Mauro Bernardi

INTRODUCTION
Ascitic decompensation represents the most frequent complication of compensated cirrhosis, with an incidence ranging from 5 to 10% per year (1,2). Its appearance represents a crucial event in the natural history of cirrhosis and has a precise negative prognostic connotation: survival at 5 years in patients affected by pre-ascitic cirrhosis ranges from 45 to 80%, whereas it drops down to 15-40% in patients who have developed ascites (1-5). In our experience, ascitic decompensation is the chief cause of hospitalisation of patients affected by hepatic cirrhosis (6) and it often involves an extension of stays in hospital. In addition, it causes a deterioration of working and social life, it involves the need to be frequently in touch with hospital facilities and forces the patient to undergo chronic treatment. Ascites is therefore a major clinical problem, whose treatment often represents the greatest demand on medical staff in charge of patients affected by advanced cirrhosis.

AN OUTLINE OF THE PHYSIOPATHOLOGICAL ASPECTS
The appearance of ascites is closely related to an alteration of the balance of Starling forces in the hepatic microcirculation. However, “local” physiopathological events are closely related to “systemic” events, some of which precede, whereas others follow, ascitic decompensation.
Local pathogenic factors foster its appearance and influence its compartmentalisation; systemic factors contribute to its first development and to its perpetuation. The most important local pathogenic factor is represented by post-sinusoidal portal hypertension: researchers have demonstrated that in animal models of cirrhosis there is a linear relation between the level of portal pressure and the production of hepatic lymph (7); in man, they have identified portal pressure levels above which (25 mmHg) ascites is almost invariably present, and beneath which (15 mmHg) it is always absent (8).
The systemic event that is associated with, or rather precedes the appearance of the ascitic effusion, is represented by sodium and water renal retention (9). These alterations in renal functions are closely related to the specific hemodynamic situation of advanced cirrhotic patients, which leads to the hyperdynamic circulation syndrome picture (10). This is due to peripheral arterial vasodilation, which mainly concerns splanchnic circulation, to such a degree that it produces a reduction in effective (or arterial) volaemia. This causes compensatory phenomena to occur, such as an increase in the cardiac outflow and the activation of the neuro-hormonal systems capable of promoting vasoconstriction and renal sodium and water retention (renin-angiotensine-aldosterone system, adrenergic nervous system, endotheline, vasopressin) (11,12).
The causes of vasodilation are not completely clear; however, it is clear that arteriolar reactivity to vasoconstricting stimuli in patients with decompensated cirrhosis is insufficient (13-16). This anomaly is ascribable to an increased production of systemic vasodilators, such as glucagon, and of autacoids, such as nitric oxide and prostaglandins (17,18). Therefore the effectiveness of the compensatory mechanisms referred to above is in any case incomplete. Indeed, patients with advanced cirrhosis, despite the increase in cardiac outflow and of total volaemia and the activation of the vasoconstricting systems, display tachycardia and arterial hypotension. With this picture, renal sodium and water retention is perpetuated and renal perfusion progressively deteriorates, until renal failure develops (19). It is important to stress that sodium retention prevalently occurs in the distal nephron area, owing to hyperaldosteronism, in patients with preserved renal perfusion, whereas when this drops, the re-absorption by the proximal tubule progressively increases, until it prevails (20).
This picture also fosters the development of dilution-related hyponatriemia: indeed, on one side, the presence of effective hypovolaemia stimulates non-osmotic ADH release and, on the other, the marked re-absorption of proximal sodium reduces distal ion transport, thus negatively interfering on the pre-urine dilution ability. (21).

TREATMENT OF ASCITES
Over the years, guidelines for the treatment of ascites have been laid down, and these have been progressively revised as knowledge of the physiopathology of this complication increased, although there still are aspects that have not been completely clarified.
In the account that follows, I shall be referring to the latest guidelines, published by the American Association for the Study of Liver Diseases (22) and by the Italian Association for the Study of the Liver (23), as well as to those laid down during the Consensus Conference held in Dallas in November 1999, which are currently being finalised by the International Ascites Club itself.

