Non-invasive assessment of liver fibrosis

Victor de Lédinghen MD PhD Bordeaux

France

Madrid 30 May 2012

Summary

Why?

How?

When?

Cirrhosis Normal liver

Hepatocellular carcinoma

Transplantation

Why?

Treatment Severity of cirrhosis

Prognosis

How?

Blood sample?

Liver stiffness?

FibroScan ARFI

Blood tests in HIV patients

APRI

FIB-4

Forns score

Fibrotest

Fibrometer

Free

AST ALT platelets..

Expensive

α2 macroglobulin, GGT,

bilirubin…

False positive or negative

Utilize non specific serum biochemical markers

Alpha-2 macroglobulin

Haptoglobin

Gamma-glutamyl transpeptidase

Total bilirubin

Apolipoprotein A1

Drugs?

Hemolysis?

Gilbert’s syndrome?

7

Liver stiffness in HIV patients

Stiffness

Portal fibrosis

Cholestasis

Portal blood flow

Inflammation

Steatosis?

Centrolobular fibrosis

Sinusoidal fibrosis

Liver stiffness measurement

10 measurements

IQR < 30%

Take home message # 1

Before making any conclusions, careful examination of the

following is required:

All parameters of blood tests

Reliable measurement of liver stiffness

In case of unreliable or doubtful results

another method should be used

A liver biopsy should be discussed

When?

Indication of treatment

• Significant fibrosis?

• Cirrhosis?

Follow-up after treatment

Severity of cirrhosis

Prognosis

Free or expensive blood tests?

“…demonstrated high accuracy and

accurately predicted significant

fibrosis and cirrhosis…“

FIB-4 in HIV-HCV patients

N=173 Shire NJ et al. Clin Gastroenterol Hepatol 2009;7:471–480

Not enough!

APRI FIB-4 FORNS in HIV-HCV patients

N=324 Tural C et al, Clin Gastroenterol Hepatol 2009;7:339–345

Not enough!

Fibrotest in HIV-HCV patients

N=158 Sebastiani G et al. J Viral Hepat 2011;34:1202-16

Not enough!

Blood tests in HIV-HCV patients

Calès P et al. J Hepatol 2010;53:238-44 Cacoub P et al. J Hepatol 2008;48:765-73

AU

RO

CS

Significant fibrosis

0,6

0,65

0,7

0,75

0,8

0,85

0,9

0,95

1

Significant fibrosis Severe fibrosis Cirrhosis

Adju

sted

AU

RO

C

FibroMeter 1G Fibrotest Hepascore

Bottero J et al. J Hepatol 2009; 50:1074-83

N=108 16 cirrhosis

Blood tests in HIV-HBV patients

Take home message # 2

Current non-invasive blood tests of fibrosis

assessment have poor discriminatory capacity in

HIV-HCV patients.

Fibrometer needs further evaluation.

N AUC F234 AUC F4

de Lédinghen 0,97

Vergara 0,89 0,93 0,96

Macias 0,86

de Lédinghen V et al. JAIDS 2006;41:175-8 Vergara S et al. CID 2007;45:969-74 Macias J et al. J Hepatol 2008;49:916-22

Liver stiffness in HIV-HCV patients FibroScan

Liver stiffness in HIV-HCV patients ARFI

N=158 Sebastiani G et al. J Viral Hepat 2011;34:1202-16

Not enough!

Liver stiffness (FibroScan) in HIV-HBV patients

N=57

Miailhes P et al. J Viral Hepat 2011;18:61-69

Take home message # 3

For the diagnosis of cirrhosis, liver stiffness

measurement using FibroScan is the best method

For the diagnosis of significant fibrosis, there is no

good method. Maybe a combination of liver stiffness

measurement + blood test could be useful.

When?

Indication of treatment

Follow-up after treatment

Severity of cirrhosis

Prognosis

Liver stiffness after treatment

Barreiro P et al. AVT 2007

Time (months)

Liver stiffness measurement: a predictive factor of response to treatment?

Prometheus Index http://www.fundacionies.com/prometheusindex.php?lang=ing

Medrano J et al. CID 2010;51:1029-16

AUROC : 0.84 – 0.89

Take home message # 4

During the follow-up of treated patients with sustained virological response, there is a decrease of biochemical tests or liver stiffness.

However, we need further studies for the interpretation of this decrease

Is it a regression of liver fibrosis?

