Albumin (Serum Albumin)

Sample

1. It is done on the serum of the patient.
   1. How to get good serum: Take 3 to 5 ml of blood in the disposable syringe or a vacutainer. Keep the syringe for 15 to 30 minutes at 37 °C and then centrifuge for 2 to 4 minutes to get the clear serum.
2. A random sample can be taken.
3. Use a freshly prepared serum or store at 4 °C, which may be stable for more than 72 hours.

Precautions

1. A fasting sample is preferred.
2. Specimens with lipemia or hemolysis should be avoided.
3. Avoid prolonged tourniquet. This may increase albumin and proteins.
4. Take into account physical exercise and fever where there is increased filtration.
5. Blood samples after the I/V therapy may give low value.
6. The drugs which increase the level are anabolic steroids, androgens, corticosteroids, insulin, progesterone, and growth hormone.
7. The drugs that can decrease the level are estrogens, hepatotoxic drugs, and oral contraceptives.

Indications

1. This test is needed:
   1. In liver diseases as a part of a liver panel test.
   2. Kidney diseases and nephrotic syndrome patients.
   3. In patients with a severe burn.
   4. As a part of other tests.
   5. In a patient suspected of malnutrition.
   6. In patients where there is a loss from the intestine.
   7. Patients with cancers, particularly lymphoma and multiple myeloma.
   8. Albumin is estimated in the third trimester of pregnancy, which may decrease the total protein level.

Pathophysiology

1. This is the most abundant protein in the blood.
   1. Around 40% of albumin is present in the plasma and 60% in the extracellular space. Albumin is the abundant protein in the plasma,  constituting 2/3 of total proteins.
2. Plasma proteins are separated into three major groups:
   1. Fibrinogen (4%).
   2. Globulins (38%).
   3. Albumin (58%).
   4. Total serum proteins are a combination of prealbumin, albumin, and globulins.
      

      Albumin and other proteins ratio in plasma

3. Albumin structure:
   1. Albumin is a globular protein with a molecular mass of 66.3 kD.
   2. Albumin consists of one polypeptide chain of 585 amino acids and contains 17 disulfide bonds.
   3. Albumin is an anion at pH 7.4 with >200 negative charges per molecule.
   4. It has no carbohydrate side chains but is highly soluble in water due to its high net negative charge at physiologic pH.
      1. Albumin can not be stored in the parenchymal cells because of a lack of side Carbohydrate chains.
   5. It accounts for approximately half of the plasma proteins.
   6. This is the major protein component of most extravascular body fluid like CSF, urine, amniotic fluid, and interstitial fluid.
      

      Albumin structure

4. The most common method to separate the proteins is electrophoresis. There are 5 bands named:
   1. Albumin. It is roughly 60% of the total serum proteins, and it will migrate farthest towards the anode.
   2. α1 fraction.
   3. α2 fraction.
   4. β fraction.
   5. γ fraction.
      

      Serum Electrophoresis, the pattern of protein and albumin

      Various proteins in the blood, cord blood,  and serum:

      Type of proteins	Cord blood g/dL	Mother’s serum g/dL	Adult values g/dL
      Albumin	3.3	4.2	3.5 to 5.0
      α1-Globulin	0.0	0.3	0.1 to 0.4
      α2-Globulin	0.4	1.2	0.3 to 0.8
      β-Globulin	0.7	1.3	0.6 to 1.1
      γ-Globulin	1.0	1.3	0.5 to 1.7
      Prealbumin			15 to 36 mg/dL

5. Distribution of the albumin:
6. Albumin makes 40% to 60% of the total proteins.
   1. There is a high concentration of albumin in the plasma. Being small molecular size, it is found in most of the extravascular fluids, CSF, amniotic fluid, urine, and interstitial fluid.
   2. CSF protein electrophoresis show albumin around 56% to 76% of the total proteins.
   3. 40% of the albumin is present in the plasma, and the other 60% present in the extracellular space.
   4. Amniotic fluid contains albumin:
      1. Second trimester = 0.4 g/dL
      2. At term = 0.9 g/dL
   5. Around 60% of the albumin is present in the extravascular space.
   6. It is highly water-soluble due to its negative charge at normal pH.
   7. Albumin’s half-life is 15 to 19 days. So the hepatic impairment for the synthesis of albumin may not be detected before this period.
      

