Indications
The two indications with the strongest clinical evidence of TIPS efficacy are secondary
prevention of esophageal variceal bleeding and treatment of refractory ascites. Meta-analyses
and multiple randomized controlled trials support TIPS in both circumstances. Additional
indications, some of which are emerging as controversial first-line treatments, are
listed in [Tables 1] and [2] and described in detail below.[2] Firm indications are likely to expand in the future.
Table 1
Indications for TIPS related to variceal bleeding
|
Indications
|
Role of TIPS
|
|
Secondary prophylaxis of variceal bleeding
|
Rescue therapy[a]
|
|
Acute variceal bleeding
|
Rescue therapy[a]
|
|
Portal hypertensive gastropathy
|
Rescue therapy
|
|
Recurrent acute variceal bleeding
|
First-line therapy[a]
|
Abbreviations: HVPG, hepatic venous pressure gradient; TIPS, transjugular intrahepatic
portosystemic shunt.
Note: Gastric varices might require variceal embolization.
a Applies to esophageal and ectopic varices.
Table 2
Indications for TIPS
|
Variceal bleeding, secondary prevention, and acute bleeding refractory to medical
and endoscopic treatments
|
|
Refractory ascites
|
|
Hepatorenal syndrome (types 1 and 2)
|
|
Budd–Chiari syndrome
|
|
Hepatic veno-occlusive disease
|
|
Hepatic hydrothorax
|
|
Portal hypertensive gastropathy
|
|
Hepatopulmonary syndrome
|
|
Portal vein thrombosis
|
Abbreviation: TIPS, transjugular intrahepatic portosystemic shunt.
Prevention of Variceal Rebleeding
Strong evidence supports the use of TIPS for secondary prevention of esophageal variceal
bleeding ([Fig. 1]). This indication has been extensively studied, and TIPS has been compared with
alternative forms of therapy in 13 randomized controlled trials (which describe results
for 948 patients) and several meta-analyses. A critical guideline is that a post-TIPS
portosystemic pressure gradient (PPG) less than 12 mm Hg should be obtained to prevent
a rebleeding episode.[3]
Figure 1 Coronal contrast-enhanced computed tomography of the abdomen demonstrates avidly
enhancing, markedly tortuous, and dilated varices surrounding the lower esophagus
(yellow arrow). There is also significant perihepatic and perisplenic ascites (black
arrows). The spleen is enlarged secondary to portal hypertension.
A meta-analysis performed in 1999 clearly demonstrated that TIPS is substantially
more effective in long-term prevention of rebleeding than is endoscopic therapy (19%
incidence of rebleeding vs. 47%, respectively).[4] A more recent meta-analysis confirmed TIPS advantage in prevention of rebleeding
in comparison to endoscopic therapy (19.0% incidence of rebleeding vs. 43.8%, respectively).[5] The reproducibility of data over the course of two decades is convincing. Further,
a large retrospective study demonstrated that variceal embolization at the time of
TIPS significantly prevented the rate of recurrent variceal bleeding in comparison
to TIPS alone (84 vs. 61% at 2 years; 81 vs. 53% at 4 years, respectively).[6] All-cause mortality rates are similar between TIPS and endoscopic therapy groups.
Unfortunately, TIPS is associated with a significantly higher rate of development
of hepatic encephalopathy (HE) than standard therapy in the management of esophageal
varices.[7] Due to this drawback, many advocate that TIPS be used predominately as a backup
to endoscopic therapy for secondary prophylaxis of variceal bleeding.
TIPS and distal splenorenal shunt were reported to be equally efficacious with no
difference in HE in the prevention of rebleeding at a follow-up of 2 to 8 years for
patients with Child–Pugh A or B cirrhosis.[8] This study also demonstrated an exceptionally low rebleeding rate following TIPS
(10.5% at 48 months), and encouraging survival rates at 2 and 5 years of 88 and 61%,
respectively. While patients undergoing TIPS required more postprocedure interventions
to maintain patency, the use of bare stents almost certainly contributed to this.
Importantly, cost analysis favored TIPS.[7] The 2009 American Association for the Study of Liver Disease (AASLD) updated guidelines
judged these two approaches equally effective.[9] These studies further emphasize that survival rates following TIPS vary widely depending
on the primary indication for the procedure and the underlying health of the patient.
