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Management of AscitesManagement of Ascites

I have no disclosures to make relative to my presentation. I have no disclosures to make relative to my presentation.

Guadalupe García-Tsao, MDProfessor of Medicine

Yale University

Chief, Digestive Diseases SectionVA-CT Healthcare System

Guadalupe García-Tsao, MDProfessor of Medicine

Yale University

Chief, Digestive Diseases SectionVA-CT Healthcare System

Cirrhosis Heart failureHeart failure

Peritoneal tuberculosisPeritoneal tuberculosis

Cirrhosis is the Most Common Cause of AscitesCirrhosis is the Most Common Cause of Ascites

Others Pancreatic Budd-Chiari syndrome Nephrogenic ascites

Others Pancreatic Budd-Chiari syndrome Nephrogenic ascites

Peritoneal malignancyPeritoneal malignancy

CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES

Source of the main 3 causes of ascitesSource of the main 3 causes of ascites

Entity Source Pathophysiology

Cirrhosis Hepatic sinusoid

Fibrosis and nodules causing sinusoidal and post-sinusoidal obstruction

Heart failure Hepatic sinusoid

Congestion of liver due to right heart failure (post-hepatic block)

Peritoneal malignancy/TB

Peritoneum Inflammation or infiltrationof the peritoneum

Patients with cirrhotic ascites have an HVPG of at

least 12 mmHg (nl 3-5)Morali et a. J Hepatol 2002

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(out of the sinusoid)(out of the sinusoid) (into the sinusoid)(into the sinusoid)

SINhydSINhyd PERoncPERonc++ SINoncSINonc PERhydPERhyd== ++

SINhydSINhyd ==

HVPGHVPG ==

SINoncSINonc PERoncPERonc--

SerumalbuminSerum

albuminAscitesalbuminAscitesalbumin

-- = SAAG= SAAG

Rationale Behind the Serum-Ascites Albumin Gradient (SAAG)

Rationale Behind the Serum-Ascites Albumin Gradient (SAAG)

Hoefs J, J Lab Clin Med 1983; 102:260Hoefs J, J Lab Clin Med 1983; 102:260

The Serum-Ascites Albumin Gradient (SAAG) Correlates With Sinusoidal Pressure

The Serum-Ascites Albumin Gradient (SAAG) Correlates With Sinusoidal Pressure

SAAG (g/dL)SAAG (g/dL)

HVPG (mmHg)HVPG (mmHg)

r = 0.73r = 0.73

3030

2020

1010

00

00 1.01.0 2.02.0 3.03.0

1111

1.11.1

Cirrhotic ascitesCirrhotic ascites Cardiac ascitesCardiac ascites

Peritoneal malignancyPeritoneal

malignancy

1.11.1

4.04.0

3.03.0

2.02.0

1.01.0

00

Serum –ascites albumin

gradient (g/dL)

Serum –ascites albumin

gradient (g/dL)

7.07.0

Serum-Ascites Albumin Gradient and Ascites Protein Levels in the Most Common Causes of Ascites

Serum-Ascites Albumin Gradient and Ascites Protein Levels in the Most Common Causes of Ascites

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

SAAG is an indicator of sinusoidal pressure. If >1.1 ascites is coming

from the sinusoid

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THE PERMEABILITY OF THE HEPATIC SINUSOID VARIES IN HEALTH AND DISEASE

In cirrhosis, the hepatic sinusoid

is less leaky

In cirrhosis, the hepatic sinusoid

is less leaky

The Permeability of the Hepatic Sinusoid Varies in Health and Disease

The Permeability of the Hepatic Sinusoid Varies in Health and Disease

HepatocytesHepatocytes

The normal sinusoid is “leaky”

The normal sinusoid is “leaky”

SinusoidSinusoid

SinusoidSinusoid

fibrous tissue deposition “capillarization” of sinusoidfibrous tissue deposition

“capillarization” of sinusoid

no basement membrane

no basement membrane

Cirrhotic ascitesCirrhotic ascites Cardiac ascitesCardiac ascites

Peritoneal malignancyPeritoneal

malignancy

1.11.1

4.04.0

3.03.0

2.02.0

1.01.0

00

Serum –ascites albumin

gradient (g/dL)

Serum –ascites albumin

gradient (g/dL)

Serum-Ascites Albumin Gradient and Ascites Protein Levels in the Most Common Causes of Ascites

