Prof. Mohammad Umar. MBBS, MCPS, FCPS, FACG (USA), FRCP (London), FRCP (Glasgow), FAGA

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2 Prof. Mohammad Umar MBBS, MCPS, FCPS, FACG (USA), FRCP (London), FRCP (Glasgow), FAGA Chairman and Head Department of Medicine Rawalpindi Medical College, Rawalpindi. Consultant Gastroenterologist / Hepatologist Holy Family Hospital, Rawalpindi. President, Rawalians Research Forum General Secretary, Pakistan Society of Hepatology

3 Pathogenesis

4 CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES Cirrhosis is the Most Common Cause of Ascites Peritoneal malignancy Cirrhosis Heart failure Peritoneal tuberculosis Others Pancreatic Budd-Chiari syndrome Nephrogenic ascites

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7 PATHOGENESIS OF ASCITES Cirrhosis Hepatic venous outflow block Arteriolar resistance (vasodilation) Sinusoidal pressure (HVPG mmhg) Effective arterial blood volume Ascites Sodium and water retention Activation of neurohumoral systems (renin, angiotensin, aldosterone)

8 Vasodilatation and Ascites Result from an Increase in Nitric Oxide Portal Hypertension Bacterial translocation Shear stress Nitric Oxide Vasodilation ( SVR) Activation of neurohumoral systems ASCITES Sodium and water retention

9 Cirrhosis Worsening liver disease Intrahepatic resistance Systemic arteriolar resistance Sinusoidal pressure Effective arterial blood volume Refractory Ascites ascites Hepatorenal syndrome Sodium and water retention Renal Vasoconstriction Activation of neurohumoral systems

10 NATURAL HISTORY OF ASCITES Natural History of Ascites Portal Hypertension No Ascites HVPG <10 mmhg Mild Vasodilation Uncomplicated Ascites HVPG >10 mmhg Moderate Vasodilation Refractory Ascites HVPG >10 mmhg Severe Vasodilation Hepatorenal Syndrome HVPG >10 mmhg Extreme Vasodilation

11 Management

12 ULTRASOUND IS THE MOST SENSITIVE METHOD TO DETECT ASCITES Ultrasound is the Most Sensitive Method to Detect Ascites Ascites Liver

13 Routine PMN count Culture? SBP Initial Workup of Ascites Diagnostic Paracentesis Protein/Albumin INITIAL WORKUP OF ASCITES: DIAGNOSIS PARACENTESIS? cirrhotic ascites Glucose, LDH? secondary infection Optional? pancreatic ascites Amylase Cytology? malignant ascites

14 Indications DIAGNOSTIC PARACENTESIS Diagnostic Paracentesis New-onset ascites Admission to hospital Symptoms/signs of SBP Renal dysfunction Unexplained encephalopathy Contraindications None

15 Site of Action of Different Therapies for Ascites Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure TIPS Albumin TIPS PVS Effective arterial blood volume LVP PVS Diuretics Ascites Sodium and water retention Activation of neurohumoral systems

16 PREVENTION OF ASCITES Treatment of Ascites Portal Hypertension No ascites No specific therapy Consider salt restriction Uncomplicated ascites Refractory ascites Hepatorenal syndrome

17 TREATMENT OF UNCOMPLICATED ASCITES Treatment of Ascites Portal Hypertension No ascites Uncomplicated ascites Refractory ascites Hepatorenal syndrome

18 Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure Diuretics Na restrictiion Effective arterial blood volume Ascites Sodium and Sodium and water water retention retention Activation of neurohumoral systems

19 Spironolactone is More Effective Than Furosemide in Cirrhotic Patients with Ascites Response No response Total Furosemide ( mg/d) Spironolactone ( mg/d) Perez-Ayuso et al. Gastroenterology 1983; 84:961

20 Different Diuretic Regimens in Patients with Cirrhotic Ascites Progressive Schedule (n=50) Spironolactone (SP) mg/d Combination Schedule (n=50) SP 100mg/d + FUR 40mg/d 4days SP 400mg/d + Furosemide (FUR) mg/d SP 200mg/d + FUR 80mg/d 4days SP 400mg/d + FUR 160mg/d Santos et al., J Hepatol 2003; 39:187

