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. 2005 Dec;22(4):278–286. doi: 10.1055/s-2005-925554

Transjugular Intrahepatic Portosystemic Shunt in the Management of Refractory Ascites

Guadalupe Garcia-Tsao 1
PMCID: PMC3036291  PMID: 21326706

ABSTRACT

The purpose of this article is to describe the pathophysiological basis for the use of transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis and refractory ascites, the short- and long-term hemodynamic, biochemical, and hormonal changes after TIPS, and the results of controlled trials of TIPS in cirrhotic patients with refractory ascites. 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 (indicative of an improvement in effective arterial blood volume). Although effective in preventing the recurrence of ascites, the efficacy of TIPS is offset by an increase in the incidence of severe hepatic encephalopathy, a high incidence of shunt dysfunction, and a higher cost without an overall survival benefit, which should be reevaluated in light of polytetrafluoroethylene-covered stents. TIPS placement is currently indicated in seleceted cirrhotic patients with refractory ascites who require more than two to three large-volume paracenteses per month.

Keywords: Refractory ascites, cirrhosis, transjugular intrahepatic portosystemic shunt, large-volume paracentesis

PATHOPHYSIOLOGY OF CIRRHOTIC ASCITES

In cirrhosis, two main mechanisms are responsible for ascites formation: sinusoidal hypertension and sodium retention.

Sinusoidal Hypertension

Sinusoidal hypertension results from hepatic venous outflow block. In cirrhosis, this block is both structural, secondary to regenerative nodules and fibrosis, and functional, due to increased intrahepatic vascular tone and hyperresponsiveness to vasoconstrictors that, in cirrhotic rats with ascites, occurs mostly in the postsinusoidal area.1 It has been shown that ascites is present only in patients in whom the hepatic venous pressure gradient (which reflects sinusoidal pressure) is above 12 mm Hg.2,3 In fact, two recent studies show that the development of ascites is significantly lower in patients in whom the hepatic venous pressure gradient decreases either below 12 mm Hg or more than 20% from baseline values.4,5

Sodium Retention

The most likely explanation for sodium retention is a decrease in effective arterial blood volume secondary to splanchnic and peripheral vasodilatation that leads to the activation of sodium-retaining neurohumoral systems (renin-angiotensin and aldosterone) and plasma volume expansion.6 Without replenishment of the intravascular space, that is, without plasma volume expansion, leakage of fluid into the peritoneal cavity would be a self-limited process.

REFRACTORY ASCITES AND RATIONALE FOR TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT USE

In the majority of cases, cirrhotic ascites responds to the use of diuretics, which act by increasing urinary sodium excretion, thereby producing a negative sodium balance. Refractory ascites, present in 10 to 20% of cirrhotic patients with ascites, assumes either diuretic-resistant ascites (ascites that is not eliminated even with maximal diuretic therapy) or diuretic-intractable ascites (ascites that is not eliminated because maximal doses of diuretics cannot be attained given the development of diuretic-induced complications such as hepatic encephalopathy, renal and/or electrolyte abnormalities).7 In the majority of patients (80%), refractory ascites is of the diuretic-intractable type. The development of refractory ascites denotes a more advanced liver disease with further vasodilatation and activation of neurohumoral systems and a higher mortality.8 Therefore, these patients should be considered for liver transplantation.

Large-volume paracentesis (LVP) is the most commonly used method to treat refractory ascites.9 It is a local therapy that does not modify any of the mechanisms that lead to ascites formation. Therefore, recurrence of ascites is practically universal, unless there is an improvement in liver disease (e.g., resolution of alcoholic hepatitis). Additionally, LVP has been associated with the postparacentesis circulatory dysfunction, an entity defined by an increase in plasma renin activity, that leads to faster reaccumulation of ascites, a higher susceptibility to develop renal dysfunction, and a higher mortality.10,11 The incidence of postparacentesis circulatory dysfunction is lowest (but not absent) when LVP is associated with the concomitant administration of intravenous albumin infusion and when quantities lower than 4 to 5 L are extracted.10 Albumin infusion has the objective of increasing effective arterial volume but its effect is transient. The need for repeated procedures, requiring albumin infusion, increases the cost of LVP, potentially increasing its morbidity, and without a survival benefit.12,13

There is a need for better therapies for refractory ascites that should ideally act on the pathophysiological mechanisms that lead to ascites formation, namely sinusoidal hypertension and reduced effective arterial blood volume.

