The human body contains countless numbers of different proteins. Literally speaking, the body’s framework and substance is proteins. The number of distinct proteins within one cell is estimated at 3,000-5,000. Not only is the variety of proteins seemingly infinite, but so are their distribution within the body, their functions, their compositions, and their structure.
The proteins are most amenable to routine laboratory evaluation is those in blood, urine, spinal fluid, amniotic fluid, saliva, feces, and peritoneal or pleural fluids. With a few exceptions, proteins found in other fluids were originally contained in the blood plasma. The plasma proteins include the immunoglobulins, enzymes and enzyme inhibitors. Most plasma proteins, with notable exception of immunoglobulins, are synthesized in the liver. Plasma proteins circulate in the blood and between the blood and extracellular tissue spaces. Functional classification of plasma proteins is useful in understanding the changes that occur in disease:
- Proteins of immune defense – Immunoglobulins for elimination of antigen
- Acute phase protein response – Proteins associated with inflammation
- Transport proteins – Proteins used to bind and transport
- Proteins of blood clotting – Proteins involved in forming clots and acting very closely with complement
- Tissue derived proteins – Protein shed into the blood during cell membrane turnover or cell death
- Oncofetal proteins – Proteins produces by tumors and/or during fetal life
Protein Metabolism and Catabolism
Generally, most serum proteins are synthesized (made) in the liver, with the exception of immunoglobulins, which are produced in the lymphatic tissues, primarily in the lymph nodes. Most protein are removed from circulation and catabolized (broken down) by the liver. Up to 15 – 20% proteins are lost in urine, feces and other fluids. Albumin is removed by all cells in the body, which use the amino acids from the catabolism of albumin for the production of other proteins.
Clinical Conditions that Affect Serum Proteins Levels
The following eight general clinical conditions, among others, either caused by physiological changes or induced by certain drugs, will affect serum protein levels:
- Acute inflammation, trauma, and tissue necrosis
The most common cause of disease related changes in serum protein concentration is the acute phase response (APR). APR is a general term that refers to a number of nonspecific changes that occur as a result of any disease processes and persist as long as the disease is active. In addition to changes in serum concentrations, other indications of APR include fever, increase or decrease white blood cell count, and an elevated erythrocyte sedimentation rate (ESR). The APR is seen in inflammation and tissue necrosis due to trauma, surgery, tumors, etc. Acute inflammation is typically caused by bacteria or viral infections.
Several serum proteins are useful in documenting and quantifying the disease process. They can be divided into
- Positive acute phase reactants
- Negative acute phase reactants
Positive acute phase reactants are proteins that increase in concentration in response to disease. Positive acute phase reactants include C-Reactive Protein (CRP), ?1-antitrypsin, ?1-antichymotrypsin, ?1-acidglycoprotein, haptoglobin, C3 and C4.
Negative acute phase reactants are proteins that decrease in concentration in response to disease. Negative acute phase reactants include albumin, prealbumin, and transferrin. Most of negative acute phase reactants have been proposed as markers of malnutrition as well, but decreases are more commonly due to an acute phase response.
- Chronic inflammation
Chronic inflammation may be caused by infection, autoimmune disease, early AIDS, some blood group disorder and other conditions. In chronic inflammatory diseases, there is typically an increase in immunoglobulin concentrations in addition to a persistent acute phase response.
- Protein loss
Protein loss may be divided into
- Selective loss
- Non – selective loss.
Selective protein loss is generally through a semi-permeable membrane or tight intracellular channels. Minimal change nephrotic syndrome, a type of chronic kidney disease, is a classic example of selective protein loss. Proteins are lost in the urine in concentrations inversely proportional to their molecular size. Small proteins pass through the kidney and into the urine in high concentrations, while large proteins pass through the kidneys minimally, if at all. As a result, serum concentration of small proteins decline, while those a larger proteins remain the same or increase.
Non-selective protein loss is due to either whole blood or serum loss, and all serum proteins are lost equally. Whole blood loss may be acute as with trauma, or chronic, as with types of gastrointestinal or uterine bleeding. Non-selective loss of serum proteins also occurs as a result of burns, severe glomerular disease, and many forms of gastrointestinal protein loss.
- Redistribution of body fluids
Most body spaces such as joints and peritoneum contain small amounts of fluid that act as lubricant. These fluids contain low levels of total protein that can increase or decrease in concentration as changes in the amount of fluid occur.
- Hormonal fluctuations
Certain hormones affect the synthesis or catabolism of many serum proteins and changes in protein levels can suggest an underlying condition such as pregnancy or an endocrine tumor. For example, an increase in estrogen levels, either from pregnancy or oral contraceptives, will cause an increase in an ?1-antitrypsin and ceruloplasmin levels and a decrease in ?1-acidglycoprotein and haptoglobin levels.
- In vivo hemolysis
Hemoglobin within red blood cells is composed of two ?-chain and two ?-chain. When red blood cells become hemolyzed, hemoglobin is released and separates quickly into ?, ? dimmers, which complex immediately with haptoglobin. This binding continues until the supply haptoglobin is depleted. The haptoglobin-hemoglobin complexes are then removed within seconds to minutes by the liver. Because of the high affinity between haptoglobin and hemoglobin and the rapid removal of these complexes, haptoglobin levels are a sensitive indicator of hemolysis and are often referred to as a ‘suicidal protein’.
