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Year : 2020  |  Volume : 12  |  Issue : 1  |  Page : 3-12

Cirrhotic ascites: A review of pathophysiology and management

Department of Medicine, Gastroenterology Unit, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Kaduna, Nigeria

Date of Submission03-May-2019
Date of Decision10-Oct-2019
Date of Acceptance17-Mar-2020
Date of Web Publication23-May-2020

Correspondence Address:
Prof. Shettima Kagu Mustapha
Department of Medicine, Ahmadu Bello University Teaching Hospital, Shika, Zaria, PMB 06, Kaduna
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/NJGH.NJGH_4_20

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Ascites describes the condition of pathologic fluid accumulation in the peritoneal cavity. Cirrhosis is the most common cause of ascites worldwide, with a half of cirrhotic patients developing ascites within 10 years of diagnosis. The “underfill” and “overflow” theories have traditionally been used to explain the pathogenesis of ascites in cirrhosis. However, with advances in hemodynamic and neurohumoral studies, it has been shown that neither of these theories fully explains the pathophysiologic mechanisms involved. The key roles of portal hypertension and vasodilators such as nitric oxide (NO) in the process of ascites formation have now been recognized. This led to the proposal of the peripheral arterial vasodilatation theory which includes components of both the “underfill” and “overflow” theories. Recently, the role of gut bacteria in the pathogenesis of ascites has been demonstrated. Bacterial translocation is now known to be a key event preceding the onset of ascites. Bacterial DNA and endotoxin have been shown to stimulate NO synthesis. This led to the proposal of a modified version of the vasodilatation hypothesis, “the systemic inflammation hypothesis,” which proposes that translocated bacteria or their products stimulate the release of proinflammatory cytokines which in turn stimulate NO synthesis. Cardiac dysfunction (cirrhotic cardiomyopathy) has also been described in cirrhosis and is believed to contribute to the reduction in effective circulating volume which stimulates renal sodium and water retention. Initial treatment measures include salt restriction and diuretics. Drugs known to reduce glomerular perfusion or directly toxic to the kidneys must be stopped. Initial therapeutic paracentesis should be done in those presenting with tense ascites. There is no need for albumin infusion if the amount of fluid removed is less than 5 liters. For those with refractory ascites, beta-blockers should be stopped. Treatment options include aquaretics; serial large-volume paracentesis with albumin infusion or midodrine in place of albumin; transjugular intrahepatic portosystemic shunt; peritoneovenous shunt; low-flow ascites pump; and liver transplantation.

Keywords: Ascites, cirrhosis, management, pathophysiology

How to cite this article:
Mustapha SK. Cirrhotic ascites: A review of pathophysiology and management. Niger J Gastroenterol Hepatol 2020;12:3-12

How to cite this URL:
Mustapha SK. Cirrhotic ascites: A review of pathophysiology and management. Niger J Gastroenterol Hepatol [serial online] 2020 [cited 2021 Dec 3];12:3-12. Available from: https://www.njghonweb.org/text.asp?2020/12/1/3/284722

  Introduction Top

Ascites refers to the pathologic accumulation of fluid within the peritoneal cavity.[1],[2],[3] The amount of peritoneal fluid normally present is 5–20 mL, but can reach as much as 50 mL in women during ovulation.[4] The word ascites is derived from the ancient Greek word “askos” meaning a leather bag or sheep skin used for carrying liquids.[5] Clinical ascites has been described as far back as 1550 BC in the ancient Egyptian medical text compilation, the Papyrus Ebers.[6]

Cirrhosis is the most common cause of ascites worldwide.[7],[8],[9] About 50% of patients develop ascites within 10 years of diagnosis of compensated cirrhosis.[10] The onset of ascites in cirrhotic patients portends an ominous sign with a 3-year mortality rate of 50%.[11] The development of refractory ascites heralds an even grimmer prognosis with 1-year survival of less than 50%.[11] Ascites is the most common cause of hospital admissions in cirrhotic patients and is now recognized as an indicator for orthotopic liver transplantation.[3],[12],[13]

