Serum Albumin · What Is It, Regulation, and More

Serum albumin is the most abundant circulating plasma protein. It constitutes about half of the total protein content of plasma (i.e., the liquid, cell-free component of the blood), with its value ranging between 3.4 to 5.4 g/dL. Albumin is a protein synthesized by hepatocytes (i.e., liver cells) and secreted in the blood in very high quantities, while only minimal amounts are stored in the liver.  

 Once albumin enters the circulation, about 30% to 40% remains in the bloodstream, while the rest enters the interstitial space. Serum albumin level is a helpful laboratory value and is easily measured with a serum albumin test, which is performed through a simple blood test.  

Serum albumin has multiple homeostatic functions in the body. Most importantly, it maintains the intravascular oncotic pressure (i.e., the pressure generated by large molecules that pulls water into blood vessels) preventing fluid leakage into the extravascular space. In addition, albumin functions as a carrier of several different endogenous (e.g., long-chain fatty acids, steroids) and exogenous (e.g., various medications) compounds in the blood. Once bound to albumin, the toxicity of those substances is reduced, as seen in the cases of unconjugated bilirubin and medications (e.g., methadone, propranolol, furosemide, warfarin, and methotrexate).   

Albumin binds at least 40% of the circulating calcium and is a transporter of hormones such as thyroxine, cortisol, and testosterone. It is also the main carrier of fatty acids, has significant antioxidant properties, and is involved in maintaining acid-base balance, acting as a blood plasma buffer. Serum albumin can also be used as a highly sensitive marker for an individual's nutritional status and severity of illness, particularly in chronically and critically ill individuals. 

Hypoalbuminemia, or low serum albumin levels, may be a result of increased loss of albumin via the kidneys, gastrointestinal (GI) tract, skin, or extravascular space; intravascular volume expansion; increased catabolism of albumin; decreased production of albumin; or a combination of the above. 

Increased Loss of Albumin 

Renal Loss 

Albumin loss from the kidneys is usually minimal (i.e., less than 30 mg per day), as its large size prevents it from passing through the glomerulus - the filtering unit of the kidney. Typically, albuminuria, or increased renal loss of albumin through urine output, results from damage to the glomerulus, which can occur in many different conditions. For example, nephrotic syndrome is characterized by renal loss of proteins (3.5 g or more per day), especially albumin, causing significant proteinuria – i.e., presence of abnormal quantity of proteins in the urine. This results in low serum albumin levels that in turn lead to edema (i.e., swelling) and ascites (i.e., accumulation of fluids within the abdomen). In addition, chronic kidney disease (CKD) often results in the loss of 30 to 300 mg of albumin per 24 hours over a period of three or more months. End-stage renal disease (ESRD) also causes significant proteinuria and consequent hypoalbuminemia. Finally, albuminuria may also occur due to high fever, intense exercise, or from certain postures. 

Gut Loss 

Protein-losing enteropathies are characterized by a considerable loss of proteins, including albumin, via the gastrointestinal tract. This loss exceeds the rate of protein synthesis, leading to hypoalbuminemia. Protein loss is usually due to conditions associated with increased lymphatic pressure (e.g., compression of the lymphatics due to lymphadenopathy or lymphangiectasis), with erosions of the intestinal mucosa (e.g., Crohn’s disease), or conditions without mucosal erosions (e.g., celiac disease, scleroderma). 

Intravascular Volume Expansion 

Hypervolemia, an increase in blood volume, can cause albumin dilution within the intravascular space, leading to hypoalbuminemia. For example, hypoalbuminemia is a common finding during pregnancy (especially second and third trimester), as the result of fluid retention, plasma volume expansion, and decreased vascular resistance.  

Increased Catabolism of Albumin 

Sepsis and Critical Illness 

Critically ill and septic individuals are characterized by an increase in vascular permeability and capillary leakage resulting in albumin loss. Additionally, such critical conditions often lead to reduced synthesis and increased catabolism (i.e., breakdown into simpler molecules) of albumin. 

Decreased Production of Albumin 

Decreased albumin production is a rare cause of hypoalbuminemia. A noticeable decrease in blood plasma albumin is evident only in severe chronic liver impairment, such as advanced hepatic cirrhosis.  

Heart Failure 

Hypoalbuminemia is very common in individuals with heart failure. Hypoalbuminemia in heart failure results from the combination of various factors including malnutrition, inflammation, liver dysfunction, protein-losing enteropathies, and increased extravasation. Within heart failure, the risk of hypoalbuminemia increases as the disease progresses.  

Burns 

Severe burns are associated with increased vascular permeability, resulting in the extravasation of albumin from the intravascular to the extravascular compartments. Moreover, the acute phase response to severe burns affects liver protein synthesis and contributes to hypoalbuminemia. Serum albumin levels are also used to evaluate the severity of burn wounds and to predict the morbidity and mortality of affected individuals. 

Nutritional Deficiency 

Hypoalbuminemia is a common finding in malnourished individuals. The effects of fasting can cause a rapid drop in albumin production, leading to a one-third decrease within the first 24 to 48 hours of fasting. Since malnourishment has been associated with adverse events in the postsurgical period, serum albumin is commonly used as a clinical indicator for nutritional optimization and readiness for surgery.   

Kwashiorkor, typical of starving children, is an example of severe malnutrition. In individuals with Kwashiorkor, serum albumin levels are low due to a decreased supply of amino acids and other nutrients (e.g., iron and zinc) to the liver, leading to fluid accumulation in tissues. Additionally, though it is not the main consequence of the disorder, individuals with anorexia nervosa may develop mild hypoalbuminemia due to their severely reduced nutritional intake. 

Different mechanisms regulate albumin synthesis and degradation. Albumin synthesis is mostly affected by alterations in the body’s osmotic pressure (i.e., a force determined by the difference in solute concentration across the cell membrane). 

 On the other hand, albumin degradation is regulated by its own blood plasma concentration. With a half-life of about 20 days, albumin is constantly degraded by lysosomal enzymes despite a non-fixed catabolic rate (i.e., the time needed to break down complex substances into simpler ones). Its sites of degradation are widespread throughout the body and include the kidneys, capillaries, and liver sinuses. The catabolic rate of albumin slowly decreases when serum albumin levels are low, as seen in protein deficiency, cirrhosis, nephrotic syndrome, and gastrointestinal diseases. Conversely, infusion of albumin may slowly increase its catabolic rate. This must be taken into consideration by clinicians when managing serum albumin levels in chronic diseases.  

This mechanism effectively regulates the serum albumin level. As a short-term regulatory mechanism, when albumin levels are low, a shift from the extravascular to the intravascular compartment may occur.