The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension
Authors: Thomas D. Boyer, Ziv J. Haskal
Journal: Hepatology (2005)

TIPS, transjugular intrahepatic portosystemic shunt; MELD, model for end-stage liver disease; HVPG, hepatic venous pressure gradient; PTFE, polytetrafluoroethylene; PHG, portal hypertensive gastropathy; GAVE, gastric antral vascular ectasia; LVP, large volume paracentesis; HRS, hepatorenal syndrome; BCS, Budd-Chiari syndrome. The recommendations in this article provide a data-supported approach. They are based on the following: (1) a formal review and analysis of recently published world literature on the topic (as listed in MEDLINE); (2) the American College of Physicians' A Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) policy guidelines, including the American Association for the Study of Liver Diseases' Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; and (4) the authors' years of experience in the care of patients with portal hypertension and use of transjugular intrahepatic portosystemic shunt in the management of these disorders. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the Society for Interventional Radiology. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases requires a grade to be assigned and reported with each recommendation (Table 1). Transjugular intrahepatic portosystemic shunt (TIPS) has been in use for more than 20 years to treat the complications of portal hypertension, and TIPS have been created in thousands of patients with liver disease worldwide.3-6 Despite the extensive use of TIPS to treat the complications of portal hypertension, there initially was a lack of consensus regarding which patients should receive TIPS instead of other forms of therapy. A 1995 conference sponsored by the National Institutes of Health concluded that TIPS was effective in the acute control and prevention of recurrent bleeding from varices, but it was unclear when TIPS should be used instead of medical and surgical therapy for these complications of portal hypertension. In addition, the efficacy of TIPS to control refractory ascites or treat Budd-Chiari syndrome was unclear but promising.7 Since then, more than 1,000 patients have been enrolled in multiple controlled trials comparing TIPS with endoscopic and pharmacological therapy in the prevention of rebleeding from varices and with large-volume paracentesis in the treatment of refractory ascites associated with cirrhosis. Furthermore, approximately 1,000 papers have been published on TIPS in the English literature alone. This body of work allows for more definitive recommendations about in whom and when to use TIPS in the treatment of the complications of portal hypertension. The guidelines are divided into two large categories. The first category is a review of the technical aspects of the procedure, its complications, and the data on which patients are most at risk for an adverse outcome following TIPS. The second category is a review of the indications for TIPS. The use of TIPS for primary prevention of variceal bleeding and the control of acute bleeding are discussed first. Next, the two indications for TIPS that have been subjected to controlled trials (prevention of recurrent bleeding from varices and refractory ascites) are discussed, and guidelines are developed. Lastly, all of the other indications for TIPS that have been described in the literature but have not been subjected to controlled trials are discussed, and guidelines are created. To prepare these guidelines, a MEDLINE search was performed on papers published between 1966 and 2004. Nine hundred eight papers were found under the subject heading "transjugular intrahepatic portosystemic shunt." Controlled trials and large series were sought. Recently published papers were also used as a source of references missed by the MEDLINE search, as were the personal files of the two authors. A TIPS is created by an interventional radiologist or, in Europe, by a specially trained physician. The technique is reviewed in several publications and will not be discussed here.3, 4, 7 The procedure may be performed under conscious sedation (most common) or general anesthesia. If the procedure is going to be prolonged or the patient is hemodynamically unstable, then general anesthesia is preferred because it allows for careful monitoring by the anesthesiologist. The success rate with TIPS for the decompression of the portal vein is high—more than 90% of cases in most series.8-14 The Society of Interventional Radiology developed guidelines for creation of a TIPS in 2001, and the consensus was that a technically successful outcome (including both creation of the shunt and a decrease in portal pressure to <12 mm Hg) should be achieved in 95% of patients, and clinical success (resolution of the complication of portal hypertension) should be achieved in 90% of