The accumulation of ascitic fluid in cirrhosis represents a state of total-body sodium and water excess as a result of a series of anatomic, pathophysiologic, and biochemical abnormalities mediated through a number of hormones and cytokines.[2],[14] Traditionally, the “overflow”[15] and the “underfill”[16] theories had been used to explain the pathogenesis of ascites in cirrhotic patients. The “overflow” theory postulates that the primary abnormality is inappropriate renal retention of sodium and water in the absence of volume depletion. According to the “underfill” theory, the primary abnormality is the inappropriate sequestration of fluid within the splanchnic vascular bed which results in decreased effective circulating volume which in turn stimulates renal sodium and water retention. However, the most recent theory, the peripheral arterial vasodilatation theory, includes components of both these theories and appears to match best with the actual hemodynamic process and has become the most widely accepted theory.[17]

With one half of all patients with cirrhosis developing ascites within 10 years of diagnosis, treatment aimed at relieving ascites is a measure preoccupation among physicians who manage cirrhotic patients. Treatment has continued to evolve as the pathophysiologic and hemodynamic changes responsible for the initiation and perpetuation of ascites become clearer. This review aims at characterizing the pathophysiologic mechanisms involved the formation of cirrhotic ascites and its medical management.

  Pathophysiology Top

Even though the exact sequence of events that leads to the formation of cirrhotic ascites remains unclear and continues to evolve, the peripheral arterial vasodilatation theory of ascites formation, which includes components of both the “overfill” and “underfill” theories, is the most widely accepted theory at present and best explains the hemodynamic changes observed in this condition.[18],[19],[20] According to the peripheral vasodilatation theory, the first step in the process of fluid retention is the development of portal hypertension. The development of portal hypertension is essential in the development of ascites and edema in the setting of cirrhosis; patients with cirrhosis but without portal hypertension do not develop ascites or edema.[14] Cirrhosis manifests as inflammation, necrosis, and deposition of collagen with regeneration, resulting in transforming the liver from a low-resistance to a high-resistance system due to the fibrosis and vascular dysfunction.[21] This mechanical disruption of the liver architecture with obstruction of portal blood flow was thought to be the sole cause of portal hypertension in cirrhosis. However, later studies have shown that increased portal venous inflow as result of splanchnic arterial vasodilatation also contributes significantly to the elevated portal pressure.[22],[23] The portal venous system normally drains blood from the stomach, intestines, spleen, pancreas, and gallbladder, and the portal vein is formed by the confluence of the superior mesenteric and splenic veins. The inferior mesenteric vein which brings blood from the distal gut drains into either of these vessels directly or at their confluence. Portal hypertension is defined as the elevation of the wedged hepatic venous pressure gradient (HVPG) to >5 mmHg.[24] Ascites formation usually occurs when the portal pressure exceeds 12 mmHg, and at this level, the patient is also at risk of variceal bleeding.[25],[26] To further support the role of portal hypertension in the genesis of ascites, ascites will usually disappear if the portal pressure is reduced to less than 12 mmHg, for example, following the placement of transjugular intrahepatic portosystemic shunt (TIPS).[14]

In the setting of portal hypertension, there is back flow, portosystemic shunting, and impaired clearance of vasodilator substances such as nitric oxide (NO), glucagon, adenosine, vasoactive intestinal peptide, platelet-activating factor, prostaglandins, and endotoxin.[14],[27],[28] It is believed that endotoxins act through the activation of systemic prostacyclin, since the selective intestinal decontamination with nonabsorbable antibiotics significantly reduces the synthesis of systemic prostacyclin.[14]

