Hypoalbuminemia

Etiology

Hypoalbuminemia is one of the most prevalent disorders among hospitalized and critically ill patients. Hypoalbuminemia may result from decreased albumin production, which is rare; increased albumin loss through the kidneys, gastrointestinal tract, skin, or extravascular space; increased albumin catabolism; or a combination of 2 or more mechanisms.

Epidemiology

The prevalence of hypoalbuminemia is higher among hospitalized patients, critically ill individuals, and older adults. Results from a report by Brock et al found that hypoalbuminemia affected more than 70% of hospitalized older adults.[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 manifests. Hypoalbuminemia is a feature of chronic and advanced hepatic cirrhosis. Most commonly, inadequate albumin synthesis combined with increased catabolism from significant systemic illness contributes to hypoalbuminemia. In many disease states, except liver failure and kwashiorkor, the measured fractional synthesis rate of albumin is normal or slightly increased.

Nutritional deficiency: Kwashiorkor, a severe form of protein-energy malnutrition, occurs in infants and children. Affected children have low serum albumin levels due to reduced amino acid supply to the liver and may have other nutritional deficiencies, notably iron and zinc. Additionally, apart from hemoglobin, albumin has more variant forms than any other protein molecule.

Very low or undetectable serum albumin levels, defined as a serum albumin concentration less than 1 g/L, characterize a rare disorder known as analbuminemia. Individuals with analbuminemia appear to retain sufficient amounts of albumin to survive under normal conditions. The disorder may present in adulthood with peripheral edema, fatigue, and hyperlipidemia, usually without associated atherosclerosis. Patients are generally hemodynamically stable.[2][4][6]

Increased Loss of Albumin

Renal loss: With a molecular weight of 66 kDa, albumin loss through the glomerulus is minimal, at less than 30 mg/d, in healthy individuals. Increased losses may occur due to physiological factors, including fever, exercise, and changes in posture. The balance between glomerular filtration and tubular reabsorption determines the presence of albumin in the urine. Glomerular damage increases urinary albumin loss and may occur in numerous disease conditions.

Nephrotic syndrome is characterized by albumin and protein loss through the kidneys. Nephrotic-range proteinuria is defined as the loss of at least 3.5 g of protein during a 24-hour period. Apart from significant proteinuria, nephrotic syndrome is characterized by hypoalbuminemia, edema, and ascites resulting from low oncotic pressure.

Hyperlipidemia is thought to result from increased hepatic lipoprotein production in response to low serum albumin levels. Nephrotic syndrome is also associated with increased production of clotting factors and an increased risk of thrombosis. Depending on its cause, nephrotic syndrome may present during childhood, adulthood, or older adulthood. Damage to the glomerulus may result from exogenous toxins, medications, heavy metals, chemotherapeutic agents, autoantibodies against the glomerular basement membrane in autoimmune diseases such as systemic lupus erythematosus, or antibodies produced after infections such as group A streptococcal infection. Malignant neoplasms, including multiple myeloma, are also associated with the development of nephrotic syndrome.[2][4][7]

Chronic kidney disease: One definition of chronic kidney disease includes significant proteinuria greater than 30 mg during a 24-hour period for at least 3 months. Proteinuria may occur with or without a decreased glomerular filtration rate. End-stage kidney disease is associated with significant proteinuria and serum hypoalbuminemia. Hypoalbuminemia in end-stage kidney disease also results from decreased protein synthesis and increased protein degradation.[2] Proteinuria may also occur in chronic diseases such as diabetes mellitus and essential hypertension, but it does not cause serum hypoalbuminemia unless the total protein loss reaches the nephrotic range.[2]

Gastrointestinal tract loss: Protein-losing enteropathy is characterized by substantial loss of proteins, including albumin, through the gastrointestinal tract at a rate that exceeds protein synthesis, leading to hypoalbuminemia. Causes of protein-losing enteropathy include gastrointestinal tract disorders and conditions involving other organ systems, such as cardiac disease and systemic lupus erythematosus. The mechanisms of protein loss in protein-losing enteropathy are divided into 3 categories: diseases associated with increased lymphatic pressure, such as lymphangiectasia; diseases with mucosal erosions, such as Crohn disease; and diseases without mucosal erosions, such as celiac disease.[2][4][7] Additionally, mutations in the diacylglycerol O-acyltransferase 1 gene (DGAT1) may cause a rare congenital form of protein-losing enteropathy.[8]

Extravascular Loss

Loss of albumin from the intravascular compartment into the extravascular compartment results in hypoalbuminemia.

