Albumin administration for refractory ascites in cirrhotic patients

A recent article published in Liver International reported that long-term administration of albumin to cirrhotic patients with refractory ascites improved survival and reduced inpatient hospitalization (1). In addition to reducing complications associated with liver cirrhosis, such as ascites and spontaneous bacterial peritonitis (SBP), long-term albumin administration also reduced complications such as hepatic encephalopathy and non-SBP infection. These findings indicated that long-term albumin infusion therapy may benefit cirrhotic patients, not only by improving hemodynamics but also by enhancing the scavenging of toxic substances, thereby improving patient prognosis.

Albumin, the most abundant protein in human plasma, has multiple biologic activities. For example, albumin is the main regulator of plasma as oncotic pressure; binds to and transports other biological molecules; has antioxidant, antithrombotic and immunomodulatory activities; and stabilizes endothelial cells (2). Albumin binds to furosemide in blood and transports it to the kidneys, which secrete furosemide into the proximal tubules, the sites of its activity. Albumin can enhance the response to diuretics in cirrhotic patients with hypoalbuminemia (3). Thus, albumin is effective in improving symptoms in cirrhotic patients with ascites. Furthermore, clinical studies have shown the usefulness of albumin administration to cirrhotic patients under some conditions. For example, albumin administration after large volume paracentesis was effective in preventing paracentesis-induced circulatory dysfunction (PICD) (4). A meta-analysis found that albumin supplementation significantly reduced the incidence of PICD, as well as hyponatremia, an independent prognostic indicator in cirrhotic patients (5). Furthermore, albumin was more effective than volume expanders such as dextran and polygeline, suggesting that the activity of albumin is due to more than its preservation of oncotic pressure (4). To prevent PICD, clinical practice guidelines recommend the administration of 6–8 g of albumin per liter of ascites to remove more than 5 L of ascites (6,7). Moreover, albumin was found to prevent the development of hepatorenal syndrome, a life-threatening complication frequently found after SBP in cirrhotic patients (8). Administration of albumin together with antibiotics was more effective at reducing renal dysfunction in patients with SBP than antibiotics alone (9). Albumin supplementation (1.5 g/kg of body weight at diagnosis and 1.0 g/kg on day 3) is recommended in patients with SBP (7,10). Taken together, these findings indicate that albumin can improve the prognosis of patients with decompensated cirrhosis under specific situations. However, it is unclear whether long-term administration of albumin improves prognosis and prolongs survival in cirrhotic patients.

Clinical studies assessing the effect of long-term albumin administration have shown limited and unclear benefits. One trial found that administration of 25 g albumin per week for 1 year and 25 g every 2 weeks for the following 2 years reduced the recurrence of ascites and readmissions, but did not improve survival (3). However, long-term follow-up of these patients for seven years found that albumin improved transplant-free survival (11). More recently, the large scale randomized ANSWER trial, involving over 400 cirrhotic patients, assessed the efficacy of long-term albumin administration (12). In this trial, administration of 40 g albumin twice weekly for two weeks and 40 g weekly for up to 18 months, together with diuretics, enhanced serum albumin concentration; reduced liver-related complications, such as SBP, hepatic encephalopathy, hepatorenal syndrome and hyponatremia; and showed survival benefits, with overall 18-month survival rates of 77% in the treated group and 66% in the control group (hazard ratio, 0.62; 95% confidence interval: 0.40–0.95, P=0.028) (12). Moreover, long-term albumin administration was more cost-effective than standard medical therapy alone, as the former reduced the need for hospitalization (12). The present study by Di Pascali et al. found that administration of 20 g albumin twice weekly (40 g per week) also reduced 24-month mortality rates in cirrhotic patients with refractory ascites (1). In contrast, another recent randomized study found that administration of 40 g albumin every 15 days plus midodrine for one year did not prevent complications of cirrhosis and did not improve the survival of cirrhotic patients (13). These findings suggest that only albumin doses greater than 40 g per week have survival benefit in cirrhotic patients.

However, the limited supply of blood-derived albumin and the potential risk of blood-derived pathogens are unsolved issues in long-term use of albumin. The clinical application of recombinant human albumin has been tested, but its cost effectiveness, biochemical properties and safety remain to be determined (14,15). Further studies are needed to test the clinical usefulness of human recombinant albumin. In such situations, long-term albumin administration may be considered for patients with decompensated cirrhosis in the upper ranks of those awaiting liver transplantation. Studies are also needed to test the effectiveness of albumin administration combined with transjugular intrahepatic portosystemic shunt, which effectively improves portal hypertension and reduces refractory ascites and mortality in cirrhotic patients (16).

Evidence has established the effectiveness of long-term albumin administration. Long-term administration of more than 40 g per week albumin may improve survival in patients with decompensated cirrhosis. Further studies are needed to develop a useful form of recombinant albumin, to optimize dose and administration and to select the most suitable candidates for long-term albumin treatment.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Medical Journal. The article did not undergo external peer review.

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2019.01.07). The authors have no conflicts of interest declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Di Pascoli M, Fasolato S, Piano S, et al. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int 2019;39:98-105. [Crossref] [PubMed]
2. Spinella R, Sawhney R, Jalan R. Albumin in chronic liver disease: structure, functions and therapeutic implications. Hepatol Int 2016;10:124-32. [Crossref] [PubMed]
3. Gentilini P, Casini-Raggi V, Di Fiore G, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol 1999;30:639-45. [Crossref] [PubMed]
4. Bernardi M, Caraceni P, Navickis RJ, et al. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology 2012;55:1172-81. [Crossref] [PubMed]
5. Biggins SW, Rodriguez HJ, Bacchetti P, et al. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005;41:32-9. [Crossref] [PubMed]
6. Runyon BA. Aasld. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57:1651-3. [Crossref] [PubMed]
7. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406-60. [Crossref]
8. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-8. [PubMed]
9. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-9. [Crossref] [PubMed]
10. Runyon BA, Committee APG. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087-107. [Crossref] [PubMed]
11. Romanelli RG, La Villa G, Barletta G, et al. Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J Gastroenterol 2006;12:1403-7. [Crossref] [PubMed]
12. Caraceni P, Riggio O, Angeli P, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391:2417-29. [Crossref] [PubMed]
13. Sola E, Sole C, Simon-Talero M, et al. Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial. J Hepatol 2018;69:1250-9. [Crossref] [PubMed]
14. Chen Z, He Y, Shi B, et al. Human serum albumin from recombinant DNA technology: challenges and strategies. Biochim Biophys Acta 2013;1830:5515-25. [Crossref] [PubMed]
15. Sharma A, Chaudhuri TK. Physicochemical characterization of E. coli-derived human serum albumin and its comparison with the human plasma counterpart reveals it as a promising biosimilar. J Biotechnol 2018;274:1-8. [Crossref] [PubMed]
16. Bureau C, Thabut D, Oberti F, et al. Transjugular Intrahepatic Portosystemic Shunts With Covered Stents Increase Transplant-Free Survival of Patients With Cirrhosis and Recurrent Ascites. Gastroenterology 2017;152:157-63. [Crossref] [PubMed]