Background
The word ascites is of Greek origin (askos) and means bag or sac. Ascites describes the condition of pathologic fluid accumulation within the abdominal cavity. Healthy men have little or no intraperitoneal fluid, but women may normally have as much as 20 mL depending on the phase of the menstrual cycle. This article focuses only on ascites associated with cirrhosis.
Pathophysiology
The accumulation of ascitic fluid represents a state of total-body sodium and water excess, but the event that initiates the unbalance is unclear. Three theories of ascites formation have been proposed.
The underfilling theory suggests that the primary abnormality is inappropriate sequestration of fluid within the splanchnic vascular bed due to portal hypertension and a consequent decrease in effective circulating blood volume. This activates the plasma renin, aldosterone, and sympathetic nervous system, resulting in renal sodium and water retention.
The overflow theory suggests that the primary abnormality is inappropriate renal retention of sodium and water in the absence of volume depletion. This theory was developed in accordance with the observation that patients with cirrhosis have intravascular hypervolemia rather than hypovolemia.
The most recent theory, the peripheral arterial vasodilation hypothesis, includes components of both of the other theories. It suggests that portal hypertension leads to vasodilation, which causes decreased effective arterial blood volume. 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. According to the vasodilation theory, the underfilling theory is proposed to be operative early and the overflow theory is proposed to be operative late in the natural history of cirrhosis.
Although the sequence of events that occurs between the development of portal hypertension and renal sodium retention is not entirely clear, portal hypertension apparently leads to an increase in nitric oxide levels. Nitric oxide mediates splanchnic and peripheral vasodilation. Patients with ascites have greater hepatic artery nitric oxide synthase activity compared to patients without ascites.
Regardless of the initiating event, a number of factors contribute to the accumulation of fluid in the abdominal cavity. Elevated levels of epinephrine and norepinephrine are well-documented factors. Hypoalbuminemia and reduced plasma oncotic pressure favor the extravasation of fluid from the plasma to the peritoneal fluid, and, thus, ascites is infrequent in patients with cirrhosis unless both portal hypertension and hypoalbuminemia are present.
Mortality/Morbidity
Ambulatory patients with an episode of cirrhotic ascites have a 3-year mortality rate of 50%. The development of refractory ascites carries a poor prognosis, with a 1-year survival rate of less than 50%.
Sex
Healthy men have little or no intraperitoneal fluid, but women may normally have as much as 20 mL depending on the phase of the menstrual cycle.
CLINICAL
History
Most cases of ascites are due to liver disease. Patients often state that their increasing abdominal girth has been noted for a short period.
- Patients with ascites should be asked about risk factors for liver diseases. These include the following:
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- Alcohol use and duration of use
- Chronic viral hepatitis or jaundice
- Intravenous drug use
- Sexual promiscuity
- Sexual orientation
- Transfusions: Hepatitis C has been linked to transfusions occurring before 1980.
- Tattoos
- Habitation or origination from an area endemic for hepatitis
- Patients with alcoholic liver disease who intermittently cease or reduce alcohol consumption may experience ascites in a cyclic fashion. When the patient has a very long history of stable cirrhosis and then develops ascites, the possibility of superimposed hepatocellular carcinoma should be considered.
- Obesity, hypercholesterolemia, and type 2 diabetes mellitus are now recognized causes of nonalcoholic steatohepatitis, which can progress to cirrhosis.
- Patients with a history of cancer, especially gastrointestinal cancer, are at risk for malignant ascites. Malignancy-related ascites is frequently painful, whereas cirrhotic ascites is usually painless.
- Patients who develop ascites in the setting of known diabetes or nephrotic syndrome may have nephrotic ascites.
Physical
The physical examination should focus on the signs of portal hypertension and chronic liver disease.
- Physical findings suggestive of liver disease include jaundice, palmar erythema, and spider angiomas.
- The liver may be difficult to palpate if a large amount of ascites is present, but often, the liver is enlarged. The puddle sign indicates that as little as 120 mL of fluid is present. When peritoneal fluid exceeds 500 mL, ascites may be demonstrated by the presence of shifting dullness or bulging flanks. A fluid-wave sign is notoriously inaccurate.
