Post on 12-Jan-2016
Non-invasive methods to assess hepatic fibrosis
MIRELLA FRAQUELLI MD PhD - DARIO CONTE MD
Gastroenterology and Endoscopy UnitFondazione IRCCS “Cà Granda”
Ospedale Maggiore Policlinico – Milano
Department of Pathophysiology and TransplantationUniversità degli Studi – Milano, Italy
Rome – June 19, 2015
Serum markers and clinical scores
Transient elastography
Acoustic Radiation Force (ARFI), Shear Wave Elastography (SWE) …
Non - invasive methods to assess hepatic fibrosis
DIRECT They are directly linked to changes in
extracellular matrix turnover occurring during
fibrogenesis
INDIRECT They reflect the derangement of hepatic
function, but not the
extracellular matrix metabolism
Serum markers to assess hepatic fibrosis
SERUM BIOMARKERS TO ASSESS FIBROSIS IN CLD – HCV ( I )
FIBROTEST : a-2-macroglobulin gGT, apolipoprotein A1, haptoglobin, bilirubin, age, gender
FORNS INDEX : age, platelet count, cholesterol, GGT
AST TO PLATELET RATIO (APRI) : AST , platelet count
FIBROSPECT : a-2-macroglobulin, hyaluronate, TIMP-1
LOK INDEX : platelet count, AST/ALT ratio, INR
MP3 : MMP-3, TIMP-1
ELF (Enhanced Liver Fibrosis score) : age, hyaluronate, MMP-3, TIMP-1
SERUM BIOMARKERS TO ASSESS FIBROSIS IN CLD – HCV ( II )
GUCI (Gotebörg University Cirrhosis Index) : AST, INR , platelet count
VIRAHEP – C MODEL : AST, platelet count, alkaline phosphatase, age
FIBROINDEX : platelet count, AST, gamma-globulin
FIB-4 : platelet count, ALT , AST
HALT-C MODEL : hyaluronic acid, TIMP-1, platelet count
HEPASCORE : bilirubin, GGT, hyaluronate, a-2-macroglobulin, age, gender
FIBROMETERS : platelet count, prothrombin index, AST, a-2-macroglobulin, hyaluronate, urea, age
SERUM BIOMARKERS TO ASSESS FIBROSIS IN CLD – HBV
Fibrotest : a-2-macroglobulin gGT, apolipoprotein A1, haptoglobin, bilirubin, age, gender
Hui score : BMI, bilirubin, platelet count and albumin
Zeng score : age, a-2-macroglobulin, hyaluronate and GGT
AST to Platelet Ratio (APRI) : AST , platelet count
Serum Panel F>2 (%)
Cut off Sens Spec LR+ LR- AUROC
Fibrotest 80 >0.48 75 85 5.0 0.3 0.87
Forns’ index 26 < 4.2 > 6.9 94-31 51-95 1.9-6 0.1-0.7 0.81
APRI 50 <0.5 > 1.5 91-41 47-95 1.7-8.2 0.2-0.6 0.80
Fibrospect 52 >0.36 77 73 2.9 0.3 0.83
Hepascore 57 >0.5 63 89 5.7 0.4 0.82
Fibrometer 56 NA 80 84 5.0 0.2 0.89
Fibroindex 50 <1.25 >2.25 40-30 97-97 10-13.3 0.6-0.2 0.83
Serum biomarkers in chronic hepatitis C
for diagnosing F >2
Optimal diagnostic test LR+ > 10 and LR- < 0.1
Serum Panel F>2 (%)
Cut off Sens Spec LR+ LR- AUROC
Fibrotest 14 >0.74 63 84 4.0 0.4 0.82
APRI 17 < 1.0 > 2.0 89-57 75-93 3.6-8.1 0.1-0.5 0.89
FiB-4 17 <1.45 > 3.35
74-38 81-98 3.9-19 0.3-0.6 0.85
Lok index 38 < 0.2 > 0.5 98-40 53-99 2.1- 40 0.04-0.6 0.81
NFS 27 ≤ 1.455 > 0.676
77-43 97-97 10-13.3 0.6-0.7 0.82
Hepascore 16 >0.84 71 8.9 6.5 0.3 0.89
HALT-C 38 < 0.2 > 0.5 88-47 45-92 1.6-5.9 0.3-0.6 0.81
Serum biomarkers in chronic hepatitis C
for diagnosing F=4
Optimal diagnostic test LR+ > 10 and LR- < 0.1
Pros Cons
Good reproducibility Not specific for the liver
High applicability Unable to discriminate intermediate stages of fibrosis
Well validated Cost and limited availability (patented)
Can be performed in outpatients
Limitations (hemolysis , inflammation, Gilbert’s syndrome..)
