In adult humans, albumin is the most abundant plasma protein with a concentration ranging from 35 to 50 g/L.[1] Albumin represents 50% of the total protein content of plasma, with globulins making up most of the rest. It is a single peptide chain of 585 amino acids in a globular structure. The molecular weight of albumin is approximately 66 kDa, and it has a half-life of 21 days. Albumin is exclusively synthesized by the liver, initially a pre-proalbumin and then proalbumin, which in the Golgi apparatus is converted to albumin, which is the final form secreted by the hepatocyte. The synthetic rate is about 10 to 15 grams per day and then secreted into the circulation of which around 40% remains in circulation with a fraction moving from the intravascular to the interstitial space.[2] Factors that stimulate albumin synthesis include the action of hormones such as insulin and growth hormone. Albumin production may be inhibited by pro-inflammatory mediators such as interleukin-6 (IL-6),  interleukin-1 (IL-1) and tumor necrosis factor.[3] In fetal life, alpha-fetoprotein (AFP) produced by the liver and yolk sac is the most abundant plasma protein. AFP is thought to be the fetal counterpart of albumin, and both are transcribed by genes located close together on chromosome 4. Approximately 100 variant forms of albumin have been described.[2]

Albumin has several physiological roles. One of the most important is to maintain the oncotic pressure within the vascular compartments preventing leaking of fluids into the extravascular spaces. It accounts for around 80% of the colloid osmotic pressure. Additionally, albumin functions as a low-affinity, high-capacity carrier of several different endogenous and exogenous compounds acting as a depot and a carrier for these compounds. Binding of compounds to albumin may reduce their toxicity such as in the case of unconjugated bilirubin in the neonate and drugs. Also, albumin binds at least 40% of the circulating calcium and is a transporter of hormones such as thyroxine, cortisol, testosterone, among others. Albumin also is the main carrier for fatty acids and has significant anti-oxidant properties. Albumin is also involved with maintaining acid-base balance as it acts as a plasma buffer. Albumin is used as a marker of nutritional status and disease severity in particular in chronic and critically ill patients.[2],[3],[4]. Renal and gut loss of albumin may account for around 6% and 10% respectively of albumin loss in healthy individuals. A decrease in serum albumin levels below the reference interval hypoalbuminemia. This article reviews the causes and diagnosis of hypoalbuminemia.[2]

Hypoalbuminaemia is one of the most prevalent disorders in hospitalized and critically ill patients. Hypoalbuminaemia may be a result of decreased production (rare) of albumin or increased loss of albumin via the kidneys, gastrointestinal (GI) tract, skin, or extravascular space or increased catabolism of albumin or a combination of 2 or more of these mechanisms.

The prevalence of hypoalbuminemia is higher amongst hospitalized, critically ill, and elderly patients. One report by Brock et al. determined the prevalence to be greater than 70% of elderly hospitalized patients.[4]

Decreased Production of Albumin

Decreased production of albumin is a rare cause of hypoalbuminemia. Significant and severe  chronic hepatic impairment is required before a noticeable decrease in plasma albumin is manifest . Hypoalbuminemia is a feature of chronic and advanced hepatic cirrhosis. Most commonly,  inadequate synthesis of albumin in the presence of increased catabolism due to significant systemic illness contributes to an overall hypoalbuminemia

Nutritional Deficiency

Kwashiorkor, a severe form of protein-energy malnutrition, presenting in infants and children. They have low serum albumin levels due to a decreased supply of amino acids to the liver as well as other nutritional deficiencies, notably iron and zinc.

Apart from hemoglobin, albumin is the protein molecule with the most number of variant forms. Very low or undetectable albumin in serum (serum albumin concentration of less than 1g/L) characterizes a rare disorder known as analbuminaemia. These individuals appear to have sufficient amounts of albumin to survive under normal conditions. They present in adulthood with peripheral edema, fatigue, and hyperlipidemia but usually no associated atherosclerosis. Patients are generally hemodynamically stable.[2],[4],[5]

Increased Loss of Albumin

Renal Loss

With a molecular weight of 66 kDa, albumin loss via the glomerulus is minimal (less than 30 mg per day) in healthy individuals. Increased losses may occur due to physiological reasons such as fever, exercise, or posture-related reasons. The balance between glomerular filtration and tubular reabsorption determines the presence of albumin in urine. Damage to the glomerulus results in increased albumin loss via urine. Injury to the glomerulus can occur in a  plethora of disease conditions.