NON-COMPLICATED ASCITES
Ascites is described as “non complicated” when it is not infected and not associated with renal failure (hepatorenal syndrome).

Stay in Bed.
The upright posture in cirrhotic patients with ascites causes an intense activation of the systems promoting vasoconstriction and sodium retention, which leads to a worsening of renal perfusion and natriuresis (24). In line with these results, researchers have demonstrated that by maintaining a supine position, response to diuretics improves (25). However, in the absence of controlled clinical studies, at the moment no indication exists for the maintaining an extended lying position.
Hyposodic Diet.
As mentioned earlier, the most important systemic event associated with the development of ascites is represented by renal sodium and water retention, with a consequent positive fluid balance. Hyposodic diets are based on this premises and are aimed at achieving a negative hydrosodic balance, which is what happens in 10-15% of cases, or at reducing the hydrosodic unbalance, thus slowing down the development of ascites and causing diuretics to become more effective. Their employment is broadly agreed to (26) and recommended (22,23). However, this consensus does not appear to be supported by controlled clinical studies, which in fact are not numerous and are often biased as regards methodology. However, the introduction of hyposodic diets has not involved an increase in the response to diuretic treatment (27-30); on the contrary, perplexities have emerged in connection with the possible negative effects associated with diets that are particularly poor in sodium (20 mmol/day), which result in a greater renal failure and hyponatriemia incidence (31). In addition, the reduction in the dietetic sodium content to a level lower than 40 mmol/day makes the diet scarcely palatable and, what is even more important, it becomes difficult to work out diets ensuring an adequate nutritional level below this limit. In our experience (30), in comparing two diets supplying 40 and 120 mmol of sodium/day respectively, no differences emerged in the response to treatment and in diuretics dosing. In addition, in patients with creatinine clearance values below 50 ml/min and/or hyponatriemia, the hyposodic diet caused a more frequent need to associate furosemide to the anti-mineralcorticoid diuretic.
Therefore, it showed no advantage compared to a controlled and moderately reduced sodium intake, and it proved prejudicial in patients with an impaired glomerular filtration speed and hyponatriemia. Despite these results, even though an exasperated diet sodium restriction is no longer indiscriminately recommended, the hyposodic diet concept is obviously deep-rooted in the clinical logic and habits of medical practitioners: the conclusion reached at the Consensus Conference of the International Ascites Club (Dallas, 1999) was that the only case in which a hyposodic diet may not be required is that of patients who display a satisfactory response to diuretics, and the indication was provided to introduce a moderate sodium content restriction in the diet (90 mmol/day; 5.4 g/day of salt); in certain cases, a more marked reduction may be required.
Diuretic Drugs.
On its own, a hyposodic diet may ensure a negative sodium balance; however, this is a rare occurrence and it cannot be predicted. The employment of diuretics is therefore recommended, and their choice cannot be made irrespective of the pathogenic mechanisms underlying renal sodium retention. In patients with a sufficiently preserved renal perfusion (e.g.: glomerular filtration speed above 60 ml/min), hyperaldosteronism plays a leading role and sodium retention mainly occurs at a distal nephron level (20): in view of this, anti-aldosteronic diuretics represent drugs of first choice.
Anti-mineralcorticoids.
The effectiveness of spironolactone and of potassium canrenoate has been demonstrated by a number of controlled clinical studies (27,30,32,33). In this context, spironolactone has proved more effective than furosemide, even though it has a much lower intrinsic natriuretic power (33). This apparent paradox can be explained by taking into account that the sodium that is not re-absorbed by the ascending limb of Henle’s loop because of the action of furosemide is re-absorbed in even significant amounts by the distal nephron, unless hyperaldosteronism is effectively antagonised.
The intestinal absorption of anti-aldosteronic drugs is facilitated by the presence of food. It should be stressed that aldosterone interacts with a cytosolic receptor and, subsequently, with a receptor located at a nuclear level (34), with the consequent production of a long half-life protein that stimulates sodium re-absorption.
