Current Use of Transjugular Intrahepatic Portosystemic Shunts

Current Use of Transjugular Intrahepatic Portosystemic Shunts Timothy M. McCashland, MD Address Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, PO Box 983285, Omaha, NE 68198-3285, USA. E-mail: tmccash@surgery.unmc.edu Current Gastroenterology Reports 2003, 5:31 38 Current Science Inc. ISSN 1522-8037 Copyright 2003 by Current Science Inc. The principal indication for transjugular intrahepatic portosystemic shunts (TIPS) continues to be rescue therapy for variceal hemorrhage that cannot be controlled by endoscopic or medical therapy. TIPS provide no survival advantage in prevention of rebleeding or refractory ascites. The indications for TIPS continue to expand, however, especially for Budd- Chiari syndrome and hydrothorax. Other more novel indications include bleeding portal hypertensive gastropathy or ectopic varices, Budd-Chiari syndrome, veno-occlusive disease, hepatorenal syndrome, hepatopulmonary syndrome, hepatocellular carcinoma, and polycystic liver disease. Great strides have been made recently in models to predict mortality and complications following TIPS placement. Graft stents hold promise based on early studies. Finally, complications are common and may be life threatening. Introduction The use of transjugular intrahepatic portosystemic shunts (TIPS) was reviewed in 1995 by Sanyal and Shiffman [1] and in 2000 by Sanyal [2 ]. A recent literature search on the terms transjugular intrahepatic portosystemic shunt revealed 320 associations in PubMed over the past 2 years. Thus, the use of TIPS continues to evolve as a therapeutic side-to-side shunt for portal hypertension in community and academic medical centers. Several complete reviews on this topic have also been published [3,4 6]. Interestingly, less than 30 randomized, controlled trials that objectively evaluate the use of TIPS have been published. However, major advances in TIPS research regarding ascites, bleeding, and models to predict post-tips survival are now documented. Further expansion of techniques, indications, and complications continues to be reported at a rapid pace. Indications The main indications for TIPS remain treatment of persistent variceal bleeding, refractory ascites, and hepatic hydrothorax. Many new published reports have expanded the indications for TIPS (Table 1). Variceal bleeding Variceal hemorrhage is the most dramatic complication of portal hypertension, occurring in up to 35% of patients with cirrhosis and accounting for up to 90% of all bleeding events in these patients [7,8]. Predictors of hemorrhage include persistent use of alcohol, poor liver function, large varices, endoscopic red signs, and high hepatic venous pressure gradient [7,9]. Therapy with beta-blockers is the standard prophylaxis for bleeding [10,11]. Once acute bleeding commences, endoscopic ligation of the esophageal varices, in combination with medications that reduce splanchnic blood flow, is successful in up to 90% of patients [12,13]. Most clinicians repeat endoscopic therapy if bleeding persists; however, proper timing and use of TIPS before multiorgan failure ensues is imperative. TIPS remain the standard treatment for variceal bleeding that is resistant to drug or endoscopic therapy [14,15]. Surgical shunts still have a role for patients with Child A cirrhosis and refractory bleeding. Excellent outcomes are reported from skilled centers [16,17]. Mortality following an episode of variceal hemorrhage without treatment is up to 70% at 1 year. A large factor contributing to mortality is the risk in up to 70% of rebleeding within 1 year [18]. Fourteen randomized, controlled studies and two meta-analyses comparing TIPS with endoscopic and medical therapy for variceal rebleeding have been reported. (Table 2) [19 34]. These studies differ in design, patient population, timing of randomization, endoscopic therapy (sclerotherapy or band ligation), medication (beta-blocker, nitrates, or both) and endpoints. Despite these differences, a common theme is noted. TIPS patients have an overall lower rebleeding rate compared with those receiving endoscopic and medical treatment. However, survival rates up to 2 years are similar. TIPs patients generally have more encephalopathy. As pointed out in a recent editorial, the trade-off in using TIPS to prevent rebleeding, compared with endoscopic therapy, is a reduction of two rebleeding episodes but an increase in one serious episode of encephalopathy for every eight TIPS placed, with no gain in survival [35]. The most recent study, by Escorsell et al. [32], further identified that the cost of therapy was double in the TIPS patients compared with the endoscopic and medical patients, in contrast to an ear-

