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Hepatic Fibrosis
Maissa El Raziky , M.D
Professor of Endemic Medicine andHepatology Cairo University
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Hepatic fibrosis represents the woundhealing response to liver injury from a widevariety of etiologies.
Cirrhosis is the most advanced stage offibrosis, connoting more than fibrosisalone, but rather distortion of the liver
parenchyma associated with septae andnodule formation, altered blood flow andthe potential development of liver failure.
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Topics covered
Process of Fibro-genesis. Diagnosis of Liver Fibrosis
Liver Biopsy .
Non-invasive tests to assess liver fibrosisSerological tests
Imaging techniques
Therapies for Hepatic Fibrosis Current andFuture
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Liver fibrosis is the result of an imbalance
between production and dissolution of
extracellular matrix.Stellate cells, portal myofibroblasts, and
bone marrow derived cells converge in a
complex interaction with hepatocytes and
immune cells to provoke scarring in
response to liver injury.
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Remarkable progress happened in the field
of hepatic fibrosis in a range of areas,
including the expansion of potentialcellular sources ofextracellular matrix
(ECM), the intimate crosstalk with immune
and inflammatory cell subsets, pathways
regulating fibrosis regression, geneticdeterminants of fibrosis risk.
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Hepatosplenic Schistosomiasis
Gross anatomical features and a complex set of
vascular changes characterize schistosomal
hepatopathy as a peculiar form of chronic liver
disease, clinically known as "hepatosplenicschistosomiasis".
Damage to the muscular walls of the portal vein
may be followed by dissociation of smooth
muscle cells and their transition toward
myofibroblasts, which appear only as transient
cells in schistosomal portal fibrosis.
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Morphology of HSCs in normal liver) .A (diagram of the hepatic sinusoid
demonstrating the relative orientation of stellate cells (in blue, indicated with
arrows) within the sinusoidal architecture .) B (higher resolution drawing of
stellate cells situated within the subendothelial space
Hepatic Stellate Cells
A
B
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Hepatic Stellate Cells
Hepatic stellate cells (HSCs) have dominatedstudies exploring mechanisms of liver fibrosis
over the last two decades.
HSCs are resident vitamin A-storing cells in the
perisinusoidal space of Disse between thesinusoidal endothelium and hepatocytes.
Following hepatic injury, HSC become
activated, proliferate and produce extracellular
matrix (ECM) .
Both the characterization of HSCs and their
behavior in hepatic injury have been well
characterized,
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PATHOGENESIS OF LIVER FIBROSIS
Alterations in Microvasculature in
Cirrhosis
Alterations in Microvasculature in
Cirrhosis
y Activation of stellate cells
y Collagen deposition in space ofDisse
y Constriction of sinusoids
y Defenestration of sinusoids
y Activation of stellate cells
y Collagen deposition in space ofDisse
y Constriction of sinusoids
y Defenestration of sinusoids
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Stellate cell activation. Stellate cell activation is a key pathogenic
feature underlying liver fibrosis and cirrhosis. Multiple and variedstimuli contribute to the induction and maintenance of activation,including (but not limited to) cytokines, peptides, and the extracellularmatrix itself. Key phenotypic features of activation include theproduction of extracellular matrix, loss of retinoids, proliferation, ofup-regulation of smooth muscle proteins, secretion of peptides andcytokines (which have autocrine effects), and up-regulation ofvarious cytokine and peptide receptors
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Initiating signals of injury
These fibrogenic stimuli include:
Reactive oxygen species.
Hypoxia. Inflammatory and immune responses.
Apoptosis .
Steatosis.
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Cellular Sources of Fibrogenesis Stellate
cell activation and Myofibroblasts
Stellate cell activation refers to the conversion
of a resting vitamin A-rich cell to one that is
proliferating, fibrogenic and contractile.
Other mesenchymal cell populations alsocontribute to extracellular matrix accumulation.
Stellate cell activation remains the most
dominant pathway leading to hepatic fibrosis.