The opening of portosystemic collaterals which is a frequent finding in cirrhosis contributes further to systemic vasodilatation and hyperdynamic circulation.[29],[30] The resultant hypoperfusion of the kidneys results in activation of the renin–angiotensin–aldosterone system (RAAS) leading to aggressive sodium and water retention. Renin, an aspartyl protease, is secreted from the juxtaglomerular apparatus located near the vascular pole of the glomerulus in response to changes in perfusion pressure, changes in serum sodium, and sympathetic nervous system activation.[31],[32],[33] Renin acts on angiotensinogen (renin substrate) which is synthesized in the liver to convert it to the decapeptide angiotensin I, which is further converted to the octapeptide angiotensin II by angiotensin-converting enzyme (ACE) principally in the lungs, but conversion also occurs in many other parts of the body.[33] Apart from its vasopressor effect, angiotensin II has several important functions geared toward fluid retention. These include stimulation of the adrenal cortex to release aldosterone, secretion of antidiuretic hormone from posterior pituitary, and stimulation of the thirst drive.[34],[35] Increased renal prostaglandin has also been observed in patients with cirrhosis, and this helps preserve renal function by maintaining glomerular filtration. That's why drugs that inhibit prostaglandin synthesis such as nonsteroidal anti-inflammatory drugs (NSAIDs) may lead to deterioration of renal function and should be avoided in cirrhotic patients with ascites.[28],[36],[37] With advanced liver disease, renal prostaglandin synthesis decreases and this may contribute to the profound renal vasoconstriction in seen patients with hepatorenal syndrome.[38],[39],[40]

Following the activation of RAAS, it is thought that the excess retained fluid leaks out directly from the surface of the liver and the mesenteric vessels into the peritoneal space. In keeping with Starling's law, the increased hydrostatic pressure due to portal hypertension, and capillary permeability, and concurrently decreased plasma oncotic pressure due to hypoalbuminemia, overwhelm the reabsorptive capacity of the peritoneum and the lymphatic system leading to peritoneal fluid accumulation.[31],[41] An additional factor which contributes to ascites in cirrhosis is increased production of hepatic lymph due to postsinusoidal obstruction by the hepatic nodules.[42]

Although several substances have been identified in contributing to the splanchnic and systemic vasodilatation in cirrhosis, NO is considered the most important factor, and most recent literature has focused on its role.[43],[44],[45] Several observations point to NO as the key mediator of vasodilatation in cirrhosis. These include increased NO synthase activity in the hepatic artery of patients with ascites compared to those without ascites; inhibiting NO synthesis using an NO synthase inhibitor, Nitro-L-arginine methyl in experimental rats with cirrhosis, significantly increases arterial pressure and systemic vascular resistance; significantly higher levels of nitrate and nitrite, which are markers ofin vivo NO synthesis, are seen in patients with cirrhosis compared to controls.[14]

What is responsible for the increased NO synthesis in cirrhosis? Studies have shown that NO production may be stimulated by bacterial endotoxin or bacterial products such as bacterial DNA from the gut which are inadequately cleared because of portosystemic shunting and reduced reticuloendothelial function in cirrhosis.[46],[47] In addition, bacterial translocation from the gut has been demonstrated in cirrhotic rats before the development of ascites.[48] In the same vein, fragments of bacterial DNA have been described in the ascitic fluid, blood, and mesenteric lymph nodes of cirrhotic patients with ascites. On the other hand, bacterial DNA is rarely present in cirrhotic patients without ascites. Furthermore, oral administration of the antibiotics colistin and norfloxacin to patients with cirrhosis significantly reduces plasma endotoxin levels and increases systemic vascular resistance in a subgroup of patients with ascites. Bacterial DNA induces peritoneal macrophages to synthesize NO[48] and may also worsen the endothelial dysfunction found in cirrhotic patients contributing further to the exudation of fluid into the peritoneal cavity.[49] The concept of bacterial translocation has led some authors to propose a new modified version of the arterial vasodilatation hypothesis, “the systemic inflammation hypothesis.”[50] According to this hypothesis, translocated bacteria or their products induce systemic inflammation by stimulating monocytes and lymphocytes to release proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6, which, in turn, stimulate NO synthesis. As has been mentioned earlier, bacterial endotoxins also stimulate the synthesis of prostacyclin which is a systemic vasodilator.[14]

Finally, cardiac dysfunction also contributes to the reduction in effective circulating volume in advanced cirrhosis, and the cirrhotic heart fails to compensate for the pronounced arterial vasodilation.[51] This led to the concept of “cirrhotic cardiomyopathy,” which denotes a chronic cardiac dysfunction characterized by a blunted contractile responsiveness to stress and altered diastolic relaxation with electrophysiological abnormalities such as prolongation of the Q-T interval.[52] In this regard, markers of myocardial dysfunction such as natriuretic peptides and cardiac troponin-1 are found to be increased in decompensated cirrhosis and are related to the progression of liver dysfunction, portal hypertension, and systemic hemodynamic imbalance.[51],[53]