Serum biomarkers in HBV or HCV CLD
Elastography - Key features
Manual compression
Acoustic Radiation Force (ARFI)
Mechanical stimulationNo imaging
Absolute quantification(shear wave technology)
Absolute quantification
STRAIN IMAGINGPOINT QUANTIFICATIONSHEARWAVE
QUANTIFICATIONKPa, m/s
2DSHEARWAVE IMAGING
(SWE)
TRANSIENT ELASTOGRAPHY
KPa, m/s
Elastography
Qualitative / Relative quantification
Elastography - Key features
Manual compression
Acoustic Radiation Force (ARFI)
Mechanical stimulationNo imaging
Absolute quantification(shear wave technology)
Absolute quantification
STRAIN IMAGINGPOINT QUANTIFICATIONSHEARWAVE
QUANTIFICATIONKPa, m/s
2DSHEARWAVE IMAGING
(SWE)
TRANSIENT ELASTOGRAPHY
KPa, m/s
Elastography
Qualitative / Relative quantification
US transducer: 3.5 MHz
Vibrator: mild amplitude and low frequency (50 Hz) elastic waves
Propagation speed of elastic waves: directly related to tissue stiffness
TE – Physical principles and functioning
Transient elastography (TE): a rapid, non-invasive
technique conceived to evaluate hepatic fibrosis by
measuring liver stiffness.
The stiffer the tissue, the faster the shear wave propagatesThe stiffer the tissue, the faster the shear wave propagates
TE – Results
De
pth
(m
m)
Time (ms)
De
pth
(m
m)
Time (ms)
De
pth
(m
m)
Time (ms)
TE – Examination
ProbeExplored volume
TE: 1/500 of the liver total mass
Liver biopsy: 1/50000 of the liver total mass
TE – Reproducibility and normal values
200 consecutive patients with CLD of various etiologies were concurrently assessed by TE and liver biopsy (800 measurements performed )
Inter-observer agreement: 0.98
(95% CI: 0.977–0.987)
Rater 1
0
10
20
30
40
50
60
70
80
0 10 20 30 40 50 60 70 80
Determination 1
Dete
rmin
ati
on
2
Intra-observer agreement: 0.98
Intra-observer agreement: 0.98
Transient elastography − Reproducibility
Fraquelli et al, Gut. 2007
0
10
20
30
40
50
60
70
80
0 10 20 30 40 50 60 70 80
Rater 1
Rate
r 2
TE – Normal values
Del Poggio et al, WJG 2009
Coperchot Roulot Colombo
Subjects, n 71Healthy
volunteers
429Medical check-up
327Blood donors
Mean stiffness (Kpa)
4.8(2.5-6.9)
5.4±1.5 4.9±1.7
95th centile - 8.6 7.8
Age No effect No effect No effect
Gender M> F M> F M> F
High BMI Increased Increased Increased
Metabolic syndrome
- Increased -
Fatty liver - - Increased
TE - Applicability and limitations
TE − Applicability
Contraindications
Pregnant women
Patients with implantable devices (pacemaker or defibrillator)
Failure of examination (3-5%)
Ascites
Narrow intercostal spaces
BMI >28 kg/m2 in 2114 patients °
BMI >30 kg/m2 in 13369 examinations *
Independent factor for failure:
° Foucher et al, Eur J Gastroenterol Hepatol 2006 * Castera et al, Hepatology 2010
Overweight / obesity
TE - Unreliable results
IQR/LSM >30%
9.2%
SR <60%
8.1%
15.8%
Castera et al, Hepatology 2010
13369 EXAMINATIONS
IQR/LSM >30%
12.8%
SR <60%
3.2%
18.3%
Colombo et al, Dig Liver Dis 2011
923 BLOOD DONORS
• LIVER CONGESTION
• INFLAMMATION
• EXTRA – HEPATIC CHOLESTASIS
• STEATOSIS
• PRIMARY LYMPHANGECTASIA
Features influencing TE
TE – Diagnostic performances in the assessment of liver fibrosis
TE − Correlation with liver fibrosis
Ziol et al, Hepatology 2005 Castera et al, Gastroenterology 2005
• However, there is a substantial overlap of TE results between adjacent stages of liver fibrosis.