Burns: Patients with burn wounds have increased vascular permeability, resulting in the extravasation of albumin from the intravascular compartment into extravascular compartments. An associated acute-phase response alters hepatic protein synthesis, further decreasing serum albumin levels. Serum albumin levels are also used to assess burn severity and predict morbidity and mortality.[7]

Sepsis: Sepsis is associated with increased vascular permeability and capillary leakage, resulting in albumin loss from the intravascular compartment. Additionally, significant sepsis and other inflammatory states reduce albumin synthesis and increase albumin catabolism.[2] Chronic inflammation in the absence of sepsis may also contribute to hypoalbuminemia.[5]

Albumin and Critical Illness

Critical illness is associated with hypoalbuminemia through multiple mechanisms. The condition alters the distribution of albumin between the intravascular and extravascular compartments, affects the rate of albumin synthesis, and increases albumin clearance and degradation. Increased capillary leakage and vascular permeability result from various factors, including tumor necrosis factor-α, IL-6, chemokines, prostaglandins, complement components, and endotoxins from gram-negative bacteria. Albumin synthesis also decreases during critical illness, possibly because of increased transcription of positive acute-phase proteins, such as C-reactive protein, and decreased transcription of albumin messenger ribonucleic acid.[2] Preexisting hypoalbuminemia may increase the risk of acute infectious disease.[5]

Cardiac Failure

Contributing factors to hypoalbuminemia in cardiac failure include malnutrition, inflammation, cachexia, hemodilution, liver dysfunction, protein-losing enteropathy, and increased extravascular loss. The risk of hypoalbuminemia among patients with cardiac failure is increased in older adults.[2]

Toxicokinetics

Hypoalbuminemia also affects drug pharmacokinetics. Hydrophobic compounds bind to albumin in the circulation. Changes in plasma albumin concentration may affect the concentration of the unbound, active drug and the bound-to-unbound drug ratio. Hypoalbuminemia may increase unbound drug levels and alter the volume of distribution.

Consequently, clinicians may need to perform more vigilant therapeutic drug monitoring, measure free drug concentrations, and adjust medication dosages. For example, patients prescribed the anticonvulsant phenytoin who have significant hypoalbuminemia may experience phenytoin toxicity due to increased free drug concentrations. Conversely, hypoalbuminemia may result in subtherapeutic concentrations of antibiotics such as ceftriaxone and ertapenem.[9] Interestingly, oxidative damage may alter the binding properties of albumin.[5]

History and Physical

Hypoalbuminemia is often identified during routine laboratory testing when patients are evaluated for other primary medical conditions. Patients with hypoalbuminemia may present with peripheral pitting edema, central edema, including ascites and effusions, and anasarca. Additional concerns may include fatigue, marked weakness, and other features of related nutritional deficiencies, such as iron-deficiency anemia in celiac disease. Patients may also exhibit manifestations of the primary disease, such as jaundice in liver disease or diarrhea in protein-losing enteropathy. Proteinuria may be detected using bedside urine dipstick analysis.

Evaluation

Measurement of serum albumin using routine assays on automated chemistry analyzers is a quick and simple method for detecting hypoalbuminemia. These assays measure the color change that occurs when albumin binds to a dye, most commonly bromocresol green or bromocresol purple. The color change is measured spectrophotometrically, and the absorbance of light passing through the sample is proportional to the albumin concentration. Other methods used to measure albumin include immunonephelometric and immunoturbidometric techniques.

Structural changes in albumin following oxidative damage and glycation may produce an albumin isoform with reduced binding capacity. Measurement techniques such as liquid chromatography–electrospray ionization mass spectrometry can differentiate this modified albumin from functional albumin. Measuring functional albumin may provide a better prognostic biomarker than standard albumin measurement. However, this method is unlikely to be readily available in most clinical settings.[5]  

Decreased albumin levels may be an incidental finding on serum protein electrophoresis; however, this test provides only a semiquantitative estimate of albumin. The technique separates serum proteins by mass and charge using an electric field. The main value of protein electrophoresis in patients with low serum albumin lies in the differential diagnosis of hypoalbuminemia. Acute inflammation produces a pattern of hypoalbuminemia with increased α1- and α2-globulin levels and normal γ-globulin levels. Conversely, chronic inflammation leads to hypoalbuminemia and a polyclonal increase in γ-globulin levels.

In nephrotic syndrome, the typical serum protein electrophoresis pattern shows hypoalbuminemia, elevated α2-globulin levels due to increased macroglobulin concentrations, and low γ-globulin levels. Chronic liver disease typically produces hypoalbuminemia with increased γ-globulin levels and β-γ bridging. These characteristic patterns may help clinicians identify the underlying cause of hypoalbuminemia.

