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THE PATHOPHYSIOLOGIC BASIS FOR THE TREATMENT OF CIRRHOTIC ASCITES
PORTAL HYPERTENSION
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THE PATHOPHYSIOLOGIC BASIS FOR THE TREATMENT OF CIRRHOTIC ASCITES Florence Wong, MD, FRACP, and Laurence Blendis, MD, FRACP
Abnormal renal sodium handling is common in patients with cirrhosis, including those patients without ascites, a stage that is known as preascitic cirrhosis.s0In these patients, the renal sodium abnormality is subtle and seems to be c o m p e n ~ a t e d . Fifty ~ ~ , ~percent ~ , ~ ~ of patients with compensated cirrhosis will develop ascites within 10 years,22but the predicting factors for this have not been clarified. The onset of ascites, necessitating diuretic therapy in previously compensated patients, is associated with a decreased survival rate of 50% at 5 years.I3 Many of these patients will eventually become resistant to diuretic therapy, and in these patients the prognosis decreases to 50% survival at 2 years.13 Cirrhotic patients with refractory ascites are particularly susceptible to the development of renal dysfunction. Renal dysfunction can occur either insidiously with gradual worsening of renal function (type I1 hepatorenal syndrome [HRS]),’ or acutely following a precipitating event (type I HRS)*; the latter has a poor prognosis. Until recently, the only permanent therapy for refractory ascites and HRS was liver transplantation.26The problem with transplantation is that donor livers are a scarce resource. With a better understanding of the pathophysiology of ascites and its complications, new and promising therapies have emerged.9,89 Therefore, this article emphasizes that continued research into, and improved understanding of, the pathophysiology of sodium retention in cirrhosis, through all the various stages, may result in further advances
From the Department of Medicine, Division of Gastroenterology, The Toronto General Hospital, University of Toronto, Ontario, Canada ~
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in therapy and possibly even in the prevention of the onset of ascites itself. THERAPIES Bed Rest
Traditionally, bed rest was used as the basic treatment for ascites. Bed rest may actually have been effective because assuming the supine position results in an increase in venous return and expansion of the central blood volume, including the atria, with a rise in plasma atrial natriuretic peptide (ANP) levels and consequently an exaggerated natri~ r e s i sThe . ~ ~central blood volume is an approximation of the effective circulating blood v0lume,3~,86 the expansion of which in the supine position results in a suppression of the plasma renin activity (PRA) and sympathetic nervous system.s2Increases in PRA and sympathetic nervous activity observed with the upright posture are associated with sodium retention4,s8; the suppression of these activities is synergistic with the rise in plasma ANP levels, which are directly related to the exaggerated n a t r i ~ r e s i sFurthermore, .~~ in cirrhotic patients assuming a supine posture, the increase in central blood volume causes an increase in cardiac output and consequently in renal blood flow (RBF) and glomerular flow rate (GFR); further enhancing the natriuretic effect of the supine p ~ s i t i o n .In ~ the current climate of economic constraints, however, treating ascitic cirrhotic patients with bed rest in hospital is impractical and too expensive. Sodium Restriction
Although there have been no studies on the effects of sodium restriction per se, sodium restriction and bed rest are effective in eliminating ascites in 10% to 20% of cirrhotic patients.19Most ascitic cirrhotic patients, in the absence of diuretic therapy, cannot eliminate more than 50 mEq of sodium in their urine per day. In the authors’ experience, most cirrhotic patients ingest approximately 150 mmoL of sodium per days3on a no-added-salt diet. Therefore, patients with ascites ingesting a no-added-salt diet will continue to accumulate ascites. The objective of a low sodium intake is to induce a negative sodium balance. Therefore, the lower the sodium intake, the more likely the patient is to achieve negative sodium balance, and the greater the magnitude of that imbalance, especially when the sodium intake is below the renal natriuretic threshold. In an animal model of portal hypertension, sodium restriction resulted in a diminution of plasma volume and a fall in portal pressure.l8 In acute animal models, sinusoidal portal hypertension,” as opposed to presinusoidal portal hypertension,” has been shown to cause sodium retention with systemic and renal hemodynamics remaining
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unchanged. In chronic animal models of portal hypertension such as the common bile duct-ligated dog, sodium retention with ascites was preceded by sinusoidal portal hypertension despite normal renal funct i ~ n Cirrhotic .~ patients with only mild sinusoidal portal hypertension (below 10 mm Hg) usually do not develop as cite^.^^, 66 Therefore, the reduction of portal pressure is considered in all the treatment modalities of ascites discussed. Other permissive factors which contribute to sodium retention in cirrhosis are also be mentioned, because, as discussed later, the correction of portal hypertension with the insertion of a transjugular intrahepatic portosystemic shunt (TIPS) does not completely normalize sodium retention in cirrhosis.36,84 Diuretics Spironolactone
To date, there have been no long-term follow-up studies on wellcharacterized groups of cirrhotic patients with preascites to clarify the predictive factors for the development of ascites in these patients. Furthermore, there is no evidence as yet supporting the use of prophylactic diuretic therapy to prevent the onset of ascites in preascitic patients. Nevertheless, in an acute study, a low but optimal dose, 7.5 mg, of losartan, an angiotensin I1 receptor antagonist, was shown to increase sodium excretion in preascitic cirrhotic patients on a diet of 200 mmoL of sodium per day diet and to restore them to complete sodium balance.= There was no effect on healthy controls. This natriuresis was associated with unchanged PRA, but a significant rise in serum angiotensin I1 Ievels, albeit still within the normal range, as compared to controls. This study indicates that one of the early pathophysiologic changes in preascites is a pertubation of the intrarenal renin-angiotensin system. This dysfunction would support the findings in recent animal studies of portal hypertension and would indicate increased aldosterone-dependent renal sodium retention in the presence of normal serum aldosterone levels.38In addition, about one third of cirrhotic patients with earlyonset ascites have normal PRA and serum aldosterone levels.69Nevertheless, the standard initial therapy for recent-onset ascites is the aldosterone antagonist spironolactone. Patients with recent-onset ascites respond to spironolactone whether the serum aldosterone levels are raised or not, but later in the natural history of ascites the level of serum aldosterone determines the diuretic response.37 This finding suggests that the distal tubular site of action of spironolactone may be nonspecific. This nonspecificity is supported by the almost equivalent effect of another group of distal diuretics such as amiloride which block the apical sodium potassium pump.92Spironolactone may have other sites of action. For example, by contracting the plasma volume, and hence the splanchnic volume, spironolactone has been shown to lower the portal pressure in animal models of portal hyperten~ion~~ and in cirrhotic
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patients without ascites.16,4o It would be of considerable interest to measure the effect of spironolactone on portal pressure in patients with ascites and compare it with that of amiloride. In recent years, aldosterone has also been shown to activate the production of fibroblasts in preference to myocytes in the myocardium,1o resulting in pathologic hypertrophy and increasing myocardial stiffness. Such changes in the myocardium of patients with cirrhosis are becoming increasingly recogni~ed.~~ These changes were initially thought to be caused by the associated alcoholism. Finding these changes in nonalcoholic cirrhotic patients42has led to the concept of a specific cardiomyopathy related to the presence of cirrhosis per se, or cirrhotic cardiomyopathy. The characteristic findings include myocardial thickening of the left ventricular wall associated with diastolic dysfunction in the presence of a normal ejection fraction.62Although these findings are found in both nonascitic and ascitic cirrhotic the contractile cardiac dysfunction is aggravated by an increased sodium intake and therefore may be involved in the pathophysiology of sodium retention.85Spironolactone has been shown to have a specific myocardial benefit in patients with congestive heart failureboand this effect may be another of the nonrenal benefits of spironolactone in cirrhosis. That is, by improving myocardial function, spironolactone, in nondiuretic doses, may help improve renal sodium excretion.
