Thomas D. Boyer

A Randomized, Prospective, Double-Blind, Placebo-Controlled Trial of Terlipressin for Type 1 Hepatorenal Syndrome

BACKGROUND & AIMS Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS. METHODS A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to </=1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1. RESULTS Fifty-six subjects were randomized to each arm. Treatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093). SCr level improved from baseline to day 14 on terlipressin (-0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level </=1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo. CONCLUSIONS Terlipressin is an effective treatment to improve renal function in HRS type 1.

The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension

The recommendations in this article provide a datasupported approach. They are based on the following: (1) a formal review and analysis of recently published world literature on the topic (as listed in MEDLINE); (2) the American College of Physicians’ A Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) policy guidelines, including the American Association for the Study of Liver Diseases’ Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines2; and (4) the authors’ years of experience in the care of patients with portal hypertension and use of transjugular intrahepatic portosystemic shunt in the management of these disorders. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the Society for Interventional Radiology. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases requires a grade to be assigned and reported with each recommendation (Table 1).

The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: Update 2009

The 2009 update of the American Association for the Study of Liver Diseases (AASLD) Practice Guideline “The Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the Management of Portal Hypertension” is now posted online at www.aasld.org. This is the first update of the original guideline published in 2005.1 The key changes in the 2009 guidelines are new recommendations on the use of covered versus bare stents in the creation of the TIPS. Use of expanded polytetrafluoroethylene (ePTFE)-covered stents is now preferred. The lower risk of shunt dysfunction and perhaps improved outcomes using covered as opposed to bare stents are the basis for this recommendation.2,3 Creation of a TIPS increases the risk of hepatic encephalopathy but the prophylactic use of nonabsorbable disaccharides or antibiotics does not appear to reduce this risk and is not recommended.4 The value of TIPS versus a surgical shunt in the prevention of variceal rebleeding in patients who have failed medical therapy has been clarified by the publication of a controlled trial comparing TIPS to distal splenorenal shunt (DSRS).5 Both were effective in preventing rebleeding (rebleeding incidence in 5.5% of DSRS versus 10.5% of TIPS; not significant) with no difference in encephalopathy or survival. The patients in whom TIPS was performed required significantly more interventions to maintain patency because of the use of bare stents. A cost analysis showed TIPS to be slightly more cost effective than DSRS at year 5,6 and these two approaches are now considered to be of equal efficacy in the prevention of variceal rebleeding. The other significant change to the guidelines is how TIPS should be used in the management of patients with Budd-Chiari syndrome. A large (221 patients) retrospective study was published in which patients who failed to improve with use of anticoagulation had a TIPS created (133 patients). One-year and 10-year transplant-free survival was 88% and 69%, respectively, which is better than predicted.7 TIPS patency was best in those who received a covered stent. The recommendation now is for creation of a TIPS in those who fail to improve with anticoagulation.

Predictors of large esophageal varices in patients with cirrhosis.

Abstract OBJECTIVE: Recent guidelines recommend that all cirrhotics undergo screening upper endoscopy to identify those patients at risk for bleeding from varices. However, this practice may not be cost effective as large esophageal varices are seen only in 9–36% of these patients. The aim of this study was to determine whether clinical variables were predictive of the presence of large esophageal varices. METHODS: This is a retrospective analysis of cirrhotics who had a screening upper endoscopy during an evaluation for liver transplantation at three different centers and who had not previously bled from varices. A multivariate model was derived on the combined cohort using logistic regression. Three hundred forty-six patients were eligible for the study. RESULTS: The prevalence of large esophageal varices was 20%. On multivariate analysis, splenomegaly detected by computed tomographic scan (odds ratio: 4.3; 95% confidence interval: 1.6–11.5) or by physical examination (odds ratio: 2.0; 95% confidence interval: 1.1–3.8), and low platelet count were independent predictors of large esophageal varices. On the basis of these variables, cirrhotics were stratified into high- and low-risk groups for the presence of large esophageal varices. Patients with a platelet count of ≥88,000/mm3 (median value) and no splenomegaly by physical examination had a risk of large esophageal varices of 7.2%. Those with splenomegaly or platelet count CONCLUSIONS: Our data show that clinical predictors could be used to stratify cirrhotic patients for the risk of large esophageal varices and such stratification could be used to improve the cost effectiveness of screening endoscopy.

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites Paolo Angeli1,⇑, Pere Ginès, Florence Wong, Mauro Bernardi, Thomas D. Boyer, Alexander Gerbes, Richard Moreau, Rajiv Jalan, Shiv K. Sarin, Salvatore Piano, Kevin Moore, Samuel S. Lee, Francois Durand, Francesco Salerno, Paolo Caraceni, W. Ray Kim, Vicente Arroyo, Guadalupe Garcia-Tsao

Transjugular intrahepatic portosystemic shunt: current status.