Selection of appropriate patients is therefore of utmost importance in determining
outcome.
Early utilization of TIPS demonstrated promising results in a study by García-Pagán
et al, who reported results of a prospective randomized study of 63 patients with
cirrhosis and acute variceal bleeding at high risk of failure with standard treatment
(Child–Pugh class C, with a score < 14, or Child–Pugh class B, but with active bleeding
at diagnostic endoscopy).[10] All were initially treated with vasoactive drugs and endoscopic therapy. They were
randomized within 24 hours of admission either: to a control group that received continued
administration of vasoactive drugs, followed by 3 to 5 days of treatment with propranolol
or naldol plus endoscopic band ligation (EBL) with insertion of TIPS reserved as rescue
therapy; or to early TIPS (within 72 hours of randomization). At 16 months median
follow-up, rebleeding or failure to control bleeding (14 patients vs. 1 patient, p = 0.001) and death (12 patients vs. 4 patients, p = 0.01) occurred significantly more frequently in the control group. No significant
difference in serious adverse events was observed between the two groups.[10]
In this same study, 1 year actuarial survival was 61% in the pharmacologic-EBL group
and 86% in the early TIPS group (p < 0.001). Seven patients in the control group, four of whom subsequently died, underwent
rescue TIPS, raising the question: would more of the patients receiving rescue TIPS
have survived had they received early TIPS? This prospective randomized controlled
trial clearly demonstrates that early TIPS significantly reduces the incidence of
treatment failure and early mortality in cirrhotic patients hospitalized for acute
variceal bleeding identified as at high risk of failure with standard treatment.
In a separate study, Monescillo et al demonstrated that patients with acute variceal
bleeds and a PPG > 20 mm Hg benefit from early TIPS intervention.[11] TIPS should therefore be considered for first-line treatment of patients identified
as likely to fail standard initial treatment.
Refractory Ascites
Six randomized controlled trials including a total of 390 patients, and two meta-analyses,
have confirmed the efficacy of TIPS in the treatment of refractory ascites ([Fig. 1]). TIPS provides a logical approach to reducing the formation of ascites by correcting
two major pathophysiologic determinants of ascites: first, it lowers the elevated
sinusoidal pressure that contributes significantly to the formation of ascites, and
second, TIPS leads to increased effective arterial blood volume, which in turn leads
to a downregulation of the renin–angiotensin–aldosterone axis and increased natriuresis.[12] TIPS also leads to increased venous return and increased cardiac output, which increases
the arterial pressure and the glomerular filtration rate; therefore, the functional
renal failure that occurs with and further promotes refractory ascites may also be
corrected.
A meta-analysis of four randomized controlled trials compared TIPS to large-volume
paracentesis in the treatment of refractory ascites.[13] TIPS was effective in controlling ascites in 70% of cases, more than three times
the 23% rate observed with large-volume paracentesis. A meta-analysis in 2005 showed
a 7.1-fold reduction in the risk of recurrence of tense ascites after TIPS.[14]
TIPS alone may not be sufficient for control of refractory ascites; many patients
still require short-term diuretics following the procedure as natriuresis slowly but
steadily increases over the course of up to 1 year. Compared with large-volume paracentesis,
TIPS improved transplant-free survival and the incidence of recurrent ascites in cirrhotic
patients with refractory ascites.[13] Survival of patients in this report was independently associated with age, bilirubin
levels, and serum sodium concentration. The probability of HE was significantly increased
following TIPS. Patients with low arterial pressure, high Model for End-Stage Liver
Disease (MELD) score, and a low PPG after TIPS had the greatest probability of experiencing
post-TIPS encephalopathy, again emphasizing the importance of proper patient evaluation
and selection in determining outcome.[13]
HE is the major adverse consequence of TIPS. Patients with refractory ascites typically
have severe cirrhosis, and 40% develop HE following TIPS.[9] In a randomized controlled trial comparing TIPS to paracentesis plus albumin, in
which the majority of patients were in the Child–Pugh C group and therefore at greater
risk of HE, significantly better survival without the need for liver transplant was
achieved in those undergoing TIPS.[15] Because TIPS is associated with an increased risk of HE and higher cost, many experts
consider repeat large-volume paracentesis to be the treatment of choice. However,
large-volume paracentesis is not without its limitations. Paracentesis does not prevent
recurrence of ascites and can instigate worsening circulatory dysfunction, leading
to the dreaded complication of hepatorenal syndrome (HRS). Paracentesis also carries
the risk of spontaneous bacterial peritonitis and incarceration of abdominal hernias.
