Effective albumin – A novel paradigm in the management of decompensated liver cirrhosis

Synthesis

Human albumin, a 66.5-kDa globular protein synthesized by hepatocytes, is the most abundant serum protein whose concentration ranges from 3.5 to 5 g/dL. Under normal conditions, albumin production is stable (10–15 g daily), but can increase up to 3–4 fold. Hormonal factors, such as insulin, cortisol, and growth hormone, stimulate, while mediators of inflammation, such as proinflammatory cytokines, inhibit albumin synthesis.^{[1, 2, 3]}

Structure and functional properties

A single chain of 585 amino acids developed through nine loops and organized into three domains constitutes the albumin structure, stabilized by 34 disulfide bonds involving cysteine residues. The circulatory half-life of albumin is approximately 16–18 h, while the total half-life varies from 13 to 18 days in healthy adult subjects.^{[1, 2, 3]}

Albumin is the principal modulator of fluid distribution among the body’s compartments, accounting for 70%–75% of the plasma oncotic pressure due to its osmotic property. Furthermore, its net negative charge attracts and binds cations, such as sodium, ultimately leading fluids to move from the extra- to the intravascular compartment. These features and its prolonged half-life explain why albumin is employed as a plasma expander in several clinical contexts.

Albumin is the most abundant circulating antioxidative system in the human body due to the sulfhydryl group in the Cys-34 position, which can scavenge reactive oxygen species (ROS). In healthy adults, most (70%–80%) of these sulfhydryl groups are in the reduced form (human mercaptalbumin), about 20% are involved in reversible disulfide bonds with sulfhydryl compounds (non-mercaptalbumin 1), and a small amount is irreversibly oxidized to sulfonic or sulfinic acid (non-mercaptalbumin 2). The N-terminal and a metal-binding domain contribute to the antioxidative capacity of albumin by binding highly reactive, toxic metals such as copper, cobalt, nickel, zinc, and iron.

The negative charges and tertiary structure of albumin account for its binding, storage, transport, solubilization, and detoxification of several endogenous and exogenous substances, including drugs, bilirubin, bile acids, hormones, metals, anions, long-chain fatty acids, l-thyroxine, nitric oxide, endotoxin, and other pathogen molecular patterns (PAMPs). Another nononcotic property of albumin is immunomodulation. Not all mechanisms underlying this function are well defined. However, there is convincing evidence that albumin modulates the immune response to sepsis. Its binding with circulating molecules, such as PAMPs and danger-associated molecular patterns (DAMPs), avoids these molecules from reacting with recognition receptors, preventing immune cell activation. Internalization of albumin into the leukocyte cytoplasm interacts with toll-like receptor trafficking and signaling, attenuating immune cell responses to stimulating molecules such as proinflammatory cytokine. Albumin prevents or attenuates macrophage dysfunction due to prostaglandin E2 (PGE2) and protects tissues from tumor necrosis factor-α (TNF-α)-induced immunopathology. These immunomodulatory mechanisms exert relevant indirect effects. The attenuation of immune system activation also leads to a decreased generation of ROS. Furthermore, along with interactions with the extracellular matrix, immunomodulation is also relevant in protecting endothelia and preserving capillary integrity and permeability. Also, albumin influences hemostasis by reducing platelet aggregation and acid-base balance by acting as a weak acid and buffering nonvolatile acids.^{[2, 3, 4, 5, 6]}

Albumin abnormalities in patients with cirrhosis

Low serum albumin concentration is a long-recognized feature in patients with cirrhosis and is associated with reduced survival.^[11] Impaired synthesis due to extensive reduction of functional liver parenchyma and sustained inflammation, hemodilution secondary to renal sodium and water retention, and enhanced transvascular escape, especially in the most advanced stages of cirrhosis, cooperate in inducing hypoalbuminemia.

More recent studies have clearly shown that, as it occurs in other chronic diseases such as diabetes mellitus, chronic renal failure, and ischemic heart disease, changes in albumin molecule also develop in cirrhosis.^[3] The systemic inflammatory and pro-oxidant milieu that characterize the disease and intensify in parallel with its progression represent the principal cause of albumin damage. These abnormalities are clinically relevant. Indeed, whereas the oncotic property of albumin is derived from highly conserved features, such as the high molecular weight and the negative net charge, the nononcotic properties are strictly related to the integrity of the molecular structure.^[1] Thus, when structural damages occur, one or more functions of albumin fail. The posttranscriptional molecular abnormalities most frequently reported, alone or in combination, consist of the oxidation of the Cys-34 residue, leading to an increase in the proportion of non-mercaptalbumin 1 and non-mercaptalbumin 2, oxidation of N-terminus (ischemia-modified albumin [IMA]), truncation of N- and C-termini, and glycosylation.^{[12, 13, 14]} These alterations generally parallel the severity of cirrhosis, from outpatients with a compensated disease to those affected by acute-on-chronic liver failure (ACLF). Some are also associated with specific complications of cirrhosis, such as ascites, renal failure, or bacterial infections.

Therefore, the alterations of serum albumin in patients with cirrhosis are not only quantitative but also qualitative, as posttranscriptional molecular abnormalities lead to impairments of nononcotic functions (Figure 1). The clinical consequences are relevant, especially in advanced cirrhosis, where the persistent systemic inflammatory and pro-oxidative state would require fully preserved albumin functions. Moreover, altered albumin isoforms may contribute to systemic inflammation. Indeed, the inflammatory response of peripheral blood mononuclear cells, assessed in vitro by measuring the production of interleukin-6 and TNF-α, is enhanced by a challenge with non-mercaptalbumin 1.^[15]

Figure 1

Graphic representation of the concept of effective albumin. In healthy subjects, the native isoform, with preserved molecular structure and functions, largely prevails among the circulating albumin isoforms. Patients with advanced cirrhosis show a reduction in total serum albumin concentration. However, the relative proportions of altered isoforms are increased, so that the amount of effective albumin can be drastically reduced. HA: human albumin; HNA1: non-mercaptalbumin 1; HNA2: non-mercaptalbumin 2; IMA: ischemia-modified albumin.

The traditional measurement of serum albumin concentration cannot provide information on the global albumin status. Thus, it would be clinically relevant to determine the proportion of circulating structurally and functionally intact albumin: the serum effective albumin concentration (EAc).^[2]