      Albumin functions summary

6. It is needed to maintain the osmotic pressure in the blood vessels without which fluids will leak out.
   1. The primary function is the maintenance of Colloidal osmotic pressure maintenance of vascular and extravascular spaces with continuous equilibrium.
   2. It is extremely sensitive to liver damage.
7. Synthesis of albumin:
   1. Albumin synthesis starts from 20 weeks of gestation and continues throughout life.
      1. During the first 20 weeks of fetal life, α-fetoprotein may serve as the albumin’s osmotic equivalent.
      2. The liver produces 12 g of albumin in 24 hours, representing about 25% of the total protein synthesized by the liver.
   2. This protein is synthesized primarily from the hepatocytes of the liver.
   3. It reflects the function of the liver, kidney, or malnutrition.
   4. The liver’s synthetic reserve is enormous, e.g, in nephrotic syndrome, maybe 300% or more of the normal rate.
      

      Albumin properties

   5. The synthetic rate is controlled by:
      1. Colloid osmotic pressure.
      2. Protein intake.
      3. Decreased by the inflammatory cytokines.
   6. The inflammatory cytokines decrease albumin synthesis.
   7. Albumin Concentration in the serum at birth is 39 g/L, then it decreases to 24 g/L at 9 months, again rises to 35 to 55 g/L at adult age, and after the age of 60 years is 38.3 g/L.
      

      Albumin concentration at various age group

   8. A gene codes albumin on the long arm of chromosome 4.
      1. More than 80 genetic variants are reported.
         

         Albumin gene present on chromosome NO: 4 long arm

8. Albumin binds bilirubin, free fatty acids, calcium, and some drugs.
   1. Low albumin results in Edema.
   2. Decreased synthesis in the liver is seen in acute or chronic liver diseases, Amyloidosis, malnutrition, and malignancy.
   3. Its role in transporting bilirubin, bile acids, metal ions, and drugs will be markedly affected by variation in its concentration.
      

      Albumin transport various substances

9. The presence of albumin in the urine indicates kidney disease.
10. Dehydration leads to an increase in albumin levels (Hyperalbuminemia).
11. Mechanism of decrease in the albumin synthesis:
    1. The mechanism for the decrease in the serum albumin may be due to:
    2. Decreased synthesis may be seen in:
       1. Injury to the hepatocytes.
       2. Decreased protein intake, like malnutrition or starvation.
       3. If there is impaired absorption of the protein products like in sprue.
    3. Extensive loss of the albumin seen in:
       1. In nephrotic syndrome, there is extensive loss of protein in the urine.
       2. There is loos of protein in the extensive burns or exfoliative dermatitis.
       3. In protein-losing intestinal diseases (protein-losing enteropathies).
    4. Shifting of the protein in ascites may happen in the liver diseases like cirrhosis.
12. Albumin catabolism:
    1. Albumin is catabolized in various tissues.
    2. It is taken up by the cells as pinocytosis.
    3. Then in the cells, there is proteolysis from the amino acids, and these amino acids go into the body pool(recycle).
       

       Albumin catabolism

13. Albumin functions:
    1. Albumin is essential for regulating water and solutes’ passage through the capillaries because the albumin molecules are large and don’t diffuse freely through the endothelium.
    2. One most important function is to maintain the colloid osmotic pressure of the intravascular fluid. Because of the high concentration, it is responsible for 75 to  80% of osmotic pressure. This will maintain the fluid in the tissues.
    3. Albumin prevents edema.
    4. Albumin provides nutrition to the tissues and binds various molecules like salicylates, fatty acids, magnesium ions, cortisol,  hormones, vitamins, and drugs.
    5. Albumin acts as a carrier protein for bilirubin, calcium, progesterone,  other drugs, hormones, and enzymes.
       1. Drugs that are bound to albumin are sulfonamide, penicillin, aspirin, and dicumarol.
    6. Albumin is an endogenous source of amino acids.
    7. Albumin binds and solubilizes nonpolar compounds such as plasma bilirubin and long-chain fatty acids.
    8. Albumin binds hormones like thyroxine, triiodothyronine, cortisol, and aldosterone.
    9. 40% of the calcium binds the albumin.
    10. Some of the drugs like phenylbutazone, warfarin, salicylates, and clofibrate are bound tightly to albumin.
    11. In low plasma albumin, allow water to move out of the vascular bed and leads to edema.
    12. Albumin has an important role in the endogenous metabolism of calcium, fatty acids, bilirubin, drugs, and hormones.

