Viral hepatitis

Assoc.Prof. Anca Streinu-Cercel MD PhD

2019
 Viral hepatitis
• Systemic infections which preferentially target the
liver, with
– inflammatory lesions, degenerative hepatocyte
alteration
– increase of transaminases
• The HAV, HBV, HCV, HDV, HDE, HGE viruses
are responsible for acute hepatitis
• HBV, HCV, HDV are responsible for chronic
hepatitis, susceptible for complication with
cirrhosis and hepatocellular carcinoma
 Hepatitis Viruses
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
virus virus virus virus virus
Virus class Picorna-virus Hepadna-virus Flavivirus Deltavirus Calcivirus

Genome RNA DNA RNA RNA RNA

Route of Faecal-oral Bodily fluids Bodily fluids Bodily fluids Faecal-oral

transmission

Incubation (days) 15–50 28–160 15–150 Variable 15–45

Chronicity No Yes Yes Yes No

•Viral hepatitis is caused by at least five viruses: A–E. Other candidates exist such
as hepatitis G, hepatitis F, transfusion transmission virus and SEN virus.
1. Purcell R, et al. Proc Natl Acad Sci 1994; 91: 2401
2. Ryder S & Beckingham I. BMJ 2001; 322: 151
3. WHO. Hepatitis C Fact Sheet no. 164. 2000
 Hepatitis A
Epidemiology
• Endemo-epidemic character
• Humans – the virus single reservoir
• Contamination:
– digestive route (water, contaminated food, manuported contact)
– transmission through bodily fluids (blood) is possible, but extremely
rare
• Receptivity: generally, the infection is frequent in children
and in young adults, depending of the hygiene conditions
( dirty hands disease )
• In underdeveloped countries (precarious food hygiene)
children are contaminated before the age of 10; in
industrialized countries a smaller % of the young population
presents natural Ab (history of infection)
• Its contagiosity is related to the virus excretion: before the
clinical onset of infection, and for 7-10 days after the onset of
jaundice
 Viral hepatitis
Clinically:
• Pre-jaundice stage: 1-3 weeks
– Anorexia, nausea, intermittent pain in the right hypochondrium
– Asthenia
– Flu-like syndrome: fever, headache, myalgias
– Arthralgias (pseudorheumatic outlines),
– Rash
These symptoms diminish after the onset of jaundice.
• Jaundice stage: sclero-tegumentar jaundice,
discolored stool, hyper chromic urine, pruritus
• The clinical exam is normal with the exception of a slight
hepatomegaly and eventual splenomegaly
• The asymptomatic or anicteric outlines (only
extrahepatic manifestations) are frequent
 Viral hepatitis
Laboratory
• Constant cytolysis with marked increase of ALT, AST; (20-
40 xN); ALT>AST

• Biliary retention (variables, with predominance of direct

bilirubin)

• Moderately lowered prothrombin concentration (decrease

<50% risk of fulminant hepatitis)

• Serology: IgM diagnostic of acute illness, IgG presents

epidemiologic value (eventually for indication of
vaccination after the age of 40)
 Acute HAV viral hepatitis
§Incubation Abnormal biologic tests §Convalescence
infection
Time of

0 1 2 3 4 5 6 7 8 9 10 11 12 14
Weeks after primary infection
Virus in stool Anti-HAV Ab IgM Anti-HAV Ab
IgG
 Hepatitis with HAV

Serology:
•IgM diagnostic of acute illness
•IgG presents epidemiologic value (eventually for indication of
vaccination after the age of 40)
 Hepatitis A
Evolution
• Favorable in most cases in approx 2 weeks. Healing-with no sequels
• Prolonged outlines (evolution over weeks, months with persistence of
asthenia and/or cytolysis. There are no chronic outlines.
• Cholestatic outlines
• Relapses: 1-2% of cases, after apparently complete healing or partial
remission. The relapse is unique and occurs at <1 month after
apparent healing. Prognosis – excellent
• Fulminant outlines – extremely rare 1/10.000
Prophylaxis
• Hygiene measures
• Vaccination: viral inactivated vaccine, 1 dose followed by boosts at 6-
12 months later (Twinrix HA+HB D0, M1, M6), booster doses not
sooner than 10 years
 Hepatitis Viruses
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
virus virus virus virus virus
Virus class Picorna-virus Hepadna-virus Flavivirus Deltavirus Calcivirus

