AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 20 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 entities, 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.

Because of the numerous possible diseases that produce hypoalbuminemia, the presentation, physical examination findings, and laboratory results vary and heavily depend on the underlying disease process.

Pathophysiology

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 ducts. 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 children in impoverished populations.

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, and regional enteritis (Crohn disease).

Race

No race predilection exists.

Sex

No sex predilection exists.

Age

Hypoalbuminemia affects persons of all age groups, depending on the underlying cause.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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 findings listed below suggest the potential underlying disease processes.

• 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 disease, and, most commonly, acute or chronic inflammation. Some of the many causes are as follows:

• 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 into burns, from compromised hepatic blood flow due to volume loss, and from inhibitory tissue factors released at the burn sites. Three of these inhibitory monokines are tumor necrosis factor, interleukin-1, and interleukin-6 (see Stress).
  • 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)

WORKUP

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Clinical suspicion of the underlying disease process should guide appropriate laboratory studies, some of which are outlined below.
• • 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. 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.

Imaging Studies

• 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

• Liver biopsy to confirm cirrhosis
• Kidney biopsy to help evaluate etiology of nephrosis

Histologic Findings

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

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment should focus on the underlying cause of hypoalbuminemia.

• Simply replacing albumin intravenously has generally been ineffective. Although prior meta-analysis of small studies suggested that albumin infusions may be harmful (increasing the mortality rate by 6% as compared with crystalloid), a large multicenter clinical trial (SAFE) documented that, except in patients with neurotrauma, albumin infusions did not measurably affect outcome. In patients with neurotrauma, these trials found a small, but significant, increase in mortality as compared with crystalloid therapy.
• Reserve colloid administration for clinical situations in which fluid resuscitation with crystalloids has failed to reduce the intravascular volume deficit. Like crystalloids, colloids produce a dilutional effect on hemoglobin and clotting factors. Clinicians need to monitor the appropriate parameters to safeguard against iatrogenic complications. Do not use exogenous albumin for the purpose of raising serum albumin levels.
• 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 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.

Surgical Care

Surgery is considered only when indicated for the underlying cause.

Consultations

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

• Gastroenterologist
• Intensivist
• Nephrologist
• Surgeon
• Endocrinologist
• Registered dietitian

Diet

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

Activity

Recommendations depend on the severity of the underlying disease.

MEDICATION

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Hypoalbuminemia is a common phenomenon in patients with serious illness. Treatment should focus on the underlying cause rather than simply replacing albumin. Results of several meta-analyses of albumin treatment in hospitalized patients have been inconsistent. A 1998 Cochrane meta-analysis found that albumin treatment increased mortality; these findings were not confirmed by the meta-analysis of Wilkes et al (2001), which found no overall effect of albumin on mortality. The SAFE study investigators found no difference in survival between albumin and saline administration for hypovolemic ICU patients. Vincent reviewed albumin's effect on morbidity in a 2004 meta-analysis; this study found albumin favorably affected morbidity in hypoalbuminemic hospitalized patients.

Limited indications for albumin supplementation exist, and considerable clinical judgment is required when albumin is administered. However, in general, albumin is not given specifically to treat hypoalbuminemia, which is a marker for serious disease.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• 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.

Patient Education

• Specific dietary recommendations are based on the underlying disease.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Administration of albumin, leading to lower serum ionized calcium levels and causing myocardial depression
• Fluid overload
• Allergic reactions
• Misdiagnosis of ARDS secondary to pulmonary edema

