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

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Presentation on theme: "Liver Fibrosis Are Non-invasive markers sufficient? William Rosenberg Prof of Hepatology University of Southampton CSO iQur Limited; Consultant to Bayer."— Presentation transcript:

1 Liver Fibrosis Are 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 Biopsy The 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  reproducibility Bedossa et al Histological scoring –Inter observer variation  =0.9 – 0.49 –Interpretation  experience Bedossa et al 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 Candidate Approach

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

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11 ELF Markers Rosenberg et al. Gastro Dec 2004 Disease AUC ScoreSensitivitySpecificityPPVNPV NAFLD %96%80%98% %98%87%96% ALD %16.7%75.0%100.0% %100.0% 85.7% HCV %31%27.5%92.3% %99%89.5%83.3% Detection of Scheuer Stage 0,1,2 versus 3,4

12 Panel Performance Applying High and Low Thresholds NPV~95% PPV~90% Fibrotest APRI Forns Bayer HA PIIINP

13 High, Mid and Low Cut-off SROCs Detecting F3/4 Differentiating F2/3 Detecting F1/2 DOR 6.52 ( ) Sens spec DOR 6.39 ( ) Sens Spec DOR 8.14 ( ) Sens Spec. 95

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

15 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

16 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

17 Case 1 Diagnosis 35 year old Female G3 HCV for 10 years Normal LFTs and USS

18 Case 2 Diagnosis 45 year Male G1 HCV 5 spiders, ? Palpable spleen Normal Bilirubin Albumin Platelets US normal

19 Excellent CV Continuous Moderate CV Categorical ? ? Will we ever know? ?

20 Prognosis ELF Follow-up Dr Julie Parkes MRC Clinician Scientist Carol Gough Preliminary data from Southampton and Newcastle

21 Clinical Follow up of ELF Cohort 224 patients 75% male Hep C 45% ALD 19% Fat 13% 62 F Liver related outcomes

22 Diagnosed F3,4DS.102Bx Sensitivity Specificity PPV NPV Prediction of Mortality

23 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

24 Case 3 Prognosis 35 year old man BMI=35 ALT=125 Concerned about his future

25 Assessment of Treatment Response Drug treatment Drug development

26 Treatment response Poynard et al Hepatology 2003;38: Not accurate for individual patients Changes in biomarkers correlate with changes in histology for cohorts Use in evaluating trials warrants further studies

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

28 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

29 Case 5 Treatment 53 year woman with BMI=33 NIDDM and HTN ALT=68  -GT=125 3 months later BMI=28 ALT=72 on Pioglitazone

30 The Future Better markers –Reverse biology Imaging Composite tests

31 Reverse Biology ProteomicsGlycomicsMetabonomics

32 Other Tests for Fibrosis Fibroelastogram –Ultrasound –Caution in obesity Micro bubbles –Performed with imaging –Invasive MRI –Additional information –Costly

33 Composite Tests Biopsy + Non-invasive markers –Selective thresholds + Imaging

34 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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