
The viral genome is represented by a double – stranded circular DNA of
approximately 3200 pairs of bases that encodes 4 overlapping open
reading frames:
1. S, for the surface or envelope gene
2. C, for the core gene
3. X, for the X gene
4. P, for the polymerase gene
HBV replication cycle
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The replication cycle of HBV begins with
attachment of the virion to the hepatocyte.
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Inside the hepatocyte nucleus the viral genome
is converted into a covalently closed circular DNA
(cccDNA).
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The cccDNA is
Serologic makers of importance in HBV
infection
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Hepatitis B core antigen (HBcAg) - represents the nucleocapsid that
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Hepatitis B ″e″ antigen( HBeAg). It is a circulating peptide derived from
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DNA polymerase (encoded by the P gene) – also serves as a witness of
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Antibodies against HBsAg (anti – HBs) are produced as a response to
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Antibodies against HBcAg (HBcAb)
encloses the viral DNA.
the core gene and then modified and exported off the liver cells and serves
as a maker of active viral replication.
reserve transcriptase activity.
the presence of the envelope (surface) Ag:
• are detected virtually in all patients who have ever been exposed to
HBV: they are not protective
• IgM subtype antibodies are associated with acute infection; usually they
disappear within 4-8 months after acute infection.
 Antibodies against HBeAg (HbeAb) appear once the antigen has been
cleared
Immune response
Immune response to acute HBV infection

Recovery from acute HBV infection is dependent on:
□ B cell response with production of antibodies to pre-S and S
antigens
□ T cell response.
Immune response to chronic HBV infection
 In patients with chronic HBV infection the HBV-specific CTL response is
weak and limited to one or a few epitopes.
Immune tolerance in perinatally acquired HBV infection
 Immune tolerance to HBV is manifested by:
□ A high rate of progression to chronic infection
□ Lack of disease activity in the presence of very high level of virus
□ Very low rate of spontaneous or interferon-induced HBeAg
seroconversion.
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Pathogenesis
1. Immune-mediated liver injury
HBV-related liver injury is related to:
• CTL-mediated lysis of infected hepatocytes;
• Non-cytolytic pathways via the release of
cytokines.
2.Direct cytopatic effects

HBV is in general not a cytopatic virus. Direct cytopathic liver injury can
occur when the viral load is very high (as in fibrosing cholestatic
hepatitis).
Hepatocarcinogenesis
Life cycle of HBV in the human host
□ 95% of infected neonates become asymptomatic chronic HBV
carriers
□ 30% of children of 3months – 6years become asymptomatic
chronic HBV carriers
□ only 3 –5% of adults become asymptomatic chronic HBV carriers.

The Four Stages of Hepatitis B Infection are:
1. First Stage (Immune Tolerence) is defined as incubation period
2. Second stage (period of symptomatic hepatitis):
□ In patients with acute HBV infection - it lasts 3 – 4 wks;
□ In patients with chronic disease, stage 2 may persist for > 10 years possibly
leading to cirrhosis.
3. Third stage (end of active viral replication)
• HBeAg is no longer present.
• HBeAb become detectable.
• There is a marked decrease in viral DNA.
• ALT becomes normal.
• The patient remain + for HBsAg.
4. Fourth stage (immune stage)
• HBsAg is absent;
• HBV DNA is absent
• HBsAb is positive testifing the development of full immunity.
Some factors can affect the evolution through
the four stages, like:
• the genetic predisposition of the host,
• the presence of other viruses,
• the treatment with immunosuppressive agents,sex,
• infections with HBV mutants.
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HBV variants
HBV mutant that are detected clinically confer survival
advantage over the wild type virus by:
• evading host immune response
• enhancing virus replication.
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Mutations in the precore, S and P genes have been most
extensively studied.
Precore mutants
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S mutants
Mutations in the HBV gene have been reported in infants
born to carrier mother who developed HBV infection
despite vaccination, and in liver transplant recipients who
developed HBV reinfection despite prophylaxis with
hepatitis B immune globuline (HBIG).
Clinical manifestations
I.
Asymptomatic hepatitis
A.Subclinical infection: abnormal blood tests, without jaundice and symptoms;
B.Inapparent infection: no symptoms or biochemical abnormalities are present,
but serologic tests are positive
II. Symptomatic hepatitis
A. Anicteric hepatitis –
B.Icteric hepatitis
Icteric phase:
- dark urine, lightening of stool color – a few days before onset of jaundice,
- as jaundice progress the constitutional symptoms become less severe,
duration of jaundice is 1 – 2 months after its onset.
The physical findings are similar to those described in HAV, adenopathy, small
spider angiomata.
Extrahepatic manifestations of viral hepatitis
•
transient serum-sickness like syndrome:
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polyarteritis nodosa:
glomerulonephritis
mixed cryoglobulinemia
acrodermatitis of childhood (Gianotti’s disease):.
Laboratory features