Nephrotic syndrome is characterized by albumin and protein loss via the kidneys. Nephrotic range proteinuria is considered to be the loss of 3.5 or more grams of protein per 24-hour period.

Apart from significant proteinuria, nephrotic syndrome is characterized by hypoalbuminemia, increased edema, and presence of ascites due to the low oncotic pressure. Hyperlipidemia thought to be a result of the liver increasing production of lipoproteins to compensate for the low serum albumin, increased production of clotting factors, and increased risk of thrombosis. Depending on the cause of nephrotic syndrome it can present in childhood, adulthood, and in the elderly. Damage to the glomerulus may occur due to exogenous toxins drugs, heavy metals, chemotherapeutic agents, via autoantibodies directed against the glomerular basement membrane such as in autoimmune diseases such as SLE, or antibodies generated following infection such as Group B streptococcus. Malignancies such as multiple myeloma also are associated with the development of nephrotic syndrome.[2],[4],[6]

Chronic kidney disease (CKD): One of the definitions of CKD includes the presence of significant albuminuria 30  to 300 mg per 24 hours over at least a period of 3 months. This can occur in the presence or absence of a decreased glomerular filtration rate (GFR). End-stage renal disease (ESRD) is associated with significant proteinuria and albuminuria together with serum hypoalbuminemia. The hypoalbuminemia in ESRD is also a result of the decreased synthesis and increased degradation of protein in this condition.[2]

Albuminuria may also occur during chronic diseases such as diabetes mellitus and essential hypertension but does not result in serum hypoalbuminemia unless total protein loss is in the nephrotic range.[2]

Gut Loss

Protein-losing enteropathy is characterized by substantial  loss of proteins including albumin via the GI tract that exceeds synthesis. This leads to hypoalbuminemia. There are several causes of PLE which include GI disease and non-gut-related conditions (such as cardiac disease and SLE). The mechanisms for protein loss in  PLE can be broadly divided into 3 categories:  (1) diseases associated with increased lymphatic pressure  (e.g., lymphangiectasis); (2) diseases with mucosal erosions (e.g., Crohn’s disease); and (3) diseases without mucosal erosions (e.g., celiac disease).[2],[4],[6]

Extravascular Loss (3 Space Loss)

Loss of albumin from the intravascular into the extravascular compartments results in hypoalbuminemia.

Burns

Patients with burn wounds have increased vascular permeability resulting in the extravasation of albumin from the intravascular to the extravascular compartments. There is also an acute phase response that affects liver protein synthesis causing a further decrease in serum albumin levels.

Serum albumin levels are also used to assess the severity of burns in these patients and as a predictor of mortality and morbidity.[6]

Sepsis

Sepsis is associated with increased vascular permeability and capillary leakage resulting  in loss of albumin from the intravascular compartment. Apart from this there is also reduced synthesis and increased catabolism of albumin in the presence of significant sepsis.[2],[7]

Albumin and Critical illness

The presence of critical illness is associated with hypoalbuminemia through a variety of mechanisms. Critical illness alters the distribution of albumin between the intravascular and extravascular compartments, affects the rate of albumin synthesis and increases albumin clearance and degradation. The increased capillary leakage responsible for the vascular permeability is a result of various factors including the effects of cytokines such as TNF-alpha and IL-6, chemokines, the action of prostaglandins and complement components as well as endotoxins from gram-negative bacteria.

The rate of synthesis is also decreased in critical illness, and this is thought to be a result of the increase in gene transcription for the positive acute phase proteins such as C-reactive protein and decreased in the rate of transcription of albumin mRNA.[2],[7]

Cardiac Failure

Hypoalbuminemia is common in patients with cardiac failure. Hypoalbuminemia in cardiac failure is a combination of various factors including malnutrition, inflammation, and cachexia as well as hemodilution, liver dysfunction, protein-losing enteropathy, and increased extravascular loss. Risk of hypoalbuminemia with cardiac failure is increased in elderly patients.[2],[7]