• TE results significantly correlate with liver fibrosis stage: correlation coefficients ranging from 0.55 to 0.84.
TE performance in diagnosing F≥2 in HCV
Author, yr Etiology Patient #
Cut-off kPa
Sensitivity %
Specificity %
-LR +LR AUROC
Ziol, 2005 HCV 251 8.6 56 91 0.48 6.6 0.79
Castera, 2005 HCV 183 7.1 67 89 0.37 6.0 0.83
Coco, 2007 HCV-HBV 228 8.3 85 91 0.16 9.4 0.93
Fraquelli, 2007 mixed 200 7.9 72 84 0.30 4.6 0.86
Arena, 2008 HCV 150 7.8 83 82 0.20 4.6 0.91
Lupşor, 2008 HCV 324 7.4 76 84 0.30 4.6 0.86
Degos, 2010 mixed 1307 5.2 90 32 0.30 1.3 0.75
Zarski, 2012 HCV 382 5.2 97 35 0.08 1.4 0.82
Optimal diagnostic test LR+ > 10 and LR- < 0.1
Author, yrEtiolog
yDisease
prev (%)
Patient #
Cut-off,kPa
Sens (%)
Spec (%)
-LR +LRAURO
C
Ziol, 2005 HCV 19 251 14.6 86 96 0.14 23.0 0.87
Castera, 2005 HCV 25 183 12.5 87 91 0.14 9.7 0.95
Ganne-Carrié 2006
Mixed 15 775 14.6 79 95 0.11 15.8 0.95
Coco, 2007HCV-HBV
20 159 14.0 78 98 0.22 39 0.96
Fraquelli, 2007 Mixed 18 200 12.0 91 89 0.10 8.2 0.90
Arena, 2008 HCV 19 150 14.8 94 92 0.07 11.3 0.98
Lupşor, 2008 HCV 21 324 11.8 87 91 0.14 9.4 0.94
Zarski, 2012 HCV 15 382 12.9 77 90 0.25 7.7 0.93
TE in diagnosing HCV - cirrhosis
Optimal diagnostic test LR+ > 10 and LR- < 0.1
TE performance in diagnosing F≥2 in HBV
Author, yr Patient #
Cut-off kPa
Sensitivity %
Specificity %
-LR +LR AUROC
Coco 2007 228 8.3 85 91 0.2 9.4 0.93
Olivieri 2008 188 7.5 94 88 0.06 7.8 0.97
Marcellin 2009 173 7.2 70 83 0.3 3.4 0.81
Wang 2009 88 8.0 80 77 0.2 3.4 0.86
Degos 2010 284 5.2 89 38 0.5 1.4 0.78
Sporea 2010 140 7.0 65 59 0.6 5.9 0.65
Cordoso 2012 202 7.2 74 88 0.2 6.1 0.87
Goyal 2013 357 6.0 82 67 0.2 3.5 0.84
Optimal diagnostic test LR+ > 10 and LR- < 0.1
TE performance in diagnosing F=4 in HBV
Author, yr Patient #
Cut-off kPa
Sensitivity %
Specificity %
-LR +LR AUROC
Coco 2007 228 14.0 78 98 0.2 39 0.96
Olivieri 2008 188 11.8 86 96 0.04 21 0.97
Marcellin 2009 173 11.0 93 87 0.08 7.1 0.93
Wang 2009 88 10.0 85 88 0.1 7.0 0.89
Degos 2010 284 12.9 52 93 0.5 7.4 0.85
Sporea 2010 140 13.6 86 99 0.1 86 0.97
Cordoso 2012 202 11.0 75 90 0.1 7.5 0.93
Goyal 2013 357 9.0 81 90 0.2 8.1 0.93
Optimal diagnostic test LR+ > 10 and LR- < 0.1
FIBROSTIC study (France, 2006–2008).ROC curves of non-invasive liver fibrosis tests
to diagnose F≥2 and F=4 in 1307 patients
Degos et al, J Hepatol 2010
F≥2 F=4
BORDEAUX ALGORITHM
Castera et al. Gastroenterology 2005Castera et al. J Hepatol 2010
AUROC
F>2 0.91 (0.86-0.96)F=4 0.93 (0.90-0.96)
Sequential diagnostic algorithms
TE – Monitoring of disease progression
Foucher et al, Gut 2006
Monitoring disease progression by TE
14 27.5 49.1 53.7 62.7 75 kPa F=4 EV Ascites HCC EV bleeding
Does TE and Fibrotest have a prognostic value in the context of cirrhosis?
