Editorial

Transjugular Intrahepatic Portosystemic Refractory Ascites: Tipping the Sodium

Shunt for Balance

Abnormal renal sodium handling is a common and early complication of cirrhosis and eventually results in the formation of ascites. The development of ascites increases poth the morbidity and mortality of these patients significantly, resulting in a 5 year survival rate of less than 50% in patients with alcohol-induced cirrhosis.' In approximately 10% of ascitic cirrhotic pa- tients, the ascites becomes resistant to diuretic ther- apy2 with a resultant deterioration in survival to 50% at 2 years.3 Refractory ascites with its many complica- tions, including spontaneous bacterial peritonitis, pre- disposes to the development of hepatorenal syndrome with a mortality of close to Therefore, attention has of necessity been focused on the pathogenesis of renal sodium retention and improved ways of manag- ing refractory ascites. With the availability of liver transplantation, ascites and its complications have be- come a major indication for this expensive and scarce resource. Therefore, the need to define the pathophysi- ology of renal sodium retention and the development of refractory ascites and to find a successful, simple and inexpensive treatment for refractory ascites has become paramount.

Treatment options available for refractory ascites in- clude repeated large-volume paracente~is,~ which de- mands significant medical manpower and frequent pa- tient visits for the procedure. Over-zealous removal of ascitic fluid can precipitate hepatic encephalopathy.6 Alternatively, peritoneovenous shunting recirculates ascitic fluid into the systemic circulation and produces an immediate na t r i~res i s .~ However, its many atten- dant complications together with the high incidence of shunt obstruction have significantly reduced the proce- dure's usefulness.' Nonetheless, recent multicenter controlled trials have confirmed peritoneovenous shunting as a viable alternative to medical therapyg or repeated paracentesis." A surgical side-to-side porto- systemic shunt, which decompresses the portal circula- tion and reduces sinusoidal portal hypertension, has also been shown to be effective in relieving cirrhotic ascites, but the surgical procedure is associated with significant morbidity and mortality.",12 The creation of a tissue tract in the liver parenchyma between the por- tal and hepatic veins using radiological techniques for the treatment of esophageal varices was first described

Abbreviation: TIPS, transjugular intrahepatic portosystemic shunt. Address reprint requests to: Laurence Blendis, MD, FRCP (C), 9EN/220,

Toronto Hospital, 200 Elizabeth St, Toronto M5G 2C4, Ontario, Canada. Copyright 0 1995 by the American Association for the Study of Liver

Diseases. 0270-9139/95/2201-0046$3.00/0

over 10 years However, the inevitable occlusion of the tissue shunt nullified its usef~1ness.l~ More re- cently, an expandable metal shunt prosthesis or trans- jugular intrahepatic portosystemic shunt (TIPS) ap- pears to be successful in maintaining shunt patency with a consequent reduction in portal pressure, thereby preventing recurrent variceal TIPS is now increasingly becoming an accepted treatment for recur- rent variceal hemorrhage, especially in patients who have failed standard therapy of sclerotherapy or band ligation. It was observed that in such patients, after TIPS placement, concomitant ascites seemed to disap-

Then published abstracts of studies docu- menting the efficacy of this procedure in the treatment of refractory ascites a ~ p e a r e d , ~ ~ . ~ ~ followed by detailed studies assessing the pathophysiological changes that lead to the improvement of ascites after TIPS.25-27

The therapies for refractory ascites appeared to throw some light on the pathogenesis of sodium and water retention in cirrhosis. Peritoneovenous shunting appeared to immediately reconstitute an underfilled circulation with a subsequent fall in plasma renin ac- tivity and aldo~terone.~,' In contrast, side-to-side porto- caval anastomosis appeared to simply reduce the sinu- soidal portal hypertension. Recently, the peripheral arterial vasodilatation hypothesis28,28a seemed to best explain the mechanism of sodium retention in cirrho- sis. It proposes that in cirrhosis, there is a pathological state of arterial vasodilatation that, in the splanchnic circulation, occurs partly as a result of sinusoidal portal hypertension. Many putative vasodilator substances including nitric oxide, glucagon, prostaglandins, y - amino-butyric acid, substance P, vasoactive intestinal peptide, and bile acids have been proposed as candi- dates for causing splanchnic h~peremia.~' This results in effective arterial underfilling with consequent acti- vation of various neurohumoral factors to promote re- nal sodium and water retention. Systemic arterial va- sodilatation also leads to the hyperdynamic circulation so commonly observed, especially in decompensated cirrh~sis.~' However, more recent data from patients with preascites and early ascites do not conform to this hypothesis. Compensated sodium retention leading to volume expansion has been clearly documented in met- abolically controlled diet studies in preascitic cirrhosis before there is any evidence of systemic vasodilatation or effective arterial ~ n d e r f i l l i n g . ~ ~ , ~ ~ Further evidence supporting such studies include the increase in cardiac output and hyperdynamic circulation induced by pos- t ~ r e , ~ ~ increased central blood volume,33 glomerular hyperf i l t ra t i~n,~~ increased atrial and ventricular

