Human Serum Albumin (HSA) plays a number of important roles in human physiology, including maintaining the colloid osmotic pressure of plasma, regulating the redox potential of plasma, transporting endogenous and exogenous compounds, and regulates the distribution of vascular fluid . HSA has an extraordinary capability to bind to various small molecules, functioning as a chemical sponge. Notably, HSA also possesses a number of enzymatic activities.

The full-length of HSA contains a signal peptide (residues 1-18), propeptide (residues 19-22) and mature protein (residues 23-609). HSA is mainly synthesized in the liver. After the removal of the signal peptide and propeptides, the mature protein of HSA (molecular weight of 66 kDa) is secreted into blood. Albumin is synthesized exclusively by hepatocytes and secreted into the bloodstream. HSA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. 

Albumin plays a crucial role in the transport of various ions, electrically neutral molecules and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind almost all known drugs, many nutraceuticals and toxic substances, determining their pharmaco- and toxicokinetics. However, albumin is not only the passive but also the active participant of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. Due to the thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. The interaction of the protein with blood cells, blood vessels, and also with tissue cells outside the vascular bed is of great importance. The interaction of albumin with endothelial glycocalyx and vascular endothelial cells largely determines its integrative role. 

Albumin is synthesized by liver hepatocytes and rapidly excreted into the bloodstream. The rate of synthesis is constant in normal individuals at 150 to 250 mg/kg/day, resulting in the production of 10 to 18 g of albumin daily. Serum albumin is the major protein produced in the liver, comprising as much as 50% of the productive effort at any one moment. The concentration of this protein in the plasma has long been used as a bellwether of health and disease. Serum albumin is a highly flexible molecule of about 65,000 molecular weight containing 575 amino acids. Albumin is characterized by its extreme solubility in water, by its negative charge of 10 at pH 7.4, and by lack of a carbohydrate moiety. 

Albumin is synthesised by hepatocytes and continuously secreted into the circulation, without being stored in the liver. Albumin is present at a concentration of 3.5–5.0 g/dl in serum and accounts for more than 50% of the total circulating protein content. It has a half-life of about 20 days in healthy adults and is continuously taken up and recycled by hepatocytes. Albumin accounts for approximately 75% of plasma oncotic pressure, due to its high concentration and net negative charge, and is therefore principally responsible for fluid distribution within the body’s compartments. Albumin also has many other biological functions termed non-oncotic properties. It reversibly binds many molecules, including drugs, metallic ions, and multiple inflammatory mediators, potentially affecting systemic inflammation, immune response, antioxidant capacity and endothelial function.

The plasma albumin level is the net result of three dynamic processes, distribution, degradation, and synthesis. Thus, at anyone moment, these processes must be in balance to maintain a stable serum albumin level. 

The albumin molecule is not covered with a carbohydrate moiety and can bind a wide variety of molecules and atoms: water and metal cations (Ca2+, Zn2+, Cu2+, Ni2+, Cd2+, Co2+, Pt2+, Au+), free fatty acids and fat soluble hormones, unconjugated bilirubin, bile salts, transferrin, nitric oxide, aspirin, warfarin, phenylbutazone, clofibrate, etc.. By binding drugs and toxic substances, albumin largely determines their pharmaco- and toxicokinetics, through transport to target tissues or sites of their biotransformation. Binding occurs at two primary sites and several secondary sites, the number of which depends on the physico-chemical properties of the substances and the state of the albumin molecule. For fatty acids—the main ligand of albumin—there are seven binding sites, with the bound fatty acids changing the polarity and volume of drug binding sites]. 

In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure. 

Hypoalbuminemia, defined as serum albumin levels below 35 g/L, is common in patients with conditions such as nephrotic syndrome, cirrhosis, or sepsis. Albumin is the main drug transporter and key binding protein, which influences the free drug concentration and drug activity. 

Many drugs need dose adjustments to achieve therapeutic levels, especially in critically ill patients. Studies emphasize the need for individualized dosing regimens based on therapeutic drug monitoring to optimize drug therapy in patients with hypoalbuminemia. 

Hypoalbuminemia is a frequent medical problem that can be caused either by increased protein loss, in such conditions as nephrotic syndrome and protein-losing enteropathy, or reduced protein synthesis in patients suffering from malnutrition and cirrhosis (Ballmer, 2001) It is defined by serum albumin less than 35 g/L. Hypoalbuminemia was found to be one of the indicators of ongoing sepsis and is associated with increased mortality and longer hospital stays regardless of the primary disease (Franch-Arcas, 2001). Although serum albumin level is a nonspecific marker it is a strong predictor of sooner and more frequent readmissions in acute illnesses (Herrmann et al., 1992). In the field of oncology albumin level correlates with negative prognosis and worsened quality of life (McSorley et al., 2017). Hypoalbuminemic state is also present in certain physiological conditions–as pregnancy–associated with increasing permeability or in childhood (Loh and Metz, 2015; Challis et al., 2009).

Albumin can be used as a drug itself in conditions such as cirrhosis with refractory ascites or nephrotic syndrome (and hemorrhagic shock, severe burn), however hypoalbuminemia is rather a syndrome than primary process of the disease so it can be used only as symptomatic treatment (Liumbruno et al., 2009)

This protein, which now occupies so much of the liver’s productive capacity in terms of an exported protein, exists intracellularly in two forms, pro-albumin and albumin. The latter is identical to serum albumin, while the former is an albumin molecule containing either a pentapeptide or hexapeptide attached to the amino terminus of albumin. This small peptide moiety is removed by an intracellular protease at some time following synthesis and just prior to secretion. More recently, it has been demonstrated that the initial albumin molecule synthesized contains eighteen additional amino acids attached to the small peptide moiety of proalbumin. It may well be that this peptide extension on proalbumin is the signal peptide necessary for the interaction of the large ribosomal subunit with the endoplasmic reticulum allowing for transfer of the nascent albumin chain across the endoplasmic membrane with subsequent proteolysis of the signal peptide to form the proalbumin. It is of interest that the amino acid sequence in the peptide extension of the pre and pro albumin molecule is quite equivalent to sequences in other precursor molecules for proteins whose eventual destiny is export from some other cellular organ. 