Surgical portosystemic shunts decrease the development of ascites.14 Although an end-to-side portocaval shunt decreases ascites by decreasing blood flow into the sinusoids (thereby decreasing sinusoidal pressure) and by decompressing splanchnic capillaries, it can also lead to greater ascites formation, particularly in patients with advanced cirrhosis in whom the hepatic venous outflow block is such that the portal vein becomes the outflow tract. Conversely, the side-to-side portocaval shunt (and the mesocaval shunt), by connecting the side of the portal vein (or the mesenteric vein) to the low-pressure inferior vena cava, effectively decompresses not only the splanchnic capillaries but also the sinusoids.15 When comparing end-to-side versus side-to-side portocaval shunts, both experimentally16 and in cirrhotic patients,15 side-to-side portocaval shunting results in less ascites formation and less ascites reaccumulation. However, given a high operative morbidity and mortality in this patient population and a high rate of severe hepatic encephalopathy,17 the surgical side-to-side portocaval shunt is practically never used for the treatment of refractory ascites.

The transjugular intrahepatic portosystemic shunt (TIPS) is a nonsurgical procedure by which an intrahepatic artificial communication between the portal and the hepatic vein is created, effectively acting as a side-to-side portocaval shunt as it decompresses the hepatic sinusoids. Therefore TIPS should be as effective as a surgical side-to-side portocaval shunt in treating ascites without the morbidity and mortality associated with major surgery.

In addition to decompressing sinusoids, TIPS has theoretical advantages in the treatment of refractory ascites because by connecting the portal vein with a systemic vein, the blood volume that is sequestered in the splanchnic circulation is transferred to the systemic circulation, increasing effective arterial blood volume and sodium excretion.

By reversing the mechanisms responsible for the formation of ascites, TIPS should be effective not only in resolving ascites but also in preventing its recurrence, thereby constituting a more definitive treatment for ascites than LVP + albumin and, by preventing other complications of portal hypertension and ascites, such as variceal hemorrhage, hepatorenal syndrome, and spontaneous bacterial peritonitis, it could have a beneficial effect on survival. On the other hand, TIPS has been shown to lead to the development of liver failure and/or hepatic encephalopathy as a result of the diversion of blood away from the liver and into the systemic circulation, and various randomized trials of TIPS for variceal hemorrhage have identified hepatic encephalopathy and shunt dysfunction as long-term complications of TIPS, with no survival benefit.18

EFFECTS OF TIPS ON HEMODYNAMICS AND SODIUM-RETAINING MECHANISMS IN CIRRHOTIC PATIENTS WITH REFRACTORY ASCITES

Immediately after TIPS, there is an increase in cardiac output and a decrease in systemic vascular resistance (already decreased in these patients), without significant changes in mean arterial pressure.19,20 These changes persist for 2 weeks21,22 to 1 month after TIPS,19,20 but are no longer present 3 months or more after TIPS insertion.19,20,22 The increase in cardiac index is most probably the result of an increase in venous return secondary to shunting of blood sequestered in the splanchnic circulation into the systemic circulation through the newly created shunt. The decrease in systemic vascular resistance is probably the result of increased flow secondary to the increase in cardiac index (as shear stress increases, the synthesis of vasodilators such as nitric oxide increases). The mean portosystemic pressure gradient (PPG) is significantly reduced compared with baseline up to 14 months after TIPS placement, although this effect appears to decrease progressively over time probably as a result of its progressive occlusion.22

Liver synthetic function deteriorates after TIPS, as evidenced by an increase in Child-Pugh score (CPS) from the first day to 1 month after TIPS,19,20,22,23 however by 3 months post-TIPS, CPS has been shown to be similar to baseline,22,24 and most studies show an improvement in CPS 7 to 14 months after TIPS placement,22,24 probably as a result of resolution/improvement of ascites.

