What is hypoalbuminemia

Hypoalbuminemia is defined as plasma albumin less than 34 g/L ¹. 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. One report by Brock et al. ² determined the prevalence to be greater than 70% of elderly hospitalized patients.

There are two important causes of low blood albumin or hypoalbuminemia:

1. Severe liver disease: since albumin is produced by the liver, its level can decrease with loss of liver function; however, this typically occurs only when the liver has been severely affected.
2. Kidney disease: one of the many functions of the kidneys is to conserve plasma proteins such as albumin so that they are not released along with waste products when urine is produced. Albumin is present in high concentrations in the blood, and when the kidneys are functioning properly, virtually no albumin is lost in the urine. However, if a person’s kidneys become damaged or diseased, they begin to lose their ability to conserve albumin and other proteins. This is frequently seen in chronic diseases, such as diabetes and hypertension. In nephrotic syndrome, very high amounts of albumin are lost through the kidneys.

In adult humans, albumin is the most abundant plasma protein with a concentration ranging from 35 to 50 g/L ³. Albumin represents 60% of the total protein in the blood and plays many roles, with globulins making up most of the rest ⁴.  Albumin keeps fluid from leaking out of blood vessels; nourishes tissues; and transports hormones, vitamins, drugs, and substances like calcium throughout the body. Levels of albumin may decrease, to a greater or lesser degree, when conditions interfere with its production by the liver, increase protein breakdown, increase protein loss via the kidneys, and/or expand plasma volume (diluting the blood).

Albumin has several physiological roles. One of the most important is to maintain the oncotic pressure within the vascular compartments preventing leaking of fluids into the extravascular spaces. It accounts for around 80% of the colloid osmotic pressure. Additionally, albumin functions as a low-affinity, high-capacity carrier of several different endogenous and exogenous compounds acting as a depot and a carrier for these compounds. Binding of compounds to albumin may reduce their toxicity such as in the case of unconjugated bilirubin in the neonate and drugs. Also, albumin binds at least 40% of the circulating calcium and is a transporter of hormones such as thyroxine, cortisol, testosterone, among others. Albumin also is the main carrier for fatty acids and has significant anti-oxidant properties. Albumin is also involved with maintaining acid-base balance as it acts as a plasma buffer. Albumin is used as a marker of nutritional status and disease severity in particular in chronic and critically ill patients ⁵. Renal and gut loss of albumin may account for around 6% and 10% respectively of albumin loss in healthy individuals. A decrease in serum albumin levels below the reference interval hypoalbuminemia. This article reviews the causes and diagnosis of hypoalbuminemia ⁵.

Albumin is a single peptide chain of 585 amino acids in a globular structure. The molecular weight of albumin is approximately 66 kDa, and it has a half-life of 21 days ⁴. Albumin is exclusively synthesized by the liver, initially a pre-proalbumin and then proalbumin, which in the Golgi apparatus is converted to albumin, which is the final form secreted by the hepatocyte. The synthetic rate is about 10 to 15 grams per day and then secreted into the circulation of which around 40% remains in circulation with a fraction moving from the intravascular to the interstitial space ⁵. Factors that stimulate albumin synthesis include the action of hormones such as insulin and growth hormone. Albumin production may be inhibited by pro-inflammatory mediators such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor ⁶. In fetal life, alpha-fetoprotein (AFP) produced by the liver and yolk sac is the most abundant plasma protein. AFP is thought to be the fetal counterpart of albumin, and both are transcribed by genes located close together on chromosome 4. Approximately 100 variant forms of albumin have been described ⁵.

Hypoalbuminemia treatment should focus on the underlying cause of hypoalbuminemia.

Hypoalbuminemia causes

Hypoalbuminaemia is one of the most prevalent disorders in hospitalized and critically ill patients. Hypoalbuminaemia may be a result of decreased production (rare) of albumin or increased loss of albumin via the kidneys, gastrointestinal (GI) tract, skin, or extravascular space or increased catabolism of albumin or a combination of 2 or more of these mechanisms.

Levels of albumin may decrease, to a greater or lesser degree, when conditions interfere with its production, increase protein breakdown, increase protein loss, and/or expand plasma volume (diluting the blood). Depending on the person’s medical history, signs and symptoms, and physical exam, additional testing may be done to investigate a low result.

Hypoalbuminemia can suggest liver disease. Liver enzyme tests or a liver panel may be ordered to determine exactly which type of liver disease may be present. A person may, however, have normal or near normal albumin levels with liver disease until the condition has reached an advanced stage. For example, in people with cirrhosis, albumin is typically (but not always) low whereas in most chronic liver diseases that have not progressed to cirrhosis, albumin is usually normal.

Hypoalbuminemia can reflect diseases in which the kidneys cannot prevent albumin from leaking from the blood into the urine and being lost. In this case, the amount of albumin or protein in the urine also may be measured (see Urine Albumin) or tests for creatinine and BUN or a renal panel may be ordered.