- Elevated jugular venous pressure may suggest a cardiac origin of ascites. A firm nodule in the umbilicus, the so-called Sister Mary Joseph nodule, is not common but suggests peritoneal carcinomatosis originating from gastric, pancreatic, or hepatic primary malignancy.
- A pathologic left-sided supraclavicular node (Virchow node) suggests the presence of upper abdominal malignancy.
- Patients with cardiac disease or nephrotic syndrome may have anasarca.
Causes
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- Portal hypertension (serum-ascites albumin gradient [SAAG] >1.1 g/dL)
- Hepatic congestion, congestive heart failure, constrictive pericarditis, tricuspid insufficiency, Budd-Chiari syndrome
- Liver disease, cirrhosis, alcoholic hepatitis, fulminant hepatic failure, massive hepatic metastases
- Hypoalbuminemia (SAAG <1.1>
- Nephrotic syndrome
- Protein-losing enteropathy
- Severe malnutrition with anasarca
- Miscellaneous conditions (SAAG <1.1>
- Chylous ascites
- Pancreatic ascites
- Bile ascites
- Nephrogenic ascites
- Urine ascites
- Ovarian disease
- Diseased peritoneum (SAAG <1.1>
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- Infections
- Bacterial peritonitis
- Tuberculous peritonitis
- Fungal peritonitis
- HIV-associated peritonitis
- Malignant conditions
- Peritoneal carcinomatosis
- Primary mesothelioma
- Pseudomyxoma peritonei
- Hepatocellular carcinoma
- Other rare conditions
- Familial Mediterranean fever
- Vasculitis
- Granulomatous peritonitis
- Eosinophilic peritonitis
DIFFERENTIALS
Acute Liver Failure
Alcoholic Hepatitis
Biliary Disease
Budd-Chiari Syndrome
Cardiomyopathy, Dilated
Cardiomyopathy, Restrictive
Cirrhosis
Hepatitis, Viral
Hepatocellular Adenoma
Hepatorenal Syndrome
Mediterranean Fever, Familial
Nephrotic Syndrome
Portal Hypertension
Primary Biliary Cirrhosis
Protein-Losing Enteropathy
WORKUP
Lab Studies
- Peritoneal fluid should be sent for cell count, albumin level, culture, total protein, Gram stain, and cytology for new-onset ascites of unknown origin.
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- Inspection: Most ascitic fluid is transparent and tinged yellow. A minimum of 10,000 red blood cells/µL is required for ascitic fluid to appear pink, and more than 20,000 red blood cells/µL is considered distinctly blood tinged. This may be attributed to either a traumatic tap or malignancy. Bloody fluid from a traumatic tap is heterogeneously bloody, and the fluid will clot. Nontraumatic bloody fluid is homogeneously red and does not clot because it has already clotted and lysed. Neutrophil counts of more than 50,000 cells/µL have a purulent cloudy consistency and indicate infection.
- Cell count:
- SAAG: The SAAG is the best single test for classifying ascites into portal hypertensive (SAAG >1.1 g/dL) and non–portal hypertensive (SAAG <1.1>
- Total protein: In the past, ascitic fluid has been classified as an exudate if the protein level is greater than or equal to 2.5 g/dL. However, the accuracy is only approximately 56% for detecting exudative causes. The total protein level may provide additional clues when used with the SAAG. An elevated SAAG and a high protein level are observed in most cases of ascites due to hepatic congestion. Those patients with malignant ascites have a low SAAG and a high protein level (see Causes).
- Culture/Gram stain: The sensitivity with bedside inoculation of blood culture bottles with ascites results in 92% detection of bacterial growth in neutrocytic ascites. Gram stain is only 10% sensitive for helping visualize bacteria in early-detected spontaneous bacterial peritonitis. Approximately 10,000 bacteria/mL are required for detection by Gram stain; the median concentration of bacteria in spontaneous bacterial peritonitis is 1 organism/mL.
- Cytology: Cytology smear results are reported to be 58-75% sensitive for helping detect malignant ascites.