32 Liver Table 1. Indications for TIPS Main indications Acute or recurrent variceal hemorrhage Refractory ascites Hepatic hydrothorax Expanding indications Bleeding portal hypertensive gastropathy or ectopic varices Budd-Chiari syndrome Veno-occlusive disease Hepatorenal syndrome Hepatopulmonary syndrome Hepatocellular carcinoma or polycystic liver disease lier study. Additionally, quality of life was no different regardless of type of treatment. These data indicate that TIPS should not be used as a first-line treatment but only as a rescue for medical treatment failures. Lastly, data conflict regarding patients with gastric varices [36]. A new study from the UK reports equal response for rebleeding with esophageal or gastric varices [37]. The portal pressure gradient (PPG) was similar in patients with gastric or esophageal variceal bleeding. Furthermore, mortality was better in the gastric variceal group, with PPG greater than 12 mm Hg. Clinicians should aim for a PPG of less than 7 mm Hg in patients who bleed at a PPG greater than 12 mm Hg. Refractory ascites Refractory ascites usually develops in end-stage liver disease with the only definitive treatment being liver transplantation. Luckily, only about 10% of patients with cirrhosis progress to refractory ascites. The role of TIPS for this complication of cirrhosis has been noted for many years, yet most publications are single-center case reports or series. Only three randomized, controlled studies have compared TIPS with large-volume paracentesis [38,39,40 ]. The first, from France, reported that TIPS was more effective in controlling ascites in Child B patients, but survival was lower compared with that of the paracentesis group, especially in Child C patients (0%). However, this study was very small, with only 13 patients assigned to TIPS and 12 to paracentesis. Rossle et al. [39 ] studied 60 patients (29 TIPS, 31 paracentesis) for a mean follow-up of 45 months. Control of ascites was achieved in 84% of TIPS patients and in 43% in the paracentesis group. Transplantfree 1-year and 2-year survival rates were 69% and 58% in the TIPS group, compared with 52% and 32% in the paracentesis group (not statistically significant). Two editorials commenting on these studies emphasize the selective nature of the patients chosen (Child score of 9, mean bilirubin of 1.8 mg/dl, and serum albumin of 3.5 g/dl) [41,42]. Consequently, these results should only be applied to similar patients. Results of the North American Study of Treatment for Refractory Ascites (NASTA) were reported in abstract this year. One hundred and nine patients (52 TIPS vs 57 paracentesis) were studied. Groups were comparable with respect to age, gender, ethnicity, cause of liver disease, ascites volume removed in previous 2 months, portosystemic hepatic encephalopathy index, liver function, Child-Pugh scores (9.2 vs 9.3), and renal function. Again, patients were excluded for bilirubin greater than 5.0 mg/ dl, prothrombin time greater than 20 seconds, creatinine greater than 1.5 mg/dl, active encephalopathy, and alcoholic hepatitis. TIPS placement was technically feasible in 49 of 52 patients. TIPS placement was superior to paracentesis in preventing recurrent ascites requiring repeat paracentesis (hazard rate=4, P<0.001). There were no significant differences in the two groups with respect to overall or transplant-free survival. In addition, no significant differences were noted in frequency of hospitalization or quality of life. Thus, in selected patients, TIPS offer better control of ascites but no survival advantage. The advantage of TIPS in this patient population may be improvement of nutritional status and reduction in the probability of spontaneous bacterial peritonitis [43]. Hepatic hydrothorax Hepatic hydrothorax occurs in up to 12% of patients with cirrhosis, caused by small defects in the diaphragm that allow ascites to track into the pleural space [44]. Most patients