Conventionally, the biologic and therapeutic effects of albumin have been thought to be due to its oncotic properties. However, albumin has a variety of biologic functions, including molecular transport, anti-oxidation, anti-inflammation, endothelial stabilisation, anti-thrombotic effects, and the adjustment of capillary permeability. Despite this, the functions of albumin have not been thoroughly investigated. Recent studies have shown non-alcoholic fatty liver disease (NAFLD), viral hepatitis, cirrhosis, and liver failure to be associated with impairments in albumin function, which are associated with impairments in liver function and disease prognosis. Post-translational modifications of albumin cause structural modifications that affect protein function. 

Randomised-controlled trials (RCTs) have produced controversial data on the efficacy and safety of HA, likely because of the great variance in terms of indications, experimental design, type of patients enrolled, length of treatment, and dosage and frequency of infusions. Current HA indications include acute or short-term (maximum 2 weeks) administration. Although proposed for the first time several decades ago, the possibility that HA can be administered for much longer to treat patients with ascites has become a major topic of scientific and clinical discussion.

Albumin binds at least 40% of the circulating calcium and is a transporter of hormones, such as thyroxine, cortisol, and testosterone. Insulin stimulates albumin production in the liver by activating gene transcription. 20% of cortisol is bound to albumin.  

Lower albumin level may point at malnutrition. Besides liver disease, this could indicate kidney disease, or inflammatory diseases. Higher albumin levels maypoint at acute infections, burns, and stress from surgery or a heart attack. Albumin can modulate inflammation by offering protection against inflammatory and oxidative stress damage. These properties can also be applied to PGE2-mediated immune response. 

Supplementation with active forms of vitamin D significantly increased serum albumin concentrations in a low-D3 test group from 3.61 ± 0.12 to 3.79 ± 0.13 g/dL (P = 0.0067). Nearly 85% of vitamin D-circulating metabolites are bound to the vitamin D-binding protein (DBP) and the remaining 15% is bound to albumin. 

Albumin can act as a source of amino acids required for wound healing. Amino acids play a role in the wound healing process, especially glutamine and arginine. Glutamine is a metabolic fuel in the process of cell proliferation, while arginine is a component needed for collagen synthesis. 

Albumin can play a scavenging and antioxidative role in the interstitial space. In cells, albumin can also be degraded at an accelerated rate, providing amino acids as building blocks for cell proliferation and matrix deposition. Low serum albumin levels are, therefore, an indicator of the severity of inflammation. 

Albumin improves neutrophils' ability to defend against pathogens.

Gillen et al. (6) showed that plasma albumin content increased immediately after upright intense exercise and remained elevated for 48 h. 

In plasma and other extracellular fluids, the majority of Zn2+ is bound to human serum albumin (HSA), which plays a vital role in controlling insulin pharmacodynamics by enabling removal of Zn2+.  The Zn2+-binding properties of HSA are attenuated by non-esterified fatty acids (NEFAs) also transported by HSA. Elevated NEFA concentrations are associated with obesity and type 2 diabetes. Higher NEFA levels in obese and/or diabetic individuals may contribute to insulin resistance and affect therapeutic insulin dose-response profiles, through modulation of HSA/Zn2+ dynamics. 

Symptoms that might indicate hypoalbuminemia

swollen hands or feet, puffy eyelids, fatigue.dry skin, itchiness, an increase or decrease in urination, foamy or bloody urine, muscle cramps.

Hepatic FcRn regulates albumin homeostasis and susceptibility to hepatotoxins. The neonatal Fc Receptor (FcRn) is responsible for maintaining the long half-life and high circulating levels of the two most abundant proteins in the bloodstream, albumin and immunoglobulin G (IgG). In the latter case, the protective mechanism derives from the ability of FcRn to bind IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells such as the endothelium, whereupon IgG is diverted from degradation in lysosomes and recycled. The cellular location and mechanism of FcRn protection of albumin are only partially understood. 

Studies demonstrate that at the site of albumin synthesis in the hepatocyte, the main function of FcRn is to direct albumin into the circulation which also increases hepatocyte sensitivity to toxicity. 

FcRn-albumin binding is critical for maintaining albumin homeostasis via scavenging, recycling, and transport of the FcRn-albumin-IgG complex through the endosomal recycling pathway. FcRn acts as a homeostatic regulator of HSA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of HSA and the potential clinical impact of decreased HSA are needed; in particular, the potential for certain treatments to reduce HSA concentration, which may affect efficacy and toxicity of medications and disease progression. 

Trimethylamine-N-oxide (TMAO) is gut microbiota-derived metabolite, plays a critical role in human health and diseases such as metabolic, cardiovascular, colorectal cancer and, neurological disorders. 

Trimethylamine (TMA) is an aliphatic tertiary amine produced by gut microbiota, starting from dietary precursors such as L-choline, L-carnitine and betaine. TMA and its metabolite trimethylamine-N-oxide (TMAO) are elevated in the plasma of cardiovascular disease (CVD) patients. Despite extensive literature on this topic, the scientific community is still divided on which of the two molecules is responsible for the harmful effects on human health. 

 trimethylamine n-oxide (TMAO) 

In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO is or the mediator or the bystander * in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

• argument for bystander role is the uptake of TMAO by albumin in healthy liver circumstances.