Francesco Vizzutti. Azienda Ospedaliero Universitaria Careggi, Firenze

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1 Francesco Vizzutti Azienda Ospedaliero Universitaria Careggi, Firenze Il sottoscritto dichiara di non aver avuto negli ultimi dodici mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label

2 HEPATIC VENOUS PRESSURE GRADIENT

3 PORTAL HYPERTENSION Complicanza ineluttabile della cirrosi epatica caratterizzata dall aumento patologico del gradiente di pressione portale o HVPG (>5 mmhg) Complicanze: Sanguinamento da rottura di varici Ascite, HRS e SBP PHG e colopatia dell ipertensione portale HPS, PPH Spillover porto-sistemico & HE

4 SBP HE Ascites PHG Bleeding Varices HRS HPS PPH HVPG (mmhg) SUBclinical Portal Hypertension 5 0

5 DIRECT METHODS USED TO MEASURE PORTAL PRESSURE Umbilical vein catheterization Transhepatic portal vein catheterization Splenic pulp pressure measurement Pre-Sinusoidal Portal Hypertension Intra-operative mesenteric vein catheterization

6 HVC IS PERFORMED UNDER STRICTLY STERILE CONDITION.. avoid spitting

7 VENOUS ACCESS SITES FOR HEPATIC VEIN CATHETERIZATION

8 HEPATIC VEIN CATHETERIZATION Balloon catheter FHVP WHVP Portal P HVPG=WHVP-FHVP PCG=portal P- cava P

9 HVPG MEASUREMENT

10 NORMAL Hepatic vein Portal vein

11 CIRRHOTIC Hepatic vein x Portal vein x x x

12 RATIONALE FOR HVC Portal Pressure (mmhg) WHVP (mmhg) Agreement RI Overall series 0.99 HCV 0.94 Alcool 0.93 HCV + Alcool 0.97 RI - interclass correlation coefficient Perelló, Hepatology 1999

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14 HVPG MEASUREMENTS AT HEPATIC VEIN CATHETERIZATION Complications: puncture site, supraventricular arrhythmias Contraindications: plt<20x10 9 /PT<30% (call repl.) allergic reaction

15 THREE IN ONE 1 1. HVPG 2. TJLB 3. CO 2 Portography 3 2

16 THE NATURAL HISTORY AND PROGNOSIS OF CHIRROSIS Compensated Stage 1 Stage 2 No varices No ascites 7% Varices No ascites 4.4% 1% Decompensated Stage 3 Stage 4 6.6% Ascites ± Varices 7.6% Bleeding ± Ascites 4% 3.4% 20% 57% 50% within 6 w. from BOV DEATH J Hep 2006, D Amico et al

17 Baveno V BACKGROUND: PRE-PRIMARY PROPHYLAXIS 20th ANNIVERSARY INTERNATIONAL CONSENSUS WORKSHOP AND POSTGRADUATE COURSE: current consensus and future directions in the diagnosis and treatment of portal hypertension PROPOSED STATEMENTS: Baveno III: Portal Pressure is predicting of varices formation. More data are needed. Baveno IV: De novo formation of varices: 4-6% per year HVPG is predictive of varices formation Stratify: HVPG: 6-10 and no varices HVPG>10 and no varices Small Varices NSBB are ineffective in preventing EV formation. (Groszmann RJ et al. NEJM 2005) Pts with small varices respond to BB because haemodynamic changes have developed yet. Prevention of the development of complications of portal hypertension is an important area of research. (5;D) Pre-primary prophylaxis should only include patients without gastro-esophageal varices.(5;d) Hepatic venous pressure gradient (HVPG) 10 mmhg is predictive of varices formation and decompensation.(1b;a) Treatment of underlying liver disease may reduce portal hypertension and prevent its clinical complications.(1b;a) There is no indication, at this time, to use beta-blockers to prevent the formation of varices.(1b;a) HVPG measurement in pre-primary prophylaxis may be recommended only in the context of clinical trials.(5; D)

18 THE NATURAL HISTORY AND PROGNOSIS OF CHIRROSIS Compensated Stage 1 Stage 2 No varices No ascites 7% Varices No ascites 4.4% 1% Decompensated Stage 3 Stage 4 6.6% Ascites ± Varices 7.6% Bleeding ± Ascites 4% 3.4% 20% 57% 50% within 6 w. from BOV DEATH J Hep 2006, D Amico et al

19 Baveno V PROPOSED STATEMENTS PRIMARY PROPHYLAXIS 20th ANNIVERSARY INTERNATIONAL CONSENSUS WORKSHOP AND POSTGRADUATE COURSE: current consensus and future directions in the diagnosis and treatment of portal hypertension HVPG BAVENO IV: A la carte treatment using HVPG-response in primary prophylaxis needs to be evaluated, especially in high-risk patients. Until then, routine use of HVPG cannot be recommended (5;D) - In centers where adequate resources and expertise are available, HVPG measurement should be routinely used for prognostic and therapeutic indications(5;d) -Controlled trials using pharmacological therapy in primary prophylaxis should include HVPG measurements(5;d) -A decrease in HVPG of at least 20% from baseline or to 12 mmhg after chronic treatment with NSBB is clinically relevant in the setting of primary prophylaxis(1a;a) - Acute HVPG response to intravenous propranolol may be used to identify responders to betablockers, specifically a decrease in HVPG of 10% or to 12 mmhg may be relevant in this setting (1b;A)