Imaging Studies
- Chest and plain abdominal films
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- Elevation of the diaphragm, with or without sympathetic pleural effusions (hepatic hydrothorax), is visible in the presence of massive ascites. More than 500 mL of fluid is usually required for ascites to be diagnosed based on findings from abdominal films.
- Many nonspecific signs indicate ascites, such as diffuse abdominal haziness, bulging of the flanks, indistinct psoas margins, poor definition of the intra-abdominal organs, erect position density increase, separation of small bowel loops, and centralization of floating gas containing small bowel.
- The direct signs are more reliable and specific. In 80% of patients with ascites, the lateral liver edge is medially displaced from the thoracoabdominal wall (Hellmer sign). Obliteration of the hepatic angle is visible in 80% of healthy patients. In the pelvis, fluid accumulates in the rectovesical pouch and then spills into the paravesical fossa. The fluid produces symmetric densities on both sides of the bladder, which is termed a "dog's ear" or "Mickey Mouse" appearance. Medial displacement of the cecum and ascending colon and lateral displacement of the properitoneal fat line are present in more than 90% of patients with significant ascites.
- Ultrasound
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- Real-time sonography is the easiest and most sensitive technique for the detection of ascitic fluid. Volumes as small as 5-10 mL can routinely be visualized. Uncomplicated ascites appears as a homogenous, freely mobile, anechoic collection in the peritoneal cavity that demonstrates deep acoustic enhancement. Free ascites does not displace organs but typically situates itself between them, contouring to organ margins and demonstrating acute angles at the point at which the fluid borders the organ.
- The smallest amounts of fluid tend to collect in the Morison pouch and around the liver as a sonolucent band. With massive ascites, the small bowel loops have a characteristic polycyclic, "lollipop," or arcuate appearance because they are arrayed on either side of the vertically floating mesentery.
- Certain sonographic findings suggest that the ascites may be infected, inflammatory, or malignant. Findings include coarse internal echoes (blood), fine internal echoes (chyle), multiple septa (tuberculous peritonitis, pseudomyxoma peritonei), loculation or atypical fluid distribution, matting or clumping of bowel loops, and thickening of interfaces between fluid and adjacent structures. In malignant ascites, the bowel loops do not float freely but may be tethered along the posterior abdominal wall plastered to the liver or other organs or they may be surrounded by loculated fluid collections.
- Most patients (95%) with carcinomatous peritonitis have a gallbladder wall that is less than 3 mm thick. Mural thickening of the gallbladder is associated with benign ascites in 82% of cases. The thickening of the gallbladder is primarily a reflection of cirrhosis and portal hypertension.
- CT scan: Ascites is demonstrated well on CT scan images. Small amounts of ascitic fluid localize in the right perihepatic space, the posterior subhepatic space (Morison pouch), and the
Other Tests
- Laparoscopy may be valuable if malignant ascites is suggested. This may be of particular importance in the diagnosis of malignant mesothelioma.
Procedures
- Abdominal paracentesis: Abdominal paracentesis is the most rapid and perhaps the most cost-effective method of diagnosing the cause of ascites formation. Therapeutic paracentesis may be performed for refractory or tense ascites. The removal of 5 L of fluid is considered large-volume paracentesis. Total paracentesis, ie, removal of all ascites (even >20 L), can usually be performed safely. Recent studies demonstrate that supplementing 5 g of albumin per each liter over 5 L decreases complications of paracentesis, such as electrolyte imbalances, and increases in serum creatinine secondary to large shifts of intravascular volume.
- Transjugular intrahepatic portacaval shunt (TIPS): This is a side-to-side portacaval shunt placed by an interventional radiologist under local anesthesia. This is often used for diuretic refractory ascites.
Staging
- Ascites may be semiquantified using the following system:
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- Stage 1+ is detectable only after careful examination.
- Stage 2+ is easily detectable but of relatively small volume.
- Stage 3+ is obvious ascites but not tense ascites.
- Stage 4+ is tense ascites.
TREATMENT
Medical Care
Sodium restriction (20-30 mEq/d) and diuretic therapy constitute the standard medical management for ascites and are effective in approximately 95% of patients.
