Non-invasive methods to assess hepatic fibrosis MIRELLA FRAQUELLI MD PhD - DARIO CONTE MD Gastroenterology and Endoscopy Unit Fondazione IRCCS “Cà Granda”

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


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


Manual compression


Mechanical stimulationNo imaging





2DSHEARWAVE IMAGING

(SWE)


KPa, m/s

Elastography


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


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


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


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


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


Manual compression


Meccanic stimulationNo imaging





2DSHEARWAVE IMAGING

(SWE)


KPa, m/s

Elastography


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


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


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)


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)


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.

Thank you for your attention!

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Non-invasive methods to assess hepatic fibrosis MIRELLA FRAQUELLI MD PhD - DARIO CONTE MD Gastroenterology and Endoscopy Unit Fondazione IRCCS “Cà Granda”