The transjugular intrahepatic portosystemic stent shunt procedure for refractory ascites

HEPATOLOGY Elsewhere 1613

HEPATOLOGYVol. 22, No. 5, 1995 pothesis proves valid, description of the gene product will provide new insight into the physiology and pathophysiology of bile secretion from hepatocytes, and allow precise case definition for natural history studies and therapeutic trials. JOSEPH WAGSTAFF, MD, PhD

Division of Genetics MAUREEN M. JONAS, MD

Center for Childhood Liver Disease Division of Gastroenterology Children's Hospital Boston, MA REFERENCES 1. D'Agata IDA, Jonas MM. Shedding light into the black box of childhoodcholestaticliver disease. HEPATOLOGY1995;21:257-260. 2. Brenard R, Geubel AP, BenhamouJP. Benign recurrent intrahepatic cholestasis. A report of 26 cases. J Clin Gastroenterol 1989; 11:546-551. 3. GoldbergDM, Hendry EB. Familial form of benign idiopathic recurrent cholestasis. Arch Intern Med 1967;120:556-564. 4. Clayton RJ, Iber FL, Ruebner BH, McKusickVA. Byler disease: fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112-124.

TRANSJUG~

INTRAHEPATIC

PORTOSYSTEMIC SHUNT: IS IT THE ULTIMATE

SOLUTION FOR REFRACTORY ASCITES?

Ochs A, Rossle M, Haag K, Hauenstein K-H, Deibert P, Siegerstetter V, Hounker M, et al. The transjugular intrahepatic portosystemic stent shunt procedure for refractory ascites. N Engl J Med 1995;332:1192-1197. ABSTRACT Background. P r e v i o u s studies h a v e s u g g e s t e d that t h e trAnajugular p l a c e m e n t o f an i n t r a h e p a t i c stent to establish a p o r t o s y s t e m i c s h u n t is an effective t r e a t m e n t o f u n c o m p l i c a t e d ascites a c c o m p a n y i n g variceal bleeding. We s t u d i e d t h e s t e n t s h u n t for u s e in patients w i t h liver cirrhosis a n d ascites refractory to m e d i c a l treatment. Methods. Fifty o f 62 c o n s e c u t i v e patients w i t h cirrhosis a n d refractory ascites w e r e t r e a t e d w i t h t h e stent s h u n t - - a n e x p a n d a b l e stent o f metallic m e s h placed bet w e e n a m a j o r b r a n c h o f t h e portal v e i n a n d o n e o f the h e p a t i c veins. P a t i e n t s w e r e f o l l o w e d for a m e a n (±SD) o f 426 +_ 333 days. Results. The stent s h u n t w a s s u c c e s s f u l l y placed in all patients a n d r e d u c e d the p r e s s u r e gradient b e t w e e n t h e portal v e i n a n d t h e inferior v e n a c a v a by an a v e r a g e of 63 percent. Thirty-seven patients (74 percent) h a d complete r e s p o n s e s (total r e m i s s i o n o f ascites w i t h i n t h r e e m o n t h s ) , a n d n i n e patients (18 percent) h a d partial responses. F o u r p a t i e n t s did n o t respond, i n c l u d i n g t w o w h o died w i t h i n t w o w e e k s o f s h u n t p l a c e m e n t . After the procedure, 25 p a t i e n t s h a d h e p a t i c e n c e p h a l o p a t h y , as c o m p a r e d w i t h 20 p a t i e n t s before the procedure; alt h o u g h e n c e p h a l o p a t h y i m p r o v e d in 3 patients, n e w enc e p h a l o p a t h y d e v e l o p e d in 8 patients. In t h e 28 o f t h e 33 p a t i e n t s f o l l o w e d for m o r e t h a n six m o n t h s w h o w e r e