358

HEPATOLOGY Vol. 22, No. 1, 1995 WONG AND BLENDIS 359

Atrial natriuretic factor \

Norepinephrine (SNS) /

/ Renin c \/ ~, Angiotinsin II Aldosterone

)- Renal sodium

water retention Prostaglandins

\ /\ Arginine vasopressin

FIG. 1. Effector mechanisms of renal sodium retention in cirrho- sis. Natriuretic versus antinatriuretic factors.

sizes,35236 increased levels of plasma atrial natriuretic f a c t ~ r , ~ ~ , ~ and the normal or suppressed levels of plasma renin activity and serum ald~sterone.~-~ All suggest an abnormal renal sodium retention leading to volume expansion before arterial underfilling second- ary to systemic vasodilatation.

An alternative explanation is the hepatorenal hy- pothesis, that is, a hepatorenal interaction that, in the presence of a filled effective arterial blood volume, is responsible for the initial renal sodium retenti~n.~ An- imal studies have confirmed the presence of this hepa- torenal i n t e r a c t i ~ n . ~ ~ ? ~ ~ Experimental data in animals and in humans have lent support to the hypothesis that either sinusoidal portal hypertension45246 and/or hepatic dysf~nct ion~~.~ play a role in the affector arm of this hepatorenal interaction, leading to renal sodium retention in cirrhosis. Indeed, a significant inverse re- lationship between the indices of portal pressure and sodium excretion has been found,50 that is, sodium re- tention worsens as portal pressure increases. Further- more, we5 and others51 have shown that in patients with cirrhosis, there is a critical level of sinusoidal por- tal hypertension of 8 mm Hg, below which ascites does not occur. As the cirrhotic process progresses, splanch- nic and peripheral vasodilatation increases and con- tributes to, and may perpetuate, the renal sodium retention as described by the peripheral arterial vaso- dilatation hypothesis.

Whatever the pathogenetic affector process in initiat- ing the renal sodium and water retention in cirrhosis, the efferent mechanisms involved in effecting or pre- venting sodium retention are multifactorial (Fig. 1). The predominance of either natriuretic or antinatri- uretic factors will ultimately decide if the patient will remain in compensated sodium balance or decompen- sated sodium retention.

The antinatriuretic, antidiuretic factors include an activated sympathetic nervous system, increased re- nin-angiotensin-aldosterone levels, as well as elevated arginine vasopressin concentrations. Chronic sympa- thetic stimulation in cirrhosis is well documented. In preascitic cirrhotic patients on a high-sodium diet, so- dium retention observed is associated with a failure of

suppression of the plasma norepinephrine levels by the volume expansion.52 Using a direct microneurographic- recording technique, cirrhotic patients with ascites have been shown to have increased skeletal muscle sympathetic nervous activity, which is directly related to elevated plasma norepinephrine levels.53 Increased sympathetic nervous activity stimulates sodium reten- tion by causing renal vasoconstriction and hence acti- vation of the renin-angiotensin-aldosterone system, as well as exerting a direct effect on the proximal renal tubule to increase sodium reabsorption at that site. When activated, the renin-angiotension-aldosterone system alters renal hemodynamics, as well as increas- ing proximal and distal tubular reabsorption of sodium independent of renal hemodynamic changes. However, up to 13% of ascitic patients have or even decreased56 plasma renin activity and aldosterone lev- els. Furthermore, in a late follow-up study of ascitic cirrhotic patients who had undergone a successful peri- toneovenous shunt, there was persistent sodium reten- tion when challenged with 100 mmol sodium diet de- spite normal plasma renin activity, aldosterone levels, and catecholamine levels. This suggests that both the renin-angiotensin-aldosterone and the systemic sym- pathetic nervous systems, although important in the pathogenesis of sodium retention, are not the sole fac- tors responsible for the abnormality.

