Definition and causes

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

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Prevalence

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, orthotopic liver transplantation, or both.

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Pathophysiology

Cirrhotic ascites forms as the result of a particular sequence of events (Fig. 1). The current accepted theory of ascites formation is the peripheral arterial vasodilation hypothesis. This does not directly refute older hypotheses, but rather incorporates them into one uniform theory that matches actual hemodynamic data most closely.

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 higher than 12 mm Hg are generally required for the accumulation of fluid in cirrhosis. This concept is important, because reducing portal pressure to lower than 12 mm Hg is the goal of many modern therapeutic maneuvers.

As portal hypertension develops, a local release of vasodilators occurs. These vasodilators affect the splanchnic arteries and thereby decrease the effective arterial blood flow and arterial pressures. The precise agent(s) responsible for vasodilation is a subject of wide debate; however, most the recent literature has focused on the role of nitric oxide. Observations that implicate nitric oxide as the likely mediator of vasodilation in cirrhosis include the following:

1. Increased activity of nitric oxide synthase detected in the arteries of cirrhotic rats
2. High serum nitrite and nitrate levels (an index of nitric oxide synthesis) measured in cirrhotic patients
3. Inhibition of nitric oxide, leading to increased arterial pressure and systemic vascular resistance in animals

Progressive vasodilation leads to the activation of vasoconstrictor and antinatriuretic mechanisms, both in an attempt 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. This explains why cirrhotic patients with ascites demonstrate urinary sodium retention, increased total body sodium, and dilutional hyponatremia, a challenging concept to many physicians.

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Signs and symptoms

The symptoms of ascites vary from patient to patient and largely depend on the quantity of fluid. If trace ascites is present, the patient may be asymptomatic and fluid can be 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—obese patients may be more technically difficult to diagnose. If 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.

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

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Diagnosis

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 case 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, SBP) even if no symptoms are present. This is particularly true in the case of a significant gastrointestinal hemorrhage.

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

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. 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. Milky-appearing 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 lymphoma, but is often related primarily to cirrhosis.

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 and a cell count with differential are determined ( Table 4 ). Less than 10 mL of fluid placed in a purple-topped tube—containing an anticoagulant—is required to perform these basic tests. The albumin concentration is used to confirm the presence of portal hypertension by calculating the serum-to-ascites albumin gradient, or SAAG. The SAAG is determined by subtracting the ascites albumin value from a serum albumin value obtained on the same day:

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 higher than 1.1 g/dL indicates that the patient has portal hypertension-related ascites with 97% accuracy. Portal hypertension is usually caused by liver cirrhosis or, less commonly, outflow obstruction from right-sided heart failure or Budd-Chiari syndrome. A SAAG value lower than 1.1 g/dL indicates that the patient does not have portal hypertension-related ascites and another cause should be sought. Determination of the SAAG does not need to be repeated after the initial measurement.

The cell count and differential are used to determine if the patient is likely to have SBP. Patients with an ascitic polymorphonuclear (PMN) or absolute neutrophil count greater higher than 250 cells/mm³ should receive empirical 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, which contains a high concentration of red blood cells, the PMN count must be corrected: 1 PMN is subtracted from the absolute PMN count for every 250 red cells/mm³ in the sample. 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, lactate dehydrogenase (LDH), glucose, amylase, triglyceride, and bilirubin levels, cytology, or tuberculosis smear and culture. These tests are generally only useful when there is suspicion of a condition other than sterile cirrhotic ascites. Tests that are not routinely helpful include determination of pH and lactate levels, and Gram staining. Results of Gram staining are of particular low yield unless a large concentration of bacteria, such as in the case of a free gut perforation, is suspected.

Summary

• Cirrhotic patients should undergo diagnostic paracentesis in cases of unexplained fever, abdominal pain, or encephalopathy, or admission to the hospital for any cause.
• Paracentesis is a safe procedure, with a low risk of serious complication.
• The serum-to-ascites albumin gradient (SAAG) can be calculated to determine whether the patient has portal hypertension-related ascites.
• The ascitic fluid cell count and differential are used to determine whether the patient is likely to have spontaneous bacterial peritonitis (SBP).

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Treatment

It is important to determine the cause of ascites before the appropriate management can be determined. For example, ascites related to cancer or carcinomatosis responds best to therapies directed at the underlying malignancy. Similarly, ascites related to myxedema generally improves with aggressive thyroid hormone replacement. This chapter will focus specifically on the treatment of ascites related to cirrhosis. Treatment of other causes of ascites will not be mentioned further here.

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. Furthermore, treatment ascites can dramatically improve one's quality of life by decreasing abdominal discomfort, dyspnea, or both. 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 largely depends on the severity of ascites and includes oral diuretics, therapeutic (or large-volume) paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), and orthotopic liver transplantation (Fig. 2).

Low-Volume Ascites

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. Patients with ascites should also minimize use of all NSAIDs; these agents inhibit the synthesis of renal prostaglandin and can lead to renal vasoconstriction, decreased diuretic response, and acute renal failure. Finally, ascites patients should be counseled to limit their sodium consumption to no more than 2 g/day. 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. Because fluid passively follows sodium, a salt restriction without a fluid restriction is generally all that is required to decrease the amount of ascites. In patients with minimal fluid, the restriction of alcohol, NSAIDs, and salt may be all that is needed to control ascites formation adequately.

