1 Management of Guadalupe García-Tsao, MD Professor of Medicine Yale University Chief, Digestive Diseases Section VA-CT Healthcare System I have no disclosures to make relative to my presentation. CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES Cirrhosis is the Most Common Cause of Peritoneal malignancy Cirrhosis Heart failure Peritoneal tuberculosis Others Pancreatic Budd-Chiari syndrome Nephrogenic ascites Source of the main 3 causes of ascites Entity Source Pathophysiology Cirrhosis Hepatic sinusoid Fibrosis Patients and with nodules cirrhotic ascites causing have sinusoidal an HVPG and of at post-sinusoidal least 12 mmhg (nl 3-5) obstruction Morali et a. J Hepatol 22 Heart failure Hepatic sinusoid Congestion of liver due to right heart failure (posthepatic block) Peritoneal malignancy/tb Peritoneum Inflammation or infiltration of the peritoneum
2 Rationale Behind the Serum- Albumin Gradient (SAAG) (out of the sinusoid) (into the sinusoid) SIN hyd + PER onc = SIN onc + PER hyd SIN hyd = SIN onc - PER onc HVPG = Serum albumin - = SAAG albumin The Serum- Albumin Gradient (SAAG) Correlates With Sinusoidal Pressure 3 2 HVPG (mmhg) 11 1 r =.73 1. 2. 3. SAAG (g/dl) 1.1 Hoefs J, J Lab Clin Med 1983; 12:26 Serum- Albumin Gradient and Protein Levels in the Most Common Causes of 4. 3. Serum ascites 2. albumin gradient (g/dl) 1. SERUM-ASCITES ALBUMIN GRADIENT (SAAG) AND ASCITES PROTEIN LEVELS IN THE MOST COMMON CAUSES OF ASCITES SAAG is an indicator of sinusoidal pressure. If >1.1 ascites is coming from the sinusoid 1.1 7. Cirrhotic ascites Cardiac ascites Peritoneal malignancy
3 THE PERMEABILITY OF THE HEPATIC SINUSOID VARIES IN HEALTH AND DISEASE The Permeability of the Hepatic Sinusoid Varies in Health and Disease no basement membrane Hepatocytes The normal sinusoid is leaky Sinusoid fibrous tissue deposition capillarization of sinusoid In cirrhosis, the hepatic sinusoid is less leaky Sinusoid Serum- Albumin Gradient and Protein Levels in the Most Common Causes of 4. 3. Serum ascites 2. albumin gradient (g/dl) 1. SERUM-ASCITES ALBUMIN GRADIENT (SAAG) AND ASCITES PROTEIN LEVELS IN THE MOST COMMON CAUSES OF ASCITES SAAG is an indicator of sinusoidal pressure. If >1.1 ascites is coming from the sinusoid 1.1 Ascitic fluid total protein (g/dl) 7. 5. 3. 2. Cirrhotic ascites Runyon, Ann Intern Med 1992; 117:215 Cardiac ascites Peritoneal malignancy (75) 2.5 protein is an indicator of leakiness of sinusoid, >2.5 the sinusoid is leaky (i.e. normal) SAAG and ascites total protein can establish the differential among the main causes of ascites CONDITION Cirrhosis Peritoneal malignancy Heart failure SAAG high low high ASCITES PROTEIN low high high Cutoff 1.1 g/dl 2.5 g/dl
4 Serum BNP has a higher diagnostic accuracy for cardiac ascites than SAAG/ascites protein 364 182 Rules in Rules out Test LR (+) (rules in) SAAG >1.1; prot >2.5 9.63 LR(-) (rules out) Serum BNP >364 pg/ml 168.9 SAAG <1.1; prot < 2.5 1.272 Serum BNP < 182 pg/ml. Patients with new onset ascites Farias et al. Hepatology 214; 59:143-51 Natural History of Chronic Liver Disease Chronic liver disease Compensated cirrhosis Decompensated cirrhosis VH Encephalopathy Death VH= variceal hemorrhage In a cohort of patients with compensated cirrhosis, ascites was the most common decompensating event 1..75 Decompensation.5.25 VH HE Jaundice. 24 48 72 96 12 144 168 192 216 24 months D Amico G. Gastroenterology 21; 12: A2
5 Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic / systemic vasodilatation Effective arterial blood volume Diuretics Sodium retention Activation of neurohumoral systems SPIRONOLACTONE IS MORE EFFECTIVE THAN FUROSEMIDE IN CIRRHOTIC PATIENTS WITH ASCITES Spironolactone is More Effective Than Furosemide in Uncomplicated Response No response Total Spironolactone 18 1 19 (15-3 mg/d) Furosemide 11 1 21 (8-16 mg/d) Perez-Ayuso et al. Gastroenterology 1983; 84:961 Treatment of ascites Not an emergency, treat ascites in a stepwise unhurried manner Other complications (GI bleed AKI, infection) are absent or have resolved If patient uncomfortable large volume paracentesis Treatment aimed at achieving a negative sodium balance
6 Less frequent dose reductions are needed when spironolactone is started alone Spironolactone alone* (n=5) Spironolactone + Furosemide (n=5) Response Rate 94% 98% Time to Response 12.8 days 12.3 days Dose reduction needed 34% p=.2 68% Santos et al., J Hepatol 23; 39:187 * Followed by furosemide if necessary In addition to spironolactone-based diuretics. Salt restriction (2g/day = ~9mEq/day) Do not compromise nutritional status Avoid non-steroidal anti-inflammatory drugs No water restriction unless serum Na <13 meq/l Low threshold to perform a diagnostic paracentesis to investigate SBP Management of Follow weight and labs (BUN, creatinine, lytes) Weight loss goals 2-3 lb a week; no more than 1 lb / day If no weight loss Make sure patient is not on NSAIDs Check urine Na. If any of the following, patient is eating too much salt: > 5 meq/l or greater than daily Na intake Spot UNa >UK (correlates with a 24-hour sodium excretion >78 meq/l)