Albumin/globulin ratio (A/G) normally found = >1.0.

1. 1. A/G ratio <1.0 is usually seen in liver diseases.

Albumin/Creatinine ratio (ACR): It evaluates patients with Diabetes Mellitus and renal function.

1. Diabetic Microalbuminuria is defined when there is the excretion of the albumin in the urine is 20 to 200 µg/min (30 to 300 mg/24 hours of the urine sample).
2. These findings to be found in at least 2 to 3 samples collected within 6 months.
   1. Albumin/creatinine ratio is the first lab test to detect early microalbuminuria on a random urine sample.
   2. It is calculated:
      1. Albumin in mg / creatinine in g.
   3. Albumin excreted in the urine is measured in µg/min (mg/24 hours), which is called Albumin excretion rate (AER).
   4. Microalbuminuria is significant when AER is 20 to 200 µg/min.
   5. Albumin/creatinine ratio >30 mg/g, suggests overnight excretion rate (AER) >30 µg/min.
      1. When 30 to 300 mg of albumin excreted in 24 hours of urine, or albumin/creatinine ratio is >3.4 mg/mmol.
   6. Creatinine in urine is measured in g.

Albumin/creatinine ratio and microalbuminuria:

Clinical parameters	Normal values	Microalbuminuria	Clinical albuminuria
Albumin excretion mg/24 hours	<20 mg/day	30 to 300 mg/day	>300 mg/day
Albumin/creatinine ratio	<30	30 to 300	>300

• Hyperalbuminemia when the albumin level is higher than the normal level.
  1. This is seen in dehydration.
• Analbuminemia is the congenital absence of albumin.
  1. These patients are usually asymptomatic or may see occasional mild edema.
  2. This is a rare autosomal recessive disorder.
  3. Serum electrophoresis shows a complete absence of the albumin band.
     

     Analbuminemia, electrophoresis showing absent albumin band

• Hypoalbuminemia when the albumin level is lower than the normal, this may be due to various factors like:
  1. Impaired syntheses of the albumin from the liver or decreased intake of the proteins.
  2. Increased catabolism due to inflammation or tissue damage.
  3. Due to malabsorption or malnutrition, leading to decreased absorption of the amino acids.
  4. In a condition where there is an increased loss of albumin in the urine like nephrotic syndrome, chronic glomerulonephritis, diabetes mellitus, and SLE.
  5. Protein loss in case of burn or protein-losing-enteropathy.
  6. In the case of ascites, where there is high pressure in the portal system, it drives the albumin into the peritoneal cavity.
  7. When the albumin level is <2.0 g/L, it will lead to edema formation. This usually takes place when the albumin loss is through the urine or feces.
  8. Serum electrophoresis shows a low albumin spike.

Normal values of Albumin

Type of individuals	Normal range
Normal range	3.4 to 5.5 g/dL (35 to 55 g/L)
Male	4.2 to 5.5 g/dL
Female	3.7 to 5.3 g/dL
Cerebrospinal fluid (CSF)	14 to 45 mg/dL
Urine	1 to 14 mg/dL 15 to 45 mg/24 hours
Newborn	2.8 to 4.8 g/dL

• Another source: albumin normal values
  • Recumbent adult = 3.5 to 5.0 g/dL
  • Ambulatory male adult = 4.2 to 5.5 g/dL
  • Ambulatory female adult = 3.7 to 5.3 g/dL
    • It is lower in the last two trimesters of the pregnancy.
  • In the upright position, the level is ∼0.3 g/dL higher because of hemoconcentration.
  • Reference ranges estimated by nephelometry:
    • Newborn 2 to 4 days = 2.8 to 4.4 g/dL
    • Adults = 3.4 to 5.0 g/dL
    • >60 years = 3.4 to 4.8 g/dL

