Transcript Non invasive fibrosis markers and/or liver biopsy Pierre Bedossa Department of Pathology, Hôpital Beaujon, Paris-Denis Diderot University FRANCE FIBROSIS IN HEPATITIS C From Z.

Non invasive fibrosis markers
and/or
liver biopsy
Pierre Bedossa
Department of Pathology, Hôpital Beaujon,
Paris-Denis Diderot University
FRANCE
FIBROSIS IN HEPATITIS C
From Z. Goodman
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Physiopathology: the hallmark of an unresolved chronic inflammatory disease
Pathologist : extracellular matrix deposit in association with architectural change
Hepatologist : A major endpoint for treatment of patient and assessing prognosis
Several tools for assessing liver fibrosis
• Physical examination
• Liver Biopsy : the gold standard
• Imaging (ultrasound, MRI)
• Serum markers
• Stiffness (US, MRI)
Liver biopsy
Evaluation of fibrosis
Staging systems
• Amount of fibrosis
• Location of fibrosis
• Architectural changes
• Stage of fibrosis is more complex than fibrosis amount
Staging of fibrosis with biopsy has clinical
relevance
Histological stage of fibrosis predict progression to cirrhosis
Cumulative rate of progression to cirrhosis over time according
to stage of fibrosis on initial biopsy
M. Yano et al. The long-term pathological evolution of chronic hepatitis C.
Hepatology 1996; 23:1334-1340
Staging of fibrosis with biopsy has clinical
relevance
Histological stage of fibrosis predict :
liver-related complications
Survival to liver-related complications
according to liver fibrosis stage on initial biopsy
liver related death
Survival to liver transplantation or liver-related death
according to liver fibrosis stage on initial biopsy
MH. Khan et al. Which patients with hepatitis C develop liver complications? Hepatology 2000; 31:513-520
Staging of fibrosis with biopsy has therapeutic
relevance
Histological stage of fibrosis predicts response to bitherapy in HCV
-Retreatment in non responder and relapser (EPIC study)EPIC study, AASLD
2007)
Sustained Virologic Response Rates by METAVIR score Overall and
Among Patients with Undetectable HCV-RNA at Treatment Week 12.
Liver biopsy : the best not the gold standard
1. Observer variation
2. Sampling error
Liver biopsy : a reliable procedure
• Interobserver variation :
– Histologic scoring systems increases reliability of
evaluation *
– Specialized liver pathologists insure low interobserver
variation **
• Sampling error :
– Biopsy of adequate length reduces risk of sampling
error ***
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Metavir, Hepatology 1994, Goldin et al, J Hepatol, 1996, Westin et al, Liver 2004
** MC Rousselet et al. Hepatology 2005;
*** Coloredo et al J Hepatol 2005, Guido et al Semin Liv Diseases, 2004, Bedossa et al. Hepatology 2004
Fibrosis is homogeneously distributed in viral hepatitis
% of accurate staging
F1
Biopsy length (mm)
F2
F4
Size
AUROC
F01 vs F234
AUROC
F0 to F1
AUROC
F1 to F2
5mm
0.81
0.70
0.72
10mm
0.92
0.78
0.78
15mm
0.95
0.80
0.83
Hepatology. 2003 Dec;38(6):1449-57.
Liver biopsy : adverse events
The risks
• Bleeding
• Pain, anxiety, discomfort
• Vaso-vagal episode
• Biliary peritonitis,
pneumothorax
• (death)
Gained informations
provided by the LB
The tricks
• Ultrasound guidance
• Transjugular route
• Follow-up in day care unit
• Experienced physician
• Reduced number of passes
Risks of an
invasive procedure
A NEED FOR AN ALTERNATIVE
TO LIVER BIOPSY
1- Non invasive, simple, reproducible
2- Staging as accurate as liver biopsy
3- Providing other histopath. informations
than fibrosis, relevant for patient
management
FIBROSCAN
• Vibration transmitted toward the liver produces elastic shear wave
• Measurement of the velocity of wave propagation with ultrasound.