Furosemide At some point in the natural history of ascites, many patients become increasingly resistant to spironolactone. At that stage, they usually respond to the addition of f~r0semide.l~ Because the site of action of furosemide is on the chloride pump of the thick ascending loop of Henle, nonresponsiveness to spironolactone indicates that the site of increased sodium reabsorption has moved proximally from the cortical portion of the collecting duct and the distal convoluted tubule in the early stage of ascites. Thereafter some patients become increasingly resistant to the combination of spironolactone and furosemide, despite stepwise increases in both diuretic doses.I7This resistance suggests that there is increasing reabsorption of sodium proximal to the ascending loop of Henle, that is, in the proximal tubule. This suggestion is supported by recent studies showing that the addition of intravenous albumin in combination with the diuretics can induce a natriuresis in previously resistant patients. Because there are no data supporting an expansion of the plasma volume in this the therapeutic effect of albumin is probably a local one of suppressing proximal reabsorption of sodium and thereby increasing the delivery of sodium to the ascending Mannitol Studies using mannitol in patients with diuretic-resistant ascites have supported the concept that diuretic resistance is caused by almost
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total proximal reabsorption of sodium along the renal tubule. These patients had ascites refractory to maximum doses of combined diuretics.z They were also totally resistant to an exogenous infusion of ANP, with a failure to increase their urinary sodium excretion.73,81 On starting treatment with an intravenous infusion of 20 g of mannitol, about one half the patients responded with a diuresis.', 50 When intravenous ANP was added to the mannitol, there was an incremental increase in natriuresis. The interpretation of these results is that mannitol is an osmotic diuretic that obligates the excretion of water by suppressing water and sodium reabsorption in the proximal tubuleg1and then in the ascending loop of Henle.8 In some patients with refractory ascites, the infusion of mannitol will result in the transport of water and electrolytes to the ascending loop of Henle and the distal nephron, at which point ANP can act, through its receptors, to cause a further natriuresis. In patients with the most severe degree of renal dysfunction, mannitol had no effect, and these patients subsequently developed HRS50Therefore, when ambulatory patients become completely resistant to diuretic therapy, it is time to turn to abdominal paracentesis. Such patients constitute only 10% of the ascitic population at any one time.68 Abdominal Paracentesis
Although abdominal paracentesis (AP) is the oldest known form of therapy for ascites, dating back 300 to 400 years, with the introduction of diuretics 50 years ago, AP went out of favor because of the number of serious, associated ~omplications.4~, 52 These complications were later explained by deleterious hemodynamic effects such as a fall in cardiac output resulting from a contraction in plasma volume.4l The mechanism of this process was clarified by the demonstration that ascites reformed at a much more rapid rate following paracentesis than the reconstitution of plasma volume by the ascitic Nonetheless, AP continued to be used as a standard therapy for resistant ascites in certain institutions, such as the VA hospitals in the United States. The debate then developed as to whether AP does or does not cause a fall in plasma volume, that is, whether volume contraction is responsible for the deleterious effects of AP. Early studies showed no significant fall in plasma volumeM especially in patients with peripheral edema undergoing a 5-liter AP.39,58 At the same time, however, Quintero et aF5 showed that a 5-liter AP combined with 40 g of intravenous albumin was the optimal treatment of resistant ascites. Subsequently, the Barcelona group showed that largevolume AP plus intravenous albumin has significantly fewer side effects and is more cost effective than diuretic therapyz3 The situation was clarified by a sentinal study by Simon and c o - w ~ r k e r swhich ~ ~ showed that, unlike patients with ascites and peripheral edema, in nonedematous patients the removal of an average of 7.5 liters of ascitic fluid, in the absence of volume expanders resulted in deleterious side effects. After an initial rise in cardiac output associated with an increased
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venous return, there was a significant fall in cardiac output together with a fall in central venous pressure after 24 hours. At the same time, there was a significant fall in systemic vascular resistance and creatinine clearance and a rise in PRA and aldosterone levels. This delayed rise in PRA and subsequently reported rise in plasma norepinephrine levels, associated with a fall in systemic vascular resistance, was noted to occur between 2 and 6 days after AP in up to 75% of nonedematous patients undergoing large-volume AP in the absence of volume expanders" but in only 25% of patients receiving volume expanders.21This condition was subsequently labelled paracentesis-induced circulatoy dysf~nction.'~ Further studies showed that in about 25% of cases paracentesis-induced circulatory dysfunction was associated with significant increases in portal pressure.'* The pathogenesis of paracentesis-induced circulatory dysfunction is now thought to be caused by further, as yet unexplained, vasodilation following AP.14 Whatever the mechanism, significant paracentesis-induced circulatory dysfunction is associated with deterioration in renal function and in overall prognosis. Therefore, it seems that AP can have significant adverse hemodynamic effects, especially if volume replacement is not given. In contrast, hemodynamic studies showed that total paracentesis (TP), or the removal of all ascitic fluid by paracentesis at one session, with administration of volume expanders,61,74 resulted in a rise in cardiac output an increase in right atrial size, and a fall in systemic vascular resistance, with an improvement in renal function.56At the same time, there is a significant fall in portal pressure and azygos blood flow and If volume expansion is delayed in PRA and serum aldosterone le~els.4~ for up to 6 hours after TP, the marked decrease in intra-abdominal pressure is accompanied by a fall in intrathoracic, pulmonary arterial, capillary wedged, and right atrial pressures; systemic vascular resistance, and PRA and serum aldosterone levels.@By 24 hours, there is also a marked suppression of muscle sympathetic By the time patients have developed diuretic-resistance ascites, removal of a large amount of ascites jeopardizes their effective arterial blood volume, unless that volume can be reconstituted rapidly from a third space, such as leg edema. The problem does not arise, as initially thought, from inadequate filling, but rather from further vasodilation associated with the removal of ascitic fluid. Therefore, it would seem unwise to perform large-volume AP in cirrhotic patients with tense ascites without volume expanders. Nonetheless, many APs are performed every day in these patients without causing deleterious effects. The difference seems to be in the volume of paracentesis. The removal of ascitic fluid, even small amounts ranging from 1 to 3 liters, results in beneficial systemic hemodynamic whereas with the removal of approximately 4 liters, there are no hemodynamic changes.57Again, in the controversy concerning whether or not to administer albumin with AP, the most important factors seems to be the volume of fluid removed; removing up to 4 liters without albumin is safe and may be