MULTIVARIATE ANALYSISHR (95% CI) P value
LIVER BIOPSY 2.6 (1.8–3.8) .0001TE 44 (15–127) .0001FIBROTEST 90 (15–549) .0001APRI 2.8 (1.6-4.7) .0002
Vergniol et al. Gastro 2012
Does TE have a prognostic value in the context of CLD?
Robic et al. J Hepatol 2011
Performances of LS and HVPG for the prediction of PH-related complications
All Cirrhotics
Elastography - Key features
Manual compression
Acoustic Radiation Force (ARFI)
Meccanic stimulationNo imaging
Absolute quantification(shear wave technology)
Absolute quantification
STRAIN IMAGINGPOINT QUANTIFICATIONSHEARWAVE
QUANTIFICATIONKPa, m/s
2DSHEARWAVE IMAGING
(SWE)
TRANSIENT ELASTOGRAPHY
KPa, m/s
Elastography
Qualitative / Relative quantification
PSWE (ElastPQ) - Reproducibility
Baccarin et al. FISMAD 2015
150 CLD patients : ICC 0.87 (95% CI 0.82- 0.90)
Learning curve
Acoustic Radiation Force Impulse (ARFI- PSWE) Volume measured: 10 mm long and 6 wide
Author, yr Etiology Patient #
Cut-off m/sec
Sensitivity %
Specificity %
-LR +LR AUROC
Lupsor 2009 HCV 112 1.34 67 92 0.3 9.4 0.86
Friedrich Rust 2012
HBV 92 1.39 50 90 0.5 5.1 0.73
Yoon 2012 mixed 204 1.13 58 84 0.5 3.6 0.74
Sporea 2013 mixed 332 1.34 75 69 0.3 2.4 -
Cassinotto 2014 mixed 349 1.51 72 81 0.3 3.7 0.81
Diagnosis of F≥2
Acoustic Radiation Force Impulse (ARFI-PSWE)
Volume measured: 10 mm long and 6 wide
Author, yr Etiology Patient #
Cut-off m/sec
Sensitivity %
Specificity %
-LR +LR AUROC
Lupsor 2009 HCV 112 2.0 80 95 0.2 17 0.93
Piscaglia 2011mixed 70 1.7 81 88 0.2 7.0 0.91
Xe 2012 HBV 204 1.88 95 91 0.05 12 0.97
Sporea 2013 mixed 332 1.8 86 77 0.1 3.7 -
Cassinotto 2014 mixed 349 2.2 81 77 0.2 3.5 0.84
Diagnosis of F=4
ARFI vs TE : meta-analysis
Bota et all. Liver Int 2013
Technique Fibrosisstage
Sens Spec LR+ LR- AUROC
TE F>2 0.78(9.72-0.83)
0.84(0.75-0.90)
4.8(2.9-7.8)
0.26(0.1-0.3)
0.87(0.83-0.89)
ARFI F>2 0.74 (0.66-0.80)
0.83 (0.85-0.89)
4.2(2.8-6.3)
0.31(0.2-0.4)
0.85(0.82-0.88)
TE F=4 0.89(0.80–0.94)
0.87(0.82-0.91)
6.7(4.7–9.8)
0.13 (0.07–0.2)
0.93(0.91-0.95
ARFI F=4 0.87 (0.79–0.92)
0.87(0.81–0.91)
6.4(4.4–9.4)
0.15 (0.09–
0.2)
0.93 (0.91–0.95)
Cumulative diagnostic estimates
Shear wave elastography (SWE/PSWE)
Study Cut off Sens Spec LR+ LR- AUROC
Ferraioli 2012(SWE)
7.1 90 97 7.2 0.1 0.92(0.85-0.96)
Sporea 2014(SWE)
7.8 76 82 4.2 0.2 0.86
Ferraioli 2014 (PSWE)
5.7 62 92 7.4 0.4 0.80 (0.71-0.87)
Diagnosis of F≥2
Shear wave elastography (SWE/PSWE)
Study Cut off Sens Spec LR+ LR- AUROC
Ferraioli 2012(SWE)
10.4 87 97 27 0.1 0.98(0.93-1)
Sporea 2014(SWE)
11.5 80 93 11.4 0.2 0.91
Ferraioli 2014*(PSWE)
7.2 90 88 7.9 0.1 0.95 (0.89-0.99)
Diagnosis of F=4
PROSTE vs ARFI vs SWE
TE ARFI SWE
- Short learning curve
- Good reproducibility
- High range of value (2- 75 KPa)
- Quality criteria well defined
-Prognostic value for cirrhosis
- Implemented on regular US devices
- ROI smaller than TE but chosen by the operator
- Higher applicability than TE (ascites, obesity)
- Performances equivalent to that of TE
- Implemented on regular US devices
- ROI can be adjusted in size and chosen by the operator
- High range of value (2-150 KPa)
- Performances may be higher than TE for F>2
CONSTE vs ARFI vs SWE
TE ARFI SWE
- Dedicated device
-ROI cannot chosen
-Unable to discriminate between intermediate stages of fibrosis
-Low applicability (80%) (obesity, ascites..)
