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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