Mar 132014
 
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Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.

Hepatology. 2013 Nov;58(5):1836-46

Authors: Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R

Abstract
Since the introduction of human serum albumin as a plasma expander in the 1940s, considerable research has allowed a better understanding of its biochemical properties and potential clinical benefits. Albumin has a complex structure, which is responsible for a variety of biological functions. In disease, the albumin molecule is susceptible to modifications that may alter its biological activity. During the last decades, different methods to measure albumin function have been developed. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver failure. This observation led to the concept of effective albumin concentration, which represents the fact that plasma albumin concentration does not reflect its function. Indeed, in liver disease albumin function is several times less than its concentration. In patients with cirrhosis, albumin infusion reduces mortality in patients with spontaneous bacterial peritonitis and improves outcome following large volume paracentesis. In combination with vasoconstrictors, albumin is useful in the management of patients with hepatorenal syndrome. Its role is being investigated in a large number of indications, which rely on its volume and nonvolume expansion functions such as stroke, severe sepsis, Alzheimer's disease, malaria, burns, and ovarian hyperstimulation syndrome. This review explores the above concepts, reviews the available evidence for the use of albumin in liver diseases, defines therapeutic limitations, and explores the challenges that should be addressed in future research.

PMID: 23423799 [PubMed - indexed for MEDLINE]

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Jan 162014
 
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To transfuse or not to transfuse in upper gastrointestinal hemorrhage? That is the question.

Hepatology. 2014 Jan 4;

Authors: Rockey DC

Abstract
Background: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. Methods: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis. Results: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 65 assigned to the liberal strategy (15%), did not receive transfusions (P<0.001). The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P = 0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P = 0.01), and adverse events occurred in 40% as compared with 48% (P = 0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P = 0.03) but not in those assigned to the restrictive strategy. Conclusions: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Hepatology 2013;).

PMID: 24390775 [PubMed - as supplied by publisher]

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Nov 122013
 

Withholding parenteral nutrition during critical illness increases plasma bilirubin but lowers the incidence of biliary sludge.

Hepatology. 2013 Nov 9;

Authors: Vanwijngaerden YM, Langouche L, Brunner R, Debaveye Y, Gielen M, Casaer M, Liddle C, Coulter S, Wouters PJ, Wilmer A, Van den Berghe G, Mesotten D

Abstract
Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in ICU (late-PN) accelerated recovery as compared with early initiation of PN (early-PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large RCT of early-PN versus late-PN (n=4640). In all patients plasma bilirubin (daily) and liver enzymes (ALT/AST/GGT/ALP; twice weekly; n=3216) were quantified. In a random predefined subset of patients also plasma bile acids (BAs) were quantified at baseline and on days 3, 5 and last ICU-day (n=280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n=776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late-PN than in the early-PN group (p<0.001). In the late-PN group, as soon as PN was started on day 8, bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP and ALT were lower in the late-PN group (p<0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (p<0.01), similarly for the two groups. Fewer patients in the late-PN than in the early-PN group developed biliary sludge on day 5 (37% vs 45%; p=0.04). In conclusion, tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early-PN. (Hepatology 2013;).

PMID: 24213952 [PubMed - as supplied by publisher]

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Aug 102013
 

Steroid use in acute liver failure.

Hepatology. 2013 Aug 8;

Authors: Karkhanis J, Verna EC, Chang MS, Stravitz RT, Schilsky M, Lee WM, Brown RS, the Acute Liver Failure Study Group

Abstract
Background/Aims: Drug-induced and indeterminate Acute Liver Failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced or indeterminate ALF, and whether this benefit varies according to the severity of illness. Methods: We conducted a retrospective analysis of autoimmune, indeterminate and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). Results: 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% vs. 66%, p=0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of MELD (MELD > 40, survival 30% vs. 57%, p=0.03). In multivariable analysis controlling for steroid use and diagnosis, age (OR 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07) and pH<7.4 (OR 3.09) were significantly associated with mortality. Though steroid use was associated with a marginal benefit in SS overall (35% v. 23%, p=0.047), this benefit did not persistent in multivariable analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and ALT (1.02) were the only significant predictors of SS. Conclusions: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. (Hepatology 2013;).

PMID: 23929808 [PubMed - as supplied by publisher]

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Jul 132013
 

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.

Hepatology. 2013 Jul 11;

Authors: Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS, Alexeeva O, Zupanets IA, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klaryts'ka I, Morozov V, Grewal P, McCashland T, Reddy KG, Reddy KR, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt BF, HALT-HE Study Group

Abstract
Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetylglutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase 2 trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the prior 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days and safety. GPB, 6 mL orally twice daily, significantly reduced the proportion of patients who experienced an HE event (21% vs. 36%, p = 0.02), time to first event (hazard ratio (HR) = 0.56, p < 0.05) as well as total events (35 vs. 57, p = 0.04) and was associated with fewer HE hospitalizations (13 vs. 25, p = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% vs. 32%, p < 0.01), time to first event (HR = 0.29, p value < 0.01 and total events (7 vs. 31, p < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2013;).

PMID: 23847109 [PubMed - as supplied by publisher]

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