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Liver Fibrosis Are Non-invasive markers sufficient?

Liver Fibrosis Are Non-invasive markers sufficient?. William Rosenberg Prof of Hepatology University of Southampton. CSO iQur Limited; Consultant to Bayer Healthcare. Why measure fibrosis?. Assessment of disease Diagnosis Prognosis Treatment decisions Monitoring disease Natural history

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Liver Fibrosis Are Non-invasive markers sufficient?

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  1. Liver FibrosisAre Non-invasive markers sufficient? William Rosenberg Prof of Hepatology University of Southampton CSO iQur Limited; Consultant to Bayer Healthcare

  2. Why measure fibrosis? • Assessment of disease • Diagnosis • Prognosis • Treatment decisions • Monitoring disease • Natural history • Treatment effects • Drug development Cross-sectional Dynamic change over time

  3. Liver BiopsyThe Reference Standard for Fibrosis

  4. Disadvantages of Liver Biopsy • Hazard to the patient • Resource usage • Bed • Imaging • Staff • Processing • Sampling Error • Interpretation Time

  5. Liver biopsy • Sampling error • 1/50,000 of the liver • Fibrosis not evenly distributed • Lt and Rt lobes difference 24% 1 Grade 30% 1 Stage • 20% error in scoring

  6. Liver biopsy analysis • Size • Biopsy size a reproducibility Bedossa et al. 2004 • Histological scoring • Inter observer variation k=0.9 – 0.49 • Interpretation a experience Bedossa et al. 2005 • Image analysis • Automation • More fields • Greater reproducibility

  7. Ideal markers of fibrosis • Performed on a serum or urine sample • Test cheap and relatively easy • A continuous variable • Allows distinction of small changes • Correlates with fibrosis over full range • Accurate for all comparisons • Provides clinically meaningful data • Prognostic information and treatment response

  8. 1 1 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 Sensitivity (true positives) Sensitivity (true positives) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1 1 1 1 - - Specificity (false positives) Specificity (false positives) Candidate Approach

  9. Candidate Biomarkers of Fibrosis • Indirect: Measures of liver function • AST, ALT, gGT, Apolipoprotein A1, bilirubin, a2-macroglobulin, haptoglobin, cholesterol • HOMA-IR • Platelets, PT • Direct: ECM components and enzymes • HA, PIIINP, Collagen IV, Collagen VI, TIMP-1, Laminin, YKL-40, Tenascin, Undulin, MMP-2

  10. ELF MarkersRosenberg et al. Gastro Dec 2004 Detection of Scheuer Stage 0,1,2 versus 3,4

  11. Panel Performance Applying High and Low ThresholdsNPV~95% PPV~90% HA PIIINP Bayer Forns Fibrotest APRI

  12. High, Mid and Low Cut-off SROCs Detecting F3/4 Specificity Differentiating F2/3 Poor Detecting F1/2 DOR 8.14 (3.61-18.38) Sens. 40.1 Spec. 95 Sensitivity DOR 6.52 ( 1.69-25.23) Sens. 59.8 spec. 87.7 DOR 6.39 (1.89-21.65) Sens. 94.8 Spec. 35.8

  13. Sufficient? • Errors in liver biopsy • Expert opinion is flawed • What matters? • Detecting Any fibrosis - F0,1 vs rest • Detecting Advanced fibrosis - F4,5,6

  14. F 0,1 versus the rest AUC=0.791 (95% CI: 0.720, 0.862) p<0.001 Notts HCV Cohort See Parkes et al. Poster 160 BSG 2006

  15. F4, 5 and 6 versus the rest AUC=0.860 (95% CI: 0.804, 0.916), p<0.001 Notts HCV Cohort See Parkes et al. Poster 160 BSG 2006

  16. Case 1 Diagnosis • 35 year old Female G3 HCV for 10 years • Normal LFTs and USS Biopsy or Serum markers?

  17. Case 2 Diagnosis • 45 year Male G1 HCV • 5 spiders, ? Palpable spleen • Normal Bilirubin Albumin Platelets • US normal Biopsy or Serum markers?

  18. Will we ever know? ? ? ? Moderate CV Categorical Excellent CV Continuous 0.4 0.49

  19. PrognosisELF Follow-up Preliminary data from Southampton and Newcastle Dr Julie Parkes MRC Clinician Scientist Carol Gough

  20. Clinical Follow up of ELF Cohort • 224 patients • 75% male • Hep C 45% ALD 19% Fat 13% • 62 F2-4 • 26 Liver related outcomes

  21. Prediction of Mortality

  22. Conclusion • ELF serum markers of liver fibrosis accurately predict liver related death over 5-8 years follow-up • Performance is at least as good as histology

  23. Case 3 Prognosis • 35 year old man • BMI=35 ALT=125 • Concerned about his future Biopsy or Serum markers?

  24. Assessment ofTreatment Response Drug treatment Drug development

  25. Treatment responsePoynard et al Hepatology 2003;38:481-492 • Not accurate for individual patients • Changes in biomarkers correlate with changes in histology for cohorts • Use in evaluating trials warrants further studies

  26. Significant difference Cumulative evidence of difference Individual and Group Differences NS Biomarkers: continuous variable, change determined by biology, low cv, repeatable at high frequency

  27. Case 4 Treatment • 55 year old man with HCV • Severe fibrosis 1 year pre-treatment • Relapse after PEGIFN and RBV • 6 months later • Concerned about the future

  28. Case 5 Treatment • 53 year woman with BMI=33 • NIDDM and HTN • ALT=68 g-GT=125 • 3 months later • BMI=28 ALT=72 on Pioglitazone Biopsy or Serum markers?

  29. The Future • Better markers • Reverse biology • Imaging • Composite tests

  30. 1 1 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Sensitivity (true positives) Sensitivity (true positives) 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1 1 1 1 - - Specificity (false positives) Specificity (false positives) Reverse Biology Proteomics Glycomics Metabonomics

  31. Other Tests for Fibrosis • Fibroelastogram • Ultrasound • Caution in obesity • Micro bubbles • Performed with imaging • Invasive • MRI • Additional information • Costly

  32. Composite Tests • Biopsy + • Non-invasive markers • Selective thresholds + • Imaging

  33. Summary • Liver biopsy • Hazardous, inaccurate • Serum Markers • Safe, Accurate • Are serum markers sufficient? • Correlate with histology • Predictive of long term outcome • Repeatable

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