  Clinical Presentation Top

The most common clinical complaints associated with ascites are an increase in abdominal girth, abdominal fullness, discomfort, early satiety, reduced mobility, and breathlessness.[2],[54] Ascites due to cirrhosis usually develops fairly rapidly over a period of few weeks.[55] Patients with cirrhosis may have symptoms associated with hepatic decompensation such as confusion or evidence of gastrointestinal bleeding. Symptoms such as fever, abdominal pain, and altered mental status may be noted in patients with spontaneous bacterial peritonitis (SBP). Ascites needs to be differentiated from other causes of abdominal distension such as gross obesity, gaseous distension, intestinal obstruction, and abdominal cysts. Flank dullness is the most sensitive physical sign and is present in up to 90% of patients.[56] Shifting dullness on percussion is more specific than flank dullness, but is less sensitive. A fluid thrill or wave may be demonstrable in patients with massive ascites, but this sign is often inaccurate. The puddle sign may be present when as little as 120 ml of fluid is present;[28] eliciting this sign requires the patient to be in the knee–elbow position, but is rarely utilized in clinical practice. Patients with cirrhosis severe enough to cause ascites usually have stigmata of chronic liver disease such as palmar erythema, finger clubbing, and spider nevi. The presence of splenomegaly and abdominal collaterals suggests portal hypertension. With advanced liver disease, jaundice, muscle wasting, and leukonychia may be noted.

Ascites may be semi-quantified using a grading system proposed by the International Ascites Club:[57]

  • Grade 1: Mild ascites detectable only by ultrasound examination
  • Grade 2: Moderate ascites manifested by moderate symmetrical distension of the abdomen
  • Grade 3: Large or gross ascites with marked abdominal distension.

  Investigations Top

Abdominal paracentesis and ascitic fluid analysis

Once the diagnosis of ascites is established with a combination of clinical examination and ultrasound scan, the next step is to perform an abdominal paracentesis to evaluate the ascitic fluid. Abdominal ultrasound and diagnostic paracentesis are recommended by the British Society of Gastroenterology, the European Association for the Study of the Liver, and the American Association for the Study of Liver Diseases (AASLD) in all patients with clinically apparent new onset ascites.[7] It should also be performed whenever clinical deterioration occurs in a patient with known ascites. Paracentesis and a careful analysis of the ascitic fluid is the single most important procedure and should be an early step in evaluating a patient with ascites. Despite the fact that over two-thirds of patients with cirrhosis have prolonged prothrombin time, abdominal paracentesis has been found to be a safe procedure, with about 1% risk of abdominal wall hematoma.[58] The procedure is well tolerated in patients with platelet counts below 20,000 cell/mm3 and an INR as high as 8.7.[59],[60] Therefore, it is unnecessary to routinely administer fresh frozen plasma or platelets to cirrhotic patients with coagulopathy undergoing paracentesis.[7] Another concern regarding paracentesis is the risk of introducing bacterial peritonitis, but this has also been shown to be unfounded.[59] The abdominal midline caudal to the umbilicus is the recommended site for paracentesis, as this site is relatively avascular.[9] Either of the lower quadrants may be used if there is a midline surgical scar. There is a risk of a needle puncturing the intestine if it is inserted close to a scar as the bowel may adhere to the abdominal wall near a scar.[28]

A diagnostic paracentesis requires approximately 30–50 mL2 and is mandatory in all new-onset ascites in cirrhotic patients or existing ascites with a change in clinical status such as fever, abdominal pain, and new onset or worsening hepatic encephalopathy. Early paracentesis is invaluable where there is suspicion of SBP as mortality increases by 3.3% per hour of delay in performing a paracentesis in patients with SBP.[61]

The ascitic fluid should be sent for albumin and total protein levels, cell counts and differentials, and ascitic fluid culture inoculated at the bedside. The following should be noted:

