Is liver biopsy still necessary for injury and fibrosis assessment

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Is liver biopsy still necessary for injury and fibrosis assessment Powered By Docstoc
					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)
                   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                Survival to liver transplantation or liver-related death
 according to liver fibrosis stage on initial biopsy          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 ***
* 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
% of accurate staging




                                                                                AUROC         AUROC         AUROC
                                                                 Size
                                                                             F01 vs F234     F0 to F1      F1 to F2


                                                                 5mm            0.81           0.70          0.72


                                                                 10mm           0.92           0.78          0.78


                                                                15mm            0.95          0.80          0.83

                               Biopsy length (mm)                                Hepatology. 2003 Dec;38(6):1449-57.
       Liver biopsy : adverse events

The risks                     The tricks
• Bleeding                    • Ultrasound guidance
• Pain, anxiety, discomfort   • Transjugular route
• Vaso-vagal episode          • Follow-up in day care unit
• Biliary peritonitis,        • Experienced physician
  pneumothorax                • Reduced number of passes
• (death)


    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 + α2macro. + 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

         A       C       E       G           I       K       M
             B       D       F       H           J       L




                         LIVER BIOPSY




                     C       G           J           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



                                              CV
                                              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 %*
     •   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