Which patients benefit the most? An update on transjugular intrahepatic portosystemic shunt

Abstract

This is a narrative review in which the advances in technical aspects, the main indications, limitations and clinical results of the transjugular intrahepatic portosystemic shunt (TIPS) in portal hypertension (PH) are addressed. With the emergence of the coated prosthesis, a better shunt patency, a lower incidence of hepatic encephalopathy (HE) and better survival when compared to TIPS with the conventional prosthesis are demonstrated. The main indications for TIPS are refractory ascites, acute variceal bleeding unresponsive to pharmacological/endoscopic therapy and, lastly, patients considered at high risk for rebleeding preemptive TIPS (pTIPS). Absolute contraindications to the use of TIPS are severe uncontrolled HE, systemic infection or sepsis, congestive heart failure, severe pulmonary arterial hypertension, and biliary obstruction. The control of hemorrhage due to variceal rupture can reach up to 90%-100% of cases, and 55% in refractory ascites. Despite evidences regarding pTIPS in patients at high risk for rebleeding, less than 20% of eligible patients are treated. TIPS may also decrease the incidence of future decompensation in cirrhosis and increase survival in selected patients. In conclusion, TIPS is an essential treatment for patients with PH, but is often neglected. It is important for the hepatologist to form a multidisciplinary team, in which the role of the radiologist with experience in interventional procedures is prominent.

Key Words: Transjugular intrahepatic portosystemic shunt; Refractory ascites; Variceal bleeding; Portal hypertension; Hepatic encephalopathy

Core Tip: This is a narrative review where the advances in technical aspects, the main indications, limitations and clinical results of the transjugular intrahepatic portosystemic shunt (TIPS) in portal hypertension (PH) are addressed. With the coated prosthesis, a better shunt patency, a lower incidence of hepatic encephalopathy and better survival when compared to the not covered prosthesis are demonstrated. The main indications for TIPS are refractory ascites, acute variceal bleeding unresponsive to pharmacological/endoscopic therapy and, lastly, patients considered at high risk for rebleeding preemptive TIPS. In conclusion, TIPS is an essential treatment for patients with PH, but is often neglected.

INTRODUCTION

When assessing the burden of chronic liver disease, it is estimated that around 1.5 billion patients worldwide are affected, with the most frequent causes being metabolic dysfunction-associated steatotic liver disease, alcoholic liver disease and hepatitis B and C viruses. Although this number is probably underestimated, chronic liver diseases are believed to be responsible for 2000000 deaths per year. When evaluating the burden of liver disease, it also corresponds to the 11^th cause of death in the world[1,2].

Cirrhosis is the most common cause of liver disease. When diagnosed, in addition to treating or eliminating the causative agent of liver disease, therapy focuses mainly on its complications. The most common causes of decompensation are the presence of ascites, upper gastrointestinal bleeding, jaundice and hepatic encephalopathy (HE)[3]. Treatment is generally clinical, but eventually it becomes necessary to launch more complex therapies. It is within this context that we will evaluate the role of the transjugular intrahepatic portosystemic shunt (TIPS).

TIPS

In 1969, Rösch et al[4] described for the first time an experimental procedure that established an intraparenchymal shunt between the venous system in the liver of animals. A few years later, in 1982, Colapinto et al[5] used the same technique, still without the use of a metal prosthesis, in just over 20 patients, but with disappointing results. Other studies followed, generally on an experimental basis, until, with the development of the metallic prosthesis, there was a new breath for TIPS enthusiasts, and in 1988, in Germany, Richter et al[6] carried out the first TIPS using a prosthesis. Throughout the 90s, several studies were published, attesting to the role of TIPS in the management of complications of portal hypertension (PH), cirrhosis being its most common cause. Initially, there were few controlled and randomized studies that allowed us to conclude that this procedure was truly effective, safe and cost-effective, making it difficult to adequately analyze the indications for TIPS[7]. Subsequently, based on more methodologically appropriate studies with promising results, it was possible to review the indications for TIPS, which were accepted by consensus among the different international scientific societies dedicated to the study of liver diseases[8-13].