More recently, endothelins, a family of potent vaso- constrictors produced by the endothelium, have also been implicated in the renal hemodynamic changes of ascitic patients.57 Their release is stimulated by epi- nephrine and a n g i ~ t e n s i n ~ ~ , ~ ~ and they in turn increase the release of the same pressor factors. This observa- tion, coupled with the fact that the renal circulation is hypersensitive to the vasoconstrictive effect of endo- thelins,60 suggests that they may also be involved in the sodium retention of these patients. Indeed, plasma levels of endothelins have been reported to be elevated in cirrhotic patients with a ~ c i t e s . ~ . ~ ~ After TIPS, endo- thelin levels decreased in ascitic patients 0nly57,64 and this was associated with improved renal hemodynam- ics in these patients. However, endothelin I acts in a paracrine fashion and therefore circulating levels may not reflect the true ~ i t u a t i o n . ~ ~

Therefore, the recent reports in HEPATOLOGY by Somberg et alZ5 and Quiroga et alZ7 showing that TIPS resulted in both a reduction in the sinusoidal portal hypertension and improvement in renal sodium excre- tion are of great interest. Although the overall results of the two studies were similar, those of Quiroga et alZ7 must be interpreted with caution. Many of the 17 patients in that study were lost to follow-up because of early death or liver transplantation. Removal of these most severely affected patients after TIPS from analy- ses will inevitably lead to an apparent improvement in all parameters, i.e., diuretic doses, liver function tests, Child-Pugh score, and so on. Interpretation of their data is also made difficult because their patients were studied while on different doses of diuretics, and

HEPATOLOGY July 1995 360 WONG AND BLENDIS

their early deaths were either excluded (first death) from all analyses or included for analyses at different time periods (the other early deaths from 1 to 3 months). Somberg et alZ5 reported that 5 patients con- tinuing on diuretics after TIPS increased their urinary sodium excretion 14 days after TIPS (13.0 2 4.3 mmoV d u 2.1 ? 0.6 mmoVd before TIPS) while consuming 44 mmol sodium per day, i.e., they remained in positive sodium balance. At 1 month, we have shown that with- out diuretics, renal sodium excretion continues to im- prove and that it reaches 15.1 ? 3.1 mmoVd on a 22 mmol sodium per day diet.26 This improved sodium ex- cretion is associated with a reduction in antinatriuretic factors, namely plasma renin activity and aldosterone levels.25F27 However, the natriuresis associated with TIPS may be delayed for 1 month or more, despite a reduction of sinusoidal portal pressure and normaliza- tion of the renin-angiotensin-aldosterone system. One possible explanation is that the hyperdynamic circula- tion and systemic vasodilatation that we so often see in these patients is markedly exacerbated immediately after TIPS.25-27,6fi This may be caused by a sudden re- lease of vasodilators from the splanchnic into the sys- temic circulation. Substance P, a potent vasodilator produced by the enteric nervous system, has been shown to be increased in c i r r h ~ s i s . ~ ~ However, TIPS placement did not result in any further changes in plasma substance P levels,68 suggesting that it does not play a significant role in the pathogenesis of the hyperdynamic circulation of cirrhosis after TIPS. The relation of vasodilatation after TIPS to other putative vasodilator candidates must await further study. In our series, the marked exacerbation of the hyperdy- namic circulation immediately after TIPS was associ- ated with a further activation of the sympathetic ner- vous system as reflected by a further increase in plasma norepinephrine levels and a tendency for renal vascular resistance to increase and glomerular filtra- tion rate to decrease. In one patient in Sombergs series who failed to respond to TIPS, significant elevation of plasma renin activity and aldosterone levels persisted to day 14, and this was attributed to worsening of sys- temic vasodilatation. In fact, natriuresis occurred de- spite systemic vascular resistance decreasing further a t 1 In our series, the natriuresis was asso- ciated with a return of the markedly increased plasma norepinephrine to the previous baseline levels, to- gether with normalization of plasma renin activity and aldosterone concentration^.^^ Quiroga et alZ7 also showed either a decrease or unchanged plasma norepi- nephrine levels at 1 month. This natriuresis was most likely not caused by improvement in renal hemody- namics as neither renal plasma flow nor glomerular filtration rate changed s i g n i f i ~ a n t l y . ~ ~ , ~ ~ , ~ However, Quiroga et a1 observed a significant increase in glomer- ular filtration rate as measured by creatinine clearance at 1 month only.26 Different methodologies for measur- ing glomerular filtration rate and the fact that diuretics of various doses were administered to their patients at

the times of their studies could have accounted for the differences in the results. In their cohort of patients, urinary sodium excretion continued to improve despite no significant increase in glomerular filtration rate at 3 months.26

