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. Although primarily in the intravascular space, albumin has a major trafficking function through the interstitium and lymphatics.
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.
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Albumin.
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.
Damage
Albumin has four binding sites, one for cobalt (metallic) and the others are for binding to various biologic and foreign molecular species. Albumin can be oxidized in a reversible fashion restored via the glutathione pathway, but in severe end-stage hepatic cirrhosis, it forms a nonreversible oxidized form that has markedly reduced molecular binding capabilities.
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.
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 reticulum–bound 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)
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.
Race
No race predilection exists.
Sex
No sex predilection exists.
Age
Hypoalbuminemia affects persons of all age groups, depending on the underlying cause.
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. However, its association with a poor prognosis remains strong.
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.
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:
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
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 levels and increased erythrocyte 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, 72-hour quantitative fecal fat collection, and fecal a-1-antitrypsin clearance are needed.
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).
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.
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 disorder, measure the ionized calcium level whenever the albumin level is low.
In end-stage cirrhosis, albumin infusions decrease the incidence of renal insufficiency and decrease the mortality rate. Furthermore, in the setting of spontaneous bacterial peritonitis, the combination of cephalosporin and albumin markedly increases survivorship, presumably by improving toxin clearance.
The significance of hypoalbuminemia appears to be its reflection of the severity of the underlying disease process. Therefore, follow-up care, in both inpatient and outpatient settings, is dictated by those processes.
Hypoalbuminemia is a common phenomenon in patients with serious illness. Treatment should focus on the underlying cause rather than simply replacing albumin. Exogenous albumin is not used for the purpose of raising serum albumin levels.
Indications and the use of albumin administration in critically ill patients is an area of controversy; studies to clarify these issues are ongoing.[3] Two major clinical trials compared albumin as a volume expander to crystalloids in the management of circulatory shock. Neither study specifically addressed the management of hypoalbuminemia. Both the SAFE[4] and the ALBIOS study[5] compared crystalloid to albumin infusions, and both documented a small but statically significant increase in serum albumin levels.
A separate question is whether or not albumin as a resuscitation fluid is useful as a volume expander or harmful for unrelated reasons. Although prior meta-analysis of small heterogeneous studies suggested that albumin infusions may be harmful as a volume expansion resuscitation fluid (increasing the mortality rate by 6% compared with crystalloid), the two large multicenter clinical trials (SAFE, ABLIOS) documented that, except in the SAFE trial, patients with neurotrauma had a worse outcome,[4] whereas in the ABLIOS trial, patients with septic shock did better with albumin as a volume expander.[5] In patients with neurotrauma, these trials found a small, but significant, increase in mortality compared with crystalloid therapy. However, neither trial was focused on treating hypoalbuminemia, but rather resuscitation from circulatory shock. In fact, outcomes are similar regardless of baseline serum albumin concentration; albumin administration for patients with hypoalbuminemia has no added benefit. Based on these studies of patients with septic shock, the benefit of colloid versus crystalloid administration for critically ill patients is not clearly demonstrated. Furthermore, the relative amount of albumin that can be effectively replenished by infusion is minimal, considering the normal albumin turnover rate.
These findings are in contrast to prior studies that also found no difference or increased mortality among those receiving albumin. Preliminary studies, including a favorable study by Dubois (2006), examined the effect of albumin on organ function in critically ill patients, but additional work is needed in this area.[6]
For patients with hypoalbuminemia and critical illness, the administration of albumin has not been shown to reduce mortality.[7]
Limited indications for albumin supplementation exist, and considerable clinical judgment is required when albumin is administered. Albumin has been used as one part of regimens designed to prevent hepatorenal syndrome in patients with cirrhosis in whom forced diuresis is being performed; however, this is controversial and survival benefit has not been clearly established. However, in general, albumin is not given specifically to treat hypoalbuminemia, which is a marker for serious disease.
Like crystalloids, colloids produce a dilutional effect on hemoglobin and clotting factors. Clinicians need to monitor the appropriate parameters to safeguard against iatrogenic complications.
Considering fluid resuscitation more generally, recent investigation found that 6% hydroxyethyl starch used for resuscitation in patients with severe sepsis was associated with a significant increase in acute renal failure, calling this approach into question.