cases. Failure to achieve this threshold should lead to a review of departmental policy and procedures.15, 16 Early mortality following TIPS placement was originally reported to be quite high as a result of poor patient selection, but subsequent analysis demonstrated that preprocedure clinical features (such as high model for end-stage liver disease [MELD] or APACHE II scores, high total bilirubin levels, emergent versus elective setting, or presence of pneumonia; see Mortality) accounted for this high death rate. In most situations, death is due to progressive liver disease, perhaps as a result of portal diversion, and is not due to complications of the procedure itself, such as intraperitoneal bleeding (see Mortality).14, 17-19 In a retrospective series of 1,750 patients, the incidence of fatal complications (intra-abdominal hemorrhage, laceration of the hepatic artery or portal vein, and right heart failure) was 1.7% (range, 0.6%-4.3%). Interestingly, the risk of fatal complications was 3% in institutions that had performed fewer than 150 TIPS total compared with 1.4% in those that had performed a greater number.14 These data suggest that there is a learning curve associated with the safe creation of a TIPS. Major procedural complications are expected in no more than 3% of cases; if rates exceed these levels, internal quality assessment should be considered.16 Authors of manuscripts on TIPS have been asked by the Society of Interventional Radiology to report the approximate number of TIPS performed in their centers before instituting the reported study to obtain a better understanding of the amount of training required to perform TIPS with an acceptable morbidity and mortality, and it is hoped these data are forthcoming.16 The purpose of a TIPS is to decompress the portal venous system and therefore prevent rebleeding from varices or stop or reduce the formation of ascites. Regarding varices, it is well established that if the hepatic venous pressure gradient (HVPG) can be reduced to less than 12 mm Hg, the risk of bleeding will fall significantly. More recent data suggest that achieving a HVPG of less than 12 mm Hg may not be required to prevent rebleeding. In one series, the risk of rebleeding following TIPS revision was 18%, 7%, and 1% in patients whose HVPG had been reduced by 0%, 25% to 50%, and more than 50%, respectively.20 In a second series, a 50% reduction in the initial HVPG was associated with a rebleeding rate at 1 year of 11%, whereas patients with a lesser reduction had a 31% probability of rebleeding during the first year.21 In the latter study, the only absolute value for prevention of rebleeding was an HVPG of less than 12 mm Hg, but at the cost of an increased incidence of encephalopathy. Although the gold standard for prevention of rebleeding remains an HVPG of less than 12 mm Hg, further studies are needed to determine if lesser reductions have acceptable efficacy with a lower incidence of encephalopathy. The optimal HVPG that needs to be obtained for the control of refractory ascites associated with cirrhosis is even less clear. In one series, the degree of portal decompression did not correlate with successful treatment of refractory ascites associated with cirrhosis, and the authors suggested that a HVPG of less than 8 mm Hg should be the hemodynamic goal.22 The selection of a value of 8 mm Hg is based on limited data, and because the development of ascites associated with cirrhosis reflects changes in both hepatic and renal function, it may be difficult to establish an absolute value of decompression that needs to be achieved in most patients with refractory ascites. In patients with significant pre-existing encephalopathy in whom a TIPS may still be necessary for ascites control, a higher gradient may be appropriate (to limit worsening encephalopathy); this affords the opportunity to further enlarge the TIPS at a later date if diuresis is inadequate and encephalopathy is satisfactorily controlled. Further study in this area is warranted. Finally, in the authors' experience the effective gradient needed to prevent rebleeding from gastric varices may be lower than 12 mm Hg and, even with apparent decompression embolization of the gastric varices, may be required to minimize the risk of early rebleeding. Also, rebleeding from gastric varices may occur with small increases in portal pressure, suggesting that surveillance of this group of patients following TIPS is of particular importance.21 Further complicating the issue is the problem of how the pressures are obtained. The classic way is to measure the free and wedged hepatic vein pressure and then subtract the two values yielding the HVPG.23 The use of the free hepatic vein or inferior vena cava pressure is necessary to correct for the intra-abdominal pressure and allows for measurement of the true pressure gradient across the liver. However, most