Editor: Moon Young Kim, Yonsei University Wonju College of Medicine, Korea
Transjugular intrahepatic portosystemic shunt (TIPS) is an effective interventional procedure to relieve portal hypertension, which is a main mechanism for the development of complications of liver cirrhosis (LC), such as variceal hemorrhage, ascites, and hepatorenal syndrome. However, the high incidence of adverse events after TIPS implementation limits its application in clinical practice. Esophageal variceal hemorrhage is one of the major indications for TIPS. Recently, preemptively performed TIPS has been recommended, as several studies have shown that TIPS significantly reduced mortality as well as rebleeding or failure to control bleeding in patients who are at high risk of treatment failure for bleeding control with endoscopic variceal ligation and vasoactive drugs. Meanwhile, recurrent ascites is another indication for TIPS with a proven survival benefit. TIPS may also be considered as an effective treatment for other LC complications, usually as an alternative therapy. Although there are concerns about the development of hepatic encephalopathy and hepatic dysfunction after TIPS implementation, careful patient selection using prognostic scores can lead to excellent outcomes. Assessments of cardiac and renal function prior to TIPS may also be considered to improve patient prognosis.
Complications of decompensated liver cirrhosis (LC) can seriously impair the quality of life and also increase the morbidity and mortality rates of patients. Although liver transplantation (LT) is the best way to reverse the clinical course of patients with decompensated LC, only a limited number of the patients may undergo LT due to a persistent shortage of viable organs. Portal hypertension is the main pathologic mechanism driving the occurrence of LC complications. First-line treatments for such complications, which include sodium restrictions and the use of diuretics for ascites or vasoactive drugs and endoscopic therapy for variceal bleeding, do not aim to alleviate portal hypertension itself but instead manage symptoms; therefore, patients may still suffer from recurrent episodes of these LC complications.
Transjugular intrahepatic portosystemic shunt (TIPS) robustly reduces portal hypertension by establishing a shunt within the liver. The procedure is performed by creating an intrahepatic portosystemic shunt connecting the right or main portal vein to the hepatic vein, aiming to reduce the porto-systemic pressure gradient (PPG) while maintaining adequate liver perfusion (
Until 2000, TIPS was performed using bare metal stents, thus carrying a significant drawback of shunt dysfunction due to stent stenosis occurring in more than 50% of patients within 1 year, mainly by the proliferation of the intima [
TIPS is usually indicated as a rescue therapy in LC patients who have developed complications with no response to first-line treatment, and sometimes as a bridging therapy for LT. However, practical clinicians often hesitate to decide whether to perform TIPS in LC patients due to the adverse effects of TIPS. In this review, we aimed to demonstrate the most suitable timing and candidates for performing TIPS in patients with LC complications. We also summarized the main complications of TIPS, as well as their countermeasures.
Since variceal bleeding or ascites usually occurs with a PPG of above 12 mmHg, TIPS is performed to reach a goal of reducing the PPG to below 12 mmHg or by 50% or more of the baseline value [
Although the incidence of shunt dysfunction significantly decreased after using PTFE-covered stents, guidelines suggest performing a doppler ultrasound to examine shunt patency at intervals of 6 or 12 months after the procedure [
The optimal timing for TIPS in LC complications is schematically shown in
Acute VH should be managed with endoscopic treatment within 12 hours of admission, if the patient is hemodynamically stable, together with the administration of antibiotics and vasoactive drugs, such as somatostatin, octreotide, or terlipressin. The implementation of TIPS can be considered for uncontrolled VH or for secondary prevention of esophageal VH. TIPS as a preemptive therapy for patients at high risk of treatment failure with standard treatment (e.g., endoscopic therapy, vasoactive drugs, and antibiotics) is nowadays highly recommended. TIPS is not indicated for primary prevention of esophageal VH.
