Covered transjugular intrahepatic portosystemic shunts

Transjugular intrahepatic portosystemic shunts (TIPS) consist of a connection created by methods of interventionist radiology between the vena porta and the vena cava through the hepatic parenchyma. By markedly decreasing the portal pressure gradient, TIPS are highly effective in controlling the complications of portal hypertension such as bleeding due to esophageal varices and refractory ascites. Nevertheless, with the use of uncovered stents, the probability of shunt dysfunction -with the consequent reappearance of portal hypertension and its complications- is very high. The use of expandable polytetrafluoroethylene (e-PTFE)-covered stents markedly reduces the incidence of dysfunction, thus decreasing the number of clinical recurrences of portal hypertension and the reinterventions required to maintain shunt patency. The greater effectiveness of e-PTFE-covered stents is not accompanied by a higher incidence of complications or hepatic encephalopathy. Therefore, e-PTFE-covered stents should be preferred over uncovered stents in the management of the complications of portal hypertension.     

Management of ascites in cirrhosis

Ascites is a common complication of liver cirrhosis associated with a poor prognosis. The treatment of ascites requires dietary sodium restriction and the judicious use of distal and loop diuretics, sequential at an earlier stage of ascites, and a combination at a later stage of ascites. The diagnosis of refractory ascites requires the demonstration of diuretic non-responsiveness, despite dietary sodium restriction, or the presence of diuretic-related complications. Patients with refractory ascites require second-line treatments of repeat large-volume paracentesis (LVP) or the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), and assessment for liver transplantation. Careful patient selection is paramount for TIPS to be successful as a treatment for ascites. Patients not suitable for TIPS insertion should receive LVP. The use of albumin as a volume expander is recommended for LVP of >5-6 L to prevent the development of circulatory dysfunction, although the clinical significance of post-paracentesis circulatory dysfunction is still debated. Significant mortality is still being observed in cirrhotic patients with ascites and relatively preserved liver and renal function, as indicated by a lower Model for End-Stage Liver Disease (MELD) score. It is proposed that patients with lower MELD scores and ascites should receive additional points in calculating their priority for liver transplantation. Potential new treatment options for ascites include the use of various vasoconstrictors, vasopressin V(2) receptor antagonists, or the insertion of a peritoneo-vesical shunt, all of which could possibly improve the management of ascites.     

Transjugular intrahepatic portosystemic shunts (TIPS): a decade later

Since the introduction of transjugular intrahepatic portosystemic shunt (TIPS) 10 years ago, it has been used increasingly in the management of portal hypertension and its complications. TIPS is now considered the procedure of choice for management of refractory variceal bleeding. Its role in the management of refractory ascites, hepatic hydrothorax, hepatorenal syndrome, and hepatopulmonary syndrome still awaits further prospective studies. The two main complications of TIPS are hepatic encephalopathy and shunt malfunction. Generally, TIPS stenosis or occlusion is a major drawback requiring routine surveillance of TIPS with doppler ultrasound. Venography with balloon dilation of the stent or placement of serial or parallel stents may be required in some cases. Promising modalities of preventing TIPS malfunction (e.g., brachy-therapy, covered stents, or anti-platelet derived growth factor) are currently being investigated.     

The use of TIPS in chronic liver disease

The development of cirrhosis and portal hypertension in the natural history of chronic liver disease is associated with many complications. A transjugular intrahepatic portosystemic stent shunt (TIPS) is a metal prosthesis that has been shown to be very effective in lowering sinusoidal portal pressure, and therefore is effective in the management of complications of cirrhosis, especially those related to portal hypertensive bleeding and sodium and water retention. In patients with acute variceal bleeding not responding to pharmacologic and endoscopic treatments, a reduction of the hepatic venous pressure gradient to < 12 mmHg or by > 20% with TIPS has been shown to be effective in controlling the acute bleed and in preventing rebleeding. For stable patients whose acute variceal bleed is controlled, TIPS is equal to combined beta-blocker and band ligation in the prevention of recurrent variceal bleed. TIPS is also more effective than large volume paracentesis in the control of refractory ascites, and may confer a survival advantage over repeated large volume paracentesis. TIPS has also been used in the management of other complications related to portal hypertension including ectopic varices, hepatic hydrothorax, and hepatorenal syndrome with some success, but experience is still rather limited. Miscellaneous uses include treatment of Budd Chiari Syndrome, portal hypertensive gastropathy and hepatopulmonary syndrome. Careful patient selection is vital to a successful outcome, as patients with severe liver dysfunction tend to die post-TIPS despite a functioning shunt. All patients who require a TIPS for treatment of complications of cirrhosis should be referred for consideration of liver transplant.     

Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis.

Transjugular intrahepatic portosystemic shunt (TIPS) is a more effective treatment for refractory ascites than large volume paracentesis (LVP), but the magnitude of its effect in terms of control of ascites, encephalopathy and survival has not been established. AIM: This meta-analysis compare TIPS to LVP in terms of control of ascites at 4 and 12 months, encephalopathy and survival at 1 and 2 years. RESULTS: Five randomized controlled trials involving 330 patients were included. In the TIPS group, control of ascites was more frequently achieved at 4 months (66% vs 23.8%, mean difference: 41.4%, 95% confidence interval (CI): 29.5-53.2%, P < 0.001) and 12 months (54.8% vs 18.9%, mean difference: 35%, 95% CI: 24.9-45.1%, P < 0.001), whereas encephalopathy was higher (54.9% vs 38.1%, mean difference: 17%, 95% CI: 7.3-26.6%, P < 0.001). Survival at 1 year (61.7% vs 56.5%, mean difference: 3.2%, 95% CI: -14.7 to 21.9%) and 2 years (50% vs 42.8%, mean difference: 6.8%, 95% CI: -10 to 23.6%) were not significantly different. CONCLUSIONS: TIPS is a more effective treatment for refractory ascites than LVP. However, TIPS increase encephalopathy and does not improve survival.     

Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis

BACKGROUND & AIMS: Several trials showed that uncovered transjugular intrahepatic portosystemic shunt (TIPS) is superior to paracentesis for the control of refractory ascites. However, the results for encephalopathy and mortality were not consistent across trials. We performed a systematic review of randomized controlled trials of TIPS for refractory ascites to assess the overall treatment effects and to explore potential reasons of heterogeneity. METHODS: Pertinent studies were retrieved trough MEDLINE (1968-2004), EMBASE (1986-2004), the Cochrane Library (2004;4), and reference lists of key articles. Outcome measures were recurrence of ascites, encephalopathy, and mortality. Metaregression analysis was used to explore heterogeneity. RESULTS: Five trials were identified including 330 patients. Successful TIPS placement ranged from 77% to 100% and portosystemic pressure gradient reduction ranged from 6.0 to 14.0 mm Hg. Metaregression analysis showed that bilirubin levels and successful TIPS placement rates were associated significantly with log-odds ratio for death after TIPS, explained heterogeneity of trials for mortality, and suggested an outlier trial. After exclusion of the outlier trial, pooled odds ratios for recurrence of ascites with TIPS was .14 (confidence interval, .07-.27), for encephalopathy was 2.26 (confidence interval, 1.35-3.76), and for mortality was .74 (confidence interval, .40-1.37), without any significant heterogeneity. CONCLUSIONS: Uncovered TIPS is significantly better than paracentesis for control of refractory ascites. Although it increases encephalopathy, it also is associated with a trend toward improvement of survival. Future TIPS trials should select patients on the basis of bilirubin levels and predictors of the risk for post-TIPS encephalopathy, and assess costs and quality of life.     