radiologists use the right atrial pressure as the reference point because the hepatic vein is now part of the shunt; thus a free hepatic vein pressure cannot be obtained after shunt creation, because the diverted portal flow artifactually raises the pressure within the outflow hepatic vein that drains the TIPS. The right atrium is of course in the chest, and the basal pressure in the chest is lower than the intra-abdominal pressure; therefore, the true HVPG is not measured using this reference point. In addition, once the TIPS has been created, the right atrial pressure tends to rise, thus complicating the measurement. One solution to this problem is to use the inferior vena cava pressure as the reference value, but this has not been adopted by the interventional radiological community. No standardization of where in the inferior vena cava the pressure should be obtained has limited this approach, and currently the right atrial pressure is used by most interventional radiologists despite the above limitations. Some of these uncertainties could be resolved with standardization of how the HVPG is measured during creation of a TIPS so that the measurements are uniform and can be used to judge hemodynamic success more accurately. Most patients who are referred for a TIPS should be under the care of a gastroenterologist or hepatologist, who in consultation with an interventional radiologist must reach the decision that TIPS is the appropriate form of treatment for a complication of portal hypertension. As discussed in the following section, it is clear that there are predictors of a poor outcome following TIPS. However, the risk of the procedure must always be balanced with the severity of the complication from which the patient is suffering and the likelihood of the patient surviving long enough to receive a liver transplant following creation of a TIPS. Thus, the decision to perform or not perform TIPS in a high-risk patient should be reached by the gastroenterologist/hepatologist and the interventional radiologist together. Ideally, in a high-risk patient, a transplant center should also be consulted preceding the final decision. In the emergent setting of acute, uncontrolled variceal hemorrhage, contacts with transplantation centers may be secondary to the need for shunt creation. Table 2 lists contraindications to the creation of a TIPS. These include both absolute contraindications to any form of portosystemic diversion, be it surgical or percutaneous. Absolute contraindications include congestive heart failure, severe tricuspid regurgitation, and severe pulmonary hypertension (mean pulmonary pressures > 45 mm Hg, as these patients are not candidates for a liver transplant).24 Whether patients with more mild pulmonary hypertension can receive a TIPS safely is unclear. Relative contraindications include anatomical ones that can complicate the creation of the shunt and reduce the technical success, including portal venous obstruction, large hepatic tumors, extensive polycystic liver disease, and hepatic vein obstruction. It is well established that shunts can be created in all of these cases with the right experience and under appropriate clinical circumstances, but the difficulty of creating the TIPS needs to be balanced with the need of the patient. Situations in which these relative contraindications might be outweighed by clinical necessity include palliative TIPS in patients with hepatoma and refractory variceal bleeding, recanalization of occluded portal veins in patients with recurrent variceal bleeding or refractory ascites, and a patient with Budd-Chiari syndrome and progressive liver failure in whom there are no patent hepatic veins. Preprocedure laboratory studies include serum electrolytes, blood count, coagulation parameters, and tests of liver and kidney function. Cross-sectional liver imaging via Duplex ultrasound, computed tomography, or magnetic resonance imaging is appropriate in all but the most life-threatening situations to assess portal vein patency or the presence of liver masses. When a history of congestive heart failure, tricuspid regurgitation, cardiomyopathy, or pulmonary hypertension is present, cardiac evaluation is appropriate before a TIPS procedure. This evaluation may include an echocardiogram, cardiology consultation, and, possibly, atrial fluid challenge. In the absence of a cardiac history, the routine performance of an echocardiogram preceding a TIPS is unnecessary in the opinion of the authors; however, others feel that because up to 16% of patients referred for liver transplantation may have pulmonary hypertension, an echocardiogram should be performed on all patients before a TIPS is created.24 Elevated right atrial pressures (typically measured at the start of the TIPS procedure) may warrant abandonment or delay of the procedure pending diuresis or further medical