Albumin, the body's predominant serum-binding protein, transports a variety of substances, including bilirubin, fatty acids, metals, ions, hormones, and exogenous drugs. Albumin comprises 75-80% of normal plasma colloid oncotic pressure and 50% of protein content. 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 per day 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 degradation of about 4% per day. Little is known about the site of degradation.
Albumin is one of the best indices of nutritional status as it relates to outcome. The level of serum albumin correlates directly with outcome; however, it is important to note that the underlying condition is of greater prognostic significance than the absolute albumin level. Because of the numerous possible diseases that produce hypoalbuminemia, the presentation, physical examination, and lab studies vary and are heavily dependent upon the underlying disease process.
The use of intravenous albumin therapy to increase intravascular osmotic pressure remains controversial, particularly when compared to nonprotein colloids (ie, dextran, hetastarch) and crystalloid solutions.
Pathophysiology: Serum albumin levels are dependent upon the rate of synthesis, secretion from the liver cell, distribution in body fluids, and degradation. Hypoalbuminemia results from a derangement in one or more of these processes.
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.
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.
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 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. 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 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 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. How many round trips that molecule makes while carrying on its functions before being degraded in approximately 20 days is unknown. Tagged albumin studies suggest that albumin may be degraded within the endothelium of the capillaries, bone marrow, and liver sinuses. Albumin molecules apparently are degraded randomly with no differentiation between old and new molecules.
In the US: Hypoalbuminemia is more frequent in older
patients that are institutionalized, patients who are hospitalized with
advanced stages of disease (eg, terminal cancer), and children in impoverished
populations. In liver disease, hypoalbuminemia is caused by
production of albumin. In nephrosis, hypoalbuminemia is caused by increased loss of albumin. Serum albumin levels are low in patients with salt and water retention due to hemodilution; total body albumin may or may not be normal in these instances.
Mortality/Morbidity: Mortality and morbidity depend upon the severity of the underlying disease; however, generally in patients who are critically ill, the risk of death is inversely related to serum albumin concentration.
When plasma proteins, especially albumin, no longer sustain sufficient colloid osmotic pressure to counterbalance hydrostatic pressure, hypo-oncotic edema develops.
Profound hypoalbuminemia combined with an increase in pulmonary capillary hydrostatic pressure can result in a net flow to the interstitial fluid of the lung that overwhelms lymphatic clearance and causes pulmonary edema, which is often misinterpreted as acute respiratory distress syndrome (ARDS).
In patients who are critically ill, measured calcium can be low due to hypoalbuminemia. Serum albumin as measured in the clinical laboratory is a determination of protein-bound albumin only. Albumin is responsible for 80% of the protein-bound calcium in plasma. A decrease in albumin decreases the amount of calcium in the protein-bound fraction, which has no clinical significance because the active fraction (ionized or unbound) is not affected. However, in order to be sure there is not a second hypocalcemic disorder, measure the ionized calcium when the albumin level is low.
Race: No race predilection exists.
Sex: No sex predilection exists.
Age: Hypoalbuminemia affects all age groups, depending on
the underlying cause.
History: The potential underlying causes of hypoalbuminemia are numerous. Patients’ histories vary significantly depending upon the underlying disease state.
Explore the past medical history for a history of liver or renal failure, hypothyroidism, malignancy, and malabsorption.
Evaluate the patient for appropriate dietary intake.
Patients may complain of weight loss or weight gain, anorexia, fatigue, dyspnea, diarrhea, greasy stools, abdominal discomfort, and distention.
Physical: Abnormal physical findings may be found in multiple organ systems depending upon the underlying disease.
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 stress-induced catabolism of body protein. Some of the many causes are as follows:
Protein malnutrition: Deficient protein intake results in the rapid loss of cellular ribonucleic acid (RNA) 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. Ornithine forms spermine, which promotes polysome aggregation and increases albumin synthesis. The levels of these stimulatory amino acids are depressed in the fasting state.
Defective synthesis: In 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 cirrhotic patients who lack ascites. Albumin synthesis may actually increase in cirrhotic patients with 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 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 to amino acids that are recycled. In chronic renal disease, in which 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 (51Cr), which measures intestinal losses, to albumin labeled with iodine-125 (125I), which measures overall degradation.
Diseases resulting in protein loss from the intestine are divided into 2 main types.
Lymphatic blockage, which can be caused by constrictive pericarditis, ataxia telangiectasia, and mesenteric blockage due to tumor
Mucosal disease with direct loss into the bowel as is seen with inflammatory bowel disease and sprue; and bacterial overgrowth, as in blind loop syndrome after intestinal bypass surgery
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 seen 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 .
