Screening for Portal Hypertension in Cirrhosis

Transcription

1 Screening for Portal Hypertension in Cirrhosis MASSIMO PINZANI, MD, PhD, FRCP Sheila Sherlock Chair of Hepatology UCL Institute for Liver and Digestive Health Royal Free Hospital, London, UK Best of EASL is a program supported by an unrestricted medical education grant by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc.

2 Is Surveillance Needed? Abougergi MS, Travis AC, Saltzman JR. The in-hospital mortality rate for upper GI hemorrhage has decreased over 2 decades in the United States: a nationwide analysis. Gastrointest Endosc. 2015; 81(4):882-8 e1. doi: /j.gie

3 WHEN?

4 Natural History of Cirrhosis: Mostly Observational! HVPG > 12 mm Hg HVPG: 5-12 mm Hg Stage 1 No Varices No Ascites Decompensating Event? Stage 3 Bleeding Stage 4 First non bleeding decompensation SEPSIS Renal Failure Death or OLT Stage 5 Varices No Ascites Second decompensation Stage 2 Hepatocellular Carcinoma Compensated Cirrhosis Decompensated Cirrhosis Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

5 Compensated Cirrhosis: A Stage with Limited Diagnostic Resources Stage 1 No Varices No Ascites Decompensating Event? Stage 3 Bleeding Stage 4 First non bleeding decompensation SEPSIS Renal Failure Death or OLT Varices No Ascites Years Stage 5 Second decompensation Months Stage 2 Hepatocellular Carcinoma Compensated Cirrhosis??? Decompensated Cirrhosis Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

6 Etiology-driven Cirrhosis HBV HCV Cholestasis Alcohol NASH One or many CIRRHOSIS?? Same Surveillance for Different Cirrhoses? Autoimmune disorders Drugs Others

7 HOW?

8 Invasive and Non-invasive Evaluation of Disease Progression in Chronic Viral Hepatitis Search for predictors of progression rate to cirrhosis Liver Stiffness Measurement Serum Markers: Direct/Indirect Search for early predictor of decompensation and ACLF Search for early predictor of HCC Liver Biopsy (PC or TJ) : Quantitative staging with CPA Spleen-related Noninvasive Indexes & Algorhythms Spleen Stiffness Measurement Serum Markers: predictors of liver related outcomes Early to Advanced Liver Fibrosis HVPG < 5 mm Hg Cirrhosis without Clinical Manifestations HVPG 5-10 mm Hg Cirrhosis with Clinical Manifestations HVPG > mm Hg Liver Failure Advanced Chronic Liver Disease Institute for Liver and Digestive Health

9 Liver Biopsy with CPA Calvaruso V, Burroughs AK et al., Hepatology 2009; 49: 1236

10 Liver Stiffness Stiffness (kpa) y = ,037 r 2 = 0,61 p < 0,0001 PH related to Fibrosis PH scarcely related to Fibrosis: CIRRHOSIS BECOMES A SYSTEMIC DISEASE HVPG (mmhg) Vizzutti F et al., Hepatology 2007; 45:

11 Diagnostic performance of transient elastography for the detection of clinically significant portal hypertension (HVPG 10 mm Hg) Authors Patients (n) Etiologies Study design Prevalence of Cinically Significant Portal hypertension Cut-offs HVPG 10 mm Hg (kpa) AUC Se (%) Sp (%) PPV (%) NPV (%) +LR -LR Carrion et al. (35) Vizzutti et al. (36) HCV-LT HCV Prospective monocentric Prospective monocentric 21% 77% 8.7* ** Sanchez-Condé et al. (39) Lemoine et al. (38) Bureau et al. (37) HIV-HCV HCV Alcohol CLD Prospective monocentric Retrospective monocentric Prospective monocentric 74% 77% 83% 51% ** * Hepatic Venous Pressure Gradient (HVPG) 6 mm Hg; ** severe portal hypertension HVPG 12 mm Hg 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; Castera L, Pinzani M, Bosch J, J Hepatology 2012

12 BAVENO VI (2015) Screening and surveillance: Invasive and non-invasive methods (changed from Baveno III-V) The introduction of transient elastography (TE) in clinical practice has allowed the early identification of patients with chronic liver disease (CLD) at risk of developing clinically significant portal hypertension (CSPH) (1b;A). For these patients, the alternative term compensated advanced chronic liver disease (cacld) has been proposed to better reflect that the spectrum of severe fibrosis and cirrhosis is a continuum in asymptomatic patients, and that distinguishing between the two is often not possible on clinical grounds (5;D).

