MASSIMO PINZANI, MD, PhD, FRCPSheila Sherlock Chair of HepatologyUCL Institute for Liver and Digestive HealthRoyal Free Hospital, London, UK

m.pinzani@ucl.ac.uk

Screening for Portal Hypertensionin Cirrhosis

www.ucl.ac.uk/medicine/liver-and-digestive-health

Best of EASL is a program supported by an unrestrictedmedical education grant by Merck Sharp & Dohme,

Corp., a subsidiary of Merck & Co., Inc.

Best of EASL is a program supported by an unrestrictedmedical education grant by Merck Sharp & Dohme,

Corp., a subsidiary of Merck & Co., Inc.

Is Surveillance Needed?

Abougergi MS, Travis AC, Saltzman JR. Thein-hospital mortality rate for upper GIhemorrhage has decreased over 2 decades inthe United States: a nationwide analysis.Gastrointest Endosc. 2015; 81(4):882-8 e1.doi: 10.1016 /j.gie.2014.09.027.

WHEN?

?

“DecompensatingEvent”

Stage 3

Bleeding

Stage 4First nonbleeding

decompensation

Stage 5

Seconddecompensation

Death orOLT

SEPSISRenalFailure

Hepatocellular Carcinoma

CompensatedCirrhosis

DecompensatedCirrhosis

Stage 1

Stage 2

No VaricesNo Ascites

VaricesNo Ascites

HVPG: 5-12 mm Hg

HVPG > 12 mm Hg

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

Natural History of Cirrhosis: Mostly “Observational” !

?

“DecompensatingEvent”

Stage 3

Bleeding

Stage 4First nonbleeding

decompensation

Stage 5

Seconddecompensation

Death orOLT

SEPSISRenalFailure

Hepatocellular Carcinoma

CompensatedCirrhosis

DecompensatedCirrhosis

? ? ?

Stage 1

Stage 2

No VaricesNo Ascites

VaricesNo Ascites

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

YearsMonths

Compensated Cirrhosis: A Stage with LimitedDiagnostic Resources

Alcohol

HCV

Autoimmunedisorders

Others

Cholestasis

One or many??

NASH

Drugs

HBV

CIRRHOSIS

Etiology-driven Cirrhosis

Same Surveillance for DifferentCirrhoses?

HOW?

Early to Advanced Liver FibrosisCirrhosis without Clinical

ManifestationsCirrhosis with Clinical

ManifestationsLiver Failure

HVPG 5-10 mm HgHVPG 5-10 mm HgHVPG < 5 mm Hg HVPG > 10-12 mm Hg

Advanced Chronic Liver Disease

Liver Biopsy (PC or TJ) : Quantitative staging with CPA

Liver Stiffness Measurement

Serum Markers: Direct/Indirect Serum Markers: predictors of liver related outcomes

Spleen Stiffness Measurement

Spleen-related Noninvasive Indexes & Algorhythms

Search for early predictor of decompensation and ACLF

Search for predictors ofprogression rate to cirrhosis

Search for early predictor of HCC

Institute for Liver and Digestive Health

Invasive and Non-invasive Evaluation ofDisease Progression in Chronic Viral Hepatitis

Liver Biopsy with CPA

Calvaruso V, Burroughs AK et al., Hepatology 2009; 49: 1236

Liver Stiffness

y = 1.5952 + 2,037r2 = 0,61p < 0,0001

0

5

10

15

20

25

30

35

40

45

50

55

60

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

HVPG (mmHg)

Stif

fne

ss(k

Pa)

Vizzutti F et al., Hepatology 2007; 45:1290-1297

PH relatedto Fibrosis

PH scarcely related to Fibrosis:CIRRHOSIS BECOMES A SYSTEMICDISEASE

Diagnostic performance of transient elastography for the detection of clinicallysignificant portal hypertension (HVPG 10 mm Hg)

Authors

Carrion et al. (35)

Vizzutti et al. (36)