Considering the high risk of liver decompensation or death after treatment failure for acute VH, the use of preemptive TIPS (pTIPS) was suggested in terms of early application of effective treatment [
In the first RCT for pTIPS, LC patients who were admitted for acute VH and a hepatic venous pressure gradient (HVPG) greater than 20 mmHg were defined as a high-risk group for treatment failure and randomly allocated to undergo pTIPS (within 24 hours after admission) or not. Preemptive TIPS significantly reduced the treatment failure, in-hospital, and 1-year mortality rates compared to medical treatment. However, interpretation of the results should consider the limitations inherent with using medical treatment different from the current standard therapy and when using bare stents, recently exchanged for PTFE-covered stents [
However, some observational studies have demonstrated no survival benefit from pTIPS; therefore, guidelines of the American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Korean Association for the Study of the Liver all recommend pTIPS, with the caveat that further studies are needed [
Regarding the timing of pTIPS, the procedure was usually performed within 3 days of index bleeding in previous studies, but the same effects have also been demonstrated when pTIPS was performed within 5 days of index bleeding [
Although RCTs are still lacking, current guidelines recommend TIPS as a rescue therapy for patients who experience persistent bleeding or severe rebleeding despite standard treatment within the first 5 days after admission for acute VH, which occurs in 10 to 15% of the patients [
Rebleeding of esophageal VH is accompanied by a significant mortality rate of up to 33%; thus, nonselective beta-blockers (NSBB) in combination with endoscopic band ligation (EBL) are recommended for secondary prevention in patients who experienced a first episode of VH [
Acute bleeding from gastroesophageal varices type 1 (GOV1) can be controlled by endoscopic therapy, either by EBL or cyanoacrylate glue injection. In the case of bleeding from cardiofundal varices (GOV2 or isolated gastric varices type 1), the guidelines of AASLD and EASL recommend TIPS as a treatment of choice for the control of acute bleeding and the prevention of rebleeding from cardiofundal varices [
Although large-volume paracentesis (LVP) is the first-line treatment for uncontrolled ascites despite high-dose diuretics and salt restriction, TIPS can be considered an effective alternative in patients who require LVP at frequent intervals [
In patients with refractory or recurrent ascites, TIPS can also improve sarcopenia due to increased absorption of intestinal nutrients by relieving portal hypertension and decreased protein loss by paracentesis [
About 5–10% of patients with LC suffer from hepatic hydrothorax, and 20–25% of them have refractory hepatic hydrothorax that does not respond to salt restriction or high-dose diuretics [
Although HCC is a relative contraindication to TIPS, it can be considered if anatomically accessible and clinically necessary [
There has been no RCT that compared the use of TIPS to medical treatment (i.e., vasoconstrictors and albumin) in patients with HRS. To date, the role of TIPS in HRS remains controversial. TIPS can alleviate circulatory and neurohormonal derangement by reducing portal hypertension; therefore, theoretically, TIPS can be beneficial for patients with HRS. In patients with type 1 or 2 HRS who received TIPS, limited data showed that renal function was improved [
Regarding BCS, current guidelines recommend TIPS to be performed in symptomatic patients if anticoagulation therapy or hepatic vein interventions, such as stenting or angioplasty, have failed [
General contraindications for TIPS, as stated in guidelines, are as follows: congestive heart failure, pulmonary hypertension (absolutely contraindicated when pulmonary pressure is above a mean value of 45 mmHg), progressive renal failure, HE of grade 2 or higher according to the West Haven criteria, uncontrolled systemic infection, severe thrombocytopenia, or coagulopathy (
TIPS is relatively contraindicated in patients with severe hepatic dysfunction, such as a serum bilirubin level of greater than 4 mg/dL or MELD score of greater than 15 to 18 points [