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beneficial. When more than 5 liters of fluid is removed in patients with peripheral edema or in patients who are noncompliant rather than diuretic-resistant, it is probably safe not to use albumin. In nonedematous patients who undergo large-volume paracentesis of more than 5 litres, the use of plasma expanders such as albumin can have beneficial hemodynamic effects. When all the hemodynamic phenomena of AP are understood, the pathophysiology of sodium retention and vasodilation in cirrhosis may also be better understood. Peritoneovenous Shunting
Peritoneovenous shunting as originally introduced by LeVee11,4~was a method of performing abdominal paracentesis continuously, by recirculating the ascitic fluid back to the right side of the heart through a subcutaneous plastic cannula with a one-way valve preventing reflux back into the peritoneal Insertion of the peritoneovenous shunt (PVS) resulted in an immediate increase in plasma volume and a dramatic diuresis and natriuresis while the patient was still on the operating table.5 These effects were associated with an immediate rise in cardiac output, a fall in systemic vascular resistance, a transient fall in systemic blood pressure, significant rises in GFR and RBF, and significant falls in PRA (to normal range within 8 hours) and in serum aldosterone levels (to normal range by 48 hours)28but not in serum norepinephrine levels.6 This dramatic natriuresis was subsequently shown to be associated with a significant rise in plasma ANP levels.I2 By 2 weeks postoperatively, many of these dramatic changes had subsided, but sodium excretion, GFR, and RBF remained significantly improved compared with preoperative level^.^ By 3 months, there was a significant fall in the hepatoportal and the patients’ ascites subsequently disappeared. When reinvestigated at around 1 year after surgery, the patients with functioning shunts were still ascites-free, with normal PRA and serum aldosterone levels, and in sodium balance on a diet of 20 mmol of sodium per day.29When challenged with a higher dietary sodium intake of 100 mmol per day, however, the patients remained in positive sodium balance, despite further physiologic suppression of PRA and serum aldosterone levels.29Of interest, these patients preoperatively were resistant to an intravenous infusion of ANP, by failing to respond with a natriureS~S.~O Successful PVS restored the normal natriuretic response to ANP in these patients.” These studies show that by the time ascitic patients have become resistant to diuretics their effective circulating blood volume is inadequate, because restoring this volume by recirculating ascitic fluid, in association with increasing plasma ANP levels and suppressing the renin-angiotensin-aldosteronesystem to within the normal range, results in a natriuresis. Despite these results, an improvement in renal function, and a significant fall in portal pressure following a successful outcome,
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renal sodium handling, although improved, is not normal. The returned responsiveness to intravenous ANP suggests that PVS has reduced sodium reabsorption in the proximal part of the nephron, thereby increasing distal delivery of sodium and thus enabling ANP, through its receptors in the medullary collecting duct, to function again. Although systemic vasodilation remains, the normalization of PRA means that it is no longer a relevant factor. Despite its sound physiologic basis, the use of a PVS to treat cirrhotic patients with diuretic-resistant ascites has fallen out of favor because of the many attendant complications. Furthermore, the insertion of a PVS does not correct other important pathogenetic factors of ascites formation, including continued portal hypertension and hepatic dysfunction. Transjugular lntrahepatic Portosystemic Stent
A TIPS is the radiographic placement of a flexible, metallic stent from the hepatic vein through the liver to the portal vein. The stent thus decompresses the portal venous system in the same way as a side-toside portocaval shunt. The procedure was originally designed for the treatment of refractory variceal bleedingz7,67 It was noted in patients who had ascites that the ascites disappeared after placement of the TIPS, and it soon become clear that TIPS is an effective treatment for refractory ascites.%Thus, in ascitic patients, TIPS functioned in the same way as side-to-side portocaval shunting, which was also used to treat ascites resistant to diuretic therapy.55The rationale for lowering the portal pressure in the treatment of cirrhotic ascites comes from a series of studies that link sodium retention to portal hypertension1',49; the result of both of these therapies is a fall in portal pressure. The lower the final pressure, the more effective the therapy. The insertion of a TIPS, the consequent fall in sinusoidal portal pressure, and then a fall in azygos blood are immediately followed by significant hernodynamic changes. There is a rise in cardiac output and a decrease in systemic vascular resistance; even while the patient is still in the angiography suite.9oThese changes occur long before there is a measurable increase in central blood volume, which may take days, if not weeks, to detect.89 Thus, as with AP, further systemic vasodilatation is a major consequence of this treatment: the mechanism remains unknown. Also, while the patient is still in the angiography suite, left atrial and left diastolic volume increase significantly, by 6% to 7%, and are associated with marked increases in right atrial, mean pulmonary artery, and capillary wedged pressures.35Such changes may be caused by underlying subclinical cardiac dysfunction, found in both alcoholic62and nonalc~holic~~ cirrhosis. Despite the fall in portal pressure, natriuresis is not immediate, but the reduction of portal pressure initiates a series of changes that culminates in the reversal of the sodium retention. By the end of the first
