Definition and Diagnosis

Ascites is the abnormal accumulation of fluid in the peritoneal cavity.¹ Patients with ascites generally present on clinical examination with abdominal distention and a fluid wave or shifting dullness on abdominal percussion, but the abdominal examination findings also may be normal if the amount of ascites is not massive.

Diagnostic imaging can confirm the diagnosis of ascites. Ultrasonography is the easiest and most sensitive technique for the detection of ascitic fluid, being capable of visualizing very small volumes (5-10 mL). Computed tomography (CT) is also very sensitive for detecting ascites (Figure 97-1). Small amounts of ascitic fluid localize in the perihepatic area and in Morrison’s pouch (the hepatorenal space).

Figure 97-1 Ascites appearance on ultrasound (Netterimages.com) of abdomen and pelvis.

A diagnostic paracentesis (20 mL)² is performed to determine the etiology of the ascites as well as to exclude or establish a diagnosis of spontaneous bacterial peritonitis (SBP). A diagnostic paracentesis should be performed in any person with new-onset ascites. Paracentesis to evaluate for SBP is also indicated for cirrhotic patients with known ascites who require hospitalization or sustain clinical deterioration, such as worsening encephalopathy or unexplained fever. A missed or delayed diagnosis of SBP can lead to sepsis and significant morbidity and mortality.

Peritoneal fluid from patients with new-onset ascites of unknown origin should be assayed for cell count, albumin level, culture, total protein concentration, Gram stain, and cytologic analysis.³ Serum albumin concentration should be measured as well.

The serum ascites albumin gradient (SAAG, serum albumin concentration—ascitic fluid albumin concentration) is the best diagnostic measure for classification of ascites (Table 97-1).⁴ The SAAG is very specific and sensitive for distinguishing ascites due to portal hypertension (SAAG > 1.1 g/dL) from that occurring as a result of other pathogenetic mechanisms such as inflammation or peritoneal malignancy (SAAG ≤ 1.1 g/dL). Ideally, specimens should be obtained simultaneously. In the past, ascites was classified as being an exudate (protein concentration ≥ 2.5 g/dL) or a transudate (protein concentration < 2.5 g/dL), but this classification scheme is no longer used because of its poor sensitivity and specificity.⁵ The total protein level may provide additional clues about diagnosis when used with the SAAG; that is, high SAAG and high protein concentration is seen in most cases of ascites due to hepatic congestion, whereas low serum ascites albumin gradient and high protein concentration characterizes malignant ascites. The terms high albumin gradient and low albumin gradient should replace the terms transudate and exudate in the description of ascites.

TABLE 97-1 Causes of Ascites Based on Normal or Diseased Peritoneum and Serum-to-Ascites Albumin Gradient (SAAG)

The ascitic fluid cell count and differential cell count are important in the evaluation of cases of possible SBP and other inflammatory peritoneal conditions. Normal peritoneal fluid contains less than 500 leukocytes/µL and less than 250 polymorphonuclear leukocytes/µL. A peritoneal fluid neutrophil count above 250 cells/µL is consistent with bacterial peritonitis. In tuberculous peritonitis and peritoneal carcinomatosis, most leukocytes in peritoneal fluid are lymphocytes. A sample of ascites should be inoculated into blood culture bottles for detection of SBP. Gram stain is not sensitive for the detection of SBP because of the low numbers of bacterial organisms present in the ascites.

The sensitivity of cytologic analysis for detecting malignancy is 58% to 75% if a large volume of fluid is analyzed. Laparoscopy is an additional invasive diagnostic study that also may be indicated if a diagnosis of malignant ascites is considered. Peritoneal or tumor implant biopsy samples can be obtained at the same time for histologic diagnosis.

Pathophysiology

Ascites is the most common complication related to liver disease and cirrhosis.⁶ It is associated with profound changes in the splanchnic and systemic circulation and with renal abnormalities (Figure 97-2). However, the pathogenesis of renal sodium retention and ascites formation in cirrhosis remains a subject of much controversy.

