Non invasive fibrosis markers

and/orliver biopsy

Pierre BedossaDepartment of Pathology, Hôpital Beaujon,

Paris-Denis Diderot UniversityFRANCE

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

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

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

MH. Khan et al. Which patients with hepatitis C develop liver complications? Hepatology 2000; 31:513-520

Histological stage of fibrosis predict :

liver-related complications liver related death

Survival to liver-related complicationsaccording to liver fibrosis stage on initial biopsy

Survival to liver transplantation or liver-related deathaccording to liver fibrosis stage on initial biopsy

Staging of fibrosis with biopsy has clinical 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.

Staging of fibrosis with biopsy has therapeutic relevance

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 ***

* 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

Size AUROC

F01 vs F234 AUROCF0 to F1

AUROCF1 to F2

5mm 0.81 0.70 0.72

10mm 0.92 0.78 0.78

15mm 0.95 0.80 0.83

Fibrosis is homogeneously distributed in viral hepatitis

F1 F2 F4

Biopsy length (mm)

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Hepatology. 2003 Dec;38(6):1449-57.

Liver biopsy : adverse events

The risks• Bleeding• Pain, anxiety,

discomfort• Vaso-vagal episode• Biliary peritonitis,

pneumothorax• (death)

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

passes

Gained informations Risks of anprovided by the LB 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

• 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

FIBROSCAN

Normal liver – soft Cirrhosis – hardHigh viscosity Low viscositySlow velocity High velocityLow stiffness High stiffness

RATIONAL OF FIBROSCAN

Friedreich-Rust et al. GASTROENTEROLOGY 2008;134:960–974

FIBROSCAN - Results

From Castera et al. J Hepatol 2008;833-847

FIBROSCAN – Stage by Stage

• Major overlap between adjacent stages

• 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

FIBROSCAN - Summary

– 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…………

SERUM MARKERS FOR FIBROSIS

Building a serum marker for fibrosis

LIVER BIOPSY

AB

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F

G

H

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

Fibrotest - Fibrosure

Poynard et al. BMC gastroenterology 2007

Mild vs significant fibrosis

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

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

PT

CV

Chronic hepatitis C (1b) with metabolic syndrom (Sirius red staining)Serum marker F4 – Elasticity: 14 Kpa

PT

CV

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

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