evaluated, the m e a n s e r u m c r e a t i n i n e c o n c e n t r a t i o n w a s 1.5 ± 0.09 m g per deciliter (133 ± 8 / ~ m o l per liter) before p l a c e m e n t o f t h e stent shunt, 1.5 ± 1.6 m g per deciliter (133 ± 141 p m o l per liter) o n e w e e k after t h e p r o c e d u r e , a n d 0.9 ± 0~3 m g p e r deciliter (80 _+ 2 7 / ~ m o l per liter) after six m o n t h s (P = 0.008 for t h e c o m p a r i s o n of c o n c e n t r a t i o n s before a n d six m o n t h s after t h e procedure). R e n a l f u n c t i o n did n o t i m p r o v e in the six patients w i t h organic k i d n e y disease. P r o c e d u r e - r e l a t e d complications d e v e l o p e d in 16 patients. D u r i n g follow-up, an a d d i t i o n a l 29 patients d i e d - - 1 0 o f p r o g r e s s i v e liver dise a s e a n d 19 o f o t h e r causes. Survival for at least o n e y e a r w a s a s s o c i a t e d w i t h a patient's b e i n g u n d e r 60 y e a r s o f age, h a v i n g a s e r u m bilirubin level before p l a c e m e n t o f t h e stent s h u n t of less t h a n 1.3 m g per deciliter (22 p m o l per liter), a n d h a v i n g a c o m p l e t e r e s p o n s e . Conclusions. Our findings in an u n c o n t r o l l e d prospective s t u d y suggest that the transjugtdar i n t r a h e p a t i c p o r t o - s y s t e m i c s t e n t - s h u n t p r o c e d u r e w a s a n effective t r e a t m e n t for m a n y patients w i t h liver cirrhosis a n d refractory ascites, but mortality f r o m u n d e r l y i n g d i s e a s e s w a s substantial. (N Engl J Med 1995;332:1192-7. Copyright 1995. M a s s a c h u s e t t s Medical Society. All rights reserved.)

COMMENTS Refractory ascites or diuretic resistant ascites is a complication of cirrhosis t h a t is associated with a significantly decreased survival. 1-3 It usually heralds the onset of progressive liver failure and predisposes the patients to the development of spontaneous bacterial peritonitis and hepatorenal syndrome, both of which have high mortality rates. 4 Therefore, recent efforts have concentrated on finding an effective t r e a t m e n t for refractory ascites. Repeated large-volume paracentesis 5 is demanding for both the physician and the patient. The alternative is the insertion of a peritoneovenous shunt, which is associated with a high incidence of shunt failure. 6 The advent of a transjugular intrahepatic portosystemic shunt (TIPS) to reduce portal pressure has added a possible new t r e a t m e n t option for these patients. TIPS is effectively a side-to-side portocaval shunt. Its attractiveness lies in the fact t h a t it is a less invasive method of achieving portal decompression t h a n a surgically created portosystemic shunt without the a t t e n d a n t high morbidity and mortality. 7,s The rationale for using TIPS as a t r e a t m e n t for refractory ascites comes from reports documenting sinusoidal portal hypertension to be associated with sodium retention in both an animal model 9 and in patients with cirrhosis. 1° Indeed, reports of uncontrolled studies documenting the efficacy of TIPS in the t r e a t m e n t of refractory ascites are now appearing. 1~-1t In the series of 50 patients studied by Ochs et al, ~4 we learn t h a t TIPS is effective in eliminating ascites in 74% of patients at 3 months, but the trade-off was a high mortality rate of 28% for the same period of time. At least 3 of those deaths occurred in patients who had completely eliminated their ascites. Similar dismal results have been reported by Quiroga et al with a 3-month mortality rate of 41% (13), and by Lebrec et

1614

HEPATOLOGY Elsewhere

al whose patients had a 1-year survival rate of only 17%. 1~ However, there are other reports suggesting that the outcome after TIPS is not uniformly disappointing in all patients with liver disease. ~1'12 In fact, in the retrospective series reported by Somberg et al, n only 1 of 24 patients died during a mean follow-up of 282 days. In our personal series of both reported 12 and unreported cases, only 2 of 15 patients followed up for a mean period of 11.2 months died at more than 6 months post-TIPS. Why is there such a discrepancy in the mortality rates between the various series? On analyzing the details of the study by Ochs et al, 14 it becomes apparent that many of the patients were severely ill at the time of their enrollment into the study. All patients studied had one or more liver-related complications or severe accompanying disease. Seven patients had infected ascites, whereas 10 others had active infection in the form of either cutaneous fistula or macerated hernia at the time of TIPS insertion. Renal impairment, whether functional or organic, was present in at least half of the study patients. Other significant illnesses included hepatic encephalopathy, heart failure, and neoplastic diseases. Could the presence of significant serious illnesses have contributed to the high mortality rate in these patients after TIPS? On the evidence provided by the available literature, this seems to be the likely explanation. Although there is no study to date assessing the presence of infection on the outcome after TIPS, one can envisage that ongoing sepsis would add to the morbidity and mortality of these patients. An analogy can be drawn from cardiac patients who have infected artificial heart valves, their mortality rate approaches 48%.16 Presence of active infection at the time of insertion of a foreign body such as TIPS will predispose to its infection. Therefore, it would seem prudent to delay TIPS insertion until active infection has been successfully treated. TIPS infection will be very difficult to eradicate, especially in cirrhotic patients with compromised immune function. 17 Renal dysfunction has been identified as an indicator of nonresponsiveness to the natriuretic effect of TIPS. 11'14 The significantly increased systemic arterial vasodilatation immediately after TIPS 12'1sresults in a marked exacerbation of sympathetic hyperactivity.12 The resultant increased renal vasoconstriction, coupled with the exquisite renal sensitivity of these patients to radiographic dye used during the procedure, could be detrimental to patients with pre-existing renal dysfunction. There are anecdotal reports of TIPS improving renal function in patients with renal insufficiency19 and even hepatorenal syndrome.2° However, until further data appear that support the beneficial use of TIPS in patients with pre-existing renal dysfunction, one should still exercise caution in including such patients for TIPS insertion. As Ochs et al clearly demonstrated, those patients who survived less than 6 months after TIPS insertion had lower baseline creatinine clearance than those who lived beyond 6 months. 14 What other factors could have contributed to the high