Despite an early deterioration in liver synthetic function and a worsening in the hyperdynamic circulatory state of cirrhosis (decreased systemic vascular resistance, increased cardiac index), urine sodium significantly increases as soon as 7 days23 and definitely 1 month after TIPS,20,21,25 persisting for up to 14 months.22,24 The increase in urinary sodium correlates closely with a decrease in plasma renin activity.19,20,21,22,23,24,25 Interestingly, one study shows that the increase in urinary sodium excretion occurs only in cirrhotic patients with ascites (particularly those with refractory ascites) but does not occur in those without ascites.23 Of note, no significant differences in glomerular filtration rate, creatinine clearance, serum creatinine, or serum sodium are observed after TIPS placement in patients with refractory ascites.

TIPS FOR REFRACTORY ASCITES

Uncontrolled Trials

Ferral et al first reported in 1993 the efficacy of TIPS in the treatment of refractory ascites.26 In this study, complete resolution of ascites was achieved in seven of 14 patients although two patients developed new encephalopathy, four patients developed shunt dysfunction, and eight patients died. Since then, four retrospective cohort studies and eight prospective cohort studies of TIPS in patients with refractory ascites in which patients have been followed for more than 6 months have been published.27 Success in TIPS placement in these studies was essentially 100%. In one of the studies, technical failures occurred in 4/50 (8%) patients, three of whom had markedly shrunken liver positioned high in the abdomen.

In uncontrolled studies, TIPS has been shown to eliminate and/or make ascites easier to manage in the majority of patients (70%); however, diuretics are still required (at lower doses) in essentially all patients. Shunt dysfunction (with consequent recurrence of ascites) occurs in a third of the patients and new or worsened hepatic encephalopathy occurs in over 25% of the patients. In a median follow-up of around 11 months, the observed mortality in these studies was quite variable but averaged around 50%.28

Controlled Trials of TIPS versus LVP

Five prospective randomized trials comparing TIPS versus LVP have been published in full to date21,29,30,31,32 and are summarized in Tables 1 and 2.

Table 1.

Baseline Characteristics of Patients Included in Controlled Studies of TIPS versus LVP for Refractory or Recidivant ascites

First Author Therapy n Age (y) ETOH (%) Refractory Ascites (%) CPS (% Child C) Bilirubin (mg/dL) Creatinine (mg/dL) Serum Na (mEq/L) (% < 130) UNa (mEq/L) (% < 10) PPG (mm Hg)
Abbreviations: LVP, large-volume paracentesis; TIPS, transjugular intrahepatic portosystemic shunt; CPS, Child-Pugh score; Na, sodium; UNa, urinary sodium; PPG, portosystemic pressure gradient; NR, not reported.
Values given are mean values or percentages.
Lebrec21 LVP 12 52 83 100 9.2 (33%) 1.6 1.0 130 < 5 22 → 20
TIPS 13 50 77 100 9.3 (31%) 2.0 1.0 130 < 5 20 → 13
Rossle29 LVP 29 61 74 52 8.7 (23%) 1.8 1.4 131 (13%) 61 (10%) —
TIPS 31 58 83 59 9.1 (38%) 1.8 1.3 130 (17%) 45 (40%) 24 → 10
Gines30 LVP 35 56 60 100 9.2 (43%) 2.4 1.4 — (48%) 9 —
TIPS 35 59 51 100 9.3 (37%) 2.0 1.4 — (54%) 7 19.1 → 8.7
Sanyal31 LVP 57 52 33 100 9.3 (NR) 1.9 0.98 NR NR —
TIPS 52 56 32 100 9.2 (NR) 1.9 1.07 NR NR 19.8 → 8.3
Salerno32 LVP 33 60 39 64 9.4 (38% B/C) 1.9 1.12 133 38 —
TIPS 33 58 45 73 9.4 (27% B/C) 1.7 1.15 133 38 22.5 → 8.7
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Table 2.