  • Gross appearance: In uncomplicated cirrhotic ascites, the ascitic fluid is clear or straw colored. A turbid fluid may indicate infection; a milky appearance suggests chylous ascites, and dark brown fluid may indicate the presence of bile. Blood-stained fluid is usually due to malignancy, but may occur in tuberculosis, pancreatitis, or hepatic vein thrombosis.[28] It may also be due a traumatic tap. Bloody fluid from a traumatic tap is heterogeneously bloody and the fluid will clot on standing. On the other hand, a nontraumatic bloody fluid is homogenously red and will not clot. A minimum of 10,000 red blood cells (RBCs)/mm3 is required for ascitic fluid to appear pink, and more than 20,000 RBCs/mm3 will produce a distinctly blood-stained fluid[62]
  • Cell count: There are fewer than 500 white blood cells (WBCs)/mm3 of normal ascitic fluid. The neutrophil count should be <250/mm3. An elevated total WBC count is indicative of an inflammation, but not necessarily of infection. However, a neutrophil count of >250/mm3 is highly suggestive of bacterial peritonitis.[63] Lymphocytes usually predominate in tuberculous peritonitis and malignancy
  • Total protein: Ascitic fluid total protein has traditionally been used to classify ascitic fluid an exudate or transudate using a protein concentration of 2.5 g/dL as a cutoff value. Ascites with a total protein concentration of >2.5 g/dL is classified as exudative and usually associated with tuberculosis, malignancy, etc., while ascites with a total protein of <2.5 g/dL is classified as transudative and usually occurs in portal hypertension or hypoalbuminemia. However, the test has accuracy of only 56% in detecting an exudate[64]
  • Ascitic fluid cholesterol: Though not routinely done, ascitic fluid cholesterol concentration has been found to be useful in differentiating between cirrhotic and malignant ascites.[65],[66] At a cutoff value of 1.2 mmol/L, it has efficiency of over 90% in differentiating between the two types of ascites, with higher values seen in malignant ascites[65],[66]
  • Serum–ascites albumin gradient (SAAG): The SAAG has been found to be superior to the ascites total protein for the differential diagnosis of ascites.[64] It is the single best test for classifying ascites into portal hypertensive and nonportal hypertensive causes. The gradient is calculated by subtracting the fluid albumin from the serum level collected at the same time. A gradient of greater than 1.1 g/dL indicates portal hypertension with an accuracy of 97% and correlates directly with portal pressure.[64] Accuracy is decreased if the serum and ascitic fluid albumin are not drawn at the same time or if the serum albumin is very low (<1.1 g/dL)[63]
  • Culture/gram stain: Culture of ascitic should be obtained routinely in patients with cirrhotic ascites as they are prone to SBP. Ten milliliters of ascitic fluid should be inoculated into a blood culture bottle immediately at the bedside. Done in this way culture has 92% sensitivity for the detection of bacteria in ascitic fluid. In contrast, Gram stain has sensitivity of only about 10% in early SBP.[67],[68]