Pathophysiology and management of pediatric ascites

Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal factors. The main pathophysiologic theories of ascites formation include the ‘underfill,’ ‘overflow,’ and peripheral arterial vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic thread: The body senses a decreased effective arterial blood volume, leading to stimulation of the sympathetic nervous system, arginine-vasopressin feedback loops, and the renin-angiotensin-aldosterone system. Cornerstones of ascites management include dietary sodium restriction and diuretics. Spironolactone is generally tried initially, with furosemide added if clinical response is suboptimal. More refractory patients require large-volume paracentesis (LVP) accompanied by volume expansion with albumin. Placement of a transjugular intrahepatic portosystemic shunt is reserved for individuals with compensated liver function who require very frequent sessions of LVP. Peritoneovenous shunts are not used in contemporary ascites management. Liver transplantation remains the definitive therapy for refractory ascites. Although treatment of ascites fails to improve survival, it benefits quality of life and limits the development of such complications as spontaneous bacterial peritonitis.     

肝硬化腹水治疗的研究现状与展望

腹水是肝硬化最常见的并发症,并与发生感染、稀释性低钠血症、肾功能衰竭和病死率增加密切相关。无并发症的少量腹水患者早期处理原则是,休息加上低钠饮食。中等量腹水患者,一般选择低剂量利尿剂就能达到利尿效果。大量腹水患者,可大量放腹水＋静点白蛋白（8g/每放腹水1000ml）。顽固性腹水患者,可用重复多次大量放腹水＋血浆扩容治疗或用经颈静脉肝内门体分流术（TIPS）治疗。新药（如V2受拮抗剂和血管收缩剂等）对肝硬化腹水的治疗可能带来希望。     

Transjugular intrahepatic portosystemic shunt--role in treating intractable variceal bleeding, ascites, and hepatic hydrothorax

Transjugular intrahepatic portosystemic shunt (TIPS) patency can be improved by the use of covered stents. Although this technical advance may lower the costs associated with TIPS, the overall role of TIPS in the management of portal hypertension may not change. Currently, bare metal TIPS is indicated in the treatment of acute refractory variceal hemorrhage, in the secondary prevention of variceal hemorrhage, for the management of ascites refractory to both medical management and large-volume paracentesis, and in the control of hepatic hydrothorax refractory to medical management.     

Effects of ascites resolution after successful TIPS on nutrition in cirrhotic patients with refractory ascites

OBJECTIVE: Malnutrition is common in patients with decompensated cirrhosis and refractory ascites. The use of transjugular intrahepatic portosystemic stent shunt (TIPS) is effective in eliminating ascites. The purpose of this study was to investigate the effect of TIPS and resolution of refractory ascites on the nutritional status of patients with decompensated cirrhosis. METHODS: Fourteen consecutive patients with refractory ascites and a Pugh score of 9.0+/-0.5 had a TIPS insertion. Biochemical data, resting energy expenditure (REE), total body nitrogen (TBN), body potassium (TBK), body fat (TBF), muscle force (MF), and food intake were recorded before TIPS, and at 3 and 12 months after the procedure. RESULTS: Ten patients completed the study. Baseline values for REE, TBN, TBF, MF, and energy intake were below normal at baseline. There was a significant increase in dry weight, TBN, and REE at 3 and 12 months compared with baseline. TBF improved significantly at 12 months. There was a trend toward an increase in energy intake (p = 0.072). There was no change in protein intake, TBK, MF, and Pugh score. CONCLUSION: In cirrhotic patients with refractory ascites, resolution of the ascites after TIPS placement resulted in improvement of several nutritional parameters, especially for body composition.     

Long-term efficacy of transjugular intrahepatic portosystemic shunt for the treatment of refractory ascites]