Hypoalbuminemia can also be seen in inflammation, shock, and malnutrition. They may be seen with conditions in which the body does not properly absorb and digest protein, such as Crohns disease or celiac disease, or in which large volumes of protein are lost from the intestines.

A low albumin may also be seen in several other conditions, such as:

• Infection
• Burns
• Surgery
• Chronic illness
• Cancer
• Diabetes
• Hypothyroidism
• Carcinoid syndrome
• Plasma volume expansion due to congestive heart failure, sometimes pregnancy

Apart from hemoglobin, albumin is the protein molecule with the most number of variant forms. Very low or undetectable albumin in serum (serum albumin concentration of less than 1g/L) characterizes a rare disorder known as analbuminaemia. These individuals appear to have sufficient amounts of albumin to survive under normal conditions. They present in adulthood with peripheral edema, fatigue, and hyperlipidemia but usually no associated atherosclerosis. Patients are generally hemodynamically stable ⁵.

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.

Kwashiorkor, a severe form of protein-energy malnutrition, presenting in infants and children. They have low serum albumin levels due to a decreased supply of amino acids to the liver as well as other nutritional deficiencies, notably iron and zinc.

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 is manifest. Hypoalbuminemia is a feature of chronic and advanced hepatic cirrhosis. 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.

Increased loss of albumin

Renal Loss

With a molecular weight of 66 kDa, albumin loss via the glomerulus is minimal (less than 30 mg per day) in healthy individuals. Increased losses may occur due to physiological reasons such as fever, exercise, or posture-related reasons. The balance between glomerular filtration and tubular reabsorption determines the presence of albumin in urine. Damage to the glomerulus results in increased albumin loss via urine. Injury to the glomerulus can occur in a plethora of disease conditions.

Nephrotic syndrome

Nephrotic syndrome is characterized by albumin and protein loss via the kidneys. Nephrotic range proteinuria is considered to be the loss of 3.5 or more grams of protein per 24-hour period. 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/day) and only when the diet is adequate is albumin synthesis increased.

Apart from significant proteinuria, nephrotic syndrome is characterized by hypoalbuminemia, increased edema, and presence of ascites due to the low oncotic pressure. Hyperlipidemia thought to be a result of the liver increasing production of lipoproteins to compensate for the low serum albumin, increased production of clotting factors, and increased risk of thrombosis. Depending on the cause of nephrotic syndrome it can present in childhood, adulthood, and in the elderly. Damage to the glomerulus may occur due to exogenous toxins drugs, heavy metals, chemotherapeutic agents, via autoantibodies directed against the glomerular basement membrane such as in autoimmune diseases such as SLE, or antibodies generated following infection such as Group B streptococcus. Malignancies such as multiple myeloma also are associated with the development of nephrotic syndrome ².

Chronic kidney disease

One of the definitions of chronic kidney disease includes the presence of significant albuminuria 30 to 300 mg per 24 hours over at least a period of 3 months. This can occur in the presence or absence of a decreased glomerular filtration rate (GFR). End-stage renal disease (ESRD) is associated with significant proteinuria and albuminuria together with serum hypoalbuminemia. The hypoalbuminemia in end-stage renal disease is also a result of the decreased synthesis and increased degradation of protein in this condition ⁵.

Albuminuria

Albuminuria may also occur during chronic diseases such as diabetes mellitus and essential hypertension but does not result in serum hypoalbuminemia unless total protein loss is in the nephrotic range ⁵.

Protein-losing enteropathy

Protein-losing enteropathy is characterized by substantial loss of proteins including albumin via the gastrointestinal tract that exceeds synthesis. This leads to hypoalbuminemia. 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.

There are several causes of protein-losing enteropathy which include GI disease and non-gut-related conditions (such as cardiac disease and SLE). The mechanisms for protein loss in protein-losing enteropathy can be broadly divided into 3 categories: (1) diseases associated with increased lymphatic pressure (e.g., lymphangiectasis); (2) diseases with mucosal erosions (e.g., Crohn’s disease); and (3) diseases without mucosal erosions (e.g., celiac disease) ⁵.

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.

Extravascular loss

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

Extensive burns

The skin is the major site for extravascular albumin storage and is the major exchangeable albumin pool needed to maintain plasma levels. Patients with burn wounds have increased vascular permeability resulting in the extravasation of albumin from the intravascular to the extravascular compartments. There is also an acute phase response that affects liver protein synthesis causing a further decrease in serum albumin levels. Serum albumin levels are also used to assess the severity of burns in these patients and as a predictor of mortality and morbidity ⁷.

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.

Sepsis

Sepsis is associated with increased vascular permeability and capillary leakage resulting in loss of albumin from the intravascular compartment. Apart from this there is also reduced synthesis and increased catabolism of albumin in the presence of significant sepsis ⁸.