evaluation. Lastly, patients with a significant coagulopathy may be able to undergo a TIPS following the use of clotting factors or platelets. The finding of a small liver during the evaluation is not a contraindication to creation of a TIPS, but it does indicate that the procedure may be difficult and prolonged. The 1-year mortality rates for TIPS are dependent somewhat on the indication for the procedure. When a TIPS has been placed for bleeding varices, 1-year survival varies from 48% to 90%. Survival rates are similar when the indication is ascites (48%-76%).25-30 In one series but not another, survival rates were significantly worse when the indication was refractory ascites compared with variceal bleeding.26, 29 These differences likely reflect variations in the severity of liver disease between the different studies. As the use of TIPS has increased, there has been interest in models that predict outcome. MELD and a number of other models have been developed to predict survival following TIPS.25-29 The modified MELD model utilizes serum bilirubin level, international normalized ratio for prothrombin time, and serum creatinine level (cause of cirrhosis was also used previously but has since been abandoned). These three variables are used to create the following equation: [3.8 loge (bilirubin [g/dL]) + 11.2 loge (international normalized ratio) + 9.6 loge (creatinine [mg/dL]. A second model used a bilirubin level of greater than 3.0 mg/dL (1 point), an alanine aminotransferase level of greater than 100 IU/L (1 point), pre-TIPS encephalopathy (1 point), and urgency of TIPS (2 points) and divided patients into three groups (low risk, 0 points; medium risk, 1-3 points; high risk, 4-5 points).26 These two models and Child-Turcotte-Pugh scores were used prospectively in a subsequent study to predict survival.30 All three accurately predicted 3-month survival to a similar degree, whereas 1-year survival was predicted best by the MELD model. Short-term mortality has also been predicted by using bilirubin alone or a combination of serum bilirubin, APACHE-II score, and TIPS urgency.31, 32 Irrespective of which model is chosen, the short-term and 1-year survival can be predicted with some accuracy. These survival estimates can be used to advise patients about expected outcomes and can also be used to decide which patients will require referral to a liver transplant center. TIPS should only be performed by experienced interventional radiologists (or specially trained physicians). Success and complication rates should be monitored; if they fail to meet expected rates, review of the program should be considered (evidence: grade III). The decision to perform a TIPS, especially in a high-risk patient, should be reached by a team consisting of a gastroenterologist/hepatologist, interventional radiologist, and, where appropriate, a transplant physician (evidence: grade III). Preceding creation of a TIPS, tests of liver and kidney function should be performed in addition to cross-sectional imaging of the liver to assess portal system patency and exclude liver masses (evidence: grade III). Reduction in HVPG to less than 12 mm Hg should be achieved when the indication is bleeding esophageal varices. Embolization of gastric varices may be required despite adequate decompression of the portal venous system (evidence: grade II-2). The degree of reduction in HVPG to control ascites is unclear, but at present a gradient of 8 mm Hg or less has been suggested to be a reasonable goal (evidence: grade II-2). Patients with high predicted 30-day mortalities should be informed of their prognosis, and TIPS should be performed only in the absence of other options (evidence: grade II-2). In high-risk patients, the need for liver transplantation should be discussed before the performance of an elective TIPS (evidence: grade III). The most common complications and their reported frequencies are listed in Table 3. TIPS dysfunction is defined as a loss of decompression of the portal venous system due to occlusion or stenosis of the TIPS. Although there is no consistency between investigators as to the exact criteria that should be used to define TIPS dysfunction in reference to degree of stenosis, a value of 50% is frequently used. In addition, a rise in the HVPG to greater than 12 mm Hg or a recurrence of the complication of portal hypertension for which the TIPS was performed indicates TIPS dysfunction.33 Occlusion of the TIPS can either be due to thrombosis or hyperplasia of the intima. Thrombosis of the TIPS usually occurs early and can happen within 24 hours of TIPS creation. The frequency of this complication is on the order of 10% to 15%.34, 35 The cause of the thrombosis may be leakage of bile into the shunt, hypercoagulable syndromes, or inadequate coverage of the TIPS tract with sufficient stents.36, 37 Thrombosis of the TIPS is identified using Doppler