21 Different Diuretic Regimens in Patients with Cirrhotic Ascites Progressive Schedule (n=50) Spironolactone (SP) mg/d Combination Schedule (n=50) SP 100mg/d + FUR 40mg/d 4days SP 400mg/d + Furosemide (FUR) mg/d SP 200mg/d + FUR 80mg/d 4days SP 400mg/d + FUR 160mg/d Santos et al., J Hepatol 2003; 39:187

22 Progessive Schedule of Diuretics is Preferred in Cirrhotic Ascites Progressive Schedule (n=50) Combination Schedule (n=50) Response Rate 94% 98% Time to Response 12.8 days 12.3 days Dose reduction needed 34% 68% p=0.002 Santos et al., J Hepatol 2003; 39:187

23 Large-Volume Paracentesis (LVP) vs. Diuretics in Uncomplicated Ascites LVP Faster resolution of ascites (of particular relevance in hospitalized patients) Fewer complications Diuretics General applicability Ease of administration Low cost

24 TREATMENT OF PATIENTS WITH UNCOMPLICATED ASCITES Treatment of Ascites Portal Hypertension No ascites Uncomplicated ascites 1) Salt restriction + diuretics 2) Large volume paracentesis (LVP) in hospitalized patients with tense ascites Refractory ascites Hepatorenal syndrome

25 MANAGEMENT OF UNCOMPLICATED ASCITES Management of Uncomplicated Ascites Definition: Ascites responsive to diuretics in the absence of infection and renal dysfunction Sodium restriction Effective in 10-20% of cases Predictors of response: mild or moderate ascites, Urine Na excretion > 50 meq/day Diuretics Should be spironolactone-based A progressive schedule (spironolactone furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide)

26 Management of Uncomplicated Ascites Sodium Restriction 2 g (or 5.2 g of dietary salt) a day Fluid restriction is not necessary unless there is hyponatremia (<125 mmol/l) Goal: negative sodium balance Side effect: unpalatability may compromise nutritional status

27 Management of Uncomplicated Ascites Dosage Diuretic Therapy Spironolactone mg/day Furosemide ( mg/d) for inadequate weight loss or if hyperkalemia develops Increase diuretics if weight loss <1 kg in the first week and < 2 kg/week thereafter Decrease diuretics if weight loss >0.5 kg/day in patients without edema and >1 kg/day in those with edema Side effects Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia

28 TREATMENT OF REFRACTORY ASCITES Treatment of Ascites Portal Hypertension No ascites Uncomplicated ascites Refractory ascites Hepatorenal syndrome

29 DEFINITION AND TYPES OF REFRACTORY ASCITES Definition and Types of Refractory Ascites Occurs in ~10% of cirrhotic patients Diuretic-intractable ascites 80% Therapeutic doses of diuretics cannot be achieved of diuretic-induced complications because Diuretic-resistant ascites 20% No response to maximal diuretic therapy (400 mg spironolactone mg furosemide/day) Arroyo et al. Hepatology 1996; 23:164

30 Patients with Refractory Ascites Have A Worse Survival than Patients with Diuretic- Responsive Ascites 1.0 Survival probability Non refractory ascites p< Refractory ascites Months Salerno et al., Am J Gastroenterol 1993; 88:514

31 Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure LVP + Albumin Effective arterial blood volume Ascites Sodium and water retention Activation of neurohumoral systems

32 Consequences of Post-Paracentesis Circulatory Dysfunction (PCD) Shorter time to ascites recurrence Higher incidence of hyponatremia and renal dysfunction Higher mortality Gines et al., Gastroenterology 1996; 111:1002; Ruiz del Arbol et al., Gastroenterology 1997; 113:579

33 Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure TIPS Effective arterial blood volume Ascites Sodium and water retention Activation of neurohumoral systems

34 Compared to LVP, TIPS Reduces Ascites Recurrence But Increases Risk of Encephalopathy LVP TIPS p (n=35) (n=35) Recurrent ascites 11.7± 2.7* 3.6 ± TIPS obstruction - 40% - Grade 3-4 PSE 0.5 ± ± Death 51% 57% ns * Episodes/patient Gines et al., Gastroenterology 2002; 123:1839

