ASCITES

Cirrhosis is the late result of any disease that causes scarring of the liver. Patients with cirrhosis are susceptible to a variety of complications that include ascites, hepatic encephalopathy, and portal hypertensive bleeding. Quality of life and survival are often improved by the prevention and treatment of these complications. This chapter will review the general principles in the diagnosis and treatment of cirrhotic ascites. (See separate Disease Management chapters for overviews of hepatic encephalopathy and portal hypertensive bleeding).

Ascites is defined as the accumulation of fluid in the peritoneal cavity. It is a common clinical finding with a variety of both extraperitoneal and peritoneal etiologies (Table 1), but it is most often caused by liver cirrhosis. The development of ascites in a cirrhotic patient generally heralds a deterioration in clinical status and portends a poor prognosis.¹

Ascites is the most common major complication of cirrhosis and is an important landmark in the natural history of chronic liver disease. If observed for 10 years, approximately 60% of patients with cirrhosis will develop ascites requiring therapy and/or orthotopic liver transplantation.²

The currently accepted theory of ascites formation is the "peripheral arterial vasodilation hypothesis" (Figure 1). This hypothesis does not directly refute older hypotheses, but rather incorporates them into one uniform theory that most matches actual hemodynamic data.³

According to this theory, development of portal hypertension is the first abnormality to occur in cirrhotic patients who develop ascites. Cirrhosis itself increases the resistance to blood flow within the liver, thereby causing the development of portal hypertension and shunting of blood to the systemic circulation. Portal pressures >12 mm Hg are generally required for the accumulation of fluid in cirrhosis.⁴ This concept is important, since reducing portal pressure to <12 mm Hg is the goal of many modern therapeutic maneuvers.

As portal hypertension develops, vasodilators are released locally. These vasodilators affect splanchnic arteries and thereby decrease the effective arterial blood flow and arterial pressures. The precise agent (or agents) responsible for vasodilation is a subject of wide debate; however, most recent literature has focused on the role of nitric oxide. Observations that implicate nitric oxide as the likely mediator of vasodilation in cirrhosis include (1) increased activity of nitric oxide synthase detected in the arteries of cirrhotic rats,⁵ (2) high serum nitrite and nitrate levels (an index of nitric oxide synthesis) measured in cirrhotic patients,⁶ and (3) inhibition of nitric oxide leading to increased arterial pressures and systemic vascular resistance in animals.⁷

Progressive vasodilation leads to the activation of vasoconstrictor and antinatriuretic mechanisms, both attempting to restore normal perfusion pressures. Mechanisms involved include the renin-angiotensin system, sympathetic nervous system, and antidiuretic hormone (vasopressin). The ultimate effect is sodium and water retention. In the late stages of cirrhosis, free water accumulation is more pronounced than the sodium retention and leads to a dilutional hyponatremia. Cirrhotic patients with ascites may therefore demonstrate urinary sodium retention, increased total body sodium, and dilutional hyponatremia, a challenging concept to many physicians.⁸

The symptoms of ascites vary from patient to patient and depend largely on the quantity of fluid. If trace ascites is present, the patient may be asymptomatic, and fluid is detected only on physical or radiologic examination. If a large amount of fluid is present, the patient may complain of abdominal fullness, early satiety, abdominal pain, or shortness of breath.

Physical examination findings are equally variable. The accuracy of detecting ascites depends on the amount of fluid present and the body habitus of the patient (detecting ascites may be more technically difficult in obese patients). If ascites is present, typical findings include generalized abdominal distention, flank fullness, and shifting dullness. If the physical examination is not definitive, abdominal ultrasonography can be used to confirm the presence or absence of ascites.⁹

Two grading systems for ascites have been used in the literature (Table 2). An older system grades ascites from 1+ to 4+, depending on the detectability of fluid on physical examination.¹⁰ More recently, the International Ascites Club has proposed a system of grading from 1 to 3. The validity of this grading system has yet to be established.¹¹

