Maria Vinci

SC di Epatologia e Gastroenterologia

Ospedale Niguarda Milano

HCV E IL RUOLO DEL SISTEMA

IMMUNITARIO: L’IMPATTO DEI

NUOVI FARMACI

Ruolo delle indagini strumentali nella

stadiazione dell’epatite cronica

Storia naturale dell’infezione da HCV

Sesso femminile Infezione in giovane età

30anni

20anni

Alcol,steatosi e/or IR, ,coinfezioni,sesso maschile, emosiderosi, infezione in età più avanzata, bassi livelli di vit.D (?)

Modified from Lauer et al., N Engl J Med 2001;345:41-52

Fegato

normale Infezione

acuta

Infezione

cronica Epatite

cronica cirrosi Rischio

di HCC

Transition from compensated to

decompensated cirrhosis

Chronic liver

disease

Compensated cirrhosis

Decompensated cirrhosis Death

Development of

clinical complications

Variceal hemorrhage Ascites Encephalopathy Jaundice

Annual rate of

decompensation:

4.6%

Annual progression rate from

decompensated HCV cirrhosis

to HCC: - 1.7% (women)

- 3.6% (men)

Child –Pugh score and

MELD usually used to determined

the severity of liver disease

in patients with cirrhosis

Survival is significantly greater in compensated vs. decompensated cirrhosis

60 40 80 100 120

0

40

60

80

20

20 0

100

Months

Decompensated

cirrhosis

D’Amico et. al., J Hepatol 2006;44:217.

Compensated

cirrhosis

Survival outcomes for All-Cause Mortality, Liver-

Related Mortality, LT,HCC and Liver Failure in pts

with CHC and advanced fibrosis with or without SVR

Why do we need to evaluate fibrosis?

Significant fibrosis?

Severe fibrosis or cirrhosis?

Indication of treatment

Treatment

Hepatocellular carcinoma screening

Oesophageal varices screening

AGENDA

Ruolo delle indagini strumentali

- Nella stadiazione della malattia

epatica

- Come indicatori di prognosi nella

cirrosi

Staging liver fibrosis

Staging

of fibrosis

Fibroscan Serum markers of liver

fibrosis

Liver biopsy Hepatic venous pressure

gradient (HVPG)

EASL Recommendations on Treatment

of Hepatits C 2014

Fibrosis stage can be assessed

by non- invasive methods initially, with liver biopsy

reserved for cases where there is uncertainty or potential a additional etiologies

Biopsia epatica : indicazioni

Presence and

localization of specific

lesions (inflammation,

steatosis, siderosis)

Biopsia epatica

Accettabilità

del paziente

Costi e

disponibilità

Morbidità

Mortalità

Accuratezza: Campionamento

Esperienza del

patologo

1:50.000 di tessuto epatico

Complicanze

clinicamente

significative

0.3 %

Biopsia epatica: campionamento e

variabilità della fibrosi

Biopsia epatica: errore di

campionamento

0

5

10

15

20

25

30

35

Variazione grading Variazione staging cirrosi in un lobo e F3nell'altro

Variabilità del grading e staging tra lobo epatico destro e sinistro in HCV

Regev et al, Am J Gastroenterol; 2002

24%

33 %

2% 2%

15 %

1 2 1 2

Biopsia epatica Impatto della lunghezza del frustolo bioptico sul n. degli spazi portali e sulla

valutazione del « grading» e dello «staging» (G.Colloredo et al J Hepatol 2003)

N. Spazi Portali

Completi

Incompleti

Grading Lieve

Moderata

Severa

Staging Lieve

Moderata

Severa

Lunghezza del frustolo

1 cm 1.5 cm ≥ 3cm P

22.4 ± 4.9

0.8 ± 1.1

80 (49.7%)

62 (38.5%)

19 (11.8%)

95 (59%)

48 (29.8%)

18 ( 11.2%)

10.3 ± 2.2

0.4 ± 0.8

97 (60.2%)

63 (39.1%)

1 (0.6%)

110 (68.3%)

39 (24.2%)

12 (7.4%)

6.4 ± 1.2

0.3 ± 0.6

133 (86.6%)

28 (17.4%)

0

129 (80.1%)

24 (14.9%)

8 (4.9%)

<0.001

<0.001

<0.001

<0.002

Biopsia epatica

Impatto del diametro dell’ago da biopsia

sul n. degli spazi portali

N. Spazi Portali

Completi

Incompleti

Lunghezza del frustolo ≥ 3cm 1.5 cm

Φ 1.4 mm Φ 1 mm Φ 1.4 mm Φ 1mm

22.4 ±4.9

0.8 ± 1.1

11.2 ± 2.4

4.1 ± 1.3

10.3 ± 2.2

0.4 ± 0.8

5.4 ±1.3

2.7 ±0.9

(G.Colloredo et al J Hepatol 2003)

Biopsia epatica

74%

[VALORE]

9%

11%

Confirmed diagnosis Changed diagnosis

Added diagnosis Changed management

Spycher et al BMC Gastroenterology 2001

365 pazienti sottoposti a biopsia epatica

6%

Liver stiffness Transient elastography (FibroScan®)

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

Confounding factors for liver stiffness

Acute Inflammation Coco et al. J Viral Hepat 2007

Arena et al. Hepatology 2008 Sagir et al. Hepatology 2008

Others ?

