Albumin Introduction

Albumin is a much misunderstood protein, both physiologically and pharmacologically. It

is the most abundant extracellular protein in the body, and has a wide variety of roles.
Until relatively recently, albumin containing solutions were popular as volume expanders
(colloids). This situation has changed due to a raging controversy, which emerged in the
late 1990s. The purpose of this tutorial is to instruct you on the physiologic role of
albumin, to discuss its role in disease and nutrition and to look at is use
pharmacologically.
Learning Objectives
To learn the physiologic role of albumin.
To assess the role of albumin in nutrition and disease
To discuss the pharmacologic role of albumin
Albumin Physiology
Albumin is the most abundant extracellular protein, its distribution is primarily
intravascular.
Albumin is the most abundant extracellular protein. It is a single polypeptide with 585
amino acids and a molecular weight of 66,200D. It is thus a medium sized compound
(IgG is 150,000) which, in addition to being highly soluble, is small enough to pass
through fenestrated endothelium, such as in the nephron. That proteinuria does not
occur in normal people is consequent of a strong negative charge (17), which rebuts
the protein in the glomerulus.
Albumin is manufactured in the liver at a rate 9-12g/day. The normal serum albumin is 30
to 40 grams per litre. There is no storage, no reserve. Being the major source of oncotic
pressure in health, it stands to reason that the rate of
production of albumin is controlled by changes in colloid osmotic pressure and
osmolality of extravascular liver space. The capacity for increased production is fairly low
(can only increase by a factor of 2 or 3). Increased synthesis is increased by the
neuroendocrine system, chiefly by insulin, thyroid hormones and cortisol.
Albumin is catabolized at a rate of 9 - 12 g/day (the same rate as it was produced) by
pinoctosis in cells adjacent to the vascular endothelium. Albumin is not catabolized in
starvation: under these circumstances, protein is derived from muscle, following
exhaustion of fat stores.
Although albumin is perceived as intravascular protein, the total extravascular albumin
actually exceeds the total intravascular amount by 30%. The ratio of albumin to water is,
however higher in the intravascular space (the extracellular fluid is 2/3 interstitial and 1/3
intravascular), hence the colloidal effect. Albumin cyclically leaves the circulation,
through the endothelial barrier at the level of the capillaries, passes into the interstitium
and returns to the bloodstream through the lymph system via thoracic duct. The
circulation half time for this process is 16 -18 hours. 4 - 5% of total intravascular albumin
extravascates in this way per hour: this rate of movement is known as the Transcapillary
Escape Rate (TER), and this is determined by:

Capillary and interstitial free albumin concentration.

Capillary permeability to albumin.

Movements of solvent / solute.

Electrical charges across the capillary wall.

The concentration of albumin in lymph protein content is approximately 80% that of

plasma.
Albumin Physiological Role
Albumin has a role in maintaining COP, binding and transport, free radical scavenging,
acid base balance, coagulation and vascular permeability.
Physiologic Roles of albumin
1.
Maintenance of the colloid osmotic pressure (COP).
2.
Binding and transport, particularly of drugs.
3.
Free radical scavenging.
4.
Acid base balance
5.
Pro and anti-coagulatory effects (inhibits platelet aggregation, enhances the
inhibitioof factor Xa by antithrombin III).
6.
Effects on vascular permeability.
Binding and transport
Albumin binds drn ugs and ligands, and therefore reduces the serum concentration of
these compounds. An example is the serum calcium, the free (ionized) concentration of
which needs to be corrected for albuminThere are actually four binding sites on albumin
and these have varying specificity for different substances. Competitive binding of drugs
may occur at the same site or at different sites (conformational changes) [eg. warfarin
and diazepam]. The drugs that are important for albumin binding are: warfarin
(coumadin), digoxin, NSAIDS, midazolam, thiopental. Although one would expect that
low serum albumin is related to higher free drug levels, the relevence of a low albumin
and drug binding is unknown.
Osmotic pressure
Albumin is responsible for 75 - 80 % of osmotic pressure.
According to Starlings equation, the flow of fluid out of capillaries is determined by
a filtration constant multiplied by the net force driving fluid out of the capillary (hydrostatic
pressure minus oncotic pressure) minus the osmotic gradient pulling the fluid out.
Starling's equation: Transcapillary Flow = k [(Pcap + Pi) - (Pi + Pcap )]
Remember that albumin is the main protein both in the plasma and in the interstitium
and it is the COP gradient rather than the absolute plasma value that is important: this is
what distinguishes hypoalbuminaemia derived from redistribution (capillary leak) from
that of pure full body deficiency.
Free Radicals
Albumin is a major source of sulphydryl groups, these "thiols" scavenge free radicals
(nitrogen and oxygen species).
Albumin may be an important free radical scavenger in sepsis.
Acid Base Balance
Albumin is a negatively charged protein in high concentration in the plasma. It
contributes heavily to what we call the anion gap: the concentration of anions
and cations in plasma should be equal, classically the anion gap is calculated as
(Na + K) - (Cl) = AG (mEq/l). The remaining anions come predominantly from albumin,
inorganic phosphate and hemoglobin. Thus, in hypoalbuminemic states, the anion gap
should be narrowed.