Genome RNA DNA RNA RNA RNA

Route of Faecal-oral Bodily fluids Bodily fluids Bodily fluids Faecal-oral

transmission

Incubation (days) 15–50 28–160 15–150 Variable 15–45

Chronicity No Yes Yes Yes No

•Viral hepatitis is caused by at least five viruses: A–E. Other candidates exist such
as hepatitis G, hepatitis F, transfusion transmission virus and SEN virus.
1. Purcell R, et al. Proc Natl Acad Sci 1994; 91: 2401
2. Ryder S & Beckingham I. BMJ 2001; 322: 151
3. WHO. Hepatitis C Fact Sheet no. 164. 2000
 Hepatitis E
• RNA virus
• Enteral contamination, stool shedding
• Frequent infection in Asia, Africa (now cases in Europe
and the US)
• Clinically: incubation 3-6 weeks, the infection is
frequently icteric
• Diagnosis: IgM HEV
• Evolution – usually benign, without chronic outline, nor
risk of hepatic cancer; severe evolution with 20-40%
mortality in pregnant women, but without
teratogenic risk
• There is no etiologic treatment
Annual number of confirmed cases of hepatitis E by year of
commencement of
surveillance, EU/EEA Member States, 2005–2015 *
Type of hepatitis E surveillance systems in
EU/EEA Member States

Administrative boundaries: © Eurogeographics © UN-FAO © Turkstat © GADM

Hepatitis with HEV
HBV
 Hepatitis B
• Epidemic jaundice was first described by
Hippocrates in the Vth century BC.

• Jaundice reported in recipients of human

serum or vaccination for yellow fever in 1930
- 1940

• Australia antigen described in 1965

• Serologic tests in the 1970s

Hepatitis B virus
 Hepatitis B virus (HBV)
• Hepadnaviridae family (DNA)

• Numerous antigenic components

• Humans: the only known host

• It can remain infectious for over 7 -14 days

at room temperature
 Infection with HBV

• Important cause of chronic hepatitis,

cirrhosis and hepatocellular carcinoma
(HCC)

• Carcinogenic-accountable for up to 80% of

the cases of HCC
 Hepatitis B
Clinically:
• The infection can be: acute, superacute, chronic
• Incubation: 1 month-6 months (most frequently 4-
6 months)
• Clinical outlines:
– Asymptomatic outlines: 90% of cases
– Common symptomatic outlines (similar to hepatitis A,
but with a rather prolonged evolution, with more
frequent extrahepatic manifestations), PC>60%
– Prolonged cholestatic outlines, or with relapses – their
evolution is similar to that of the common outlines
– Fulminant outlines – acute hepatic failure
 Hepatitis B
Clinically:
Fulminant outlines – acute hepatic failure
– Digestive symptoms - not diminished after onset of jaundice
– Fever
– Neuropsychological symptomatology: agitation, insomnia,
followed by extreme somnolence, altered consciousness
(encephalopathy)
– Hemorrhagic manifestations-clinical
– Liver with tendency to decrease
– Biologically: PC< 50% - severe outlines, potentially fulminant,
<30% hepatic failure; HG-leukocytosis with neutrophilia,
hypoglycemia, important cytolysis
– Mortality 80% in the absence of hepatic transplant
– Healing- without sequelae
 Spectrum of Disease

90–95% neonatal infection Chronic 15–40%* Chronic

Acute
viral
hepatitis 50% childhood infection hepatitis B hepatitis B
B
5–10% adult infection
~2%
Cirrhosis
HCC
fulminant
hepatic
failure Cirrhosis
Death
decompensated

Lok AS et al. Chronic hepatitis B. N Eng J Med 2002;346:1682–3

 Clinical spectrum of infection
Acute HBV infection

90% newborns 25–30% children

<10% adults
~2%
Chronic infection
15–40%
Fulminant hepatic Chronic progressive Inactive carrier
failure hepatitis

Cirrhosis

Decompensated
Death HCC
cirrhosis
EASL Consensus Guidelines. J Hepatol 2003;
Lok, McMahon. Hepatology 2004 (AASLD Guidelines)
 Viral markers in hepatitis B
HBs: HBsAg presence of the virus, HBsAb-protection >100u, (+) > 10u (history of
infection/vaccination)
HBe: HBeAg associated to viral replication, correlated with high infectiousness,
may be absent (HBeAg neg mutants), HBeAb
HBc: HBcAb IgM-acute infection/reactivation, IgG chronic infection
(persistence/healed),
HBcAb are not determined from blood samples-only from the liver
HBV-DNA-PCR: quantification of viral replication-important in chronic hepatitis
Viral DNA integrated in the genome of hepatocytes –specialized laboratories

Hepatitis B –
Self-limited outline
 Evolution of viral markers
HBsAg
in acute B hepatitis
•Precedes the onset of biologic (ALT) or clinical signs (jaundice) with 2-4 weeks
•Disappears a few weeks after normalization of ALT
•Is followed by appearance of HBsAb after 1-3 months (serological window)
HBsAb appear after the self-limited infection (they are protective) and persist for at least 10
years, but there also are outlines which include rapid disappearance of HBsAb
HBeAg disappears in self-limited outlines before HBsAg and is followed by apparition of
HBeAb, without serological window
 Chronic hepatitis B
• Appears in 10% of cases with HBV infection (HBsAg carrier > 6
months). HBsAg carriage appears after symptomatic or
asymptomatic outlines; it is more frequent in patients with
immunodepression.

