Textbook of Gastroenterology
4th Edition

CAUSES OF ASCITES AND MECHANISMS OF ASCITES FORMATION
Table 46-1 lists the causes of ascites formation in a prospective series of 901 paracenteses performed on the general medical and gastroenterology/hepatology wards of two academic institutions.1 Cirrhosis and alcoholic hepatitis cause most cases of ascites in these settings; only 15.9% of patients had a cause other than chronic parenchymal liver disease.
TABLE 46-1 Causes of Ascites in a Series of 901 Samples
Ascites Formation in Liver Disease
Portal hypertension appears to be a prerequisite for ascites formation in the setting of liver disease, even in fulminant hepatic failure.2 Three theories of ascites formation have been developed. The underfill theory postulates that an alteration in oncotic-hydrostatic balance leads to loss of intravascular fluid into the peritoneal cavity with resulting intravascular underfilling. This activates plasma renin, aldosterone, and the sympathetic nervous system and results in renal sodium retention. The observation that patients with cirrhosis have intravascular hyper volemia rather than hypo volemia led to the overflow theory. In this hypothesis, primary renal sodium retention is proposed to lead to intravascular hypervolemia and resulting overflow of fluid into the peritoneal cavity. The most recent theory, the peripheral arterial vasodilation theory, includes components of both prior theories.3 This newest theory proposes that portal hypertension leads to vasodilatation, which causes decreased effective arterial blood volume. These events are hypothesized to characterize early compensated cirrhosis, before ascites formation. As the natural history of the disease progresses, neurohumoral excitation increases, more renal sodium is retained, and plasma volume expands; this leads to overflow of fluid into the peritoneal cavity. The underfill theory is proposed to be operative early, and the overflow theory is proposed to be operative late in the natural history of cirrhosis, according to the vasodilation theory.3
In general, the kidneys retain sodium in response to hypovolemia to regain a euvolemic state. In patients with advanced cirrhosis, however, the kidneys retain sodium despite hypervolemia. The paradox of avid renal sodium retention in the presence of hypervolemia is explained, at least in part, by the lack of a good sensor for intravascular volume. In general, the kidneys rely on blood pressure to assess volume status indirectly; when doing so, hypotension equates with hypovolemia. Patients with advanced cirrhosis are hypotensive.4 The kidneys retain sodium in response to this hypotensive, vasodilated state.
Since popularization of the vasodilation theory, there has been an international search for the mediator of the vascular dilation. Many substances have been investigated and ruled out, and nitric oxide appears to be the currently favored mediator.5
In summary, although the exact sequence of events that occur between development of portal hypertension and renal sodium retention is not entirely clear, it appears that portal hypertension leads to an increase in nitric oxide levels. Nitric oxide, in turn, mediates the splanchnic and peripheral vasodilation associated with portal hypertension. The neurohumoral excitation state (involving the renin-aldosterone system, sympathetic nervous system, vasopressin, and endothelin-1) of advanced cirrhosis is an attempt to maintain the perfusion pressure in the presence of the nitric oxide–mediated hypotension.4 Fluid forms in the abdomen when the lymph filtering across the hypertensive sinusoid and then across the Glisson capsule exceeds the diaphragmatic lymphatics’ ability to reabsorb the escaping fluid.3
Ascites Formation in Other Diseases
“Mixed” Ascites
Approximately 5% of patients will have “mixed” ascites: that is, underlying portal hypertension as well as a second cause for ascites formation, such as cirrhosis plus peritoneal tuberculosis or cirrhosis plus peritoneal carcinomatosis (see Table 46-1).1 A clue to the presence of a second cause of ascites formation in a patient with obvious cirrhosis is an inappropriately high ascitic fluid lymphocyte count. The assumption that a patient with cirrhosis can have only one cause for ascites formation could lead to a missed diagnosis of a curable but potentially fatal disease such as tuberculous peritonitis.
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Malignant Disease
Fortunately, cancer is an uncommon cause of ascites formation, but unfortunately most patients with malignancy-related ascites survive only a few weeks after the onset of fluid retention.6 An exception to this very short life expectancy is the patient with ovarian carcinoma, who may respond to debulking surgery and chemotherapy.7 Not all malignancy-related ascites results from peritoneal carcinomatosis; the characteristics of the ascitic fluid and the treatments vary depending on pathophysiology of ascites formation8 (Table 46-2).
TABLE 46-2 Subtypes of Malignancy-Related Ascites and Their Prevalence
The mechanism of ascites formation in patients with malignant ascites depends on the location of the tumor. Peritoneal carcinomatosis appears to cause ascites formation by “exudation” of proteinaceous fluid from tumor cells lining the peritoneum and entry of extracellular fluid into the peritoneal cavity for reestablishment of oncotic balance.8 In patients with massive liver metastases, liver replacement by tumor or occlusion of portal veins with tumor emboli leads to portal hypertension; then ascites forms as it does in patients with parenchymal liver disease and portal hypertension. In the United States, most patients with hepatocellular carcinoma have underlying cirrhosis and portal hypertension; some of these patients do not develop fluid retention until the tumor becomes relatively large and replaces a significant percentage of the liver parenchyma.6 Alternatively, tumor-induced portal vein thrombosis or arteriovenous fistulae within the tumor may contribute to the patient’s portal hypertension and predispose to fluid retention. Chylous ascites resulting from malignant disease appears to be caused by lymph node involvement by tumor and rupture of chyle-containing lymphatics.6 Tumor can occlude the hepatic veins and can lead to ascites formation.