  Treatment Top

  • General measures: The general measures in management include determining the baseline weight, serum urea, electrolytes and creatinine, and urinary sodium concentration in a random urine sample. Reversible behaviors contributing to the primary process, e.g., alcohol intake in alcoholic cirrhosis or diabetes and hyperlipidemia in nonalcoholic steatohepatitis patients, should be controlled.[2],[3] In addition, drugs such as NSAIDs and ACE inhibitors (ACEI) and aminoglycosides should be avoided in patients with cirrhotic ascites. NSAIDs inhibit prostaglandin synthesis leading to diminished glomerular perfusion, while aminoglycosides are directly nephrotoxic. Strict bed rest is also recommended because the upright posture in cirrhotic patients with ascites is associated with marked activation of the RAAS and sympathetic nervous system, reduction in GFR and sodium excretion, and decreased response to loop diuretics[69]
  • Sodium restriction: Restriction of salt intake to 2 g or less/day (equivalent to 88 mmol/d of sodium) is advocated to induce a negative sodium balance and induce diuresis.[70] Patients with new-onset ascites, normal renal function, and high urinary sodium excretion are most likely to respond to salt restriction. High urinary sodium concentration occurs in about 20% of patients with cirrhotic ascites, and in these patients, salt restriction and bed rest alone may result in disappearance of ascites.[27] Dietary adherence can be evaluated by measuring 24-h urinary sodium excretion; urinary excretion of less than 78 mmol/d indicates nonadherence.[54] A spot urinary sodium-to-potassium ratio can also be used to assess dietary compliance, wherein a ratio of >1 in setting of weight gain indicates noncompliance.[54] Fluid restriction is not necessary unless there is hyponatremia (serum Na <125 mmol/L)[3]
  • Diuretics: Majority of the patients will eventually need diuretics in addition to salt restriction. The goal of diuretic treatment is gradual weight loss at a rate of not more than 1 kg/day if the patient has both ascites and edema and not more than 0.5 kg/day if there is only ascites. The standard combination includes spironolactone, an aldosterone antagonist and frusemide, a loop diuretic. The combination of oral spironolactone and frusemide has been shown to be the most successful therapeutic regimen for cirrhotic ascites, starting with 100 mg and 40 mg, respectively.[71] Doses can be increased by 100 mg and 40 mg, respectively, every 5–7 days as needed for response to a maximum dose of 400 mg for spironolactone and 160 mg for frusemide.[54],[71] It should be emphasized that fluid overload in cirrhotic patients with ascites should not be treated with intravenous frusemide as oral frusemide is well absorbed in cirrhotic patients. In addition, giving intravenous frusemide to these patients often causes acute reduction in renal function which cannot be explained by the diuresis alone and may be mistaken for hepatorenal syndrome.[72] Intravenous frusemide should therefore be avoided in cirrhotic ascites unless there is an unavoidable reason, e.g., patients with concomitant pulmonary edema or not taking orally. Volume depletion and hypokalemia which may precipitate hepatic encephalopathy are the side effects commonly associated with frusemide. Side effects related to spironolactone include hyperkalemia, sexual dysfunction, painful gynecomastia, and muscle cramps. Alternatives to spironolactone include amiloride, a direct inhibitor of the apical Na channel in the renal cortical collecting duct; and eplerenone, a newer highly selective mineralocorticoid receptor blocker[72]
  • Abdominal paracentesis: An initial therapeutic paracentesis should be performed in patients presenting with tense ascites.[2] This will relieve dyspnea and decrease early satiety. Albumin infusion may not be necessary for a single paracentesis of <4–5 L2
  • Liver transplantation: The AASLD recommends that patients with cirrhosis and ascites should be considered for liver transplantation.[2]

Treatment of refractory ascites

About 10% of patients with cirrhotic ascites will develop refractory ascites.[28] The International Ascites Club defines refractory ascites as the ascites that cannot be mobilized or early recurrence of which (i.e., after therapeutic paracentesis) cannot be satisfactorily prevented by medical therapy.[73] It includes two subtypes: diuretic-resistant ascites and diuretic-intractable ascites. Diuretic-resistant ascites refers to ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to dietary sodium restriction and intensive diuretic treatment, while diuretic-intractable ascites refers to ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of development of diuretic-induced complications that preclude use of an effective diuretic dosage.

Refractory ascites in patients with cirrhosis is considered to be present if at least one of the following criteria is fulfilled in the absence of therapy with an NSAID, which can induce renal vasoconstriction and diminish diuretic responsiveness:[74]

  1. An inability to mobilize ascites (manifested by minimal to no weight loss) despite confirmed adherence to the dietary sodium restriction (88 mEq [2000 mg] per day) and the administration of maximum tolerable doses of oral diuretics (400 mg per day of spironolactone and 160 mg per day of frusemide)
  2. Rapid reaccumulation of fluid after therapeutic paracentesis despite adherence to a sodium-restricted diet
  3. The development of diuretic-related complications such as progressive azotemia, hepatic encephalopathy, or progressive electrolyte imbalances.

Adherence to the sodium restriction must be confirmed with either a 24-h urine collection containing less than 78 mEq of sodium or a spot urine sodium less than the urine potassium.