Another possible explanation for the delayed natri- uresis is the deterioration of hepatic function immedi- ately after TIPS. Somberg et alZ5 did not report changes in liver function in the early period after TIPS. In our experience, the Pugh score remained increased or dete- riorated further after TIPS, partly because of rising serum bilirubin levels.26 Seven out of 17 patients (41%) in the series by Quiroga et a1 either died or underwent liver transplantation within the first 3 months after TIPS.27 Although they did not report the reason for liver transplantation, the cause of death was liver fail- ure, once again confirming deterioration of liver func- tion after TIPS. The corollary from this observation is that patients with severe pre-existing liver dysfunction should not undergo TIPS placement. Inappropriate pa- tient selection could have accounted for the high death and transplantation rates in the series by Quiroga et al.27 The hyperbilirubinemia after TIPS may have been caused by intravascular hemolysis secondary to me- chanical damage to erythrocytes, related to turbulent flow in the metallic nonendothelialized tent.^'-^' When followed with weekly indocyanine-green clearance studies, a measurement of hepatic function, these pa- tients showed an initial increased indocyanine-green retention immediately after TIPS, and this remained unchanged for the next 4 weeks (personal unpublished data, 1995). Early responders to TIPS had better base- line indocyanine-green clearance and less-active liver disease as judged by their transaminase profile (per- sonal unpublished data, 1995). The initial worsening of hepatic function may be related to shunting of a percentage of portal blood directly into the hepatic vein away from hepatocytes. However, when followed for a longer period, hepatic function tends to stabilize and may even i m p r ~ v e . ~ ~ ~

The retrospective series of Somberg et alZ5 shows that patients with refractory ascites treated with TIPS over- all fare reasonably well, with a 74% response. Because in some patients the natriuretic response is greatly delayed to beyond 1 month, their response rate may improve further if they had extended their definition of failure to beyond 1 month. There was only one death in their cohort of 24 patients. This was not the experi- ence of Quiroga et aIz7 who only had 6 of 17 patients (35%) surviving beyond 1 year without undergoing liver transplantation. Likewise, those patients in the study of Lebrec et a16 had a mean 1 year survival rate of only 17 t 15%. In this latter study, TIPS was not effective in improving ascites in any of the Pugh-Child class C patients, although the experience of others suggests that ascites in these patients does respond to the inser- tion of TIPS.25 Once again, patient selection could have accounted for their dismal results. It is certainly our experience and that of others73 that patients with se-

HEPATOLOGY Vol. 22, No. 1, 1995 WONG AND BLENDIS 361

verely decompensated disease do not fare as well, espe- cially those with severe hyperbilirubinemia (> 100 pmoVL) before TIPS. We are not informed of the patient characteristics in this study. The low survival rate sug- gests that their Childs B patients were dying from causes other than severe liver disease. One can only speculate that technical problems related to the inser- tion of TIPS could have contributed to their high death rate, because TIPS insertion was not successful in 3 of the 13 patients in the TIPS arm. Somberg et alZ5 have identified renal dysfunction before TIPS as a common denominator in the nonre~ponders ,~~ and our experi- ence is similar irrespective of whether the renal dys- function is caused by parenchymal disease25 or func- tional impairment (personal unpublished data, 1994). The question of pre-existing renal dysfunction was not addressed by Quiroga et a127 or Lebrec et al.69 This is not surprising, because there is marked exacerbation of sympathetic hyperactivity immediately after TIPS insertion.21 The resultant renal vasoconstriction, cou- pled with the exquisite renal sensitivity of these pa- tients to radiographic dye used during the procedure, could be detrimental in patients with pre-existing renal dysfunction. In contrast, there are anecdotal reports of TIPS improving renal function in patients with renal ins~fficiency~~ and even hepatorenal ~ y n d r o m e . ~ ~ , ~ ~ Nevertheless, the consensus opinion in the literature at the time of writing is that patients with renal dys- function tend to respond less well. At the present time, in our institution, serum creatinine 2250 pmol/L is a contraindication for TIPS insertion. The role of TIPS in the treatment for hepatorenal syndrome still awaits further study.