described in prior reports with hepatic hydrothorax have associated ascites, but some present only with pleural effusion [44]. The therapeutic value of TIPS in cirrhotic patients with hydrothorax has been reported in four series [45,46,47,48]. Siegerstetter et al. [47 ] report response to TIPS in 40 patients, noting that 84% had early (3 months) response (55% complete resolution) and 82% had late (1 year) response. Six of 40 patients were nonresponders to TIPS, of which four died rapidly (<30 days). The most recent case series reports that 64% of patients had complete resolution of respiratory symptoms, 10% had partial resolution, and 26% had no resolution [48]. In this study, only 30% had complete resolution of the effusion, whereas 50% had partial resolution, and 20% had either no change or worsening of effusion. Prior studies indicate that such alternative treatments as pleurodesis, peritoneovenous, or portosystemic shunts are unpredictable, requiring multiple attempts with eventual failure. No randomized trials have compared TIPS with these alternative treatments. Expanding indications Bleeding portal hypertensive gastropathy or ectopic varices Limited data are available on portal hypertensive gastropathy (PHG) and TIPS use [49]. Kamath et al. [50 ] have expanded our understanding of the pathogenesis and treatment of PHG and gastric vascular ectasia (GVE) in their study of 54 patients with gastric varices and mild PHG (n=30), severe PHG (n=10), and GVE (n=14). Endoscopic resolution and reduction in transfusions were noted in

Current Use of Transjugular Intrahepatic Portosystemic Shunts McCashland 33 Table 2. Randomized, controlled trials for rebleeding of TIPS versus endoscopic therapy Study Type of endoscopic treatment (ET) Patients (TIPS/ET), n Rebleed (TIPS/ET), % Death (TIPS/ ET), % GEAIH [19] Sclero 65 (32/33) 41/61 50/43 Cabrera et al. [20] Sclero 63 (31/32) 23/50 19/16 Rossle et al. [21] Sclero + propranolol 126 (61/65) 15/45 12/12 Sanyal et al. [22] Sclero 80 (41/39) 22/21 29/18 Cello et al. [23] Sclero 49 (24/25) 12/48 33/32 Sauer et al. [24] Sclero + propranolol 83 (42/41) 14/51 29/27 Jalan et al. [25] Ligation 58 (38/43) 10/55 42/37 Merli et al. [26] Sclero 81 (38/43) 18/40 24/19 Sauer et al. [27] Ligation 85 (43/42) 16/43 26/29 Garcia-Villareal et al. [28] Sclero 46 (22/24) 9/50 14/33 Pomier-Layrargues et al. [29] Ligation 80 (41/39) 20/56 42/42 Narahara et al. [30] Sclero 78 (38/40) 18/32 29/18 Gulberg et al. [31] Ligation 54 (25/27) 25/27 14/15 Escorsell et al. [32] Propranolol + 91 (47/44) 13/39 28/28 ISMN + ligation Overall Sclero (9), ligation (5) 1039 (37/38) 18/44 28/26 GEAIH Groupe d'etude des Anastomoses Intra-Hepatiques; ISMN isosorbide-s-mononitrate; sclero sclerotherapy. 89% of their patients, 71% had mild and severe PHG, and only 12% had GVE. These outcome data add further to the hypothesis that the pathogenesis of PHG is more related to portal hypertension, whereas GVE is more likely to be related to increased mucosal flow and splanchnic vasodilation. A reasonable management approach would be to start with beta-blockers as first-line therapy to prevent recurrent bleeding, but with failure proceed to TIPS. However, TIPS would not provide relief for GVE. Selective surgical shunts for PHG also bring excellent results in patients with preserved liver function [51]. TIPS can be a uniquely effective remedy for treatment of peristomal or rectal varices [52]. Only 10% of patients with anorectal varices have clinical bleeding. Hidajat et al. [53] show that the addition of transjugular embolization of rectal varices to TIPS may improve results. Budd-Chiari syndrome Budd-Chiari syndrome (BCS) is a rare disease most often associated with hypercoagulable states that cause partial or complete obstruction of the hepatic venous outflow. This obstruction can result in hepatic congestion, portal hypertension, and hepatocyte necrosis [54]. TIPS have been used in BCS for a number of years [55 57]. Case report numbers continue to accumulate, and the largest series still have small numbers of patients [8 13,58 ]. No controlled clinical trials have compared TIPS with surgery. TIPS placement is technically feasible in BCS, even in patients with extensive thrombosis, but requires diligent follow-up and multiple revisions [59]. The most encouraging study is by Perello et