TIPS TECHNICAL CONSIDERATIONS

Technical success in performing TIPS is reported in approximately 97% of cases. Hemodynamic success is measured as a satisfactory reduction in the hepatic venous pressure gradient (HVPG), which occurs in approximately 95% of cases. Clinical success varies according to its indication. Thus, the control of digestive hemorrhage due to variceal rupture can reach up to 90%-100% of cases[7,14], with less control (around 55%) of refractory ascites in patients with cirrhosis[15].

TIPS can be performed with anesthetic sedation or general anesthesia, and is classically performed under contrast fluoroscopy, generating images that guide the procedure[7,16].

Its technique consists of puncturing the internal jugular vein, through which a catheter is introduced, which passes through the right heart chamber until it reaches the inferior vena cava, in its retrohepatic portion[11,15,17]. Subsequently, selective catheterization of one of the hepatic veins is performed, at which time systemic and portal venous pressures are measured to define HVPG[7,18]. Next comes the technically most complex stage of the procedure, that is, the puncture of the portal vein branch[19,20]. If the puncture of the portal branch is successful, the path between the hepatic vein and the portal vein branch is dilated within the liver parenchyma using a balloon catheter. After dilation of the parenchymal path, the prosthesis is inserted[11,15,17].

A specific observation for patients with tense ascites is to perform therapeutic paracentesis prior to TIPS placement to avoid changing the position of the liver and its main venous branches and to facilitate the extubation when general anesthesia is used[21].

More recently, a new evolutionary milestone emerged with the development of a prosthesis coated with polytetrafluoroethylene (PTFE). With the emergence of the coated prosthesis, new studies began to be published and better shunt patency, a lower incidence of HE and better survival were observed when compared to TIPS with the conventional prosthesis[22-24]. In this way, TIPS thrombosis, a complication that frequently occurred with the use of conventional prosthesis, was greatly reduced with the covered TIPS. The patency rates of PTFE stents exceed 90% at 1 year and 75% at 3 years[25].

The average time to perform TIPS is up to 3 hours. However, it must always be taken into account that a longer procedure time corresponds to greater exposure to ionizing radiation, the use of a greater volume of contrast medium and a greater risk of complications, in general, resulting from repeated punctures through the liver parenchyma, reflecting the difficulty of reaching a branch of the portal vein[26]. Considering that TIPS is often performed in critically ill patients, in an attempt to contain portal bleeding, carrying it out quickly in a short period of time can be crucial to preserving the patient's life.

The use of abdominal ultrasound to guide portal puncture is a technique that, although described in the early 1990s[27], is little explored with few reports in the literature[19,28-31]. By reducing the number of punctures through the liver parenchyma for catheterization of the portal vein branches, its use favors the reduction of procedure execution time, the exposure to ionizing radiation and the volume of contrast medium used[19]. Some authors recommend performing TIPS guided by ultrasound, suggesting another professional to perform it[32]. In our local experience, using ultrasound performed by the interventional radiologist, we obtained excellent results[33], reaching technical success in 100% of cases, with an average procedure time of around one hour and with an irradiation dose of around 85 Gy.cm², with no complications related to inadvertent puncture of non-target structures or deaths resulting from TIPS.

The indication of TIPS in the treatment of patients with variceal bleeding or refractory ascites must always be weighted with the possibility of development or worsening of HE, development of heart failure and increased liver function deficit. Therefore, the creation of a smaller caliber shunt seems to be desirable for a good risk/benefit ratio. Within this context, recent studies suggest that the use of covered prosthesis with 8 mm in diameter appears to be sufficient to prevent variceal rebleeding and potentially reduce the incidence of HE, while reducing the possibility of worsening hepatic decompensation. The use of the 8 mm stent may lead to a survival advantage compared to the 10 mm stent[34-36].

More recently, prosthesis have been developed that allow the interventional radiologist to calibrate the diameter of the shunt, between 8 and 10 mm (“controlled expansion” endoprosthesis), facilitating the results of the procedure. The use of the controlled expansion prosthesis seems to favor better survival both in patients with bleeding due to rupture of the variceal veins and in refractory ascites[37].

