Pathophysiology of Portal Hypertension

Transcription

1 Pathophysiology of Portal Hypertension Jaime Bosch, M.D. Professor of Medicine, University of Barcelona Liver Unit, Hospital Clínic-IDIBAPS, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (Ciberehd)

2 Impact of Portal Hypertension in Chronic Liver Diseases Encephalopathy Palmar erithema Cirrhosis Spider nevi Hepatopulmonary Sd Portopulmonary HT Cardiomyopathy Varices, PHG Ascites, SBP Hepatorenal sd Splenomegaly First cause of death and of liver transplantation in cirrhotic patients Edema

3 Natural History Increased Portal Pressure (HVPG > 10 mmhg) Stage 1 1-y y mortality: 1% untreated Formation of Varices Na retention Dilatation of Varices Ascites Rupture of Varices (HVPG > 12 mmhg) Stage 2 Drugs treated 1-y y mortality: 3% TIPS Stage 3 Local Treatments 1-y y mortality: 20% Stage 4 1-y y mortality: 50%

4 HVPG: what is it? An indirect measurement of the portal pressure gradient based on hepatic vein catherisation Wedged pressure Free pressure HVPG = WHVP FHVP

5 Hemodynamic factors in the pathophysiology of portal hypertension 1. Increased hepatic vascular resistance 3. Formation of portosystemic collaterals 2. Increased portal blood inflow Pressure = Resistance x Blood flow

6 1. Increased Hepatic Resistance Two different components Mechanical Architectural changes Fibrosis Vascular occlusion Dynamic Endothelial dysfunction Vascular tone

7 The Increased Hepatic Vascular Tone: Vasodilator / Vasocontrictor Imbalance in the Pathogenesis A New Therapeutic of the IncreasedTarget Intrahepatic Vascular Resistance in Cirrhosis Cirrhotic Liver Vasoconstrictors Vasodilators Vasoconstrictors Endothelin Angiotensin Norepinephrine Leukotrienes Thromboxane COX 2 -Prostanoids A2 Other? Vasodilators Nitric Oxide Carbon Monoxide Prostaglandins,SH Other? 2 Increasing hepatic NO availability increasing liver NO production reducing NO scavenging Selective delivery of NO to the liver (NCX-1000)

8 Mechanisms for Decreased Hepatic NO Synthesis in Cirrhosis - Decreased enos expression not proven - Decreased enos activity well demonstrated Intrahepatic Endothelial Dysfunction Increased caveolin expression (cholestasis) Decreased Akt-p dependent enos phosphorilation Decreased production of BH Decreased production of BH 4 statins supplements Scavenging of NO by O. (reduced SOD activity) Increased levels of asymetric-dma antioxydants

9 2. Increased Portal Inflow β-blockers Terlipressin Somatostatin Splanchnic vasodilation Increased NO, CO, glucagon, endocannabinoids New targets Hyperkinetic syndrome Increased cardiac index Decreased peripheral resistance Hypotension & Effective hypovolemia Activation of vasoactive factors Na retention

10 3. Formation of portal-systemic collaterals and varices How portosystemic collateral blood vessels develop during portal hypertension? Opening of pre- existing blood vessels (increased pressure) Growth of new blood vessels (angiogenesis)

11 Baseline HVPG is the strongest predictor of the development of varices 1 Baseline HVPG<10mmHg and HVPG>10% Free of Varices (%) Baseline HVPG<10mmHg alone Baseline HVPG 10mmHg alone Months of Follow-up Development of varices is lower in patients with a baseline HVPG <10 and an HVPG reduction >10%

12 VEGFR-2 blockade by SU5416 decreases the formation of portosystemic collaterals in portal hypertensive rats Fernández et al, Gastroenterology (2004)

13 Mechanisms of increased splanchnic blood flow in portal hypertension Increased splanchnic arteriolar vasodilatation Increased splanchnic neovascularization (angiogenesis) Increased splanchnic blood flow

14 VEGFR-2 blockade by SU5416 decreases mesenteric and intestinal blood flows in portal hypertensive rats Fernández et al, J Hepatol (2005)

15 Mechanisms of increased splanchnic blood flow in portal hypertension Initiation (adaptative responses) Vasodilatation Maintenance (chronic scenario) Angiogenesis Rx: vasoconstrictors + anti-angiogenics angiogenics

16 Gleevec maturation PDGF c Rapamycin c VEGF formation

17 Combined VEGF and PDGF blockade reduces portal pressure, SMA blood flow and portosystemic collaterals Fernández et al, Hepatology 2007

18 New Therapeutic Perspectives in Portal Hypertension Cirrhosis of the liver Increased resistance Liver dysfunction Structural abnormalities + Increased hepatic vascular tone x Increased portal pressure Multi-target target anti-angiogenic angiogenic agents Dilation of pre-existing vessels Local anatomical factors Enhanced angiogenic factors (VEGF, PDGF, NO, CO) Formation of new vessels (Venous and Arterial) x x x Ascites Collaterals and Varices Splanchnic hyperemia

19 4. Dilation and Rupture of Varices Varix P Flow WT= ΔP P x r Repeat brisk increases in portal pressure and collateral blood flow caused by meals,, alcohol, exercise and increased intra-abdominal pressure

20 Factors Influencing the Severity of Variceal Bleeding Severity of Bleeding = Portal Pressure x Area of Varix Rent Blood viscosity x H* * H = Defects in hemostasis (partly correctable by rfviia)

21 HVPG Determines the Prognosis of Variceal Bleeding 60% 40% p < % p < % p < % 23% 0% 12% 20% 0% Failure to Control AVB p <0.01 Early Rebleeding p < year Mortality p <0.02 Transfusions (UU) Days in ICU Days in Hospital HVPG > 20 mmhg HVPG < 20 mmhg Moitinho et al, Gastroenterology 1999

22 Factors Influencing the Outcome of Variceal Hemorrhage Blood in GI Tract Abnormal Hemostasis Portal Pressure Variceal Pressure Somatostatin Octreotide rf-viia persistent bleeding infections enhanced fibrinolysis Unstable clot

23 Acknowledgements Staff & fellows Hepatic Hemodynamic Lab Juan Carlos García-Pag Pagán Juan G-AbraldesG Mercedes Fernández ndez Aina Rodriguez Annalisa Berzigotti Sebastián Raffa Carolina Tiani Filippo Scheppis Eva Erice Elba Llop Andrea De Gottardi Angels Baringo Laura Rocabert Rosa Saez

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25 Hepatology, September 2007

26 Pathophysiology of Portal Hypertension Δ Portal Pressure = Resistance x Blood Flow Increased Resistance (dynamic / mechanic) TIPS New targets Increased Blood Flow (splanchnic vasodilation) Current treatments Increased Portal Pressure β-blockers Terlipressin Somatostatin

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28 Assessment of Portal Pressure by HVPG Hepatic Venous Pressure Gradient Equivalent to Portal Pressure Gradient Gold standard in the assessment of portal hypertension*, the most common and lethal complication of cirrhosis * defined by an HVPG > 5 mmhg

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30 Typical measurement of HVPG using a balloon catheter mmhg 30 WHVP WHVP 20 HVPG= 24 mmhg 10 FHVP 0