• In severely immunodepressed patients, there are reports of outlines

with reappearance of HBsAg, even in patients which had HBsAb
(administration of corticoids or other immunosuppressants requires
monitoring of ALT for diagnosis of an eventual reactivation)

• Rate of virus elimination 3%/year

• It is most frequently asymptomatic or with asthenia, pain in the right

hypochondrium, normal clinical exam

• Moderately increased ALTs (<5N) or > in case of reactivation

• Positive HBsAg which persists for 6 months after diagnosis, with

absence of IgM HBcAb affirm diagnosis of chronic HBV hepatitis

• Absence of HBsAg does not exclude a chronic HBV infection (in the
presence of HBcAb and cytolysis of no other mentioned cause –
HBV-DNA is recommended)
 Staging of the HBV infection
HBsAg HBsAb HBeAg HBeAb HBcAbIg HBcAbIgG HBV-DNA ALT Disease
M

+ - + - + + + ↑ HAV-HBV

- + - + - + - N Healed

+ - + - + + - ↑ Protracted HAV
HBV DNAneg.
HC/HBV DNAneg.
+ - + - + + - ↑
+ - + - + + - N Convalescence
HAV/HBV DNAneg.
PSHBeAg +
+ - + - - + - N
PSHBAge-
+ - - + - + - N
+ + - + + - N HAV-HBV with
primary Ab response

+ - - + + - ↑ HAV-HBV with
primary Ab response
with autoimmune
component?

+ - + - + + ↑ HC-HBV HBVDNA
pos.
HC HBVDNA pos.
+ - - - - + + ↑
+ - - - + N Convalescence
HAVHBV
Epidemiology
Worldwide prevalence of HBV
 Prevalence of HBsAg in Europe (2018)

≥8% = high

2–7% = intermediate

<2% = low

Adapted after CDC MMWR. Recommendations and Reports., 2018 / 57(RR08);1–20

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm [
• HBV- 50 - 100 times more infectious than HIV
• Worldwide:
– 2 billion infected people
– 350 million live with chronic infection
– 1.000.000 deaths per year by HBV
• Important cause of hepatic cancer and
cirrhosis
• A vaccine exists!

http://www.who.int/mediacentre/factsheets/fs204/en/index.html
Transmission routes for
hepatitis B
Transmission routes for hepatitis B
• In the infected individual, HBV can be found in all bodily fluids
(blood, saliva, vaginal secretion, sperm, sweat, milk, urine)

Transmission routes:
• Vertical transmission / perinatal (from mother-to-child)
• Horizontal transmission (from other infected individuals)
– Sexual contact
– Transfusions
– Re-use of non-sterilized syringes and needles
– Acupuncture
– Tattoos, piercings
• As opposed to HCV, HBV is transmitted extremely quickly by sexual
route (even faster than HIV)
Transmission routes:

• Sexual

• Parenteral

• Perinatal
 Concentrations of HBV in various
bodily fluids

High Moderate Low/Undetectable

Blood Sperm urine

serum vaginal secretion tears
wounds saliva mother milk
 Hepatitis B
Treatment
Curative
• Common acute outline:
• Treatment protocol
– Corticotherapy ameliorates the clinical and biological picture
( cosmetic cure ), but is contraindicated due to the fact that it
aggravates the medium-term and long-term prognosis
– Avoiding hepatotoxic drugs
– Study for identifying the source and surveillance of contacts
(family)
• Fulminant outline
– Treatment is symptomatic and pathogenic:
• cerebral edema,
• fighting hypoglycemia, collapse,
• control of diuresis, hydroelectrolyte, acido-basic balance and
coagulation issues.
– Hepatic transplant
 Hepatitis B
Treatment
Curative-in chronic outlines

• Indicated in biologically and histologically active

outlines, but also in the outlines with intense
viral replication (carcinogenetic risk)

• Therapeutic options:
• Lamivudine
• Entecavir
• Tenofovir/TAF
• Adefovir
• Telbivudine
 The time for starting treatment

Non-pathogenic Pathogenic Non-pathogenic Pathogenic

 The time for starting treatment
Clinical strategies:
treatment vs monitoring (for treatment)

• Immediate treatment
– ALT > 2 x N
– HBV-DNA> 104 copies/ml
– +/- histological evolution

• Monitoring ( “Watch and wait”)

– Immunotolerance phase
– Immune control phase
 Treatment: NNA / PegIFN

• Lamivudine
• Entecavir
• Tenofovir
• Adefovir
• Telbivudine

Peg IFN
 Pros and cons NNA

ADVANTAGES
antiviral potency

ease of DISADVANTAGES
long-term therapy (“long-
administration
life”)

decrease in the ROMANIA: lack of backup

incidence of HCC options !

