**5.2 Oxidation of albumin**

Albumin is a high molecular weight protein (MW 66.5 kD), which is a fundamental determinant since it provides 75% of the oncotic pressure, necessary to maintain fluids in the intravascular compartment, and represents 54% of the plasma proteins, with a hepatic synthesis rate of 150 m/kg/day [14]. Albumin is formed by a polypeptide chain of 585 amino acids, divided into three domains I, II and III. Each domain is subdivided in types A and B, it is composed of 35 cysteine residues, of which 34 residues form 17 disulfide bridges and leave the cysteine residue (Cys) 34 free to interact with others molecules (**Table 3**) [15].

The important functions of albumin include being a regulator of extracellular fluids, it allows the reversible transport of endogenous products, such as fat-soluble hormones and free fatty acids, transporting unconjugated bilirubin, and exogenous products such as metals, drugs, and drugs. It also fulfills a function important in PH control, buffering non-volatile acids, and competitive binding to calcium ions. Antioxidant properties are described because it is a source of reduced sulfhydryl groups with properties to eliminate ROS, with anti-inflammatory and endothelial protection effects [14].

Albumin mostly circulates in a reduced state, called human mercaptoalbumin (HMA) with a free thiol group at residue Cys 34, to which ROS and nitrogen bind, allowing their uptake and removal of free radicals. Albumin can undergo several posttranslational modifications in physiological or pathological conditions, which undergoes oxidation through disulfide bonding between Cys34 and sulfhydryl-containing compounds such as glutathione, homocysteine, and cysteine. This reversibly oxidized form of albumin is called non-mercaptoalbumin type 1 (HNA-1) and the complete and irreversible oxidation of Cys 34 albumin to sulfonic or sulfinic acid confers the


#### **Table 3.**

*Each albumin domain allows the transport of different substances, and the CYS 34 residue has the capacity to eliminate ROS.*

#### *Artificial Liver Support Systems DOI: http://dx.doi.org/10.5772/intechopen.109843*

name non-mercaptoalbumin type 2 (HNA-2) [16, 17]. Other forms of modified albumin are also described, such as ischemia-modified albumin (IMA), in which it undergoes a conformational change in the N-terminal portion, decreasing the metal transport capacity, and the IMA/albumin ratio is also increased in patients. with cirrhosis and ACLF, described as a marker associated with higher mortality. Other forms of cystei-nylated, glycated and truncated modified alumina are mentioned, all the described forms of oxidized albumin lose the capacity to transport molecules and detoxify, increasing the free component of many toxic substances that alter the functions of organs and systems [17].

The expression of non-mercaptoalbumin types 1 and 2 has an effect on the activation of mononuclear cells by stimulating the release of cytokines (IL 1β, IL 6, IL 8, and TNF-α), amplifying or perpetuating the inflammatory response, by which a relationship between the levels of oxidized albumin and the pro-inflammatory state exists. In a cohort study of 79 patients, non-mercaptoalbumin type 1 phosphorylated the mitogen-activated protein kinase (MAP) p38α [18] was observed, which increases the activity of the transcription factor NF-κB, induces the production of cytokines, and also increases the production of inflammatory COX2 eicosanoides such as thromboxane A 2 (TXA2), leukotriene B 4 (LTB4), and prostaglandin G2 (PG2) [18].

We see that albumin oxidation is a mechanism that by itself induces and perpetuates inflammation in patients with decompensated cirrhosis and acute-on-chronic liver failure, which opens the way for the search for other applications of extracorporeal liver support therapies.

In a randomized crossover design trial of eight patients with ACLF, who underwent alternate eight treatments with MARS and Prometheus, non-mercaptoalbumin types 1 and 2 levels were measured and found to be elevated, and there was a transient change in status redox, from non-mercaptoalbumin to mercaptoalbumin that lasted a short time, returning to the oxidized forms of albumin after 24 hours [19].

There are few studies that evaluate extracorporeal liver support techniques as an alternative for albumin detoxification or regeneration. The Molecular Adsorbent Recirculating System (MARS) was found to be useful in removing substances bound to albumin and improving hepatic encephalopathy, but in a small study of 34 MARS patients [20], it did not show benefit in improving functional capacity or regenerating capacity and normal functionality of albumin. It is possible that liver damage and inflammation lead to irreversible damage to albumin and extracorporeal liver support techniques based only on albumin recirculation with small-capacity and easily saturated adsorbents.