- Water restriction is used only if persistent hyponatremia is present.
- Therapeutic paracentesis should be reserved for patients who need rapid symptomatic relief of tense ascites.
- TIPS is an interventional radiologic technique that reduces portal pressure and may be the most efficacious for treatment of patients with diuretic-resistant ascites. This procedure consists of inserting a long metal needle from the right jugular vein into the hepatic vein. This is slowly becoming the standard of care in patients with diuretic-refractory ascites.
Surgical Care
The peritoneovenous shunt is an alternative for patients with medically intractable ascites. This is a megalymphatic shunt that returns the ascitic fluid to the central venous system. Beneficial effects of these shunts include increased cardiac output, renal blood flow, glomerular filtration rate, urinary volume, and sodium excretion and decreased plasma renin activity and plasma aldosterone concentration. No evidence indicates that these shunts improve patient survival. With the advent of the TIPS procedure, this form of therapy is almost obsolete.
Consultations
Consultation with a gastrointestinal specialist and/or hepatologist should be considered for all patients with ascites, particularly if the ascites is refractory to medical treatment.
Diet
Sodium restriction of 500 mg/d (22 mmol/d) is feasible in a hospital setting; however, it is unrealistic in most outpatient settings. A more appropriate sodium restriction is 2000 mg/d (88 mmol). Indiscriminate fluid restriction is inappropriate. Fluids need not be restricted unless the serum sodium level drops below 120 mmol/L.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Diuretics
Mainstay of medical therapy in ascites.
| Drug Name | Spironolactone (Aldactone) |
| Description | For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. The peak effect of Aldactone is approximately 3 d. |
| Adult Dose | 25-200 mg/d |
| Pediatric Dose | 1.5-3.5 mg/kg/d |
| Contraindications | Documented hypersensitivity; anuria; renal failure; hyperkalemia |
| Interactions | May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Caution in renal and hepatic impairment; may cause gynecomastia and impotence in men |
| Drug Name | Furosemide (Lasix) |
| Description | Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. |
| Adult Dose | 20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states |
| Pediatric Dose | 1-2 mg/kg/dose |
| Contraindications | Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion |
| Interactions | Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides, hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter |
| Drug Name | Amiloride (Midamor) |
| Description | A pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug which, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. |
| Adult Dose | 5-20 mg |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function, acute or chronic renal insufficiency, and evidence of diabetic nephropathy; monitor electrolytes closely if evidence of renal functional impairment is present, BUN is >30 mg/100 mL, or serum creatinine level is >1.5 mg/100 mL |
| Interactions | Concomitant therapy with potassium supplementation may increase serum potassium levels; if concomitant use of these agents is indicated because of demonstrated hypokalemia, use caution and monitor serum potassium level frequently; generally, lithium should not be administered with diuretics because may reduce renal clearance and add a high risk of lithium toxicity; administration of NSAIDs can reduce diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics; when used concomitantly, observe patient closely to determine if desired effect of diuretic obtained |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Potassium retention associated with use of an antikaliuretic agent accentuated in presence of renal impairment and may result in rapid development of hyperkalemia; monitor serum potassium level; mild hyperkalemia usually not associated with abnormal ECG findings |
| Drug Name | Metolazone (Mykrox, Zaroxolyn) |
| Description | Helps treat edema in congestive heart failure. Increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. May be more effective in those with impaired renal function. |
| Adult Dose | 5-20 mg/dose |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; hepatic coma or anuria |
| Interactions | Thiazides may decrease effect of anticoagulants, sulfonylureas, and gout treatments; anticholinergics and amphotericin B may increase toxicity of thiazides; effects of thiazides may decrease when used concurrently with bile acid sequestrants, NSAIDs, or methenamine; when administered concurrently, thiazides increase toxicity of anesthetics, diazoxide, digitoxin, lithium, loop diuretics, antineoplastics, allopurinol, calcium salts, vitamin D, and nondepolarizing muscle relaxants |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in hepatic or renal disease, diabetes mellitus, gout, or lupus erythematosus |
| Drug Name | Mannitol (Osmitrol) |
| Description | Inhibits tubular reabsorption of electrolytes by increasing osmotic pressure of glomerular filtrate. Increases urinary output. |
| Adult Dose | 0.5-2 g/kg IV over 30-60 min as a 15-25% solution; repeat q6-8h |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; anuria, severe pulmonary congestion, progressive renal damage, severe dehydration, active intracranial bleeding, and progressive heart failure |
| Interactions | May decrease serum lithium levels |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Carefully evaluate cardiovascular status before rapid administration because a sudden increase in extracellular fluid may lead to fulminating CHF; avoid pseudoagglutination; when blood given simultaneously, add at least 20 mEq of sodium chloride to each liter of mannitol solution; do not give electrolyte-free mannitol solutions with blood |
FOLLOW-UP
Further Inpatient Care
- Patients can actually be maintained free of ascites if sodium intake is limited to 10 mmol/d. This is not practical outside a metabolic ward.
