Valutazione non invasiva e

misurazione diretta della

pressione portale

• Background

• Impact of the therapy

• Diagnosis and scores

Wilma Debernardi Venon

UOADU Gastroepatologia

Molinette - Torino

Liver fibrosis and Natural History

Cirrhosis

Chronic hepatitis

Health liver

Injury

chronic tissue damage, inflamation, fibrogenesis

tissue ipoxia, angiogenesis

liver dysfunction

carcinogenesis

Portal Hypertension

Systemic disease

Esophageal varices

Ascitis

Refractory ascitis

HRS

Alcoohol

virus

iron

autoimmunity

Hemodynamic Factors in the Pathophysiology

of Cirrhotic Portal Hypertension

antiangiogenetic drugs

Antifibrotic drugs

Statins ?

Antioxidants ?

BB + vasodilators

carvedilol

splanchnic vasoconstrictors

terlipressin, somatostatin

non selective BBlockers

Anticoagulation ?

Etiologic treatments

TIPS

Portal Pressure

Diet

Steroids

Antivirals

Hepatic Fibrosis and Reversibility

fibronectin

Extensive collagen cross linking

Elastin

Paucicellular ECM

MMP expression

Resistance to apoptosis

expression lysyl oxidase 2-->

fibrosis reversibility

advanced stages

Irreversibility ?

Friedman SL. J Hepatology 2015

Classification of chronic liver disease based on histological,

clinical, hemodynamics and biological parameters

Rebleeding,

Refractory ascites

HRS/AKI

SBP

> 16-20

1 yr mortality 1% 3% 10-30% 60- 100%

Main outcome decompensation, decompensation HCC, mortali ty

to prevent HCC, varices HCC

AT1 receptor blockers

statins B Blockers

Antiviral therapy

TIPS

…. more or less severe cirrhosis? clinical decompensation?

regression of cirrhosis? response to antiviral therapy?

Sethasine S and Garcia Tsao. Hepatology 2012

Fibrosis area= area of fibrosis/ total biopsy area

• Impact of therapy

47 cirrhotics,

peg-Inf + Riba, 48 w,

HVPG 0-6 months

Roberts S. Am J Gastr 2006

96 patients, INF + Riba

Score F4

Liver biopsy

Metavir 42

18/96 (18.7%): regression of fibrosis

0 clinical events

Transplant-free survival rate at 10 yrs:

100% vs 74% without regression

Mallet V. Ann Int Med 2008

The relationship of regression of cirrhosis

to outcome in chronic hepatitis C

HCV

Prospective cohort, 933 pts,Fibrotest and

fibroscan

Regression of fibrosis=

minimum 0.20 decrease test= -1 Metavir stage

At 10 yrs, 415 pts

15 new cirrhosis, HCC (4 vs 13) Poynard T. J Hepatology 2013

Association Between Severe Portal Hypertension and Risk of Liver

Decompensation in Patients with Hepatitis C, Regardless of Response to Antiviral

Therapy

Liver decompensation at 1, 5 and 7 yrs: 3%, 19% e 22%

Lens L. Clin Gastr Hepat 2015

n=5 n=5 n=2 n=3

(+10)

CPT B CPT C

12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

*Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.; discontinuation 13/337 (4%)

Death in 10 for decompensation; 6 LTs

LABORATORY RESULTS: MELD SCORE

CHANGE FROM BASELINE TO FOLLOW-UP WEEK 4

36% not improved 35% not improved

Charlton et al Gastroenterology 2015

Charlton et al. Gastroenterology; 2015.

SOFOSBUVIR+LEDIPASVIR+RBV FOR RECURRENT HCV:

MELD SCORE CHANGE FROM BASELINE TO POST-TREATMENT WEEK 4

33% not improved

or worse

30% not improved

or worse

60% not improved

or worse

33% not improved

or worse

HVPG Change Over Time

Afdhal, EASL, 2015, LP13

There were clinically meaningful improvements in portal hypertension in addition to

improvements in liver biochemistry, CTP and MELD scores

The effect of SVR12 and viral suppression on HVPG is being monitored at 1 year post-

treatment

Observation Period in Patients with

BL HVPG ≥12 mmHg* (24 weeks) Changes After Treatment in Patients

with BL HVPG ≥12 mmHg (n=33)

SOF+RBV in Compensated and Decompensated Cirrhotics with Portal Hypertension

-30

-20

-10

0

10

20

30

40

n=2

HV

PG

Ch

an

ge (

%)

n=2 a

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80 H

VP

G C

han

ge (

%)

Patients with >20% decrease (8/33)

Baseline MELD Score <10 ≥10

aPatients with HVPG ≤12 mm Hg at end of treatment

*No patient had HVPG ≤12 mm Hg at end of observation period

HVPG = hepatic venous pressure gradient

A reduction in HVPG ≥20% or below the 12-mm Hg threshold markedly reduces the risk of variceal bleeding, and varices may decrease in size

a a a

Mostly in MELD < 10

Hepatitis B

Antiviral therapy reduces portal pressure in patients with

cirrhosis due to HBeAg-negative chronic hepatitis B and

significant portal hypertension

19 cirrotics, HVPG > 10mmHg, lamivudine 100 mg/d

Manolacopoulus S. H Hepatology 2009

ALT, HBV-DNA

MELD reduction

HBV

Antiviral Therapy reduces Portal Hypertension

5/7 (71%) OV disappearance

Debernardi Venon W et al; AISF 2013

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120 Months

27 24 19 9 4 3

80%

21 27 15 8 4

27 26 23 2

0

14 9 24 27 21 18 14

12% EV progression

EV regression

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120

Patients

at risk 80 78 74 62 45 33 80 67 78 56 39

8%

EV progression

Changes of esophageal varices (EV) in

compensated cirrhotics treated with LAM±TDF for 10 years

No varices at baseline (n=80)