al. [58 ], who describe 13 patients who failed medical therapy with a mean follow-up of 4 years. All but one patient had prothrombotic diseases, one died of multiorgan failure 4 months after TIPS placement, and another required liver transplantation 2 years later, but all others were alive and well. Initial management options for BCS have always been difficult, but this study suggests the types of patients who might benefit from TIPS. All patients in the TIPS portion of the study had BCS prognostic index scores above 5.4 [60]. These results and those from other studies suggest that TIPS might improve survival either as a single therapy or as palliation until transplantation. Veno-occlusive disease Veno-occlusive disease (VOD) is a devastating complication of bone marrow transplantation. Increased sinusoidal pressure by the occlusion of hepatic and central veins results in the characteristic triad of hyperbilirubinemia, weight gain, and hepatomegaly [61]. Unlike reported success with BCS, TIPS deployment in VOD has a 2-month mortality rate greater than 85% [62]. As noted in an editorial by Rajvanshi and McDonald [63], mortality associated with TIPS and VOD is multifactorial. With the intrinsically high mortality rate of VOD, TIPS may fall into the category of last resort. The most recent reports encourage early identification and TIPS placement as a means to improve on these dismal survival results [64]. Hepatorenal syndrome The onset of hepatorenal syndrome (HRS) is usually a harbinger of terminal events in end-stage liver disease. Liver transplantation remains the optimal treatment for HRS. Major strides in understanding the pathophysiology and treatment with medical therapy for HRS have been reported in the last 5 years [65]. The role of TIPS in HRS remains controversial, with differing early anecdotal results [66,67]. The best study, by Brensing et al. [68], is a phase II trial of 31 nontransplant patients (14 patients with type I and 17 with type II HRS) compared with 10 patients not receiving TIPS. Patients were excluded for bilirubin greater

34 Liver than 15 mg/dl, Child-Pugh score greater than 12, or severe encephalopathy. Renal function improved (creatinine clearance, 18 to 48 ml/min) in those receiving TIPS, and hemodialysis was withdrawn in four of seven patients. Of greater interest, the overall survival rates after TIPS placement at 3, 6, 12, and 18 months were 81%, 71%, 48%, and 35%, respectively, compared with a 10% 3-month survival rate in the non-tips group. The survival rate was 70% at 1 year for type II HRS patients and only 20% for type I HRS patients. In addition, 23% of the study patients did not respond to TIPS, and all such patients died within 3 months. Multivariate regression analysis revealed bilirubin and type of HRS as independent survival variables. Experts in this field recommend that use of TIPS in patients with HRS be reserved for clinical trials [65]. Miscellaneous Unpredictable outcomes associated with TIPS in hepatopulmonary syndrome (HPS) have been reported [69 72]. However, four case reports note successful results in HPS, the most recent acting as a bridge to transplantation [73]. The key is to differentiate the use of TIPS in HPS from that in portopulmonary hypertension. Like HPS, polycystic liver disease was considered a contraindication for TIPS placement. Shin and Darcy [74] add one more successful TIPS placement in a patient with polycystic liver disease, for a total of three favorable cases in the literature. However, TIPS use in these two conditions must still be cautious because the reported numbers are profoundly low. The most unusual recent case report involves decompression of portal hypertension that occurred secondary to extramedullary hematopoiesis in a patient with idiopathic myelofibrosis [75]. Models and Scores to Predict Survival Following TIPS For purposes of decision making and informed consent, physicians would like to be able to predict the outcome of a TIPS procedure. Advances in this area have been reported in the past few years. Earlier studies identified independent predictors of early (30-day) mortality in TIPS patients, including age over 60 years, presence of encephalopathy or ascites, male gender, and emergent versus elective procedure [76,77]. Laboratory variables of bilirubin, albumin, sodium, and prothrombin time