the only option for developing resistance

cirrhosis (cross resistance LAM –
ETV)

high cumulative costs

potentially teratogenic
effect
 Clearance of HBsAg

• = the result closest to healing

• = serum marker easy to measure
- correlated with the level of ccc DNA
• = accurate indicator of the immunologic
response to IFN
 Objective in the management
of CBH
Stopping the
evolution to HC/HCC

HBsAg clearance

Suppression of
viral replication

Normalizing ALT

Adaptat după Marcellin şi col. EASL 2008; Perrillo şi col. Hepatology 2006; Fattovich şi col. Am J Gastroenterol 1998
 In chronic hepatitis B

Objective
• short-term:
reducing the level of HBV-DNA
normalizing transaminases
HBeAg seroconversion

• long-term:
preventing/reverting of complications through
severe hepatic illness, death
 Anti-HBV vaccine
• Available since 1981
• Produced with recombined DNA
technology, it contains fragments of
HBV

• It is administered IM

• It is administered in 3 doses:
– (1) day 0
– (2) month 1
– (3) month 6
• Costs: 68 RON / dose
 Anti HBV vaccination regimen
• Intramuscular administration of a series of three vaccine
doses:
– rapid regimen
• Administered at 0, 1 and 2 months
• more rapidly generated protection
• after immunization with the 0,1, 2 months regimes, a boost is
recommended at 12 months from the first dose. A next booster dose is
not required during the following 8 years.
– regimens with longer time-spans between doses two and three
• at 0, 1 and 6 months.
• induce higher antibody titers
• after the immunization regimen 0, 1, 6 months, a boost is
recommended at five years after the primary vaccination.
• An antibody titer of over 10miliU.I./ml is considered
efficient.
 Who should be vaccinated?

• Anyone under the age of 18

• People > 18 years with risk of infection:
• Medical personnel
• Other occupational categories at high risk
• Firefighters/Emergency units personnel
• Sexually active individuals with multiple
partners
• MSM/bisexual men
• IVDU (IV drug users)
• Patients with hemodialisis
• Family members of patients with chronic B hepatitis
 Hepatitis B
In case of accidental exposure of a subject not
vaccinated to blood from an infected subject or
susceptible to be contaminated – serovaccination (Ig +
vaccine).
Vaccination is continued according to the results of serologic
exams:
• Receptive subject HBsAg (-), HBsAb (-)=continues
vaccination
• Infective subject HBsAg (+), HBsAb (-)=infection
assessment
• Protected subject HBsAg (-), HBsAb (+)=may or may not
continue according to Ab titre
 Hepatitis B
Unspecific prophylaxis
• Employ single use materials for all processes of drawing blood,
injected treatment, vaccination, stomatologic, surgical interventions,
endoscopic explorations etc;
• Sanitary education of patients but also of the whole population, on
the routes of virus transmission so as to apply methods of
prevention for virus transmission (using condoms, individual
manicure sets, shaving kits, toothbrushes, etc);
• Use of gloves, masks and glasses by the medical personnel working
with blood or potentially contaminated samples (universal
precautions)
• Rigorous screening of blood donors, control of drawn samples
(ALAT, HBsAg, HBcAb, anti HCV Ab or, if possible, HCV RNA);
• Use of autotransfusion, possible for scheduled surgical
interventions, the patient being able to store an amount of his/her
own blood for the intervention;
HDV
 Hepatitis D
RNA defective virus, which uses the HBV capsule
(HBsAg) having a unique property in human
pathology, that of being symbiotic with another
hepatotropic virus

Epidemiology
• Frequent in the Mediterranean basin, Eastern
Europe, certain countries in Africa and Latin
America
• Transmission- similar to that of HBV (direct
inoculation of blood/derivatives or direct contact)
• Prevention of HDV hepatitis is the
prevention of HBV hepatitis
 Hepatitis D
Clinically: 2 circumstances

• Coinfection (simultaneous HBV and HDV infection),

which manifests as B hepatitis, with increased risk for
fulminant hepatitis. A stop in HBV replication is
concomitant to the stop of HDV replication.