The PPG required for effective control of refractory ascites in most patients is uncertain;
a gradient < 8 mm Hg has been suggested based on limited data.[16] Initially aiming for higher gradients may limit worsening of encephalopathy in individuals
with pre-existing HE, providing the potential for later enlargement of the TIPS if
HE is adequately controlled and diuresis is inadequate.[8]
As with other indications for the TIPS procedure, patient selection is paramount.
Early use of TIPS in selected candidates appears reasonable.[16] Regarding patient selection, the pre-TIPS bilirubin level is the parameter most
clearly associated with increased mortality.[16]
Acute Variceal Bleeding
TIPS is established as second-line therapy for acute variceal bleeding when medical
management, including pharmacologic and endoscopic therapy, has failed. The combination
of vasoactive drugs and endoscopic sclerotherapy is generally quite effective, achieving
hemostasis in > 80% of cases.[17] TIPS is more effective, controlling acute bleeding in 95% of cases, with a rebleeding
rate of just 18%, but due to post-TIPS encephalopathy, the need for post-TIPS evaluations,
and the cost of the procedure, many experts consider the TIPS procedure appropriate
only as rescue therapy.[9]
Results of surgical portocaval shunting must also be considered. Operative shunts,
such as distal splenorenal shunt, may be preferred in some patients in the Child–Pugh
A group because fewer postoperative interventions are required to ensure patency than
seen with TIPS. However, over the last two decades, the use of PTFE-covered stent
grafts in patients with TIPS has significantly reduced reintervention rates, resulting
in reduction in cost burden on the health care system.[7] Child–Pugh C patients are generally unable to tolerate general anesthesia or surgery,
and since TIPS may be performed without general anesthesia, TIPS provides these patients
with a unique opportunity for definitive treatment.
Acute Ectopic Variceal Bleeding
Ectopic varices comprise 1 to 5% of variceal bleeds in patients with intrahepatic
portal hypertension secondary to cirrhosis, and 20 to 30% of those with extrahepatic
portal hypertension ([Fig. 2]).[18]
Figure 2 Coronal contrast-enhanced computed tomography demonstrates avidly enhancing tortuous
and dilated rectal (hemorrhoidal) varices (arrow).
Since TIPS directly decompresses portal pressure, which is the cause of variceal rupture
(whether esophageal, gastric, intestinal, peritoneal, or stomal), patients with all
forms of varices should benefit from the portal pressure decompression achieved with
TIPS. Patients with varices inaccessible by means of endoscopy in whom banding or
injection cannot be performed particularly benefit from portal decompression procedures.
Gastric variceal bleeds require particular attention as they have a worse outcome
than esophageal variceal bleeds, with a mortality rate of 45 to 55% ([Fig. 3]).[19] Since gastric varices rebleed at even lower portal pressures following TIPS, additional
therapy, such as variceal embolization at the time of the TIPS, may be necessary.[9] Variceal embolization has also been achieved using the balloon-occluded retrograde
obliteration technique via gastrorenal shunts. Periodic surveillance of these patients
is vital since small increases in portal pressure may cause rebleeding.[20]
Figure 3 Axial contrast-enhanced computed tomography image through the abdomen demonstrates
enhancing, tortuous dilated varices (arrows) in the region of the gastric fundus.
Budd–Chiari Syndrome
TIPS is often more technically challenging in Budd–Chiari syndrome (BCS) as there
may be absence of normal hepatic veins to use as a starting point for the initial
puncture. A small segment of the origin of a hepatic vein from the inferior vena cava
(IVC), or a “stump,” is sometimes discovered at IVC venography. If the stump can be
accessed, the liver can be punctured via the stump and carbon dioxide portal venography
can assist in locating the portal venous system for subsequent access. In the case
of inaccessible hepatic veins secondary to occlusion of the ostia, a direct shunt
between the retrohepatic vena cava and portal vein may be established.