Eighteen patients with refractory ascites (Child-Pugh score 9.9) defined by our criteria were treated with transjugular intrahepatic portosystemic shunt (TIPS). The long-term efficacy of the treatment was studied in these patients. The complete and partial response rate of refractory ascites was 73% at 6 months, 90% at 1 year and 100% at 2 years. The cumulative survival rate was 89% at 6 months, 78% at 1 year and 48% at 2 years. A statistically significant(p < 0.05) increase was observed in performance status score following TIPS: Mean performance status score prior to TIPS was 43%, as opposed to 62% at 3 months after TIPS and 85% at 2 years. Child-Pugh score and liver function tests showed no significant change. During follow-up, shunt stenosis was noted in 14 patients, requiring shunt revision. Ascites recurrence was observed in 70% of patients with shunt stenosis and shunt revision resulted in good control of ascites. Post-TIPS encephalopathy was seen in 15 patients during follow-up. In conclusion, TIPS is effective on the treatment of refractory ascites and results in an improvement in quality of life. TIPS also may improve survival of the patients with refractory ascites. However, shunt stenosis and encephalopathy are common and require careful follow-up and adequate treatment.     

The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.     

Current diagnosis and management of post‐transjugular intrahepatic portosystemic shunt refractory hepatic encephalopathy

Transjugular intrahepatic portosystemic shunt has evolved into an important option for management of complications of portal hypertension. The use of polytetrafluoroethylene covered stents enhances shunt patency. Hepatic encephalopathy (HE) remains a significant problem after TIPS placement. The approach to management of patients with refractory hepatic encephalopathy typically requires collaboration between different specialties. Patient selection for TIPS requires careful evaluation of risk factors for HE. TIPS procedure‐related technical factors like stent size, attention to portosystemic pressure gradient reduction and use of adjunctive variceal embolization maybe important. Conservative medical therapy in combination with endovascular therapies often results in resolution or substantial reduction of symptoms. Liver transplantation is, however, the ultimate treatment.     

The transjugular intrahepatic portosystemic shunt in the treatment of portal hypertension

The transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. It is most commonly used in the management of refractory variceal bleeding, where it can be life-saving. Two other indications have been studied in randomized controlled trials: prevention of variceal rebleeding and refractory cirrhotic ascites. These trials have demonstrated that TIPS is superior to standard therapy but is associated with a higher rate of hepatic encephalopathy and with no improvement in survival. Consequently, TIPS is considered a second-line therapy in these situations. TIPS has also been used successfully in the treatment of hepatic hydrothorax, hepatorenal syndrome, severe portal hypertensive gastropathy, Budd-Chiari syndrome and veno-occlusive disease. Its use in these indications has only been reported in small uncontrolled series. TIPS usefulness is limited by two major problems: shunt dysfunction and hepatic encephalopathy. Shunt dysfunction is frequently responsible for the recurrence of complications of portal hypertension, and requires a surveillance program to monitor shunt patency. The use of polytetrafluoroethylene-covered stents may help prevent this complication.     

Transjugular intrahepatic portosystemic shunt for refractory ascites: an analysis of the literature on efficacy, morbidity, and mortality

OBJECTIVES: Transjugular intrahepatic portosystemic shunt (TIPS) is frequently used to treat patients with refractory ascites, but its role is controversial. We sought to determine from the literature the efficacy, morbidity, and mortality associated with TIPS for refractory ascites. METHODS: We searched MEDLINE and identified studies published in English from January, 1985, to March, 2003, that evaluated the effect of TIPS in patients with refractory ascites. Outcomes that were analyzed included complete resolution of ascites, reduction in ascites, mortality, encephalopathy, stenosis, and renal function. Data were analyzed on an intention to treat basis. RESULTS: Of 25 studies identified, 16 were included in the analysis. The pooled estimate for complete response at 6 months was 45% and for any response (complete and partial) was 63%. Pooled 6-month mortality after TIPS was 36%. Risk factors for mortality included renal insufficiency (serum creatinine >1.5 mg/dl), hyperbilirubinemia (total bilirubin >3 mg/dl), advanced age (>60 yr), and poor response to TIPS. The pooled rate of new or worsening encephalopathy after TIPS was 32%. In most cases, encephalopathy was managed medically or by reduction in shunt size; however, refractory cases were associated with 100% mortality in most studies. Studies reporting the effect of TIPS on kidney function showed improvement in creatinine clearance and urinary sodium excretion. CONCLUSIONS: TIPS is effective in eliminating ascites or substantially reducing ascites in cases refractory to medical therapy. Renal insufficiency, refractory encephalopathy, and hyperbilirubinemia were consistently associated with mortality after TIPS. In individuals with risk factors for mortality, alternative strategies should be recommended.     

