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

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

5. NCPF EHPVO SPLEEN SMV Non-Cirrhotic Portal Hypertension

6. Non-cirrhotic Portal Hypertension, predominantly presents with bleed G.B.Pant Hospital (1983 - 1995) Bleeder 53.0% (1133) NB 47.0% (1004) Bleeder 84.5% (207) NB 15.50% (32) NB 5.50% (13) Bleeder 94.5% (223) Total Patients (n=2137) NCPF (n=207) EHPVO (n=236) Digestion 1998

7. NORMAL NCPF Hepatic vein Hepatic vein Sinusoid Portal vein Portal vein Sinusoid Increased Resistance

8. NCPF : PATHOLOGY

9. NCPF : PATHOLOGY Thickening of portal venules Increased collagen in portal vein wall

11. LIVER PORTAL VEIN STOMACH SPLEEN GASTROSPLENIC VEIN ANTERIOR MESENTERIC POSTERIOR MESENTERIC SPLENIC TRIBUTARY SITE OF CANNULATION ATTACHED TO A THREE WAY STOP COCK

13. NCPF EHPVO SPLEEN SMV

14. Cavernoma Porto-porto collateral circulation Dilated hepatic artery

15. Portal Vein Thrombosis Pathogenesis Acquired prothrombic disorders Inherited prothrombic disorders Venous thrombosis Local precipitating factors

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

17. CIRRHOTIC PORTAL HYPERTENSION

18. Clinical Consequences of CIRRHOTIC Portal Hypertension Portal hypertension Ascites Hypersplenism Collateral formation Encephalopathy Decreased liver function Portal gastropathy Esophago-gastric varices Altered homeostasis Hypoxemia, PPS, HPS

19. Large Oesophageal Varices With Red Signs

20. Fibrous septa Regenerative nodules Increased Intra Hepatic Vascular Resistance (IHVR) to portal flow Portal hypertension Disruption architecture of microcirculation Increased porto- collateral resistance Contraction of myofibroblasts Splanchnic vasodilatation Increased portal flow Alcohol, HBV, HCV, autoinmmune, metabolic, Wilson’s disease Pathophysiology of “Cirrhotic” Portal Hypertension. Increased vascular tone REVERSIBLE

21. Hepatocyte Sinusoidal endothelium Space of Disse Hepatic Stellate Cell Kupffer Cell Cells of the Hepatic Sinusoid

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

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.

28. Molecular regulation eNOS eNOS gene Golgi PKB Hsp90/ Caveolin  arginine NO citrulline eNOS caveolae Relaxation GTP GMP PDE PKG CNG  Ca Endothelial Cells Stellate Cell Regulation Shear force, growth factors Lipids, hormones, HMGCoA reductase inhibitors Shah 2001

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

31. Molecular regulation of ET-1 ET-1 gene AP1/GATA Prepro ET-1 Big ET-1 ECE ET-1 eNOS activation ET-A ET-B Contractile cell Contraction  Ca/PKC IP 3 /DAG PLC G-proteins ET-B Endothelial Cells Regulationof ET-1 Hormones, Mechanical forces Growth factors Vasoactive peptides Shah 2001

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 ?

38. Clinical Consequences of CIRRHOTIC Portal Hypertension Portal hypertension Ascites Hypersplenism Collateral formation Encephalopathy Decreased liver function Portal gastropathy Esophago-gastric varices Altered homeostasis Hypoxemia, PPS, HPS

40. Bleeding GOV1 Varix

41. Bleeding Gastric Varix

44. Patients with good outcome HVPG  20 mmHg HVPG  20 mmHg 0 20 40 60 80 100 1 2 3 4 5 6 7 Days after admission p<0.0003

49. Acute Variceal Bleed: TEST STUDY Probability of Remaining Bleed Free Hepatology Sept. 2000 0 0 1 2 3 4 5 6 7 25 50 75 100 Days 67% 68% NS Sclerotherapy Terlipressin

50. Acute Variceal Bleed: TEST STUDY Probability of Survival 75% 82% NS 0 0 7 14 21 28 35 42 20 40 60 100 Days Sclerotherapy Terlipressin 80

51. Intravariceal Sclerotherapy Alcohol, EO

52. Endoscopic Variceal Ligation

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

55. TIPS in Acute Variceal Bleed

57. SIGNIFICANCE OF HEPATIC GRADIENT 5 10 12 15 20 25 30 35 0 1 2 3 4 5 Esophageal Varices NORMAL BLEEDERS NON-BLEEDERS HEPATIC GRADIENT (mm Hg)

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

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

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

71. mm Hg Portal Pressure Portal systemic shunting * * * Murine Schistosomiasis model Sarin et al , JCI 1991 Pre-primary Prophylaxis

73. SEVERE = Red Marks of any type MILD = Mosaic Pattern of any type

74. GASTRIC ANTRAL VASCULAR ECTASIA

75. GASTRIC ANTRAL VASCULAR ECTASIA

77. SUMMARY: Cirrhotic Portal Hypertension HVPG (mmHg) varices BLEEDING ASCITES PHG SBP HE 0 5 12 10 subclinical portal hypertension HRS

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

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)

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

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

87. GOV2 GOV1

88. IGV 1

90. Bleeding gastric varix

91. Glue injection

92. SUMMARY: Cirrhotic Portal Hypertension HVPG (mmHg) varices BLEEDING ASCITES PHG SBP HE 0 5 12 10 subclinical portal hypertension HRS

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