• Superinfection (of a chronic HBV hepatitis),

manifested as an acute hepatitis which progressed in
80% of cases to a chronic hepatitis which complicates the
chronic HBV hepatitis increasing the risk of cirrhosis.
The consequence of superinfection:
– HDV generated a diminish/disappearance of the tissue or serum
replication markers of HBV
– HDV increases the severity of hepatic lesions
 Hepatitis D
Diagnosis
Indications for hepatitis D serology in subjects with positive
HBsAg
• Epidemiologic context: drug users or their sexual partners,
MSM, patients from endemic areas
• Clinical context: acute HBV hepatitis, acute hepatitis in a
subject chronically infected with HBV, chronic hepatitis or
cirrhosis in a young patient, relapse of an HA, fulminant
hepatitis
Coinfection Superinfection Chronic
HBV
HBsAg + + +/-
IgM HBcAb + -
HDV
HDVAg Transient Transient -
IgM HDVAb + + -/+
Anti HDV Ab(total) + + +
HBV
 Summary
• Define acute hepatitis
• -ALAT ASAT ññ
• -serological markers
– HAV Ab IgM
– HBVc Ab IgM
– HBVs Ag
– HCV Ab IgM
– HEV Ab
• -PCR for HBV HCV
• Acute hepatitis
• HAV
• HEV
• HBV
• HBV + HDV

• Tommorow
• ..HCV
• Tests…
HCV
 The characteristics of HCV
• Flaviviridae family1
• Viral envelope2
• RNA virus (9.6 kb)1,3
• Poliproteins from 3000 amino acids3
• 6 genotypes > over 80 subtypes4
• Survival time: »2.7 hours2
• Proliferation rate: 1012 virions / day2

1. Purcell R. NIH Consensus Conference on Hepatitis C. 1997

2. Neumann A, et al. Science 1998; 282: 103 4. Lauer G & Walker B. N Engl J Med 2001; 345: 41
3. Rosenberg S. J Mol Biol 2001; 313: 451 5. Hoofnagle J. NIH Consensus Conference on Hepatitis C. 1997
 HCV viral structure
Envelope

RNA genome The hepatitis C virus (HCV)

was identified in 1989.

Core protein
- nucleocapsid

1. Purcell R. NIH Consensus Conference on Hepatitis C. 1997

2. Neumann A, et al. Science 1998; 282: 103
3. Rosenberg S. J Mol Biol 2001; 313: 451
 HCV life cycle

Translation and
Binding polyprotein processing
Membrane
fusion
Uncoating
Endocytosis
RNA replication
Virion assembly
and maturation + strands – strands

Vesicle fusion and

virion release

Davis G et al. Semin Liver Dis. 1999; 19(suppl 1): 103

 HCV
Epidemiology
 Hepatitis C is a public
health problem worldwide
• Hepatitis C is a pandemic illness, 5 times
more common than HIV infection.

• According to WHO data:

– It is estimated that over 170 million people are
infected with hepatitis C virus, approx 3% of the
world s population1
– Each year, 3-4 million people are infected with
HCV
– 85% of the new cases develop into chronic disease
1. WHO. Hepatitis C. Fact sheet no. 164. 2. CDC. MMWR. 1998.
3. CDC. Hepatitis C slide kit. September 25, 2000.
 HCV
• It is the main cause of cirrhosis,
hepatocellular carcinoma, liver transplant

• 1 of 5 cases progress to cirrhosis in 30

years2, these cases registering a mortality
of 1-5 % per year3

• The annual incidence of hepatocellular

carcinoma cases in patients with cirrhosis
is 4%2
1. WHO. Hepatitis C. Fact sheet no. 164. 2. CDC. MMWR. 1998.
3. CDC. Hepatitis C slide kit. September 25, 2000.
170 million people are chronically
infected with HCV

Europe
USA 9M
~3 M
Eastern
Mediterranean South East
21 M Asia
32 M
Western Pacific
South 62 M
America Africa
~10 M 32 M

1. WHO. Wkly Epidemiol Rec 1999; 74: 421

2. NIH. Hepatology 2002; 36: S3
Prevalence of infection

>10% 2.5–10% 1–2.5%

WHO. Wkly Epidemiol Rec 2002; 77: 41

Hepatitis C prevalence in first-
time blood donors: anti-HCV

ECDC Wkly Epidemiol Rec 2010; date accesate 10/02/2011

Genotype prevalence varies according to
geographic region

1a, 1b,
2, 1b
75% 2, 3
1a, 1b
4 1a, 1b,
3 3, 6

1a, 1b, 2, 3
5 1a, 1b, 3

1. Hoofnagle J. Hepatology 2002; 36: S21

2. Zein N. Clin Microbiol Rev 2000; 13: 223
3. Alter M, et al. N Engl J Med 1999; 341: 556
How is the disease transmitted?

