Albumin, the body's predominant serum-binding protein, has several important functions.

Albumin comprises 75-80% of normal plasma colloid oncotic pressure and 50% of protein
content. When plasma proteins, especially albumin, no longer sustain sufficient colloid osmotic
pressure to counterbalance hydrostatic pressure, edema develops.
Albumin transports various substances, including bilirubin, fatty acids, metals, ions, hormones,
and exogenous drugs. One consequence of hypoalbuminemia is that drugs that are usually
protein bound are free in the plasma, allowing for higher drug levels, more rapid hepatic
metabolism, or both.
Alterations in albumin level affect platelet function.
Reference serum values range from 3.5-4.5 g/dL, with a total body content of 300-500 g.
Synthesis occurs only in hepatic cells at a rate of approximately 15 g/d in a healthy person, but
the rate can vary significantly with various types of physiologic stress. The half-life of albumin is
approximately 21 days, with a degradation rate of approximately 4% per day.
Hypoalbuminemia is a common problem among persons with acute and chronic medical
conditions. At the time of hospital admission, 20% of patients have hypoalbuminemia.
Hypoalbuminemia can be caused by various conditions, including nephrotic syndrome, hepatic
cirrhosis, heart failure, and malnutrition; however, most cases of hypoalbuminemia are caused by
acute and chronic inflammatory responses.
Serum albumin level is an important prognostic indicator. Among hospitalized patients, lower
serum albumin levels correlate with an increased risk of morbidity and mortality.
The presentation, physical examination findings, and laboratory results associated with
hypoalbuminemia depending on the underlying disease process.
Serum albumin levels are dependent on the rate of synthesis, the amount secreted from the liver
cell, the distribution in body fluids, and the level of degradation. Hypoalbuminemia results from
a derangement in one or more of these processes.

Synthesis
Albumin synthesis begins in the nucleus, where genes are transcribed into messenger ribonucleic
acid (mRNA). The mRNA is secreted into the cytoplasm, where it is bound to ribosomes,
forming polysomes that synthesize preproalbumin. Preproalbumin is an albumin molecule with a
24 amino acid extension at the N terminus. The amino acid extension signals insertion of
preproalbumin into the membrane of the endoplasmic reticulum. Once inside the lumen of the
endoplasmic reticulum, the leading 18 amino acids of this extension are cleaved, leaving
proalbumin (albumin with the remaining extension of 6 amino acids). Proalbumin is the principal
intracellular form of albumin. Proalbumin is exported to the Golgi apparatus, where the

extension of 6 amino acids is removed prior to secretion of albumin by the hepatocyte. Once
synthesized, albumin is secreted immediately; it is not stored in the liver.

Distribution
Tracer studies with iodinated albumin show that intravascular albumin is distributed into the
extravascular spaces of all tissues, with the majority being distributed in the skin. Approximately
30-40% (210 g) of albumin in the body is found within the vascular compartments of the muscle,
skin, liver, gut, and other tissues.
Albumin enters the intravascular space via 2 pathways. First, albumin enters this space by
entering the hepatic lymphatic system and moving into the thoracic duct. Second, albumin passes
directly from hepatocytes into the sinusoids after traversing the Space of Disse.
After 2 hours, 90% of secreted albumin remains within the intravascular space. The half-life of
intravascular albumin is 16 hours. Daily losses of albumin from the intravascular space are
approximately 10%. Certain pathological conditions, such as nephrosis, ascites, lymphedema,
intestinal lymphangiectasia, and edema, can increase the daily loss of albumin from the plasma.
Albumin distributes into the hepatic interstitial volume, and the concentration of colloids in this
small volume is believed to be an osmotic regulator for albumin synthesis. This is the principal
regulator of albumin synthesis during normal periods without stress.

Degradation
Degradation of albumin is poorly understood. After secretion into the plasma, the albumin
molecule passes into tissue spaces and returns to the plasma via the thoracic duct. Tagged
albumin studies suggest that albumin may be degraded within the endothelium of the capillaries,
bone marrow, and liver sinuses. Albumin molecules apparently degrade randomly, with no
differentiation between old and new molecules.
Frequency

United States
Hypoalbuminemia is more frequent in older patients who are institutionalized, patients who are
hospitalized with advanced stages of disease (eg, terminal cancer), and malnourished children.
Mortality/Morbidity

Low serum albumin levels are an important predictor of morbidity and mortality. A meta-analysis
of cohort studies found that, with every 10 g/L decrease in serum albumin, mortality was
increased by 137% and morbidity increased by 89%. Patients with serum albumin levels of less
than 35 at 3 months following discharge from the hospital have a 2.6 times greater 5-year
mortality than those with a serum albumin levels greater than 40.

Hypoalbuminemia has also been studied as an important prognostic factor among subsets of
patients, such as patients with severe sepsis, burns,[1] and regional enteritis (Crohn disease) and
has recently been associated with an increased risk of reintubation.[2]
Whether or not hypoalbuminemia is merely a marker of severe protein malnutrition, which itself
is a cause of increased morbidity and mortality or an independent risk factor for death, is unclear.
Race

No race predilection exists.