Hepatic dysfunction can develop after TIPS, since the portal blood flow bypasses intrahepatic circulation and travels directly to the inferior vena cava through a portosystemic shunt. The liver can also be affected by hypotension during the procedure. A previous study reported a significant incidence of hepatic failure (death, LT, or MELD score >18 points) within 3 months after TIPS as 9.3% among patients with baseline MELD scores of 9.6 points (range, 6–12). In these patients, MELD scores of 11–12 points, low hemoglobin concentrations, and low platelet counts were independently associated with the development of early hepatic failure. However, the relatively high rate of hepatic failure might be due to the fact that this study enrolled patients who underwent TIPS between 1999 and 2012 at a single center [
The deterioration of hepatic function is usually a transient event after TIPS, and is manifested by the elevation of bilirubin level [
HE is the most concerning complication that may develop after TIPS; therefore, guidelines do not recommend TIPS implementation in patients on recurrent or persistent overt HE (grade ≥2 according to the West Haven criteria) [
A significant proportion of LC patients have sarcopenia and are at an increased risk of developing HE, as the role of muscle in the disposal of ammonia is enhanced in LC patients [
A previous RCT showed that prophylactic use of rifaximin or lactitol was not effective in reducing the development of post-TIPS HE [
LC patients are in a vulnerable state for developing cardiac dysfunction. The prevalence of cirrhotic cardiomyopathy, which refers to cardiac dysfunction in LC patients without known cardiac disease, ranges from 26% to 81%, according to existing studies [
Several previous studies have focused on predicting cardiac complications after TIPS. In a retrospective study, 50.4% of LC patients had abnormal findings on echocardiography performed before TIPS, but the results of the exam did not predict mortality. However, this study was limited in that the predictive role of echocardiography for the development of cardiac complications after TIPS was not evaluated [
TIPS restores hemodynamic and neurohormonal derangement, increasing natriuresis within 4 weeks, which may lead to an improvement in renal function [
Several prognostic scores for predicting survival after TIPS have been developed, such as the CTP, MELD, or MELD-Na scores [
Although clinicians may have concerns about performing TIPS due to the non-negligible complications, recent studies have shown high efficacy of TIPS compared to other treatments and presented an acceptable complication rate, albeit not different from when TIP was not performed. Moreover, the survival benefit of pTIPS was proved in patients who are at high risk for treatment failure of esophageal VH. Early TIPS before patients suffer from repeated LVP for refractory or recurrent ascites showed improved quality of life and cost-effectiveness compared to LVP, as well as a significantly higher 1-year transplant-free survival. In the context of organ shortage for LT, the role of TIPS needs to be actively considered in clinical practice. However, to achieve the benefits of TIPS, proper timing and patient selection are crucial.
Guarantor of the article: Sung Won Lee
Specific author contributions: Study concept and design: Sung Won Lee and Hae Lim Lee; Wrote the paper: Sung Won Lee and Hae Lim Lee. All authors have approved this final version of the manuscript.
American Association for the Study of Liver Diseases
acute on chronic liver failure
adjusted hazard ratio
Budd-Chiari syndrome
brain natriuretic peptide
balloon occluded retrograde transvenous obliteration
confidence interval
Child-Turcotte-Pugh
European Association for the Study of the Liver
endoscopic band ligation
estimated glomerular filtration rate
Freiburg index of post-TIP survival
gastroesophageal varices type 1
hepatocellular carcinoma
hepatic encephalopathy
hepatorenal syndrome
hepatic venous pressure gradient
liver cirrhosis
liver transplantation
large-volume paracentesis
model for end-stage liver disease
nonselective beta-blockers
odds ratio
porto-systemic pressure gradient
polytetrafluoroethylene
preemptive transjugular intrahepatic portosystemic shunt
randomized controlled trial
skeletal muscle index
transarterial chemoembolization
transjugular intrahepatic portosystemic shunt
Overview of TIPS. The main complications of TIPS and their countermeasures are presented. TIPS, transjugular intrahepatic portosystemic shunt; PPG, porto-systemic pressure gradient.
The main indications for TIPS are presented. CTP, Child-Turcotte-Pugh; EBL, endoscopic band ligation; NSBB, nonselective beta-blockers; GOV, gastroesophageal varices; IGV, isolated gastric varices; EVO, endoscopic variceal obliteration; BRTO, balloon occluded retrograde transvenous obliteration; PARTO, plug-assisted retrograde transvenous obliteration; TIPS, transjugular intrahepatic portosystemic shunt. *The survival benefit of TIPS was demonstrated in randomized controlled trials.