Transjugular intrahepatic portosystemic shunt placement for refractory ascites: a single-centre experience

Abstract

Background. The presence of refractory ascites is a common indication for transjugular intrahepatic portosystemic shunt (TIPS). Different models have been proposed for the prediction of survival after TIPS. The aim of this study was to evaluate the predictive factors associated with patients' survival after TIPS placement for refractory ascites. Methods. Data from all consecutive patients undergoing TIPS placement in our center for refractory ascites between February 2003 and January 2008 were prospectively recorded. Results. Seventy-three patients (52M/21F; 57 ± 10 years) met the inclusion criteria; mean follow-up was 17 ± 2 months. Mean MELD value, before TIPS placement, was 15.7 ± 5.3. TIPS placement led to an effective resolution of refractory ascites in 54% of patients (n = 40) with no significant increase in severe portosystemic encephalopathy. The 1-year survival rate observed was 65.7%, while the overall mortality was 23.3% (n = 17) with a mean survival of 17 ± 14 months. MELD score (B = 0.161, p = 0.042), basal AST (B = 0.020, p = 0.090), and pre-TIPS HVPG (B = 0.016, p = 0.093) were independent predictors of overall mortality, while MELD (B = 0.419, p = 0.018) and HVPG (B = 0.223, p = 0.060) independently predicted 1-year survival. ROC curves identified MELD ≥ 19 and HVPG ≥ 25 mmHg as the best cut-off points for the prediction of 1-year mortality. Conclusions. TIPS is an effective treatment for refractory ascites in cirrhotic patients, leading to an effective ascites control in more than half patients. Improvement in patients' selection criteria could lead to better outcome and survival after this procedure. Liver function (MELD), presence of active necroinflammation (AST), and portal hypertension (HVPG) are independent predictors of patients' outcome after TIPS.     

Transjugular intrahepatic portosystemic shunt for cirrhosis and ascites: Effects in patients with organic or functional renal failure

BACKGROUND: A transjugular intrahepatic portosystemic shunt (TIPS) is increasingly being used for treatment of patients with refractory ascites and functional renal failure. In contrast, organic renal disease is commonly considered a relative contraindication for TIPS placement. The aim of this pilot study was to investigate the effects of TIPS in patients with refractory ascites and organic or functional renal impairment. METHODS: A TIPS was placed for refractory or intractable ascites in 10 consecutive patients with liver cirrhosis and impaired renal function (serum creatinine > 1.5 mg/100 ml). Four of them had organic kidney disorders. Of these patients, three had moderate renal impairment, and one had end-stage renal disease and needed hemodialysis every other day. The other six patients had functional renal impairment due to the underlying liver disease. RESULTS: TIPS was effective in reducing ascites in 8 of 10 patients, including all patients with organic renal disease. Furthermore, after TIPS the renal function improved in all patients. Serum creatinine and serum urea levels decreased significantly from 1.8 +/- 0.1 to 1.5 +/- 0.1 mg/100 ml (P < 0.05) and from 107 +/- 13 to 78 +/- 14 mg/100 ml (P < 0.05), respectively. The renal function of the three patients with organic renal failure improved similarly, as observed in the six patients with functional renal failure. In the patient on hemodialysis, TIPS was effective in reducing the frequency of paracenteses. CONCLUSION: TIPS may be useful in patients with functional and in patients with organic renal disease, resulting in improvement of ascites and renal function.     