The TIPS can be progressively dilated (starting at 8 mm in diameter) to the smallest diameter necessary to achieve a portosystemic pressure gradient of less than 12 mmHg. When the pressure gradient does not decrease, despite the maximum dilation of the TIPS (10 mm), a non-specific beta-blocker[13] should be added.

When monitoring patients who underwent TIPS, to assess their patency, control with doppler ultrasound performed at 1 week, 3 months, 6 months and every 6 months is suggested. When necessary, perform venography and pressure measurements to confirm TIPS dysfunction[13].

INDICATIONS, CONTRAINDICATIONS AND COMPLICATIONS OF TIPS

The main indications for TIPS in cirrhosis are the management of refractory ascites, the treatment of acute variceal bleeding unresponsive to pharmacological treatment combined with endoscopic therapy and lastly, in patients considered at high risk for rebleeding named preemptive TIPS (pTIPS)[8-10,12,14]. However, depending on the case, it can also be used in patients with hepatic hydrothorax, Budd-Chiari syndrome, portosinusoidal vascular disorder and hepatorenal syndrome not associated with acute kidney injury[12].

Absolute contraindications to the use of TIPS would be severe uncontrolled HE, systemic infection or sepsis, congestive heart failure (stage C or D, or a documented ejection fraction < 50%); severe pulmonary arterial hypertension, untreated biliary obstruction[13,38].

Relative contraindications would be considered for its use in patients with very high model for end stage liver diseases (MELD) score, Child-Pugh score > 13 points, severe coagulopathy, polycystic liver disease, portal or hepatic vein occlusion and intrahepatic tumors. Acute or chronic bland portal vein thrombosis, although it makes the procedure more complex, does not prevent the placement of TIPS[13,38].

Regarding mortality after its use in elderly patients with cirrhosis, the position is not definitive since, as a rule, patients over 75 years of age were excluded from controlled and randomized studies. Performing TIPS in patients over 70 years of age has been infrequent, but the results appear acceptable in highly selected patients. In these cases, creatinine and sodium levels are useful predictors[39].

This is a procedure with reported morbidity of up to 20% and a low mortality rate, which is around 1%. Its complications can be classified as major (hemoperitoneum, coleperitoneum, hemobilia, hepatic artery injury, hepatic infarction, liver failure, intractable HE, renal failure requiring chronic dialysis) and minor (hematoma at the puncture site, transient pulmonary edema, treatable HE, transient renal failure without the need for chronic dialysis)[15,18,40].

Liver function remains the main determinant of morbidity and mortality after TIPS. Although MELD score has been extensively evaluated to predict mortality after TIPS placement, no specific threshold has been definitively established to contraindicate the procedure. Given the risk of exacerbation of liver failure after its use, it is suggested that when there is liver failure (Child-Pugh C, MELD > 18, bilirubin > 3 mg/dL and platelets < 75000), the cases should be evaluated very carefully and, when performed, prioritize centers where transplantation is a viable option in the case of complications[12]. In patients with cirrhosis, the etiological treatment, when available, is always recommended, as it can improve liver function[41].

The most relevant long-term complications are mainly HE, deterioration of liver function and complications related to cardiac overload[13].

In the vast majority of cases, HE after TIPS can be treated with lactulose and/or rifaximin. In those patients with HE, despite the medical therapy used, endovascular reduction of the prosthesis diameter[13] should be attempted. In a recent controlled and randomized multicenter study in patients with alcoholic cirrhosis, prophylaxis with rifaximin 600 mg twice daily, started two weeks before TIPS placement and maintained for 6 months, reduced the risk of HE, despite not having brought benefits in survival[42].

The study that evaluated the predictive factors of cardiac decompensation after TIPS (The Toulouse Algorithm)[43] seems relevant. In this study, cardiac decompensation occurred in 20% of patients. However, low-risk patients were identified as those with a brain natriuretic peptide (BNP) of less than 40 pg/mL; N-terminal pro-BNP less than 125 pg/mL and with the absence of a prolonged QT interval corrected by the Frederica method on the electrocardiogram and diastolic dysfunction criteria on the echocardiogram.

