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 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)

Stage of fibrosis is more complex than fibrosis amount 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 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; 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 Observer variation Sampling error and this has been recently underline in several recent reports. The main limits of the LB are there

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

Fibrosis is homogeneously distributed in viral hepatitis F1 F2 F4 Size AUROC F01 vs F234 F0 to F1 F1 to F2 5mm 0.81 0.70 0.72 10mm 0.92 0.78 15mm 0.95 0.80 0.83 % of accurate staging Biopsy length (mm) Hepatology. 2003 Dec;38(6):1449-57.

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

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 Cirrhosis – hard High viscosity Low viscosity Slow velocity High velocity Low stiffness 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 C E G I K M B D F H J L LIVER BIOPSY C J G M 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 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 CV 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 %* 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