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Albumin

Declaration of sponsorship CSL Behring
Read time: 30 mins
Last updated:27th Apr 2023
Published:27th Apr 2023
In this section

Albumin functions and features

Introduction to albumin

Preclinical and clinical studies highlight the potential of albumin for a variety of applications, including drug delivery1

Albumin is a highly versatile protein thanks to both its oncotic and non-oncotic properties. It is the most abundant protein in extracellular fluid and in the blood, representing around half of all serum proteins2,3. Albumin weighs approximately 67 kDa, is water-soluble, globular and negatively charged at neutral pH3. Albumin is one of the most important proteins1, with multiple functions including ligand-binding, transportation and compound distribution and metabolism4.

In this video, Alastair O’Brien, Professor of Experimental Hepatology at University College London, describes the various roles of albumin in the body. Professor O’Brien describes the oncotic and non-oncotic properties of albumin, including its role in drug transportation, its binding properties and anti-inflammatory effects.

Albumin is a heart-shaped molecule consisting of three domains of similar size, each divided into two subdomains. Within subdomains IIA and IIIA are two important binding sites named Sudlow I and II, which bind hydrophobic compounds, including hydrophobic drugs1. Figure 1 illustrates the molecular structure of human albumin.

Albumin_T1_Fig1.jpg

Figure 1. Molecular structure of human serum albumin5. Molecular structure of human serum albumin is licensed under CC BY-NC-ND 4.0. The crystal structure (pdb code 1e7i) of human serum albumin shows the six subdomains (IA, IB, IIA, IIB, IIIA and IIIB), the N and C termini, Sudlow’s sites I and II, and the seven long-chain fatty acid (LCFA) binding sites (FA1 to FA7). The heavy atoms of the side chain of residue Cys34 are shown as purple spheres. LCFA binding sites also bind prostaglandins. Cys34 binds reactive oxygen species and reactive nitrogen species, including nitric oxide.

Synthesis and metabolism of albumin

Albumin is synthesised by hepatocytes and excreted into the bloodstream3. Up to 60% of albumin is stored in the interstitial space rather than in circulating blood, lasting just 16–18 hours in circulation, compared with its biological half-life of 19 days1. The normal concentration of human albumin is 35–50 g/L4 and the effective concentration depends on its movement between interstitial and intravascular spaces, and the balance between albumin production and degradation1.

Albumin is constantly synthesised and recycled by hepatocytes, recycling accounting for its longer biological half-life. Albumin is regulated by the neonatal crystallisable fragment receptor (FcRN), which binds albumin on the surface of epithelial cells and hepatocytes3. FcRn redirects albumin away from the extracellular space and bile, and into the vascular space3. The expression of FcRn by epithelial cells and hepatocytes is the primary driver of circulating albumin levels and recycling, and its absence contributes to hypoalbuminaemia3. Figure 2 illustrates albumin metabolism. 

Albumin_T3_Fig3.png

Figure 2. The metabolism of albumin by Bernardi et al3. Albumin recycling by endothelial cells is licensed under CC BY-NC 4.0 / image redrawn and colours altered. FcRN, neonatal crystallisable fragment receptor.

Given the reversible transcapillary movement of albumin, plasma concentrations can be maintained at a constant level1. The body’s requirements regulate its production, with thyroxine, cortisol, insulin and conditions such as hypoalbuminaemia being particular stimulants for production. In contrast, high levels of osmotic pressure on hepatocytes reduce its production1. Nutrient supply must be at adequate levels to trigger the production of albumin, and indeed the liver’s ability to produce protein is hindered when nutrient absorption is poor1. Albumin degradation mainly occurs in the liver and kidney but can occur in any tissue1.

As it is produced by the liver, functional liver loss can lead to decreased albumin levels1. Its levels can decrease when production by the liver is affected, in which case there may be an increase in protein breakdown and greater protein loss via the kidneys, expanding plasma volume and diluting the blood1. Albumin concentration can also be affected by kidney disease1.

Functions and features of albumin

Albumin has several roles in the body, its two key roles being to maintain osmotic pressure in the blood, and to be the primary carrier of hydrophobic materials such as hormones and fatty acids1.