Blood chemistry was shown above. Minor elevation of
ALT values may persist for a few months, even if the
bilirubin level turned normal.
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Serologic Tests
• HBsAg is the first identifiable marker (before the level
of ALT start to Increase) by ELISA, RIA. It’s persistence
beyond 6 months suggests the development of HBV
carrier state.
• HBeAg it will be detectable in the next days to weeks
after the appearance of HBsAg and in uncomplicated
HBV infections it will disappear priory to the HBsAg.
• HBeAb become detectable shortly after the disappearance of
HBeAg. They may persist for long periods.
• DNA- HBV: is detectable during the early phase of infection and →
undetectable several wks later.
• HBcAb (anti - HBc) are detectable in serum shortly after the
HBsAg′s discovery and before the appearance of anti-HBs.
• IgM anti – HBc peak in several weeks from the onset of infection;
is the most sensitive test for acute HBV infection. They persist for 4
to 8 months after their appearance.
• IgG anti – HBc are synthetised in late convalescence and are found
thereafter for years, but levels decline slowly.
• Anti – HBs. As the titer of HBsAg declines, corresponding antibodies
become detectable and reach a peak level in a few months. They
are neutralizing,
Evolution of HBV infection
1.Full recovery
2.Fulminant hepatitis
3.Persistence of HBsAg
4.Chronic hepatitis B
5.Cirrhosis
6.Hepatocellular carcinoma
1. Full recovery is assumed if the ALT reaches normal or close to
normal levels and if HBsAg becomes negative in EIA. This takes
more than 6 months in some cases.
2. Fulminant hepatic failure (FHF) was defined as a potentially
reversible condition, the consequence of severe liver injury, in
which encephalopathy developed within 8 weeks of the
appearance of the first symptoms, in the absence of pre-existing
liver disease
Pathophisiology
Pathophisiologically, the terminal event in
this illness is injury and/or death of
hepatocytes.
Although the actual pathogenesis is not
well understood, this damage is probably
due to liberation of chemical and
immunological mediators.
FHF is announced by some signs, such as:
• severe jaundice (> 15 mg% in adults or > 7 mg% in infants); • mild
jaundice does not excluded the fulminant hepatitis;
• persistence of vomiting and anorexia after the jaundice have installed;
• presence of bleedings
• persistence of fever in the presence of jaundice
• quickly decreased in size of liver;
• tachicardia instead of bradicardia in an icteric and afebrile patient
• foetor hepaticus
In stage I coma, mild mental changes are present, but asterixis is
minimal or absent.
Stage II coma is marked by worsening of mental changes and
definite asterixis.
In stage III coma, the patient develops stupor and semicoma, but
can still be roused.
With stage IV coma, the patient no longer is arousable, and there
may or may not be a response to deep pain stimuli. Patients with
hepatic failure, may demonstrate other neurologic sign - flapping of
the tongue, involuntary movements, long-tract signs, and
decerebrate posturing.
Biological data that announced the FHF
are:
• decreased of Prothrombin - time (Quick index < 30%)
•
•
•
•
decreased of plasminogen (<20%)
raised blood ammonia (>120 mg%)
leukocytosis with increased level of neutrophils
sudden decreased of ALT.
Table 2. Complications of FHF and their treatment:
(1)
Cerebral oedema
*Monitor intracranial pressure (extradural monitor) if
encephalopathy reaches grade III or IV
*Avoid manoeuvres that increase intracranial pressure
*Control restlessness
*If intracranial pressure > 20-30 mm Hg, apply:
1.Hyperventilation (PaCO2 25 -3- mm Hg) then
2.Mannitol 0,5 g/kg in bolus then
3.Haemodialysis or haemofiltration then
4.Barbiturate coma
Renal failure
*Avoid arterial hypotension, nephrotoxic drugs, control
infection*Dopamine 2 - 4 microgm/min*Haemodialysis or
haemofiltration*Careful hygienic measures*High index of
suspicion of infection*Daily cultures of blood, urine, and
other biological fluids*Start empiric antibiotic
therapy*Possible selective intestinal
decontamination*Possible parenteral antibiotic prophylaxis
Table 2. Complications of FHF and their treatment:
(2)
Bacterial infection
*Careful hygienic measures
*High index of suspicion of infection
*Daily cultures of blood, urine, and other biological fluids
*Start empiric antibiotic therapy
*Possible selective intestinal decontamination
*Possible parenteral antibiotic prophylaxis
Circulatory dysfunction
*Insert pulmonary-artery catheter and measure indicators of tissue
hypoxia frequently
*Avoid vasoconstrictors
*Possibly treat with N-acetylcysteine
Haemorrhagic
complications
*Upper gastrointestinal bleeding; ranitidine or sucralfate
*Fresh frozen plasma only in cases of bleeding and before
invazive procedures
Hypoglicemia
*Measure blood glucose concentration every 1 hour
*Intravenopus hypertonic glucose
Other complications
*Pulmonary oedema, respiratory alkalosis, hyponatremia,
hypophosphatemia, pancreatitis, aplastic anaemia