Controlled Studies of TIPS versus Large-Volume Paracentesis for Refractory or Recidivant Ascites

First Author Therapy n Follow-up (mo) Favorable Response New or Worse Encephalopathy TIPS Dysfunction Mortality Predictors of Death
Values given are mean values or percentages.
Abbreviations: LVP, large-volume paracentesis; TIPS, transjugular intrahepatic portosystemic shunt; CPS, Child-Pugh score; BUN, blood urea nitrogen; MELD, model of end-stage liver disease; NR, not reported.
Lebrec21 LVP 12 NR 0 (4 months) 0 — 4 (33%) Child C
TIPS 13 NR 5 (38%) 3 (23%) 3 (23%) 9 (69%)
Rossle29 LVP 29 44 7 (24%) (3 months) 3 (10%) — 23 (79%) Age > 60; bilirubin > 3; serum sodium < 125; treatment assigned
TIPS 31 45 20 (64%) 6 (19%) 13 (42%) 15 (48%)
Gines30 LVP 35 11 6 (17%) 12 (34%)* — 18 (51%) CPS
TIPS 35 9 18 (51%) 21 (60%)* 13 (37%) 20 (57%) BUN
Sanyal31 LVP 57 NR 9 (16%) 12 (21%) — 19 (33%) None found
TIPS 52 NR 30 (58%) 20 (38%) 53% (6 months) 18 (35%)
Salerno32 LVP 33 15 14 (42%) 0.36† — 20 (61%) MELD; treatment assigned
TIPS 33 21 26 (79%) 0.97† 12 (36%) 13 (39%)
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*

Severe encephalopathy.

†

Episodes of severe encephalopathy per patient.

Not unexpectedly, all five trials demonstrate that TIPS is more effective than LVP in the control of ascites (Table 2), and except for one,29 all studies demonstrate a higher incidence of encephalopathy21,31 or of severe encephalopathy30,32 in patients treated with TIPS. Regarding mortality, the most important end point, one study shows a higher mortality in patients randomized to TIPS due to a higher mortality in Child C patients21; two trials, which include the largest number of patients, show no differences in mortality between the TIPS and LVP groups30,31; one trial shows a significant survival benefit in favor of the TIPS group32; and in the remaining trial, treatment with TIPS was independently predictive of a better survival; however, differences in survival probability were not statistically different.29 Of note, in these studies TIPS was technically unsuccessful in ~5% of cases.

As can be observed in Table 1, cirrhotic patients included in these trials are quite homogeneous, with a median age of 56 years, a CPS around 9.2, and a comparable decrease in PPG after TIPS insertion. However, the two trials that showed a survival benefit may have included patients with less severe liver disease as indicated by higher urinary sodium excretion levels and the inclusion of patients with recidivant ascites.29,32 A higher sodium excretion is an indirect indicator of lesser activation of sodium-retaining neurohumoral systems and therefore of less vasodilatation and less advanced liver disease. Contrary to refractory ascites that is defined as a weight loss < 200 g/d despite maximal diuretic therapy, patients with recidivant ascites are those in whom tense ascites recurs at least three times in the course of 12 months but these patients still respond to diuretics and therefore have a less severe liver disease.7 Furthermore, unlike all other trials, in the trial by Rossle et al,29 LVP was not routinely associated to albumin administration, a factor that could have potentially increased mortality in the group randomized to LVP.

The highest mortality was observed in patients included in the study by Gines et al,30 in whom hyponatremia was more frequent and who also had higher creatinine levels (Table 1). This is not surprising as hyponatremia and renal dysfunction have both been described as being predictors of poor survival in cirrhosis,33,34 and, more recently, a serum sodium < 130 mmol/L and a serum creatinine > 1.7 mg/dL have been identified as the only independent predictors of survival in patients undergoing TIPS for variceal hemorrhage.35

Two recent meta-analysis, one that included four of the above-mentioned trials with a total of 264 patients36 and a more recent one that included all five trials with a total of 330 patients,37 come to the same conclusions. That is, that TIPS is more effective than LVP in the control of ascites (up to 12 months after randomization), that mortality does not differ between these two treatments and that hepatic encephalopathy occurs significantly more often in TIPS-treated patients.

Aside from these end points, a preventive effect of TIPS on the development of hepatorenal syndrome was observed in the trial by Gines et al,30 effect that is likely related to suppression of the renin-angiotensin-aldosterone system; however, this beneficial effect was not confirmed in a meta-analysis.36 Another potential benefit of TIPS is an improvement in quality of life demonstrated in an uncontrolled study particularly in patients with a complete response (elimination of ascites).38 However, these results could not be confirmed in the only randomized controlled study that evaluated quality of life using the SF-36 questionnaire.31

Furthermore, in the study by Gines et al, costs were greater in the TIPS group compared with the LVP group,30 partly due to an occlusion rate of 37% requiring shunt revision. It should be noted that all these studies used uncovered stents. Polytetrafluoroethylene-covered stents improve TIPS patency and decrease the number of clinical relapses and reinterventions while actually decreasing the risk of encephalopathy.39 A retrospective study suggests that patients undergoing TIPS with covered stents (50% for refractory ascites) have higher 2-year survival rates when compared with patients undergoing TIPS placement with bare stents.40 The benefits of covered-stents in the setting of refractory ascites require evaluation in prospective studies.