35 Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure PVS Effective arterial blood volume Ascites Ascites Sodium and water retention Activation of neurohumoral systems

36 Peritoneo-Venous Shunt (PVS) is Useful in the Treatment of Refractory Ascites Use of jugular vein will hinder TIPS placement One-way valve Intraabdominal adhesions may complicate liver transplant surgery

37 LARGE VOLUME PARACENTESIS (LVP) VS. PERITONEOVENOUS SHUNT (PVS) IN REFRACTORY ASCITES Large Volume Paracentesis (LVP) vs Peritoneovenous Shunt (PVS) in Refractory Ascites LVP PVS p value Episodes of recurrent ascites <0.001 PVS obstruction - 40% - Hospital stay 48 ± 8 44 ± 6 ns Survival 57% 44% ns Gines et al., N Engl J Med 1991; 325:829

38 TREATMENT OF REFRACTORY ASCITES Treatment of Ascites Portal Hypertension No Ascites Uncomplicated Ascites Refractory Ascites 1) LVP + albumin 2) TIPS 3) PVS (in non-tips, non-transplant candidates) Hepatorenal Syndrome LVP = large volume paracentesis TIPS = transjugular intrahepatic portosystemic shunt

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40 Thanks

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42 Thanks

43 Underfilling Theory Splanchnic Pooling (venous vasodilatation) Effective Blood Volume (EBV) Renin-Angiotensin- Aldosteron-System Sec. Retention of Sodium / Water Ascites

44 Underfilling Theory Splanchnic Pooling (venous vasodilatation) Effective Blood Volume (EBV) Cardic Output Plasma Volume = Systemic Hypervolaemia Renin-Angiotensin- Aldosteron-System Sec. Retention of Sodium / Water Ascites

45 Overflow Theory Portal Hypertension "Hepatorenal Reflex" Prim. tubular Retention of Sodium/Water Effective Blood Volume Ascites Liebermann et al. Gastroenterology 1989

46 Overflow Theory Portal Hypertension Hepatorenal Reflex Prim. tubular Retention of Sodium/Water Effective Blood Volume low blood pressure Ascites Liebermann et al. Gastroenterology 1989

47 Blood Pressure in Health and Cirrhosis mmhg SYST p<0.005 Normal subjects NS Patients with liver cirrhosis 90 MABP p< NS NS DIAST p< h Nacht Night Tag Day Henriksen et al. 1996

48 Splanchnic Pooling (venous vasodilatation) Portal Hypertension Effective Blood Volume hepatorenal Reflex Renin-Angiotensin- Aldosteron-System Prim. tubular Retention of Sodium/Water Sec. Retention of Sodium / Water Effective Blood Volume Ascites Ascites

49 Peripheral Arterial Vasodilatation Portal Hypertension NO Arterial Splanchnic Vasodilatation EBV Right Atrial Volume Receptors ANP Sympathetic Nervous System SNS RAAS Sec. Retention of Sodium / Water Ascites Schrier et al. Hepatology 1988

50 Peripheral Arterial Vasodilation Portal Hypertension Arterial Splanchnic Vasodilatation EBV Right Atrial Volume Receptors ANP reflectory arterial Vasoconstriction Kidney Brain Muscles SNS RAAS Sec. Retention of Sodium / Water Ascites

51 Peripheral Arterial Vasodilatation Portal Hypertension Arterial Splanchnic Vasodilatation EBV Right Atrial Volume Receptors ANP reflectory arterial Vasoconstriction Kidney Brain Muscles SNS RAAS Sec. Retention of Sodium / Water Ascites

52 Liver Cirrhosis Portal Hypertension Splanchnic Vasodilatation EBV RAAS SNS ADH Na + Retention Water Retention Renal Vasoconstriction Ascites Hepatorenal Syndrome

53 pre ascitic Ascites refractory Ascites HRS II HRS I

54 pre ascitic Ascites Refractory Ascites HRS II HRS I I : detectable by ultrasound II : ascites clinically evident III : tense ascites Uncomplicated ascites: no infection, no HRS