The further selection criteria of Somberg et a125 could also have contributed to their overall better response and survival rates. The presence of chronic hepatic en- cephalopathy before TIPS significantly predicts more severe encephalopathy after TIPS76 and, therefore, should be regarded as a contraindication. A throm- bosed portal vein technically precludes the procedure and therefore excludes the patients as a candidate for TIPS. Another absolute contraindication to TIPS inser- tion is the presence of ongoing sepsis, because infection of the TIPS, being a foreign body, will be very difficult to eradicate. Our institution recommends clearance of dental sepsis and treating spontaneous bacterial peri- tonitis before considering the patient for TIPS inser- tion. The influence of the etiology of cirrhosis on out- come has not been formally assessed, although our personal experience indicates that alcoholic cirrhotic patients tend to do better. Within a particular etiology group, those patients with inactive disease, as judged by normal transaminase levels, also tend to respond more favorably with their ascites improving much more quickly. Patients with pre-existing cardiopulmonary disease should not undergo TIPS insertion, because the sudden increase in cardiac output26266 after TIPS may precipitate pulmonary edema. Finally, noncompliance with sodium restriction after TIPS is a common cause

TABLE 1. Patient Selection for TIPS Procedure

Absolute contraindications Hepatic encephalopathy Cardiac or pulmonary disease Renal failure (creatinine >250 pmoVL) Liver failure (serum bilirubin > 100 pmol/L) Ongoing sepsis Portal vein thrombosis

Relative contraindications Noncompliance with sodium and fluid restriction Hepatoma or other terminal cancers

of a failed response. Our study26 showed that increased sodium excretion is neither immediate nor completely normalized at 1 month. Therefore, continued sodium and fluid restriction are mandatory after TIPS, because patients consuming a no-added-salt diet containing an average of 100 mmol of sodiudday will continue to be in positive sodium balance and gain weight. This is well-illustrated in the study of Quiroga et al.27 Despite their patients excreting 78 +- 12 mmol sodiudday at 1 month, 7 of 17 patients still had moderate or tense ascites, suggesting that they might be noncompliant with their prescribed sodium restriction of 44 mmol/ day. Therefore, we recommend the selection criteria as set out in Table 1.

Because TIPS is gaining acceptance as a treatment for recurrent variceal bleeding and refractory ascites, there is now a wave of enthusiasm for the procedure. Yet there are still many unresolved questions. Have we learned more about the pathophysiology of ascites formation from this procedure? How has TIPS im- pacted on our practice of hepatology? Is it a better treat- ment option for refractory ascites than conventional treatment, such as repeated paracentesis or perito- neovenous shunting? Will TIPS in any way influence patient selection and recruitment for liver transplant programs? Finally, what is the cost effectiveness of the procedure compared with other therapies?

One cannot attempt to answer all these questions in an Editorial. However, our experience with TIPS has helped to clarify our understanding of the pathophysi- ology of ascites formation. Systemic arterial vasodilata- tion is not solely responsible for renal sodium retention in cirrhosis, because natriuresis occurs in the presence of further systemic arterial v a ~ o d i l a t a t i o n . ~ ~ , ~ ~ , ~ ~ Con- versely, one could argue that systemic arterial vasodi- latation could have contributed to sodium retention and that the natriuresis after TIPS would have been greater and occurred earlier had it not been for the systemic arterial vasodilatation. This issue will be set- tled, because renal sodium handling continues to im- prove in the responders. Will they continue to show significant systemic arterial vasodilatation? Sinusoidal portal hypertension is certainly an important factor in the pathogenesis of sodium retention. However, low- ering the pressure even below the critical levels associ- ated with sodium retention does not result in an imme-

362 WONG AND BLENDIS HEPATOLOGY July 1995

diate significant natriuresis. It appears that hepatic dysfunction does play a permissive role in effecting a natriuresis. Even a reduction in all antinatriuretic forces has not been shown as yet to result in normaliza- tion of sodium excretion.

The question of whether TIPS is more therapeuti- cally effective and cost-effective than repeated large- volume paracentesis or peritoneovenous shunting in eliminating refractory ascites still needs to be an- swered by randomized controlled trials. Certainly, the studies so far tell us that TIPS is not a panacea for every patient with refractory a ~ c i t e s . ~ ~ , ~ ~ Careful pa- tient selection will make TIPS a more cost-effective procedure. In the long term, TIPS should have an im- pact on liver transplantation. Patients improve both physically and psychologically as they lose their asci- tes. The risk of developing spontaneous bacterial peri- tonitis may be reduced. The quality of life of many of the decompensated cirrhotic patients appears to im- prove, and, therefore, liver transplantation may be de- layed or indefinitely postponed. Alternatively, TIPS can be used as a bridging procedure for patients who would otherwise have died while waiting for a new liver. However, this is not to suggest that TIPS should be inserted in all patients who are dying from liver failure, because TIPS does not seem to salvage every dying liver ~a t ien t . '~ ,~ ' What remains is for us to fur- ther refine our understanding of the mechanisms by which TIPS improves ascites, so to better select the patients who would most benefit from the procedure.

FLORENCE WONG, MD, FRACP LAURENCE BLENDIS, MD, FRCP(C) Department of Medicine Toronto Hospital Toronto, Canada

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