Persistence of HBsAg for more than 6 months
after onset in high concentrations (>100 PEI
units/ml) means that:
1. the acute hepatitis B evolved to chronicity;
2.a pre-existing chronic HBV infection was superimposed
by an acute hepatitis of another etiology; or
3. the acute disease may actualy be an exacerbation of chronic
hepatitis B. Full recovery is assumed if the ALT reaches normal or
close to normal levels and if HBsAg becomes negative in EIA.
Chronic hepatitis B

Clinical manifestations of chronic hepatitis are
mild and non-specific : lack of energy, malaise,
ease fatigability, myalgias, arthralgias, and skin
rash.

The evolution is usually intermittent with acute
exacerbations consisting on: abdominal
discomfort, nausea, weight loss, dark urine,
jaundice, loss of appetite.
Cirrhosis

The above mentioned symptoms are more important, associated or
not with signs of hepatic encephalopathy, blood coagulation is
decreased, serum albumin is decreased; the ALT levels are only
moderately enhanced, and often fluctuate. The liver status can be
assessed by histology, liver function tests, and determination of
serum proteins with liver metabolism.
Hepatocellular carcinoma


In highly epidemic areas, persons positive for HbsAg are 100 times
more likely to develop HCC compared to those who have anti-HBs.
Abdominal imaging by ultrasound of HbsAg-positive patients with
liver cirrhosis is advisable at intervals of 3-4 months.
Complications
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Neurological complication: encephalitis,
meningoencephalitis, Guillain-Barre syndrome,
mononeuritis affecting cranial or peripheral nerves.
Myocardial involvement: myocarditis and
electrocardiographic changes
Pancreatitis
Pleural effusions and ascites
Aplastic anemia
Polyarteritis nodosa
Membranoprolipherative glomerulonephritis
Leucocytoclastic vasculitis
Treatment
The main aims of treatment of chronic HBV infection are:
• Viral suppression (as shown by loss of HBeAg with or
without seroconversion to anti-HBe) and a decrease in
HBV DNA;
• Reduction in liver damage (return to normal values of
serum aminotransferases, histological improvement on
liver biopsy samples;
• Complete eradication of the virus (as shown by loss of
HBsAg, with seroconversion to anti-HBs) and the
absence of HBV DNA detection.
Agents for the treatment of chronic hepatitis B
Interferon alfa – it is given parenterally either 5 MU daily
or 10 MU three times per week with loss of HBeAg and
HBV DNA in only 20% of cases, and loss of HBsAg in
only 6% of cases.
Lamivudine
Entecavir
Telbivudina
Adefovir
Tenofovir
Hepatitis B vaccines

Long-term immunity against HBV infection is conferred
by the presence in the blood of adequate levels of antiBHs, the antibody to the surface antigen. It is generaly
accepted that the threshold anti-HBs titre for protection
is 10mIU/ml.

