Pathophysiology of human albumin
Human albumin is a multifunctional transport protein present in the blood that has been widely used in clinical practice for decades in the treatment of hypovolaemia and hypoalbuminaemia
Huibo Li Suodi Zhai PhD Department of Pharmacy , Peking University Third Hospital , Beijing , China ; Institute for Drug Evaluation , Peking University Health Science Center , Beijing , China
Human albumin is a multifunctional transport protein present in the blood that has been widely used in clinical practice for decades in the treatment of volume deficits and conditions exacerbated by hypoalbuminaemia . Because these conditions present unique and heterogeneous pathophysiological features , albumin supplementation is used with different therapeutic objectives for each affected individual and may not always be essential in the context of critical care . 1 Nonetheless , owing to its various physiological and biochemical properties , albumin shows the potential to function as a transporter for drugs targeting many life-threatening diseases . 2
Structure , biological properties and functions Structurally , human albumin is a water-soluble , single-peptide chain protein produced in the liver , consisting of 585 amino acids organised into three homologous alpha-helix domains stabilised by disulphide bonds that assume an ellipsoid configuration in solution . Although these domains present a similar structure , they exhibit different ligand-binding affinities , which contributes to the biological versatility of this protein . 3 , 4 Albumin is the most abundant protein in the bloods , accounting for 55−60 % of all plasma proteins , although small amounts can be stored in the liver ( approximately 2g ). In a healthy adult , a total of 12−25g are produced per day , and content varies from 4 to 5g / kg of body weight , with approximately 40 % seen in the intravascular compartment and the remainder in the interstitial space . A total of 80 % of the extravascular pool is known to reside in the muscle and the skin . The molecular weight ( 66 kDa ) of albumin is relatively low when compared to that of immunoglobulins and other intravascular proteins , but it is a highly stable protein , with a halflife in plasma of approximately 19 days in healthy individuals . 1 , 5
Albumin is translated from a single gene in the form of preproalbumin and undergoes cleavage of its prepropeptide terminal in the endoplasmic reticulum of hepatocytes . The mature form of the protein is subsequently formed in the Golgi apparatus and is then released into the intravascular space . 2 , 3 Post-translational modifications include glycation , cysteinylation , S-nitrosylation , and S-guanylation , mainly in free cysteine residue 34 , which seem to partly affect the ability of the protein to interact with exogenous molecules in specific environments . 3 Naturally , the most significant factor influencing synthesis is the plasma concentration of albumin itself , but its production can also be induced by changes in interstitial colloid osmotic pressure ( known as oncotic pressure ) as well as changes in the supply of amino acids and energy to the cells , variations in the levels of hormones such as insulin , steroids , and growth hormone , and presence of systemic inflammation . By contrast , albumin catabolism can be more pronounced than synthesis and is essentially regulated by the total albumin pool . 1 , 5
Albumin is responsible for up to 80 % of the plasma oncotic pressure by inhibiting the displacement of fluid from the intravascular compartment into the interstitial space and , in reverse , by promoting its reabsorption from the interstitial space . 1 , 4 Owing to its flexible shape conferred by its movable domains , the protein reversibly binds to multiple endogenous ligands , such as fatty acids and bile salts , bilirubin , hormones and enzymes , essential metals , amino acids , and nitric oxide . Albumin is also capable of interacting with a multitude of exogenous substances , including antibiotics and other drugs , thus contributing to their metabolism , inactivation , or stabilisation . 1 In addition , interactions with drugs can be modified by small molecules such as fatty acid chains , and the protein is known to have seven long-chain fatty acid binding sites across its three domains . 3
Albumin also plays a role in the transport of substances derived from cell catabolism that are targeted for excretion by the liver and the kidneys , and in the transport of hormones and drugs to their target cells . Albumin is an important carrier for many endogenous and exogenous substances , and alterations in serum albumin concentration may affect pharmacokinetics and pharmacodynamics of highly protein-bound drugs . In addition , it is known to be involved in the elimination of toxic substances that accumulate under abnormal physiological conditions , in the inhibition of production of oxygen free radicals by polymorphonuclear leukocytes , and in the prevention of oxidative events through direct binding to reactive oxygen and nitrogen species . 1 , 4 In the physiological range of blood pH , albumin behaves as a weak acid , and the presence of many charged amino acid residues makes it an effective plasma buffer . When albumin production is decreased due to liver disease or malnutrition , or its loss increases as a result of nephrotic syndrome , chronic wounds or intestinal loss , mild metabolic alkalosis may develop , whereas liver decompensation or critical illness can result in metabolic acidosis . By contrast , exogenous albumin infusions to correct endogenous low levels in the context of liver and kidney failure may lead to net metabolic acidaemia , but this effect is very small
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