20 THE NATURAL HISTORY AND PROGNOSIS OF CHIRROSIS Compensated Stage 1 Stage 2 No varices No ascites 7% Varices No ascites 4.4% 1% Decompensated Stage 3 Stage 4 6.6% Ascites ± Varices 7.6% Bleeding ± Ascites 4% 3.4% 20% 57% 50% within 6 w. from BOV DEATH J Hep 2006, D Amico et al

21 Baveno V SECONDARY PROPHYLAXIS 20th ANNIVERSARY INTERNATIONAL CONSENSUS WORKSHOP AND POSTGRADUATE COURSE: current consensus and future directions in the diagnosis and treatment of portal hypertension Time to start secondary prophylaxis Secondary prophylaxis should start as soon as possible from day 6 of the index variceal episode (5, D) The start time of secondary prohylaxis should be documented (Baveno IV) (Baveno V: No Changes) BACKGROUND: Baveno IV: Patients with cirrhosis who have not received primary prophylaxis: NSBB (1a;A), EVL (1a;A) or both (1b;A) should be used for prevention of recurrent bleeding Combination of NSBB and EVL is probably the best treatment(1a;a) but more trial are needed Assessment of haemodynamic response to drug therapy provides prognostic information about rebleeding risk(2b B) Patients with cirrhosis who are on NSBB for PP and bleed: EVL should be added(5d) PROPOSED STATEMENTS: Patients with Cirrhosis Combination of beta-blockers and band ligation is the preferred therapy as it results in lower rebleeding compared to either therapy alone.(1a;a) Hemodynamic response to drug therapy provides information about rebleeding risk and survival(1a;a) The addition of ISMN to beta-blockers may improve the efficacy of treatment in hemodynamic non-responders (2;A Check) Cirrhotics unable/unwilling to VBL NSBB + ISMN is the preferred option(1a;a) Cirrhotics and contraindication/intolerance to NSBB EVL is the preferred treatment(5d)

22 Baveno V BACKGROUND: TREATMENT OF ACUTE BLEEDING 20th ANNIVERSARY INTERNATIONAL CONSENSUS WORKSHOP AND POSTGRADUATE COURSE: current consensus and future directions in the diagnosis and treatment of portal hypertension PROPOSED STATEMENTS: Baveno IV: No adequate prognostic model has been developed to predict outcomes(2b;b) No individual characteristics sufficiently predict prognosis(2b;b) Child-Pugh class, active bleeding at endoscopy, hepatic venous pressure gradient (HVPG), infection, renal failure, severity of initial bleeding, presence of portal vein thrombosis or of hepatocellular carcinoma and ALT have been identified as indicators of poor prognosis (2b;B) POST BAVENO IV: HVPG 20 independent predictor of 5-day failure in AVB (Abrdaldes JG et al 2008) Role for early TIPS in HVPG>20? (Thabut 2007) HVPG >20 mmhg, Child-Pugh Class C, and active bleeding at endoscopy are the variables most consistently found to predict 5-day treatment failure.(2b;b) Child-Pugh class C, MELD score > 18, and failure to control bleeding or early rebleeding are the variables most consistently found to predict 6-week mortality.(2b;b) Patients with GI bleeding and features suggesting cirrhosis should have upper endoscopy as soon as possible after admission(within 12 hours)(5d) In suspected variceal bleeding, vasoactive drugs should be started as soon as possible, before diagnostic endoscopy. (1B) Endoscopic therapy is recommended in any patient who presents with documented upper GI bleeding and in whom esophageal varices are the cause of bleeding(1a;a)

23 APPLICATIONS OF HVPG MEASUREMENT Diagnosis of portal hypertension Classification of portal hypertension Presinusoidal: normal WHVP and FHVP Assessment of disease severity Sinusoidal: increased WHVP and normal FHVP Response Postsinusoidal: to therapy both for WHVP portal and hypertension FHVP increased

24 reduction to <12 mmhg reduction of 20% 12 mmhg variceal rupture reduction of 10-12% at acute propranolol 20 mmhg treatment failure and mortality in VB reduction of 10% 10 mmhg clinicaly significant PH CHRONIC LIVER DISEASE COMPENSATED CIRRHOSIS DECOMPENSATED CIRRHOSIS DEATH 6 mmhg risk of disease progression post OLT HCV SINGLE HVPG MEASUREMENT CHANGES IN HVPG 16 mmhg increased risk of mortality 22 mmhg risk of mortality in AAH reduction of 20%

25 APPLICATIONS OF HVPG MEASUREMENT Diagnosis of portal hypertension Classification of portal hypertension Assessment of disease severity Response to therapy for portal hypertension Assessment of new therapeutic agents Changes in HVPG and guidance of therapy Identification of high-risck populations