Serum-Ascites Albumin Gradient and Ascites Protein Levels in the Most Common Causes of Ascites

Runyon, Ann Intern Med 1992; 117:215Runyon, Ann Intern Med 1992; 117:215

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

SAAG is an indicator of sinusoidal pressure. If >1.1 ascites is coming

from the sinusoid

Ascitic fluid total protein

(g/dL)

Ascitic fluid total protein

(g/dL)

7.07.0

5.05.0

3.03.0

2.02.0

00

2.52.5

(75)(75)

Ascites protein is an indicator of leakiness of sinusoid, >2.5 the sinusoid is leaky (i.e. normal)

Ascites protein is an indicator of leakiness of sinusoid, >2.5 the sinusoid is leaky (i.e. normal)

CONDITIONCONDITION SAAGSAAGASCITESPROTEINASCITESPROTEIN

Cirrhosis

Peritoneal malignancy

Heart failure

Cirrhosis

Peritoneal malignancy

Heart failure

high low

low high

high high

high low

low high

high high

CutoffCutoff 1.1 g/dL1.1 g/dL 2.5 g/dL2.5 g/dL

SAAG and ascites total protein can establish the differential among the main causes of ascites

SAAG and ascites total protein can establish the differential among the main causes of ascites

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Serum BNP has a higher diagnostic accuracy for cardiac ascites than SAAG/ascites protein

Serum BNP has a higher diagnostic accuracy for cardiac ascites than SAAG/ascites protein

Farias et al. Hepatology 2014; 59:1043-51

Test LR (+)(rules in)

LR(-) (rules out)

SAAG >1.1; prot >2.5 9.63

Serum BNP >364 pg/mL 168.09

SAAG <1.1; prot < 2.5 1.272

Serum BNP < 182 pg/mL 0.000

Patients with new onset ascites

364

182

Rules in

Rules out

Compensatedcirrhosis

Compensatedcirrhosis

Decompensatedcirrhosis

Decompensatedcirrhosis

Natural History of Chronic Liver DiseaseNatural History of Chronic Liver Disease

Ascites VH Encephalopathy

Ascites VH Encephalopathy

Chronic liver

disease

Chronic liver

disease

VH= variceal hemorrhage

DeathDeath

In a cohort of patients with compensated cirrhosis, ascites was the most common decompensating event

0 24 48 72 96 120 144 168 192 216 240

0.00

0.25

0.50

0.75

1.00

AscitesAscites

HEHE

JaundiceJaundice

VHVH

DecompensationDecompensation

months

D’Amico G. Gastroenterology 2001; 120: A2D’Amico G. Gastroenterology 2001; 120: A2

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Intrahepatic resistance

Portal (sinusoidal) hypertension

Cirrhosis

Ascites

Splanchnic / systemic vasodilatationSplanchnic / systemic vasodilatation

Effective arterial blood volume

Sodium retention

Activation of neurohumoral systems

DiureticsDiuretics

Spironolactone is More Effective Than Furosemide in Uncomplicated AscitesSpironolactone is More Effective Than Furosemide in Uncomplicated Ascites

Response No response Total

Spironolactone 18 1 19(150-300 mg/d)

Response No response Total

Spironolactone 18 1 19(150-300 mg/d)

Perez-Ayuso et al. Gastroenterology 1983; 84:961 Perez-Ayuso et al. Gastroenterology 1983; 84:961

SPIRONOLACTONE IS MORE EFFECTIVE THAN FUROSEMIDE IN CIRRHOTIC PATIENTS WITH ASCITESSPIRONOLACTONE IS MORE EFFECTIVE THAN FUROSEMIDE IN CIRRHOTIC PATIENTS WITH ASCITES

Furosemide 11 10 21(80-160 mg/d)Furosemide 11 10 21(80-160 mg/d)

Treatment of ascitesTreatment 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

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

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Less frequent dose reductions are needed when spironolactone is started alone

Spironolactone + Furosemide

(n=50)

Spironolactone + Furosemide

(n=50)

Spironolactone alone*(n=50)

Spironolactone alone*(n=50)

Response Rate 94% 98%

Time to Response 12.8 days 12.3 days

Dose reductionneeded 34% 68%

Response Rate 94% 98%

Time to Response 12.8 days 12.3 days

Dose reductionneeded 34% 68%p=0.002p=0.002

Santos et al., J Hepatol 2003; 39:187Santos et al., J Hepatol 2003; 39:187 * Followed by furosemide if necessary* Followed by furosemide if necessary

In addition to spironolactone-based diuretics….

