10/24/24, 12:25 PM Hypoalbuminemia - StatPearls - NCBI Bookshelf
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Hypoalbuminemia
Authors
Verena Gounden1; Rishik Vashisht; Ishwarlal Jialal2.
Affiliations
1 University of KwaZulu Natal
2 VA MEDICAL CENTER, MATHER , CA
Last Update: August 28, 2023.
Continuing Education Activity
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. This activity reviews the evaluation and management of and highlights the role of
the interprofessional team in educating patients with this condition about follow up care.
Objectives:
Outline the differential diagnosis of hypoalbuminemia.
Summarize the risk factor of developing hypoalbuminemia.
Describe the pathophysiology of hypoalbuminemia.
Explain the interprofessional team strategies for improving care coordination and communication regarding the
management of patients with hypoalbuminemia.
Access free multiple choice questions on this topic.
Introduction
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
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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]
Etiology
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.
Epidemiology
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]
Pathophysiology
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]
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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]
History and Physical
Hypoalbuminemia is often a finding on routine laboratory testing following the presentation of patients for other
primary medical conditions or diseases.
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Patients with hypoalbuminemia present with peripheral (pitting) and central edema (ascites and effusions) and
anasarca. They may also complain of fatigue and excessive weakness and other features of related nutritional
deficiencies, for example, iron deficiency anemia in Celiac disease.
Patients may present with features of the primary disease, for example, jaundice in liver disease, diarrhea (PLE).
Proteinuria may be detected by the performance of urine dipsticks.
Evaluation
Measurement of serum albumin using routine assays on automated chemistry analyzers is a quick and simple method
of determining the presence of hypoalbuminemia. Assays are based on the color change that occurs when albumin
binds to a particular dye that is measured spectrophotometrically. Other methods used to measure albumin include
immunonephelometric and immunoturbidometric techniques.
Decreased albumin levels may be an incidental finding on protein electrophoresis; however, protein electrophoresis
provides a semi-quantitative albumin value. The main value of protein electrophoresis in a patient with low serum
albumin is with the differential diagnosis of hypoalbuminemia. In the presence of acute inflammation,
hypoalbuminemia will be present with an increase in alpha-1 and 2 globulins and normal gamma globulins. In chronic
inflammation, the protein electrophoresis pattern will show hypoalbuminemia with a polyclonal increase in gamma
globulins.
In the presence of nephrotic syndrome, hypoalbuminemia with an increase in alpha-2 globulins, due to increased
macroglobulin, and low gamma globulins are the typical pattern on serum protein electrophoresis.
With chronic liver disease, hypoalbuminemia with increase gamma globulins and beta-gamma bridging is typical.
Further evaluations are targeted at determining the cause of hypoalbuminemia and monitoring disease. These include
liver function tests to determine a presence of liver disease, urine albumin, protein measurement to evaluate urine
protein loss, and brain natriuretic peptide for evaluation of heart failure as well as radiological imaging.
Specific tests include alpha-1 antitrypsin clearance for the determination of protein loss via gut distal to the pylorus.
This involves a timed collection of stool together with a serum sample. Alpha-1-antitrypsin is resistant to degradation
by digestive enzymes. It is used as an endogenous marker for the presence of blood proteins in the intestinal tract.
Elevated alpha-1-antitrypsin (A1A) clearance suggests excessive GI protein loss.[7]
Treatment / Management
Treatment is directed at the cause of the hypoalbuminemia since it is a consequence of some disease. In the critically
ill, in particular, burn patients, albumin infusions may be given. It is controversial whether albumin infusions are of
clinical benefit to other groups of critically ill patients. It also has some value in patients with cirrhosis with certain
complications.
Differential Diagnosis
The differential diagnosis for the causes of hypoalbuminemia is wide and includes diseases affecting albumin
production, for example, cirrhosis, albumin and protein absorption, for example, PLE, albumin loss via kidneys, for
example, nephrotic syndrome, and increased catabolism that may occur in critically ill patients.
Prognosis
The presence of hypoalbuminemia is used as a prognosticator for morbidity and mortality in hospitalized patients, in
particular in the critical care setting.[7]
Complications
Complications of significant hypoalbuminemia include circulatory collapse due to the effect on oncotic pressure, the
presence of edema, and anasarca and are associated with risk for other complications in the critically ill.
Pearls and Other Issues
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Hypoalbuminemia is a common finding among hospitalized individuals. The presence of a decreased serum albumin
is related to Increased patient morbidity and mortality. Management of the hypoalbuminemia is contingent on the
treatment of the underlying disease.
Enhancing Healthcare Team Outcomes
It is essential that healthcare workers be cognizant of the impact of hypoalbuminemia in patient outcomes, particularly
in the critically ill to ensure that appropriate attention is given to managing both the low albumin as well as the
primary pathology.
Review Questions
Access free multiple choice questions on this topic.
Click here for a simplified version.
Comment on this article.
References
1. Weaving G, Batstone GF, Jones RG. Age and sex variation in serum albumin concentration: an observational
study. Ann Clin Biochem. 2016 Jan;53(Pt 1):106-11. [PubMed: 26071488]
2. Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal
and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int J Gen Med. 2016;9:229-
55. [PMC free article: PMC4956071] [PubMed: 27486341]
3. Cabrerizo S, Cuadras D, Gomez-Busto F, Artaza-Artabe I, Marín-Ciancas F, Malafarina V. Serum albumin and
health in older people: Review and meta analysis. Maturitas. 2015 May;81(1):17-27. [PubMed: 25782627]
4. Brock F, Bettinelli LA, Dobner T, Stobbe JC, Pomatti G, Telles CT. Prevalence of hypoalbuminemia and
nutritional issues in hospitalized elders. Rev Lat Am Enfermagem. 2016 Aug 08;24:e2736. [PMC free article:
PMC4990035] [PubMed: 27508908]
5. Ballmer PE. Causes and mechanisms of hypoalbuminaemia. Clin Nutr. 2001 Jun;20(3):271-3. [PubMed:
11407876]
6. Gatta A, Verardo A, Bolognesi M. Hypoalbuminemia. Intern Emerg Med. 2012 Oct;7 Suppl 3:S193-9. [PubMed:
23073857]
7. Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J
Pediatr. 2010 Oct;169(10):1179-85. [PMC free article: PMC2926439] [PubMed: 20571826]
Disclosure: Verena Gounden declares no relevant financial relationships with ineligible companies.
Disclosure: Rishik Vashisht declares no relevant financial relationships with ineligible companies.
Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.
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