We believe that a study that evaluated the experience with the use of TIPS and its impact on mortality[44] is of interest. After evaluating the use of more than 5500 TIPS in centers in the United States of America, mortality varied depending on the expertise of each center. The authors concluded that centers that use more than 20 TIPS/year have lower mortality.

THE ROLE OF TIPS IN CONTROLLING BLEEDING FROM RUPTURED VARICES

There seems to be a consensus on the indication of covered TIPS in patients with persistent bleeding after combined therapy (pharmacology and elastic variceal ligation), as well as in patients with rebleeding in the first 5 days[9,10,45,46]. When we use conventional TIPS for these indications, we can control bleeding in almost 80% of cases[47].

It is important to highlight that when TIPS is used, it can be combined with vessel embolization to control or reduce the risk of recurrence of gastric/ectopic varices and to reduce the risk of HE[9,12,46].

More complex, however, is the use of pTIPS. Its role was initially proposed by García-Pagán et al[48], when indicating the use of the prosthesis in Child C score < 14 points or Child B patients with active bleeding on endoscopy, in the first 72 hours after combined treatment (endoscopic and vasoactive drugs), regardless of whether they responded to initial standard therapy. In this study it was demonstrated that patients who did the pTIPS had less control failure or rebleeding; a greater probability of not bleeding in 1 year, a low rate of HE and a higher actuarial survival in 1 year.

Several studies followed, occasionally with conflicting results. However, what seems certain is that advances in the treatment of bleeding have resulted in the majority of deaths no longer being due to bleeding per se, but to infections and/or worsening liver and kidney function. The idea is that most patients with early rebleeding are also those at greater risk of death, that is, those with greater liver impairment would not tolerate a second hit[49]. Thus, the proposal to place pTIPS in patients who were at high risk of rebleeding, even if the hemorrhage was initially controlled with combined treatment, is interesting and had already been praised at the Baveno VI meeting[50].

An important systematic review and metanalysis of individual data[51] evaluated the role of pTIPS in at-risk patients. Seven studies (three of which were controlled and randomized) with more than 1300 patients demonstrated that pTIPS increased overall survival in at-risk patients. It also increased the survival of Child B patients with bleeding, but only in those with a score greater than 7, thus refining patient selection. In relation to Child C patients with a score below 14, an increase in survival was also observed. The authors conclude that pTIPS increases control of bleeding and ascites, without causing more HE.

As a prospective controlled and randomized study with negative results was published later[52] and was not included in the previously mentioned metanalysis, it was recently revisited, confirming the greater survival with the use of pTIPS in high-risk patients with cirrhosis and bleeding due to ruptured varicose veins[53].

Despite the need for more randomized studies to validate the findings, the study[54] that evaluates the effect of pTIPS placement time on results is interesting, given the possible difficulties in providing the prosthesis within 72 hours. The aforementioned study demonstrated that when pTIPS is placed after this period, the transplant-free survival rate at 1 year; long-term survival and frequency of rebleeding, HE and new/worsened ascites did not differ. In this way, pTIPS would offer similar short- and long-term survival benefits.

It is also interesting to highlight the study that demonstrates that HE is not a contraindication for pTIPS[55]. In this observational study of more than 2000 patients evaluating those considered high-risk with HE at admission, pTIPS was associated with lower 1-year mortality when compared to conventional treatment. We emphasize that the incidence of HE was similar between patients with pTIPS and those who did not undergo this treatment. Currently, both Baveno VII and the American Association for the Study of Liver Diseases (AASLD) do not contraindicate its use in patients with HE on admission[9,46].

Despite the advantages of using pTIPS in patients with gastroesophageal varices, its use is challenging and has not been incorporated into clinical practice. Thus, despite evidence and clinical guidelines regarding pTIPS, less than 20% of eligible patients are treated with pTIPS[45,56].

