Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites

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 oedema. The mechanisms responsible for ascites formation include alterations in the splanchnic circulation as well as renal functional abnormalities that favour sodium and water retention. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increase cardiac output, a reduction in total vascular resistance and an 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 nitric oxide (NO), a potent vasodilator that is elevated in the splanchnic circulation of patients with cirrhosis. This event 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 mechanisms of sodium and water retention and ascites formation in patients with cirrhosis are discussed in this review.     

Pathophysiology of ascites formation in cirrhosis of the liver.

Current concepts of the pathophysiology of ascites formation in cirrhosis of the liver have become more complex. Traditionally, the initiating event of renal sodium and water retention in cirrhosis was considered to be ascites formation ("underfilling" hypothesis) or primary renal dysfunction ("overflow" hypothesis). Changes in systemic, splanchnic and renal hemodynamics, as well as of volume regulating hormones observed in cirrhosis are compatible with a decrease in effective blood volume as suggested by the "underfilling" hypothesis. These changes, however, have been shown to precede ascites formation. This observation, together with the demonstration of an increase in total blood volume in cirrhosis prompted the "overflow" hypothesis. However, many studies are incompatible with this concept and, in addition, the agent causing primary renal sodium retention in cirrhosis still remains to be defined. The recently proposed "vasodilation" hypothesis reconciles the most salient features of both theories, proposing peripheral arterial vasodilation as the initiating event of decreased effective blood volume and renal sodium retention. Further studies are needed to elucidate the temporal relationship and more precisely define the character of hemodynamic, humoral and renal changes in cirrhosis of the liver.     

Mechanisms of ascites formation

Ascites is the most common complication of cirrhosis. It is associated with profound changes in the splanchnic and systemic circulation and with renal abnormalities. 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. Splanchnic arterial vasodilation also produces arterial vascular underfilling, arterial hypotension, compensatory activation of the RAAS, SNS, and AVP, and a continuous sodium and water retention, leading to ascites formation. Now, therefore, the splanchnic arterial circulation, rather than the venous portal system, is believed to be involved in the pathogenesis of ascites formation.     

Treatment of cirrhotic ascites

Cirrhosis is the most common cause of ascites and accounts for almost 85% of all cases. It is the most common complication of cirrhosis, after development of ascites only 50% of patients will survive for 2 to 5 years. Successful treatment is dependent on accurate diagnosis of the cause of ascites. Because sodium and water retention is the basic abnormality leading to ascites formation, restriction of sodium intake and enhancing sodium excretion is the mainstay of the treatment of ascites. Patients with cirrhosis and ascites must limit sodium intake to 2 gram per day. Enhancement of sodium excretion can be accomplished by usage of oral diuretics. The recommended initial dose is spironolactone 100-200 mg/d and furosemide 20-40 mg/d. usual maximum doses are 400 mg/d of spironolactone and 160 mg/d of furosemide. The recommended weight loss in patients without peripheral edema is 300 to 500 g/d. There is no limit to the daily weight loss of patients who have edema. About 90% of patients respond well to medical therapy for ascites. Refractory ascites is defined as fluid overload that is unresponsive to sodium restricted diet and high dose diuretic treatment (diuretic resistant) or when there is an inability to reach maximal dose of diuretics because of adverse effects (diuretic-intractable). It has a poor prognosis. Treatment options for patients with refractory ascites are serial therapeutic paracentesis, transjugular intrahepatic stent-shunt (TIPS) or peritoneovenous shunt and liver transplantation. TIPS should be considered in patients who repeatedly fail large-volume paracentesis and have relatively preserved liver functions. Liver transplantation is the only modality that is associated with improved survival.     

Management of ascites in cirrhosis

Onset of ascites in cirrhosis of the liver is associated with worsened quality of life, increased risk of spontaneous bacterial peritonitis, and renal failure. Portal hypertension produces splanchnic vasodilation that triggers the cascade of events leading to release of Na retentive vasoconstrictor hormones. Management of ascites caused by cirrhosis is based on improving the Na excretion with diuretics and Na restriction in diet. Refractory ascites and hepatorenal syndrome are the complications of ascites that carry a very high mortality. Large volume paracentesis and transjugular intrahepatic porto-systemic shunts are useful in managing patients with refractory ascites. Liver transplant is the only way to improve survival in ascites caused by cirrhosis.     