7 Hepatic Hydrothorax Occurs in ~6% of patients with cirrhosis Krok KL, Cardenas A. Semin Respir Crit Care Med 212; 33: 3-1. Due to transdiaphragmatic movement of fluid from the peritoneum to the pleural space through diaphragmatic defects Management same as for cirrhotic ascites Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Splanchnic / systemic vasodilatation Effective arterial blood volume Activation of neurohumoral systems Sodium retention Refractory Large volume-paracentesis (LVP): Local therapy Recurrence of ascites is the rule May be associated with postparacentesis circulatory dysfunction
8 LVP WITHOUT ALBUMIN LEADS TO INCREASES INCIDENCE OF POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD) LVP Without Albumin Leads to Increases in Renin, Renal Failure and Hyponatremia 12 8 4 Plasma renin activity (ng/ml/h) ns p<.1 Postparacentesis circulatory dysfunction (PCD) % 2 15 1 5 Renal failure / Hyponatremia p<.1 Before After Albumin Before After No albumin Albumin No albumin Gines et al., Gastroenterology 1988; 94:1493 CONSEQUENCES OF POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD) 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; 111:12; Ruiz del Arbol et al., Gastroenterology 1997; 113:579 Post-paracentesis circulatory dysfunction (PCD) is lowest in patients receiving albumin after LVP % Development of PCD 7 6 5 4 3 2 No expander Saline Synthetic expander Albumin* 1 Overall Gines et al., Gastroenterology 1988; 94:1493; Gines et al., Gastroenterology 1996; 111:12; Sola-Vera et al., Hepatology 23; 37:1147 <5-6 L >5-6 L removed *6-8 g per liter of ascites removed
9 Cirrhosis Intrahepatic resistance Portal (sinusoidal) hypertension Other volume expanders? Vasoconstrictors? LVP Splanchnic / systemic vasodilatation Effective arterial blood volume ALBUMIN Activation of neurohumoral systems Sodium retention Water retention Renal vasoconstriction Refractory Hyponatremia Hepatorenal syndrome Compared to alternative treatment, albumin reduces the rate of PCD Favors albumin Favors control Bernardi et al. Hepatology 212;55:1172. Recurrence of ascites is no different in patients treated with LVP + albumin vs. octreotide/midodrine PCD : 18% (2/11) with Albumin 25% (2/8) with Octreotide/Midodrine (p=.574) Bari et al. Accepted Clin Gastroenterol Hepatol.
1 THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Transjugular Intrahepatic Portosystemic Shunt Hepatic vein TIPS Portal vein Splenic vein Superior mesenteric vein In Lebrec refractory (1996) 2 ascites, TIPS is more effective than LVP in preventing ascites recurrence Recurrence of ascites.14 (.8-.26) Encephalopathy Death Death (excluding Lebrec) 2.34 (1.41-3.87).9 (.44-1.81) Heterogeneity 2 p=.5.74 (.4-1.37).1.1.5 1 5 1 Better TIPS Better LVP Odds ratio D Amico et al. Gastroenterology 25; 129:1282 In a meta-analysis of individual patient data, survival was better with TIPS than LVP Survival Encephalopathy p=.36 P=.5 Greater survival benefit in patients treated with TIPS who had a MELD score <15 TIPS= transjugular intrahepatic portosystemic shunt LVP= large-volume paracentesis *individual data meta-analysis Salerno et al. Gastroenterology 27;133:825 834
11 Refractory hepatic hydrothorax A trial of in-hospital diuretic therapy should be attempted Serial thoracenteses may be required too frequently Chest tube or indwelling catheter should not be placed ( infection, AKI) TIPS may need to be considered earlier Clinical response (67%) and survival are also associated with pre-tips MELD <15 Dhanasekaran et al. Am J GE 21. Peritoneo-Venous Shunt (PVS) is Useful in the Treatment of Refractory Use of jugular vein will hinder TIPS placement Indicated in malignant ascites or patients who are not transplant or TIPS candidates One-way valve Intraabdominal adhesions may complicate liver transplant surgery Pilot safety study of Automated Low-Flow pump for refractory (ALFA) (n=4) ALFA pump transfers ascites into the bladder Placed under general anesthesia 6-month followup LVP 3.4.2 per month Infections antibiotic prophylaxis (76% 42%) Catheter dislodgement/problems (1/4=25%) Surgical complications (5/4) Progressive decrease in serum albumin 13 early termination, 8 died, 2 txp Bellot et al. J Hepatol 213;58:922-7
12 In patients with large varices that have not bled, a decrease in HVPG >1% leads to less ascites, RA and HRS Refractory ascites Hepatorenal syndrome Hernandez-Gea et al. Am J Gastroenterol 212; 17:418-27 Cirrhotic ascites The most common decompensating event in cirrhosis It is not an emergency unless complicated by infection or hepatorenal syndrome Ideal treatment strategies should be based on its pathophysiology Increase sodium excretion Decrease sinusoidal pressure Remove fluid while replenishing intravascular volume