- Twenty-four–hour urinary sodium measurements are useful in patients with ascites related to portal hypertension in order to assess the degree of sodium avidity, monitor the response to diuretics, and assess compliance with diet.
- For grade 3 or 4 ascites, therapeutic paracentesis may be necessary intermittently.
Further Outpatient Care
- The best method of assessing the effectiveness of diuretic therapy is by monitoring body weight and urinary sodium levels.
- In general, the goal of diuretic treatment should be to achieve weight loss of 300-500 g/d in patients without edema and 800-1000 g/d in patients with edema.
- Once ascites has disappeared, diuretic treatment should be adjusted to maintain the patient free of ascites.
In/Out Patient Meds
- Diuretics should be initiated in patients who do not respond to sodium restriction. A useful regimen is to start with spironolactone at 100 mg/d. The addition of loop diuretics may be necessary in some cases to increase the natriuretic effect. If no response occurs after 4-5 days, the dosage may be increased stepwise up to spironolactone at 400 mg/d plus furosemide at 160 mg/d.
Complications
- The most common complication of ascites is the development of spontaneous bacterial peritonitis (ascitic fluid with polymorphonuclear leukocyte count of >250 µL).
- Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication. In a recent study of 133 hospitalized patients with ascites, abdominal pain and abdominal tenderness were more common in patients with spontaneous bacterial peritonitis (P <.01), but no other physical sign or laboratory test could separate spontaneous bacterial peritonitis cases from other cases.
- Any patient with ascites and fever should have a paracentesis with bedside blood culture inoculation and cell count. Patients with a protein level of less than 1 g/dL in ascitic fluid are at high risk for the development of spontaneous bacterial peritonitis. Prophylactic antibiotic therapy with a quinolone is often recommended.
- Complications of paracentesis include infection, electrolyte imbalances, bleeding, and bowel perforation. Bowel perforation should be considered in any patient with recent paracentesis who develops a new onset of fever and/or abdominal pain. All patients with long-standing ascites are at risk of developing umbilical hernias. Large-volume paracentesis often results in large intravascular fluid shifts. This can be avoided by administering albumin replacement if more than 5 liters is removed.
Prognosis
- The prognosis for patients with ascites due to liver disease depends on the underlying disorder, the degree of reversibility of a given disease process, and the response to treatment.
Patient Education
- The most important aspect of patient education is determining when therapy is failing and recognizing the need to see a physician. Unfortunately, in most cases, liver failure has a dismal prognosis. All patients must be taught which complications are potentially fatal and the signs and symptoms that precede them.
- Abdominal distention and/or pain despite maximal diuretic therapy are common problems, and patients must realize the importance of seeing a physician immediately.
MISCELLANEOUS
Medical/Legal Pitfalls
- The most important consideration in a patient with a new onset of ascites is to perform a peritoneal tap and to ascertain the cause. A peritoneal tap is also indicated in a patient with known liver disease who presents with sudden clinical deterioration, worsening encephalopathy, or unexplained fever. A missed or delayed diagnosis of spontaneous bacterial peritonitis could potentially lead to sepsis and significant morbidity and mortality.
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