Risk factors
Which are the transmission routes for HCV?
Transmission through transfusions,
medical instruments ( < 1992), shared use of
syringes by drug users (in the past years)

Transmission through hemodialysis

Transmission through tattoos, piercings

Transmission through dental procedures

Transmission through shared use of personal

hygiene instruments
 p = 0.002 – 0.389

n= 496 676 545 666 519 2902

An increased prevalence in age groups 40 – 50 – 60 - 70 years seems to

confirm an increased exposure to the risk of accidental transmission
(transfusions, surgical procedures) prior to 1990
Gheorghe L., Sibiu, 2007, Congresul National de Gastroenterologie
Increasingly important
transmission routes...
 What can we do?
• Inform patients

• Active screening and identification; an

early diagnosis increases the chance of
response to treatment

• Prophylaxis of vertical transmission:

recommending C-sections and prohibiting
breastfeeding!
 Hepatitis C
Clinically
• HA is most frequently subclinical, anicteric in 90% of cases
• The increase of ALT is moderate (5-10N), with frequent fluctuations
• Seroconversion occurs 15-30 days after the peak of ALT
Diagnosis
• Serology: 3rd generation ELISA, the RIBA confirmation test has
lost its utility after the generalization of quantitative PCR
Serologic tests cannot serve for distinguishing between chronic HCV
carriers and patients which are immunized and have healed from
hepatitis C

Certain diagnosis: seroconversion

• HCV-RNA used for confirming the infection and quantifying
viremia (it is not useful for diagnosis of acute infection)
• Genotyping; there are 6 genotypes: 1a and 1b especially in patients
contaminated through transfusions or unknown transmission route,
3a-drug users, 2a, 4, 5, 6 are infrequent
 Hepatitis C
Evolution
Acute hepatitis
• 15 % healing
• Fulminant outlines are extremely rare
• 85% progression to chronic disease
Chronic hepatitis
• Outlines with minimal histological and biological
activity 25%
• Cirrhosis in the active outlines (20% in 10-20
years)
• Hepatocarcinoma 1-4%/year, patients with
cirrhosis
 Natural history of hepatitis C
Acute hepatitis C

Recovery Chronic hepatitis C

≈15% ≈85%

Mild Moderate Severe

20% cirrhosis in 20 years

Decompensation HCC
4%/year 1–4%/year

Adapted from: NIH Consensus Development Conference Statement. Gastroenterology Death 5%

2002;123:2082−99; Serfaty L et al. Hepatology 1998;27:1435−40; EASL International
Consensus Conference on Hepatitis C. J Hepatol 1999;30:956−61; Fattovich G et al.
Gastroenterology 1997;112:463−72 HCC: hepatocellular carcinoma
 Acute infection with HCV

Symptoms HCVAb-IgM HCVAb-IgG

Titre

ALT

Normal
0 1 2 3 4 5 6 1 2 3
4 5
Months Years
Time from infection
 Acute infection with HCV
HCV-RNA

Symptoms HCVAb-IgM HCVAb-IgG

Titre

ALT

Normal
0 1 2 3 4 5 6 1 2 3
4 5
Months Years
Time from infection
 Acute infection with HCV

Symptoms HCVAb

HCV-RNA
Titre

ALT

Normal
0 1 2 3 4 5 6 1 2 3
25 30
Months Years
Time from infection
 Disease progression in hepatitis C:
person-to-person variability
(Slow)

≥ 30 years after infection

Female sex, young age

Decompensation
Rate of disease progression

(~ 20%)

HCC
Normal Acute Chronic Chronic Cirrhosis (1-4%
liver infection infection hepatitis (20%) per
(80%) year)

Infection Stable Slowly

resolves hepatitis progressive
spontaneously (80%) (~ 75%)
(20%)
(Fast)

≤ 20 years after infection

Alcohol use, co-infection with HIV or hepatitis B virus

Lauer & Walker. N Engl J Med 2001; 345:41–52
 Current treatment options

The following is general information. Available

treatments may differ by country, and
country-specific information may be available
on the website of your local health authority
2019
 Goals of HCV therapy

• CURE = SVR defined as the absence of

HCV RNA in serum by a sensitive test at
the end of treatment and 6 months later1

• Beneficial effect on:2

– Mortality
– Complications of liver disease
– Hepatic necroinflammatory activity and fibrosis
– Quality of life

HCV: hepatitis C virus 1.Strader et al. Hepatology. 2004;39:1147–71

SVR: sustained virologic response 2. Dienstag JL, McHutchison JG. Gastroenterology 2006;130:231–64
Hepatitis C pipeline by mechanism of action
(April 2017)
 Increase of efficiency over the years
75%

47%- - - - 60%

35-43%

18-23%
6-16%

IFN PEG-IFN IFN+RBV PEG-IFN+RBV PEG-IFN + RBV

+ IP

1989 2012
T. Asselah, Paris Hepatitis Conference, ianuarie 2009
... and in chronic hepatitis C:

the marker which predicts and

establishes therapeutic success is
clearly defined:

The level of HCV-RNA

• No vaccine exists for hepatitis C,
• So please follow precaution measures.
ACUTE HEPATITES
DIAG/DIFF DIAG
 Diagnosis of hepatites
Laboratory exams

• Cytolysis syndrome is essential for the diagnosis

of HAV, values over 10-20N of ALAT (ALAT
>ASAT);