Activation consists of two major phases,Initiation and Perpetuation, followed by
Resolution of fibrosis if injury subsides
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Pathways of stellate cell activation and resolution. Following liver injury,HSCs undergo activation, which connotes a transition from quiescentvitamin A-rich cells into proliferative, fibrogenic, and contractilemyofibroblasts. The major phenotypic changes after activation includeproliferation, contractility, fibrogenesis, matrix degradation, chemotaxis,retinoid loss, and WBC chemoattraction. Key mediators underlyingthese effects are shown. The fate of activated stellate cells duringresolution of liver injury is uncertain but may include reversion to aquiescent phenotype and/or selective clearance by apoptosis
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Initiation (also called a "pre-inflammatory stage"),refers to early changes in gene expression and
phenotype that render the cells responsive to
other cytokines and stimuli.
Initiation results mostly from paracrine stimulation,including altered surrounding extracellular matrix,
as well as exposure to lipid peroxide, LPS and
products of damaged hepatocytes.
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Perpetuation results from the effects ofthese stimuli on maintaining the activatedphenotype and generating fibrosis.
Perpetuation involves autocrine as well asparacrine loops. It is comprised of several
discrete responses including : proliferation,
contractility,
fibrogenesis,
matrix degradation,
retinoid loss,
inflammatory cell infiltration.
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Resolution of fibrosis refers to pathways
that either drive the stellate cell to
apoptosis, senescence, or contribute to
reversion of activated stellate cells to a
more quiescent phenotype.
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Immunoregulatory roles of stellate cells
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Diagram of lymphocyte recruitment and trafficking within the liverparenchyma. Hepatic sinusoids have specialized features including afenestrated endothelium, a low-velocity flow rate, and the absence ofendothelial cell selectins. The initial capture of lymphocytes in hepatic
sinusoids occurs through integrin-mediated interactions with adhesionmolecules. During the triggering phase, lymphocyte G-coupled receptorsrespond to chemokine signals on endothelial cells, leading to aconformational change in lymphocyte-associated integrins. Chemokines aresynthesized by endothelial and hepatic parenchymal cells. Transendothelialmigration (diapedesis) into the surrounding tissue is facilitated by both
chemokine recognition and intracellular cytoskeletal changes
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Diagnosis of Liver Fibrosis
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Currently
Liver Biopsy is still considered
the gold standardfor assessing liver histology.
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Clinicians depend mainly on liver biopsy toestimate the degree of liver fibrosis.
Knowing the rate of progression of fibrosis
represents an important surrogateendpoint for evaluation of the vulnerability
of patients for complications.
For assessment of any treatment's impacton natural history.
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Finding non-invasive tests to assess liver
fibrosiswould be very useful in follow-up.
These tests include:Serological tests.
Imaging techniques.
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Serological tests
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.Over the past decade, there has been renewedenthusiasmto develop noninvasive serummarkers or tests to assess the presence and
severity of fibrosis in chronic liver disease.
. Although a single marker or test has lackedthe necessary accuracy to predict fibrosis,
different combinations of these markers
or tests have shown encouraging results.
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Many different parameters have been
evaluated including:
Circulating products of collagen synthesis or
degradation.
Enzymes involved in collagen biosynthesis,
extracellular matrix glycoproteins andproteoglycans or matrix-degrading enzymes
and their inhibitors.
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In 2001, FibroTest for the assessment of
fibrosis; ActiTest for the assessment ofnecroinflammatory activity (FT-AT) were
introduced.
These are a panel of biochemical markers :2-macroglobulin, haptoglobin,
apolipoprotein A1, -glutamyl
transpeptidase, and total bilirubin
(FibroTest) plus alanine aminotransferase(ActiTest).