13 Criteria to suspect cacld (new) BAVENO VI (2015) Screening and surveillance: Invasive and non-invasive methods (changed from Baveno III-V) Liver stiffness by TE is sufficient to suspect cacld in asymptomatic subjects with known causes of CLD (1b;A). TE often has false positive results; hence two measurements on different days are recommended in fasting conditions (5;D). TE values <10 kpa in the absence of other known clinical signs rule out cacld; values between 10 and 15 kpa are suggestive of cacld but need further test for confirmation; values >15 kpa are highly suggestive of cacld (1b;A).

14 BAVENO VI (2015) Screening and surveillance: Invasive and non-invasive methods (changed from Baveno III-V) Criteria to confirm cacld (new) Invasive methods are employed in referral centres in a stepwise approach 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 histology provides quantitative data on the amount of fibrosis and holds prognostic 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).

15 BAVENO VI (2015) Screening and surveillance: Invasive and non-invasive methods (changed from Baveno III-V) Diagnosis of CSPH in patients with Viral cacld (new) Liver stiffness by TE ( kpa; at least two measurements on different days in fasting condition; caution should be paid to flares of ALT; refer to EASL guidelines for correct 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 with cacld of all aetiologies (2b;B). Identification of patients with cacld who can safely avoid screening endoscopy (new) Patients with a liver stiffness <20 kpa and with a platelet count >150,000 have a very low risk of having varices requiring treatment, and can avoid screening endoscopy (1b;A).

16 The Spleen in the Assessment of Advanced Chronic Liver Disease INCREASE IN SPLEEN STIFFNESS?? Congestion Hypertrophy and Hyperplasia Fibrosis

17 Measurement of Spleen Stiffness by Fibroscan 1. Sufficient intercostal space width 2. - Splenic parenchymal thickness > 4 cm (by US) 3. Success rate > 60% and IQR < 30% of median value 4. Intra-observer reproducibility 96%, inter-observer reproducibility 94% 5. Probe upper limit 75 kpa

18 Spleen Stiffness Colecchia A. et al., Gastroenterology 2012 ; 143(3): P = R² = 0, HVPG (mm Hg) 25 HVPG (mm Hg) P = R2 = 0, Compensated Cirrhosis Liver Stiffness (kpa) Spleen Stiffness (kpa) Esophageal Varices: NO Esophageal Varices: YES 70 80

19 Liver and Spleen Stiffness for the Prediction of the Presence of Esophageal Varices Colecchia A. et al., Gastroenterology 2012 ; 143(3): EV: NO EV: YES EV: NO EV: YES

20 PINZANI M Non Invasive Measures Including Spleen Parameters

21 Non Invasive Measures Including Spleen Parameters

22 Molecular Imaging of Collagen DEC-MRI with EP-3533 contrast Fuchs BC et al. J Hepatol 2013 Courtesy of Dr. Annalisa Berzigotti, Hospital Clinic Barcelona

23 Measuring Collagen: What are we missing? Hepatocyte necrosis/apoptosis,inflammatory infiltration Neoangiogenesis and microthrombosis Activation of the stem cell compartment All potential targets for bioimaging and functional imaging Increasing tissue hypoxia and endothelial dysfunction Ductular reaction and reactive cholangiocytes Unbalanced vasoconstrictors and scar contraction

24 To Be Exploited Elastin, Collagen cross-linking: IRREVERSIBILITY Immunophenotype, macrophage markers: REVERSIBILITY + + BR55: A lipopeptide-based VEGFR2targeted US contrast agent for molecular imaging of angiogenesis Pochon et al. Invest Radiol 2010 Willmann et al Radiology 2008 Binding is amplified by ARF Frinking et al. Ultras Med Biol 2012

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