serum marker

4th AISF POST-MEETING COURSE
“Unmet Clinical Needs in Hepatology”
Auditorium, Centro Congressi Frentani
Course Directors: M. Fraquelli, Milan and G. Missale, Parma
Noninvasive diagnostic tools for
staging liver disease: serological
markers
Fabio Marra
Dipartimento di Medicina Interna
Università di Firenze
Chronic liver diseases:
Markers of disease progression
Imaging: US, CT, MRI
Serum Markers
Stiffness
HVPG
Liver Biopsy: 1:50,000 of liver tissue
Progression of chronic hepatitis and the
METAVIR score
F0
No fibrosis
F1
Fibrosis
without septa
F2
Few septa
F3
F4
Numerous
Numerous
septa
septa
NO cirrhosis WITH cirrhosis
“SIGNIFICANT” FIBROSIS
CIRRHOSIS
“SIMPLE” STEATOSIS
IDENTIFICATION OF
PATIENTS WITH NAFLD
STEATOHEPATITIS
DIFFERENTIATION OF
NAFLD FROM NASH
EVALUATION
OF FIBROSIS
CIRRHOSIS
Hepatic decompensation
HEPATOCELLULAR CARCINOMA
DEATH
What we would like to have from a noninvasive tool
1. Diagnostic accuracy >0.8 for advanced fibrosis
2. Diagnostic accuracy >0.9 for cirrhosis
3. Ability to detect major changes in fibrosis (e.g. >2
METAVIR stages)
4. Correlate with long-term clinical outcomes
5. Applicability across different types of liver diseases
6. Known profile in control subjects
7. Possibility to be combined with other staging
modalities to build an algorithm
Gressner et al., World J Gastroenterol 2009; 28:2433
Mann & Marra, J Hepatol 2010; 52:949
Currently available serum markers
Indirect markers
Direct markers
Combination markers
Indirect markers of liver fibrosis
Alterations in liver function that do not
necessarily reflect extracellular matrix
metabolism
e.g.:
platelet count
AST
INR
γGT
bilirubin
albumin
cholesterol
Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
Predicting clinical outcomes with standard
laboratory tests in chronic hepatitis C
Ghany et al., Gastroenterology 2010;138:136
Ghany et al., Gastroenterology 2010;138:136
Direct markers of liver fibrosis
Tests that reflect the actual extracellular
matrix turnover within the liver:
e.g.:
Procollagen III N-terminal peptide
Type IV collagen
Hyaluronic acid
YKL-40
Matrix metalloproteases (MMPs)
Tissue inhibitors of metalloproteases (TIMPs)
Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95
ELF panel in NASH
12.
#
#
ELF Score
*
*
10.
8.
indeterminate
avoid bx incorrectly
0
1
2
3
4
Fibrosis Stage (Kleiner)
avoid bx correctly
Guha et al. Hepatology 2008;47:455
Nobili et al. Gastroenterology 2009;136:160
Serum Fibrosis Markers, Fibrosis Stage,
and Liver Collagen Content
Stage
3
Collagen .0205
6
.0112
6
.0521
Some DIRECT fibrosis
markers correlate better with
the presence of cirrhosis than
with hepatic collagen content
Fontana et al., Hepatology 2008;47:789
Biochemical markers: interpretative issues
“SPECTRUM BIAS” Over-representation of extreme
stages (F0-F4) leads to higher sensitivity and specificity
“DISCORDANT CASES”: Failure of the marker or failure
of the biopsy?
Biochemical markers: interpretative issues
1.- MILD/NO FIBROSIS vs. SIGNIFICANT FIBROSIS:
MEDIAN AUC = 0.77
2.- CIRRHOSIS vs. NON CIRRHOSIS: MEDIAN
AUC = 0.87
Inaccuracy of biopsy affects marker perfomance
When errors in the diagnostic test and the gold
standard are independent, the observed
sensitivity and specificity of the diagnostic test
will be underestimated
Mehta et al., J Hepatol 2009;50:36
Algorythms?
SAFE biopsy for significant fibrosis (> F2)
Castera et al., J Hepatol 2010;52:191
The Castera algorythm for significant fibrosis
Castera et al., J Hepatol 2010;52:191
In search for a better standard
Performance of serum markers in
alcoholic liver disease
<0.32
>0.32, <0.58
>0.58
AUROC 0.83±0.03
Clinical outcomes as
“reference standard” for
biomarker development
Naveau et al., Hepatology 2009;49:97
The ELF panel predicts decompensation
after OLT
Carrion et al., Gastroenterology 2010;138:147
ELF test can predict clinical outcomes
Parkes et al., Gut 2010;59:1245
Parkes et al., Gut 2010;59:1245
Genes instead of biochemical markers?
A 7 gene signature identifies the risk of
developing cirrhosis during chronic hepatitis C
Huang et al., Hepatology 2007;46:297
Marcolongo et al., Hepatology 2009;
General considerations on
serum markers of fibrosis
Minimal (F0-F1) vs. significant (≥ F2) fibrosis:
Detection of advanced (≥F3) fibrosis:
Detection of cirrhosis:
☺
☺
Stepwise differentiation of fibrosis stages:
Fibrogenic process monitoring:
Selection of patients to be biopsied
☺
☺
Schuppan & Afdhal, Lancet 2008;371:838
Biopsy
Clinical
evaluation
Imaging
Patient
categorization
Follow-up with
noninvasive
markers
Serum markers
Unstable
Fibroscan
Repeat biopsy
Stable
Assessment of fibrosis progression and
regression in different disease stages
HVPG
Stage at liver biopsy
Biopsy (TJLB?) + morphometry
Liver stiffness
Liver stiffness
Biochemical markers
Biochemical markers?
COMPENSATED CIRRHOSIS
F0
F1
F2
F3
F4
or
HVPG > 5 mmHg
HVPG < 10 mmHg
The need for a ‘dynamic’ serum marker
1. Not for cross-sectional staging or diagnosis
2. Sensitive to rapid changes in fibrogenesis and/or
fibrolysis
3. Possibly related to ECM turnover
4. Specific for a given chronic liver disease
Massimo Pinzani
Umberto Arena
Francesco Vizzutti
Stefania Moscarella
Cristina Stasi
Giacomo Laffi
Stefano Colagrande