Letters to the Editor

The importance of prognostic factors in cirrhosis To the Editor: We read with great interest the study by Simón-Talero and colleagues [1]. 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]. Administration of human albumin has been shown to be beneficial in patients with spontaneous bacterial peritonitis (SBP) [3], hepatorenal syndrome [4], large volume paracentesis, and bacterial infections other than SBP [5]. 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], i.e., the fact that higher portal pressure is related to increased mortality [7]. The use of albumin has important theoretical potential in cirrhosis [2]. It is therefore of vital importance that both authors and reviewers are rigorous in the interpretation of studies evaluating the therapeutic use of albumin.

Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [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;59:1184–1192. [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;58:1836–1846. [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;341:403–409. [4] Ortega R, Gines P, Uriz J, Cardenas A, Calahorra B, De Las HD, et al. Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 2002;36:941–948. [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;57:759–765. [6] Serste T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022. [7] Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key. Hepatology 2010;51:1894–1896.

Journal of Hepatology 2014 vol. 60

Ulrich Thalheimer The Exeter Liver Unit, Royal Devon & Exeter Foundation Trust, Exeter, UK ⇑Corresponding author. E-mail address: [email protected] Andrew K. Burroughs Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK



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