Tuberculous Peritonitis
In the United States, tuberculous peritonitis was a rare disease in the past but has become more common as the human immunodeficiency virus epidemic has evolved.9 More than one half of patients with tuberculous peritonitis in the United States are found to have underlying cirrhosis, usually alcoholic in origin.10
As in peritoneal carcinomatosis, tuberculous peritonitis probably causes ascites formation because of “exudation” of proteinaceous fluid by tubercles lining the peritoneum and entry of extracellular fluid into the peritoneal cavity for reestablishment of oncotic balance. At peritoneoscopy, the diffuse studding of the peritoneum by these lesions substantiates the plausibility of this mode of pathogenesis. Presumably, Coccidioides (a very cause form of inflammatory ascites) results in ascites formation by the same mechanism as tuberculosis.11
Heart Failure
Ascites is currently an uncommon complication of heart disease.12,13 It forms in high-output and low-output heart failure.14 In the former situation, decreased peripheral resistance appears to initiate salt and water retention, whereas in the latter condition, a diminished cardiac output is the first event.14 Both these initial events lead to a decreased effective arterial blood volume and subsequent activation of the vasopressin, renin-aldosterone, and sympathetic nervous systems. In turn, renal vasoconstriction and sodium and water retention occur.14 Fluid then weeps from the congested hepatic sinusoids as lymph, as in the formation of cirrhotic ascites.
Pancreatic Ascites
This rare form of ascites develops as part of severe acute (even hemorrhagic) pancreatitis or as a result of pancreatic duct rupture or leakage from a pseudocyst as a complication of chronic pancreatitis.15 Patients with this form of ascites may also have underlying cirrhosis. Pancreatic ascites may occasionally be complicated by bacterial infection. Pleural effusions (left-sided, usually) may be associated.
Ascites forms in this situation either by leakage of pancreatic juice into the peritoneal cavity or by a “chemical burn” of the peritoneum. Extracellular fluid then enters to reestablish oncotic equilibrium. The ascitic fluid retains the unique characteristics of the source fluid (e.g., high amylase concentration), modified to some degree by the added extracellular fluid.15
Fulminant Hepatic Failure
Ascites may develop as a manifestation of acute liver failure in viral hepatitis. Because fulminant liver failure is uncommon,
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however, the total number of patients with ascites who have acute liver failure is small (see Table 46-1).
The ascites that forms in this setting has a high (≥1.1 g/dL) serum-ascites albumin concentration gradient indicating portal hypertension.1 Ascites thus presumably forms in fulminant hepatic failure by mechanisms similar to those of the fluid that forms in parenchymal liver disease.1
Biliary Ascites
Bile can accumulate in the peritoneal cavity when the gallbladder, bile duct, or gut ruptures, or it can develop after biliary surgery. This is an uncommon form of ascites. Biliary ascites is most commonly the result of rupture of the gallbladder, usually a complication of gangrene of the gallbladder in elderly men.16
Lymphatic Tear
After extensive retroperitoneal dissection, as in distal splenorenal shunt or radical pelvic lymphadenectomy for testicular carcinoma, lymphatics may be transected and may leak lymph for variable periods.17
The formation of ascites in this condition is similar to that of malignant chylous ascites, that is, lymphatic leak. The presence or absence of chyle in the ascitic fluid depends on where the tear is in the lymphatic system—in chyle-containing channels or not.
Miscellaneous Causes of Ascites
In sexually active, otherwise healthy young women with fever and inflammatory ascites, chlamydial infection must be very high in the differential diagnosis. Chlamydia apparently now causes more cases of Fitz-Hugh-Curtis syndrome than does the gonococcus.18 Chlamydia peritonitis is one of the few curable causes of ascites formation.
Nephrogenous ascites develops in patients who are undergoing hemodialysis.19 On careful evaluation, many of these patients are found to have underlying chronic liver disease, which may be the reason they develop fluid overload more readily than patients without liver disease who are undergoing dialysis. Evaluation of patients with nephrogenous ascites may include peritoneoscopy, which will assist with the differential diagnosis and will confirm or rule out tuberculosis and cirrhosis.19 The proper treatment of this condition is uncertain, and the prognosis is poor.19
Nephrotic syndrome is always listed as a cause of ascites as if it were common, but in fact it is rare in adults.20 Usually, a second cause of ascites formation is also present.20 It is postulated that, in nephrotic syndrome in the absence of another cause of fluid retention, loss of protein (in particular albumin) in the urine leads to decreased effective arterial blood volume, activated vasopressin, renin-aldosterone, and sympathetic nervous systems with resulting renal sodium and water retention.14
Continuous ambulatory peritoneal dialysis causes an iatrogenic form of ascites that is usually under the management of nephrologists. The major problem is infection, which occurs approximately once per patient-year of treatment.
Urine may accumulate in the peritoneal cavity as a result of trauma, as a complication of renal transplantation, or in the newborn—a condition known as “urine ascites.”21 Reabsorption of urea can lead to “pseudorenal failure.”21
Serositis with ascites formation may complicate systemic lupus erythematosus.22 This form of ascites has been reported to respond to steroid therapy.22 Pathogenesis presumably involves inflammation of the peritoneum, with resultant exudation of proteinaceous fluid into the cavity.
In recent years, most cases of ascites caused by ovarian disease are the result of peritoneal carcinomatosis.7 Meig syndrome—ascites and pleural effusion caused by benign ovarian neoplasms—is no longer a common cause of ascites formation (see Table 46-1).
Ascites in patients with myxedema appears to be cardiac ascites, related to the subtle heart failure these patients develop.23 As in other forms of cardiac ascites, this ascitic fluid is high in protein and has a high albumin gradient.23,24 Treatment of the thyroid insufficiency cures the fluid retention.
Patients with either acute or chronic Budd-Chiari syndrome frequently develop ascites from portal hypertension and venous outflow obstruction. The protein concentration of this fluid is variable, but the albumin gradient is high.