Albumin and critical illness

The presence of critical illness is associated with hypoalbuminemia through a variety of mechanisms. Critical illness alters the distribution of albumin between the intravascular and extravascular compartments, affects the rate of albumin synthesis and increases albumin clearance and degradation. The increased capillary leakage responsible for the vascular permeability is a result of various factors including the effects of cytokines such as TNF-alpha and IL-6, chemokines, the action of prostaglandins and complement components as well as endotoxins from gram-negative bacteria.

The rate of synthesis is also decreased in critical illness, and this is thought to be a result of the increase in gene transcription for the positive acute phase proteins such as C-reactive protein and decreased in the rate of transcription of albumin mRNA ⁸.

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 in cardiac failure is a combination of various factors including malnutrition, inflammation, and cachexia as well as hemodilution, liver dysfunction, protein-losing enteropathy, and increased extravascular loss. Risk of hypoalbuminemia with cardiac failure is increased in elderly patients ⁸.

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 signs and symptoms

Patients with hypoalbuminemia present with peripheral (pitting) and central edema (ascites and effusions) and anasarca. They may also complain of fatigue and excessive weakness and other features of related nutritional deficiencies, for example, iron deficiency anemia in Celiac disease.

Patients may present with features of the primary disease, for example, jaundice in liver disease and diarrhea of protein-losing enteropathy. Proteinuria may be detected by the performance of urine dipsticks.

Liver disorder symptoms:

• Yellowing of eyes or skin (jaundice)
• Weakness, fatigue
• Unexplained weight loss
• Loss of appetite
• Abdominal swelling and/or pain
• Dark urine, light-colored stool
• Itching (pruritus)

Nephrotic syndrome symptoms:

• Swelling or puffiness, particularly around the eyes or in the face, wrists, abdomen, thighs or ankles
• Urine that is foamy, bloody, or coffee-colored
• A decrease in the amount of urine
• Problems urinating, such as a burning feeling or abnormal discharge during urination, or a change in the frequency of urination, especially at night
• Mid-back pain (flank), below the ribs, near where the kidneys are located
• High blood pressure (hypertension)

Hypoalbuminemia is often a finding on routine laboratory testing following the presentation of patients for other primary medical conditions or diseases.

Hypoalbuminemia complications

Complications of significant hypoalbuminemia include circulatory collapse due to the effect on oncotic pressure, the presence of edema, and anasarca and are associated with risk for other complications in the critically ill.

Hypoalbuminemia diagnosis

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.

Measurement of serum albumin using routine assays on automated chemistry analyzers is a quick and simple method of determining the presence of hypoalbuminemia. Assays are based on the color change that occurs when albumin binds to a particular dye that is measured spectrophotometrically. Other methods used to measure albumin include immunonephelometric and immunoturbidometric techniques.

Serum protein electrophoresis results help to determine if hypergammaglobulinemia is present. Decreased albumin levels may be an incidental finding on protein electrophoresis; however, protein electrophoresis provides a semi-quantitative albumin value. The main value of protein electrophoresis in a patient with low serum albumin is with the differential diagnosis of hypoalbuminemia. In the presence of acute inflammation, hypoalbuminemia will be present with an increase in alpha-1 and 2 globulins and normal gamma globulins. In chronic inflammation, the protein electrophoresis pattern will show hypoalbuminemia with a polyclonal increase in gamma globulins.

In the presence of nephrotic syndrome, hypoalbuminemia with an increase in alpha-2 globulins, due to increased macroglobulin, and low gamma globulins are the typical pattern on serum protein electrophoresis.

With chronic liver disease, hypoalbuminemia with increase gamma globulins and beta-gamma bridging is typical.

Further evaluations are targeted at determining the cause of hypoalbuminemia and monitoring disease. These include liver function tests to determine a presence of liver disease, urine albumin, protein measurement to evaluate urine protein loss, and brain natriuretic peptide for evaluation of heart failure as well as radiological imaging.

Specific tests include alpha-1 antitrypsin clearance for the determination of protein loss via gut distal to the pylorus. This involves a timed collection of stool together with a serum sample. Alpha-1-antitrypsin is resistant to degradation by digestive enzymes. It is used as an endogenous marker for the presence of blood proteins in the intestinal tract. Elevated alpha-1-antitrypsin (A1A) clearance suggests excessive gastrointestinal protein loss ⁹.

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).

Imaging studies

Imaging studies can be performed for the following:

• 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

Procedures can be performed for the following:

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

Hypoalbuminemia treatment

Treatment is directed at the cause of the hypoalbuminemia since it is a consequence of some disease. In the critically ill, in particular, burn patients, albumin infusions may be given. It is controversial whether albumin infusions are of clinical benefit to other groups of critically ill patients. It also has some value in patients with cirrhosis with certain complications.

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.

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.

Hypoalbuminemia prognosis

Hypoalbuminemia is an important predictor of morbidity and mortality. The presence of hypoalbuminemia is used as a prognosticator for morbidity and mortality in hospitalized patients, in particular in the critical care setting ¹⁰. 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 ¹¹ and regional enteritis (Crohn disease) and has recently been associated with an increased risk of reintubation ¹².

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.

References

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