Anticoagulant effects
The anticoagulant and antithrombotic effects of albumin are poorly understood this may
be due to binding nitric oxide radicals inhibiting inactivation and permitting a more
prolonged anti-aggregatory effect. In diabetes, glycosylated albumin may increase the
incidence of thrombotic events and atherosclerosis.
Vascular Permeability
It is possible that albumin has a role in limiting the leakage from capillary beds during
stress induced increases in capillary permeability. This is related to the ability of
endothelial cells to control the permeability of their walls, and the spaces between them.
Albumin may plug this gap or may have a deflecting effect, owing to its negative charge.
This has led to the hypotheis that colloids are effective at maintaining vascular
architecture.
Albumin Hypoalbuminemia
Serum albumin concentration falls due to decreased synthesis, increased
catabolism, increased loss and redistribution.
Plasma albumin concentration is calculated as: intravascular albumin mass / plasma
volume
Causes of decreased plasma albumin:
1. Decreased synthesis.
2. Increased catabolism [very slow]
3. Increased loss:
Nephrotic syndrome
Exudative loss in burns
Haemorrhage
Gut loss
4. Redistribution:
Haemodilution
Increased capillary permeability (leakage into the interstitium)
Decreased lymph clearance.
Capillary leak syndrome occurs in systemic inflammatory response syndrome.
Due to widespread damage to the capillary endothelium, there is increased loss of
medium to high molecular weigh compounds, particularly albumin, into the extravascular
space and therefore loss of the normal Starling relationship.
What diseases is hypoalbuminaemia associated with?
Hypoalbuminemia is associated with liver and renal disease, PET, SIRS / including
burns, trauma. Low preoperative albumin is an indicator of poor outcome from surgery.
Liver Dysfunction
Albumin is a poor marker of liver dysfunction; prothrombin time is more reliable.
Renal disease
Albumin loss occurs in nephropathies (nephrotic syndrome).
There is a small loss of albumin in dialysis circuits.
Pre-Eclampsia (PET)
In normal pregnancy there is an increase in plasma volume. In PET there is a
paradoxical decrease in plasma volume, widespread capillary leak and albuminuria.
Stress response
Interleukins cause a marked decease in synthesis of plasma proteins other than
albumin.