Sanchez-Condé et al. (39)

Lemoine et al. (38)

Bureau et al. (37)

AUC

0.92

0.990.92

0.800.80

0.76

0.94

0.94

Se(%)

90

9794

9383

63

90

90

Sp(%)

81

9281

5067

70

88

93

Etiologies

HCV-LT

HCV

HIV-HCV

HCV

Alcohol

CLD

* Hepatic Venous Pressure Gradient (HVPG) ≥6 mm Hg; ** severe portal hypertension HVPG ≥12 mm Hg

Patients(n)

124

61

38

44

48

150

+LR

4.7

13.74.9

3.52.5

2.1

7.5

12.8

-LR

0.12

0.020.08

0.620.49

0.53

0.13

0.10

AUC: area under ROC curve; Se sensitivity; Sp specificity; +LR positive likelihood ratio; -LR negative likelihood ratio;HCV chronic hepatitis C; HCV-LT Liver transplant for hepatitis C; CLD chronic liver diseases;

Study design

Prospectivemonocentric

Prospectivemonocentric

Prospectivemonocentric

Retrospectivemonocentric

Prospectivemonocentric

Cut-offsHVPG 10 mm Hg

(kPa)

8.7*

13.617.6**

14.023.0**

20.5

34.9

21.0

Prevalence ofCinically SignificantPortal hypertension

21%

77%

74%

77%

83%

51%

PPV(%)

81

9786

8479

88

97

93

NPV(%)

90

9291

7171

35

64

91

Castera L, Pinzani M, Bosch J, J Hepatology 2012

Screening and surveillance: Invasive and non-invasivemethods (changed from Baveno III-V)

BAVENO VI (2015)

The introduction of transient elastography (TE) in clinical practicehas allowed the early identification of patients with chronic liverdisease (CLD) at risk of developing clinically significant portalhypertension (CSPH) (1b;A).

For these patients, the alternative term “compensated advancedchronic liver disease (cACLD)” has been proposed to better reflectthat the spectrum of severe fibrosis and cirrhosis is a continuumin asymptomatic patients, and that distinguishing between thetwo is often not possible on clinical grounds (5;D).

BAVENO VI (2015)

Criteria to suspect cACLD (new)

•Liver stiffness by TE is sufficient to suspect cACLD in asymptomaticsubjects with known causes of CLD (1b;A).

•TE often has false positive results; hence two measurements ondifferent days are recommended in fasting conditions (5;D).

•TE values <10 kPa in the absence of other known clinical signs ruleout cACLD; values between 10 and 15 kPa are suggestive of cACLDbut need further test for confirmation; values >15 kPa are highlysuggestive of cACLD (1b;A).

Screening and surveillance: Invasive and non-invasivemethods (changed from Baveno III-V)

BAVENO VI (2015)

Criteria to confirm cACLD (new)•Invasive methods are employed in referral centres in a stepwiseapproach when the diagnosis is in doubt or as confirmatory tests

•Methods and findings that confirm the diagnosis of cACLD are:-Liver biopsy showing severe fibrosis or established cirrhosis(1a;A).-Collagen proportionate area (CPA) measurement on histologyprovides quantitative data on the amount of fibrosis and holdsprognostic value (2b;B) and its assessment is recommended (5;D).-Upper GI endoscopy showing gastroesophageal varices (1b;A).-Hepatic venous pressure gradient (HVPG) measurement; values>5 mmHg indicate sinusoidal portal hypertension (1b;A).

Screening and surveillance: Invasive and non-invasivemethods (changed from Baveno III-V)

BAVENO VI (2015)

Diagnosis of CSPH in patients with Viral cACLD (new)

• Liver stiffness by TE ( 20–25 kPa; at least two measurements on different days infasting condition; caution should be paid to flares of ALT; refer to EASL guidelines forcorrect interpretation criteria), alone or combined to platelets and spleen size.•The diagnostic value of TE for CSPH in other aetiologies remains to be ascertained(5;D).•Imaging showing collateral circulation is sufficient to rule-in CSPH in patients withcACLD of all aetiologies (2b;B).