This explains the latent period, of approximately 48 hours, in the pharmacological effect of anti-mineralcorticoids, which competitively inhibit the link between aldosterone and the cytoplasmatic receptor. (34). The initial recommended dose is of 100-200 mg/day (20,21). The amount of anti-aldosteronic to be administered in order to promote natriuresis must be proportional to the severity of hyperaldosteronism (35); if necessary, the dosage should be progressively increased every third day, until it reaches 400 mg/day, which ensures a therapeutic response in approximately 75% of cases (30). Further increases produce natriuresis in a relatively limited number of patients, whilst producing a greater number of side effects. The chief side effect of spironolactone is represented by painful gynecomasty, which can be substantially reduced through the employment of its hydrophilic derivative potassium canrenoate (36). Metabolic acidosis (type IV renal tubular acidosis) rarely becomes a clinically relevant problem (37). In patients with renal failure or, in any case, significantly impaired glomerular filtration speed, anti-aldosteronics may produce serious hyperkaliemia; should this not be the case, even high dosages do not produce this ion exchange disorder (30). “Distal” Diuretics.
Amiloride and triamterene block the sodium ducts located in the basolateral membrane of the collector tubule cells (38).
There are no controlled clinical studies on the employment of triamterene. Amiloride is not marketed in Italy except for the cases in which it is associated with hydroclorotiazide; the only randomised study that has compared its effect to that of potassium canrenoate has shown that it is less effective (39).
Furosemide.
In patients with advanced cirrhosis and impaired renal perfusion (glomerular filtration speed lower than 60 ml/min), sodium re-absorption in the proximal tubule area progressively increases, until it becomes prominent (19). Under such circumstances, isolated employment of anti-aldosteronic drugs is bound to fail and it becomes necessary to associate these with diuretics that have an action on the ascending limb of Henle’s loop.
The employment of loop diuretics is formally advisable also in the event that no response has been obtained with a 400 mg/day administration of an anti-aldosteronic drug; however, in clinical practice, many experts associate furosemide when the treatment with 200 mg/day of spironolactone has not achieved a satisfactory therapeutic response. (22). The initial dose of furosemide, which is the most frequently employed loop diuretic, is of 25-50 mg/day (20-40 mg i.v.); if required, it is increased on alternate days up to a maximum of 150 mg/day (160 i.v.) (22,23). High dosages of furosemide may produce even serious side effects, such as potassium depletion, hypocloremic metabolic alkalosis, hyponatriemia and hyperammoniemia.
Their powerful and abrupt action may produce a hemodynamically significant reduction of volaemia, with a consequent deterioration of renal perfusion (40,41). It is therefore advisable to conduct a careful evaluation of the fluid balance, which may be easily carried out by monitoring body weight; this must not drop more than 500 g/day without edemas, or 1 Kg/day with edemas, which are more easily mobilized than ascites. Controlled clinical studies have demonstrated that medical treatment based on the employment of anti-mineralcorticoids, furosemide and a hyposodic diet ensure therapeutic success in approximately 90% of cases (30). However, in non-selected patients, the treatment may fail in over 20% of cases.
The appearance of side effects (natriemia < 120 mmol/L; kaliemia > 6 or < 3,5 mmol/L; grade II encephalopathy; renal failure) compels an at least temporary interruption of the diuretic treatment.
Other Loop Diuretics.
There are no controlled clinical studies that have demonstrated the superiority of other loop diuretics (etacrinic acid, bumetanide, piretanide) compared to furosemide. Torasemide (16 mg are equipotent compared to 40 mg of furosemide), which displays a longer action, appears to be more effective and, above all, better tolerated (42).

Therapeutic Paracentesis.
In the event of a massive ascitic effusion, which may directly lead to complications such as restrictive respiratory failure due to diaphragm superelevation, hernial sac laceration or strangulation of the herniated loop and pain caused by abdominal wall tension, evacuative paracentesis is indicated. This may either be partial and repeated on several consecutive days, or be total (43-46). At present, the latter option is preferred, once controlled clinical studies have confirmed its safety.