Moderate-Volume Ascites

Patients with moderate fluid overload who do not respond to more conservative measures should be considered for pharmacologic therapy. A rapid reduction of ascites is often accomplished simply with the addition of low-dose oral diuretics in the outpatient setting. In general, patients with mild or moderate ascites generally do not need to be admitted to the hospital unless there are other accompanying complications.

First-line diuretic therapy for cirrhotic ascites is the combined use of spironolactone (Aldactone) and furosemide (Lasix). Beginning dosages are 100 mg of spironolactone and 40 mg of furosemide by mouth daily. 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 dosages are 400 and 160 mg/day of spironolactone and furosemide, respectively.

The response to diuretics should be carefully monitored on the basis of changes in body weight, laboratory tests, and clinical assessment. Patients on diuretics should be weighed daily and the rate of weight loss should not exceed more than 0.5 kg/day in the absence of edema and more than 1 kg/day when edema is present. Serum potassium, blood urea nitrogen (BUN), and creatinine levels should be serially followed. In the event of marked hyponatremia, hyperkalemia or hypokalemia, renal insufficiency, dehydration, or encephalopathy, diuretics should be reduced or discontinued. Routine measurement of the urinary sodium level is not necessary, but can be helpful to identify noncompliance with dietary sodium restriction. Patients excreting more than 78 mmol of sodium/day (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 dietitian. The spot urine sodium-to-potassium ratio may ultimately replace the cumbersome 24-hour collection—a random urine sodium concentration higher than the potassium concentration has been shown to correlate with a 24-hour sodium excretion higher than 78 mmol/day with approximately 90% accuracy. Because of the potentially severe complications associated with diuretic use, patients with ascites should be assessed by a health care provider at least once weekly until clinically stable.

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. Similar to low- or moderate-volume ascites, large-volume ascites can usually be managed in the outpatient setting, as long as no additional complications are present.

Therapeutic (or large-volume) paracentesis is a well-established therapy for large-volume ascites. 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 electrolyte, creatinine, and renin levels. 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. In view of the high cost of albumin and its uncertain clinical role, more studies certainly need to be conducted. Until these studies are carried out, current American Association for the Study of Liver Diseases (AASLD) practice guidelines state that it is reasonable, although not mandatory, to give albumin for paracenteses more than 5 L. Although no direct comparisons have been studied, 25% albumin at doses of 5 to 10 g/L of ascites removed is generally used.

To prevent the reaccumulation of ascites fluid, patients with large-volume ascites should be counseled about 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.

Refractory Ascites

Refractory ascites occurs in 5% to 10% of cirrhotic ascites patients and portends a poor prognosis. The definition of refractory ascites is (1) lack of response to high-dose diuretics (400 mg of spironolactone and 160 mg of furosemide/day) while remaining compliant with a low-sodium diet or (2) frequent ascites recurrence shortly after therapeutic paracentesis. Patients with recurrent side effects from diuretic therapy, including symptomatic hyponatremia, hyperkalemia or hypokalemia, renal insufficiency, or hepatic encephalopathy, are also considered to have refractory ascites. Treatment options include large-volume paracentesis with albumin infusion, placement of a TIPS, or liver transplantation. Surgical peritoneovenous shunts (e.g., LeVeen or Denver shunt) have essentially been abandoned since controlled trials have shown poor long-term patency, excessive complications, and no survival advantage over medical therapy.

Frequent therapeutic paracentesis with or without albumin infusion is the most widely accepted treatment for patients with refractory ascites (see “Large-Volume Ascites” for controversy and dosing of 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. Ongoing studies will determine whether 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 below 12 mm Hg, the level at which ascites begins to accumulate. Complications are common; these include hemorrhage (intrahepatic or intra-abdominal) and stent stenosis or thrombosis. Other important complications include hepatic encephalopathy and decompensation of liver or cardiac function. Therefore, TIPS is generally not recommended for patients with preexisting encephalopathy, an ejection fraction lower than 55%, or a Child-Pugh Score higher than 12 ( Table 5 ). Additional disadvantages of the procedure are 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.

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

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Suggested Readings

• Management of cirrhosis and ascites. N Engl J Med. 350: 2004; 1646-1654.
• Pathogenesis of ascites in cirrhosis. Semin Liver Dis. 17: 1997; 175-189.
• Compensated cirrhosis: Natural history and prognostic factors. Hepatology. 7: 1987; 122-128.
• Randomized study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology. 94: 1988; 1493-1502.
• The management of ascites in cirrhosis: Report on the consensus conference of the International Ascites Club. Hepatology. 38: 2003; 258-266.
• A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med. 342: 2000; 1701-1747.
• Historical aspects of treatment of patients with cirrhosis and ascites. Semin Liver Dis. 17: 1997; 163-173.
• Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD): Management of adult patients with ascites due to cirrhosis. Hepatology. 39: 2004; 841-856.
• The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med. 117: 1992; 215-220.
• The North American Study for the Treatment of Refractory Ascites. Gastroenterology. 124: 2003; 634-641.