HEPATOLOGYNovember 1995

mortality rate of the patients of Ochs et al? Ten of the twenty-nine patients who died during follow-up died of liver failure 1 to 9 months after TIPS insertion. This was also the experience of Quiroga et al la with 7 of 17 study patients (41%) dying or requiring liver transplantation within the first 3 months post-TIPS because of progressive liver failure. Hepatic function tends to worsen initially after TIPS insertion as judged using the Pugh score. 12 This may be related to shunting of portal blood directly into the hepatic vein away from hepatocytes. One could argue that the Pugh score is artificially elevated immediately post-TIPS because of hyperbilirubinemia, which may largely be the result of shunt hemolysis.21'22 However, indocyanine green clearance, a measure of global hepatic function, has been shown to decrease immediately post-TIPS and this decrease remains unchanged for the first month (Personal unpublished data, 1995). It is interesting to note that early responders to TIPS in our series had better baseline indocyanine green clearance and less active liver disease as judged by their serum transaminase profile (Personal unpublished data). It is also the experience of others 23 that patients with severely decompensated liver disease do not fare as well, especially those with severe pre-TIPS hyperbilirubinemia (>6 mg/dL). Ochs et al also identified a pre-TIPS bilirubin of > 1.3 mg/dL as being associated with a shortened survival post-TIPS. ~4 Therefore, patients who are bordering on liver failure pre-TIPS will likely develop liver failure post TIPS. No mention was made as to how many patients in Ochs' series underwent liver transplantation. In those patients who underwent transplantation, it begs the question as to whether TIPS was really necessary pretransplantation. If liver transplantation was not suitable for some of the patients, was it justifiable to subject them to a procedure when their prognosis was already unfavorable, especially in those with known neoplastic disease or end-stage heart failure? Furthermore, TIPS is known to challenge cardiac function and exacerbate the hyperdynamic circulation that exists in these patients.~S The sudden increase in cardiac output ~2'18'24 post-TIPS may precipitate pulmonary edema. Therefore, it is not surprising that 1 patient died of myocardial infarction immediately postTIPS and 5 more died of heart failure during followup.

If TIPS did not seem to improve the prognosis of the patients studied by Ochs et al, did it improve their quality of life? Hepatic encephalopathy was a problem in 20 patients pre-TIPS. Not only was the number of patients with encephalopathy increased post-TIPS, it was actually debilitating and resistant to medical treatment in 8 patients. The presence of chronic hepatic encephalopathy pre-TIPS significantly predicts more severe encephalopathy post-TIPS, 25 and presumably contributed to the subsequent death of all 8 patients. Finally, what have we learned from this series of patients who underwent TIPS for their refractory ascites. TIPS is not a panacea for every patient with refrac-

HEPATOLOGYVol. 22, No. 5, 1995

tory ascites. Inappropriate patient selection will result in a high mortality rate. As we go through the learning curve of using TIPS as a treatment for refractory ascites, we will become more experienced in selecting those patients better served by either liver transplantation or TIPS. In the mean time, further advances will come from randomized controlled trials comparing TIPS with abdominal paracentesis or other therapies. However, such trials must include cost-effectiveness studies because TIPS is a costly procedure. FLORENCE WONG, MD, F R A C P LAURENCE BLENDIS, MD, FRCP(C)

Department of Medicine The Toronto Hospital University of Toronto Toronto, Canada REFERENCES

