Albumin Substitution in Decompensated Liver Cirrhosis: Don't Forget Zinc

Abstract

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.

Keywords: albumin; liver cirrhosis; zinc.

Figure 1

Schematic depiction of interactions between zinc homeostasis and the liver; factors influencing zinc in plasma/serum, symptoms of zinc deficiency and liver diseases.

Figure 2

Structural aspects of zinc and FFA binding to HSA. (A) Domain structure and location of the major zinc binding site (golden sphere) on human serum albumin (pdb 5ijf; [83]). (B) Zinc is bound by three amino acid residues as indicated, with water as a fourth ligand. (C) Location of the five major FFA-binding sites on HSA as observed in presence of myristate (pdb 1bj5; [84]). FA2, 4 and 5 are high-affinity sites, whilst FA1 and FA3 are medium-affinity sites. Two further low-affinity sites are not occupied in this structure. (D) Disruption of the major zinc binding site by FFA binding to site FA2. His67 in domain I moves (as indicated by the orange arrow) by ca. 6 Å relative to His247 and Asp249 in domain II (see [14,15]).

Figure 3

Schematic presentation of the influence of albumin and zinc on the pathogenesis of liver cirrhosis. Arrows indicate the relations and the interactions between bacterial infections, immune dysfunctions, and metabolic alterations.