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week, there is a fall in PRA and serum aldosterone levels,2O with the beginning of a natriuresis that increases gradually over the next few weeks. By 4 weeks after the procedure the patient is in negative sodium balance, despite no change in plasma norepinephrine levels.90Improvement in renal function occurs even and these changes persist for at least 1 year. Therefore, TIPS lowers portal pressure and also gradually improves intravascular filling, leading to improved hemodynamics, with consequent improved renal sodium handling. At this stage, these postTIPS patients have been challenged with a high sodium diet84 or acute saline infusion,32 and found to have improved natriuretic responses compared with preascitic patients.37,83 Natural or balloon obstruction of the TIPS leads to reversal of these hemodynamic changes and return of sodium r e t e n t i ~ n The . ~ ~ extension of these observations has led to the use of TIPS in patients with hepatorenal syndrome. In these patients, TIPS has now been shown to improve renal function and sodium excret i ~ n .30~ , Liver Transplantation
Renal sodium handling in patients who have received a TIPS does not return completely normal, suggesting that other factors such as liver function may be involved.78Therefore, it stands to reason that liver transplantation should eliminate ascites. Clinically, the replacement of a diseased cirrhotic liver by a normal liver eventually results in an improvement in renal sodium handling and the disappearance of ascites by 3 to 6 months after transplantation. Portal hypertension is reversed immediately and completely, and liver function is restored to within the normal range so the reason for the delay in disappearance of ascites is not yet fully understood. Several studies have shown that the hyperdynamic circulation with systemic vasodilatation persists for several months after tran~plantation.~~, 32, 51, 59 Formal studies have not yet elucidated the order of the postoperative changes relating to renal sodium handling, changes in blood volume, and changes in the systemic vasodilatation. The determination of the order of these events might well help clarify the pathophysiology of sodium retention in cirrhosis. SUMMARY
Advances in the understanding of the pathophysiology of sodium retention and ascites formation in cirrhosis has helped improve the treatment of ascites in these patients. It is likely that further unraveling of these pathophysiologic changes will lead to the development of novel and better treatment options. For example, the development of aquaretic agents for the management of hyponatremia in cirrhosis may allow more effective use of diuretic therapy. The ultimate challenge is to use the
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understanding of the pathophysiology to develop new strategies to prevent the development of ascites in cirrhosis.
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42. Laffi G, Barletta G, La Villa G, et a1 Altered cardiovascular responsiveness to active tilting in nonalcoholic cirrhosis. Gastroenterology 113:891-898, 1997 43. LeVeen HH, Christoudias G, Ip M, et al: Peritoneovenous shunting for ascites. Ann Surg 180:580-591, 1974 44. Lieberman FL, Denison EK, Reynolds TB: The relationship of plasma volume, portal hypertension, ascites, and sodium retention in cirrhosis: The overflow theory of ascites formation. Ann N Y Acad Sci 170:202-212, 1970 45. Liebowitz H R Hazards of abdominal paracentesis in the cirrhotic patient. New York State Journal of Medicine 62:1822-1826, 1997-2004, 2223-2229, 1962 46. Lotterer E, Wengert A, Fleig WE: Transjugular intrahepatic portosystemic shunt: Shortterm and long-term effects on hepatic and systemic hemodynamics in patients with cirrhosis. Hepatology 29:632-639, 1999 47. Luca A, Feu F, Garcia-Pagan JC, et a1 Favorable effects of total paracentesis on splanchnic hemodynamics in cirrhotic patients with tense ascites. Hepatology 20:3033,1994 48. Ma 2, Lee SS: Cirrhotic cardiomyopathy, getting to the heart of the matter. Hepatology 24451459, 1996 49. Morali GA, Sniderman KW, Deitel KM, et al: Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites. J Hepatology 16:249-250, 1992 50. Morali GA, Tobe SW, Skorecki KL, Blendis LM. Refractory ascites: Modulation of atrial natriuretic factor unresponsiveness by mannitol. Hepatology 16:4243, 1992 51. Navasa M, Feu F, Garcia-Pagan JC, et a1 Hernodynamics and humoral changes after liver transplantation in patients with cirrhosis. Hepatology 17355-360, 1993 52. Nelson WP, Rosenbaum JD, Strauss MB: Hyponatremia in hepatic cirrhosis following paracentesis. J Clin Invest 30:738-744,1951 53. Oberti F, Pilette C, Rifflet H, et al: Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation. J Hepatology 26:1363-1371, 1997 54. Ochs A, Rossle M, Haag K, et a1 Transjugular intrahepatic portosystemic stent shunt procedure for refractory ascites. N Engl J Med 332:1192-1197, 1995 55. Orloff MJ: Surgical treatment of intractable cirrhotic ascites. Ann Surg 164:69-80, 1966 56. Panos MZ, Moore K, Vlavianos P, et al: Single, total paracentesis for tense ascites: Sequential hemodynamic changes and right atrial size. Hepatology 11:662467, 1990 57. Peltekian KM, Wong F, Liu PP, et al: Cardiovascular, renal and neurohumoral responses to single large volume paracentesis in patients with cirrhosis and diuretic-resistant ascites. 92:394-399, 1997 58. Pinto PC, Amerian J, Reynolds T B Large-volume paracentesis in nonedematous patients with tense ascites: Its effect on intravascular volume. Hepatology 8:207-210,1988 59. Piscaglia F, Zironi G, Gaiani S, et a1 Systemic and splanchnic hemodynamic changes after liver transplantation for cirrhosis: A long-term prospective study. Hepatology 30:58-64, 1999 60. Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709-717, 1999 61. Planas R, Gines P, Arroyo V, et al: Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis: Results of a randomized study. Gastroenterology 99:1736-1744, 1990 62. Pozzi M, Carugo S, Boari G, et al: Functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology 26:1131-1137, 1997 63. Pozzi M, Grassi G, Pecci V, et a1 Early effects of total paracentesis and albumin infusion on muscle sympathetic nerve activity in cirrhotic patients with tense ascites. J Hepatology 30:95-100, 1999 64. Pozzi M, Osculati G, Boari G, et al: Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites. Gastroenterology 108~709-719,1994 65. Quintero E, Gines P, Arroyo V, et al: Paracentesis versus diuretics in the treatment of cirrhotics with tense ascites. Lancet 1:611412, 1985 66. Rector WG Jr, Lewis F, Robertson AD, et al: Renal sodium retention complicating