The therapeutic options for this group of patients

Initial measures

The first step in the treatment of patients with refractory ascites is the discontinuation of all drugs that decrease systemic blood pressure (and thus renal perfusion) such as beta blockers, ACEI, and angiotensin II receptor blockers.[3],[74] NSAIDs should also be discontinued because they can cause renal vasoconstriction.[1],[2] It may be particularly important to discontinue beta blockers (which are commonly used in preventing variceal bleeding) because their use in patients with refractory ascites is associated with increased mortality.[75],[76] This increased mortality may be as a result of failure to maintain an adequate mean arterial blood pressure which is strongly correlated with survival in patients with advanced cirrhosis.[76] In addition to these measures, low sodium diet (2 g/day) and diuretics at the lowest tolerated dose should be continued. However, diuretics should be stopped if urinary sodium excretion falls to <30 mEq/day.[77] In patients who continue to have diuretic resistance despite these interventions, oral midodrine, an alpha-1 agonist vasopressor, may be effective. Its addition can improve renal perfusion, increase renal sodium excretion, reduce ascites, and improve survival.[78],[79] The vasopressin V1 receptor agonist terlipressin has also been shown to be effective in this regard, but has to be given intravenously.[80]

Serial large-volume paracentesis

Repeated large-volume paracenteses (LVPs) are mainstays in the treatment of refractory ascites.[74] The procedure can be performed on an outpatient or inpatient basis at intervals of 2–3 weeks depending on the severity of sodium retention and amount of fluid removed at each time.[28] The aim is to remove as much fluid as possible without excessive manipulation of the patient.[74] It has been shown to be a generally safe procedure, although up to 15% of LVP may be associated with paracentesis-induced circulatory dysfunction (PICD).[81],[82] Given this concern, intravenous albumin replacement (6–8 g/L of ascitic fluid removed) is indicated in cases where >5 L of ascitic fluid is removed. Apart from relieving discomfort in these patients, LVP may also reduce the risk of variceal of bleeding through reductions in HVPG, intravariceal pressure and variceal wall tension.[74] However, the very high cost of intravenous albumin makes serial LVP with albumin replacement unsustainable in a resource-constrained setting. Midodrine and terlipressin have been shown to be as effective as intravenous albumin in preventing PICD in patients with refractory ascites undergoing LVP. They have minimal side effects and are more cost-efficient than albumin.[83],[84]

Transjugular intrahepatic portosystemic shunt

According to the AASLD guidelines,[85] TIPS should be considered only in patients who are intolerant of repeated LVP. TIPS is directed at reduction in portal pressure as portal hypertension is a prerequisite for the development of cirrhotic ascites. In this procedure, an interventional radiologist places a stent percutaneously from the right jugular vein and inferior vena cave into the hepatic vein, thereby creating a connection between the portal and systemic circulations. Postprocedure TIPS stent thrombosis was a major problem, but with advent of polytetrafluoroethylene-covered stents, this complication is now minimal.[86] A major disadvantage of TIPS is the worsening of hepatic encephalopathy because of the creation of portosystemic shunting. TIPS is contraindicated in (i) patients with cardiac decompensation (ejection fraction <60) as it will place undue volume load on the heart; (ii) patients with spontaneous hepatic encephalopathy; (iii) patients with Child–Pugh class C or Model for End-Stage liver Disease (MELD) score >18; (iv) polycystic liver, hepatic abscess, or malignancy; and (v) active infection.[74],[87],[88] Meta-analyses comparing TIPS to LVP have shown that TIPS is more effective than LVP in preventing recurrent ascites and may have survival advantage over LVP.[89],[90]

Peritoneovenous shunt

These are of two types, the LeVeen and Denver shunts. Both are one-way valve stents which drain ascitic fluid into the superior vena cava, thereby returning ascites into the vascular compartment. Flow is maintained by the peritoneovenous pressure gradient. Even though it is an effective treatment for refractory ascites, it has largely been abandoned because of the high rate of complications associated with it. These complications include sepsis, peritonitis, disseminated intravascular coagulation, and variceal hemorrhage.[74] The only remaining indication for peritoneovenous shunt (PVS) is the rare patient with refractory ascites who is not a candidate for transplantation or TIPS and is too obese or has too many abdominal surgical scars to permit safe successful paracentesis.[3],[74]