Liver

congestion Millonig et al. J Hepatol 2010

Extra-hepatic cholestasis

Millonig et al. Hepatology 2008

Median liver stiffness

Interquartile range

Number of valid measurement

At least 10 <30% of median value

SR 100%

Success Rate

At least 60%

FibroScan:

Quality criteria

for reliable results

Applicability of transient elastography

Failure 3.1%

Valid shot = 0

Unreliable 15.8%

IQR/LSM > 30%

9.2%

SR < 60%

8.1%

VS < 10

3.1%

FibroScan

not applicable

in 20%

of cases

Obesity Operator experience

N=13669 examinations Castéra et al. Hepatology 2010; 51: 828-35

TE- Correlation with liver fibrosis

Liver stiffness and cirrhosis (assessed by Metavir scoring system)

F0F1 F1F2 F2 F3 F3F4 F4

2 7.1 8.7 9.5 12.5 14.5 75 kPa

In HCV patients the most validated TE cutoff

points are :

• 7.1 kPa to identify significant fibrosis

• 12.5 kPa to recognize cirrhosis

N. of

studies

N. of

patient

≥ F2

Auroc

≥ F3

F4

Cut -

≥ F2

off

≥ F3

(kPa)

F4

Talwalkar

et al*

9 2083 0.87 N/A 0.96 N/A N/A N/A

Stebbing

et al**

22 4760 0.84 0.89 0.94 7.81 N/A 15.56

Friedrich-

Rust et al§

50 8206 0.84 0.89 0.94 7.65 N/A 13.01

Tsochatzis

et al#

40 7723 N/A N/A N/A 7.3 10.2 15

Chon

et al+

18 2772 0.86 0.89 0.93 7.9 8.8 11.7

*Clin Gastroenterol Hepatol 2007 ** J Clin Gatroenterol 2010 § J Viral.Hepatol 2012

#J Hepatol 2011 + Plos One 2012

Transient elastography: diagnostic accuracy

Biomarkers

• GGT

• Bilirubin

• ALT

• Haptoglobin

• Apolipoprotein A1

• α2 macroglobulin

• Platelet count

• Prothrombin time

• Hyaluronate

False positive values with hemolysis,

inflammation, Gilbert’s syndrome

Score Variables Performance in HCV patients

(original Significant fibrosis( ≥ F2) Cirrhosis

reference) AUROC Sens Spec AUROC Sens Spec

FIBROTEST GGT, Haptoglobin

bilirubin, ApoA1,

alfa- 2 macroglob.

FORNS Age, GGT,Cholest

Platelets

APRI AST,Platelets

FIB4 Age, AST, ALT

Platelets

FIBROMETER Platelets, PT, AST

Age,urea,macroglob,

hyaluronate

HEPASCORE age,sex,alfa2

macrog, GGT

Hyal.,bil.

0.79 92% 96% 0.86 85% 81%

0.76 88% 94% 0.87 98% 91%

0.77 81% 95% 0.84 77% 94%

0.74 64% 79% 0.87 90% 92%

0.82 69% 81% 0.91 - -

0.79 66% 79% 0.89 72% 86%

Chou et al Ann Intern Med 2013

Combination of markers:

The Sequential Algorithm for Fibrosis Evaluation (SAFE)

Sebastiani et al Hepatol 2009

Biopsia epatica evitata

nel 36% dei casi:

- 475 paz con fibrosi

≥ F2 senza cirrosi

- 258 pazienti con

cirrosi

• Dati discordanti nel

9.9% (fibrosi severa) e

nel 7.5% (cirrosi)

The Bordeaux Algorithm

Castera et al J of Hepatol 2010

The Bordeaux vs SAFE algorithm

N=302 chronic hepatitis C

71.9% of liver biopsies avoided (vs 48% with SAFE)

78.8% of liver biopsies avoided (vs 74.8% with SAFE)

