The importance of prognostic factors in cirrhosis
Authors: Ulrich Thalheimer, Andrew K. Burroughs
Journal: Journal of Hepatology (2014)

We read with great interest the study by Simón-Talero and colleagues [[1]Simon-Talero M. Garcia-Martinez R. Torrens M. Augustin S. Gomez S. Pereira G. et al.Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study.J Hepatol. 2013; 59: 1184-1192Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. They explore the potential benefit of human albumin infusions in the treatment of hepatic encephalopathy, adopting an infusion regimen used with success in the treatment of spontaneous bacterial peritonitis (1.5 g/kg on day 1 and 1.0 g/kg on day 3) and comparing it with an equivalent volume of normal saline solution. Despite no difference in resolution of encephalopathy between the two treatment arms (the primary end point), the trial was terminated early after randomising 56 patients (out of an initial calculated sample size of 124) due to an improved 90 day survival in the albumin group (69.2% vs. 40.0%), even though this was one of the secondary end points. Human albumin is not only quantitatively reduced in patients with cirrhosis, but it also seems to be functionally impaired [[2]Garcia-Martinez R. Caraceni P. Bernardi M. Gines P. Arroyo V. Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.Hepatology. 2013; 58: 1836-1846Crossref PubMed Scopus (222) Google Scholar]. Administration of human albumin has been shown to be beneficial in patients with spontaneous bacterial peritonitis (SBP) [[3]Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-del-Arbol L. et al.Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1236) Google Scholar], hepatorenal syndrome [[4]Ortega R. Gines P. Uriz J. Cardenas A. Calahorra B. De Las H.D. et al.Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.Hepatology. 2002; 36: 941-948Crossref PubMed Google Scholar], large volume paracentesis, and bacterial infections other than SBP [[5]Guevara M. Terra C. Nazar A. Sola E. Fernandez J. Pavesi M. et al.Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.J Hepatol. 2012; 57: 759-765Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar]. A survival benefit in patients with encephalopathy treated with albumin might therefore not be entirely surprising, but the results of this study need to be taken with great caution. Apart from the fact (acknowledged by the authors) that mortality was only a secondary end point, a closer examination of the baseline characteristics yields further potentially confounding factors. Most importantly, more than twice as many patients in the normal saline arm had a history of SBP, gastrointestinal bleeding, and hepatocellular carcinoma, and a substantially larger number had a history of ascites and previous episodes of encephalopathy. None of these differences reached statistical significance, but this is clearly linked to the low number of patients in each arm. Unsurprisingly, more than twice as many patients in the normal saline arm were on norfloxacin prophylaxis for SBP and on beta-blockers. Finally, renal function was worse in the normal saline group, with a mean creatinine of 1.4 mg/dl vs. 0.9 mg/dl in the albumin arm; this reached statistical significance even despite the low numbers. Episodes of spontaneous bacterial peritonitis, variceal bleeding, hepatocellular carcinoma, and renal impairment are prognostically adverse factors in patients with cirrhosis, and their increased prevalence in the normal saline arm could certainly have contributed to, if not explained, the difference in mortality between the two groups. Indeed, the higher incidence of clinically significant portal hypertension in the normal saline group (as suggested by the higher number of patients on beta blockers) may well express the same bias present in a much debated recent paper on the effect of beta blockers in refractory ascites [[6]Serste T. Melot C. Francoz C. Durand F. Rautou P.E. Valla D. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (392) Google Scholar], i.e., the fact that higher portal pressure is related to increased mortality [[7]Burroughs A.K. Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key.Hepatology. 2010; 51: 1894-1896Crossref PubMed Scopus (42) Google Scholar]. The use of albumin has important theoretical potential in cirrhosis [[2]Garcia-Martinez R. Caraceni P. Bernardi M. Gines P. Arroyo V. Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.Hepatology. 2013; 58: 1836-1846Crossref PubMed Scopus (222) Google Scholar]. It is therefore of vital importance that both authors and reviewers are rigorous in the interpretation of studies evaluating the therapeutic use of albumin. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: A randomized double-blind studyJournal of HepatologyVol. 59Issue 6PreviewEpisodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial ( ClinicalTrials.gov number, NCT00886925 ). Full-Text PDF Reply to: “The importance of prognostic factors in cirrhosis”Journal of HepatologyVol. 60Issue 6PreviewWe appreciate the interest of Dr. Thalheimer and Dr. Burroughs in our study [1]. It is true that the baseline characteristics of our patients showed a slightly greater percentage of previous spontaneous bacterial peritonitis, variceal bleeding, and hepatocellular carcinoma in the saline arm, but without significant differences. We agree that the presence of renal failure in the saline group could be a confounding factor that might help explain the differences in survival between both groups. However, the MELD score, used to predict survival, had no differences in both arms. Full-Text PDF Open Access