The most effective method of minimizing hypoalbuminemia and restoring serum oncotic pressure is by creating a positive nitrogen balance. This is usually accomplished by enteral protein feeding and reversing the inflammatory state, if present. Clearly, those patients with nephrotic syndrome need the nephrosis treated as a primary problem. The importance of enteral nutrition as an early and continued treatment for hypoalbuminemia cannot be overemphasized.
What is the function of albumin in the human body?What are the reference serum values of albumin and what is its half-life?How prevalent is hypoalbuminemia, and what are its common etiologies?What is the prognostic significance of a finding of hypoalbuminemia?Which molecular processes have a role in the pathogenesis of hypoalbuminemia?What is the physiology of albumin synthesis?What is the physiology of albumin distribution in the human body?What is the physiology of albumin damage in severe end-stage hepatic cirrhosis?What is the physiology of albumin degradation?What causes hypoalbuminemia?How does malnutrition cause hypoalbuminemia?How does cirrhosis cause hypoalbuminemia?How does nephrotic syndrome cause hypoalbuminemia?What is the role of enteropathy in the pathogenesis of hypoalbuminemia?How do burns cause hypoalbuminemia?Which GI disorders cause hypoalbuminemia?What is the role of ascites in the etiology of hypoalbuminemia?What is the role of congestive heart failure in the etiology of hypoalbuminemia?What is the role of oncotic pressure in the etiology of hypoalbuminemia?What is the role of chronic inflammation in the etiology of hypoalbuminemia?Which groups are at highest risk for hypoalbuminemia?How does the prevalence of hypoalbuminemia vary by race?How does the prevalence of hypoalbuminemia vary by sex?How does the prevalence of hypoalbuminemia vary by age?What is an important predictor of morbidity and mortality in hypoalbuminemia?For which conditions does hypoalbuminemia predict a poor prognosis?What are specific dietary recommendations for hypoalbuminemia?What leads to variance in the history of patients with hypoalbuminemia?What should be the focus of medical history in the diagnosis of hypoalbuminemia?How do physical findings help determine the etiology of hypoalbuminemia?What is the role of lab studies in the evaluation of hypoalbuminemia?How is hypocalcemia identified in persons with hypoalbuminemia?Which comorbidities should be considered in elderly patients with hypoalbuminemia?What is the role of imaging studies in the evaluation of hypoalbuminemia?Which procedures are indicated in the evaluation of hypoalbuminemia?Which histologic findings are characteristic of hypoalbuminemia due to cirrhosis?Which histologic findings are characteristic of hypoalbuminemia due to nephrotic syndrome?What is the focus of treatment for hypoalbuminemia?How is volume status monitored in hypoalbuminemia?When is the ionized calcium level measured in patients with hypoalbuminemia?When is surgery indicated in the treatment of hypoalbuminemia?Which specialist consultations are needed for the management of hypoalbuminemia?What is a recommended diet for the treatment of hypoalbuminemia?How should activity be modified in patients with hypoalbuminemia?What long-term monitoring is required for patients with hypoalbuminemia?Which medications are used in the treatment of hypoalbuminemia?What is the role of albumin administration in the treatment of critically ill patients with hypoalbuminemia?What are the indications for albumin supplementation for the treatment of hypoalbuminemia?What is the role of fluid resuscitation in the treatment of hypoalbuminemia?What is the most effective method of minimizing hypoalbuminemia?
Ruben Peralta, MD, FACS, Professor of Surgery, Anesthesia and Emergency Medicine, Senior Medical Advisor, Board of Directors, Program Chief of Trauma, Emergency and Critical Care, Consulting Staff, Professor Juan Bosch Trauma Hospital, Dominican Republic
Disclosure: Nothing to disclose.
Coauthor(s)
Brad A Rubery, MD, Consulting Staff, Department of Internal Medicine, Division of Emergency Medicine, Gastroenterology Associates
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Harold L Manning, MD, Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School
Disclosure: Nothing to disclose.
Chief Editor
Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM, Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Masimo, Edwards Lifesciences, Cheetah Medical, Exostat<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED for board membership; Received honoraria from Edwards Lifesciences for consulting; Received honoraria from Masimo, Inc for board membership.
Additional Contributors
Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba Faculty of Medicine; Site Director, Respiratory Medicine, St Boniface General Hospital, Canada
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