Although studies report a decrease in diuretic requirement in patients treated with TIPS, it appears that all patients continue to require diuretics (Table 3), probably because TIPS improves but does not normalize sodium excretion. In fact, the use of diuretics immediately after the procedure is theoretically advantageous as it will reduce central pressure and increase flow through the shunt.

Table 3.

Uncontrolled Prospective Cohort Studies of TIPS for Refractory Ascites That Report on Predictors of Response and/or Mortality

First Author n Favorable Response Responders Requiring Diuretics Predictors of an Unfavorable Response Mortality Predictors of Survival
Abbreviations: NR, not reported; PCG, portocaval gradient.
Quiroga22 17 15 (88%) NR NR 5 (29%) Plasma norepinephrine
Ochs51 50 46 (92%) 46 (100%) None found 31 (62%) Age < 60; bilirubin < 1.3; complete response
Somberg25 24 19 (79%) 2/5 (40%) Serum creatinine > 2 NR NR
Crenshaw48 54 40 (74%) 40 (100%) Serum creatinine > 1.5 27 (50%) Complete response
Martinet45 30 26 (87%) 26 (100%) Post-TIPS PCG > 16 mm Hg 17 (57%) Child-Pugh score
Nazarian49 50 23 (46%) NR Creatinine > 1.9 and bilirubin > 3.0 30 (60%) Creatinine < 1.9 and bilirubin < 3.0
Deschenes50 53 25 (47%) NR Creatinine clearance < 36 mL/min 23 (43%) (6 months) NR
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Controlled Trial of TIPS versus Peritoneovenous Shunt

The peritoneovenous shunt (PVS) leads to expansion of blood volume, suppression of sodium-retaining neurohumoral systems, and increased responsiveness to diuretics. In controlled trials comparing PVS versus LVP, PVS has shown to be better than LVP in the long-term control of ascites without differences in survival.12,13 However, the frequent occlusion and complication rates have led to considering that PVS has only a small role in the treatment of refractory ascites.9 In fact, a recent randomized trial comparing TIPS versus PVS in 32 patients with refractory ascites shows that although ascites control was achieved sooner with PVS (73% versus 46% after 1 month), TIPS provided significantly longer long-term efficacy (86% versus 40% after 3 years), without differences in survival.41 There was a high rate of shunt occlusion in both groups with median shunt patencies of 4.4 months and 4 months for TIPS and PVS, respectively; however, the assisted shunt patency after PVS was lower than after TIPS (13 versus 31 months). Therefore, PVS should be restricted to non-TIPS candidates.

COMPLICATIONS OF TIPS FOR REFRACTORY ASCITES

In uncontrolled studies of TIPS placement in patients with refractory ascites, the procedure-related complication rate is around 9%, distributed as follows: intraperitoneal hemorrhage (3%), acute renal failure (3%) most described as being secondary to contrast media, sepsis (1.5%), and hemolysis (1.2%). A unique complication that has been described in these patients is the development of strangulated umbilical hernia following resolution after TIPS.42 In controlled studies, the procedure-related complications were only specified in the study by Gines et al30 and consisted of heart failure in 4 (11%) and severe hemolysis in 3 (9%) patients.

The most frequent complication related to TIPS placement is the development of hepatic encephalopathy, especially during the first months. As mentioned previously, this complication appears to develop less frequently with the use of covered stents.39 A recent controlled trial performed in 75 patients evaluated whether prophylactic therapies for encephalopathy (lactitol or rifaximin) were useful in preventing post-TIPS encephalopathy.43 The incidence of encephalopathy in this study was 33% and the 1-month cumulative probability of developing encephalopathy (or severe encephalopathy) was not significantly different among the three groups (lactitol, rifaximin, and no treatment). Results were the same when the 25 patients in which TIPS was performed for refractory ascites were analyzed. Therefore, prophylactic therapy for encephalopathy cannot be recommended in this setting. Previous hepatic encephalopathy was the most important independent predictor of post-TIPS encephalopathy.