In addition to spironolactone-based diuretics….

Salt restriction (2g/day = ~90mEq/day) Do not compromise nutritional status

Avoid non-steroidal anti-inflammatory drugs

No water restriction unless serum Na <130 mEq/L

Low threshold to perform a diagnostic paracentesis to investigate SBP

Salt restriction (2g/day = ~90mEq/day) Do not compromise nutritional status

Avoid non-steroidal anti-inflammatory drugs

No water restriction unless serum Na <130 mEq/L

Low threshold to perform a diagnostic paracentesis to investigate SBP

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: > 50 mEq/L or greater than daily Na intake Spot UNa >UK (correlates with a 24-hour sodium

excretion >78 mEq/L)

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: > 50 mEq/L or greater than daily Na intake Spot UNa >UK (correlates with a 24-hour sodium

excretion >78 mEq/L)

Management of AscitesManagement of Ascites

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Hepatic HydrothoraxHepatic Hydrothorax

Occurs in ~6% of patients with cirrhosis Occurs in ~6% of patients with cirrhosis Krok KL, Cardenas A. Semin Respir Crit Care Med 2012; 33: 3-10.

Due to trans-diaphragmatic movement of fluid from the peritoneum to the pleural space through diaphragmatic defects

Due to trans-diaphragmatic movement of fluid from the peritoneum to the pleural space through diaphragmatic defects

Management same as for cirrhotic ascites Management same as for cirrhotic ascites

Intrahepatic resistance

Portal (sinusoidal) hypertension

Cirrhosis

Ascites

Splanchnic / systemic vasodilatationSplanchnic / systemic vasodilatation

Effective arterial blood volume

Sodium retention

Refractory Ascites

Activation of neurohumoral systems

Large volume-paracentesis (LVP):• Local therapy• Recurrence of ascites is the rule• May be associated with post-paracentesis circulatory dysfunction

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LVP Without Albumin Leads to Increases in Renin, Renal Failure and HyponatremiaLVP Without Albumin Leads to Increases in Renin, Renal Failure and Hyponatremia

BeforeBefore BeforeBeforeAfterAfter AfterAfter

AlbuminAlbumin No albuminNo albumin

1212

88

44

00

Plasma renin activity (ng/mL/h)Plasma renin activity (ng/mL/h) Renal failure / HyponatremiaRenal failure / Hyponatremia

AlbuminAlbumin No albuminNo albumin

2020

1515

1010

00

55

p<0.1p<0.1

p<0.1p<0.1

nsns

Post-paracentesis circulatory

dysfunction (PCD)

Post-paracentesis circulatory

dysfunction (PCD)

%%

Gines et al., Gastroenterology 1988; 94:1493Gines et al., Gastroenterology 1988; 94:1493

LVP WITHOUT ALBUMIN LEADS TO INCREASES INCIDENCE OF POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD)

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

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 Gines et al., Gastroenterology 1996; 111:1002; Ruiz del Arbol et al., Gastroenterology 1997; 113:579

CONSEQUENCES OF POST-PARACENTESIS CIRCULATORY DYSFUNCTION (PCD)

Post-paracentesis circulatory dysfunction (PCD) is lowest in patients receiving albumin after LVPPost-paracentesis circulatory dysfunction (PCD) is lowest in patients receiving albumin after LVP

Development of PCD

Development of PCD

%%

Ascites removedAscites removedOverallOverall <5-6 L<5-6 L >5-6 L>5-6 L

7070

6060

5050

4040

3030

2020

1010

00

No expanderSalineSynthetic expanderAlbumin*

No expanderSalineSynthetic expanderAlbumin*

Gines et al., Gastroenterology 1988; 94:1493; Gines et al., Gastroenterology 1996; 111:1002;Sola-Vera et al., Hepatology 2003; 37:1147

Gines et al., Gastroenterology 1988; 94:1493; Gines et al., Gastroenterology 1996; 111:1002;Sola-Vera et al., Hepatology 2003; 37:1147

*6-8 g per liter of ascites removed*6-8 g per liter of ascites removed

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Intrahepatic resistance

Portal (sinusoidal) hypertension

Cirrhosis

Ascites

Splanchnic / systemic vasodilatationSplanchnic / systemic vasodilatation

Effective arterial blood volume

Renal vasoconstriction

Water retention

Sodium retention

Refractory Ascites

Hypo-natremia

Hepatorenal syndrome

Activation of neurohumoral systems

ALBUMINALBUMIN

LVPLVP

Other volume expanders?Vasoconstrictors?