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A total of 16 publications were identified. An
integrated database was constructed
using 1,570 individual data, to which
applied analytical recommendations. The
control group consisted of 300
prospectively studied blood donors(Poynard ,et al. Comp Hepatol. 2004; Sep 3: 8. )
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Positivepredictive
value
Negativepredictive
value
Specificity
Sensitivity
Cut off used forMETAVIR stages
conversion
AUROC (SE)
Stage/Prevalence
MarkerPatientnumber
Integrateddatabase
0.480.940.550.920.210.83
(0.01)
F2F3F
4/0.31
FibroTest1,570WithBlood
Donors
0.510.920.620.870.27
0.540.910.680.840.31
0.610.850.810.680.48
0.670.820.870.560.58
0.760.770.950.380.72
0.760.760.950.350.74
0.780.760.960.330.75
0.490.890.410.920.210.78
(0.01)F2F3F4/0.38
FibroTest1,270Withoutblood
donors
0.510.860.480.870.27
0.540.850.550.840.31
0.610.790.730.680.48
0.670.750.830.560.58
0.760.700.950.380.72
0.760.700.930.350.74
0.780.690.940.330.75
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The use of the FibroTest and ActiTest can
be recommended as an alternative to liverbiopsy for the assessment of liver injury in
patients with chronic hepatitis C.
In clinical practice, liver biopsy should berecommended only as a second line test,
i.e., in case of high risk of error of
biochemical tests.
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Several models have been developed whichconsist of the measurement of routine laboratory data:a) a model combining platelets, GT, cholesterol and age
(Forns model)
b) a model using an AST to platelet ratio index (APRI).
The Forns's model predicted mild fibrosis in 71.4% whilethe APRI model did it in 72.7%. The Forns's modelconfirmed advanced fibrosis in 78.6% against 54.2%
from the APRI one.The predictive capacity of advanced fibrosis or exclusion of
significant fibrosis reached more than 90% when bothmodels were used together. (Romero Gomez et al,2005)
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A total score of 3 biological parameterscombined PT, platelets and transminases,was significantly more enabled in the severe
fibrosis than in the mild fibrosis but it was not of
much importance in 30% of cases. This scoredoes not seem to grant exemption from needle
liver biopsy, but it can be improved by the
association of other direct markers of fibrosis.
(Mohammed et al.,2005)
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Imaging techniques
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Ultrasonography is a relatively inexpensive,portable, safe, readily accepted by mostpatients, and real-time modality, all of whichmake it one of the most widely used imagingmodalities in medicine.
Ultrasound is accurate for predicting the finaldiagnosis in patients with established cirrhosisand its sequlae (splenomegaly, ascites, focallesions).
However the diagnostic accuracy of routine USfor early liver cirrhosis is low.
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Portal Tracts
Grading
Grade I : 3-5 mm
Grade II :>5-7 mm
Grade III :> 7 mm
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Portal Tracts
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Gray scale and color Doppler
epa s c y nde
epa
c
arery
res
s
en
de
P=0.03
ros s rades
P=0.01
There is controversy with regard to the reproducibility
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Hepatic vein transit times
The relative transit time through the splanchnic bed of
a bolus of microbubbles agent Levovist is
measured.
HVTT can assess HCV related liver disease with
clear differentiation between mild hepatitis and
cirrhosis. There were significant differencesbetween these two groups and the
moderate/severe hepatitis group.
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Copyright 2005 BMJ Publishing Group Ltd.
Illustration of a normal hepatic vein transit time (HVTT) (43 seconds) and a comparative earlyHVTT in a patient with cirrhosis (14 seconds). Note 20 seconds of baseline are collected beforeinjection of the microbubbles. The continuous horizontal line denotes a Doppler intensity 10%
above baseline and hence HVTTs are taken as the intersection of this line with that of the Dopplerintensity trace.
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FibroScan
Transient elastography (FibroScan) is a new non-invasive rapid bedside and reproducible method,allowing evaluating liver fibrosis bymeasurement of liver stiffness.
The shear elasticity probe is a device based onone-dimensional (1-D) transient elastography, atechnique that uses both ultrasound (5 MHz)and low-frequency (50 Hz) elastic waves, whosepropagation velocity is directly related toelasticity.