Pathogenetic factors and clinical elements in ascites and hepatorenal syndrome during liver cirrhosis

Ascites is the most frequent major complication of liver cirrhosis. Even if a significant decrease in renal clearances may be observed in the first stages of chronic active hepatitis, true renal impairment, often with the typical signs of hepatorenal syndrome, only occurs in patients with ascites, especially when tense and refractory. Experimental and clinical data suggest the presence of primary sodium and water retention, perhaps as a consequence of an increase in intrahepatic hydrostatic pressure. The abnormal sodium retention leads to plasma volume expansion, followed by decreased peripheral vascular resistances and increased cardiac output. This second stage concords with the peripheral arterial vasodilation theory, characterized by an increase in total blood volume, but with a decrease in effective arterial blood volume. This discrepancy leads to the activation of sympathetic nervous and renin-angiotensin-aldosterone systems. This activation, while protective against splanchnic and systemic vasodilation, provoked by the increased availability of nitric oxide and other vasodilating substances, induces renal vasoconstriction. This phenomenon can be considered as the basis of the progressive renal failure that leads to hepatorenal syndrome, favored by progressive exhaustion of the renal autacoid vasodilating substances. The first therapeutic approach to ascites is sequential and based on diuretic administration. Subsequently, paracentesis with albumin infusion is carried out, as well as transjugular intrahepatic portosystemic shunting, surgical portosystemic shunting, and liver transplantation: these procedures are essential for the treatment of hepatorenal syndrome.     

Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis

Renal sodium and water retention and plasma volume expansion have been shown to precede ascites formation in experimental cirrhosis. The classical "underfilling" theory, in which ascites formation causes hypovolemia and initiates secondary renal sodium and water retention, thus seems unlikely. While the occurrence of primary renal sodium and water retention and plasma volume expansion prior to ascites formation favors the "overflow" hypothesis, the stimulation of the renin-angiotensin-aldosterone system, vasopressin release and sympathetic nervous system associated with cirrhosis is not consonant with primary volume expansion. In this present article, the "Peripheral Arterial Vasodilation Hypothesis" is proposed as the initiator of sodium and water retention in cirrhosis. Peripheral arterial vasodilation is one of the earliest observations in the cirrhotic patient and experimental animals with cirrhosis. Arterial vasodilators and arteriovenous fistula are other examples in which renal sodium and water retention occur secondary to a decreased filling of the arterial vascular tree. An increase in cardiac output and hormonal stimulation are common features of cirrhosis, arteriovenous fistula and drug-induced peripheral arterial vasodilation. However, a predilection for the retained sodium and water to transudate into the abdominal cavity occurs with cirrhosis because of the presence of portal hypertension. The Peripheral Arterial Vasodilation Hypothesis also explains the continuum from compensated to decompensated cirrhosis to the hepatorenal syndrome.     

Management of ascites in cirrhosis

Ascites is one of the earliest and most common complications of patients with cirrhosis. A typical circulatory dysfunction characterized by arterial vasodilation, high cardiac output and stimulation of vasoactive systems is commonly present in these patients and is associated with a poor prognosis. The treatment of ascites has been based on the combination of a low-sodium diet and the administration of diuretics. The reintroduction of paracentesis and the recent introduction of the transjugular intrahepatic portosystemic shunt (TIPS) are the most relevant innovations in the treatment of ascites during the past two decades, although controlled trials in large series of patients are needed to delineate whether TIPS is a safe and useful treatment for these patients.     

The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.     

Treatment of ascites in cirrhosis. Diuretics, peritoneovenous shunt, and large-volume paracentesis.