Another recently described complication of TIPS appears to be a higher incidence of hepatocellular carcinoma (HCC) in cirrhotic patients treated with bare-stent TIPS. In a case-control study, the cumulative probability of developing HCC at 1, 3, and 5 years was 3, 24, and 34% for the TIPS cohort (138 patients) and 1, 6, and 25%, for the non-TIPS cohort, respectively.44 This observation suggests the need for a strict HCC surveillance program for these patients.

PORTOSYSTEMIC PRESSURE GOALS AND POST-TIPS MONITORING

As mentioned above, a hepatic venous pressure gradient of 12 mm Hg has been identified as a threshold PPG necessary for ascites development. Therefore, achieving a PPG of less than 12 mm Hg should be the goal of therapy. In fact, a post-TIPS PPG > 16 mm Hg was found to be a predictor of nonresponse in one study,45 and another study of TIPS for portal hypertension demonstrates that the portosystemic pressure gradient increased to 12 mm Hg in all patients who developed ascites post-TIPS placement.46

On the other hand, two studies have shown that a low PPG is an independent predictor of the development of post-TIPS encephalopathy. In one of them, performed in 47 patients, the portocaval gradient cutoff was < 10 mm Hg.47 Interestingly, in a more recent study from the same group of investigators, performed in 75 patients, a post-TIPS portosystemic gradient of < 5 mm Hg was the cutoff pressure related to the occurrence of encephalopathy.43 Therefore, although the post-TIPS PPG goal should be less than 12 mm Hg, it should also be greater than 5 mm Hg.

As opposed to the performance of TIPS for variceal hemorrhage, where serial assessments of TIPS patency and pressure monitoring may be warranted, when TIPS is performed for refractory ascites, TIPS functional assessment is not necessary unless there is recurrence of ascites, a clinically obvious event indicative of TIPS dysfunction.

PREDICTORS OF RESPONSE AND MORTALITY

In prospective cohort studies of TIPS for refractory ascites (Table 3), the most common predictive factor of an unfavorable response is serum creatinine25,48,49 or creatinine clearance.50 On the other hand, patients with a complete response after TIPS have been shown to have a better survival.48,51 Creatinine, bilirubin, and CPS have also been identified as predictors of survival in these studies.

The MELD (model of end-stage liver disease) model was designed to predict 3-month post-TIPS survival and uses a continuous function of serum bilirubin levels, international normalized ratio for prothrombin time, and serum creatinine.52 Only 25% of patients in this study had TIPS placed for management of refractory ascites. Several recent studies have compared MELD with the CPS in predicting post-TIPS survival with divergent results. One study shows that the MELD score is better than CPS score in predicting 3-month survival but not in predicting long-term survival,53 although another study finds no differences in short-term survival and only a marginal advantage of MELD in long-term survival.54 Another study shows that both scores are equally predictive of 1-month, 3-month, and 1-year post-TIPS survival,55 with a cutoff for the CPS of 11. In these studies refractory ascites is the reason for TIPS placement in only a minority of patients, and it has been shown that patients undergoing TIPS for refractory ascites have a significantly poorer survival than patients with variceal bleeding.55,56 In prospective randomized trials of TIPS for refractory ascites (Table 2), CPS is identified as a predictor of survival in two studies21,30 and MELD is the strongest predictor of survival in the most recent study32; however, the CPS is still more useful in clinical practice.

CANDIDATES FOR TIPS

The evidence-based consensus recommendation put forward recently is that first-line treatment of refractory ascites is repeated LVP + albumin and that TIPS should be considered when the frequency of paracentesis is greater than two to three times per month.9 A good predictor of post-TIPS survival is the CPS, and a score higher than 11 should be considered a contraindication for TIPS placement. TIPS should also be avoided in elderly patients and in those with heart dysfunction.9 Patients with alcoholic cirrhosis who are drinking alcohol may improve with abstinence and therefore TIPS should be delayed in these patients. The efficacy of the newly available covered stents needs to be prospectively evaluated in patients with refractory ascites.

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