Research Notes: Hypoalbuminemia

• Lab results for some neonates and infants with children shows low and borderline low plasma albumin.

From eMedicine:

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

• Distribution

• Degradation

Frequency:

• In the US: 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 [due to malnutrition].

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.

Race: No race predilection exists.

Sex: No sex predilection exists.

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

CLINICAL

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

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.

TREATMENT

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

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.

J Clin Gastroenterol. 2005 Apr.
Inhibition of albumin synthesis in chronic diseases: molecular mechanisms.
Chojkier M.
Department of Medicine and Cancer Center, University of California San Diego, San Diego, CA, USA.

The albumin gene is expressed specifically in the liver after birth, and this expression is regulated predominantly at the transcriptional level. Regulatory proteins occupy specific DNA sequences within the promoter and enhancer of the albumin gene. The interaction between the CCAAT/enhancer binding protein (C/EBP)-beta and the albumin DNA is critical for albumin synthesis. Cachexia-induced hypoalbuminemia is mediated by tumor necrosis factor (TNF)-alpha. In turn, TNF-alpha stimulates oxidative stress, NO synthesis, and phosphorylation of C/EBP-beta within its nuclear localization signal (NLS). Consequently, C/EBP-beta is exported from the nucleus, preventing it to act as a transcriptional factor on the albumin gene. Antioxidants, NOS inhibitors. and dominant negative, nonphosphorylatable C/EBP-beta peptides block phosphorylation of C/EBP-beta within the NLS and its nuclear export as well as rescue the abnormal albumin gene expression, suggesting potential therapeutic interventions.

Semin Dial. 2004 Nov-Dec.
Serum albumin: relationship to inflammation and nutrition.
Don BR, Kaysen G.
Division of Nephrology, Department of Medicine, University of California-Davis, One Shields Avenue, Davis, CA, USA.

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.

Hepatology. 1988 Mar-Apr.
Serum albumin.
Rothschild MA, Oratz M, Schreiber SS.
Nuclear Medicine Service, Veterans Administration Medical Center, New York, New York.

The liver manufactures albumin at a massive rate and decreases production in times of environmental, nutritional, toxic and trauma stress. Osmotic pressure is a basic evolutionary regulatory factor, and hormonal control over albumin production has been demonstrated. Where and why new or old albumin is degraded are questions which have not been clarified, although the vascular endothelium may well be the degradative site. Albumin is important as a transport protein, as a measure of evolution and as a model to study secretion following synthesis without the intervening steps of glycosylation. Investigations as to how this protein enters the endoplasmic membrane may well answer some of the questions concerning signal peptide insertion (288). The role of the urea cycle intermediate ornithine and its participation in polyamine synthesis, which has a positive effect on albumin synthesis, is under study. Likewise, the inverse relation between acute-phase protein synthesis and albumin synthesis regulated by interleukin 1 and other cytokines will merit further study. These are a few of the concepts which will be tested in the future.