Identification of patients with cACLD who can safely avoidscreening endoscopy (new)Patients with a liver stiffness <20 kPa and with a platelet count >150,000 have a very lowrisk of having varices requiring treatment, and can avoid screening endoscopy (1b;A).

Screening and surveillance: Invasive and non-invasivemethods (changed from Baveno III-V)

Congestion

Hypertrophy andHyperplasia

Fibrosis

INCREASE INSPLEEN

STIFFNESS ??

The Spleen in the Assessment of AdvancedChronic Liver Disease

Measurement of Spleen Stiffness by Fibroscan

2. - Splenic parenchymal thickness > 4 cm (by US)

1. – Sufficient intercostal space width

3. – Success rate > 60% and IQR < 30% of median value

4. – Intra-observer reproducibility 96%, inter-observerreproducibility 94%

5. – Probe upper limit 75 kPa

Spleen Stiffness

P = 0.0000R2 = 0,78

0

5

10

15

20

25

30

35

20 30 40 50 60 70 80

Spleen Stiffness (kPa)H

VP

G(m

mH

g)

P = 0.0000R² = 0,70

0

5

10

15

20

25

30

35

10 20 30 40 50 60 70

Liver Stiffness (kPa)

HV

PG

(mm

Hg)

“Compensated”Cirrhosis

Esophageal Varices: NO

Esophageal Varices: YES

Colecchia A. et al., Gastroenterology 2012 ; 143(3):646-54

EV: NO EV: YES EV: NO EV: YES

Liver and Spleen Stiffness for the Predictionof the Presence of Esophageal Varices

Colecchia A. et al., Gastroenterology 2012 ; 143(3):646-54

Non Invasive Measures Including Spleen ParametersP

INZA

NIM

-2

01

3

Non Invasive Measures Including Spleen Parameters

Fuchs BC et al. J Hepatol 2013

DEC-MRI withEP-3533 contrast

Courtesy of Dr. AnnalisaBerzigotti, Hospital ClinicBarcelona

Molecular Imaging of Collagen

Increasing tissue hypoxiaand endothelial dysfunction

Neoangiogenesis and microthrombosis

Activation of the stem cell compartment

Ductular reaction and “reactive”cholangiocytes

Unbalanced vasoconstrictors and scarcontraction

Hepatocyte necrosis/apoptosis,inflammatoryinfiltration

All potential targets for bio-imaging and functional imaging

Measuring Collagen: What are we missing?

BR55: A lipopeptide-based VEGFR2-targeted US contrast agent for

molecular imaging of angiogenesisPochon et al. Invest Radiol 2010Willmann et al Radiology 2008

Binding is amplified by ARFFrinking et al. Ultras Med Biol 2012

+ +

To Be ExploitedElastin, Collagen cross-linking: IRREVERSIBILITYImmunophenotype, macrophage markers: REVERSIBILITY

Get notified atwww.ilc-congress.eu/get-notified-ilc-2016-barcelona-spain

Liver disease in resource-limited settingsEASL Monothematic ConferenceBUCHAREST, ROMANIAMAY 29-30

Liver cirrhosis and complicationsClinical School of Hepatology Course 24MOSCOW, RUSSIAJUNE 5-6

Autoimmune hepatitisEASL Monothematic ConferenceLONDON, UNITED KINGDOMSEPTEMBER 3-5

Management of critically ill cirrhotic patientsEASL Clinical School of Hepatology Course 25BARCELONA, SPAINOCTOBER 22-23

EASL MasterclassMILAN, ITALYDECEMBER 3-5

EVENTS 2015

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Addressing end-stage liver disease-A multi-faceted challengeEASL Special ConferenceGLASGOW, UNITED KINGDOMSEPTEMBER 25-27

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