The medical treatment of ascites in cirrhosis is based on sodium restriction and the administration of diuretics. Because the natriuretic potency of spironolactone is greater than that of loop diuretics (i.e., furosemide) in patients with marked sodium retention, spironolactone is the basic drug for the treatment of ascites. The simultaneous administration of spironolactone and furosemide increases the natriuretic effect of each drug and diminishes their effects on potassium metabolism. Recent studies indicate that large-volume paracentesis associated with intravenous albumin infusion is more effective than diuretic therapy in eliminating the ascitic fluid; is associated with a lower incidence of complications (hepatic encephalopathy, renal impairment, and hyponatremia); and considerably reduces the duration of hospital stay. Therapeutic paracentesis associated with intravenous albumin infusion is therefore the treatment of choice for cirrhotic patients with tense ascites. The mobilization of the ascitic fluid by paracentesis without plasma volume expansion is constantly associated with a deterioration of effective circulating blood volume and may induce renal impairment and severe hyponatremia. Dextran 70 and polygeline appear as effective as albumin in preventing these abnormalities. Cirrhotic patients treated with paracentesis require the administration of diuretics to avoid reaccumulation of ascites. Peritoneovenous shunt, a prosthesis capable to correct most abnormalities involved in the accumulation of fluid in the abdominal cavity, is an effective treatment of ascites in cirrhosis. It is especially indicated in patients who do not respond to diuretics and develop repeated episodes of ascites despite adequate treatment. The use of peritoneovenous shunting is limited by the high incidence of complications induced by the procedure, however. In addition, approximately 40% of patients develop an obstruction of the prosthesis within the first postoperative year.     

Pathophysiology and treatment of ascites and the hepatorenal syndrome

Ascites indicates the accumulation of fluid in the peritoneal cavity, due to a wide range of causes. These causes can be classified according to the presence of portal hypertension, severe blood dyscrasia and peritoneal disease. Cirrhosis is the most frequent cause of ascites. The occurrence of ascites in cirrhosis is due to portal hypertension, which is responsible for the increase in hydrostatic pressure at the sinusoidal level and the alterations of splanchnic and systemic haemodynamics. These latter include increased splanchnic inflow, reduced systemic resistance and increased plasma volume and cardiac output. Portal hypertension also plays a major role in determining sodium retention, which occurs in the setting of increased RAA system and SNS activity. The mechanisms by which portal hypertension leads to the activation of antinatriuretic factors and sodium retention are not completely understood; three main hypotheses have been proposed to explain this relationship, namely the underfilling, the overflow and the peripheral arterial vasodilatation theories.In patients with cirrhosis and ascites, there is an overall activation of the renal prostaglandin system, which probably acts to maintain renal haemodynamics and GFR by counteracting the vasoconstricting effects of AII and noradrenaline on renal circulation. In advanced stages, ascites may become refractory to medical treatment and renal function shows a progressive impairment and eventually acute renal failure, the so-called HRS, due to a marked vasoconstriction of the renal arteries and the opening of the intrarenal-arteriovenous (A-V) shunts. In this condition, the reduced renal synthesis of vasodilating prostaglandins is probably of pathogenic importance. Treatment of ascites is usually based on bed rest, low-sodium diet and administration of aldosterone antagonists and loop diuretics. A sequential treatment of ascites based on the progressive addition of more potent drugs is the best way to relieve ascites while avoiding potentially dangerous side-effects. Patients who fail to respond to the above manoeuvres are said to have refractory ascites. Current treatment of this latter condition is mainly based on therapeutic paracentesis and the application of the LeVeen shunt, but long-term results are unsatisfactory.     

肝硬化腹水治疗的研究现状与展望

腹水是肝硬化最常见的并发症,并与发生感染、稀释性低钠血症、肾功能衰竭和病死率增加密切相关。无并发症的少量腹水患者早期处理原则是,休息加上低钠饮食。中等量腹水患者,一般选择低剂量利尿剂就能达到利尿效果。大量腹水患者,可大量放腹水＋静点白蛋白（8g/每放腹水1000ml）。顽固性腹水患者,可用重复多次大量放腹水＋血浆扩容治疗或用经颈静脉肝内门体分流术（TIPS）治疗。新药（如V2受拮抗剂和血管收缩剂等）对肝硬化腹水的治疗可能带来希望。     

Pathophysiology of ascites and dilutional hyponatremia: contemporary use of aquaretic agents

Ascites, the most common complication of cirrhosis, is associated with a poor quality of life, an increased risk of infection, and renal failure. Twenty percent of cirrhotic patients have ascites at the time of diagnosis, while 30% and 50% will develop ascites by 5 and 10 years, respectively. There are several factors that contribute to ascites formation in cirrhotic patients, these include splanchnic vasodilatation, arterial hypotension, high cardiac output, and decreased vascular resistance. These factors lead to ineffective intravascular volume (hyperdynamic state), impairment of renal function, and subsequent water and sodium retention, all of which lead to dilutional hyponatremia (serum sodium <130 mEq/L), one of the most important prognostic factors in these patients. In conclusion, the therapeutic objective is to improve sodium balance and circulatory function through non-pharmacological measures, such as dietary sodium and water restriction as well as bed rest. Spironolactone (100-400 mg/day) is the initial drug of choice, while loop diuretics (like furosemide, 40-60 mg/day) are frequently used as adjuvants. Recently, agent that interfere with the renal effects of vasopressin by inhibiting water reabsorption in collecting ducts and producing free water diuresis have been used. These agents are called aquaretics and can be useful in the treatment o ascites unresponsive to conventional therapy.
     

Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration

Hyponatraemia is common in patients with advanced cirrhosis and is associated with remarkable changes in brain cells, particularly a reduction in myoinositol and other intracellular organic osmolytes related to the hypo‐osmolality of the extracellular fluid. It has been recently suggested that hyponatraemia may be an important factor associated with the development of overt hepatic encephalopathy (HE). To test this hypothesis, we retrospectively analysed the incidence and predictive factors of overt HE using a database of 70 patients with cirrhosis included in a prospective study comparing transjugular intrahepatic portosystemic shunts (TIPS) vs large‐volume paracentesis in the management of refractory of ascites. Variables used in the analysis included age, sex, previous history of HE, treatment assignment (TIPS vs large volume paracentesis plus albumin), treatment with diuretics, serum bilirubin, serum creatinine and serum sodium concentration. Laboratory parameters were measured at entry, at 1 month and every 3 months during follow‐up and at the time of development of HE in patients who developed this complication. During a mean follow‐up of 10 months, 50 patients (71%) developed 117 episodes of HE. In the whole population of patients, the occurrence of HE was independently associated with serum hyponatraemia, serum bilirubin and serum creatinine. In conclusion, in patients with refractory ascites, the occurrence of HE is related to the impairment of liver and renal function and presence of hyponatraemia.     

Is the use of albumin of value in the treatment of ascites in cirrhosis? The case in favour

In patients with cirrhosis, ascites accumulates because of sodium retention, triggered by a reduction of the effective arterial blood volume, and imbalanced Starling forces in the splanchnic area due to portal hypertension and hypoalbuminemia. Albumin is the ideal plasma expander in this setting, since it ameliorates systemic and reneal haemodynamics, so reducing sodium retention, and increases oncotic pressure in the splanchnic compartment. In particular, albumin proved useful in patients treated with diuretics, as demonstrated by a randomised study performed at our Instituition in which 126 ascitic inpatients were treated according to a stepped-care diuretic regimen. In fact, patients receiving diuretics plus albumin (n = 63) had a higher cummulative rate of response (p < 0.05) and a shorter hospital stay (20 +/- 1 versus 24 +/- 2 days, p < 0.05) than those given diuretics alone. Treatment with albumin on an outpatient basis (25 g/week) resulted in a lower probability of developing ascites (p < 0.02 vs. patients not given albumin) and a lower probability of readmission (p < 0.02). Patients given albumin also had a better quality of life. As discussed in another article, evidence also supports the use of albumin in patients treated for paracentesis, as well as in patients with spontaneous peritonitis or hepatorenal syndrome.     

The transjugular intrahepatic portosystemic shunt for the management of cirrhotic refractory ascites

Cirrhotic ascites results from sinusoidal hypertension and sodium retention, which is secondary to a decreased effective arterial blood volume. Transjugular intrahepatic portosystemic shunt (TIPS) placement is currently indicated in cirrhotic patients with refractory ascites who require large-volume paracentesis (LVP) more than two or three times per month. TIPS placement is associated with normalization of sinusoidal pressure and a significant improvement in urinary sodium excretion that correlates with suppression of plasma renin activity, which is, itself, indicative of an improvement in effective arterial blood volume. Compared with serial LVP, placement of an uncovered TIPS stent is more effective at preventing ascites from recurring; however, increased incidence of hepatic encephalopathy and shunt dysfunction rates after TIPS placement are important issues that increase its cost. Although evidence suggests that TIPS placement might result in better patient survival, this needs to be confirmed, particularly in light of the development of polytetrafluoroethylene-covered stents. Favorable results apply to centers experienced in placing the TIPS, with the aim being to decrease the portosystemic gradient to <12 mmHg but >5 mmHg. This article reviews the pathophysiologic basis for the use of a TIPS in patients with refractory ascites, the results of controlled trials comparing TIPS placement (using uncovered stents) versus LVP, and a systematic review of predictors of death after TIPS placement for refractory ascites.     