Figure 97-2 Pathophysiology of cirrhosis and ascites. Cirrhosis is associated with splanchnic arterial vasodilation, leading to a decrease in effective circulating volume and a hyperdynamic circulation. The decrease in effective circulating volume causes activation of renal sodium and water retentive pathways (e.g., RAAS, renal SNS, and ADH). Resulting sodium and water retention leads to ascites due to spillage of excess sodium and water from hepatic lymph into peritoneal cavity. As disease progresses, progressive decrease in effective circulating volume develops, causing severe renal vasoconstriction and decrease in glomerular filtration rate. Onset of cirrhotic cardiomyopathy accentuates this problem and tips patient into hepatorenal syndrome. Accompanying circulatory disturbance leads to organ failure and death. Sepsis is frequently associated with this process.

(From Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133:825-34.)

One accepted theory of ascites formation is the forward theory, which states that the development of ascites is related to the existence of severe sinusoidal portal hypertension that causes marked splanchnic arterial vasodilation and a forward increase in the splanchnic production of lymph.⁷ Splanchnic arterial vasodilation also produces arterial vascular underfilling, a significant reduction of the effective blood volume, and arterial hypotension. These pathophysiologic changes lead to compensatory activation of sodium- and water-retaining mechanisms (the renin-angiotensin-aldosterone system, sympathetic nervous system, and nonosmotic release of vasopressin) and promote ascites formation. Therefore, according to this theory, derangements in the splanchnic arterial circulation rather than the venous portal system are primary in the pathogenesis of ascites formation.⁸

This theory is supported by the observation that interventions that markedly decrease portal pressure, such as surgical portacaval shunts or transjugular intrahepatic portosystemic shunts (TIPS), reduce ascites. In the advanced stages of cirrhosis, the extreme underfilling of the arterial circulation leads to maximal stimulation of vasoconstrictor mechanisms which override the protective effects of renal vasodilator factors and cause renal vasoconstriction, further aggravating ascites formation and leading to functional renal insufficiency. Renal insufficiency is also one of the main causes of resistance to diuretic therapy.

Patients with advanced cirrhosis and portal hypertension often show an abnormal regulation of extracellular fluid volume, resulting in the accumulation of fluid as ascites, pleural effusion, or edema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favor sodium and water retention.⁹ The renal functional abnormalities occur in the setting of a hyperdynamic circulatory state that is characterized by increased cardiac output, decreased systemic vascular resistance, and activation of neurohormonal vasoactive systems. This circulatory dysfunction, due mainly to intense arterial vasodilation in the splanchnic circulation, is considered to be a primary feature in the pathogenesis of ascites.

A major factor involved in the development of splanchnic arterial vasodilation is increased synthesis of nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. Excessive production of NO decreases effective arterial blood volume and leads to fluid accumulation and renal function abnormalities, which are a consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction.

The peripheral arterial vasodilation hypothesis incriminates relative underfilling of the arterial vascular compartment as the primary problem. Relative arterial underfilling leads to the same neurohumoral responses that occur in states characterized by low cardiac output (e.g., chronic congestive heart failure).¹⁰ Activation of the renin-angiotensin-aldosterone axis and the sympathetic system, as well as nonosmotic release of vasopressin, are well documented in cases of cirrhosis. This sequence of events results in renal water and sodium retention, failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. Dilutional hyponatremia is the strongest predictor of the occurrence of hepatorenal syndrome.

The pathogenesis of peripheral arterial vasodilation in cirrhosis is not completely elucidated, but there is evidence for a major role of NO.¹¹ Increased vascular NO production has been demonstrated in cirrhosis. In patients with ascites, the hepatic artery produces more NO than it does in patients without ascites. In a rat model of cirrhosis, normalization of vascular NO production with administration of a NO synthase inhibitor corrects the hyperdynamic circulation, improves sodium and water excretion, and decreases neurohumoral activation. This insight into the mechanisms of the peripheral arterial vasodilation in cirrhosis should provide new tools in the treatment of edema and ascites, a major cause of morbidity and mortality in patients with cirrhosis.

