Hypoalbuminemia may be asymptomatic. Symptoms usually occur with very significant reduction in plasma albumin levels. The symptoms of hypoalbuminemia include peripheral edema, muscle weakness and cramps. In cases of an underlying hepatic pathology, ascites may occur.

The peripheral edema and ascites usually occur as a result of low oncotic pressure owing to the hypoalbuminemia. Low oncotic pressure causes fluid flow out of the intravascular space into the extravascular spaces and tissues.

The symptoms of hypoalbuminemia and a detailed history of the underlying disease increase the suspicion of hypoalbuminemia. Investigations are carried out depending upon the clinical presentation.

Serum prealbumin, transferrin, and retinol-binding protein rather than albumin are used to asses the nutritional status of an individual. This is because these proteins have shorter half-lives than albumin. Furthermore, lymphocyte count and  the levels of blood urea nitrogen are also reduced in malnourished patients. Elevated levels of C-reactive protein and erythrocyte sedimentation rate (ESR) are seen in inflammatory conditions.

In hypoalbuminemia caused by nephrotic syndrome, proteinuria is observed after analysis of a 24-hour urine. Liver function tests are necessary in suspected liver disease such as cirrhosis. In patients with cirrhosis, transaminase levels may be normal or elevated, clotting profile shows significant abnormalities. Further investigations are required to determine the cause of the hepatic cirrhosis.

Malabsorption syndromes can be investigated via certain laboratory studies including fecal fat studies such as fecal 72-hour quantitative fat analysis, Sudan qualitative fat studies, and fecal alpha-1-antitrypsin clearance. Small bowel barium imaging series may be necessary to detect intestinal mucosal changes characteristic of malabsorption syndromes.

For suspected cardiac causes, echocardiogram and chest X-rays are necessary. Serum protein electrophoresis may also be necessary to determine the presence of hypergammaglobulinemia.

Elderly patients who are being cared for in certain institutions such as nursing homes should be investigated for certain diseases which may contribute to malnutrition. Examples of these diseases include thyroid diseases, diabetes, depression, and dementia.

The basic approach for treatment of hypoalbulinemia is correction of the underlying cause, and not replenishing albumin levels. However, supportive care is necessary. In critically ill patients, fluid resuscitation with colloids is necessary and it is best done via a central venous access. Fluid input should also be well monitored.

Albumin administration and its effectiveness in critically-ill patients with hypoalbuminemia is still a subject of debate [9].

A meta-analysis of some studies has suggested that albumin administration may be detrimental, resulting in a 6% increase in mortality rate in comparison to infusion of crystalloids. Furthermore, a large clinical trial observed that albumin infusions significantly reduce the prognosis only in patients with neurotrauma [10].

In critically-ill patients, hypocalcemia may result from the hypoalbuminemia; however, this is clinically irrelevant because the active form of calcium, the ionized fraction, is usually intact. However, it is safe to assess the level of the ionized calcium, so as to detect a coexisting hypocalcemia.

Hypoalbuminemia is a vital negative prognostic factor in patients with certain diseases including regional enteritis, sepsis, and burns [5].
Hypoalbuminemia risk has also been associated with reintubation [6]. However, it is unclear whether hypoalbuminemia increases morbidity and mortality via its direct clinical effects or as an independent prognostic factor.

A study found that mortality and morbidity increased by 137% and 89%, respectively, with every 10g/L reduction in plasma albumin level. Patients having serum albumin levels below 35g/L by 3 months of discharge had almost three times greater mortality in 5 years than those who had a serum albumin levels above 40g/L.

Hypoalbuminemia carries similar prognosis irrespective of the level of serum albumin. Administration of albumin to such patients is of no benefit. Furthermore, the benefit of colloids as compared to that of crystalloids in the management of septic shock is not clearly understood. However, other studies revealed no significant changes or reduction in mortality among those who received albumin.

A study by Dubois in 2006 aimed to determine the effectiveness of albumin administration on functioning of organs in critically-ill patients. The results were inconclusive and the available data was found short to substantiate the results [7]. Generally, there is evidence to support that albumin administration is effective in reducing mortality [8].