1. Forns X, Gines A, Gines P, Arroyo V. Management of ascites and renal failure in cirrhosis. Semin Liver Dis 1994; 14:82-96. 2. Capone RR, Buhac I, Kohberger RC, Balint JA. Resistant ascites in alcoholic liver cirrhosis: course and prognosis. Dig Dis Sci 1978;23:867-871. 3. Salerno F, Borroni G, Moser P, Badalamenti S, Cassara L, Maggi A, Fusini M, et al. Survival and prognostic factors of cirrhotic patients with ascites" a study of 134 patients. Am J Gasteroenterol 1993;88:514-519. 4. Levy M. Hepatorenal syndrome. Kidney Int 1993;43:737-753. 5. Arroyo V, Gines P, Planas R. Treatment of ascites in cirrhosis. Diuretics, peritoneovenous shunt and large volume paraeentesis. Gastroenterol Clin North Am 1992;21"237-256. 6. Greig PD, Blendis LM, Langer B. The renal and hemodynamic effects of the peritoneovenous shunt. Long term effect. Gastroenterology 1981;80:119-125. 7. Orloff MJ. Surgical treatment of intractable aseites. Curr Probl Surg 1966;Ju1:28-51. 8. Franco D, Vons C, Traynor O, de Smadja C. Should portosystemic shunt be reconsidered in the treatment of intractable aseites in cirrhosis? Arch Surg 1988; 123:987-991. 9. Campbell V, Greig P, Cranford J, Langer B, Silverman M, Blendis L. A comparison of acute reversible pre and post-sinusoidal portal hypertension on salt and water retention in the dog. HEPATOLOGY 1982;2:54-58. 10. Morali G, Sniderman K, Deitel KM, Tobe S, Witt-Sullivan H, Simon M, Heathcote J, et al. Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites. J Hepatol 1992; 16:249-250. 11. Somberg KA, Lake JR, Tomlanovich SJ, LaBerge JM, Feldstein V, Bass NM. Transjugular intrahepatic portosystemic shunts for refractory ascites: assessment of clinical and hormonal response and renal function. HEPATOLOGY1995;21:709-716.

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12. Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Ann Intern Med 1995; 122:816-822. 13. Quiroga J, Sangro B, Nunez M, Bilbao I, Longo J, Garcia-Villarreal L, Zoyaya JM, et al. Transjugular intrahepatic portosystemic shunt in the treatment of refractory ascites: effect on clinical, renal, humoral and hemodynamic parameters. HEPATOLOGY 1995;21:986-994. 14. Ochs A, Rossle M, Haag K, Hauenstein K-H, Deibert P, Siegerstetter V, Hounker M, et al. The transjugular intrahepatic portosystemic stent shunt procedure for refractory ascites. N Engl J Med 1995;332:1192-1197. 15. Lebrec D, Giuily N, Hadengue A, Vilgrain V, Lassen C, Poynard T, and a group of clinicians. Transjugular intrahepatic portosystemic shunt (TIPS) versus paracentesis for refractory ascites. Results of a randomised trial [Abstract]. HEPATOLOGY1994;20 (Part 2):201A. 16. Gordon SM, Keys TF. Bloodstream infections in patients with implanted prosthetic cardiac valves. Semin Thorac Cardiovasc Surg 1995; 7:2-6. 17. Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infection and prognosis. HEPATOLOGY1984; 4:5358. 18. Azoulay D, Castaing D, Dennison A, Martino W, Eyraud D, Bismuth H. Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: preliminary report of a prospective study. HEPATOLOGY 1994;19: 129-132. 19. Lake JR, Ring E, LaBerge J, Gordon R, Roberts J, Archer N. Transjugular intrahepatic portosystemic stent shunts in patients with renal insufficiency. Transplant Proc 1993;25:17661767. 20. Ochs A, Rossle M, Haag K, Gerbes A, Morgenroth A, Deibert P, Hauenstein KH, et al. TIPS for hepatorenal syndrome [Abstract]. HEPATOLOGY 1994;20(Part 2):114A. 21. Cheng KM, Lameris JS, de Man RA, Pieterman H, van Buuren HR. Haemolysis and cholestasis following implantation of a transjugular intrahepatic portosystemic shunt. Eur J Gastro Hepatol 1994;6:749-751. 22. Tong L, Ferral H, Castenada W, Hunter D, Bloomer J, Rank J. Hemolysis following transjugular intrahepatic portosystemic shunt (TIPS) [Abstract]. Gastroenterology 1993;104(Part 2): A1009. 23. Benner KG, Sahaqun G, Saxon R, Barton RE, Keller F, Rabkin J, Reed M, et al. Selection of patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites [Abstract]. HEPATOLOGY1994;20(Part 2):114A. 24. Pidlich J, Lenz K, Wilding R, Radosavljevic M, Kramer L. Effect of transjugular intrahepatic portosystemic shunt (TIPSS) on central blood volume and hemodynamic changes in patients with therapy resistant ascites [Abstract]. HEPATOLOGY1994;20(Part 2):114A. 25. Sanyal AJ, Freeman AM, Shiffman ML, Purdum PP, Luketic VA, Cheatham AI~ Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. HEPATOLOGY1994;20:46-55.