It is significant to note that a 3-dose schedule of
Engerix-B (10microg/dose) alone gives protective
efficacy rates of 94,8%- not significantly different from
the efficacy rates of 97,6% and 97,4% for vaccinees who
also received HBIG.
Passive immunization

A special immunoglobulin is produced from
donors who are naturally immune and boosted
with plasma-derived vaccine.

Passive immunization is recommended together
with active immunization to prevent HBV
infection in newborns from HBsAg and HBeAg
mothers, and after proven accidental exposure
of a non-immune person.
HEPATITIS D
Hepatitis D virus is a defective RNA virus
that uses HBsAg to produce delta
hepatitis.

Transmission is similar to that of HBV.
A high prevalence of HDV infection is seen in South America, Central
Africa, southern Italy and Eastern European countries.
Acute HDV infection occurs in two forms depending on the state of HBV
infection:
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Co-infection-acute delta hepatitis occurs simultaneously with acute
hepatitis B. Most patients in this situation recover. The rate of
fulminant infection is higher than in superinfection.
Superinfection- acute delta hepatitis developed on a chronic
hepatitis B.
Laboratory data
Delta antigen can sometimes be detected in serum during the early
phase of acute delta hepatitis.
HDV RNA can be detected in the serum and liver using molecular
hybridization technology.
Anti-HDV arises with the disappearance of the Delta antigen.
HBsAg is present concomitantly with IgM anti-HBc in early phases of
co-infection and with IgG anti HBc in superinfection.
Diagnosis of chronic HDV infection involves:
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High titers of anti HDV (>1:100 by radioimmunoassay)
Detection of HDV antigen
Persistence of IgM anti HDV in serum.
Evolution
 Chronic
delta hepatitis is more severely
than chronic hepatitis B alone or chronic
hepatitis C, and 60-70% of patients
develops cirrhosis.
HEPATITIS C

It is a small single-stranded RNA virus that is
distantly related to members of the Flaviviridae
family (e.g., Dengue viruses, Yellow fever virus,
and the Japanese encephalitis virus).

According to WHO data, it is estimated that 3%
of the world population has been infected with
hepatitis C virus.

Therefore, there may be more than 170 million
chronic carriers in the world
1. Blood products
2. Intravenous drug users
3. Donor organs (4. The importance of sexual transmission
is controversial. The frequency of HCV transmission to
female sexual partners was 5 times higher when HIV
was also transmitted, possibly because co-infection with
HIV leads to higher levels of HCV in serum.
5. The risk of developing hepatitis following needle-stick
exposure is
6. Vertical transmission of this virus –the risk of
transmission is much lower than for hepatitis B infection.
Nosocomial risk is a major point of concern, as documented
in oncology units
Pathogenesis

Hepatitis C virus is a member of the Flaviviridae
family, which includes the flaviviruses and
pestiviruses.

that encodes a large single polyprotein of 3000
amino-acids:
□ the N-terminal one third harbors the structural
proteins;
□ the C-terminal two thirds contains the nonstructural
proteins:
Antiviral immune response

Th1: interferon-gamma and interleukin-2, which are
important stimuli for the development of the host
antiviral immune responses, including cytotoxic Tlymphocyte (CTL) generation and NK-cell activation

Th2: interleukin-4, interleukin-5 and interleukin-10,
which enhance antibody production and downregulate
the Th1 response.