Etiological factors which are responsible for hypoalbuminemia include poor protein intake and diseases which cause protein depletion or loss such as protein-losing enteropathy, renal failure and glomerular diseases, liver diseases, and cardiac abnormalities such as congestive cardiac failure and pericarditis.

Gastrointestinal diseases which result in hypoalbuminemia include inflammatory bowel diseases, gastric lymphomas, hepatic carcinoma, hepatic cirrhosis, and hepatitis.  

Malignant tumors including sarcomas as well as infiltrative diseases such as amyloidosis also predispose to hypoalbuminemia. Certain infections and medications may also result in hypoalbuminemia.

Hypoalbuminemia occurs more commonly among children who are malnourished and elderly patients admitted in hospitals for treatment or management of advanced stages of chronic or terminal diseases such as cancer.

Interference in the synthesis, distribution, and degradation of albumin are the factors which cause hypoalbuminemia.

Albumin synthesis in the body is localized in the liver cells. The process of albumin synthesis commences in the nucleus where the genes are transcribed to form messenger ribonucleic acid (mRNA), which is released into the cytoplasm. By joining with the ribosomes, mRNA forms polysomes. These polysomes are responsible for the formation of preproalbumin, which is a premolecule of albumin which contains an additional 24 amino acid chain at the N terminus. This extra chain helps the molecule to get inserted into the endoplasmic reticulum. In the endoplasmic reticulum, the extra 18 amino acid chains are cleaved off, the remaining molecule with the 6 amino acid chain is the proalbumin which is the main form of albumin intracellularly. Proalbumin is, subsequently, transported to the golgi bodies where the remaining 6-amino acid extension is cleaved off and the newly formed albumin is secreted immediately. Albumin is not stored at all in the liver after synthesis.

Albumin is transported into the intravascular space via the hepatic lymphatic vessels into the thoracic duct and via direct diffusion into the hepatic sinusoids from the hepatocytes. Approximately 90% of the secreted albumin stays within the intravascular compartment after 2 hours of release into the blood. Albumin has a serum half-life of 16 hours, furthermore, 10% of serum albumin is excreted daily. There are certain diseases that cause a daily loss of albumin; these conditions include ascites, intestinal lymphangiectasia, edema, and lymphedema.

Some amount of albumin remains in the hepatic interstitial space, where its concentration serves as an osmotic regulator of the synthesis of albumin. This serves as the main control of albumin synthesis in resting physiologic state.

Tracer studies using iodinated albumin reveals that serum albumin is distributed into all extravascular spaces, especially of the skin. About 30-40% of the body albumin is found in the intravascular compartments of the muscle, gut, liver, skin, and other tissues in the body. Albumin enters into the tissue spaces from the hepatocytes through the lymphatic system and returns to the blood via the thoracic duct. 

The degradation and metabolism of albumin is not fully documented. Albumin tracing studies suggest that the endothelium of the bone marrow, liver sinuses, and capillaries may be the sites of albumin breakdown.

Prevention of hypoalbuminemia is achieved by preventing the risk factors or underlying diseases. Avoiding alcohol and overdose of certain medications may contribute to the prevention of hepatic cirrhosis. It is also imperative to take medications as prescribed to prevent liver damage.

Treatment for hypoalbuminemia is based on the underlying cause, therefore, malnutrition can be avoided by taking high-protein diets.

There are three main plasma proteins: albumin, fibrinogen, and globulins. In a healthy individual, albumin is the most predominant of plasma proteins.

Albumin is an acute-phase protein which is produced by the liver. Albumin has a half-life of 15-19 days and a degradation rate of 4% daily, however its plasma level can drop significantly in 3-5 days in severely-ill persons [1].

Hypoalbuminemia is referred to as serum albumin levels lower than 3.5mg/dL (reference range being 3.5-4.5mg/dL). The total body content of albumin is 300-500g. The hepatocytes produce albumin at a rate of 15g/d in a healthy individual. However, the rate of production may be altered significantly in the presence of certain physiologic stressors. 