Summary of current international guidelines
AASLD [ |
EASL [ |
Baveno VI [ |
KASL [ |
|
---|---|---|---|---|
Esophageal VH | ||||
Rescue therapy | Recommended | Strong (1) | Recommended (B) | Weak (2) |
Secondary prevention |
Recommended | Strong (1) | Recommended (B) | Strong (1) |
Preemptive therapy |
Recommended | Weak (2) | Strongest (A) | Weak (2) |
Debatable in patients with CTP B | ||||
Gastric VH: GOV2 or IGV1 | ||||
Control of bleeding | Recommended | Strong (1) | Preemptive TIPS for GOV2 |
TIPS or RTO, strong (1) |
Cf. BRTO; weak (2) | Cf. EVO for IGV (A) and GOV2 (D) | |||
Secondary prevention | Recommended | Strong (1) | Weakest (D) | Weak (2) |
Cf. BRTO is also TOC | ||||
Refractory/recurrent ascites | Recommended | Strong (1) | No mention | Weak (2) |
Refractory/recurrent hepatic hydrothorax | Recommended | Strong (1) | No mention | Weak (2) |
Hepatorenal syndrome | Insufficient data | Insufficient data in HRS-AKI | No mention | Insufficient data |
HRS-NAKI, weak (2) |
The recommendation level for each indication is shown in parentheses.
The grade of recommendations ranges from 1 (strong) to 2 (weak) in the guidelines of EASL and KASL, and from A (strongest) to D (weakest) in the BAVENO VI guideline. The AASLD guideline does not report levels of recommendation.
AASLD, American Association for the Study of Liver Disease; EASL, European Association for the Study of the Liver; KASL, Korean Association for the Study of the Liver; VH, variceal hemorrhage; CTP, Child-Turcotte-Pugh; GVO, gastroesophageal varices; BRTO, balloon-occluded retrograde transvenous obliteration; TIPS, transjugular intrahepatic portosystemic shunt; EVO, endoscopic variceal obliteration; IGV, isolated gastric varices; RTO retrograde transvenous obliteration; TOC, treatment of choice; HRS, hepatorenal syndrome; AKI, acute kidney injury; NAKI, non-acute kidney injury.
For secondary prevention of esophageal VH, guidelines suggest TIPS if the first-line treatment (endoscopic band ligation [EBL] + non-selective beta-blockers [NSBB]) fails or if patients are intolerant to NSBB.
Preemptive TIPS (placed within 72 hours after initial endoscopy) is recommended in patients at high risk of treatment failure with endoscopic therapy and vasoactive drugs for esophageal variceal hemorrhage. Patients with CTP class C (<14 points) or those with CTP class B and active bleeding at endoscopy are at high risk of treatment failure.
KASL recommends EVO as the first-line line treatment for gastric VH; strong (1). TIPS or RTO (BRTO or PARTO) can be performed instead of EVO.
KASL recommends EVO or BRTO as well as TIPS for secondary prevention of gastric VH (GOV2 or ICG1); weak (2).
Absolute and relative contraindications for TIPS
Absolute | Relative |
---|---|
Primary prevention of variceal hemorrhage | Age >65 years |
Hepatic encephalopathy (grade ≥2) |
MELD score >15–18 |
Uncontrolled systemic infection or sepsis | Total bilirubin >3–4 mg/dL |
Severe pulmonary hypertension (>45 mmHg) | Severe thrombocytopenia or coagulopathy |
Congestive heart failure | Progressive renal failure |
Severe tricuspid regurgitation | Anatomical problems (such as central tumor, polycystic liver disease) |
Unrelieved biliary obstruction |
TIPS, transjugular intrahepatic portosystemic shunt; MELD, model for end-stage liver disease.
The grade of hepatic encephalopathy was according to the West Haven criteria.