Liver stiffness measurement (Fibroscan®)Principles - indications - results - limitations

Samir Haffar M.D.Assistant Professor of Gastroenterology

Fibrose

Blood markers

FibroScan®

Imaging(US, MRI, endoscopy)

Hepatic biopsy

Biological work-up

Clinical Examination

Ideal non-invasive test for diagnosis of liver fibrosis

• Simple

• Reproducible

• Readily available

• Less expensive than biopsy

• Predicts full spectrum of fibrosis

• Reflects changes occurring with therapy

Evaluation of chronic liver injury according to health care level

Physical examination

Liver function tests

Serum Hyaluronate

APRI or other simple tests

Primary health care

Ultrasound

Fibroscan®

Serum markers & algorithms

Secondary health care

Fibroscan®

ARFI*

MR elastography*

Tertiary health care

Liver biopsy

HVPG

* Promising but currently under investigationARFI: Acoustic Radiation Force Impulse Imaging

HVPG: Hepatic Venous Pressure GradientCastéra L et al. Gut 2010 ; 59 : 861 – 866.

Liver stiffness

• Assessed by US (FibroScan®) & more recently by MRI

• Evaluates velocity of propagation of a shock wavewithin liver tissue (examines a physical parameter ofliver tissue which is related to its elasticity)

• Rationale Normal liver is viscousNot favorable to wave propagation Fibrosis increases hardness of tissueFavors more rapid propagation

Bedossa P. Liver Int 2009 ; 29 (s1): 19 – 22.

Fibroscan® device• Electronic platform

– Ultrasonic signals acquisition– Numerical signal processing

• Integrated computer– Stiffness measurement– Examinations database

• Dedicated probes with unique technology

Vibrator (50 Hz)US Transducer

(3,5 MHz)

Fibroscan® (Echosens, Paris, France)

Position of probe & explored volume

Cylinder of 1 cm wide & 4 cm longFrom 25 mm to 65 mm below skin surface

This volume is at least 100 times bigger than a biopsy sample

Results

Stiffness (kPa)Median value of 10 shots

3.9 Kilo Pascals

At least 10 shots Success Rate: ≥ 60%

IQR * (kPa)Interval around median

Contains 50% of valid shots≤ 25% of median value

Manufacturer’s criteria for LSM interpretation

• First step Number of shots ≥ 10

• Second stepSuccess rate ≥ 60 %

• Third step Interquantile range (IQR) ≤ 25%

Failure

Zero valid shot

Unreliable results

< 10 valid shots Success rate ≤ 60%

IQR ≥ 25%

Liver stiffness values in healthy subjects

429 subjects

Roulot D et al. J Hepatol 2008 ; 48 : 606 – 613.

5.2 ± 1.5 kPa 5.8 ± 1.5 kPa

p = 0.0002

Liver stiffness values in healthy subjectswith & without metabolic syndrome

Roulot D et al. J Hepatol 2008; 48 : 606 – 613.

5.3 ± 1.5 kPa 6.5 ± 1.6 kPa

p < 0.0001

Liver stiffness cut-offs in chronic liver diseases

F2

Sign

F3

Severe

F4

Cirrhosis

Matavir F0-F1

MildFibrosis

Castéra L et al. J Hepatol 2008 ; 48 : 835 – 847.

LSM 2.5 – 7 kPa → Mild or absent fibrosis is likely LSM > 12.5 kPa → Cirrhosis is likely

Progression of fibrosis in viral hepatitis Photomicrographs (magnification ×40; trichrome stains)

Faria SC et al. RadioGraphics 2009 ; 29 : 1615 – 1635.

F 0 F 1 F 2

F 3F 4

Perform LSM

≤ 6 kPa

No significant fibrosis

No biopsy

F0 F1F

Intermediate values

Grey area

Biopsy if resultsinfluence management

F2

Implementation of other NI tests

≥ 12 kPa

Advanced fibrosis

No biopsy

F4

Treatment or Follow-up

F3

Vizzutti et al. Gut 2009;58:156-60.

Shear wave propagation velocity according to severity of hepatic fibrosis (Metavir score)

Sandrin L. Ultrasound Med Biol 2003 ; 29 : 1705 – 1713.

E = 3.0 kPaF 0

E = 7.7 kPaF 2

E = 27 kPaF 4

Liver stiffness for each Metavir stage in CHC

Box-and-whiskers plot

Vertical axis is in logarithmic scale (wide range of F4 values)

Gastroenterology 2005; 28:343 – 350.Hepatology 2005;41:48 – 54.

Correlation between LSM & fibrosis stage

* Gastroentérol Clin Biol 2008;32,58-67.** J Hepatol 2009;49:1062-68, Aliment Pharmacol Ther 2008;28:1188-98.*** Hepatology 2010;51:454-62. Gastroentérol Clin Biol 2008;32:58-67.