• Assessment of stiffness (2.5 – 75 kPa)
• Hypothesis : Fibrosis // stiffness
RATIONAL OF FIBROSCAN
Normal liver – soft
High viscosity
Slow velocity
Low stiffness
Cirrhosis – hard
Low viscosity
High velocity
High stiffness
FIBROSCAN - Results
Friedreich-Rust et al. GASTROENTEROLOGY 2008;134:960–974
FIBROSCAN – Stage by Stage
From Castera et al. J Hepatol 2008;833-847
• Major overlap between adjacent stages
FIBROSCAN - Summary
• Rational behind
• Easy and quick to perform
• Excellent performance to dichotomizing between
advanced / non advanced fibrosis
• Overlap between adjacent stages
• Assess stiffness, not fibrosis
• Other histopathologic lesions influencing liver stiffness :
steatosis, acute inflammation, congestion…….
• Pending questions :
– stiffness // fibrosis ?
– Stiffness > fibrosis : study with clinical end-points needed
SERUM MARKERS FOR FIBROSIS
– Fibrotest®
(Imbert-Bismuth et al. Lancet 2001)
Haptoglobine + 2macro. + ApoA1 + GGT + ALAT + Bilirubine
– APRI (Way et al., Hepatology 2003)
Plaquettes + ASAT
– Forns et al. (Hepatology 2002)
Plaquette + GGT + âge + cholesterol
– Fibrometre, Fib 4, Hepascore, SHASTA, Fibrospect,
Glycomics…………
Building a serum marker for fibrosis
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LIVER BIOPSY
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• Non hypothesis-based research
• Modelization of histological staging
• Dependent of liver biopsy performance
Fibrotest - Fibrosure
Mild vs significant fibrosis
Poynard et al. BMC gastroenterology 2007
SERUM MARKER : Summary
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Non invasive
Easily accessible
Highly reproducible
Performant for distinction between significant
and non significant fibrosis
• Not approved for distinction between adjacent
stages
• Impacted by limits of the biopsy procedure
Liver biopsy and/or non invasive markers
Where are we now ?
• Reluctance for biopsy from patients and
physicians
• High commercial pressure
• Biopsy is not any more a mandatory procedure in
chronic hepatitis C
• No consensus, actualised official
recommendations should be useful
A biopsy is not useful
• Obvious cirrhosis, no comorbidity, no macronodule
• No discussion for treatment :
– Patient belongs to a subgroup with high probability of
treatment response
– Treatment is indicated because of extra-hepatic manifestation
– Patients will not be treated because of contraindications to the
treatment
• Screening of advanced fibrosis : non-invasive markers
A biopsy is useful
• A biopsy is needed only when the patient will have
potential benefit from the informations provided
by the biopsy
• Any unclear situation
• Comorbidity :
– Obesity or overweight, diabetes, metabolic syndrom
– Alcohol consumption
– Immunosupression….
• Staging of fibrosis (F0,1,2,3,4) is needed
When fibrosis staging (biopsy) is needed ?
• Patients difficult to treat or to manage: staging needed for
adequate timing of treatment
– not too early: antiviral therapies have adverse effects, are costly and
only partly efficient
– not too late: decrease SVR if septal fibrosis or cirrhosis*
• Accuracy provided by biopsy useful for adequate treatment of
most patient with CHC to avoiding lost chance or unnecessary
treatment.
• Non invasive procedure have not a sufficient degree of precision
* Heathcote EJ et al. NEJM 2000
Liver biopsy and comorbidity in Hepatitis C
CV
PT
PT
Chronic hepatitis C (1b) with metabolic syndrom (Sirius red staining)
Serum marker F4 – Elasticity: 14 Kpa
Liver biopsy and unexpected features in
hepatitis C
• In the context of the high burden of CHC,
clinical symptoms or abnormal liver tests
can be related to unsuspected disease
• Added diagnosis in CHC : 2.3% - 13.9 %*
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Steatohepatitis (9%)**
Granuloma
Auto-immunity
Iron overload
* Saadeh, Hepatology 2001, Spycher, BMC Gastro 2001
** Bedossa P Hepatology 2007
Take-home messages
• Liver biopsy remains the best standard available to assess
fibrosis
• Non invasive markers and biopsy have not the same
accuracy for fibrosis evaluation:
– When only screening for advanced fibrosis is required, non-invasive
markers or Fibroscan can be used
– When staging of fibrosis is needed, liver biopsy is the only tool
available
• Performance of surrogate markers are close each others
• In hepatitis C, liver biopsy can provide other clinically
relevant informations than an histological score of fibrosis
American Gastroenterological Association
“Technical Review on the Management of Hepatitis C”
JL Dienstag, J MacHutchison. GASTROENTEROLOGY 2006;130:231–264