These experiences have also demonstrated that paracentesis, compared to diuretic treatment, is more effective in eliminating ascites, it produce fewer complications and significantly reduces the hospitalisation period. In order to prevent hypovolaemia caused by paracentesis, which may be responsible for arterial hypotension, renal failure, hyponatriemia and hepatic encephalopathy (47), it is crucial to carry out an adequate plasma expansion, which is to start once paracentesis has been completed, by means of:
· Human albumin: 40 g for partial 4-6 litre paracentesis (43);
· Human albumin: 6-8 g for each litre of ascites removed with total paracentesis (44);
· Poligeline (Emagel): 150 ml for each litre of ascites removed with total paracentesis (45);
· Dextran 70: 8 g for each litre of ascites removed with total paracentesis (46);
· Normal saline: 170 ml for each litre of ascites removed with total paracentesis (48).
Among these substances, human albumin insures the best protection from hypovolaemia following paracentesis exceeding 5 litres, as it has been demonstrated not only through the seriate assessment of the plasmatic reninic activity, a sensitive index of effective volaemia, but also from a clinical point of view. Indeed, patients treated with albumin display an improved stability of the hemodynamic state and of renal functions, longer intervals between one paracentesis and the next and a higher survival rate compared to those treated with dextran or poligeline (49).
On the other hand, in the case of paracenteses below 5 litres, it is possible to employ artificial plasma expanders whose effectives is comparable to that of human albumin (49). On the whole, there are no contraindications to therapeutic paracentesis, except for severe coagulopathy associated with disseminated intravascular coagulation. In patients who have undergone abdominal surgery, owing to the possible presence of adhesions, there is a greater risk of intestinal loop perforation and of an ineffectiveness of the paracentesis (loculated ascites). Paracentesis does not eliminate the need for diuretic treatment: in one study, ascites reappeared within 4 weeks in 18% of the patients who had been administered diuretics and in 93% of those who had been given placebo (50).

REFRACTORY ASCITES
Ascites is described as “refractory” when it cannot be mobilised or its appearance after following therapeutic paracentesis cannot be prevented through medical treatment (51). A distinction is drawn between diuretic-resistant ascites, in the event of non-response to the therapeutic regime including hyposodic diet, spironolactone (400 mg/day) and furosemide (160 mg/day), and ascites not treatable with diuretics, when the diuretic therapy is not possible, owing to serious side effects.
The causes of ascites refractoriness are numerous and are not all definitely clear; however, a major role is played by the intense activation of neuro-hormonal systems, capable of antagonising the action of diuretics, and by reduced renal perfusion, which influences, on one side, a prevailing sodium re-absorption in the proximal renal tubule area, with a reduced distal ion transport, and on the other an insufficient transport of diuretics themselves to the respective action sites.
As previously recalled, based on the results obtained through controlled clinical studies, the incidence of refractory ascites ranges from 5 to 10%. However, taking into account that the patients enrolled in the studies are subject to a selection which, as rule, excludes cases displaying particularly severe pathologies, it is likely that in clinical practice this rate is in fact higher: in our experience, gained in a II-III level reference Centre, this rate is of approximately 20%.
Refractory ascites appears, as a rule, in patients with advanced cirrhosis and involves an adverse prognosis: as mentioned, the survival rate for ascitic patients is of approximately 50% at two years, whereas life expectancy in the event of refractory ascites drops to 50% at six months (3).
Therapeutic Paracentesis.
