1. PATHOGENESIS AND MANAGEMENT OF PORTAL HYPERTENSION Dr. S.K.Sarin, MD, DM Professor and Head Dept. of Gastroenterology, G.B.Pant Hospital University of Delhi, India
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3. Hemodynamic Assessment of Portal Hypertension IVC Sinusoid Hepatic vein Portal vein Splenic vein Pre-hepatic Post-hepatic Pre-sinusoidal Post-sinusoidal Sinusoidal Hepatic vein P Gradient Portal P N N N N N N
9. NCPF : PATHOLOGY Thickening of portal venules Increased collagen in portal vein wall
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11. LIVER PORTAL VEIN STOMACH SPLEEN GASTROSPLENIC VEIN ANTERIOR MESENTERIC POSTERIOR MESENTERIC SPLENIC TRIBUTARY SITE OF CANNULATION ATTACHED TO A THREE WAY STOP COCK
16. Pathogenesis of NCPH Infection, other agents Severe EARLY, LATE AGE Chronic / mild LATE AGE Portal Pyemia Large thrombus PV Chronic antigenemia Phelbosclerosis Occlusion of Main PV, Cavernoma Occlusion of 3 , 4 PV branches, RES Pre-sinusoidal Resistance EHPVO NCPF PHT Pro-thrombotic State
22. Capillarization of Sinusoids Normal Liver Basal membrane-like ECM in space of Disse Quiescent vitamin A-rich hepatic stellate cells Hepatocytic microvilli and sinusoidal fenestrations Liver with chronic injury Fibrillar ECM in space of Disse Activated hepatic stellate cells Loss of hepatocytic microvilli and sinusoidal fenestrations
23. Contractile Features of Hepatic Stellate Cells Pinzani M. et al. J.Clin.Invest. 1992;90:642-646
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26. NO-Synthases (NOS) nNOS (NOS1) - “nervous” NOS Constitutively present in nervous system. iNOS (NOS2) - “inducible” NOS Synthesized “de novo” in macrophages, SMC, hepatocytes and other cell types. Production of large amounts of NO independently of hemodynamic/mechanical stimuli. eNOS (NOS3) - “endothelial” NOS Found in endothelial cells. Small amounts produced in response to endogenous and exogenous stimuli, including shear stress.
29. Nitric Oxide (NO) eNOS iNOS NO Post-translational defect in liver NO Vasoconstriction In splanchnic vesels Hypo-responsiveness To vasoconstrictors, NE, ET Vasodilation Induced by endotoxemia TNF alpha Caveolin-1 Calmodulin Shear Stress
30. NO ET-1 Dilation Angiogensis Collateral circulation Splanchnic circulation NO Dilation Hepatic circulation E.C. E.C. E.C. NO NO CC CC PATHOGENESIS OF PORTAL HYEPERTENSION
34. NO ET-1 Dilation Angiogensis Collateral circulation Splanchnic circulation NO Dilation Hepatic circulation E.C. E.C. E.C. NO NO CC CC PATHOGENESIS OF PHT
35. Nitric Oxide (NO) eNOS Inos and eNOS NO Post-translational defect in liver NO Vasoconstriction In splanchnic vessels Hypo-responsiveness To vasoconstrictors, NE, ET Vasodilation Induced by endotoxemia TNF alpha Caveolin-1 Calmodulin Shear Stress
36. Causes of vascular hyporeactivity in cirrhosis Vasoconstrictors Catecholamines vasopressin Angiotensin II ET-1 Others ? All Intracellular Ca + Vasodilators ANP CGRP ET-3 Others? Postreceptor mechanisms Postreceptor defect Central nervous syustem vasorelaxation Smooth muscle cell Prostacyclin NO
37. Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown Hepatology, 2002 Vascular tone Decreased vascular tone Vascular NO overproduction Increased eNOS-derived NO synthesis reduced eNOS-derived NO synthesis Microcirculatory NO deficiency Increased Vascular tone Hepatic Microvascularture Splanchnic and systemic vascularture ?