In patients presenting weeks to months after the initial formation of hepatic vein
thrombosis, the thrombus may no longer be amenable to anticoagulation alone, nor to
interventional procedures such as angioplasty or thrombolysis. TIPS is recommended
as the next step in management.[21] In those who have already failed thrombolytic therapy, and in those with poor hepatic
reserve, an occluded IVC, or a portal vein-infrahepatic vena caval pressure gradient
more than 10 mm Hg, TIPS is also recommended.
At European centers, TIPS is the most common form of intervention for BCS. Multiple
studies have demonstrated its technical success as well as its relatively low rate
of complications.[22] Rössle et al demonstrated an initial technical success in 33 out of 35 patients,
followed by 1- and 5-year transplant-free survival rates of 93 and 74%, respectively.[23]
In another series of patients with BCS who failed to improve with anticoagulation,
patients who had TIPS had transplant-free survival rates at 1 year of 88% and at 10
years of 69%, which were better than predicted.[24] TIPS patency was superior in those receiving covered stents.
The success of TIPS in the emergent acute setting of BCS, or “rescue TIPS,” has also
been validated.[25] TIPS may also serve as a bridge to liver transplant in this patient population.[22]
TIPS has the advantage over surgical side-to-side portocaval, mesocaval, and splenorenal
portosystemic shunts in that it may bypass caval stenosis or thrombus. Like a mesoatrial
shunt, TIPS provides outflow into the suprahepatic IVC, at a site proximal to a potential
intrahepatic stenosis. As patients with BCS are typically hypercoagulable, simultaneous
portal vein thrombosis (PVT) may be present; extended TIPS have been described in
such cases and have demonstrated success.[26]
The 2009 guidelines recommended TIPS in those patients with BCS who fail to improve
with anticoagulation alone.[8]
Portal Vein Thrombosis
PVT is characterized by the presence of a completely or partially obstructing thrombus
within the main portal vein or its intrahepatic portal branches, and can involve the
portal tributaries including the splenic vein or superior mesenteric vein (SMV). PVT
occurs in 4.4 to 15% of cirrhotic patients.[27] Hypercoagulable states, tumors, infection, pancreatitis, and trauma are common underlying
causes of noncirrhotic PVT. Early detection of PVT permits timely intervention and
prevention of complications, including variceal hemorrhage and intestinal ischemia.
The creation of a TIPS can be technically challenging in the presence of PVT, especially
when the thrombus is chronic and cavernous transformation of the portal vein has occurred.
Several approaches, including transhepatic, transjugular, transmesenteric using a
combined surgical approach, and transsplenic for recanalization of the portal vein,
have been described.[28] Advanced imaging tools, such as cone beam computed tomography and iGuide (Syngo
iGuide; Siemens Healthcare, Forchheim, Germany), are very useful in accessing patent
segments of the portal venous system in patients with PVT and cavernous transformation
of the portal vein. Wedged hepatic venography using carbon dioxide may better define
portal venous anatomy in cases of PVT. Once a puncture is performed, a guidewire is
used as a probe in an attempt to access the main portal vein. Portography obtained
via an angiographic catheter can confirm position. Interventions including pulse-spray
thrombolysis, reverse Fogarty maneuver, mechanical thrombectomy, or stent placement
can be implemented. Once the portal clot is maximally removed, the TIPS can be created.