Therapeutic paracentesis represents the approach of first choice in the treatment of refractory ascites. However, it should be stressed that all controlled clinical studies have evaluated patients with massive or tense, but not necessarily refractory, ascites. Therefore, we cannot conclude that the results obtained can be automatically transferred to the context of refractory ascites proper. Since these patients are in most cases affected by advanced cirrhosis, and display a marked hemodynamic instability, it is necessary to scrupulously comply with the measures fit to promote plasma expansion and it may be appropriate to implement a greater volumetric supplementation than that normally indicated. Whilst cirrhotics with tense ascites subject to paracentesis may be subsequently treated with diuretics in 90% of cases, this is very rarely the case with refractory ascites (6), which involves the need for repeated paracenteses. This approach can therefore become unpractical and particularly expensive when human albumin is employed for plasma expansion purposes. Alternative treatments are therefore required and should be taken into account whenever more than 3 paracenteses/month are required.
Peritoneovenous shunts.
Peritoneovenous shunts (Le-Veen, Denver) consist of a catheter equipped with a unidirectional valve; one end is placed in the peritoneum and the other, though a subcutaneous tunnel, reaches the internal jugular vein, thus enabling removal of ascites and its reinfusion into the circulation. The consequent plasma expansion improves renal perfusion and aids diuresis (52). Controlled clinical studies have shown that hospitalisation due to reappearance of ascites is less frequent in patients with massive ascites whom have been applied a peritoneovenous shunt, compared to those treated with paracentesis (53-55); however, the survival rate has not shown significant differences. Although likely, it has not be proved that such results may also be valid for patients with refractory ascites. The employment of peritoneovenous shunts in patients with advanced cirrhosis displays high morbidity and mortality rates: immediate complications, ascribable to the rapid infusion of significant amounts of ascitic fluid, include acute pulmonary edema, rupture of esophageal varices, disseminated intravascular coagulation and sepsis. Their incidence has been reduced by removing pre-operative peritoneal infusion and implementing a prophylactic antibiotic therapy. Long-term complications are represented by displacement of the shunt, by its obstruction (» 50% in one year), superior caval thrombosis and plastic peritonitis. For these reasons, the employment of peritoneovenous shunts is not indicated in liver transplantation candidates; more generally, their employment has today become obsolete.
Transjugular Intrahepatic Portosystemic Shunt (TIPS).
The TIPS is a certainly effective means of reducing portal pressure and is definitely indicated for the treatment of digestive haemorrhages which cannot be controlled through medical therapy and/or sclerotherapy or ligation of esophageal varices (56). The application of a TIPS may give rise to immediate complications (intraperitoneal bleeding) or to later complications (thrombosis or stenosis of the shunt in 50-80% of cases at one year). Another consequence is represented by the development or worsening of hepatic encephalopathy, which occurs in approximately 65% of cases; the incidence of this complication is particularly high in patients aged over 60 or affected by encephalopathy prior to the application of the shunt. The logic which should lead to the employment of a TIPS in the treatment of refractory ascites is related to the fact that portal hypertension plays a leading role in the genesis of ascitic decompensation; in addition, the TIPS improves effective volaemia and therefore renal perfusion and natriuresis (57-60). Indeed, a number of non-controlled clinical studies have suggested its effectiveness in this context.
The controlled clinical studies that have compared the effectiveness of the TIPS to that of therapeutic paracentesis in patients with refractory ascites are only a few. In a first study, which was carried out on a limited number of cases, the application of the TIPS led to the control of the ascitic effusion, but the mortality rate proved significantly higher (61), owing to the extremely high mortality rate reported for patients with Child-Pugh stage C cirrhosis. More recently, in a study conducted on 60 patients with refractory or recurring ascites, the application of the TIPS has proved more effective in controlling ascites, whereas the actual survival rate observed without hepatic transplantation at two years did not show significant differences between the two groups (58 vs 32%). However, the multivariate analysis has shown that the application of TIPS was independently associated with the probabilities of survival without transplantation (62). Even though the results obtained are extremely encouraging, the indication for TIPS in patients with refractory ascites requires further experience before it can be definitely ratified. In particular, we still need to better clarify the features of the patients for whom a better result is expectable, and this is the direction in which new researches are moving. The natriuretic response appears to be correlated to the pre-existing renal function degree and to the patient’s age: subjects aged over 60 and displaying a glomerular filtration speed below 40 ml/min tend to show a delayed natriuretic response, exceeding three month of application of the shunt, or else an unsatisfactory response (63,64).