Surgical repair of umbilical hernias in cirrhosis with ascites

The most common complications of umbilical hernias in patients with cirrhosis and ascites include leakage, ulceration, rupture and incarceration. If such a complication is present, there is a high mortality rate after surgical repair. Elective repair is the most effective choice, as it prevents complications with a lower mortality. However, the control of ascites before and/or after repair is mandatory but may not always be possible with diuretics and paracentesis. Portal decompression by transjugular intrahepatic portosystemic shunt (TIPS) with better control of ascites may allow these patients to undergo surgery. Patients with cirrhosis and umbilical hernias should be referred for consideration of an elective surgical repair with mesh, preferably after optimal management of ascites. There should be a low threshold for placement of a TIPS to facilitate surgery and reduce the chance of severe recurrence of ascites. If surgery is contraindicated, a TIPS must be considered for control of ascites.     

Refractory ascites and dilutional hyponatremia: current management and new aquaretics

Ascites is the most common complication of cirrhosis and is associated with 50% mortality at 2 years if patients do not receive orthotopic liver transplantation. Recently the International Ascites Club defined ascites into three groups: In grade I ascites fluid is detected only by ultrasound; in grade II, ascites is moderate with symmetrical distention of the abdomen; and in Grade 3 ascites is large or tense with marked abdominal distention. About 10% of patients with ascites are refractory to treatment with diuretics. In refractory ascites, patients do not respond to highest doses of diuretics (spironolactone 400 mg/day and furosemide 160 mg/ day) or develop side effects (hyperkalemia, hyponatremia, hepatic encephalopathy, or renal failure) that prohibit their use. Patients may be treated either by repeated large volume paracentesis plus albumin or transjugular intrahepatic portosystemic shunts (TIPS). Dilutional hyponatremia in cirrhotic patients is defined as serum sodium < or = 130 mEq/L in the presence of an expanded extracellular fluid volume, as indicated by the presence of ascites and/or edema. This complication of cirrhotic patients with ascites has recently gained attention given that several reports indicate that when serum sodium concentration is combined with the Model for End-Stage liver disease (MELD) it improves the prognostic accuracy of MELD score in patients awaiting orthotopic liver transplant (OLT). The first step in the management of dilutional hyponatremia is fluid restriction and discontinuation of diuretics. Water restriction at 1,000 mL/day helps prevent the progressive decrease in serum sodium concentration but usually does not correct hyponatremia in most cases. Actually are developing drugs that are active orally and act by selectively antagonizing the specific receptors (V2 receptor) of arginine vasopressin. These agents act in the distal collecting ducts of the kidneys, by increasing solute free water excretion and, thus, improving serum sodium concentration in hyponatremic patients.     

The use of TIPS in chronic liver disease

The development of cirrhosis and portal hypertension in the natural history of chronic liver disease is associated with many complications. A transjugular intrahepatic portosystemic stent shunt (TIPS) is a metal prosthesis that has been shown to be very effective in lowering sinusoidal portal pressure, and therefore is effective in the management of complications of cirrhosis, especially those related to portal hypertensive bleeding and sodium and water retention. In patients with acute variceal bleeding not responding to pharmacologic and endoscopic treatments, a reduction of the hepatic venous pressure gradient to < 12 mmHg or by > 20% with TIPS has been shown to be effective in controlling the acute bleed and in preventing rebleeding. For stable patients whose acute variceal bleed is controlled, TIPS is equal to combined beta-blocker and band ligation in the prevention of recurrent variceal bleed. TIPS is also more effective than large volume paracentesis in the control of refractory ascites, and may confer a survival advantage over repeated large volume paracentesis. TIPS has also been used in the management of other complications related to portal hypertension including ectopic varices, hepatic hydrothorax, and hepatorenal syndrome with some success, but experience is still rather limited. Miscellaneous uses include treatment of Budd Chiari Syndrome, portal hypertensive gastropathy and hepatopulmonary syndrome. Careful patient selection is vital to a successful outcome, as patients with severe liver dysfunction tend to die post-TIPS despite a functioning shunt. All patients who require a TIPS for treatment of complications of cirrhosis should be referred for consideration of liver transplant.