Accuracy of a diagnostic test

• Dichotomous test (only 2 results)Sensibility (Sn)Specificity (Sp)Positive Predictive Value (PPV)Negative Predictive Value (NPV)Likelihood Ratios + & – (LRs) Diagnostic Odds Ratio (OR)

• Multilevel test (> 2 results)Receiver Operating Characteristic (ROC)

Newman TB & Kohn MA. Evidence-based diagnosis. Cambridge University Press, Cambridge, UK, 1st edition, 2009.

CIs

Hypothetical ROC curve

Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical decision rules. Blackwell’s publishing, West Sussex, UK, 2008.

Accuracy of diagnostic test using AUC of ROC

Value Accuracy

0.90 - 1.00 Excellent

Pines JM & Everett WW. Evidence-Based emergency care: diagnostic testing & clinical decision rules. Blackwell’s publishing – West Sussex – UK – 2008.

AUROC of a ‘‘good” test should be ≥ 0.80

0.80 - 0.90 Good

0.70 - 0.80 Fair

0.60 - 0.70 Poor

Meta-analysis of TE for staging liver fibrosis

Severe fibrosis (F3): 0.89(95% CI: 0.88 – 0.91)

Friedrich R et al. Gastroenterology 2008 ; 134 : 960 – 974.

Cirrhosis (F4): 0.94(95% CI: 0.93 – 0.95)

Cut-off value: 13.0 kPa

Significant fibrosis (F2): 0.84(95% CI: 0.82 – 0.86)Cut-off value: 7.7 kPa

50 studies – random effect – all type of CLD

Significance of wide range of LSM in cirrhosis13 - 75 kPa

Ascites

HCC ?

Variceal bleeding

Foucher J et al. Gut 2006 ; 55 : 403 – 408.

EV stage 2 or 3

26

Child-Pugh B or C

36 49 53 622.5 7513

Cumulative incidence of HCC based on LSM866 CHC – Mean follow-up 3 years

LSM: Liver Stiffness Measurement – HR: Hazard Ratio Masuzaki R et al. Hepatology 2009 ; 49 : 1954 – 1961.

LSM > 25 kPa HR 45.5 (p< 0.001)

LSM ≤ 10 kPa HR 010 < LSM ≤ 15 kPa HR 16.7 (p< 0.001) 15 < LSM ≤ 20 kPa HR 20.9 (p< 0.001) 20 < LSM ≤ 25 HR 25.6 (p< 0.001)

Reproducibility of TE in assessing hepatic fibrosis. Bland Altman Plot

Fraquelli M et al. Gut 2007 ; 56 : 968 – 973.

200 patients with chronic liver disease2 different operators within 3 days (800 exams)

8 patients scored outside limits of agreement

Upper limit

Lower limit

Mean 95% limit of agreement

Cost of FibroScan® versus liver biopsy

• Liver biopsy*Cost of liver biopsy 703 – 1 566 € in a French hospitalwith a one day observation period

• Fibroscan® ** FibroScan equipment 70 000 € Low running cost except probe calibration twice/year Cost per FibroScan exam 100 € with 150 exams annually

* Blanc J et al. Hepatol Res 2005 ; 32 : 1 – 8.** Canadian Agency for Drugs and Technologies in Health (CADTH).

Transient Elastography (FibroScan) for Non-invasive Assessment of Liver Fibrosis; 2006.

Liver biopsy size

• Because grading, & staging of nonneoplastic diffuseparenchymal liver disease is dependent on adequate sized biopsy, a biopsy of at least 2-3 cm in length & 16-gauge in caliber is recommended

• Presence of fewer than 11 complete portal tracts in pathology report may be incorrect in recognition of grading, & staging due to insufficient sample size

AASLD guidelines. Hepatology, 2009 ; 49 : 1017 – 1044.

Limitations of liver biopsy

• Sampling errorsExtremely small portion of liver (1/50 000)

• Intraobserver & interobserver variationEven when widely validated systems used for score

• Invasive procedureMorbidity: pain in 20% of patientsMajor complications: bleeding or hemobilia in 0.5%Mortality:

Grading & staging systems for chronic hepatitisIASL1 Batts–Ludwig2 Metavir3

1 Desmet VJ et all. Hepatology 1994;19:1513-1520.2 Batts KP et all. Am J Surg Pathol 1995;19:1409-1417.

3 Bedossa P et all. Hepatology 1996;24:289-293.

Grading system

Minimal activityMild activity

Moderate activityMarked activity

Marked activity & bridging

Grade 1Grade 2Grade 3Grade 4Grade 4

A1A2A3A3A3

Staging system

No fibrosisFibrous portal expansion

Few bridges or septaNumerous bridges

Cirrhosis

Stage 0Stage 1Stage 2Stage 3Stage 4

F0F1F2F3F4

(kappa 0.2 – 0.6)

(kappa 0.5 – 0.9)

kappa score ≥ 0.6 indicates good agreement

Interpretation of different values of kappa

Kappa from Greek letter κ

Value of kappa Strength of agreement

0 – 0.20 Poor

0.21– 0.40 Fair

0.41– 0.60 Moderate

0.61– 0.80 Good

0.81–1.00 Very good

Perera R, Heneghan C & Badenoch D. Statistics toolkit.Blackwell Publishing & BMJ Books, Oxford, 1st edition, 2008.