55 Maintenance Therapy with Diuretics after Paracentesis Paracentesis Paracentesis + Diuretics 0 Recurrent Ascites 4 Weeks after Paracentesis Fernandez-Esparrach et al. J Hepatol 1997

56 Normally, Sinusoids Lack a Basement Membrane and Endothelial Cells Have Fenestrae Sinusoid Fenestra Endothelial cell Hepatocyte microvilli

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58 Neurohumoral Systems are Activated in Cirrhotic Patients with Ascites Plasma renin activity (ng/ml-h) Plasma aldosterone activity (ng/dl) Controls Cirrhosis no ascites Cirrhotic patients with ascites Controls Cirrhosis no ascites Cirrhotic patients with ascites

59 LVP Without Albumin Leads to Increases in Renin, Renal Failure and Hyponatremia Plasma renin activity (ng/ml/h) ns p<0.1 Postparacentes is circulatory dysfunctio n (PCD) % Renal failure / Hyponatremia 5 p<0.1 0 Before After Before After 0 Albumin No albumin Albumin No albumin Gines et al., Gastroenterology 1988; 94:1493

60 Survival in Cirrhotic Patients is Significantly Lower in Patients Developing Post-Paracentesis Circulatory Dysfunction (PCD) Did not develop PCD Survival probability.6.4 Developed PCD p< Months Gines et al., Gastroenterology 1996; 111:1002

61 ALBUMIN IS MORE EFFECTIVE THAN SYNTHETIC PLASMA VOLUME EXPANDERS IN PREVENTING POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD) Albumin is More Effective than Synthetic Plasma Volume Expanders in Preventing Post- Paracentesis Circulatory Dysfunction (PCD) Expander n Dose PCD Albumin 97 8 g/l 18% Dextran g/l 34% Polygeline 99 8 g/l 38% Gines et al., Gastroenterology 1996; 111:1002

62 Post-Paracentesis Circulatory Dysfunction (PCD) Depends on the Type of Plasma Volume Expander and the Amount of Ascites Removed % Development of PCD POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD) DEPENDS ON THE TYPE OF PLASMA VOLUME EXPANDER AND THE AMOUNT OF ASCITES REMOVED No expander Saline Synthetic expander Albumin 10 0 Overall <5-6 L >5-6 L Ascites removed Gines et al., Gastroenterology 1988; 94:1493; Gines et al., Gastroenterology 1996; 111:1002; Sola-Vera et al., Hepatology 2003; 37:1147

63 Survival is Not Different Between Patients Treated With LVP or TIPS Paracentesis and albumin TIPS p = 0.51 Probability of survival Months Gines et al., Gastroenterology 2002; 123:1839

64 Meta-Analysis of TIPS vs. LVP + Albumin for Refractory Ascites Ascites control (month 4) Ascites control (month 12) Survival (month 12) Encephalopathy More with LVP 0 More with TIPS Risk Differenc e Deltenre et al., Liver International 2005; 25:349

65 Medical Treatment of uncomplicated Ascites Dietary Sodium restriction 3 (-7) g/d Fluid intake 1 (-1,5) l/d Diuretics stepwise increase of Spironolactone Furosemide Maintain Ratio! Aim Weight loss circa 0.5 kg/d Ascites mobilisation: decrease of ascites to I No recurrence of ascites

66 What do we accomplish? Refractory Ascites 10% Sodium/Water Restriction 10% + Furosemide 90% + Spironolactone 70%

67 pre ascitic Ascites Refractory Ascites HRS II HRS I Glomerular filtration rate Serum Creatinine

68 TIPS increases Sodium Excretion Brensing et al. GUT 2000

69 TIPS increases Creatinine Clearance Brensing et al. GUT 2000

70 TIPS decreases Serum Creatinine Brensing et al. GUT 2000

71 TIPS for Refractory Ascites Author Treatment n Control of Ascites Survival Lebrec 1996 LVP 12 1/12 (1y) 60% (2y) TIPS 13 3/13 (1y) 29% (2y)* Rössle 2000 LVP 31 6/31 (6M) 30% (2y) TIPS 29 16/29 (6M)* 58% (2y)* Gines 2002 LVP 35 6/35 (1y) 30% (2y) TIPS 35 18/35 (1y)* 26% (2y) Sanyal 2003 LVP 57 9/57 (1y) 12.4 M (median) TIPS 52 30/52 (1y)* 19.6 M (median)

