Factors That Modify Albumin Metabolism

Albumin

Albumin is a carbohydrate-free protein and comprises 60% of the total serum protein and 60 to 80% of colloid osmotic pressure. Serum albumin is synthesized solely by the liver.

Synthesis

In humans the liver manufactures albumin at a massive rate and decreases production in times of environmental, nutritional, toxic and trauma stress.

Albumin is not stored by the liver but is secreted into the portal circulation as soon as it is manufactured. The rate of synthesis rate varies with nutritional and disease states. The liver can increase albumin synthesis to only 2–2.7 times normal. Albumin will be synthesized only in a suitable nutritional, hormonal and osmotic environment. The colloid osmotic pressure (COP) of the interstitial fluid bathing the hepatocyte is the most important regulator of albumin synthesis.

The rate of synthesis depends on nutritional intake, more so than for other hepatic proteins.Fasting reduces albumin production, but specifically omitting protein from the diet causes a greater reduction in synthesis.

Factors that modify albumin metabolism

Reduced albumin synthesis

·  Decreased gene transcription

·  Trauma,

·  sepsis (cytokines)

·  Hepatic disease

·  Diabetes

·  Decreased growth hormone

·  Decreased corticosteroids (in vitro)

Ribosome disaggregation

·  Fasting, especially protein depletion

Degradation

Total daily albumin degradation in a 70kg adult is around 14g day–1or 5% of daily whole‐body protein turnover. Albumin is broken down in most organs of the body. Muscle and skin break down 40–60%.The liver, despite its high rate of protein metabolism, degrades 15% or less of the total. The kidneys are responsible for about 10%, while another 10% leaks through the stomach wall into the gastrointestinal tract.

Albumin Metabolism

The serum albumin concentration depends on its rates of synthesis and degradation and its distribution between the intravascular and extravascular compartments.

·  The total body albumin pool measures about 3.5–5.0gkg–1body weight (250–300g for a healthy 70kg adult).

·  The plasma compartment holds about 42% of this pool, the rest being in extravascular compartments. Some of this is tissue‐bound and is therefore unavailable to the circulation.

·  Daily 120–145g of albumin is lost into the extravascular space. Most of this is recovered back into the circulation by lymphatic drainage.

·  Albumin is also lost into the intestinal tract (about 1g each day), where digestion releases amino acids and peptides, which are reabsorbed.

There is minimal urinary loss of albumin in healthy subjects. Urinary loss is usually not more than 10–20mgday–1.

Normally, about 4% of the total body albumin is replenished each day and 120 mg/kg/dl of albumin is synthesised per day. The rate of production is dependent on the supply of amino acids, plasma oncotic pressure, inhibitory cytokine (especially IL-6) concentration, and the number of functioning hepatocytes. The liver is the primary site of albumin synthesis. Circulating half-life of plasma albumin is 19 to 21 days.

Functions of albumin

Albumin has extensively studied and well‐established physiological functions in health. There are, however, few studies on the function of albumin in the critically ill.

Physiologic Roles of albumin

·  Maintenance of the colloid osmotic pressure (COP).

·  Binding and transport, particularly of drugs.

·  Free radical scavenging.

·  Acid base balance

·  Pro and anti-coagulatory effects (inhibits platelet aggregation, enhances the inhibition of factor Xa by antithrombin III).

·  Effects on vascular permeability.

Binding and transport

Albumin binds drugs and ligands, and therefore reduces the serum concentration of these compounds. The drugs that are important for albumin binding are: warfarin (coumadin), digoxin, NSAIDS, midazolam, thiopental.

Osmotic pressure

Albumin is responsible for 75 - 80 % of osmotic pressure. Albumin is the main protein both in the plasma and in the interstitium. It is the Colloidal Osmotic Pressure 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.

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.

Falsely low values of albumin

·  Plasma albumin levels are low in neonates, between 2.8 and 4.4 g/dL. Adult levels are reached after the first week of life. Levels are slightly higher in children (4.5 - 5.5 g/dL) between the age of 6 years and young adulthood. Thereafter, levels decline to adult levels.

·  Albumin levels show a downward trend throughout pregnancy and with aging, especially after age 70.

·  Serum albumin levels are normally lower in hospitalized than ambulatory patients. Albumin levels can decrease as much as 1 g/dL after a patient becomes recumbent.

·  Albumin concentration may decrease after crystalloid infusion or in patients with fluid retention.

·  Falsely low values will be obtained if a blood sample is drawn above an IV site.

Hypoalbuminemia

Serum albumin concentration falls due to decreased synthesis, increased catabolism, increased loss and redistribution.

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 weight compounds, particularly albumin, into the extravascular space and therefore loss of the normal Starling relationship.

Diseases associated with hypoalbuminaemia

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

Plasma albumin is seldom decreased in acute hepatitis, because of its long circulating half-life. Decreased serum albumin usually indicates liver disease of more than 3 weeks duration. Albumin is a good indicator of decompensation and prognosis in cirrhosis.

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 decrease 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 of bacterial endotoxin and cytotoxic T cells. In sepsis there is a profound reduction in plasma albumin associated with marked fluid shifts. .

Postoperative patients and patients with severe infection inevitably have low plasma albumin. The more severe the disease is, the lower the albumin, and therefore the lower the albumin, the worse the prognosis.

Plasma albumin is of virtually no value in assessment or monitoring of nutritional status.

Hypo-albuminemia is associated with poor surgical outcome and increased length of stay. Serum albumin levels less than 2 g/dL are associated with a 60% thirty-day mortality rate.
Hypoalbuminemia in Critical Illness

Hypoalbuminemia in critical illness is caused by:

1. Decreased hepatic production.

2. Redistribution into the extravascular space.

3. Dilution due to fluid administration.

Low serum albumin is a non specific marker of disease. A fall in the albumin concentration appears to reflect deterioration, and a rise, recovery. Very low levels of albumin appear to reflect a poor outcome. The relevance of low albumin on ligand binding is unknown.

The serum albumin falls when patients become sick, and comes back up when patients get better.

Increased serum albumin levels are seen only with dehydration or after excessive albumin infusion.Artefactual causes of high levels include specimen evaporation and prolonged use of a tourniquet during venipuncture.

Specimen Type: Serum

Specimen RequiredContainer/Tube:Plain, red-top tube(s) or serum gel tube(s)

Reject Due To

Specimens other than Serum

Hemolysis Mild OK; Gross reject

Reference range is 3.5 - 5.0 gm/dL.

Referance

·  Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER and Bruns DE, eds. 4th ed. St. Louis, Missouri: Elsevier Saunders; 2006, Pp 543-546.

·  Nicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness.Br J Anaesth 2000; 85: 599-610.

·  Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and pathophysiology.J Parent Enteral Nutr1991;15:207–11

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