Further evaluations focus on identifying the cause of hypoalbuminemia and monitoring the underlying disease. Testing may include liver function tests to assess liver disease, urinary protein measurements to evaluate urinary protein loss, B-type natriuretic peptide measurement to evaluate heart failure, and radiologic imaging. The selection of additional tests depends on the suspected cause and associated clinical findings.

Specific tests include fecal α1-antitrypsin clearance, which assesses gastrointestinal tract protein loss distal to the pylorus. The test requires the collection of stool and serum samples. α1-Antitrypsin is resistant to degradation by digestive enzymes and therefore serves as an endogenous marker of blood protein within the intestinal tract.

Increased fecal α1-antitrypsin clearance with a serum α1-antitrypsin level within the reference range indicates gastrointestinal tract protein loss.[10] Fecal α1-antitrypsin levels may also increase with gastrointestinal tract bleeding and do not identify the specific disease process causing gastrointestinal tract protein loss. Additional tests may include tissue transglutaminase antibodies for celiac disease and fecal calprotectin measurement for inflammatory bowel disease.

Hypoalbuminemia may affect the measurement of other common laboratory values. For example, low serum albumin reduces calcium binding and may produce a decreased total serum calcium result, termed pseudohypocalcemia. Many laboratories use an equation to correct the total calcium value for the albumin concentration and report a corrected calcium result. However, results from recent studies suggested that correction may be unnecessary and that the unadjusted total serum calcium value may adequately reflect serum calcium status.[11]

Treatment / Management

Treatment is directed at the underlying cause of hypoalbuminemia because the condition is a consequence of another disease process. Albumin infusions may be given to critically ill individuals, particularly those with burns, although supporting evidence from randomized clinical trials is limited. Albumin infusion may also benefit patients with cirrhosis and complications such as spontaneous bacterial peritonitis, large-volume paracentesis, and hepatorenal syndrome.[12] The Surviving Sepsis Campaign guidelines do not recommend albumin infusion as the first-choice fluid for resuscitation in patients with sepsis. Whether albumin infusions provide clinical benefit to other groups of critically ill individuals remains controversial.[13]

Differential Diagnosis

The differential diagnosis of hypoalbuminemia is broad and includes disorders that impair albumin production, such as cirrhosis; cause gastrointestinal tract protein loss, such as protein-losing enteropathy; increase renal albumin loss, such as nephrotic syndrome; or increase albumin catabolism, as may occur during critical illness.

Prognosis

Hypoalbuminemia is used as a prognostic marker of illness and death in hospitalized patients, particularly in critical care settings. The Child-Pugh scoring system, which is used to assess the severity and prognosis of cirrhosis, includes hypoalbuminemia as a parameter.[5] Albumin is also included in other predictive scoring systems for critically ill patients, such as the Acute Physiology and Chronic Health Evaluation III and Critical Illness Severity Scoring System. Additionally, the SMART-COP score incorporates systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH to identify patients with community-acquired pneumonia who may require vasopressor or respiratory support. Albumin levels have also been used to predict surgical site infection.[5]

Results from a recent meta-analysis of postoperative outcomes in patients with colorectal cancer showed that preoperative hypoalbuminemia was associated with surgical complications, prolonged hospitalization, and increased illness.[14] Results from studies also demonstrated that hypoalbuminemia was an independent risk factor for poor response to chemotherapy and mortality in patients with cancer. Consequently, serum albumin levels may provide useful prognostic information before cancer treatment and surgical procedures.

Results from further studies linked hypoalbuminemia with poor prognosis in infectious diseases and identified low serum albumin levels as a marker of complications associated with acute viral, bacterial, and fungal infections. Findings also demonstrated that hypoalbuminemia was an independent risk factor for mortality in patients with Clostridioides difficile infection and COVID-19.[5][15] Additionally, results from studies supported the use of low serum albumin levels as a predictor of cardiovascular risk.[16]

Results from studies demonstrated a strong inverse correlation between serum albumin levels and the inflammatory marker C-reactive protein. Serum albumin and C-reactive protein are incorporated into the Glasgow Prognostic Score. Hypoalbuminemia has also been associated with adverse outcomes among children with a wide range of disease processes.[8]

Complications

Complications of significant hypoalbuminemia include circulatory collapse resulting from reduced oncotic pressure. Edema and anasarca increase the risk of complications, including infection, among critically ill individuals.