Non%20invasive%20fibrosis%20markers%20%20%20and/or%20liver%20biopsy

1
Non invasive fibrosis markers and/orliver
biopsy

• Pierre Bedossa
• Department of Pathology, Hôpital Beaujon,
• Paris-Denis Diderot University
• FRANCE

2
FIBROSIS IN HEPATITIS C
From Z. Goodman

• 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

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Several tools for assessing liver fibrosis

• Physical examination
• Liver Biopsy the gold standard
• Imaging (ultrasound, MRI)
• Serum markers
• Stiffness (US, MRI)

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Liver biopsy

• Evaluation of fibrosis Staging
  systems

• Amount of fibrosis
• Location of fibrosis
• Architectural changes

• Stage of fibrosis is more complex than fibrosis
  amount

5
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 231334-1340
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Staging of fibrosis with biopsy has clinical
relevance
Histological stage of fibrosis predict
liver-related complications liver related
death
Survival to liver-related complications according
to liver fibrosis stage on initial biopsy
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
  31513-520

7
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.
8
Liver biopsy the best not the gold standard

• Observer variation
• Sampling error

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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
• 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

10
Fibrosis is homogeneously distributed in viral
hepatitis
F1 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
of accurate staging
Biopsy length (mm)
Hepatology. 2003 Dec38(6)1449-57.
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Liver biopsy adverse events

• The risks

• The tricks

• Bleeding
• Pain, anxiety, discomfort
• Vaso-vagal episode
• Biliary peritonitis, pneumothorax
• (death)

• Ultrasound guidance
• Transjugular route
• Follow-up in day care unit
• Experienced physician
• Reduced number of passes

Gained informations Risks of an provided by
the LB invasive procedure
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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
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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

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RATIONAL OF FIBROSCAN
Normal liver soft
Cirrhosis hard High viscosity Low
viscosity Slow velocity High
velocity Low stiffness High stiffness
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FIBROSCAN - Results
Friedreich-Rust et al. GASTROENTEROLOGY
2008134960974
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FIBROSCAN Stage by Stage
From Castera et al. J Hepatol 2008833-847

• Major overlap between adjacent stages

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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 gt fibrosis study with clinical
  end-points needed

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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

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Building a serum marker for fibrosis
A
C
E
G
I
K
M
B
D
F
H
J
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LIVER BIOPSY
C
J
G
M

• Non hypothesis-based research
• Modelization of histological staging
• Dependent of liver biopsy performance

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Fibrotest - Fibrosure
Mild vs significant fibrosis
Poynard et al. BMC gastroenterology 2007
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SERUM MARKER Summary

• 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

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Liver biopsy and/or non invasive markersWhere
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

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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

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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

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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
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Liver biopsy and comorbidity in Hepatitis C
CV
PT
Chronic hepatitis C (1b) with metabolic syndrom
(Sirius red staining) Serum marker F4
Elasticity 14 Kpa
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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
• Steatohepatitis (9)
• Granuloma
• Auto-immunity
• Iron overload

Saadeh, Hepatology 2001, Spycher, BMC Gastro
2001 Bedossa P Hepatology 2007
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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

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American Gastroenterological Association
Technical Review on the Management of Hepatitis
C JL Dienstag, J MacHutchison. GASTROENTEROLOGY
2006130231264