If a noncirrhotic patient develops ascites, diagnostic paracentesis with ascites fluid analysis is an essential part of the medical evaluation. In a patient with well-established cirrhosis, the exact role of a diagnostic paracentesis is less clear. Our opinion is that for a highly functional outpatient with documented cirrhosis, the new development of ascites does not routinely require paracentesis. Cirrhotic patients should, however, undergo paracentesis in cases of (1) unexplained fever, abdominal pain, or encephalopathy, or (2) admission to the hospital for any cause. It is common for hospitalized cirrhotic patients to have infected ascites fluid (spontaneous bacterial peritonitis), even if no symptoms are present. This is particularly true in the event of a significant gastrointestinal hemorrhage.³

Complications from abdominal paracentesis are rare, occurring in less than 1% of cases.¹² A low platelet count or elevated prothrombin time is not considered a contraindication, and prophylactic transfusion of platelets or plasma is almost never indicated.⁹ Insertion of the paracentesis needle is most commonly performed in the left or right lower quadrants but can also be performed safely in the midline. To minimize bleeding complications, care should be taken to avoid any engorged and/or superficial blood vessels. The course of the inferior hypogastric artery (along the midportion of the rectus abdominal muscle) should also be avoided. Abdominal ultrasound can guide the procedure if the fluid is difficult to localize or if initial attempts to obtain fluid are unsuccessful.³

Valuable clinical information can often be obtained by gross examination of the ascitic fluid (Table 3). Uncomplicated cirrhotic ascites is usually translucent and yellow. If the patient is deeply jaundiced, the fluid may appear brown. Turbidity or cloudiness of the ascitic fluid suggests that infection may be present, and further diagnostic testing should be performed.³ Pink or bloody fluid is most often caused by mild trauma, with subcutaneous blood contaminating the sample. Bloody ascites is also associated with hepatocellular carcinoma or any malignancy-associated ascites.^{13 Milky fluid usually has an elevated triglyceride concentration. Such fluid, commonly referred to as "chylous ascites," can be related to thoracic duct injury or obstruction or to lymphoma, but it is often related primarily to cirrhosis.14}

Many ascitic fluid tests are currently available, yet the optimal testing strategy has not been well established. Generally, if uncomplicated cirrhotic ascites is suspected, only an albumin concentration test and a cell count with differential are performed (Table 4). Less than 10 mL of fluid placed in a "purple top" tube (containing an anticoagulant) is required to perform these basic tests. The albumin concentration test is used to confirm the presence of portal hypertension by calculating the serum-to-ascites albumin gradient, (SAAG), which is determined by subtracting the ascites albumin value from a serum albumin value obtained on the same day (ie., Albumin_serum - Albumin_ascites = SAAG). The SAAG has been proven in prospective studies to categorize ascites better than any previous criteria. The presence of a gradient >1.1 g/dL indicates with 97% accuracy that the patient has portal hypertension-related ascites.¹ Portal hypertension is usually caused by liver cirrhosis or, less commonly, outflow obstruction from right-sided heart failure or Budd-Chiari syndrome. A SAAG of <1.1 g/dL indicates that the patient does not have portal hypertension-related ascites, and another cause should be sought. The SAAG does not need to be repeated after the initial measurement.

The cell count and differential are used to determine whether the patient is likely to have spontaneous bacterial peritonitis. Patients with an ascitic polymorphonuclear (PMN, or absolute neutrophil) count greater >250 cells/mm³ should receive empiric antibiotics, and additional fluid should be inoculated into blood culture bottles to be sent for culture. The PMN count is calculated by multiplying the white cells/mm³ by the percentage of neutrophils in the differential. In a "bloody" sample that contains a high concentration of red blood cells, the PMN count must be corrected: one PMN is subtracted from the absolute PMN count for every 250 red cells/mm³ in the sample.³ It is imperative that these results be made available within 1 hour, so that important diagnostic and therapeutic decisions can be made.

Based on clinical judgment, additional testing can be performed on ascites fluid including total protein, lactose dehydrogenase, glucose, amylase, triglycerides, bilirubin, cytology or tuberculosis smear and culture.⁹ These tests are generally useful only when there is suspicion of something other than sterile cirrhotic ascites. Tests that are not routinely helpful include pH, lactate, and a Gram stain.¹⁵ A Gram stain is of particular low yield unless a large concentration of bacteria, such as in a free gut perforation, is suspected.³

It is important to know the cause of ascites before the appropriate treatment can be determined. For example, ascites related to cancer and/or carcinomatosis responds best to therapies directed at the underlying malignancy. Likewise, ascites related to myxedema generally improves with aggressive thyroid hormone replacement. This chapter will focus specifically on the treatment of ascites related to cirrhosis.