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alcoholic liver disease: Relation to portosystemic shunting and liver function. Hepatology 12455459, 1990 67. Ring EJ, Lake JR, Roberts JP, et al: Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. AM Intern Med 116:304-309, 1992 68. Runyon BA: Patient selection is important in studying the impact of large-volume paracentesis on intravascular volume. Am J Gastroenterology 92:371-373, 1997 69. Salo J, Guevara M, Fernandez-Esparrach G, et al: Impairment of renal function during moderate physical exercise in cirrhotic patients with ascites, relationship with the activity of neurohormonal systems. Hepatology 25:1338-1342, 1997 70. Shear L, Ching S, Gabuzda GJ: Compartmentalization of ascites and edema in patients with hepatic cirrhosis. N Engl J Med 282:1391-1396,1970 71. Savino JA, Cerabona T, Aganval N, et al: Manipulation of ascitic fluid pressure in cirrhotics to optimize hemodynamic and renal function. AM Surg 208:504-511, 1988 72. Simon DM, McCain JR, Bonkovsky HL, et al: Effects of therapeutic paracentesis on systemic and hepatic hemodynamics and on renal and hormonal function. Hepatology 7423-429, 1987 73. Skorecki KL, Leung WM, Campbell P, et al: Role of atrial natriuretic peptide in the natriuretic response to central volume expansion induced by head out water immersion in sodium retaining cirrhotic subjects. Am J Med 85:375-382, 1988 74. Tito L, Gines P, Arroyo V, et al: Total paracentesis associated with intravenous albumin in the management of patients with cirrhosis and ascites. Gastroenterology 98:146151, 1990 75. Tobe SW, Morali GA, Greig PD, et al: Peritoneovenous shunting restores ANF responsiveness in refractory ascites. Gastroenterology 105:202-207, 1993 76. Trevisani F, Bemardi M, Gasbarrini A, et a1 Bed-rest induced hypematriuresis in cirrhotic patients without ascites: Does it contribute to maintained "compensation"? J Hepatology 16:160-196, 1992 77. Warner LC, Campbell PJ, Morali GA, et al: The response of atrial natriuretic factor and sodium excretion to dietary sodium challenges in patients with chronic liver disease. Hepatology 12:460466, 1990 78. Wensing G, Sabra R, Branch RA: The onset of sodium retention in experimental cirrhosis in rats is related to a critical threshold of liver function. Hepatology 11:779786, 1990 79. Wong F, Blendis L M Intravenous albumin with diuretics. Protean lessons to be learnt? J Hepatology 30:727-730, 1999 80. Wong F, Girgrah N, Blendis LM: The controversy of the pathophysiology of ascites in cirrhosis. J Gastroenterol Hepatol 12:437444, 1997 81. Wong F, Legault L, Tobe S, et a 1 Refractory ascites in cirrhosis: The roles of volume expansion and plasma atrial natriuretic factor elevation. Hepatology 18:519-528, 1993 82. Wonn F, Liu P, Allidina Y, et al: The effects of sodium restriction and Dosture on cent& blood volume in pre-ascitic cirrhosis. Hepatology 23:1141-1147, 199k 83. Wong F, Liu P, Allidina Y, et al: Pattern of sodium handling and its consequences in pre-ascitic cirrhosis. Gastroenterology 108:1820-1827, 1995 84. Wong W, Liu P, Blendis L, et al: Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic portosystemic shunts for refractory ascites. Am J Med 106315-322, 1999 85. Wong F, Liu P, Lilly L, et al: The role of cardiac structural and functional abnormalities in the pathogenesis of hyperdynamic circulation and renal sodium retention in cirrhosis. Clin Sci 97259-267, 1999 86. Wong F, Liu P, Tobe S, et al: Central blood volume in cirrhosis: Measurement by radionuclide angiography. Hepatology 19:312-321, 1994 87. Wong F, Massie D, Hsu P, et al: The renal response to a saline load in well compensated alcoholic cirrhosis. Hepatology 202373-881, 1994 88. Wong F, Sniderman K, Blendis LM: The renal sympathetic and renin-angiotensin response to lower body negative pressure in well-compensated cirrhosis. Gastroenterology 115:397405, 1998
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89. Wong F, Sniderman K, Liu P, et al: The effects of transjugular intrahepatic portosystemic shunt on systemic and renal hernodynamics and sodium homeostasis in cirrhotic patients with refractory ascites. Ann Intern Med 122816-822, 1995 90. Wong F, Sniderman K, Liu P, et al: The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt. Gastroenterology 112:899-907, 1997 91. Wong NL, Quamme GA, Sutton RA, et al: Effects of mannitol on water and electrolyte transport in the dog kidney. J Lab Clin Med 94:683-692,1979 92. Yamada S, Reynolds TB Amiloride (MK-870), a new antikaluretic diuretic. Comparison to other antikaluretic diuretics in patients with liver disease and ascites. Gastroenterology 59533-841, 1970
Address reprint requests to Florence Wong Room 220, 9th floor Eaton Wing Toronto General Hospital 200 Elizabeth Street Toronto M5G 2C4, Ontario Canada e-mail: florence.wong8utoronto.ca
1089-3261/01 $15.00
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THE PATHOPHYSIOLOGIC BASIS FOR THE TREATMENT OF CIRRHOTIC ASCITES Florence Wong, MD, FRACP, and Laurence Blendis, MD, FRACP
Abnormal renal sodium handling is common in patients with cirrhosis, including those patients without ascites, a stage that is known as preascitic cirrhosis.s0In these patients, the renal sodium abnormality is subtle and seems to be c o m p e n ~ a t e d . Fifty ~ ~ , ~percent ~ , ~ ~ of patients with compensated cirrhosis will develop ascites within 10 years,22but the predicting factors for this have not been clarified. The onset of ascites, necessitating diuretic therapy in previously compensated patients, is associated with a decreased survival rate of 50% at 5 years.I3 Many of these patients will eventually become resistant to diuretic therapy, and in these patients the prognosis decreases to 50% survival at 2 years.13 Cirrhotic patients with refractory ascites are particularly susceptible to the development of renal dysfunction. Renal dysfunction can occur either insidiously with gradual worsening of renal function (type I1 hepatorenal syndrome [HRS]),’ or acutely following a precipitating event (type I HRS)*; the latter has a poor prognosis. Until recently, the only permanent therapy for refractory ascites and HRS was liver transplantation.26The problem with transplantation is that donor livers are a scarce resource. With a better understanding of the pathophysiology of ascites and its complications, new and promising therapies have emerged.9,89 Therefore, this article emphasizes that continued research into, and improved understanding of, the pathophysiology of sodium retention in cirrhosis, through all the various stages, may result in further advances
From the Department of Medicine, Division of Gastroenterology, The Toronto General Hospital, University of Toronto, Ontario, Canada ~
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in therapy and possibly even in the prevention of the onset of ascites itself. THERAPIES Bed Rest