Favors albumin

Favors control

Compared to alternative treatment, albumin reduces the rate of PCD

Compared to alternative treatment, albumin reduces the rate of PCD

Bernardi et al. Hepatology 2012;55:1172.Bernardi et al. Hepatology 2012;55:1172.

PCD : 18% (2/11) with Albumin25% (2/8) with Octreotide/Midodrine

(p=0.574)

Recurrence of ascites is no different in patients treated with LVP + albumin vs. octreotide/midodrine

Recurrence of ascites is no different in patients treated with LVP + albumin vs. octreotide/midodrine

Bari et al. Accepted Clin Gastroenterol Hepatol.Bari et al. Accepted Clin Gastroenterol Hepatol.

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Transjugular Intrahepatic Portosystemic ShuntTransjugular Intrahepatic Portosystemic Shunt

Hepatic veinHepatic vein

Portal veinPortal veinSplenic veinSplenic vein

Superior mesenteric veinSuperior mesenteric vein

TIPSTIPS

THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

Recurrence of ascitesRecurrence of ascites

Lebrec (1996) 20

EncephalopathyEncephalopathy

DeathDeath

Death (excluding Lebrec)Death (excluding Lebrec)

Better TIPSBetter TIPS Better LVPBetter LVP

.01.01

0.14 (0.08-0.26)0.14 (0.08-0.26)

2.34 (1.41-3.87)2.34 (1.41-3.87)

0.90 (0.44-1.81) Heterogeneity 2 p=0.050.90 (0.44-1.81) Heterogeneity 2 p=0.05

.1.1 .5.5 11 55 1010

0.74 (0.40-1.37)0.74 (0.40-1.37)

In refractory ascites, TIPS is more effective than LVP in preventing ascites recurrence In refractory ascites, TIPS is more effective than LVP in preventing ascites recurrence

D’Amico et al. Gastroenterology 2005; 129:1282D’Amico et al. Gastroenterology 2005; 129:1282

Odds ratioOdds ratio

Salerno et al. Gastroenterology 2007;133:825–834Salerno et al. Gastroenterology 2007;133:825–834

In a meta-analysis of individual patient data, survival was better with TIPS than LVP

In a meta-analysis of individual patient data, survival was better with TIPS than LVP

SurvivalSurvival EncephalopathyEncephalopathy

P=0.005

p=0.36

Greater survival benefit in patients treated with TIPS who had a MELD

score <15

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

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Refractory hepatic hydrothoraxRefractory 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

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 2010.

Peritoneo-Venous Shunt (PVS) is Useful in the Treatment of Refractory Ascites

Use of jugular vein will hinder TIPS placement

Use of jugular vein will hinder TIPS placement

Intraabdominal adhesions may complicate liver

transplant surgery

Intraabdominal adhesions may complicate liver

transplant surgery

One-way valve

One-way valve

Indicated in malignant ascites or patients who are not transplant or TIPS

candidates

ALFA pump transfersascites into the bladder

Pilot safety study of Automated Low-Flow pump for refractory Ascites (ALFA) (n=40)Pilot safety study of Automated Low-Flow pump for refractory Ascites (ALFA) (n=40)

Placed under general anesthesia

6-month followup

LVP 3.4 0.2 per month

Infections antibiotic prophylaxis (76%42%)

Catheter dislodgement/problems (10/40=25%)

Surgical complications (5/40)

Progressive decrease in serum albumin

13 early termination, 8 died, 2 txp

Placed under general anesthesia

6-month followup

LVP 3.4 0.2 per month

Infections antibiotic prophylaxis (76%42%)

Catheter dislodgement/problems (10/40=25%)

Surgical complications (5/40)

Progressive decrease in serum albumin

13 early termination, 8 died, 2 txp

Bellot et al. J Hepatol 2013;58:922-7

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Hernandez-Gea et al. Am J Gastroenterol 2012; 107:418-27Hernandez-Gea et al. Am J Gastroenterol 2012; 107:418-27

In patients with large varices that have not bled, a decrease in HVPG >10% leads to less ascites, RA and HRS

Ascites

Hepatorenalsyndrome

Refractory ascites

Cirrhotic ascitesCirrhotic 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

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