Stating that “There is no established management algorithm for PVT in cirrhotic patients,”
Senzolo et al prospectively compared a control group of patients with nonmalignant
PVT who neither were anticoagulated nor had received TIPS, versus a study group, in
whom administration of low-molecular-weight heparin (LMWH) was planned.[29] If the patient had a contraindication to anticoagulation or the PVT progressed while
on LMWH, the patient was designated to undergo TIPS. The use of anticoagulation and
TIPS improved the chance of complete reperfusion, reduced portal hypertensive complications
(mainly variceal bleeding and intestinal venous ischemic episodes), and decreased
the rate of thrombus progression. Blum et al demonstrated that TIPS and recanalization
of the main portal vein is a safe and effective treatment for patients with cirrhosis
and noncavernous portal vein occlusion.[30] The presence of portal cavernous transformation and the degree of thrombus within
the main portal vein, the portal vein branches, and the SMV are independent predictors
of success.[31]
In PVT in noncirrhotic patients, studies have clearly demonstrated that anticoagulation
is safe and effective and the therapy of choice.[32] Anticoagulation prevents not only rethrombosis but also extension of thrombus into
the portal venous system, thereby preventing an increase in portal pressure. In approximately
10% of cases of acute PVT in noncirrhotics, however, the thrombus is resistant to
anticoagulation.[33] For chronic PVT in noncirrhotics, anticoagulant treatment is administered to only
30% of patients, reflecting concerns about the use of anticoagulation in the presence
of gastroesophageal varices, low platelet counts, and impaired coagulation.[34] Two separate studies demonstrated the effectiveness of combined TIPS and localized
thrombolytic therapy in noncirrhotic patients with symptomatic massive PVT.[35]
[36]
Hepatic Veno-occlusive Disease
Following hematopoietic cell transplantation, veno-occlusive disease of the liver
is a life-threatening complication. Liver failure and acute portal hypertension are
frequently present. In a case series of 10 patients with veno-occlusive disease, TIPS
controlled portal hypertension in all 10 patients, supporting consideration of early
TIPS to improve survival rates in those patients with veno-occlusive disease.[37]
Hepatic Hydrothorax
Several retrospective case series support the use of TIPS in the setting of hepatic
hydrothorax, defined as a significant pleural effusion, typically larger than 500
mL, in a cirrhotic patient without primary pulmonary or cardiac disease.[38] Approximately 5% of cirrhotic patients are affected with hepatic hydrothorax.[38] Complete resolution of hydrothorax occurs in 57 to 71% of patients, and at least
partial improvement in dyspnea and decrease in frequency of thoracenteses has been
reported in 68 to 82% of patients.[38]
[39]
Hepatorenal Syndrome
TIPS significantly reduces the PPG, significantly improves renal function within 2
weeks of the procedure (creatinine clearance from 18 to 48 mL/min), and improves survival
rates of both types I and II HRS.[40] Serum bilirubin level and HRS subtype are independent predictors of survival following
TIPS.[40]
Hepatopulmonary Syndrome
In a small series, TIPS neither improved nor worsened pulmonary gas exchange in patients
with hepatopulmonary syndrome (HPS).[41] While this does not directly support TIPS in HPS, it demonstrates its relative safety
when performed for the treatment of other complications of portal hypertension in
patients with HPS.
Portal Hypertensive Gastropathy
Portal hypertensive gastropathy (PHG) is characterized by an endoscopic abnormality
of the gastric mucosa that is classically described as a “snakeskin” pattern, with
or without red spots, typically located in the fundus or body of the stomach.[42]
In patients with PHG, level 4 evidence in the form of case series supports the usefulness
of TIPS.[43] TIPS improves endoscopic findings of PHG, and in one patient with massive hematemesis
hemorrhage completely stopped following TIPS. The mechanism by which PHG improves
following TIPS may be closely related to the improvement of the injured gastric perfusion
in cirrhotic patients with PHG.
Contraindications
The contraindications to TIPS are best appreciated with an understanding of its hemodynamic
consequences.
Hemodynamic Consequences of Portosystemic Shunting
Creation of a TIPS shunts ammonia and other neurotoxins directly into the systemic
circulation, increasing the incidence of HE. HE often occurs soon after TIPS (90%
within the first 3 months), before the apparent eventual cerebral adaptation to gut-derived
neurotoxins. A major risk factor for postprocedural development of HE is a prior history
of HE.[44]
As a consequence of TIPS, hepatic arterial flow assumes increased responsibility for
sinusoidal perfusion since portal flow normally supplies 60% of oxygen delivery to
the liver. In some patients, such as those with hepatic artery stenosis, hepatic artery
flow may be insufficient to adequately compensate for the lack of portal flow, resulting
in relative ischemia and progressive hepatic failure.[45]
In decompressing the portal system, portal blood is shunted to the systemic circulation,
leading to increased systemic venous blood return. The post-TIPS elevation in preload
can precipitate heart failure not only in patients with pre-existing overt heart failure
or severe tricuspid regurgitation but also in patients with an underlying subclinical
cardiac insufficiency. The increased preload may also worsen undiagnosed portopulmonary
hypertension.