Traditionally, bed rest was used as the basic treatment for ascites. Bed rest may actually have been effective because assuming the supine position results in an increase in venous return and expansion of the central blood volume, including the atria, with a rise in plasma atrial natriuretic peptide (ANP) levels and consequently an exaggerated natri~ r e s i sThe . ~ ~central blood volume is an approximation of the effective circulating blood v0lume,3~,86 the expansion of which in the supine position results in a suppression of the plasma renin activity (PRA) and sympathetic nervous system.s2Increases in PRA and sympathetic nervous activity observed with the upright posture are associated with sodium retention4,s8; the suppression of these activities is synergistic with the rise in plasma ANP levels, which are directly related to the exaggerated n a t r i ~ r e s i sFurthermore, .~~ in cirrhotic patients assuming a supine posture, the increase in central blood volume causes an increase in cardiac output and consequently in renal blood flow (RBF) and glomerular flow rate (GFR); further enhancing the natriuretic effect of the supine p ~ s i t i o n .In ~ the current climate of economic constraints, however, treating ascitic cirrhotic patients with bed rest in hospital is impractical and too expensive. Sodium Restriction
Although there have been no studies on the effects of sodium restriction per se, sodium restriction and bed rest are effective in eliminating ascites in 10% to 20% of cirrhotic patients.19Most ascitic cirrhotic patients, in the absence of diuretic therapy, cannot eliminate more than 50 mEq of sodium in their urine per day. In the authors’ experience, most cirrhotic patients ingest approximately 150 mmoL of sodium per days3on a no-added-salt diet. Therefore, patients with ascites ingesting a no-added-salt diet will continue to accumulate ascites. The objective of a low sodium intake is to induce a negative sodium balance. Therefore, the lower the sodium intake, the more likely the patient is to achieve negative sodium balance, and the greater the magnitude of that imbalance, especially when the sodium intake is below the renal natriuretic threshold. In an animal model of portal hypertension, sodium restriction resulted in a diminution of plasma volume and a fall in portal pressure.l8 In acute animal models, sinusoidal portal hypertension,” as opposed to presinusoidal portal hypertension,” has been shown to cause sodium retention with systemic and renal hemodynamics remaining
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unchanged. In chronic animal models of portal hypertension such as the common bile duct-ligated dog, sodium retention with ascites was preceded by sinusoidal portal hypertension despite normal renal funct i ~ n Cirrhotic .~ patients with only mild sinusoidal portal hypertension (below 10 mm Hg) usually do not develop as cite^.^^, 66 Therefore, the reduction of portal pressure is considered in all the treatment modalities of ascites discussed. Other permissive factors which contribute to sodium retention in cirrhosis are also be mentioned, because, as discussed later, the correction of portal hypertension with the insertion of a transjugular intrahepatic portosystemic shunt (TIPS) does not completely normalize sodium retention in cirrhosis.36,84 Diuretics Spironolactone
To date, there have been no long-term follow-up studies on wellcharacterized groups of cirrhotic patients with preascites to clarify the predictive factors for the development of ascites in these patients. Furthermore, there is no evidence as yet supporting the use of prophylactic diuretic therapy to prevent the onset of ascites in preascitic patients. Nevertheless, in an acute study, a low but optimal dose, 7.5 mg, of losartan, an angiotensin I1 receptor antagonist, was shown to increase sodium excretion in preascitic cirrhotic patients on a diet of 200 mmoL of sodium per day diet and to restore them to complete sodium balance.= There was no effect on healthy controls. This natriuresis was associated with unchanged PRA, but a significant rise in serum angiotensin I1 Ievels, albeit still within the normal range, as compared to controls. This study indicates that one of the early pathophysiologic changes in preascites is a pertubation of the intrarenal renin-angiotensin system. This dysfunction would support the findings in recent animal studies of portal hypertension and would indicate increased aldosterone-dependent renal sodium retention in the presence of normal serum aldosterone levels.38In addition, about one third of cirrhotic patients with earlyonset ascites have normal PRA and serum aldosterone levels.69Nevertheless, the standard initial therapy for recent-onset ascites is the aldosterone antagonist spironolactone. Patients with recent-onset ascites respond to spironolactone whether the serum aldosterone levels are raised or not, but later in the natural history of ascites the level of serum aldosterone determines the diuretic response.37 This finding suggests that the distal tubular site of action of spironolactone may be nonspecific. This nonspecificity is supported by the almost equivalent effect of another group of distal diuretics such as amiloride which block the apical sodium potassium pump.92Spironolactone may have other sites of action. For example, by contracting the plasma volume, and hence the splanchnic volume, spironolactone has been shown to lower the portal pressure in animal models of portal hyperten~ion~~ and in cirrhotic
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patients without ascites.16,4o It would be of considerable interest to measure the effect of spironolactone on portal pressure in patients with ascites and compare it with that of amiloride. In recent years, aldosterone has also been shown to activate the production of fibroblasts in preference to myocytes in the myocardium,1o resulting in pathologic hypertrophy and increasing myocardial stiffness. Such changes in the myocardium of patients with cirrhosis are becoming increasingly recogni~ed.~~ These changes were initially thought to be caused by the associated alcoholism. Finding these changes in nonalcoholic cirrhotic patients42has led to the concept of a specific cardiomyopathy related to the presence of cirrhosis per se, or cirrhotic cardiomyopathy. The characteristic findings include myocardial thickening of the left ventricular wall associated with diastolic dysfunction in the presence of a normal ejection fraction.62Although these findings are found in both nonascitic and ascitic cirrhotic the contractile cardiac dysfunction is aggravated by an increased sodium intake and therefore may be involved in the pathophysiology of sodium retention.85Spironolactone has been shown to have a specific myocardial benefit in patients with congestive heart failureboand this effect may be another of the nonrenal benefits of spironolactone in cirrhosis. That is, by improving myocardial function, spironolactone, in nondiuretic doses, may help improve renal sodium excretion.