TIPS IN THE TREATMENT OF PATIENTS WITH ASCITES

The presence of ascites is the main cause of decompensation in advanced chronic liver disease. In its treatment, it is essential that the cause of the liver disease is identified, ruled out or treated, when possible, and, whenever necessary, a sodium-restricted diet and the use of diuretics are followed. In patients with massive peritoneal effusion (tense ascites), the therapeutic proposal is therapeutic paracentesis with albumin replacement. By doing so, it is possible to obtain the control ascites in most cases[9,57]. In less than 10% of cases in which therapeutic success is not achieved, we may be faced with a patient with refractory ascites[58]. In these patients, the initial treatment proposal is also therapeutic paracentesis with volume replacement with albumin. However, some authors suggest that the use of TIPS is a proposal to be discussed. In this sense, seven prospective controlled and randomized studies were carried out, comparing therapeutic paracentesis and TIPS, including, in total, more than 450 patients. Thereafter, seven metanalyses were performed in patients with refractory ascites (some patients had recurrent ascites)[21,59-64]. As a rule, ascites control was better with TIPS despite a higher incidence of HE. However, regarding survival, the results were discordant. Despite the methodological bias that can be considered in some of the studies included, some metanalyses did not show an increase in survival[21,59-61,63], while others demonstrated a better prognosis in patients with refractory ascites[62,64]. We emphasize that none of the studies used covered TIPS.

Both the European Association for the Study of the Liver (EASL) and AASLD understand that the initial treatment of patients with refractory ascites should be therapeutic paracentesis with albumin replacement, with TIPS having a role in those who do not respond to treatment[9,57].

The potential effect of TIPS on patients with ascites may be debatable when it is not categorized as refractory. However, in those patients with recurrent ascites that are difficult to manage and unresponsive to therapeutic paracentesis, TIPS may be recommended[9,49,65]. In this regard, it is of interest the study by Bureau et al[66], which evaluated the role of covered TIPS in the survival of patients with recurrent ascites. In this prospective and randomized study, it was observed that in patients who used TIPS, the number of paracenteses was lower, there was less bleeding related to PH and a shorter hospitalization time. Interestingly, the probability of HE in one year was similar in both groups. However, the most significant was the gain in 1-year survival without transplantation. We emphasize that patient selection is essential, always paying attention to contraindications to its use, as well as potential adverse effects.

Regarding the treatment of patients with refractory ascites, a recent systematic review and metanalysis which evaluates different treatment proposals for this population is noteworthy[67]. In this study, among patients who used TIPS, mortality at 1 year was 33%, but the most interesting is that when evaluating the most recent studies, in addition to a lower incidence of HE, mortality was even lower (26% vs 44%), probably reflecting the improved technique and better patient selection.

Careful cardiac evaluation and prophylactic treatment of pre-TIPS HE can reduce complications after its use, as well as controlled expansion sub dilated TIPS can significantly reduce the incidence of HE. Technical advances with the use of these prosthesis have provided greater survival in these patients[68].

An interesting study that, despite being retrospective, investigated 341 patients undergoing TIPS for therapy of refractory or recurrent ascites. The authors demonstrated that the extent of reduction in the HVPG and/or the lowering of HVPG under than 10 mmHg after TIPS placement, promotes a better control of ascites and greater survival of patients[69].

It is important to highlight the fact that although sarcopenia is a risk factor for patients to develop HE after TIPS, the TIPS insertion favors the gain of muscle mass, reducing the possibility of sarcopenia and even favoring greater survival. This apparent paradox may be related to patient selection or different definitions of sacopenia.

Likewise, the importance of renal injury in the context of ascites treated with TIPS can be analyzed. Therefore, the impact of renal failure before TIPS on the clinical outcome of these patients and its role on renal function in patients with pre-existing renal dysfunction must be evaluated. The answer to this dilemma is complex since, if on the one hand creatinine levels can even be considered a contraindication for the use of the prosthesis, its use improves patients' renal function and may even be indicated in patients with syndrome hepatorenal. Therefore, the decision to place TIPS in patients with renal dysfunction is generally made on a case-by-case basis and taking into account other predictors of outcome[36].

In the series evaluated in our medical center, it was observed that after using TIPS, refractory ascites resolved in 3.1% and was controlled in 50.0% of cases[47].