Absolute and Relative Contraindications
Several pre-existing clinical conditions increase the likelihood of an unfavorable
outcome following TIPS ([Table 3]). Absolute contraindications to TIPS placement include severe pulmonary hypertension
(mean pulmonary pressure > 45 mm Hg), severe tricuspid regurgitation, congestive heart
failure, severe liver failure, and polycystic liver disease. Also, no patients with
active sepsis should undergo TIPS. Relative contraindications include severe obstructive
arteriopathy, and hepatic artery and celiac trunk stenosis, which may prevent adequate
sinusoidal perfusion by the hepatic artery. Other relative contraindications include
recurrent HE, hepatocellular carcinoma and other liver tumors, and bile duct dilation.
Table 3
Contraindications to placement of a TIPS
|
Absolute
|
Relative
|
|
Primary prevention of variceal bleeding
|
Hepatoma, particularly if central
|
|
Severe congestive heart failure
|
Obstruction of all hepatic veins
|
|
Tricuspid regurgitation
|
Hepatic encephalopathy
|
|
Multiple hepatic cysts
|
Significant portal vein thrombosis
|
|
Uncontrolled systemic infection or sepsis
|
Severe uncorrectable coagulopathy (INR > 5)
|
|
Unrelieved biliary obstruction
|
Thrombocytopenia (< 20,000 platelets/mm3)
|
|
Severe pulmonary hypertension
|
Moderate pulmonary hypertension
|
Abbreviations: INR, international normalized ratio; TIPS, transjugular intrahepatic
portosystemic shunt.
Patient Work-Up
Determining whether or not a patient should undergo a TIPS procedure should be a team-based
decision involving the hepatologist or gastroenterologist caring for the patient as
well as the interventional radiologist. A general anesthesia consultation is typically
required. Several clinical questions must first be answered, including: Is TIPS indicated
for treatment of this specific complication of portal hypertension? Are absolute or
relative contraindications present? Does the patient have a history of HE? What is
the patient's MELD score?
Post-TIPS HE occurs more commonly in cirrhotic patients with refractory ascites than
in those undergoing TIPS for variceal bleeding, suggesting that patients with severe
cirrhosis are more likely to experience encephalopathy. This factor should be considered
in the selection of patients for the TIPS procedure.[12] The main risk factors for developing HE include age > 65 years, Child score > 12,
prior HE, placement of a large diameter stent (> 10 mm), and low PPG (< 5 mm Hg).[44] The risk of HE may outweigh the potential benefit of the procedure in patients possessing
these risk factors.
One series reported that careful selection of patients who received TIPS for variceal
bleeding, and aiming for a PPG reduction to just below the 12 mm Hg threshold required
to prevent rebleeding, led to post-TIPS HE that was usually short-lived and easily
managed (i.e., withdrawal of diuretics or psychotropic medication, commencement of
lactulose, use of antimicrobials).[44] While this study reported an HE incidence of 34.5%, the majority of the cases were
“low grade” and resolved with conservative management. Since HE can also be precipitated
by variceal bleeding, arrest of bleeding with TIPS can actually improve encephalopathy.
The MELD score is calculated based on the patients creatinine, bilirubin, and international
normalized ratio (INR), and has proven superior to the Child–Pugh score at predicting
post-TIPS mortality.[46] A MELD score above 18 predicts a significantly higher mortality 3 months after TIPS
in comparison to those with a MELD score of 18 or lower.[46]
If the patient is deemed an appropriate candidate for TIPS, a comprehensive clinical
history and physical exam are necessary. Within 24 hours of the TIPS procedure, a
complete blood count, comprehensive metabolic panel, liver function tests, and coagulation
profile should be obtained. Appropriate blood products should be administered if there
is significant coagulopathy (INR > 1.5), thrombocytopenia (platelets < 50,000/mm3), or anemia (hematocrit < 25%).
An echocardiogram should be obtained in patients with known pulmonary or cardiac disease.
If recent cross-sectional imaging is available, such as contrast-enhanced cross-sectional
imaging or Doppler ultrasound, this should be reviewed. If no hepatic imaging within
the past month is available, or if the patient has experienced recent deterioration
in liver function, portal vein patency should be evaluated with a Doppler ultrasound.
Large-volume paracentesis or thoracentesis may be performed the day before or the
day of the TIPS procedure for patients with refractory ascites and hepatic hydrothorax,
respectively.