Sex

No sex predilection exists.

Age

Hypoalbuminemia affects persons of all age groups, depending on the underlying cause.
The potential underlying causes of hypoalbuminemia are numerous. Patients' histories vary
significantly depending on the underlying disease state.
Gather past medical history for a history of liver or renal failure, hypothyroidism, malignancy,
and malabsorption. Evaluate the patient for appropriate dietary intake. Seek potential causes of
acute or chronic inflammation that could explain the low albumin levels.

Physical
Abnormal physical examination findings may be found in multiple organ systems depending on
the underlying disease. The following findings suggest the potential underlying disease processes
rather than the underlying hypoalbuminemia, per se:

Head, eyes, ears, nose, and throat - Facial edema, macroglossia, parotid
swelling, conjunctival icterus, temporal wasting

Integumentary - Loss of subcutaneous fat, delayed wound healing, dry coarse

skin, painful dermatoses, peripheral edema, thin hair, spider angiomas,
palmar erythema, changes due to surgery and burns, jaundice

Cardiovascular - Bradycardia, hypotension, cardiomegaly

Respiratory - Decreased respiratory expansion due to pleural effusion and

weakened intercostal muscles

Gastrointestinal - Hepatosplenomegaly, ascites

Musculoskeletal - Muscle wasting, growth retardation in children, atrophy of

the interosseus hand muscles

Neurological - Encephalopathy, asterixis

Genitourinary - Testicular atrophy

Endocrine - Gynecomastia, hypothermia, thyromegaly

Other - Various other signs related to associated specific nutrient deficiencies

Causes
Hypoalbuminemia can result from decreased albumin production, defective synthesis because of
hepatocyte damage, deficient intake of amino acids, increased losses of albumin via GI or renal
processes, and, most commonly, acute or chronic inflammation. Some of the many causes are
discussed below.
Protein malnutrition

Deficient protein intake results in the rapid loss of cellular ribonucleic acid and disaggregation of
the endoplasmic reticulumbound polysomes and, therefore, decreased albumin synthesis.
Albumin synthesis can decrease by more than one third during a 24-hour fast. Albumin synthesis
may be stimulated by amino acids produced in the urea cycle, such as ornithine.
Defective synthesis

In patients with cirrhosis, synthesis is decreased because of the loss of hepatic cell mass. Also,
portal blood flow is often decreased and poorly distributed, leading to maldistribution of
nutrients and oxygen. The flow of substrate may affect certain functions of the liver, including
protein synthesis, which is decreased in patients with cirrhosis who lack ascites. Albumin
synthesis may actually increase in patients with cirrhosis who have ascites, possibly because of a
change in hepatic interstitial colloid levels, which may act as an overriding stimulus for albumin
production. Although synthesis is increased, the concentration of albumin is decreased because
of dilution.
Extravascular protein loss

Nephrotic syndrome
This can produce hypoalbuminemia by massive proteinuria, with 3.5 g or more of protein lost
within 24 hours. Albumin is filtered by the glomerulus and catabolized by the renal tubules into
amino acids that are recycled. In patients with chronic renal disease, in whom both glomerular
and tubular diseases are present, excessive protein filtration may lead to both increased protein
loss and increased degradation. Only at higher rates of albuminuria (>100 mg/kg/d) and only
when the diet is adequate is albumin synthesis increased.
Protein-losing enteropathy

Under normal conditions, less than 10% of the total albumin is lost through the intestine. This
fact has been confirmed by comparing albumin labeled with chromium-51, which helps measure
intestinal losses, to albumin labeled with iodine-125, which helps measure overall degradation.
In cases of protein-losing enteropathy related to bacterial overgrowth, hypoalbuminemia is
exacerbated by peripheral factors that inhibit albumin synthesis by mechanisms similar to those
observed with burns, trauma, infection, and carcinoma.
Extensive burns
The skin is the major site for extravascular albumin storage and is the major exchangeable
albumin pool needed to maintain plasma levels. Hypoalbuminemia results from direct losses of
albumin from tissue damage, from compromised hepatic blood flow due to volume loss, and
from inhibitory tissue factors (eg, tumor necrosis factor, interleukin-1, interleukin-6) released at
the burn sites.
Lymphatic blockage or mucosal disease
Diseases that result in protein loss from the intestine are divided into 2 main types. The first is
lymphatic blockage, which can be caused by constrictive pericarditis, ataxia telangiectasia, and
mesenteric blockage due to tumor. The second is mucosal disease with direct loss into the bowel,
which is observed with (1) inflammatory bowel disease and sprue and (2) bacterial overgrowth,
as in blind loop syndrome after intestinal bypass surgery.
Hemodilution

In the presence of ascites from any cause, the serum albumin level is not a good index of the
residual synthetic capacity of the liver unless actual radioisotopic measurements of production
are used. With ascites, synthesis may be normal or even increased, but serum levels are low
because of the larger volume of distribution. This is true even for ascites due to cirrhosis.
Congestive heart failure