• Biliary retention syndrome with increase of

bilirubin, predominantly of direct bilirubin
– through discharge of conjugated bilirubin in the
vascular pole
– it may be absent, certain hepatites being anicteric
– it is associated with increase of cholestasis enzymes
(alkaline phosphatase and gamma-glutamyl
transpeptidase GGT).
 Diagnosis of hepatites

• Hepatocelullar insufficiency syndrome

– Prothrombin time and concentration (TP, CP) – used in clinical
practice,
– serum albumin levels
– fibrinogen

• Etiologic diagnosis: indirect (antibody detection )

• In clinical practice, we employ an immunologic
diagnosis, combining detection of antibodies and/or
antigens, rarely using techniques of DNA or RNA
detection and basically never detecting the virus itself
 Hepatites-differential diagnosis
Preicteric stage (differential diagnosis of
extrahepatic manifestations: arthralgias,
rash, digestive manifestations…)
– biliary dyskinesia,
– ulcerous disease,
– food poisoning,
– flu,
– rheumatism,
– rash,
– nevrosis or psychiatric illness,
– acute abdomen.
 Hepatites-differential diagnosis
Icteric stage
• Prehepatic jaundice:
– hemolytic post-transfusion jaundice, through
hemoglobinopathies, enzymopathies, or erythrocyte
membrane anomalies, intrainfectious hemolysis, toxic or
immunologic hemolysis, jaundice through defects of
hemoglobin uptake and conjugation.
– In hemolytic jaundice
• urine is normal or mildly hyperchromic (increased
urobilinogen), and
• stool is never discolored.
• changes characteristic for hemolysis (increased serum
iron levels, indirect bilirubin, reticulocytes, and, in
urine, increased urobilinogen, with absent bile
pigments).
 Hepatites-differential diagnosis
• Posthepatic jaundice through complete or incomplete
obstruction of biliary ducts
– lithiasis, neoplasm, choledochitis, parasites etc.
– Clinically,
• hyperchrome urines (increased direct bilirubin-bile pigments, in
complete obstructions urinary urobilinogen is absent),
• discolored stool (at times completely colorless);
• Laboratory exams: hyperbilirubinemia with increased direct bilirubin,
increased cholestasis enzymes, decreased prothrombin concentration
in outlines with complete and prolonged obstruction through absence
of vitamin K absorption.
– Differential diagnosis with jaundice through angiocholitis or
cholecystitis may be problematic because these entities are at times
accompanied by a satellite hepatitis with cytolysis.
 Hepatites-differential diagnosis
• Hepatic jaundice
Hepatic jaundice associated with cytolysis has a large number of causes:
• Bacterial infections (Q fever, systemic salmonellosis, severe bacterial
pneumonia, leptospirosis, severe sepsis),
• Viral infections (Epstein Barr virus, cytomegalovirus, herpes simplex virus,
certain enteroviruses, adenoviruses),
• Toxic substances (alcohol, drugs).
– Acute ethanolic hepatitis:
• fever, jaundice, pain in right hypochondrium and hepatomegaly
• biologically, cytolysis (ASAT/ALAT ratio >1, increased gamma-glutamyl transpeptidase).
– Drug-related hepatitis can present
• jaundice, fever, sometimes pain in right hypochondrium.
• Certain drugs generate cytolytic hepatites (halothane, isoniazid , sulfamids, ketoconazole),
others are responsible for cholestatic or mixed hepatitis (tricyclic antidepressants,
macrolides, phenothiazines, gold salts, carbamazepine, oral contraceptives, anabolic
steroids).
• Granulomatous hepatitis, infectious or not (tuberculosis, brucellosis,
yersiniosis, sarcoidosis) are less frequent icteric, but are associated with
cytolysis.
• Cardiac liver can be responsible for an overt jaundice with cytolysis and possible
decrease of TP and CP.
• Chronic hepatites in cytolytic flares
 Normal liver

Chronic liver
disease
Liver with advanced
fibrosis

§Bataller R & Brenner DA., J Clin Invest. 2005;115:209-18.

 What else do we need to
evaluate ?
• Necroinflammatory activity
• Fibrosis
• Steatosis
• Alcohol correlation
• Correlations other than alcohol
 How do we do that ?

• We have two options:

– Liver puncture biopsy
– Non-invasive tests
FibroTest®
FibroMAX / Results
FibroTest® vs FibroScan®
 Two for thruth?
FibroTest FibroScan

Simplicity serum markers rapid results

Applicability 95% 80% succes rate
IQR<30%, 10 measurements,
ascitis, acute necrosis
At risk Gilbert, hemolysis, acute Adipose tissue,
categories inflammation necroinflammatory activity,
thoracic fold, small intercostal
space
Variability small (CV<10%), analysers The best spot was not defined;
and validated kits extremely variable intra and inter
observators data
Accuracy No false positives at 1000 Highly specific for F4;
blood donors; high sensitivity standardized cutoffs; requires
for discrimination between studies on donors; cannot
F0F1F2; highly specific for F4 discriminate F0F1F2
Prognostic Better than that of biopsy with Undetermined
value easy yearly evaluation
 Transient elastography (TE)
FibroScan ®