F1 varices at baseline (n=27)

Overall, EV worsening rate per year: 0.9%*

* 6 of 7 progressors (86%) had either LMV-R and/or HCC

Marengo, & Marzano Antiviral Therapy 2013

Decompensation Death

* 2 CH

CH

Cirrhosis

Clinical experience with III gen NUCs:

Entecavir 100 pts (55 compensated cirrhosis)

Decompensated cirrhosis

Mutimer DJ, Gut 2012

• Diagnosis and scores

• Septal fibrosis

• Small nodularity

• Portal tracts lost

• Interface inflammation

• Alcohol

Clinical Significant Portal Hypertension HVPG > 10 mmHg

43 cirrhotics, 56% viral etiology

Nagula S. J Hepatology 2006. Garcia Tsao. Hepatology 2010

HVPG

Fibrosis stage

Relationship between Fibrosis Stage and HVPG

Blasco. Hepatology 2006

Vizzuti. Hepatology 2007

Fibroscan Liver Stiffness predicts Severe

Portal Hypertension in Cirrhosis

Liver stiffnes > 13 kaP cirrhosis

Gaia, J Hepatol 2011

Gaia, J Hepatol 2011

Fibroscan

Figura patologia non-HBV

Non invasive scores to detect Liver Fibrosis

APRI

Fibrotest*

Forns index

HUI

AST/ALT

Platelet count/Ø spleen

Platelets

Type IV collagen

GUCI

SAPI

Hyaluronic acid

Transient elastography*

LSPS (Liver stiffness X Ø spleen/platelet count*)

* Compared to liver biopsy or HVPG

algorytm

LSPS is a predictor for EBV risk in B viral liver cirrhosis Berzigotti A. Gastr 2013

KIM B. Am J Gastr 2011

LSPS ed HCC

• <1.13.5%

• > 2.5 32%

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

123 pts

Antiviral therapy: 23 LAM, 17 LAM+NUC, 77 NUC (53 NUC ab initio)

Time of treatment: mean 8.7 yrs (1-17)

49% with PH (32% EV)

111 pts with Fibroscan, HVPG

ALT 27.8 (9-138)

Ø Spleen 12.5 (8.2-14.8)

LS 9.3 (3-22.5)

PLTS 153 (34-653)

HBsAg q 2596 (0-47000)

LSPS 1.25 (0.15-11.25)

(LSxØ spleen/PLTS)

Marzano. Personal data

LSPS in HBV: our experience

0

10

20

30

40

50

60

70

80

90

100 after T

after T

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

%

P<0.05

New EV reduction or

desappearance EV

0

20

40

60

80

100

LSPS < 0.62

LSPS > 0.62

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

LSPS ≤ 0.62 after therapy has 100% NPV for predicting an HVPG < 6 mmHg

HVPG

< 6 mmHg > 6 mmHg

% pts

56 pts

44pts

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

ALT 27.46 30.93 ns

Age 62 63 ns

LS 6.6 13.6 < 0.0001

Ø spleen 10.6 14.2 < 0.0001

PLTS 195.9 112.7 < 0.0001

56 pts 44 pts

LSPS ≤ 0.62 LSPS >0.62 p

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

56 pts 44 pts

LSPS ≤ 0.62 LSPS >0.62

ALT mean N pts ALT mean N pts

ALT

≤ 19

≤ 30

16.6

20.7

32%

77%

15.7

20.5

34%

42%*

HBsAg q

≤ 19

≤ 30

3014.7°°

2143°°

29%**

71%**

1918,6 °

1708,2 °

32%*

58%*

*p< 0.05 vs **, ° p<0.05 vs °°

Liver fibrosis and portal hypertension in HBV compensated cirrhotics

long term treated with antiviral therapy

Incidence of HCC: 20%

HCC vs no HCC: no significant difference in ALT, LS, Ø spleen, PLTS,HBsAg q

≤ 0.62 > 0.62

HCC 2/56 (3%) 6/44 (14%)*

HbsAg q (mean) 3122.88 2119.1*

LS ≥ 11 5/56 ( 13.9) 18/44 (17.1)*

ALT (mean) 27 41*

Ø spleen (cm) 10.6 14.2*

PLTS 195000 112000*

* p < 0.05 vs patients group with LSPS ≤0.62

Conclusions

• Portal hypertension can influence outcome post antiviral therapy, also in responders

• The degree of portal hypertension and a “more severe” cirrhosis should be

consider before treating decompensated cirrhotics

• Fibroscan is a good predictor of cirrhosis and is a usefull non invasive tool for monitoring

patients during antiviral therapy in HCV+ patients

• In HBV + patients LSPS, performed at the bedside,is predictor of portal hypertension and

of clinical response to antiviral theraphy. In compensated patients can avoid the EGDS.

• The risk of HCC in patiens with >0.62 seems to be related to viral activity.