were also thought to be predictive of survival. Several studies with large numbers of patients have examined these and other variables and incorporated them into scores to predict short-term survival (30 to 60 days). Chalasani et al. [78] suggest that emergent TIPS placement within 48 hours of bleeding and a total bilirubin level greater than 3.0 mg/dl have independent effects on 30-day mortality (relative risk=5.4). Rajan et al. [79] report an extensive experience with 220 consecutive patients undergoing TIPS. Multivariate regression analysis demonstrated the following independent predictors of 30-day mortality: total bilirubin level of 4.0 mg/dl or higher (odds ratio [OR]= 5), Child-Pugh class C versus A/B (OR=4), and intubation (OR=5.1). Each 1 mg/dl of total bilirubin above 3.0 mg/dl was associated with a 40% increase in the risk of death. Patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores greater than 18 and Child-Pugh C classification had a mortality rate of 42%. Unfortunately, routine use of these scores is not easy. Malinchoc et al. [80 ] used objective variables to predict 30-day post-tips mortality using the Model for End Stage Liver Disease (MELD). This model uses the variables creatinine, bilirubin, international normalized ratio (INR) for prothrombin time, and cause of liver disease. MELD predicted survival whether the patient underwent the procedure for prevention of recurrent bleeding or treatment of refractory ascites and was superior to Child-Pugh classification in predicting mortality. A disadvantage in this model is that it requires an elaborate calculation or use of a nomogram. Salerno et al. [81] confirmed that MELD scoring is superior to Child-Pugh scoring for prediction of 3- month survival, but the accuracy of predicting 6- and 12- month survival was much less. Unfortunately, MELD scores tend to overestimate the risk of death in those with a low risk (risk score <1.17), as seen in the majority of these patients. Brensing et al. [82] developed an alternative scoring method called the Bonn TIPSS Early Mortality (BOTEM) score. The variables of the latter bilirubin, comorbidity, and TIPS-urgency combined to predict survival with good sensitivity, specificity, and positive predictive value. Unfortunately, this score was not compared with the MELD score. Lastly, results from two studies indicate that measurement of hepatic artery blood flow and hepatic perfusion before or after the procedure is not predictive of clinical outcomes following TIPS [83,84]. Technique and Methodology The technique for TIPS placement was described decades ago. The most difficult step is gaining access to the portal vein [85]. Most gastroenterologists consider successful placement a foregone conclusion. However, a recent study by Rose et al. [86] illustrates the difficulties of this procedure. Using three-dimensional ultrasound to evaluate TIPS placement, these authors found that the operator s opinion of which hepatic vein had been selected was incorrect in 45% of patients, that portal vein anatomy requiring technique modifications occurred in 35% of patients, and that the number of needle passes needed for deployment decreased from 10 to five with use of this technique. The authors believe that three-dimensional ultrasound offers promise as an adjunctive and complementary imaging modality for TIPS. The major shortcoming of TIPS is its limited and unpredictable patency (20% 70% at 1 year), which results in recurrent portal hypertension. The latest studies com-

Current Use of Transjugular Intrahepatic Portosystemic Shunts McCashland 35 Table 3. Complications associated with TIPS Technique/procedure Rupture of liver capsule Puncture of portal vein Perihepatic hematoma Arrhythmia Arterioportal fistula Portobiliary fistula Aorto-atrial fistula Migration to heart Portosystemic shunting Hepatic encephalopathy Liver failure Hemolysis Infection pare several new stent-grafts with bare stents [87 89]. Otal et al. [90] report primary and secondary patency rates of 80% and 100% in 20 patients with a new expanded-polytetrafluoroethylene covered stent-graft (WL Gore, Viattor, Flagstaff, AZ) at a mean follow-up of 387 days. Using the same stent-graft, Cejna et al. [91] improved patency to 100% at 289 days and revealed no inflammatory or neointimal formation in explants at transplantation. In