Diagnosis of advanced
fibrosis/cirrhosis by measurement
of liver stiffness

The probe acts as

A generator of the shear wave
An ultrasound transducer

1. Marcellin P et al., Liver Int 2008; in press. 2. FibroScan® Echosens product literature. Accessed January 2009.
 Transthoracic elastography:
principle
— Probe position and explored volume
• The analyzed fragment (4 cm x 1 cm) is a lot
larger than any fragment obtained through LPB
• Yet, the explored area is still small compared to
the volume of the whole liver

2.5 cm Explored Volume

1 cm
4 cm

Castera L, et al., J Hepatology 2008;48:835-47

 Predictive factors for disease
progression
• The following factors need to be
evaluated:
– Fibrosis stage versus length of disease
– Necroinflammatory activity
– ALT profile over time
– Cofactors
• These elements are useful but far from
perfect
• Pay attention to the fact that disease
progression reduces efficacy of therapy
 What is the result ?

• The answer .........

• Good question.
FibroMAX / Results
 Conversion between Fibro Test and fibrosis
stages using Metavir, Knodell and Ishak.
Fibrosing scoring systems

Metavir Knodell Ishak

Fibro Test Fibrosis Fibrosis Fibrosis
stage stage stage
estimate estimate estimate
0.75 – 1.00 F4 F4 F6
0.73 – 0.74 F3-F4 F3-F4 F5
0,59 – 0.72 F3 F3 F4
0.49 – 0.58 F2 F1-F3 F3
0.32 – 0.48 F1-F2 F1-F3 F2-F3
0.28 – 0.31 F1 F1 F2
0.22 – 0.27 F0-F1 F0-F1 F1
0.00 – 0.21 F0 F0 F0
Conversion between Acti Test and activity grades
using Metavir, Knodell and Ishak.
Necrotico-inflammatory activity scoring systems

Metavir Knodell Ishak

Acti Test Fibrosis Fibrosis Fibrosis
stage stage stage
estimate estimate Estimate
0.63 – 1.00 A3 A5 A4
0.61 – 0.62 A2-A3 A4 A3
0,53 – 0.60 A2 A3 A2
0.37 – 0.52 A1-A2 A1-A3 A1-A2
0.30 – 0.36 A1 A1 A1
0.18 – 0.29 A0-A1 A0-A1 A0-A1
0.00 – 0.17 A0 A0 A0
 Multifactorial pathogenesis of
HCC1-5
Persistent/chronic hepatitis
Fibrosis

Cell death
Normal
Hepatitis Cirrhosis HCC
liver Regeneration

Risk increment
•HBV
•HCV
• Alcohol
• Metabolic disorders
- Hemochromatosis

HBV=hepatitis B virus; HCV=hepatitis C virus; NASH=non-alcoholic steato-hepatitis.

1. Adapted after Rivenbark AG, et al. Clin Cancer Res. 2007;13:2309-2312; 2. Marotta F, et al. Clin Ther. 2004;155:187-199;
3. Thorgeirsson S, et al. Nat Genet. 2002;31:339-346; 4. Wang XW, et al. Toxicology. 2002;181-182:43-47;
5. Koike K. Hepatol Res. 2005;33:145-150.
114
 The potential role of monitoring &
anti-fibrotic therapy

Hepatocellular carcinom

Chronic hepatitis with fibrosis

10-50 years

Normal liver Cirrhosis

Anti-fibrotic therapy

Liver transplant
Prof. Dr. Vedat Goral,Turkey- Current trends in treatment of liver fibrosis, Oral presentation,IASGO 5-8 Sept 2007,Bucharest
 Conclusion

• Thank you for your attention

• …….
 Overview: main distinctive viral dynamic
features of HIV, HBV and HCV
Virus HIV HBV HCV
Daily production of
1010 1012–1013 1012
virions per day

Half-life of free virions (h) 1 3–24 2–3

Half-life of intracellular Days (dependent on Months (dependent on Hours (not dependent on

virions infected cells t1/2) infected cells t1/2) infected cells t1/2)
Mutation rate Very high High Very high
Constraints due to open
reading frames in Moderate High None
targeted viral enzymes
Immune-mediated escape
Frequent Infrequent Frequent
mutants

Main target cells CD4+ T cells Hepatocytes Hepatocytes

Half-life of infected cells Days Months Weeks

Intracellular viral
Yes (integrated cDNA) Yes (cccDNA) No
reservoir

HIV: human immunodeficiency virus

HBV: hepatitis B virus
cDNA: complementary DNA
cccDNA: covalently closed circular DNA Soriano V, et al. J Antimicrob Chemother 2008;62:1–4, by permission of Oxford University Press