By serum electrophoresis the normal values are:

Fraction of the protein	Normal range	% of the total proteins
Albumin	3.5 to 5.2 g/dL	50 % to 65%
α1-globulin	0.1 to 0.4 g/dL	2% to 6%
α2-globulin	0.5 to 1.0 g/dL	6% to 13%
β-globulin	0.6 to 1.2 g/dL	8% to 15%
γ-globulin	0.6 to 1.6 g/dL	10% to 20%

Albumin level decreases in:

1. The hypoalbuminemia may take place from one of the following mechanisms:
   1. Impaired synthesis.
   2. Increased catabolism.
   3. Protein loss.
   4. Reduced absorption of the amino acids.
   5. Altered distribution of the albumin-like ascites.
      1. Severe hypoalbuminemia is due to the loss of albumin in the urine or feces. The level is below 2 g/L, and edema is usually present.
2. Acute and chronic inflammations:
   1. The cause is hemodilution, loss into extravascular space, increased consumption by the cells, and decreased synthesis.
   2. Rheumatoid arthritis, granulomatous process, most bacterial infections, vasculitis, ulcerative bowel disease, and certain parasitic infestation.
3. Due to decreased synthesis by the liver:
   1. This may be due to the increased amount of immunoglobulins, loss of albumin into the extravascular space.
   2. This may also be due to decreased synthesis because of toxins or alcohol.
   3. The liver can compensate for the synthesis of albumin approximately up to 95% of liver function loss.
      1. In acute and chronic liver diseases, Amyloidosis, Malignancies, Congestive heart disease, and constrictive pericarditis.
4. Urinary loss:
   1. As albumin is relatively small and globular, a significant amount is filtered into the glomerular urine. Then the majority is reabsorbed by the proximal tubular cells.
   2. Normal urine contains 20 mg of albumin per gram of creatinine.
      1. Excretion above this level is seen in:
         1. Increased glomerular filtration.
         2. Tubular damage.
         3. Hematuria.
         4. Or a combination of the above factors.
   3. Examples are:
      1. In  Nephrotic syndrome.
      2. Thermal burns.
      3. Trauma and crush injuries.
      4. Transudation and exudation from any hollow organs.
      5. Increased loss via body fluids.
         

         Mechanism of the nephrotic syndrome

4. Increased catabolism:
   1. 1. leads to decrease albumins like fever, antimetabolites, thyrotoxicosis, and certain malignancies.
5. A gastrointestinal loss:
   1. 1. With the inflammatory disease of GIT.
      2. Chronic protein-losing enteropathy.
6. Increased blood volume (hypervolemia):
   4. 4. This leads to a decrease in albumins like exogenous estrogen therapy, Myeloma, and congestive heart failure.
      5. The serum level decreases in pregnant ladies.
      6. The person on a low protein diet.
   5. It decreases:
      1. After weight loss surgery.
      2. Whipple disease.
      3. Sprue.
      4. Crohn’s disease.
7. Analbuminemia is a rare genetic deficiency where plasma albumin level is <0.5 g/L.
   4. Electrophoresis shows no albumin bands.
   5. Major clinical manifestations are related to abnormal lipid transport. Edema is surprisingly very mild.
8. Summary of decreased albumin:
   1. 1. Inflammations.
      2. Hepatic diseases.
      3. Urinary loss.
      4. Gastrointestinal loss.
      5. Edema and ascites.
      6. Protein malnutrition.

 Albumin level increases in:

1. 1. 1. Naturally, there is no reason for the increase in albumin levels.
      2. Dehydration or any other cause leading to a decrease in the plasma volume causes an increase in the level.
      3. High protein diet.
      4. When the tourniquet is applied for a long time.

Tabulated causes of Hyperalbuminemia and Hypoalbuminemia:

Hypoalbuminemia	Hyperalbuminemia
Nephrotic syndrome	Dehydration
Burns	High protein diet
Blood loss	False value due to prolonged tourniquet
Malignancies
Inflammatory process
Liver diseases
Decreased protein intake
Ascites

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