ultrasound, and patency is re-established through repeat catheterization. In one controlled trial, use of the anticoagulant phenprocoumon was associated with a lower rate of complete occlusion within the first 3 months following TIPS placement.38 However, in the absence of more studies, the routine use of anticoagulation is not recommended. The major difficulty with TIPS is the unpredictable patency of the shunts as a result of pseudointimal hyperplasia within the parenchymal tract or within the outflow hepatic vein. The occluded stents are coated by a collagenous matrix that is covered by endothelial cells.36, 37, 39-41 The incidence of stenosis varies from 18% to 78% depending upon the surveillance techniques used, frequency of assessment, and definitions of failure, (e.g., elevated portasystemic gradient, ultrasound velocity criteria, or percent diameter stenosis).9, 11, 12, 42-46 Most physicians rely on Doppler ultrasound to identify TIPS stenosis. Unfortunately, the earlier studies claiming greater than 90% accuracy for sonographic prediction of shunt dysfunction have failed to stand under the light of larger prospective or retrospective studies. In one series, several ultrasonographic features were used to identify TIPS stenosis, including flow reversal, jet lesion, and decreased flow in the TIPS or portal vein. The sensitivity of each of these tests varied from 10% to 26% with a specificity of 88% to 100%. Thus the negative predictive value was poor and the positive predictive value was acceptable.47 In a second series of 31 occluded or stenotic stents, ultrasound predicted shunt malfunction in only 11 and incorrectly predicted patency in 20; thus the sensitivity was only 35%.48 Many of the sonographic studies are methodologically flawed, because sonographic criteria of shunt dysfunction were used to trigger TIPS venography; however, when sonography suggested no shunt dysfunction, proof of shunt patency via venography was not performed. Part of the difficulty of using sonography is that it is an imaging technique that measures velocity, from which diameter within a conduit can be estimated. However, with TIPS it is portal decompression—not percent shunt stenosis—that is important in assessing TIPS function. One prospective study compared 151 Doppler sonograms with TIPS venograms and assessment of portal pressure. Using a success or failure definition of a portosystemic gradient of less than 15 mm Hg or 15 mm Hg or more, respectively, sonography provided a sensitivity and specificity of only 86% and 48%, respectively.49 Thus an abnormal Doppler ultrasound is predictive of occlusion or stenosis, whereas a normal ultrasound does not exclude TIPS dysfunction. The best indicator of TIPS dysfunction is a recurrence of the problem for which the TIPS was originally inserted: either variceal bleeding, hepatic hydrothorax, or ascites. If recurrent varices are identified by upper endoscopy, then the TIPS most likely is insufficient.47 Documentation of patency can only be achieved with certainty through recatheterization of the shunt. The development of covered stents should reduce the frequency of TIPS dysfunction.50 Two large series have recently been published that have examined the use of polytetrafluoroethylene (PTFE)-covered stent grafts for TIPS. One of the reports is of a series of 71 patients, all of whom received the covered stents, whereas the second report is a randomized controlled trial comparing the covered stents with the standard bare stents.33, 51 In the nonrandomized series, a total of 8 shunt revisions were performed for an incidence of 11.3%, and primary patency rates at 6 and 12 months were calculated to be 87% and 81%, respectively.51 Although these results are better than what would be expected with bare stents, all patients did not undergo venography and therefore the true incidence of shunt stenosis is unknown. In the randomized study, 80 patients with cirrhosis and either uncontrolled or recurrent bleeding from varices or refractory ascites were enrolled in the study. Patients were followed with Doppler ultrasound, and venography was performed at 6, 12, and 24 months post-TIPS. Five (13%) of the 39 patients receiving the PTFE-covered stent grafts had shunt dysfunction, whereas 18 (44%) of those receiving the bare stent had shunt dysfunction (P < .001). In addition, early thrombosis of the TIPS was observed in three patients who received the bare stents. The actuarial rates of primary patency in the covered and bare stent groups were 86% and 47%, respectively, at year 1 and 80% and 19%, respectively, at year 2. Recurrence of the complication of portal hypertension for which the TIPS was placed was also significantly more common in the bare stent group compared with the PTFE-covered stent group. The incidence of hepatic encephalopathy was less in the PTFE-covered stent group (difference not