Albumin transports vitamins, hormones, drugs and divalent cations such as zinc and calcium, and it nourishes tissues1. It is involved in wound healing and coagulation, has antioxidant properties, enhances antithrombin III activity and, in inflammatory conditions, it acts as a free radical scavenger1. Albumin is the key factor determining plasma oncotic pressure and is pivotal in controlling fluid distribution between compartments6.

Albumin is the primary antioxidant in the human body that7:

  • Regulates immunological and inflammatory pathways
  • Helps regulate endothelial integrity
  • Plays an essential role in detoxification and transport
  • Counteracts reactive nitrogen and oxygen species

The many functions of human serum albumin are summarised in Figure 3.

Albumin_T1_Fig2.png

Figure 3. The functions of albumin (Adapted8).

The roles of albumin in the body9:

  • Anti-inflammatory activity
  • Binding and transport of materials (naturally occurring, therapeutic and toxic)
    • β-amyloid peptide
    • Bilirubin
    • Drugs
    • Circulating ions
    • LCFAs
    • L-tryptophan
    • Steroids
  • Contributes to plasma pH
  • Determines plasma oncotic pressure
  • Immunomodulation
  • Regulates haemostasis
  • Regulates intercompartmental tissue fluid distribution
  • Scavenges oxidative and nitrosative reactive species
  • Stabilises endothelium, capillary permeability and vascular integrity

Clinical applications of albumin

While albumin can be extracted from various sources including egg white and human, rat or bovine serum, bovine serum albumin and human albumin are the most common forms used for drug delivery1. Human albumin solution (HAS) is also primarily used for fluid resuscitation and to treat critically ill patients with hypoproteinaemia10.

HAS is nonimmunogenic and the body does not recognise it as foreign material unless it is altered or damaged1. It is a highly versatile carrier protein, possessing many functions, and is used in a wide range of clinical applications including volume replacement, drug delivery, and as a prognostic biomarker4,9. Researchers postulate that albumin could also be used for other applications such as the production of nanovaccines1. Given its ability to actively target disease sites without the need for addition of specific ligands, it could potentially promote half-life extension and targeted drug delivery1. 

The wide variety of clinical uses of albumin has been attributed to its following features1:

  • Albumin has high nonimmunogenicity, biocompatibility, biodegradability and safety for its clinical application
  • Albumin interacts with a range of drugs, potentially protecting them from metabolism and elimination, thus enhancing their pharmacokinetic properties
  • Albumin can interact with receptors that are overexpressed in diseased cells and tissues, actively targeting disease sites without the need for specific ligands being added to the nanocarrier

In the clinic, albumin is administered intravenously, with a number of formulations available. The 5% formulation is more commonly used for volume loss caused by dehydration, and the 25% concentration is typically administered for oncotic deficiencies or when sodium or fluid is restricted11.

Examples of evidence-based clinical uses of albumin (5% and/or 25%)9:

  • Acute nephrosis
  • Adult respiratory distress syndrome (ARDS)
  • Cardiopulmonary bypass procedures
  • Hypoalbuminaemia
  • Hypovolaemia
  • Ovarian hyperstimulation syndrome
  • Neonatal hyperbilirubinaemia
  • Plasma exchange
  • Prevention of central volume depletion after paracentesis from cirrhotic ascites

Albumin as fluid therapy

Clinically, albumin solutions have been used as plasma expanders and as volume replacement6 and therapeutic albumin has been administered in a range of diseases for decades, demonstrating safety in people who are critically ill12. Figure 4 illustrates how albumin is used in therapeutic plasma exchange.

Albumin_T1_Fig3.png

Figure 4: The role of albumin in therapeutic plasma exchange (Adapted9).

The first use of HAS as a therapeutic agent occurred approximately 80 years ago, when it was administered to a young adult with traumatic shock9. Since then, albumin has been used in a range of clinical applications including burns, gastrointestinal and other internal bleeding, hypovolaemia, cardiopulmonary bypass, prevention of central volume depletion following paracentesis, and hypoalbuminaemia, including therapeutic plasmapheresis9.

Albumin use in drug and vaccine delivery

Thanks to its long half-life and being nonimmunogenic, HAS is used in drug delivery1. This is achieved either by covalent binding or noncovalent interaction1, noncovalent being generally preferred because of its reversibility, which allows for drugs to be released where required1.