More recent research has focused on the use of aquaretics in the treatment of refractory ascites with hyponatremia.[91],[92] They are vasopressin V2 receptor antagonists that promote renal excretion of electrolyte-free water. The massive aquaresis results in correction of the volume state and normalization of serum sodium concentration. Given the massive aquaresis following the administration of these drugs, it should be insured that (i) the patients are not hypovolemic, (ii) they should have intact thirst mechanism and access to water, and (iii) rapid overcorrection should be avoided to prevent osmotic demyelination syndrome.[91] Tolvaptan, satavaptan, and lixivaptan are oral formulations of specific V2 receptor antagonists available for clinical use.[92],[93] Of these, only tolvaptan has been approved by the US Food and Drugs Administration. However, following concern about hepatotoxicity, its use in liver disease has been restricted only to patients with end-stage liver disease with hyponatremia awaiting transplant.[74]

Low-flow ascites pump

The Alfapump® system (Sequana Medical AG, Zurich, Switzerland) is a novel system for the treatment of refractory ascites as an alternative to LVP in patients with contraindication to TIPS or liver transplantation.[94] The device is a subcutaneously implanted battery-powered pump, connected to a catheter placed in the abdominal cavity that aspirates AF and transports it through a second subcutaneous catheter to the urinary bladder. Ascites is then eliminated through normal urination. Internal sensors in the device monitor the pressures in the peritoneal cavity and the bladder in order to prevent pump operation when there is no ascites or when the bladder is full. The pump is usually programmed to transport fluid only during the day and deactivated at night not to disturb the patient's sleep.[94]

In a study of 21 patients with refractory ascites, the pump decreased the number of paracentesis from 2.3 to 0 per week.[95] Major complications included catheter dislocation and/or blockage, infection, and pump dysfunction. In another study comparing the pump to LVP, it was shown to be effective in reducing the need for paracentesis and improving quality of life in cirrhotic patients with refractory ascites; survival was similar in the two groups.[96]

Liver transplantation

This is the definitive therapy for refractory ascites. Overall, 1-year survival after liver transplantation exceeds 85%.[97] Therefore, patients with refractory ascites should be referred for liver transplantation, provided there are no contraindications, such as active alcohol use.[3]

Experimental treatments

Hypertonic saline solution with intravenous high-dose frusemide, antibiotics (rifaximin), probiotics (Lactobacillus).[98],[99],[100]

  Conclusion Top

Cirrhotic ascites is one of the most common clinical conditions a gastroenterologist/hepatologist is faced with. Although exact mechanisms leading to ascites formation in cirrhosis are not completely understood, it is now clear that development of portal hypertension is essential for the development of cirrhotic ascites as it has been shown that cirrhosis without portal hypertension does not usually result in ascites. The role of gut bacteria in the pathogenesis of cirrhotic ascites has recently been recognized. Bacterial DNA and endotoxins play a major role in the synthesis of NO, which is mainly responsible for the systemic and splanchnic vasodilatation resulting in reduced renal perfusion and activation of RAAS resulting in renal sodium and water retention.

Once the diagnosis of ascites is established through clinical examination and imaging, a diagnostic paracentesis should be done to evaluate the ascites. An initial therapeutic paracentesis can be done in those presenting with tense ascites; up to 5 liters can be removed without the need for albumin infusion.

Majority of the patients respond to initial therapy with salt restriction and diuretics. For the minority with refractory ascites, an array of therapeutic options are available including, aquaretics, repeated LVPs with albumin infusion (or midodrine/terlipressin), TIPS, PVS, and the recently developed low-flow ascites pump. Experimental treatments such as hypertonic saline with high-dose intravenous frusemide are promising. With the realization of the role of gut bacteria in the pathogenesis of cirrhotic ascites, treatment with antibiotics (rifaximin) and probiotics (Lactobacillus) have also been tried and found encouraging. However, liver transplantation remains the definitive treatment, and all patients with refractory ascites should be referred for it. According to the most recent indications, the onset of ascites itself (not necessarily refractory ascites) is indication for transplantation.

It is important to emphasize the need to stop beta blockers, which are commonly used for prophylaxis against variceal bleeding, once refractory ascites develops because of the increased mortality reported with its use such patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Runyon BA. Care of patients with ascites. N Engl J Med 1994;330:337-42.  Back to cited text no. 1
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