Castera et al J of Hepatol 2010

Combination of FibroScan and blood test: well-classified

patients and theoretically avoided liver biopsies

Zarski JP, et al. J Hepatol 2012

Liver fibrosis

• The results of non-invasive tests for the diagnosis

of significant fibrosis and cirrhosis are

approximately equal

• However, combination of Fibroscan with a blood

test markedly improves the percentage of well-

classified patients for the diagnosis of significant

fibrosis

AGENDA

Ruolo delle indagini strumentali

- Nella stadiazione della malattia

epatica

- Come indicatori di prognosi nella

cirrosi

Natural History of chronic liver disesase

•Increasing liver

Fibrosis

•Increased portal

Pressure

HVPG 6-10 mmHg

•Increasing liver

Fibrosis

HVPG>10mmHg

•Hyperdinamic circulation

•Increasing portal pressure

HVPG > 16-20

•Increasing hyperdinamic

circulation

Chronic

liver

disease

Compensated

cirrhosis

Decompensated

Cirrhosis

Further

Decompensate

cirrhosis

•Recurrent variceal

hemorrage

•Refractory ascites

•Hepatorenal sindrome

•Bacterial infection

•Variceal hemorrage

•Ascites

•Encephalopaty

•Jaundice

•No varices

•Varices

Garcia-Tsao G Dis Mark 2011 ; 31:121-128

HVPG is the goal standard technique to

diagnosis of portal hypertension and

its severity

SAFE

ACCURATE

REPRODUCIBLE

WELL

ACCEPTED

SPECIFIC

TRAINING

INVASIVE

Hepatic vein catheterization

HVPG 10 mmHg is an independent predictor of

decompensation in patients with compensated cirrhosis

Probability of

decompensation

(ascites, VH, HE))

Log rank test: P<0.01

HR 3.95 (2.29–6.83)

Baseline HVPG ≥10mmHg

90% NPP, i.e. patients with an HVPG <10

mmHg have a 90% chance of not developing

clinical decompensation in a 4-year period

Baseline HVPG <10mmHg

1.0

0.8

0.6

0.4

0.2

Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:481-488.

0 20 40 60 80 100 months

In patients with compensated cirrhosis, HVPG is a

predictor of HCC independent of the duration and

severity of cirrhosis

Probability of

developing

hepatocellular

carcinoma (HCC)

Log rank test: P=0.001

Hazard Ratio 6.0 (1.8-20.1)

Baseline HVPG <10mmHg

Baseline HVPG

≥10mmHg

Ripoll et al J Hepatology

1.0

0.8

0.6

0.4

0.2

100 80 60 40 20 0 months

HVPG and surgical resection of HCC

HVPG predicts the risk of hepatic decompensation and

survival in Child A cirrhotic patients

Bruix J, Gastroenterology 1996 Llovet JM, Hepatology 1999

FibroScan and severity of cirrhosis

15 27.5 49

No EV stage 2/3

No Child-Pugh B or C

No past history of ascites

No hepatocellular carcinoma

No variceal bleeding

Foucher J, et al. Gut 2006;55:403–8

37.5 54 63 75 kPa

EV: esophageal varices

Sopravvivenza e stadio della fibrosi

valutata mediante Fibroscan

1025 pazienti con ECA HCV+ seguiti

prospetticamente, ripetono un Fibroscan

dopo 3 anni (Mediana FU: 38 mesi)

Sopravvivenza a

3 anni

Fibroscan ≤ 7 kPa 99%

Fibroscan >7- <14 kPa 96%

Fibroscan > 14 kPa

77%

J Vergniol ;Hepatol 2014

Sopravvivenza e stadio della fibrosi

valutata mediante Fibroscan

J Vergniol ; Hepatol 2014

Staging chronic hepatitis C in seven categories using

fibrosis marker (FibroTest) and

Transient elastography (Fibroscan)

(Poynard et al J Hepatol 2014 ; vol 60 n 4: 706-714 )

TE performance for prediction

of first severe complications

• TE predetermined cut off for stages

F0 0 ≤ 5 kPa 1.6% 0 % 3.7%

F1>5 ≤7.1 kPa 5.0% 1.1% 4.2%

F2>7.1 ≤9.5 kPa 11 % 2.1% 3.5%

F3>9.5 ≤12.5 kPa 25.7% 24.6% 11.8%

F4.1 >12.5 ≤20 kPa 23.4% 12.7% 20.3%

F4.2>20 ≤55 kPa 55.9% 33.6% 30.3%

F4.3>50-75 kPa 71 % 58.7% 14.8%

Severe complicance

defining stage F4.3 Primary

liver cancer

Death

Poynard et al J Hepatol 2014 ; vol 60 n 4: 706-714

Survival without liver complications according baseline TE cc

Fibrotest performance for the

prediction of complications

• FT predetermined cut off for stages

F0 ≤0.28 2.2% 0% 2.8%

F1>0.28 ≤0.48 4.1% 0.9% 5.6%

F2>0.48 ≤0.58 4.8% 1.5% 5.8%

F3>0.58 ≤0.74 7.7% 12% 16.9%

F4.1 >0.74 ≤0.85 36.4% 16.8% 14.4%

F4.2>0.85 ≤0.95 46.8% 26.1% 29.1%

F4.3>0.95 60.3% 30.8% 53.1%

Severe complicance

defining stage F4.3 Primary

liver cancer

Death

Poynard et al J Hepatol 2014 ; vol 60 n 4: 706-714

Survival without liver complications according baseline FT

Grazie per l’attenzione