Successful treatment of ascites is defined as the minimization of intraperitoneal fluid without intravascular volume depletion. Despite a lack of data supporting decreased mortality, minimizing the amount of ascites fluid may decrease infection-related morbidity.^16,17 Furthermore, treating ascites can dramatically improve quality of life by decreasing abdominal discomfort and/or dyspnea. General ascites management in all patients should include minimizing consumption of alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and dietary sodium. The use of more aggressive interventions depends on the severity of ascites and nonresponse to these general measures. This includes use of oral diuretics, therapeutic (or large-volume) paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), and orthotopic liver transplantation (Figure 2).

General Management
All patients with cirrhotic ascites should be encouraged to minimize consumption of alcohol. Even if alcohol is not the cause of their liver disease, cessation may lead to decreased fluid and improved response to medical therapies.¹⁸ Patients with ascites should also minimize use of all NSAIDs. NSAIDs inhibit the synthesis of renal prostaglandin and can lead to renal vasoconstriction, decreased diuretic response, and acute renal failure.¹⁹ Lastly, ascites patients should be counseled to limit their sodium consumption to no more than 2 g/day.⁹ Avoiding frozen or canned foods in combination with "throwing away the salt shaker" (using other spices or salt-substitutes to season freshly prepared foods) can usually accomplish this restriction. Since fluid passively follows sodium, a salt restriction without a fluid restriction is generally all that is required to decrease the amount of ascites.²⁰ In patients with minimal fluid, the restriction of alcohol, NSAIDs, and salt may be all that is needed to adequately control ascites formation.

Moderate-Volume Ascites
Patients with moderate fluid overload who do not respond to the above measures should be considered for the addition of pharmacologic therapy. A rapid reduction of ascites is often accomplished simply with initiation of low-dose oral diuretics. In general, patients with moderate ascites do not need to be admitted to the hospital unless there are other, accompanying complications.⁸

First-line diuretic therapy for cirrhotic ascites is dual use of oral spironolactone (Aldactone) and furosemide (Lasix). Beginning daily doses are 100 mg of spironolactone and 40 mg of furosemide orally. If weight loss and natriuresis are inadequate, both drugs can be simultaneously increased after 3 to 5 days to 200 mg of spironolactone and 80 mg of furosemide. To maintain normal electrolyte balance, the use of the 100:40-mg ratio of spironolactone to furosemide is generally recommended. Maximum accepted doses are 400 mg and 160 mg daily of spironolactone and furosemide, respectively.⁹

The response to diuretics should be carefully monitored on the basis of changes in body weight, laboratory tests, and clinical assessment. Patients taking diuretics should be weighed daily, and the rate of weight loss should not exceed >0.5 kg/day in the absence of edema and >1 kg/day when edema is present.²¹ Serum potassium, blood urea nitrogen (BUN) and creatinine should be serially followed. In the event of marked hyponatremia, hyper- or hypokalemia, renal insufficiency, dehydration, or encephalopathy, diuretics should be reduced or discontinued.⁹ Routine measurement of urinary sodium is not necessary but can be helpful in identifying noncompliance with dietary sodium restriction. Patients excreting >78 mmol/day of sodium (88 mmol dietary intake—10 mmol nonurinary excretion) detected on a 24-hour urinary collection should be losing weight. If not, they are noncompliant with their diet and should be referred to a dietician. The spot urine sodium-to-potassium ratio may ultimately replace the cumbersome 24-hour collection: a random urine sodium concentration that is greater than the potassium concentration has been shown to correlate with a 24-hour sodium excretion > 78 mmol per day with approximately 90% accuracy.²² Because of the potential severe complications associated with diuretic use, patients with ascites should be assessed by a health care provider at least once weekly until they are clinically stable.⁹

Large-Volume Ascites
Large-volume ascites is defined as intraperitoneal fluid in an amount that significantly limits the activities of daily life. With additional fluid retention, the abdomen can become progressively distended and painful. This is commonly referred to as "massive" or "tense" ascites. Large-volume ascites can usually be managed in the outpatient setting as long as no additional complications are present.⁸