From what has been exposed, we understand a relevant role for TIPS in patients with refractory ascites who are contraindicated to liver transplantation or in those who are expected to remain on the list for a long time, as well as in patients with recurrent ascites, after careful evaluation. We understand that the effectiveness and risk of adverse effects of TIPS used to treat ascites depend on a combination of characteristics such as age, degree of liver, kidney and heart dysfunction, as well as the type of ascites (recurrent or refractory), but we believe that once the patient is selected judiciously, the benefit will be evident.

TIPS AND FUTURE DECOMPENSATION

According to the last meeting by Baveno[46], future decompensation in cirrhosis represents a stage of the disease that translates into a poor prognosis, since it is associated with an even higher mortality than that observed during the first decompensation. It can be defined as a second episode of decompensation related to PH (ascites, variceal hemorrhage or HE) and/or jaundice; development of recurrent variceal bleeding, ascites requiring three or more large-volume paracenteses in 1 year, recurrent HE, development of spontaneous bacterial peritonitis (SBP) and/or hepatorenal syndrome associated with acute kidney injury (HRS-AKI) or in patients who presented only with hemorrhage and who develop ascites, HE or jaundice after recovering from the bleeding episode.

Given the poor evolution of these patients, it is essential to prevent future decompensation and within this context we must consider the role of TIPS. In this regard, a systematic review and metanalysis[70] was recently carried out, evaluating almost 4000 patients and, after carrying out a propensity score, 2338 patients with similar characteristics were evaluated after the use of covered TIPS in comparison with standard treatment in the management of refractory ascites and in the prevention of rebleeding. It was thus demonstrated, that TIPS decreased the incidence of a new decompensation event (new or worsening ascites, variceal bleeding or rebleeding, HE, jaundice, HRS-AKI and SBP) and increased survival in selected patients. The key aspects regarding TIPS are highlighted in Table 1.

Table 1 Key points concerning transjugular intrahepatic portosystemic shunt.

Technical aspects	Perform TIPS with anesthetic sedation or general anesthesia
	Use prosthesis coated with PTFE
	Measure HVPG
	Puncture the portal vein branch guided by abdominal ultrasound
	Use preferably a prosthesis of 8 mm
	Monitoring patients to assess TIPS patency, with doppler ultrasound performed at 1 week, 3 months, 6 months and then every 6 months
Indications	Refractory ascites
	Recurrent ascites that are difficult to manage
	Variceal bleeding unresponsive to pharmacological treatment combined with endoscopic therapy
	Variceal rebleeding in the first 5 days
	High risk for rebleeding (pTIPS): Child C score < 14 points or Child B with a score > 7 with active bleeding on endoscopy, in the first 72 hours after combined treatment (endoscopic and vasoactive drugs), regardless of whether they responded to initial standard therapy
	Hepatic hydrothorax
	Budd-Chiari syndrome
	Portosinusoidal vascular disorder
	Hepatorenal syndrome not associated with AKI
	To prevent future decompensation in cirrhosis
Contraindications	Absolute: Severe uncontrolled HE, systemic infection or sepsis, congestive heart failure (stage C or D, or a documented ejection fraction < 50%); severe pulmonary arterial hypertension, untreated biliary obstruction
	Relative: Very high MELD score, Child-Pugh score > 13 points, severe coagulopathy, polycystic liver disease, portal or hepatic vein occlusion and intrahepatic tumors
Complications	HE, deterioration of liver function and complications related to cardiac overload (low-risk if BNP < 40 pg/mL; NT-proBNP < 125 pg/mL; absence of a prolonged QT interval and diastolic dysfunction criteria on the echocardiogram)

TIPS: Transjugular intrahepatic portosystemic shunt; HVPG: Hepatic venous pressure gradient; PTFE: Polytetrafluoroethylene; pTIPS: Preemptive transjugular intrahepatic portosystemic shunt; MELD: Model for end stage liver diseases; HE: Hepatic encephalopathy BNP: Brain natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide; AKI: Acute kidney injury.

CONCLUSION

In conclusion, although TIPS is a procedure introduced more than 30 years ago, and is sometimes an essential treatment for patients with PH, it is often neglected, which is why we believe it is very important for the hepatologist to form a multidisciplinary team, where the role of the radiologist with experience in interventional procedures is highlighted.