Pathophysiology, diagnosis and treatment of ascites in cirrhosis

The mechanism by which ascites develops in cirrhosis is multifactorial Severe sinusoidal portal hypertension and hepatic insufficiency are the initial factors. They lead to a circulatory dysfunction characterized by arterial vasodilation, arterial hypotension, high cardiac output and hypervolemia and to renal sodium and water retention. There are evidences that arterial vasodilation in cirrhosis occurs in the splanchnic circulation and is related to an increased synthesis of local vasodilators. Vascular resistance is normal or increased in the remaining major vascular territories (kidney, muscle and skin and brain). Splanchnic arterial vasodilation not only impairs systemic hemodynamics and renal function but also alters hemodynamics in the splanchnic microcirculation. The rapid and high inflow of arterial blood into the splanchnic microcirculation is the main factor increasing hydrostatic pressure in the splanchnic capillaries leading to an excessive production of splanchnic lymph over lymphatic return. Lymph leakage from the liver and other splanchnic organs is the mechanism of fluid accumulation in the abdominal cavity. Continuous renal sodium and water retention perpetuates ascites formation. Large volume paracentesis associated with albumin infusion is the treatment of choice of tense ascites because it is very effective and rapid and is associated with fewer complications that the traditional treatment (sodium restriction and diuretics). However, diuretic should be given after paracentesis to prevent reaccumulation of ascites. In patients with moderate ascites diuretics should be preferred as initial therapy. Patients with refractory ascites could be treated by paracentesis or percutaneous transjugular portacaval shunt (TIPS). TIPS is more effective in the long term control of ascites but may impair hepatic function and induce chronic hepatic encephalopathy.     

Treatment of refractory ascites

Opinion statement In 1996, the International Ascites Club defined “refractory ascites” as ascites that cannot be mobilized by medical therapy or that recurs early after initial mobilization despite continued treatment. Of all patients with ascites, 5% to 10% will become refractory to medical therapy. Management of refractory ascites should attempt to control fluid accumulation, reduce the likelihood of developing complications such as spontaneous bacterial peritonitis (SBP) and the hepatorenal syndrome, and improve the patient’s nutritional status and overall well-being. Measures to control ascites accumulation include documenting medication and dietary compliance and eliminating potentially nephrotoxic agents that promote sodium retention. Large volume paracentesis is an effective first step in managing these patients and can be performed routinely in an outpatient setting. When more than 5 L of fluid are removed during a paracentesis, intravenous albumin should be infused to reduce the likelihood of the patient developing postparacentesis circulatory dysfunction. Transjugular intrahepatic portosystemic shunt (TIPS) placement effectively eliminates ascites; however, there is no convincing evidence that the shunt improves mortality. Furthermore, it is associated with frequent complications of encephalopathy and shunt malfunction. We feel TIPS should be reserved for patients requiring extremely frequent paracentesis, those who develop significant postparacentesis circulatory dysfunction, or those with hepatic hydrothorax. Patients who have evidence of SBP should be treated with antibiotics and intravenous albumin infusion. Patients who have had a previous episode of SBP or an ascitic fluid protein level of less than 1.0 should receive prophylactic antibiotics. Overall, the prognosis for patients with refractory ascites remains grim, and liver transplantation is the only definitive therapy. Appropriate candidates should be identified promptly and referred for transplant evaluation.     

An Algorithm for Management After Transjugular Intrahepatic Portosystemic Shunt Placement According to Clinical Manifestations

We propose an algorithm for management after transjugular intrahepatic portosystemic shunt (TIPS) placement according to clinical manifestations. For patients with an initial good clinical response, surveillance Doppler ultrasound is recommended to detect stenosis or occlusion. A TIPS revision can be performed using basic or advanced techniques to treat stenosis or occlusion. In patients with an initial poor clinical response, a TIPS venogram with pressure measurements should be performed to assess shunt patency. The creation of a parallel TIPS may also be required if the patient is symptomatic and the portal pressure remains high after TIPS revision. Additional procedures may also be necessary, such as peritoneovenous shunt (Denver shunt) placement for refractory ascites, tunneled pleural catheter for hepatic hydrothorax, and balloon-occluded retrograde transvenous obliteration procedure for gastric variceal bleeding. A TIPS reduction procedure can also be performed in patients with uncontrolled hepatic encephalopathy or hepatic failure.