Therapeutic (or large-volume) paracentesis is a well-established therapy for large-volume ascites.⁸ However, the use of postprocedural colloid, usually albumin, continues to be a controversial issue. Studies have shown that patients who do not receive intravenous albumin after large-volume paracentesis develop significantly more changes in their serum electrolytes, creatinine, and renin levels.²³ The clinical relevance of these findings, however, is not well established. In fact, no study to date has been able to demonstrate decreased morbidity or mortality in patients given no plasma expanders compared with patients given albumin after paracentesis.²⁴ In view of the high cost of albumin and its uncertain clinical role, more studies certainly need to be conducted. In the meanwhile, current practice guidelines of the American Association for the Study of Liver Diseases (AASLD) state that it is reasonable, although not mandatory, to give albumin for paracenteses greater that 5 L. Although no direct comparisons have ever been studied, 25% albumin at doses of 5 to 10 grams per liter of ascites removed are generally used.^23,24

In order to prevent reaccumulation of ascites fluid, patients with large-volume ascites should be counseled on limiting consumption of alcohol, NSAIDs, and sodium. They should also be placed on an aggressive diuretic regimen. Diuretic-sensitive patients are generally treated with lifestyle modifications and medications, not serial paracentesis.9

Refractory Ascites
Refractory ascites occurs in 5% to 10% of cirrhotic ascites patients and portends a poor prognosis.⁸ The definition of refractory ascites is (1) lack of response to high-dose diuretics (400 mg of spironolactone and 160 mg of furosemide per day) while remaining compliant with a low-sodium diet, or (2) frequent ascites recurrence shortly after therapeutic paracentesis.²⁵ Patients with recurrent side effects from diuretic therapy, including symptomatic hyponatremia, hyper- or hypokalemia, renal insufficiency, or hepatic encephalopathy, are also considered to have refractory ascites. Treatment options include frequent large-volume paracentesis with or without albumin infusion, placement of a transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation. Surgical peritoneovenous shunts (ie, LeVeen or Denver) have essentially been abandoned since controlled trials showed poor long-term patency, an excessive number of complications, and no survival advantage over medical therapy.^10,26

Frequent therapeutic paracentesis with or without albumin infusion is the most widely accepted treatment for patients with refractory ascites (see Large-Volume Ascites section above for controversy and dosing regarding albumin use). For those who have loculated fluid or are unwilling or unable to receive frequent paracentesis, TIPS placement can also be considered. In the appropriately selected patient, TIPS is highly effective for preventing ascites recurrence by decreasing the activity of sodium-retaining mechanisms and improving renal function.^27-29 Ongoing studies will determine if TIPS may also provide a survival benefit.

In the United States, TIPS is most commonly performed under conscious sedation by an interventional radiologist. The portal system is accessed through the jugular vein, and the operator inserts a self-expanding shunt between the portal (high-pressure) and hepatic (low-pressure) veins. The ultimate goal of the procedure is to lower portal pressures to <12 mm Hg, the level at which ascites begins to accumulate. Complications are common and include hemorrhage (intrahepatic or intra-abdominal) and stent stenosis or thrombosis. Other important complications include hepatic encephalopathy and decompensation of liver or cardiac function. It is for these reasons that TIPS is generally not recommended for patients with preexisting encephalopathy, an ejection fraction <55%, or a Child-Pugh score >12 (Table 5).^11,30 Additional disadvantages of the procedure are its high cost and lack of availability at some medical centers.

Liver transplantation is the ultimate treatment of cirrhosis and cirrhotic ascites. Appropriate timing for referral is debated, but should be considered when a cirrhotic patient first presents with a complication from cirrhosis, such as ascites. Because refractory ascites portends a particularly poor prognosis, immediate referral to an experienced liver transplantation center is recommended.

Two-year survival for a patient with cirrhotic ascites is approximately 50%.³¹ Once patients become refractory to routine medical therapy, 50% die within 6 months and 75% within 1 year.⁸ Because liver transplantation is associated with 2-year survival rates of almost 85%, it should be considered an important treatment option in all appropriate patients.¹¹

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