Furosemide At some point in the natural history of ascites, many patients become increasingly resistant to spironolactone. At that stage, they usually respond to the addition of f~r0semide.l~ Because the site of action of furosemide is on the chloride pump of the thick ascending loop of Henle, nonresponsiveness to spironolactone indicates that the site of increased sodium reabsorption has moved proximally from the cortical portion of the collecting duct and the distal convoluted tubule in the early stage of ascites. Thereafter some patients become increasingly resistant to the combination of spironolactone and furosemide, despite stepwise increases in both diuretic doses.I7This resistance suggests that there is increasing reabsorption of sodium proximal to the ascending loop of Henle, that is, in the proximal tubule. This suggestion is supported by recent studies showing that the addition of intravenous albumin in combination with the diuretics can induce a natriuresis in previously resistant patients. Because there are no data supporting an expansion of the plasma volume in this the therapeutic effect of albumin is probably a local one of suppressing proximal reabsorption of sodium and thereby increasing the delivery of sodium to the ascending Mannitol Studies using mannitol in patients with diuretic-resistant ascites have supported the concept that diuretic resistance is caused by almost
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total proximal reabsorption of sodium along the renal tubule. These patients had ascites refractory to maximum doses of combined diuretics.z They were also totally resistant to an exogenous infusion of ANP, with a failure to increase their urinary sodium excretion.73,81 On starting treatment with an intravenous infusion of 20 g of mannitol, about one half the patients responded with a diuresis.', 50 When intravenous ANP was added to the mannitol, there was an incremental increase in natriuresis. The interpretation of these results is that mannitol is an osmotic diuretic that obligates the excretion of water by suppressing water and sodium reabsorption in the proximal tubuleg1and then in the ascending loop of Henle.8 In some patients with refractory ascites, the infusion of mannitol will result in the transport of water and electrolytes to the ascending loop of Henle and the distal nephron, at which point ANP can act, through its receptors, to cause a further natriuresis. In patients with the most severe degree of renal dysfunction, mannitol had no effect, and these patients subsequently developed HRS50Therefore, when ambulatory patients become completely resistant to diuretic therapy, it is time to turn to abdominal paracentesis. Such patients constitute only 10% of the ascitic population at any one time.68 Abdominal Paracentesis
Although abdominal paracentesis (AP) is the oldest known form of therapy for ascites, dating back 300 to 400 years, with the introduction of diuretics 50 years ago, AP went out of favor because of the number of serious, associated ~omplications.4~, 52 These complications were later explained by deleterious hemodynamic effects such as a fall in cardiac output resulting from a contraction in plasma volume.4l The mechanism of this process was clarified by the demonstration that ascites reformed at a much more rapid rate following paracentesis than the reconstitution of plasma volume by the ascitic Nonetheless, AP continued to be used as a standard therapy for resistant ascites in certain institutions, such as the VA hospitals in the United States. The debate then developed as to whether AP does or does not cause a fall in plasma volume, that is, whether volume contraction is responsible for the deleterious effects of AP. Early studies showed no significant fall in plasma volumeM especially in patients with peripheral edema undergoing a 5-liter AP.39,58 At the same time, however, Quintero et aF5 showed that a 5-liter AP combined with 40 g of intravenous albumin was the optimal treatment of resistant ascites. Subsequently, the Barcelona group showed that largevolume AP plus intravenous albumin has significantly fewer side effects and is more cost effective than diuretic therapyz3 The situation was clarified by a sentinal study by Simon and c o - w ~ r k e r swhich ~ ~ showed that, unlike patients with ascites and peripheral edema, in nonedematous patients the removal of an average of 7.5 liters of ascitic fluid, in the absence of volume expanders resulted in deleterious side effects. After an initial rise in cardiac output associated with an increased
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venous return, there was a significant fall in cardiac output together with a fall in central venous pressure after 24 hours. At the same time, there was a significant fall in systemic vascular resistance and creatinine clearance and a rise in PRA and aldosterone levels. This delayed rise in PRA and subsequently reported rise in plasma norepinephrine levels, associated with a fall in systemic vascular resistance, was noted to occur between 2 and 6 days after AP in up to 75% of nonedematous patients undergoing large-volume AP in the absence of volume expanders" but in only 25% of patients receiving volume expanders.21This condition was subsequently labelled paracentesis-induced circulatoy dysf~nction.'~ Further studies showed that in about 25% of cases paracentesis-induced circulatory dysfunction was associated with significant increases in portal pressure.'* The pathogenesis of paracentesis-induced circulatory dysfunction is now thought to be caused by further, as yet unexplained, vasodilation following AP.14 Whatever the mechanism, significant paracentesis-induced circulatory dysfunction is associated with deterioration in renal function and in overall prognosis. Therefore, it seems that AP can have significant adverse hemodynamic effects, especially if volume replacement is not given. In contrast, hemodynamic studies showed that total paracentesis (TP), or the removal of all ascitic fluid by paracentesis at one session, with administration of volume expanders,61,74 resulted in a rise in cardiac output an increase in right atrial size, and a fall in systemic vascular resistance, with an improvement in renal function.56At the same time, there is a significant fall in portal pressure and azygos blood flow and If volume expansion is delayed in PRA and serum aldosterone le~els.4~ for up to 6 hours after TP, the marked decrease in intra-abdominal pressure is accompanied by a fall in intrathoracic, pulmonary arterial, capillary wedged, and right atrial pressures; systemic vascular resistance, and PRA and serum aldosterone levels.@By 24 hours, there is also a marked suppression of muscle sympathetic By the time patients have developed diuretic-resistance ascites, removal of a large amount of ascites jeopardizes their effective arterial blood volume, unless that volume can be reconstituted rapidly from a third space, such as leg edema. The problem does not arise, as initially thought, from inadequate filling, but rather from further vasodilation associated with the removal of ascitic fluid. Therefore, it would seem unwise to perform large-volume AP in cirrhotic patients with tense ascites without volume expanders. Nonetheless, many APs are performed every day in these patients without causing deleterious effects. The difference seems to be in the volume of paracentesis. The removal of ascitic fluid, even small amounts ranging from 1 to 3 liters, results in beneficial systemic hemodynamic whereas with the removal of approximately 4 liters, there are no hemodynamic changes.57Again, in the controversy concerning whether or not to administer albumin with AP, the most important factors seems to be the volume of fluid removed; removing up to 4 liters without albumin is safe and may be
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beneficial. When more than 5 liters of fluid is removed in patients with peripheral edema or in patients who are noncompliant rather than diuretic-resistant, it is probably safe not to use albumin. In nonedematous patients who undergo large-volume paracentesis of more than 5 litres, the use of plasma expanders such as albumin can have beneficial hemodynamic effects. When all the hemodynamic phenomena of AP are understood, the pathophysiology of sodium retention and vasodilation in cirrhosis may also be better understood. Peritoneovenous Shunting