significant), and survival was the same.33 The PTFE-covered stents have recently been approved for use in the United States by the Food and Drug Administration.52 The use of the PTFE-coated stent grafts should decrease significantly the incidence of shunt dysfunction and recurrence of the complications of portal hypertension. It is unclear, however, whether this development will improve the cost-effectiveness of TIPS compared with other forms of therapy. Puncture of the liver capsule is common, but serious intraperitoneal bleeding is infrequent (1% to 2% of cases). Similarly, creation of a biliary venous or hepatic artery–portal vein fistula is rare. The development of jaundice or sepsis following TIPS suggests the former, whereas pulsatile flow in the portal vein suggests the latter.53, 54 Hemolysis may occur following TIPS placement and appears to be due to damage to the red cells by the stent.55-57 Recognition that the rise in bilirubin levels is due to hemolysis is an important diagnosis, because an alternative diagnosis is liver failure following TIPS, which caries a poor prognosis.58 Hepatic infarction is a rare complication of TIPS and is generally related to injury and/or thrombosis of the hepatic artery that supplies the affected segment.59 Hepatic encephalopathy and TIPS dysfunction are the two complications that have limited the effectiveness of TIPS most significantly. The incidence of new or worsening encephalopathy following TIPS is 20% to 31%.25, 60, 61 In controlled trials comparing TIPS with alternative forms of therapy, the incidence of encephalopathy is always greater in those who received a TIPS (see sections Esophageal Variceal Bleeding and Ascites Associated With Cirrhosis). Pre-TIPS factors associated with an increased risk of post-TIPS encephalopathy in one study included etiology of liver disease other than alcohol, female sex, and hypoalbuminemia.61 In a second series, increasing age, past history of encephalopathy, and evidence of encephalopathy at the time of TIPS were predictive of post-TIPS encephalopathy.60 It is important to note that if encephalopathy is precipitated by variceal bleeding, prevention of rebleeding should make it less likely that the patient will have recurrent encephalopathy. Only if the hepatic encephalopathy is uncontrollable is a TIPS contraindicated.15 In most patients, the encephalopathy responds to standard therapy, and only rarely (≈5%) must the TIPS be occluded to control the encephalopathy.62, 63 A TIPS also can be reduced in caliber should excessive encephalopathy prove difficult to control and yet allow for continued portal decompression.64 There is no data supporting the use of lactulose in all patients following a TIPS to reduce the incidence of encephalopathy. Patients awaiting liver transplantation frequently bleed from varices or have refractory ascites associated with cirrhosis and therefore are candidates for a TIPS. Because these patients will subsequently undergo a hepatectomy, there are complications involved with TIPS that are unique to this population. A TIPS is created within the substance of the liver, and most interventional radiologists attempt to place the stent as close as possible to the hepatic vein/inferior vena cava ostium to reduce the risk of developing stenosis within the hepatic vein. With the exception of cases of benign or malignant portal vein thrombosis, the stent should extend the shortest possible distance into the main portal vein, both to allow creation of a durable shunt and yet not complicate the portal-to-portal vein anastomosis performed during transplantation. When the stent extends into the inferior vena cava (or atrium) or deep into the main portal vein, transplantation difficulties can arise. In one series of 12 patients who had a TIPS preceding liver transplantation, 4 patients had portal vein stents near the coronary vein or extending into the superior mesenteric vein, and venous reconstruction was required in 1 patient.65 In a second series of 24 patients who had a TIPS created before transplantation, 8 patients had more complicated surgeries that were attributable to the presence of a TIPS. Four of the stents were in the inferior vena cava, one was in the superior mesenteric vein, and in three the portal vein was thrombosed. Despite being able to complete the transplant in all 8 patients, patient and graft survival were somewhat worse in those with complications related to the presence of the TIPS.66 However, in other series, despite the technical issues that arose during the transplant because of the presence of the shunt, operative time and patient and graft survival were the same in patients who were transplanted in the presence and absence of a TIPS.67, 68 All patients who have a TIPS created should be considered possible liver transplant candidates; thus care should be taken to not extend the stents beyond the minimum