hepatic fibrosis

8/6/2019 Hepatic Fibrosis

1/56

Hepatic Fibrosis

Maissa El Raziky , M.D

Professor of Endemic Medicine andHepatology Cairo University


2/56

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.


3/56

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


4/56

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.


5/56

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.


6/56


7/56


8/56


9/56

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.


10/56

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


11/56

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,


12/56


13/56

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


14/56

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


15/56

Initiating signals of injury

These fibrogenic stimuli include:

Reactive oxygen species.

Hypoxia. Inflammatory and immune responses.

Apoptosis .

Steatosis.


16/56

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


17/56

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


18/56

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.


19/56

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.


20/56

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.


21/56

Immunoregulatory roles of stellate cells


22/56

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


23/56


24/56

Diagnosis of Liver Fibrosis


25/56

Currently

Liver Biopsy is still considered

the gold standardfor assessing liver histology.


26/56

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.


27/56

Finding non-invasive tests to assess liver

fibrosiswould be very useful in follow-up.

These tests include:Serological tests.

Imaging techniques.


28/56

Serological tests


29/56

.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.


30/56

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.


31/56

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).


32/56

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. )


33/56

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


34/56

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.


35/56

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)


36/56

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)


37/56

Imaging techniques


38/56

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.


39/56

Portal Tracts

Grading

Grade I : 3-5 mm

Grade II :>5-7 mm

Grade III :> 7 mm


40/56

Portal Tracts


41/56

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


42/56

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.


43/56

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.


44/56

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.


45/56

2.5

cm

4 cm

1 cm

Explored volume


46/56

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


47/56

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


48/56

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


49/56

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


50/56

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 .


51/56

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.


52/56

Therapies for Hepatic Fibrosis

Current and Future


53/56

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


54/56

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


55/56

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.


56/56

hepatic fibrosis

Documents