The transjugular intrahepatic portosystemic shunt (TIPS) was developed in the 1980s for treatment of complications of portal hypertension. Once it was shown that the shunt could be placed with relative ease, TIPS was rapidly applied to the treatment of many of the complications of portal hypertension. These complications include actively bleeding gastroesophageal varices, prevention of rebleeding from varices, control of refractory cirrhotic ascites and hepatic hydrothorax, and treatment of hepatorenal failure and hepatopulmonary syndrome. TIPS has also been used as therapy for Budd-Chiari syndrome and veno-occlusive disease. Despite these broad applications, TIPS has been compared with other forms of therapy in only 2 situations: prevention of rebleeding from varices and control of refractory cirrhotic ascites. In the trials, TIPS was shown to provide better control of these 2 complications of portal hypertension than standard forms of therapy. However, there was no improvement in survival and the incidence of encephalopathy was greater for patients receiving a TIPS. Thus, the use of TIPS for the control of ascites and prevention of rebleeding from varices should be limited to a select group of patients. There have been no controlled trials for the other indications listed. Despite the apparent efficacy of TIPS in many of these situations, its use should be limited to salvage therapy pending the publication of controlled trials showing it is a better treatment than other forms of therapy.

Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: Relationship of serum creatinine to hemodynamics

BACKGROUND & AIMS Administration of terlipressin plus albumin is effective in reversing type 1 HRS as compared to albumin alone. However, only about 1/3 of patients respond to treatment, therefore, predictors of response and survival would help identify the patients most likely to benefit from treatment. METHODS We analyzed our controlled trial of terlipressin vs. placebo (Gastroenterology 2008;134:1360) to define factors predictive of a response and to correlate hemodynamic changes to changes in renal function. RESULTS Single variant analysis showed treatment with terlipressin, MELD score, and baseline serum creatinine to be predictive of HRS reversal. Alcoholic hepatitis, baseline serum creatinine, and MELD score were predictive of survival. When treatment was not considered as a variable, only baseline serum creatinine predicted HRS reversal. Baseline serum creatinine, presence of alcoholic hepatitis, and Child-Pugh score were also predictive of survival on multivariate analysis. The rise in mean arterial pressure (MAP) following terlipressin administration was not predictive of HRS reversal. However, in those who achieved HRS reversal from terlipressin, there was a significant rise in MAP from beginning to end of treatment. CONCLUSIONS The most consistent predictor of response to terlipressin and of survival is the baseline serum creatinine. Patients most likely to benefit from terlipressin have earlier onset renal failure (i.e. serum creatinine <5.0mg/dl). A sustained rise in MAP is required for HRS reversal. As MAP is a surrogate marker for the hyperdynamic circulation, it is only with improvement in the hyperdynamic circulation that HRS reversal is observed.

American Association for the Study of Liver Diseases Practice Guidelines: the role of transjugular intrahepatic portosystemic shunt creation in the management of portal hypertension.

THE recommendations in this article provide a data supported approach. They are based on the following: (i) a formal review and analysis of recently published world literature on the topic (as listed in MEDLINE); (ii) the American College of Physicians’ A Manual for Assessing Health Practices and Designing Practice Guidelines (1); (iii) policy guidelines, including the American Association for the Study of Liver Diseases’ Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines (2); and (iv) the authors’ years of experience in the care of patients with portal hypertension and use of transjugular intrahepatic portosystemic shunt in the management of these disorders. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the Society for Interventional Radiology. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases requires a grade to be assigned and reported with each recommendation (Table 1).

Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites

Acute renal failure (ARF) is a common complication in patients with decompensated cirrhosis. The traditional diagnostic criteria of renal failure in these patients were proposed in 19961 and have been refined in subsequent years.2 According to these criteria, ARF is defined as an increase in serum creatinine (sCr) of ≥50% from baseline to a final value >1.5 mg/dL (133 µmol/L). However, the threshold value of 1.5 mg/dL (133 µmol/L) sCr to define renal failure in patients with decompensated cirrhosis has been challenged.3 ,4 In addition, the timeframe to distinguish acute from chronic renal failure has not been clearly identified, the only exception being type 1 hepatorenal syndrome (HRS). Meanwhile, new definitions for ARF, now termed acute kidney injury (AKI), have been proposed and validated in patients without cirrhosis.5–7 Recently these new criteria were also proposed and applied in the diagnosis of AKI in patients with cirrhosis.3 ,8–15 Thus, in December 2012, the International Club of Ascites (ICA) organised a consensus development meeting in Venice, Italy, in order to reach a new definition of AKI in patients with cirrhosis. The discussion among the experts continued thereafter for 2 years, both online and through several meetings, between those experts who had different positions on crucial points on the subject. This paper reports the scientific evidence supporting the final proposal of a new approach to the diagnosis and treatment of this condition, on which the experts agreed. AKI is defined as an acute significant reduction in the glomerular filtration rate (GFR). sCr remains the most practical biomarker of renal function in patients with ARF (with or without cirrhosis). However, sCr as a biomarker of renal function has many limitations in clinical practice since it is influenced by bodyweight, race, age, and gender. The use of sCr in patients with cirrhosis is …

Constitutional telomerase mutations are genetic risk factors for cirrhosis

Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation‐containing vectors into telomerase‐deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age‐matched controls (P = 0.0004). Conclusion: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss‐of‐function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis. (HEPATOLOGY 2011;)