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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 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

Liver FibrosisAre Non-invasive markers sufficient?

William Rosenberg

Prof of Hepatology

University of Southampton

CSO iQur Limited; Consultant to Bayer Healthcare

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

disadvantages of liver biopsy
Disadvantages of Liver Biopsy
  • Hazard to the patient
  • Resource usage
    • Bed
    • Imaging
    • Staff
    • Processing
  • Sampling Error
  • Interpretation

Time

liver biopsy
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
liver biopsy analysis
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
ideal markers of fibrosis
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
candidate approach

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Sensitivity (true positives)

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Specificity (false positives)

Specificity (false positives)

Candidate Approach
candidate biomarkers of fibrosis
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
elf markers rosenberg et al gastro dec 2004
ELF MarkersRosenberg et al. Gastro Dec 2004

Detection of Scheuer Stage 0,1,2 versus 3,4

high mid and low cut off srocs
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

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
f 0 1 versus the rest
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

f4 5 and 6 versus the rest
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

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

Biopsy or Serum markers?

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

Biopsy or Serum markers?

will we ever know
Will we ever know?

?

?

?

Moderate CV

Categorical

Excellent CV

Continuous

0.4

0.49

prognosis elf follow up

PrognosisELF Follow-up

Preliminary data from Southampton and Newcastle

Dr Julie Parkes

MRC Clinician Scientist

Carol Gough

clinical follow up of elf cohort
Clinical Follow up of ELF Cohort
  • 224 patients
  • 75% male
  • Hep C 45% ALD 19% Fat 13%
  • 62 F2-4
  • 26 Liver related outcomes
conclusion
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
case 3 prognosis
Case 3 Prognosis
  • 35 year old man
  • BMI=35 ALT=125
  • Concerned about his future

Biopsy or Serum markers?

assessment of treatment response

Assessment ofTreatment Response

Drug treatment

Drug development

treatment response poynard et al hepatology 2003 38 481 492
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
individual and group differences

Significant difference

Cumulative evidence of difference

Individual and Group Differences

NS

Biomarkers: continuous variable,

change determined by biology,

low cv, repeatable at high frequency

case 4 treatment
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
case 5 treatment
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?

the future
The Future
  • Better markers
    • Reverse biology
  • Imaging
  • Composite tests
reverse biology

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Sensitivity (true positives)

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Specificity (false positives)

Specificity (false positives)

Reverse Biology

Proteomics

Glycomics

Metabonomics

other tests for fibrosis
Other Tests for Fibrosis
  • Fibroelastogram
    • Ultrasound
    • Caution in obesity
  • Micro bubbles
    • Performed with imaging
    • Invasive
  • MRI
    • Additional information
    • Costly
composite tests
Composite Tests
  • Biopsy

+

  • Non-invasive markers
    • Selective thresholds

+

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