Peritoneovenous shunting as originally introduced by LeVee11,4~was a method of performing abdominal paracentesis continuously, by recirculating the ascitic fluid back to the right side of the heart through a subcutaneous plastic cannula with a one-way valve preventing reflux back into the peritoneal Insertion of the peritoneovenous shunt (PVS) resulted in an immediate increase in plasma volume and a dramatic diuresis and natriuresis while the patient was still on the operating table.5 These effects were associated with an immediate rise in cardiac output, a fall in systemic vascular resistance, a transient fall in systemic blood pressure, significant rises in GFR and RBF, and significant falls in PRA (to normal range within 8 hours) and in serum aldosterone levels (to normal range by 48 hours)28but not in serum norepinephrine levels.6 This dramatic natriuresis was subsequently shown to be associated with a significant rise in plasma ANP levels.I2 By 2 weeks postoperatively, many of these dramatic changes had subsided, but sodium excretion, GFR, and RBF remained significantly improved compared with preoperative level^.^ By 3 months, there was a significant fall in the hepatoportal and the patients’ ascites subsequently disappeared. When reinvestigated at around 1 year after surgery, the patients with functioning shunts were still ascites-free, with normal PRA and serum aldosterone levels, and in sodium balance on a diet of 20 mmol of sodium per day.29When challenged with a higher dietary sodium intake of 100 mmol per day, however, the patients remained in positive sodium balance, despite further physiologic suppression of PRA and serum aldosterone levels.29Of interest, these patients preoperatively were resistant to an intravenous infusion of ANP, by failing to respond with a natriureS~S.~O Successful PVS restored the normal natriuretic response to ANP in these patients.” These studies show that by the time ascitic patients have become resistant to diuretics their effective circulating blood volume is inadequate, because restoring this volume by recirculating ascitic fluid, in association with increasing plasma ANP levels and suppressing the renin-angiotensin-aldosteronesystem to within the normal range, results in a natriuresis. Despite these results, an improvement in renal function, and a significant fall in portal pressure following a successful outcome,
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renal sodium handling, although improved, is not normal. The returned responsiveness to intravenous ANP suggests that PVS has reduced sodium reabsorption in the proximal part of the nephron, thereby increasing distal delivery of sodium and thus enabling ANP, through its receptors in the medullary collecting duct, to function again. Although systemic vasodilation remains, the normalization of PRA means that it is no longer a relevant factor. Despite its sound physiologic basis, the use of a PVS to treat cirrhotic patients with diuretic-resistant ascites has fallen out of favor because of the many attendant complications. Furthermore, the insertion of a PVS does not correct other important pathogenetic factors of ascites formation, including continued portal hypertension and hepatic dysfunction. Transjugular lntrahepatic Portosystemic Stent
A TIPS is the radiographic placement of a flexible, metallic stent from the hepatic vein through the liver to the portal vein. The stent thus decompresses the portal venous system in the same way as a side-toside portocaval shunt. The procedure was originally designed for the treatment of refractory variceal bleedingz7,67 It was noted in patients who had ascites that the ascites disappeared after placement of the TIPS, and it soon become clear that TIPS is an effective treatment for refractory ascites.%Thus, in ascitic patients, TIPS functioned in the same way as side-to-side portocaval shunting, which was also used to treat ascites resistant to diuretic therapy.55The rationale for lowering the portal pressure in the treatment of cirrhotic ascites comes from a series of studies that link sodium retention to portal hypertension1',49; the result of both of these therapies is a fall in portal pressure. The lower the final pressure, the more effective the therapy. The insertion of a TIPS, the consequent fall in sinusoidal portal pressure, and then a fall in azygos blood are immediately followed by significant hernodynamic changes. There is a rise in cardiac output and a decrease in systemic vascular resistance; even while the patient is still in the angiography suite.9oThese changes occur long before there is a measurable increase in central blood volume, which may take days, if not weeks, to detect.89 Thus, as with AP, further systemic vasodilatation is a major consequence of this treatment: the mechanism remains unknown. Also, while the patient is still in the angiography suite, left atrial and left diastolic volume increase significantly, by 6% to 7%, and are associated with marked increases in right atrial, mean pulmonary artery, and capillary wedged pressures.35Such changes may be caused by underlying subclinical cardiac dysfunction, found in both alcoholic62and nonalc~holic~~ cirrhosis. Despite the fall in portal pressure, natriuresis is not immediate, but the reduction of portal pressure initiates a series of changes that culminates in the reversal of the sodium retention. By the end of the first
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week, there is a fall in PRA and serum aldosterone levels,2O with the beginning of a natriuresis that increases gradually over the next few weeks. By 4 weeks after the procedure the patient is in negative sodium balance, despite no change in plasma norepinephrine levels.90Improvement in renal function occurs even and these changes persist for at least 1 year. Therefore, TIPS lowers portal pressure and also gradually improves intravascular filling, leading to improved hemodynamics, with consequent improved renal sodium handling. At this stage, these postTIPS patients have been challenged with a high sodium diet84 or acute saline infusion,32 and found to have improved natriuretic responses compared with preascitic patients.37,83 Natural or balloon obstruction of the TIPS leads to reversal of these hemodynamic changes and return of sodium r e t e n t i ~ n The . ~ ~ extension of these observations has led to the use of TIPS in patients with hepatorenal syndrome. In these patients, TIPS has now been shown to improve renal function and sodium excret i ~ n .30~ , Liver Transplantation
Renal sodium handling in patients who have received a TIPS does not return completely normal, suggesting that other factors such as liver function may be involved.78Therefore, it stands to reason that liver transplantation should eliminate ascites. Clinically, the replacement of a diseased cirrhotic liver by a normal liver eventually results in an improvement in renal sodium handling and the disappearance of ascites by 3 to 6 months after transplantation. Portal hypertension is reversed immediately and completely, and liver function is restored to within the normal range so the reason for the delay in disappearance of ascites is not yet fully understood. Several studies have shown that the hyperdynamic circulation with systemic vasodilatation persists for several months after tran~plantation.~~, 32, 51, 59 Formal studies have not yet elucidated the order of the postoperative changes relating to renal sodium handling, changes in blood volume, and changes in the systemic vasodilatation. The determination of the order of these events might well help clarify the pathophysiology of sodium retention in cirrhosis. SUMMARY
Advances in the understanding of the pathophysiology of sodium retention and ascites formation in cirrhosis has helped improve the treatment of ascites in these patients. It is likely that further unraveling of these pathophysiologic changes will lead to the development of novel and better treatment options. For example, the development of aquaretic agents for the management of hyponatremia in cirrhosis may allow more effective use of diuretic therapy. The ultimate challenge is to use the
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understanding of the pathophysiology to develop new strategies to prevent the development of ascites in cirrhosis.
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