Ascites: 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: In congestive heart failure, the synthesis of albumin is normal. Hypoalbuminemia results from an increased volume of distribution.
Oncotic pressure increase: Albumin synthesis is regulated, in part, by the serum oncotic pressure. The site of regulation 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 the following:
Elevated serum globulins in hepatitis
Infusion of other colloids (dextran and gammaglobulins)
Stress: Physiologic stress of any kind, whether tissue damage (severe burns), infection, or carcinoma, can result in hypoalbuminemia. This occurs through messenger substances released at the site of injury. Tumor necrosis factor, interleukin-1, and interleukin-6 are examples of such messengers. These messengers decrease albumin synthesis by modifying mRNA availability. In addition, even more severe degrees of hypoalbuminemia can result from the massive local protein losses in severe burns.
Potential etiologies for hypoalbuminemia are numerous. Clinical suspicion of the underlying disease process should guide appropriate laboratory studies, some of which are outlined below.
Decreased lymphocyte count and decreased blood urea are seen in malnutrition. Tranferrin, prealbumin, and retinol-binding protein have shorter half-lives than albumin and better reflect short-term changes in nutritional status than albumin, which has a long half-life. Prealbumin, unlike preproalbumin and proalbumin, is not a precursor of albumin. Prealbumin is an entirely different plasma protein that happens to have an earlier electrophoretic migration than albumin, hence, prealbumin.
An elevation in C-reactive protein levels suggests that inflammation is contributing to the hypoalbuminemia.
A 24-hour urine collection containing greater than 3 g protein/24 hours is consistent with nephrotic syndrome.
Liver function tests (transaminases) may be elevated or normal in patients who are cirrhotic. There are numerous potential etiologies of cirrhosis and more specific studies may be needed.
Fecal fat studies include Sudan qualitative stain for fat and a 72-hour quantitative fecal fat collection.
Fecal alpha-1-antitrypsin clearance can help establish the presence of protein-losing malabsorption.
Serum protein electrophoresis for hypergammaglobulinemia.
None of the various correction factors for determining the effects of hypoalbuminemia on the plasma calcium concentration have proven reliable. Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (average normal albumin level of 4.4 - serum albumin [g/dL]). The only method of identifying true (ionized) hypocalcemia in the presence of hypoalbuminemia is to measure the ionized fraction directly.
Liver ultrasound for evidence of cirrhosis
Small bowel barium series for mucosal abnormalities typical of malabsorption syndromes
Chest x-ray to rule out tuberculosis or other pulmonary infection
Echocardiogram for congestive heart failure
Liver biopsy to confirm cirrhosis
Kidney biopsy to help evaluate etiology of nephrosis
Histologic Findings: When hypoalbuminemia is due to cirrhosis, liver biopsy shows 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 (IgA nephropathy), or no changes (minimal change disease). Electron microscopy may show subepithelial immunoglobulin (IgG) deposits (membranous glomerulonephritis). A very large differential exists for secondary causes of nephrotic syndrome.TREATMENT
Medical Care: Treatment should focus on the underlying cause of hypoalbuminemia. Simply replacing albumin intravenously generally has been found to be ineffective and may be harmful.
The administration of albumin may increase mortality by 6% as compared to crystalloid (Cochrane meta-analysis).
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 or pulmonary artery catheter.
In patients who are critically ill, low calcium 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 is low.
Surgical Care: Only when indicated for underlying cause
Consultations: Depending upon the clinical situation, multiple consultations may be necessary.
Diet: Support the underlying cause with adequate nutrition (sufficient high biological value protein and caloric intake for anabolism).
Activity: Depends on severity of underlying
Hypoalbuminemia is a
common phenomenon in patients with serious illness. Treatment should focus on
the underlying cause rather than simply replacing albumin. In general, albumin
supplementation transiently increases serum albumin, but it does not influence
the clinical course. In fact, albumin administration can be harmful. Limited
indications for albumin do exist, and considerable clinical judgment is required
when administering albumin. However, in general, albumin is not given
specifically to treat hypoalbuminemia, which is a marker for serious
Further Inpatient Care:
The significance of hypoalbuminemia appears to lie in its reflection of the severity of the underlying disease process. Therefore, follow-up care, for both inpatients and outpatients, is dictated by those processes.
Specific dietary recommendations based on underlying disease
Administration of albumin can lower serum-ionized calcium causing myocardial depression.
Misdiagnosis of ARDS secondary to pulmonary edema
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