The imbalance between the Th1 and the Th2 responses
is implicated in disease progression and the inability to
clear the infection.
 Humoral
immune response
 Cellular immune response
The cellular immune response has the
ability to recognize and eliminate
Clinical manifestations
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HCV infection is infrequently diagnosed during the acute phase of
infection.
Incubation period is usually 7 to 8 weeks (range 2 to 26).
The majority of persons have either no symptoms or only mild
symptoms.
Symptoms of acute hepatitis usually consist of: jaundice, malaise
and nausea.
A characteristic feature of all these patients is marked fluctuation
of aminotransferase level. Although the aminotransferase level (ALT)
may occasionally peak as high as 1000 to 2000IU/L,
Extrahepatic manifestations of HCV infection are associated with
autoimmune or lymphoproliferative states
Lymphoproliferative disorders
1. Mixed cryoglobulinemia..
2. Lymphoma.
Other extrahepatic diseases
Autoimmune thyroiditis
 Dermatological manifestations- apart from the palpable
purpura due to leukocytoclasic vasculitis (the most
frequently seen dermatological manifestation of HCVrelated EMC) other cutaneous disorders are: sporadic
porphyria cutanea tarda and cutaneous/mucosal lichen
planus
 Sjogren’s syndrome
 Idiopatic pulmonary fibrosis
 Mooren corneal ulcers

Tests for HCV
There are still no tests for antigens of hepatitis C virus in serum.
Infection is usually diagnosed by detecting hepatitis C virus
antibodies based on immunoassay detection.
1. HCV antibody testing
2. Detection of serum HCV RNA
Detection of serum HCV RNA by PCR is the best test for early diagnosis
of acute HCV infection (it is positive as soon as 1 week after
exposure).
3. HCV genotypes.
HCV was classified into 6 types (1 to 6) each including subtypes (a, b,
c...)
4. Quasispecies
There is a correlation between a high quasispecies heterogeneity an a
more severe liver disease and a poor response to interferon therapy.
Evolution

The infection becomes chronic in most cases (80%), and
chronic infection is typically characterized by a prolonged
period in which there are no symptoms.

At the cirrhotic stage, about 3-5% of patients per year
develops hepatocarcinoma, which may develop in up to
50% within 10 years.

Chronically infected individuals generally have fluctuating
or continuously abnormal levels of ALT and are viraemic.
Treatment of Hepatitis C infection
Prior to treatment, the investigation should:
ascertain that chronic hepatitis C virus infection
(HCV) is present;
 exclude contraindication of treatment;
 evaluate histological findings
 determine the viral genotype, and for genotype
1 patients, also, the viral load.

Exclude contraindication for treatment
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Contraindications for interferon (IFN) and IFN/ribavirin combination
therapy are:
Pregnancy or no optimal contraception(ribavirin)
Severe heart disease
CNS dysfunction/epilepsy
Decompensated liver disease(interferon)
Organ transplant, except liver transplant
Severe renal failure(ribavirin)
Untreated severe anemia(ribavirin)
Hemoglobinopathies(ribavirin)
Autoimmune hepatitis(interferon)
Ongoing or recent drug or alcohol abuse
Leukopenia(WBC<1500/mm3, neutrophols<750/mm3)
Thrombocytopenia(<50000/mm3)
Relative contraindications:
-Psychiatric disease/depression
-Not well controlled thyroid disease or
diabetes melitus
-Autoimmune disease
-Mild bone marrow suppression.
Evaluation of the histological damage

Patients with mild histological inflammation without
fibrosis will probably not develop serious liver disease,
not even with prolonged follow-up. A second histological
evaluation after 2-5 years is therefore recommended for
this patient cathegory.