a retrospective review comparing Palmaz Long-Medium stents (Cordis, Johnson & Johnson, Warren, NJ) with Wallstents (Boston Scientific, Natick, MA), Borsa et al. [92] report a primary patency of 70% with Palmaz stents and 50% with Wallstents. Evidence suggests that covered stents are an advance without any unexpected penalties. Doppler sonography is routinely used to appraise the presence of significant shunt stenosis; unfortunately, studies have differed in their definitions of patency. Two studies with differing techniques are illuminating in this regard. Zizka et al. [93] studied 1192 ultrasound examinations and found that defining peak intrashunt velocity as 250 cm/sec or more, maximum velocity in the portal third of the shunt as 50 cm/sec or less, or maximum portal vein velocity to two thirds or less of the baseline value revealed shunt stenosis in 103 of 110 cases (sensitivity, 94%). In contrast, Sheiman et al. [94] studied venous pulsatility index (VPI, V max - V min /V max ) in TIPS placement. A VPI of less than 0.16 was 94% sensitive and 87% specific for shunt dysfunction. Finally, one study demonstrated that helical CT angiography had sensitivity and specificity for hemodynamically significant abnormalities of the stent of 92% and 77%, respectively [95]. As Johnson [96] has noted, many questions remain regarding cost, ease of use, contraindications, and interobserver agreement for the routine use of helical CT angiography for TIPS evaluation. Therefore, helical CT angiography might be reserved for those patients in whom ultrasound is not diagnostic or technically feasible. Complications Complications associated with TIPS can be classified into two broad groups: those related to technique or procedure and those related to portosystemic shunting (Table 3) [5]. Fortunately, technical or procedural complications are rare, occurring in less than 1% to 2% of patients. Many unique complications, along with their management, continue to be reported. Three cases of migration of the Wallstent into the tricuspid valve and right ventricle were described over the last 2 years [97 99]. Two of the three patients had the stent removed by open cardiotomy after liver transplantation. Another distinctive cardiovascular complication was reported by Sehgal et al. [100]: the development of an aorto-right-atrial fistula resulting in right heart failure and subsequent death. Interestingly, data regarding the incidence and causes of bacteremia associated with TIPS are few. In a retrospective review of 99 TIPS patients by DeSimone et al. [101], five were thought to have developed TIPS-related infections. Bacterial infections developed at a median of 100 days after TIPS, with two of five patients dying from the infection. Bacterial organisms included Enterococcus faecalis, Gemell morbillorum, Staphylococcus aureus, and Lactobacillus acidophilus [2 ]. Hepatic encephalopathy occurs in approximately 30% of patients after TIPS placement but is usually correctable with medical management of lactulose or neomycin. Earlier studies illustrated worsening of post-tips encephalopathy with increasing age, shunt diameter greater than 10 mm, Child-Pugh class C, nonalcoholic etiology, female gender, renal dysfunction, and prior history of encephalopathy. A study from Canada names loss of portal perfusion and age greater than 65 years as the only two independent predictors of post-tips encephalopathy [102]. Four cases of fatal liver infarction are documented [103]. Interestingly, Nolte et al. [104] report that androstenedione and estradiol increase after TIPS placement, and that erectile dysfunction increases from 30% to 70%. Conclusions The principal indication for TIPS continues to be as rescue therapy for variceal hemorrhage that cannot be controlled by endoscopic or medical therapy. TIPS provide no survival advantage in prevention of rebleeding or refractory ascites. Other indications for TIPS continue to expand, especially in BCS and hydrothorax, but further study is needed. Great strides have been made recently in models to predict post-tips mortality and complications. Covered stents hold promise in early studies. Finally, because complications in TIPS placement are common and may be life threatening, they should be explained in detail to patients.

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