Albumin functions primarily as a serum-binding protein, serving to transport certain substances including hormones and fatty acids in the blood. It also protects against thrombotic diseases. One of its most critical functions, however, is its effect on the plasma colloid pressure or oncotic pressure [2]. Albumin is responsible for 75-80% of the normal plasma oncotic pressure. If plasma protein levels, especially albumin levels drop, it leads to a reduction or loss of colloid oncotic pressure to counter the outward hydrostatic pressure, this imbalance results in outflow of fluid into the extra vascular spaces and tissues causing edema.

Albumin acts as a transporter of various biologically important substances including bilirubin, hormones, fatty acids, exogenous drugs, metals and ions in the blood. Therefore, a complication of hypoalbuminemia could lead to high levels of unbound drugs or a higher rate of hepatic metabolism of such drugs.

Hypoalbuminemia is a common finding in both, acute as well as chronic medical conditions. Studies have shown that 20% of patients reporting for admission in the hospital have hypoalbuminemia. Low plasma albumin is caused basically by diseases which reduce protein intake, reduce protein synthesis, and increase protein loss. These include nephrotic syndrome, heart failure, liver cirrhosis, and malnutrition [3]. However, hypoalbuminemia results as a response to acute and chronic inflammatory conditions.

Hypoalbuminemia is a strong negative prognostic factor, being associated with a high mortality rate, high morbidity, and increased length of hospital stay [4]. A large study involving patients from emergency departments revealed that hypoalbuminemia increased the risk of mortality by three times in comparison to patients which had normal albumin levels.

Overview

Albumin is one of the proteins in the blood which are described as plasma proteins. Other plasma proteins include fibrinogen and globulins; however, albumins are the most abundant.

These plasma proteins constitute blood as one of the most important constituents of the plasma. The plasma is the fluid component of the blood.

Hypoalbuminemia is a condition in which the level of albumin in blood is lower than the normal value. Plasma albumin lower than 3.5g/L is considered as hypoalbuminemia.

Causes

Albumin, like most other plasma proteins are produced by the liver and distributed through the blood to all tissues of the body. Therefore, hypoalbuminemia can be possibly caused by diseases which impair the liver's ability to produce albumin, impair its distribution in the blood and body, and increase its loss via the kidneys. These diseases include liver cirrhosis from factors such as chronic alcoholism and hepatitis, liver cancer, kidney failure, kidney diseases such as nephrotic syndrome, glomerulonephritis, and autoimmune neuropathy, certain cancers and infection.

However, one important cause of hypoalbiminemia especially in children and elderly patients is malnourishment or malnutrition. A disease of the gut called protein-losing enteropathy is another common cause of hypoalbuminemia.

Epidemiology

Hypoalbuminemia is common among malnourished children and elderly patients who have been institutionalized. Research has also shown that any patient who has hypoalbuminemia may get sicker or may be more likely to die than other patients with the same disease but with normal blood albumin levels.

Presentation

The plasma proteins, especially albumin help to keep water in the blood through the inward pressure they exert. They balance the water content in the blood so that when the water content in blood is reduced, the pressure they exert pulls fluid from the tissues around into the blood. Therefore, in cases of hypoalbuminemia, the forces which pull fluid into the blood are lost, therefore, fluids leave the blood into the tissues causing swelling of the body, what's termed edema, especially of the abdomen where it is termed ascites.

Other symptoms of hypoalbuminemia include muscle weakness and pain, dry skin, delayed wound healing, and thin hair. Hypoalbuminemia affects virtually all the systems in the body.

Workup

The presence of the typical symptoms of hypoalbuminemia leads doctors to investigate for all the causes of hypoalbuminemia. The urine is collected and examined for findings which indicate kidney disease, ultrasound scans are done to detect liver cirrhosis, and the blood levels of other proteins are assessed to determine if malnutrition is the cause.

The gut is also evaluated by using imaging studies, endoscopy, and stool analysis to detect gut diseases which can cause hypoalbuminemia.

For suspected heart diseases, chest X-rays and electrocardiograms are carried out.

Treatment

The treatment of hypoalbuminemia focuses on treating the underlying factors responsible for the disease rather than replenishing the blood levels of albumin. However, it is also important to administer intravenous fluids since the blood is getting depleted of fluids.

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