Nanoparticle albumin-bound (NAB)-technology is one of the most popular drug-delivery systems that involve albumin1. It is nanotechnology-based and leverages the properties of albumin to deliver hydrophobic drugs selectively and efficiently without the use of toxic solvents1. This system has been considered a breakthrough technology, given that many chemotherapeutics are hydrophobic, which has traditionally presented challenges1. Nab-paclitaxel was created using NAB technology, and was approved by the US Food and Drug Administration (FDA) in 20051. It consists of albumin-based nanoparticles loaded with paclitaxel and is used to treat bladder cancer, gastric cancer (in Japan), non-small cell lung cancer, metastatic breast cancer, and metastatic adenocarcinoma of the pancreas1. Being a versatile carrier and able to bind numerous different drugs, other albumin-based nanoparticles have been developed for a range of indications and utilising a variety of binding strategies1.

Albumin may also have a role in vaccine delivery. For a vaccine to be efficient, the antigen must reach the lymph nodes and activate the innate and adaptive immune systems1. Albumin’s molecular weight of about 67 kDa may prevent antigen from being disseminated into the blood, thereby allowing it to be taken to the lymphatics where it accumulates, leading to greater immunogenicity than the equivalent soluble antigen can achieve1. Researchers hypothesise that nanovaccines could be created by combining exogenous molecular vaccines and endogenous nanocarriers such as albumin, to improve lymph node vaccine bioavailability and for enhanced immune response1.

Albumin’s affinity for particular receptors on epithelial and other cell surfaces in diseased organs allows for recognition and active targeting of the albumin-based formulation. Its versatility in carrying drugs could be extended to applications in imaging and gene therapy1.

Albumin as a prognostic factor

Native human albumin has been demonstrated as a more accurate predictor of 1-year survival in patients with cirrhosis than serum albumin concentration, which is commonly measured in clinical practice13

Among the many roles of albumin is its value as a prognostic tool in many clinical settings14. Low levels of circulating human albumin have been associated with higher risk of morbidity and mortality in the following conditions14:

  • Heart failure
  • Cancer
  • Malnutrition
  • Acute and chronic liver and kidney disease
  • Inflammatory conditions

For example in oncology, secreted protein acidic rich in cysteine (SPARC) is absent in normal tissues, but is overexpressed by numerous tumour types1. SPARC attracts albumin, leading to accumulation within the tumour1. In albumin-based drug delivery, high levels of SPARC can indicate how efficacious the albumin-based drug delivery system will be at inhibiting cancer proliferation1.

It has been proposed that the quality of circulating human albumin may be a useful biomarker in conditions such as renal and liver disease14. In advanced cirrhosis, for example, human albumin undergoes several structural alterations, the accumulation of which leads to a considerable reduction of human albumin in its native form13. Analysis of albumin quality is possible thanks to methods that can both quantify and characterise changes to native human albumin14.

Across a lifetime, alterations occur in the redox state of human albumin and other circulating plasma proteins, mostly through increases in systemic oxidative stress in ageing, observable as lower proportions of a particular form of human albumin in older persons14. Further, oxidised human albumin drives endothelial injury and senescence in older persons, directly contributing to greater cardiovascular disease risk14.

In people with chronic kidney disease, changes in the binding capacity of Sudlow II and the N-terminal portion have been observed, with higher levels of ischaemia-modified albumin (IMA) found in people with end-stage renal disease; therefore, IMA levels may provide an independent prognostic indicator of clinical outcomes14.

Cirrhosis is associated with quantitative alterations and qualitative abnormalities in human albumin functions and structure, and higher levels of human albumin in oxidised forms have been observed in cirrhotic patients14. In fact, increased levels of two particular forms of altered human albumin, human non-mercaptalbumin (HNA) 1 and HNA2, have been observed in people with decompensated cirrhosis and acute-on-chronic-liver failure (ACLF)14. In ACLF patients, there is a direct relationship between HNA2 level and disease prognosis14.

While absolute albumin concentration is commonly measured in clinical practice, the identification and measurement of structurally altered human albumin isoforms could be used to calculate the quantity of native human albumin still in circulation, which may provide a more reliable estimate of 1-year patient survival than absolute human albumin concentration14.

Albumin as a colloid for volume replacement

Administration of fluid therapy is common for people who are critically ill or undergoing surgery, to help restore and maintain tissue perfusion15. Significant risks of fluid therapy relate to pharmacological side effects and under- or over-administration15. 