The generally accepted peripheral arterial vasodilation hypothesis seems to best explain the mechanism of sodium retention and other clinical findings such as hyperdynamic circulation in patients with cirrhosis. However, recent data in patients with pre-ascites or early ascites do not seem to conform to the peripheral arterial vasodilation hypothesis.¹² Renal sodium handling abnormalities can be demonstrated in patients with cirrhosis prior to the development of ascites when these individuals are challenged with a sodium load. These changes are apparent even in the absence of systemic vasodilation or arterial underfilling. Therefore, an alternative hypothesis with a direct hepatorenal interaction, acting via sinusoidal portal hypertension and/or hepatic dysfunction as the effector mechanism, is proposed to be the initiating event promoting renal sodium retention in patients with cirrhosis. The second and later process is the development of systemic arterial vasodilation, possibly due to the presence of excess systemic vasodilators and/or decreased responsiveness of the vasculature to endogenous vasoconstrictors. These changes in turn lead to a relatively underfilled circulation with consequent activation of neurohumoral systems, promoting further renal sodium retention as described by the peripheral arterial vasodilation hypothesis. When compensatory natriuretic mechanisms fail, refractory ascites develops and hepatorenal syndrome sets in. Thus renal sodium retention in patients with cirrhosis is the result of an interplay of many factors; direct hepatorenal interaction predominates in the earlier stages of the cirrhotic process, whereas systemic vasodilation becomes a more important pathogenetic mechanism as the disease progresses.

Etiology

Liver disease, particularly cirrhosis, is a common cause of ascites. In patients with liver disease, ascites develops as a result of portal hypertension, which can be prehepatic (e.g., due to portal vein thrombosis), intrahepatic (e.g., due to cirrhosis), or posthepatic (e.g., due to Budd-Chiari syndrome). Patients with chronic liver disease develop portal hypertension and subsequent ascites from increased resistance of blood flow through the hepatic parenchyma. Circulatory changes such as increased plasma volume and increased cardiac output develop in conjunction with decreased systemic vascular resistance and blood pressure.

Ascites is one of the most frequent complications of cirrhosis, accounting for approximately 85% of cases of ascites in the United States. Its appearance is considered a key marker of the transition from the compensated to the decompensated stage of the disease. In compensated cirrhotic patients, ascites develops at a 5-year cumulative rate of approximately 30%. The appearance of ascites also has prognostic significance, as it causes a sharp drop in the expected survival rate. Once ascites develops, the 1-year survival rate is 50% compared with the 1-year survival rate of over 90% in patients with compensated cirrhosis. Prognosis is particularly poor in patients who develop refractory ascites or hepatorenal syndrome.

Most cases of ascites are due to liver disease. However, a number of disorders may be associated with ascites, and these include portal vein thrombosis, cardiac disorders (constrictive pericarditis, congestive heart failure), liver cancer, nephrotic syndrome, protein-losing enteropathy, and pancreatitis (see Table 97-1). Nonhepatic causes include cardiac failure, malignancy, renal failure, and intraabdominal inflammation. It is important to diagnose nonhepatic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites, since these occur with increased frequency in patients with liver disease.

Management

Ascites is the most common presentation of decompensated cirrhosis. It occurs in more than half of all patients with cirrhosis, and its development heralds a poor prognosis (50% 2-year survival rate). Ascites is characterized by three grades of severity, and treatment is based on grade (Table 97-2). Effective first-line medical therapy for ascites includes dietary sodium restriction (2 g/d) and use of diuretics.¹³

TABLE 97-2 Grades of Ascites and Recommended Treatment