In fact Albumin and Transferrins decrease in the stress response, a process often
termed "negative acute phase proteins".
IL6 directly decreases the _expression of albumin messenger RNA.
Overall, the picture in the stress response is:
1. Initial decrease in albumin associated with increase in acute phase proteins.
2. Subsequent global increase in hepatic protein synthesis; including albumin.
Burns
There is massive protein loss from the burn site & increased vascular permeability &
decreased albumin synthesis & protein losing nephropathy. The use of albumin in
patients with >15% burns after 24 hours has been recommended.
Trauma
In trauma there is increased redistribution and transcapillary escape of albumin.
Surgery
Decreased serum albumin preoperatively is an independent indicator of poor outcome.
Sepsis
SIRS - associated with increased capillary permeability, due to the effects, amongst
others, of bacterial endotoxin and cytotoxic T cells. In sepsis there is a profound
reduction in plasma albumin associated with marked fluid shifts.
Hypoalbuminemia
What is the relationship between serum albumin concentration and malnutrition?
Decreased albumin in adults is a marker of associated disease (a negative acute phase
reactant) not a feature of isolated protein-energy malnutrition.
Serum albumin does not decrease significantly in starvation, although production is
affected. The body maintains the serum albumin at the expense of muscular protein:
There is decreased synthesis, increased redistribution & decreased catabolism.
Moreover, albumin has a long half life, compared with pre-albumin. As a result, when the
patient's nutritional status is improving, the pre-albumin will tend to bounce back earlier.
If critical illness persists, catabolism persists, and the levels of both of these markers will
remain low. In general it is unwise to rely on these as markers of nutrition in critical care.
Is there any relationship between hypoalbuminemia and outcome?
Low serum albumin is an independent indicator of (poor) outcome in critical illness.
There is a considerable body of evidence indicating that serum albumin is a prognostic
indicator. Goldwasser (1997) suggests that albumin may well be an independent
indicator of outcome in a variety of clinical settings. The lower the serum albumin
plunges, the greater the mortality, morbidity, length of stay and complication rate. Blunt
(1998) and colleagues have shown that non-survivors in intensive care had lower mean
albumin concentrations than survivors, and there was, significantly, no difference
between the COPs of the two groups.
Albumin Therapeutic Uses
There is no evidence that correcting hypoalbuminemia improves outcome, indeed
therapeutic albumin administration may worsen outcome.
A number of strategies have utilized albumin as a therapeutic agent:
1. Correcting hypoalbuminemia to improve outcome no evidence of
improvement.
2. Using albumin as a hypertonic-hyperoncotic agent to reduce tissue prefusion,
with or without diuretics no evidence of improvement.

3. For volume replacement in cirrhosis (spontaneous bacterial peritonitis) some

evidence.
As the colloid of choice in infants no evidence either way.
In burns no evidence either way.
Following paracentesis for ascites no evidence.
To treat nephrotic syndrome no evidence.
As a colloid agent in critical illness: little supportive evidence.
A meta-analysis by the Cochrane Collaboration (BMJ June 1998), has suggested that
the administration of albumin may, in fact, worsen outcome. Whilst this paper was
heavily criticized in terms of methodology and outcome measures, it has had a
significant impact on practice. A subsequent widened meta-analysis (Wilkes MM 2001)
found that albumin administration did not significantly alter outcome.
The inclusion of albumin in colloid versus crystalloid debates has led to claims
that the latter are safer than the former. However these papers demonstrate the
significant weaknesses that exists in the performance of meta-analysis and the
geographic bias in publication versus practice.
Why would albumin be harmful?
There are concerns about the manufacturing process of commercially available albumin:
Commercially available albumin is fractionated in ethanol and purified and heat treated
for 10 hours at 60oC.
This process:
Probably alters the charge on albumin - making it more permeable.
Contains significant quantities of residual ions - aluminum and vanadium.
It appears that, without strong data supporting the use of this agent, and with
alternatives available (hydroxyethyl starch), the continued prescription of albumin as a
volume expander is neither clinically indicated nor cost effective. Nonetheless, there is
little evidence to reject the use of this agent in it's conventional setting - as a volume
expander in babies and in burns. Currently, albumin is the fluid of choice in preventing
renal failure in patients with spontaneous bacterial peritonitis (Sort P, 1999).
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Albumin Key Points

1. Albumin is the most abundant extracellular protein, its distribution is
primarily intravascular.
2. Albumin has a role in maintaining COP, binding and transport, free radical
scavenging, acid base balance, coagulation and vascular permeability.
3. Albumin is measured using BCG or BCP. This overestimates a low serum
albumin.
4. Serum albumin concentration falls due to decreased synthesis, increased
catabolism, increased loss and redistribution.
5. The serum albumin falls when patients become sick, and comes back up when
patients get better. The liver stops producing albumin in critical illness: low
albumin is a non specific marker of disease.
6. Edema formation is determined by the rate of fluid flux: COP is determined by
total protein concentration, and the state of the lymphatic system.
7. Hypoalbuminemia is associated with liver and renal disease, PET, SIRS including
burns, trauma and surgery.
8. Decreased albumin in adults is a marker of associated disease (a negative acute
phase reactant) not a feature of isolated protein-energy malnutrition. It is a poor
indicator of nutritional status (so too is prealbumin).
9. Low serum albumin is an independent indicator of (poor) outcome in critical
illness.

10. There is no evidence that correcting hypoalbuminemia improves outcome,

indeed therapeutic albumin administration may worsen outcome.