Liver biopsy is not the “gold standard”

but is the “best available gold standard”

Contraindications of liver biopsy

• Uncooperated patients • Disorders in coagulation profile• Severe ascites• Cystic lesions• Vascular tumors (hemangiomas)• Amiloidosis• Congestive liver disease

R0C curves for FibroScan, FibroTest, & APRI for cirrhosis (F0 – F3 vs F4)

Castera L et al. Gastroenterology 2005 ;128 : 343 – 50.Castera L et al. Lancet 2010 ; 375 : 1419 – 20.

Pitfalls of liver stiffness measurement

Obesity

Operator experience

Acute liver injury

Extrahepatic cholestasis

Increased CVP

Ascites

Narrow intercostal spaces

Obesity & operator experience

Limitations of liver stiffness measurement 13 369 examinations – 5 year prospective study – 5 operators

BMI > 30 kg/m2 (OR 7.5)

Operator experience (OR 2.5)

Age > 52 years (OR 2.3)

Type 2 diabetes (OR 1.6)

Failure (3%)

BMI > 30 kg/m2 (OR 3.3)

Operator experience (OR 3.1)

Age > 52 years (OR 1.8)

Female sex (OR 1.4)

Hypertension (OR 1.3)

Type 2 diabetes (OR 1.1)

Unreliable results (16%)

Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

LSM uninterpretable in one of five casesMain raisons: obesity ( WC) – operator experience

Failure rates according to BMI7261 patients at the time of first examination

Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

Unreliable results according to BMI 6968 patients at the time of first examination

Castéra L et al. Hepatology 2010 ; 51 : 828 – 835.

Feasibility of LSM with FibroScan® using XL probeNew probe for obese patients

de Lédinghen V et al. Liver International 2010 ; : 1043 – 1048.

60% not measured by M probe successfully measured by XL probe

Acute liver injury

Acute viral hepatitis increases liver stiffness

18 patients with acute viral hepatitis

I Peak increase in aminotransferaseII Aminotransferase ≤ 50% of the peakIII aminotransferase levels ≤ 2 ULN

Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

Acute viral hepatitis increases liver stiffness

18 patients with acute viral hepatitis

I Peak increase in aminotransferaseII Aminotransferase ≤ 50% of the peakIII aminotransferase levels ≤ 2 ULN

Arena U et al. Hepatology 2008 ; 47 : 380 – 384.

Extrahepatic cholestasis

Obstructive jaundice due to GIST occluding CBD

Millonig G et al. Hepatology 2008 ; 48 : 1718 – 1723.

Stent occlusionBilirubin 8 mg/dL Stiffness 10 kPa

Bilirubin 3.5 mg/dL Stiffness 5.7 kPaStent placement

Bilirubin 2 mg/dL Stiffness 5 kPa

Liver stiffness as a function of bile duct ligation10 German landrace pigs: 5 controls – 5 BD ligation

Millonig G et al. Hepatology 2008 ;48 : 1718 – 1723.

Control

4.6 kPa

120 min after

Bile duct

ligation

8.8 kPa

30 min after

decompression

6.1 kPa

Increased CVP

Representation of clamping site of the IVC5 German landrace pigs

Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

Experiment approved by local committee for Animal WelfareUniversity of Heidelberg – Germany

LSM after clamping & reopening of IVC5 anesthesized landrace pigs

Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

P < 0.001 P < 0.001

Before clamping

3.1 kPa

5 min after reopening

5.1 kPa

27.8 kPa

5 min after clamping

Liver stiffness directly influenced by CVP

10 patients with CHF before & after recompensation

Millonig G et al. J Hepatol 2010 ; 52 : 206 – 210.

Median 40.7 Median 17.8

p = 0.004

Ascites

Ascites in liver cirrhosis

Ascites grade 1: detectable only by ultrasound

Diagnosis of

cirrhosis

is obvious

Narrow intercostal spaces

Position of FibreScan® probe

Dorsal decubitus position Right arm in maximal abduction

Interpretation of the results of LSM should

always be done by expert clinicians according

to clinical context

Transient elastography in clinical practice

Examination quality 10 shots at least Success rate ≥ 60% IQR ≤ 25% of median value

Liver disease Not used in acute hepatitis Not used in acute exacerbation Not used in ascites & EH cholestasis

Choice of cutoff point Cutoffs different for each CLD Range of value rather than cutoff

De Lédinghen V et al. Gastroentérol Clin Biol 2008 ; 32 : 58 – 67.

Questions

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