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2.5
cm
4 cm
1 cm
Explored volume
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Liver stiffness in the normal population and factors
influencing its measurement
ColomboRoulotCorpechot
32742971Number of subjects
Blood donorsMedical check-upHealthy volunteersPopulation
4.9 1.725.4 1.524.8 (2.5-6.9)Mean stiffness
(KPa)7.88.6-95th centile
No effectNo effectNo effectAge
M = FM > FM > FGender
IncreasedIncreasedIncreasedHigh BMI
Increased--Fatty liver
-Increased-Metabolic
syndrome
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Diagnostic performance of TE in the
diagnosis of significant fibrosis
Yone
da
KelleherCorpechotFraquelliZiolCasteraMarcellinOliveri
6712995200251183170268Patients
4950605065746969F2 or
higher(%)
NAFL
D
NAFLDPBC/PSCHCVHCVHCVHBVHBVEtiology
6.68.77.37.98.87.17.27.5Cut Off(KPa)
8281847256677093Sensitivity (%)
8178878491898388Specificity (%)
0.870.860.920.860.790.830.810.96AUROC
C l iR ltN bSt d
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ConclusionResultsNumberStudy
TE is a promising method for the
detection of cirrhosis. Its use for the
follow-up and management could be
of great interest and should be
further evaluated.
Stiffness was significantly correlated
to the fibrosis stage
Cut- off value of 17.6 kPa, patientswith cirrhosis were detected with
both PPV and NPV of 90%.
711Foucher et al. 2005
FibroScan is a simple and effective
method for assessing liver fibrosis,
with similar performance to FibroTest
and APRI. The combined use of
FibroScan and FibroTest could avoida biopsy procedure in most patients
with chronic hepatitis C.
Cut-off values were 7.1 kPa183Castera et al. 2005
The Fibroscan is a noninvasive,
painless, rapid and objective method
to quantify liver fibrosis.
Liver elasticity measurements were
reproducible (standardized
coefficient of variation: 3%),
operator-independent and well
correlated (partial correlation
coefficient = 0.71, p < < 0.0001) to
fibrosis grade (METAVIR).
106Sandrin et al. 2003
LSM appears as a reliable tool to
detect significant fibrosis or cirrhosis
in patients with chronic hepatitis C.
LSM was well correlated with
fibrosis stage
327Ziol et al. 2005
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Fibroscan is a sensitive tool in detection ofsignificant fibrosis F2 as assessed by theMETAVIR score at a cut off level of 6.35 kpa
and in detection of cirrhosis F4 at a cut offlevel of 10.75 kpa
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MRI
The use of apparent diffusion coefficient (ADC)measurements based on diffusion-weighted MRI(DWI) are potentially useful for the evaluation offibrosis staging in the liver.
The sensitivity of MRI in diagnosing liver cirrhosiswas 87% and the specificity 92%. The mostcharacteristic MRI features were enlargement ofsegment one , narrowing of hepatic veins , signsof portal hypertension , fibrosis , and nodularliver margin .
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Conclusion
The advantage of the non-invasive tests or
techniques is that they provide a rapid and
quantitative estimation of fibrosis.
With these new methods, it is possible to followthe progression of the disease and its regression
either spontaneously or under treatment.
Clinicians have in their hands several painless
tools to explore liver fibrosis that can be easilyrepeated.
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Therapies for Hepatic Fibrosis
Current and Future
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The ideal therapies will be those that are orally,
available, well tolerated during chronic usage,
and do not simply prevent progression of
fibrosis, but rather regress scar, leading to
stabilization or improvement in liver function.
f f
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The broad targets of anti-fibrotic therapy can
be divided among several categories
Cure the primary disease to prevent injury. Reduce inflammation or the host response in order to avoid
stimulating stellate cell activation. (RAAS-UDCA)
Hepatoprotection to reduce hepatocyte injury, thus
attenuating downstream signals of activation to stellate cells
Directly down-regulate stellate cell activation (Antioxidants,including vitamin E)
Neutralize proliferative, fibrogenic, contractile and/orproinflammatory responses of stellate cells (vitamin A).
Stimulate apoptosis of stellate cells.
Increase the degradation of scar matrix
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A variety of approaches have been
successful in attenuating fibrosis in animal
models, but these need to be tested in
human trials.
Directly targeting accumulated fibrotic
matrix with protease activity merits further
development.
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