liver fibrosis are non-invasive markers sufficient? william rosenberg prof of hepatology university...
TRANSCRIPT
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Liver FibrosisLiver FibrosisAre Non-invasive markers Are Non-invasive markers
sufficient?sufficient?
William Rosenberg
Prof of Hepatology
University of Southampton
CSO iQur Limited; Consultant to Bayer Healthcare
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Why measure fibrosis?Why measure fibrosis?
• Assessment of disease– Diagnosis– Prognosis– Treatment decisions
• Monitoring disease– Natural history– Treatment effects– Drug development
Cross-sectional
Dynamic change over time
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Liver BiopsyLiver BiopsyThe Reference Standard for The Reference Standard for
FibrosisFibrosis
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Disadvantages of Liver BiopsyDisadvantages of Liver Biopsy
• Hazard to the patient
• Resource usage– Bed– Imaging– Staff– Processing
• Sampling Error
• Interpretation
Time
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Liver biopsyLiver 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
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Liver biopsy analysisLiver biopsy analysis• Size
– Biopsy size reproducibility Bedossa et al. 2004
• Histological scoring– Inter observer variation =0.9 – 0.49– Interpretation experience Bedossa et al. 2005
• Image analysis– Automation
• More fields• Greater reproducibility
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Ideal markers of fibrosisIdeal 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
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Candidate ApproachCandidate Approach
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Candidate Biomarkers of FibrosisCandidate Biomarkers of Fibrosis
• Indirect: Indirect: Measures of liver functionMeasures of liver function– AST, ALT, GT, Apolipoprotein A1, bilirubin,
2-macroglobulin, haptoglobin, cholesterol– HOMA-IR– Platelets, PT
• Direct: Direct: ECM components and enzymesECM components and enzymes– HA, PIIINP, Collagen IV, Collagen VI, TIMP-1,
Laminin, YKL-40, Tenascin, Undulin, MMP-2
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ELF MarkersELF MarkersRosenberg et al. Gastro Dec 2004Rosenberg et al. Gastro Dec 2004
Disease AUC Score Sensitivity Specificity PPV NPV
NAFLD 0.87 0.375 89% 96% 80% 98%
0.462 78% 98% 87% 96%
ALD 0.944 0.087 100.0% 16.7% 75.0% 100.0%
0.431 93.3% 100.0% 100.0% 85.7%
HCV 0.773 0.067 90% 31% 27.5% 92.3%
0.564 30% 99% 89.5% 83.3%
Detection of Scheuer Stage 0,1,2 versus 3,4
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0%
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IMBERT ROSSI POYNARD LEROY WAI LE CALVEZ FORNS THABUT SUD ELF
Correct Incorrect Inaccurate
Panel Performance Panel Performance Applying High and Low ThresholdsApplying High and Low Thresholds
NPV~95% PPV~90%NPV~95% PPV~90%
Fibrotest APRI Forns BayerHA
PIIINP
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High, Mid and Low Cut-off SROCsHigh, Mid and Low Cut-off SROCs
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Detecting F3/4
Differentiating F2/3
Detecting F1/2
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
DOR 8.14 (3.61-18.38)
Sens. 40.1 Spec. 95
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Sufficient?Sufficient?
• Errors in liver biopsy– Expert opinion is flawed
• What matters?– Detecting Any fibrosis - F0,1 vs rest– Detecting Advanced fibrosis - F4,5,6
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F 0,1 versus the restF 0,1 versus the rest
1.00.90.80.70.60.50.40.30.20.10.0
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Validation data ROC Curve
AUC=0.791 AUC=0.791 (95% CI: 0.720, 0.862)
p<0.001
Notts HCV CohortSee Parkes et al.
Poster 160 BSG 2006
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F4, 5 and 6 versus the restF4, 5 and 6 versus the rest
1.00.90.80.70.60.50.40.30.20.10.0
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Validation data ROC Curve
AUC=0.860 AUC=0.860 (95% CI: 0.804, 0.916),
p<0.001
Notts HCV CohortSee Parkes et al.
Poster 160 BSG 2006
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Case 1 DiagnosisCase 1 Diagnosis
• 35 year old Female G3 HCV for 10 years
• Normal LFTs and USS
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Case 2 DiagnosisCase 2 Diagnosis
• 45 year Male G1 HCV
• 5 spiders, ? Palpable spleen
• Normal Bilirubin Albumin Platelets
• US normal
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0.490.4
Excellent CVContinuous
Moderate CVCategorical
? ?
Will we ever know?Will we ever know??
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PrognosisPrognosisELF Follow-upELF Follow-up
Dr Julie Parkes
MRC Clinician Scientist
Carol Gough
Preliminary data from Southampton and Newcastle
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Clinical Follow up of ELF CohortClinical Follow up of ELF Cohort
• 224 patients
• 75% male
• Hep C 45% ALD 19% Fat 13%
• 62 F2-4
• 26 Liver related outcomes
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Diagnosed F3,4 DS .102 Bx
Sensitivity 84.6 80.7
Specificity 27.3 31.8
PPV 28.9 25.0
NPV 97.3 96.4
Prediction of MortalityPrediction of Mortality
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ConclusionConclusion
• 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
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Case 3 PrognosisCase 3 Prognosis
• 35 year old man
• BMI=35 ALT=125
• Concerned about his future
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Assessment Assessment ofof
Treatment ResponseTreatment Response
Drug treatment
Drug development
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Treatment responseTreatment responsePoynard et al Hepatology 2003;38:481-492Poynard 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
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Individual and Group DifferencesIndividual and Group Differences
NS
Significant difference
Cumulative evidence of difference
Biomarkers: continuous variable, change determined by biology,low cv, repeatable at high frequency
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Case 4Case 4 Treatment 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
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Case 5 TreatmentCase 5 Treatment
• 53 year woman with BMI=33
• NIDDM and HTN
• ALT=68 -GT=125
• 3 months later
• BMI=28 ALT=72 on Pioglitazone
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The FutureThe Future
• Better markers– Reverse biology
• Imaging
• Composite tests
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Reverse BiologyReverse Biology
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ProteomicsProteomicsGlycomicsGlycomicsMetabonomicsMetabonomics
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Other Tests for FibrosisOther Tests for Fibrosis
• Fibroelastogram– Ultrasound – Caution in obesity
• Micro bubbles– Performed with imaging– Invasive
• MRI– Additional information– Costly
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Composite TestsComposite Tests
• Biopsy
+
• Non-invasive markers– Selective thresholds
+• Imaging
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SummarySummary
• Liver biopsy– Hazardous, inaccurate
• Serum Markers– Safe, Accurate
• Are serum markers sufficient?– Correlate with histology– Predictive of long term outcome– Repeatable