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Chojkier M. Inhibition of albumin synthesis in chronic diseases: molecular mechanisms. J Clin Gastroenterol. Apr 2005;39(4 Suppl 2):S143-6.
• Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. ALYSIS. Jul 25 1998;317(7153):235-40. [Medline].
• Don BR, Kaysen G. Serum albumin: relationship to inflammation and nutrition. Semin Dial. Nov-Dec 2004;17(6):432-7.
• Finfer S, Bellomo R, Boyce N. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. May 27 2004;350(22):2247-56.
• Gibbs J, Cull W, Henderson W. Preoperative serum albumin level as a predictor of operative mortality and morbidity: Results from the National VA Surgical Risk Study. Arch Surg. 1999;134:36-42.
• Haller C. Hypoalbuminemia in renal failure: pathogenesis and therapeutic considerations. Kidney Blood Press Res. 2005;28(5-6):307-10.
• Haynes GR, Navickis RJ, Wilkes MM. Albumin administration--what is the evidence of clinical benefit? A systematic review of randomized controlled trials. Eur J Anaesthesiol. Oct 2003;20(10):771-93. [Medline].
• Herrmann FR, Safran C, Levkoff SE, Minaker KL. Serum albumin level on admission as a predictor of death, length of stay, and readmission. Arch Intern Med. Jan 1992;152(1):125-30.
• Johnson AM. Low levels of plasma proteins: Malnutrition or inflammation?. Clin Chem Lab Med. 1999;37:91-96.
• Kalantar-Zadeh K, Kilpatrick RD, Kuwae N, et al. Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction. Nephrol Dial Transplant. Sep 2005;20(9):1880-8.
• Kalantar-Zadeh K, Block G, McAllister CJ, et al. Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients. Am J Clin Nutr. Aug 2004;80(2):299-307.
• Kalantar-Zadeh K, Kopple JD, Humphreys MH, Block G. Comparing outcome predictability of markers of malnutrition-inflammation complex syndrome in haemodialysis patients. Nephrol Dial Transplant. Jun 2004;19(6):1507-19.
• Kaysen GA, Chertow GM, Adhikarla R, et al. Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. Kidney Int. Jul 2001;60(1):333-40. [Medline].
• Kaysen GA, Dubin JA, Muller HG. Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int. Apr 2004;65(4):1408-15.
• Kaysen GA, Dubin JA, Muller HG, et al. Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients. Kidney Int. Jun 2002;61(6):2240-9. [Medline].
• Kerr RM, Du Bois JJ, Holt PR. Use of 125-I- and 51-Cr-labeled albumin for the measurement of gastrointestinal and total albumin catabolism. J Clin Invest. Dec 1967;46(12):2064-82. [Medline].
• Offringa M. Excess mortality after human albumin administration in critically ill patients. Clinical and pathophysiological evidence suggests albumin is harmful. BMJ. Jul 25 1998;317(7153):223-4. [Medline].
• Pulimood TB, Park GR. Debate: Albumin administration should be avoided in the critically ill. Crit Care. 2000;4(3):151-5. [Medline].
• Puskarich-May CL, Sullivan DH, Nelson CL, et al. The change in serum protein concentration in response to the stress of total joint surgery: a comparison of older versus younger patients. J Am Geriatr Soc. May 1996;44(5):555-8. [Medline].
• Rothschild MA, Oratz M, Schreiber SS. Alcohol, amino acids, and albumin synthesis. Gastroenterology. Dec 1974;67(6):1200-13. [Medline].
• Rothschild MA, Oratz M, Schreiber SS. Serum albumin. Hepatology. Mar-Apr 1988;8(2):385-401. [Medline].
• Rothschild MA, Oratz M, Schreiber SS. Albumin synthesis (second of two parts). N Engl J Med. Apr 13 1972;286(15):816-21. [Medline].
• Rothschild MA, Oratz M, Schreiber SS. Albumin synthesis. 1. N Engl J Med. Apr 6 1972;286(14):748-57. [Medline].
• Sullivan DH, Roberson PK, Bopp MM. Hypoalbuminemia 3 months after hospital discharge: significance for long-term survival. J Am Geriatr Soc. Jul 2005;53(7):1222-6.
• Sung J, Bochicchio GV, Joshi M. Admission serum albumin is predicitve of outcome in critically ill trauma patients. Am Surg. Dec 2004;70(12):1099-102. [Medline].
• Vermeulen LC, Ratko TA, Erstad BL, et al. A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. Arch Intern Med. Feb 27 1995;155(4):373-9. [Medline].
• Vincent J, Dubois M, Navickis RJ, Wilkes MM. Hypoalbuminemia in Acute Illness: Is there a rationale for intervention?. Annals of Surgery. 2003;237:319-334.
• Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med. Oct 2004;32(10):2029-38.
• Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. Aug 7 2001;135(3):149-64. [Medline].

Article Last Updated: May 25, 2006