There are two main types of intravenous fluids used for volume resuscitation: colloids and crystalloids15. Figure 5 illustrates the physical differences between the two types.

Albumin_T2_Fig2.png

Figure 5. Crystalloid and colloid solutions (Adapted16).

Table 1. Features of crystalloids and colloids17.

Crystalloids versus colloids
Crystalloids Colloids
• Salt solutions
• Small molecules
• Easy to use
• Lowcost
• Provide immediate
   fluid resuscitation 
• May increase oedema		 • Can be man-made or naturally occurring
• Larger molecules
• More costly
• May provide faster volume expansion
   in the intravascular space 
• May induce kidney failure, allergic reactions,
   blood clotting disorders 

Colloid solutions were more frequently administered for volume resuscitation in the past, compared with crystalloid; however, some may cause harm, and their costs exceed that of crystalloid solutions15. Currently, crystalloid solutions are more commonly used for this indication, with buffered solutions often favoured over saline15.

Human albumin solution (HAS) is the standard colloid solution used as a resuscitation fluid in critically ill patients, and could play a role in the treatment of conditions such as sepsis and decompensated cirrhosis3,15. Typically, HAS is preferred over synthetic colloid solutions, especially hydroxyethyl starch (HES)15.

Approved human albumin indications

In Europe, the UK and the US, preparations of human albumin (including at 5% and 20% concentration) are approved for restoration and maintenance of circulating blood volume where deficiency has been demonstrated and use of a colloid is appropriate18–32. Prescribing information for some preparations notes that the choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations22–27,29. In the US, the approved prescribing information for three preparations of human albumin preparations lists specific indications, including hypovolaemia, ascites, hypoalbuminaemia (including from burns), acute nephrosis, acute respiratory distress syndrome, haemodialysis and cardiopulmonary bypass33–35. Note that the treatment of hypoalbuminemia is not indicated in certain countries. Refer to local guidelines for further information including contraindications and side effects.

Table 2. Brief overview of studies that support albumin administration for its approved indications7,17,36–40. Note that this is a high-level summary. For more information, please consult the source material.

Studies supporting the use of albumin for its approved indications
Trial Investigation Key results
SAFE trial Albumin versus saline as a resuscitation fluid in a heterogenous group of critical care patients • No statistically significant difference in all-cause mortality at 28 days
• Post-hoc analyses suggest albumin should be avoided in patients who have had traumatic brain injury
ALBIOS trial Albumin + crystalloids versus crystalloids in patients with sepsis or septic shock • No significant difference in mortality at 28 days nor 90 days
Cochrane Review (2018) Crystalloids vs colloids in critically ill people requiring fluid volume replacement • Either choice probably makes little to no difference to mortality
ANSWER study Standard medical treatment versus standard medical treatment + albumin in patients with cirrhosis and uncomplicated ascites • Long-term administration of human albumin in decompensated cirrhosis improved 18-month survival
• Significant reductions in paracentesis, the incidence of refractory ascites, spontaneous bacterial peritonitis and other cirrhotic complications
• Fewer hospitalisations and shorter hospital stays
Pilot-PRECIOSA and INFECIR-2 trials Patients with decompensated cirrhosis treated with albumin • Reductions in cardiocirculatory dysfunction and systemic inflammation

Learn how albumin is used in sepsis and septic shock

References

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  3. Bernardi M, Angeli P, Claria J, Moreau R, Gines P, Jalan R, et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020;69(6):1127-1138.
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  28. Zenalb® 20 (200 g/l) solution for infusion Summary of Product Characteristics. 2021. Available at: https://www.medicines.org.uk/emc/product/5546/smpc#DOCREVISION. Accessed 25 July 2022.
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  37. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin Replacement in Patients with Severe Sepsis or Septic Shock. New England Journal of Medicine. 2014;370(15):1412-1421.
  38. Piotti A, Novelli D, Meessen JMTA, Ferlicca D, Coppolecchia S, Marino A, et al. Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS. Critical Care. 2021;25(1).
  39. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. The Lancet. 2018;391(10138):2417-2429.
  40. Fernández J, Clària J, Amorós A, Aguilar F, Castro M, Casulleras M, et al. Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis. Gastroenterology. 2019;157(1):149-162.
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