72 Decompensation means Transplantation! median survival 2 years 6 months pre ascitic Ascites Refractory Ascites HRS II HRS I Transplantation

73 Nitric Oxide Inhibition Results in an Increase in Urinary Sodium and a Decrease in Plasma Aldosterone Urinary sodium excretion (mmol/day) Plasma aldostero ne (ng/dl) P <0.05 P < Control (n=10) L-NAME (n=10) 0 Control (n=7) L-NAME (n=7) Martin et al, J Clin Invest 1998; 101:235

74 Neurohumoral Systems are Maximally Activated in Hepatorenal Syndrome Plasma renin activity (ng/mlh) Plasma aldosterone activity (ng/dl) Control s Controls without ascites Cirrhotics with ascites without renal failure with renal failure 0 Control s Control s without ascites Cirrhotics with ascites without renal failure with renal failur e

75 ASCITES FLUID ANALYSIS Ascites Fluid Analysis Routine Optional Albumin Protein PMN cell count Cultures Glucose LDH Amylase Red blood cell count TB smear and culture Cytology Triglycerides

76 Ascites Can Be Characterized by Serum- Ascites Albumin Gradient (SAAG) and Ascites Protein Capillarized sinusoid Ascites protein < 2.5 Hepatic sinusoids SAAG > 1.1 Source of ascites Normal leaky sinusoid Peritoneum SAAG < 1.1 Peritoneal lymph Ascites protein > 2.5 Ascites protein > 2.5 Sinusoidal hypertension -Cirrhosis -Late Budd- Chiari Post-sinusoidal hypertension - Cardiac ascites - Early Budd-Chiari - Veno-occlusive disease Peritoneal pathology - Malignancy - Tuberculosis

77 Serum-Ascites Albumin Gradient and Ascites Protein Levels in the Most Common Causes of Ascites Serum ascites albumin gradient (g/dl) Ascitic fluid total protein (g/dl) Cirrhotic ascites Runyon, Ann Intern Med 1992; 117:215 Cardiac ascites Peritoneal malignancy (75)

78 Serum-Ascites Albumin Gradient is High in Portal Hypertensive Causes of Ascites 4. 0 Serum ascites albumin gradient (g/dl) Cirrhotic ascites Cardiac ascites Peritoneal malignancy Runyon, Ann Intern Med 1992; 117:215

79 Ascites Total Protein is Elevated in Cardiac Ascites and Peritoneal Malignancy Ascitic fluid total protein (g/dl) Cirrhotic ascites Cardiac ascites Peritoneal malignancy 2.5 Runyon, Ann Intern Med 1992; 117:215

80 Post-paracentesis Renin Levels Correlate Inversely with Systemic Vascular Resistance D Systemic vascular resistance (dyn-sec/cm -5 ) Ruiz del Arbol et al., Gastroenterology 1997; 113:579 D Plasma renin activity (ng/ml/hr)

81 HVPG > 12 mmhg is Necessary for Ascites to Develop and is Associated with Low Sodium Excretion No ascites Ascites Urinary sodium (meq/l) HVPG (mmhg) Morali et al., J Hepatol 1992; 16:249

82 Urinary Sodium Excretion is Decreased in Cirrhotic Patients with Ascites Urinary sodium excretion (mmol/da y) No ascites Eisenmenger et al, J Clin Invest 1950; 29:1491 Moderat e ascites Tense ascites

83 pre ascitic Ascites Refractory Ascites HRS II HRS I Glomerular filtration rate Serum Creatinine

84 The Serum-Ascites Albumin Gradient (SAAG) Correlates With Sinusoidal Pressure HVPG (mmhg) r = SAAG (g/dl) Hoefs J, J Lab Clin Med 1983; 102:260

85 EBV- is reduced in Cirrhosis

86 Definition HRS is a functional renal failure in patients with chronic liver disease/liver failure/portal hypertension, which is characterized by a renal hypoperfusion due to activation of neurohumeral vasoactive