The synthesis of albumin is normal in patients with congestive heart failure. Hypoalbuminemia
results from an increased volume of distribution.
Oncotic pressure increase
The serum oncotic pressure partially regulates albumin synthesis. The regulation site may be the
oncotic content in the hepatic interstitial volume because albumin synthesis is inversely related
to the content of this volume. Conditions that increase other osmotically active substances in the
serum tend to decrease the serum albumin concentration by decreasing synthesis. Examples
include elevated serum globulin levels in hepatitis and hypergammaglobulinemia.
Acute and chronic inflammation

Albumin levels that are low because of acute inflammation should normalize within weeks of
resolution of the inflammation. Persistent hypoalbuminemia beyond this point should prompt an
investigation for an ongoing inflammatory process. The cytokines (TNF, IL-6) released as part of
the inflammatory response to physiologic stress (infection, surgery, trauma) can decrease serum
albumin by the following mechanisms:

Increased vascular permeability (allowing albumin to diffuse into the

extravascular space)

Increased degradation

Decreased synthesis (among other mechanisms, by activating TNF-a, which

decreases transcription of the albumin gene)

Laboratory Studies
Clinical suspicion of the underlying disease process should guide appropriate laboratory studies,
some of which are as follows:

Malnutrition: Lymphocyte count and blood urea nitrogen levels are decreased.
Transferrin, prealbumin, and retinol-binding protein have shorter half-lives
compared with albumin and better reflect short-term changes in nutritional
status than albumin, which has a long half-life.

Inflammation: C-reactive protein

sedimentation rate are elevated.

Nephrotic syndrome: The 24-hour urine collection contains more than 3 g of

protein in 24 hours.

Cirrhosis: Liver function test findings (transaminase levels) may be elevated

or normal in patients who are cirrhotic. Coagulation studies may be abnormal.
Cirrhosis has numerous potential etiologies, and more specific studies, such
as hepatitis screening, may be needed.

Malabsorption: Fecal fat studies including Sudan qualitative stain for fat, 72hour quantitative fecal fat collection, and fecal a-1-antitrypsin clearance are
needed.

levels

and

increased

erythrocyte

Serum protein electrophoresis results help to determine if hypergammaglobulinemia is present.

None of the various correction factors for determining the effects of hypoalbuminemia on the
plasma calcium concentration has proven reliable. Corrected calcium (mg/dL) is equal to
measured total calcium (mg/dL) plus 0.8 (average normal albumin level of 4.4 minus serum
albumin [g/dL]). The only method of identifying true (ionized) hypocalcemia in the presence of
hypoalbuminemia is to measure the ionized fraction directly.

Elderly patients living in nursing homes or other institutionalized settings who have
hypoalbuminemia should be evaluated for treatable comorbid conditions contributing to the
malnutrition (eg, medications causing decreased appetite, thyroid dysfunction, diabetes,
malabsorption, depression, cognitive impairment).

maging Studies
Imaging studies can be performed for the following:

Liver ultrasound for evidence of cirrhosis

Small bowel barium series for mucosal abnormalities typical of malabsorption

syndromes

Imaging studies as appropriate to seek infectious causes of inflammation and

hypoalbuminemia (eg, chest radiography)

Echocardiogram for congestive heart failure

Procedures can be performed for the following:

Liver biopsy to confirm cirrhosis

Kidney biopsy to help evaluate etiology of nephrosis

When hypoalbuminemia is due to cirrhosis, liver biopsy findings show a loss of hepatic
architecture, fibrosis, and nodular regeneration. The pattern of injury and special stains
can help determine the etiology of cirrhosis.
When hypoalbuminemia is due to nephrotic syndrome secondary to a primary renal
disorder, light microscopy may show sclerosis (focal glomerulosclerosis), mesangial
immunoglobulin A (immunoglobulin A nephropathy), or no changes (minimal change
disease). Electron microscopy may show subepithelial immunoglobulin G deposits
(membranous glomerulonephritis).
Treatment should focus on the underlying cause of hypoalbuminemia. See the Medication
section below.
To help optimize fluid resuscitation with colloids in patients who are critically ill, volume
status may be monitored with a central venous, pulmonary artery catheter or other
minimal invasive techniques (see the article Distributive Shock).
In patients who are critically ill, low calcium levels can be simply due to
hypoalbuminemia, which has no clinical significance because the active fraction
(ionized) is not affected. However, to prevent missing a second hypocalcemic

Depending on the clinical situation, multiple consultations may be necessary.

Gastroenterologist

Intensivist

Nephrologist

Surgeon

Endocrinologist

Registered dietitian

t
Support the underlying cause with adequate nutrition (sufficient high biological value protein
and energy intake for anabolism).

Surgical Care

Consultations

Diet

Activity

Show All

Multimedia Library
References

Activity
Recommendations depend on the severity of the underlying disease.