Cirrhotic patients, with manifest disease, should only be
treated if they are in compensated phase, while those
with decompensated cirrhosis should be evaluated and
considered for possible liver transplantation.
Recommend treatment if:
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
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HCV-RNA is detectable
ALT above the upper normal reference level
No contraindications for treatment
Liver biopsy showing fibrosis stage >=2 and ongoing inflammation
or/ fibrosis stage 1 and inflammation grade >2
Treatment with:
-alfa-IFN 3MU s.c., 3 times a week + ribavirin 1000-1200 mg /day.
Non-responders to previous IFN monotherapy:
-Lack of sufficient information - no recommendation given.
Pegylated Interferon

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Indication of pegylated interferon (with ribavirin):
first intention therapy of patients with: fibrosis-stage 3
(Knodell or Metavir score), necroinflamatory score>9,
hemophilia/thalasemia, age<55 years
recurrences /absence of response after the standard
therapy with interferon and ribavirin, coinfections.
Inhibition of viral replication might also be achieved by:
- Antisense oligonucleotides that bind to specific sequences
in the HCV RNA.
-Ribozymes that catalyze cleavage of HCV RNA.
- Gene transfer of interfering proteins, that specifically
interrupt virion assembly in the hepatocyte.
HEPATITIS E
 Hepatitis
E virus was identified by Balayan
et al. (1983) in human fecal samples. In
1995 this virus has been classified within
the Caliciviridae.
 HEV
is a non-enveloped, RNA virus with
single-stranded genome
Epidemiology

Hepatitis E could be a sporadic disease or may
evolve in outbreaks with contaminated drinking
water as the source of infection. The most
frequently involved regions are: India, China,
Pakistan, Egypt, Algeria, Sudan, Ethiopia,
Mexico.

HEV infections generally occurred after the age
of 16 years
Pathogenesis
Pathological changes in the liver include
hepatocyte necrosis and inflammatory cell
infiltration
Clinical manifestations

Incubation period has an average of 40 days.

HEV produces an acute, self-limited disease
without progression through chronic hepatitis.

The prodromal symptoms include: malaise,
anorexia, abdominal discomfort. In women
infected during the third trimester of pregnancy
was noted a high rate of fulminant disease and a
15-20% case-fatality rate.
Diagnosis

Detection of HEV-RNA by PCR

Detection of HEV-Ag by electronic
immunomicroscopy

Detection of HEV-antibody:
• immunofluorescence inhibition
• ELISA (IgM, IgG)
• Immunotransfert (IgM, IgG)
GB VIRUS-C/HEPATITIS G VIRUS
Virology and tissue tropism

GBV-C/HGV is an enveloped RNA virus which belongs to
the Flaviviridae family. The envelope 2 (E2) region
encodes a glycoprotein which is located on the outer
surface of the virion. At least 4 major genotypes exists.

GBV-C/HGV may replicate in human peripheral blood
mononuclear cells and endotelial cells, in liver tissue,
spleen and bone marrow.
Prevalence and transmission

There is a high prevalence of viremia in healthy
persons in Europe and North America (1-4%)
and a higher prevalence rate in South America
and Africa (10-33%).

GBV-C/HGV may be transmitted via blood/blood
products, by sexual contacts, by close social
contact, and from mother to infant.
Clinical features
 The
majority of adults have a transient
infection with clearence of viremia and
development of E2 antibodies.
 GBV-C/HGV
viremia after vertical or
perinatal transmission may persist for at
least 36 months.
Diagnostic

Reverse transcription polymerase chain reaction (RT-PCR) –

PCR is used to diagnose ongoing infections and does not give any
information on a resolved infection (may underestimate the
prevalence/occurrence of these infections).

EIA

In situ hybridization to detect GBV-C RNA

Immunofluorescence.

Liver biopsy
Infection with TT Virus

TTV is a unenveloped, single stranded, circular DNA virus that was
isolated from a Japanese patient with post-transfusion hepatitis of
unknown etiology.

Although TTV DNA titers have been shown to be closely correlated
with aminotransferase levels in the sera of some patients during
post-transfusion hepatitis, no clear association between TTV
infection and human liver disease has been establish at this time.
TTV is a parenterally transmissible virus

TTV DNA was detected in 10% of normal population in England, in
34% of voluntary US blood-donors and in 47% of patients with
acute and chronic non A-G hepatitis. Very high prevalences of
viremia (>50%), observed in healthy populations in different
countries, indicate that persistent infection is common and that
routes of transmission other than the parenteral route do exist.
However, the main mode of TTV transmission remains to be
determined.