53. Meta-analysis of Treatments of Acute Variceal Bleeding 0.5 1.0 1.5 Pooled odds ratio a) Better b) Better a) Sclerotherapy Vs. b) Balloon tamponade a) Sclerotherapy Vs. b) Vasopressin / terlipr a) Sclerotherapy Vs. b) Somatostatin a) Sclerotherapy Vs. b) Octreotide a) Band ligation Vs. b) Sclerotherapy a) EST or EVL + drugs Vs. b) Sclerotherapy No. of Trials 5/1 4 3 3 14 5 Failure to control bleeding Mortality
58. 100 50 0 0 25 50 75 100 Survival NS Rebleed 40% Control Control Meta-Anlaysis of Beta Blockers for Secondary Prophylaxis (Luketic GCNA, 2000)
59. 0.5 1.5 1 Treated Better Treated Worse Recurrent bleeding Mortality Sclerotherapy Vs. non active treatment Sclerotherapy Vs. -Blockers Sclerotherapy + -Blockers Vs. sclerotherapy Banding Vs. Sclerotherapy No. Trials (Patients) 10 1259 9 752 10 600 13 1091 Meta-analysis of Treatments for Prevention of Variceal Rebleeding
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62. Child-Pugh Class A Small varices Large varices Child-Pugh Class B+C Small varices Large varices 1 year: 5% 1 year: 13% 6 years:19% 6 years: 44% Bleeding 1 year: 16% 1 year = 26% 6 years:19% 6 years = 66% 11% 1 year:22% 2 years:31% B:15% C:50% 1 year:43% 2 years:62% 42-day deaths Rebleeding INCIDENCE OF VARICEAL BLEED
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69. Approach to Primary Prophylaxis for EV High risk varices Drug therapy Propranolol + ISMN Propranolol Beta-Blockers contraindicated/ Side-effects EVL HVPG > 12mmHg < 12mmHg EVL Continue drug R X
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71. mm Hg Portal Pressure Portal systemic shunting * * * Murine Schistosomiasis model Sarin et al , JCI 1991 Pre-primary Prophylaxis
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73. SEVERE = Red Marks of any type MILD = Mosaic Pattern of any type
78. URINE OUTPUT MEAN ARTERIAL PR. GFR SPLANCH NIC VASODILATION -NO, PC, GLUCAGON RENAL VASOCONSTRICTION -RAAS, SNS, ENDOTHELINS CHILD’S A CHILD’S B CHILD’S C HEPATORENAL SYNDROME
79. ROLE OF ENDOTOXINS: The Vallance Moncada hypothesis for the Role of NO in the hyperdynamic circulation in cirrhosis Cirrhosis Portal hypertension Endotoxaemia cytokines iNOS NO Ascites Sodium & water retention Effective blood volume Resistance Blood flow Cardiac output Blood pressure
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81. Systemic hemodynamics in cirrhosis with ascites P<0.001 for all values (ANOVA) Healthy Cirrhosis with ascites Subjects no HRS HRS 5.5±0.5 5.7±0.2 3.0±0.2 Cardiac index (L/min m 3) 59±4 66±2 44±2 Plasma volume (mL/Kg) 69±5 82±2 87±3 MAP (mmHg)
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83. Ml/24 h p <0.05 Group A, n=12 Group B, n=12 HRS: Creatinine clearance (ml/min) at baseline, day-4, day-8, day-15 in group A (Terlipressin) and group B (placebo) patients. (Solanki 2003) HRS: TERLIPRESSIN
84. HRS: 24 hour urine output (ml) at baseline, day-4, day-8, day-15 in group A (Terlipressin) and group B (placebo) patients. HRS: TERLIPRESSIN Ml/24 h p <0.05 Group A Group B
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86. Gastro Oesophageal Varices (GOV) Isolated Gastric Varices (IGV) Classification of GV Based on location Based on presentation Primary Secondary Am J Gastroenterol 1989 GOV1 GOV2 IGV1 IGV2
93. Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown Hepatology, 2002 Vascular tone Decreased vascular tone Vascular NO overproduction Increased eNOS-derived NO synthesis reduced eNOS-derived NO synthesis Microcirculatory NO deficiency Increased Vascular tone Hepatic Microvascularture Splanchnic and systemic vascularture ?
94. NO ET-1 Dilation Angiogensis Collateral circulation Splanchnic circulation NOS inhibitors, Antibiotic Vasoconstictora NO Dilation Hepatic circulation E.C. E.C. E.C. NO NO CC CC Over express NOS ET A Receptor Antagonist PATHOGENESIS TO THERAPY OF PHT
Notes de l'éditeur
At a previous international Consensus Conference it was decided to define PHG as mild when only MLP of any grade was present, and severe when RPL,CRS or BBS were present. This decision was based on common experience of participants, but it was agreed that the definition was tentative and needed prospective evaluation One of the aims of the study was to ascertain whether mild and severe PHG are different in term of the risk of bleeding
Another important lesion seen in portal hypertensive patients is GVE. This is a distinct clinical, endoscopic and histopathologic entity reported in association with scleroderma, atrophic gastritis and cirrhosis of the liver. This lesion is characterized by aggregates of red spots. When these aggregates are arranged in a linear pattern in the antrum of the stomach, as in these pictures, the term gastric antral vascular ectasia (GAVE) or “watermelon stomach is used”. The ectatic red spots may be more diffuse and involve the proximal antrum as well when they are termed as the “diffuse” variety of GVE. When red spots are present within the mosaic mucosa, the term most often used to describe these changes is severe PHG. However, if the background mucosa have no mosaic appearance, the term used to describe these spots is gastric vascular ectasia (GVE) Thus it would appear that PHG can be diagnosed if the MLP lesion is the underlying lesion, otherwise the diagnosis is GVE. While it is considered a distinct entity from PHG, it may be seen in liver cirrhosis and the differential diagnosis might be difficult. In the Baveno classification GAVE is included and considered as a part of the PHG syndrome.