-FP in case of acute hepatitis, extra hepatic cholestasis, vascular congestion
- Ongoing validation
- Unit different from that of TE (m/sec)
- Unable to discriminate between intermediate stages of fibrosis
-Narrow range of values (0.5-4 m/sec)
-Influence of inflammation?
-Prognostic value in cirrhosis ?
- Ongoing validation
-Limited data on reproducibility
- Unable to discriminate between intermediate stages of fibrosis
-Learning curve ?-Quality criteria ?
-Influence of inflammation?
-Prognostic value in cirrhosis ?
TE – Assessment of spleen stiffness
113 patients with HCV related cirrhosis underwent : TE, HVPG and LB
Colecchia et al Gastro 2012
TE – Assessment of spleen stiffness (SS) and portal hypertension (PH)
Study Cut off Sens Spec LR+ LR- AUROC
Stefaneuscu 2011
46 83 71 2.8 0.2 0.78
Colecchia 2012
4155
9871
6696
2.916.8
0.020.2
0.94(0.90-0.98)
Calvaruso 2013
50 65 61 1.7 0.6 0.70
Fraquelli 2014
4865
10091
6080
2.54.5
0.010.1
0.90(0.79-100)
Sharma 2014
41 94 76 3.9 0.08 0.89(0.84-0.95)
SS and the diagnosis of EV
No events (n=43; 54%) Clinical decompensatio
n (n=26; 32%)
Other events without previous
decompensation(n=11; 14%)
Events occurred during a 2 years f-up period
80 HCV patients
SS and LS for clinical complications in compensated cirrhotics - A prospective
study.
Colecchia et al. J Hepatol 2014
Risk of clinical decompensation Cox regression analysis
Variable
Univariate Multivariate
HR (95%CI) p HR (95%CI)
p β Std error β
HVPG 1.21 (1.11-1.32)
<0.0001 - - - -
LS 1.06 (1.03-1.08)
<0.0001 - - - -
SS 1.09 (1.05-1.13)
<0.0001 1.08 (1.04-1.13)
<0.0001
0.081 0.020
MELD 1.63 (1.26-2.10)
0.0002 1.43 (1.07-1.91)
0.0160 0.357 0.148
LS = liver stiffness; SS = spleen stiffness Colecchia et al. J Hepatol 2014
• TE is a user-friendly and reproducible technique that
accurately predicts cirrhosis in patients with CLD
• It is less accurate in diagnosing significant fibrosis when
used as single diagnostic non-invasive tool
• Newly developed US-based elastographic techniques
(ARFI etc.) showed similar diagnostic accuracy in
fibrosis staging but further validation is needed
TE − Conclusions ( I )
• Given its prognostic value TE could be used to
better categorize patients with cirrhosis and assign
them to different classes of risk for clinically
relevant outcomes
• Spleen stiffness measurement allow a reliable
prediction of the presence of EV and of hepatic
decompensation.
TE − Conclusions ( II )
Acknowledgements
I would thank Francesco Di Mario, MD and Ludovico
Abenavoli, MD for the kind invitation and all of you
for having attended this lecture, which is dedicated to
all my Colleagues, daily involved in taking care
of difficult patients.