Is it a regression of inflammation?

When?

Indication of treatment

Follow-up after treatment

Severity of cirrhosis

Prognosis

Liver stiffness and Hepatic Vein Pressure Gradient

Sanchez-Conde M et al. J Viral Hepat 2011;18:685-91

HIV-HCV patients N=38

Diagnosis of oesophageal varices stage 2 or 3

AU

RO

CS

Castéral L et al. J Hepatol 2012;56:696-703

No EV stage 2/3

No Child-Pugh B or C

No variceal bleeding

No past history of ascites

No hepatocellular carcinoma

15 75 kPa

Liver stiffness

27.5 37.5 49 54 63

Liver stiffness and severity of cirrhosis

Foucher J, et al. Gut 2006;55:403–8 EV: esophageal varices

Liver stiffness and hepatocellular carcinoma

0 1 2 3

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

511 142 79 47 87

501 130 76 41 75

476 111 63 36 54

427 94 51 29 41

Years After Enrollment No. At risk < 10 kPa

10.1 – 15 kPa 15.1 – 20 kPa 20.1 – 25 kPa

> 25 kPa

20 < LSM < 25 kPa

LSM > 25 kPa

15 < LSM < 20 kPa 10 < LSM < 15 kPa LSM < 10 kPa

P < 0.001

Cu

mu

lati

ve I

nci

den

ce

Masuzaki R et al, Hepatology 2009;49:1954-61

866 patients with HCV infection, 3-year follow up

Hepatocellular carcinoma during follow-up: 77

Natural history of fibrosis and cirrhosis

Garcia-Tsao G et al. Hepatology 2010;51:1-5

2 75

Natural history of fibrosis and cirrhosis

Garcia-Tsao G et al. Hepatology 2010;51:1-5

Foucher J, et al. Gut 2006;55:403–8

Liver stiffness kPa 20

Take home message # 5

Non-invasive methods are insufficient to confidently predict the presence of oesophageal varices in clinical practice

Liver stiffness is associated with the severity of

cirrhosis and offers a mean for rapid discrimination

of different steps of progression within the stage of

compensated cirrhosis.

When?

Indication of treatment

Follow-up after treatmenr

Severity of cirrhosis

Prognosis

Fibrotest and survival HCV patients

Ngo S et al, Clin Chemistry 2006;52:1887-96

N=537

Median follow-up: 5 years

Overall survival AUROC

0.76 (0.63-0.84)

Liver stiffness and survival HCV patients

Fibrotest FibroScan

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60

Follow-up (months)

Ove

rall

surv

ival

(%

)

P < 0.0001

< 0.75

> 0.75 > 0.80

> 0.85

> 0.90

1.0

0,8

0,6

0,4

0,2

0,0

0 20 40 60 80

Follow-up (months)

Ove

rall

surv

ival

(%

)

< 9.5 kPa > 9.5 kPa

> 30 kPa > 20 kPa

> 40 kPa

> 50 kPa

P < 0.0001

> 0.95

Vergniol J, et al. Gastroenterology 2011;140:1970–9

1457 HCV patients; follow-up 5 years

Overall survival: 91.7%

APRI and liver related mortality HIV-HCV patients

N=303 (207 HIVHCV)

Follow-up: 3 years Nunes D et al. Am J Gastroenterol 2010;105:1346-53

<1.5

>1.5

Survival of HIV patients with cirrhosis according to liver stiffness

194 HIV infected patients (+ HBV or HCV)

All with FS > 14.5 kPa at inclusion

Death: 5.8 yearly

Predictive factors of mortality:

MELD > 11

LSM > 28.7 kPa

Tuma P et al. AIDS 2010, 24:745–753

Take home message # 6

Fibrotest and liver stiffness measurement are strong

predictors of survival in HCV and co-infected patients

CONCLUSION In clinical practice

Before making any conclusions, careful examination of the

following is required:

All parameters of blood tests

Reliable measurement of liver stiffness

Current non-invasive blood tests of fibrosis assessment have

poor discriminatory capacity in HIV-HCV patients.

For the diagnosis of cirrhosis and its severity, liver stiffness

measurement using FibroScan is the best method.

Clinical signs

Blood sample

Liver biopsy

Imaging (US, MRI, endoscopy)

Stiffness

Biomarkers

For the assessment of the severity of chronic liver diseases, we have…