Furthermore, we should also take into account that the sudden increase in cardiac pre-load brought about by this procedure may cause sudden cardiac failure in subjects suffering from subclinic cardiopathy. In addition, the diversion of portal blood may contribute to a worsening of the residual hepatic function, which may explain why, in almost all cases, the TIPS may have detrimental effects on patients with advanced cirrhosis (Child-Pugh class C) (65,66). Therefore, at the moment, partial contraindications to the application of a TIPS are represented by the existence of pre-operative hepatic encephalopathy and heart dysfunction, by an age over 70 and by a Child-Pugh score above 12 (International Ascites Club Consensus Conference, Dallas, 1999).
Treatment of Hyponatriemia
This is required with natriemia values below 130 mmol/L and is based on a restriction of water intake to 500-1.000 ml/day and, when this alteration develops during treatment with diuretics, on an at least temporary interruption of this treatment. The effectiveness of water restriction is often limited, since it does not influence the pathogenic mechanisms that cause hyponatriemia. In this case, it may prove useful to promote an improvement of effective volaemia and of renal perfusion through plasma expansion and the employment of vasoconstrictors (glypressin, midodrine), but there are no controlled clinical studies that have checked the effectiveness of this therapeutic approach. On the other hand, the employment of hypertonic saline solutions is inadvisable, since they cause a sodium overload and, in the event of a rapid hyponatriemia correction, they may result in the sudden appearance of irreversible neurological complications, such as pontine myelinolysis (67). In the near future, the availability of aquaretic drugs may represent a valid means for the treatment of hyponatriemia in cirrhotic patients (21).

THE ROLE OF LIVER TRANSPLANTATION IN THE TREATMENT OF ASCITES As mentioned earlier, the prognosis of hepatic cirrhosis with ascites, especially if refractory, is adverse. The survival rate at 5 and 8 years in patients subject to liver transplantation is approximately 66 and 61% respectively, and it grows considerably (» 75% at 5 years) in the absence of adverse factors, such as transplantation for hepatocarcinoma, acute hepatic failure and re-transplantation (68). All patients with ascites and irreversible hepatic pathology should therefore be transplantation candidates unless contraindications exist. Indeed, despite the undoubted improvement in the treatment of ascitic decompensation, there is no evidence that the means currently available can extend the survival of these patients.
The pre-operative existence of ascites unfavourable influences the outcome of transplantation: besides involving the appearance of more serious haemostatic problems during transplantation (69), it is associated with a greater incidence of renal failure and greater risk of operative mortality (70,71). Despite these results, the long-term survival rate does not differ significantly from that of patients without ascites subject to transplantation (72). It should also be stressed that advanced cirrhotic transplantation candidates often (approximately 25% of cases) display renal failure (hepatorenal syndrome), which has an even more negative influence on the outcome of the operation in terms of morbidity (septic and hemorrhagic complications, multiorgan failure syndrome), mortality, impairment of post-operative renal function with the need for dialytic support and extensive stays in intensive care departments (73-75). It is therefore necessary to make every possible effort to carry out the transplantation before significant alterations in renal function occur.
The choice of the time in which the patient is to be placed on the waiting list therefore acquires crucial importance; and this of course largely depends on the availability of organs and on the length of the waiting time itself. In the Centres in which the waiting time is rather long, and in any case exceeds 1 year, candidacy must be made upon the appearance of ascitic decompensation. In other cases, other negative prognostic factors may be taken into account, such refractoriness of ascites, previous episodes of spontaneous bacterial peritonitis, hyponatriemia, persistent arterial hypotension (mean arterial pressure below 80 mmHg), renal sodium excretion below 10 mmol/day and appearance of hepatorenal syndrome (International Ascites Club Consensus Conference, Dallas, 1999). (transl.Interpres)
Mauro Bernardi
Semeiotica Medica
Policlinico S.Orsola-Malpighi Bologna