- Iron deficiency anemia
Transferrin is the protein responsible for transporting iron in the body. Low serum iron and ferritin concentrations and elevated transferrin concentrations are nearly diagnostic of iron deficiency anemia. Decreased hemoglobin production results in small and pale RBC’s when examine under the microscope. Total iron binding capacity (TIBC) is often assayed instead of transferrin, and iron ‘saturation’ is expressed as the ratio of actual serum iron to TIBC. However, free iron binds to other proteins, including albumin. Immunochemical assay of transferrin and calculated transferrin iron saturation are much specific. Ferritin is another serum protein associated with iron metabolism, serum levels reflecting total iron stores.
- Drug therapy
Non-steroidal anti-inflammatory agents such as aspirin or ibuprofen can affect the synthesis of acute phase protein concentrations such as prealbumin, haptoglobin, or ?1-acidglycoprotein, even if the underlying disease state is not affected. Reduction of the inflammatory response may result in a return of all acute phase proteins towards normal. Some drugs suppress the immune response and may also depress synthesis of one or all classes of immunoglobulin as well.
Changes in Protein Concentrations Associated with Specific Diseases
Liver Disease
Liver disease can be categorized into hepatocellular disease (often associated with hepatitis or cirrhosis) or biliary obstruction (which often occurs in combination with hepatocellular disease). When liver disease is suspected, the physician may order a liver panel. A suggested liver panel includes the following serum proteins: IgA, IgG, IgM, C3, ?1-antitrypsin, haptoglobin, and albumin.
Urinary Tract Disease
Change in serum or urine protein concentrations associated with urinary tract disease may result from
- Increase loss into the urine
- Decrease reabsorption by the renal tubules
- Local inflammation within the kidney or bladder
- Systemic effects of underlying disease processes, such as infection or autoimmune disease
Polyclonal Hyperimmunoglobulinemia
Polyclonal increases in immunoglobulins (multiple types) are common in most immune responses to infections and in autoimmune disease. Typically all three major immunoglobulin classes are elevated with one or two types predominant in specific diseases:
- IgA : skin, gastrointestinal, respiratory, urinary tract
- IgA and IgG : liver disease
- IgM : blood stream infections
- IgE : asthma and other allergies
- IgG : autoimmune and immune complex diseases
Diseases of the Immune System
Autoimmune disease and immunodeficiency represent the most significant categories of immune-related disorders that affect serum protein concentrations. Autoimmune diseases display varying combinations of acute and chronic inflammation responses although most of these disorders are associated with elevated levels of immonoglobulins, esp. IgG. Diagnosis is ultimately based on the clinical profile of the patient, but specific autoantibody studies such as Rheumatoid Factor (RF) in rheumatoid arthritis can be very helpful in differential diagnosis. Typically, C3 and C4 levels are decreases in autoimmune disease. A suggested autoimmune profile includes the following serum proteins: C3, C4, IgA, IgG, IgM, CRP, and haptoglobin.
Immunodeficiency may be genetic or acquired as the result of disease or therapy (such as immunosuppressive drug following organ transplant). Immunodeficiency seriously compromises the body’s ability to fight against infections agents such as viruses, bacteria, or fungi. As would expect, some or all immunoglobulin levels are severely decreased with most immune deficiency disorder.
Arteriosclerotic Cardiovascular Disease (ASCVD)
Many factor increase susceptibility to arteriosclerotic cardiovascular disease, commonly referred to as hardening of the arteries. However, abnormalities in the lipid transport system of the blood, including the lipoproteins play a major role. Lipoproteins consist of several ‘package’ of lipids including cholesterol, triglyceride, phospholipids and apolipoproteins. Very low density lipoprotein (VLDL) and low density lipoprotein (LDL) contain apolipoprotein B. High density lipoprotein (HDL) contain apolipoprotein A-1. Recent studies have shown that elevated levels of Apo B are predictive of ASCVD and subsequent myocardial infarction, similar to elevated levels of LDL cholesterol or total cholesterol.
Apo A1, in contrast, is associated with HDL and is involved with the removal of cholesterol from cells in the body. Decreased levels of Apo A1 are predictive of ASCVD and subsequent myocardial infarction, similar to low levels of HDL cholesterol. Thus, Apo B and Apo A1 assays can be used in addition to or instead of the more traditional LDL and HDL cholesterol assays to assess risk of developing cardiovascular disease. Concentrations of the apolipoproteins are affected by several other factors, including exercise, inflammation and hormones or drugs.
Protein Energy Malnutrition (PEM)
Protein Energy Malnutrition is associated with inadequate protein intake. Although synthesis of all proteins may be decreased, prealbumin is the protein most commonly used to evaluate protein energy malnutrition because its half-life is relatively short. It must be remembered, however, that low levels are seen with a multitude of other disorders including acute phase responses, which are more common than protein energy malnutrition in developed countries.
Many patients who are being evaluated for possible protein energy malnutrition are on anti inflammatory therapy which significantly increases prealbumin and haptoglobin concentrations. Therefore, caution must be used in interpreting prealbumin concentration, whether low, normal, or elevated. Clinical evaluation should be given as least as much priority as protein assays in determining protein malnutrition status.
Implication of Changes in Some Clinically Important Proteins
|
Specific Protein |
Decreased Levels |
Increased Levels |
|
Apolipoprotein A |
Arteriosclerosis |
Low risk of coronary disease |
|
Apolipoprotein B |
Severe hepatic dysfunction |
Arteriosclerosis, hyperlipidemias |
|
C-reactive Protein (CRP) |
|
Inflammation, acute and chronic tissue destruction, tumors |
|
Complement 3 (C3) |
Autoimmune disease, chronic hepatitis, lupus |
Inflammation disease |
|
Complement 4 (C4) |
Autoimmune disease, chronic hepatitis, lupus, acute gromerular nephritis |
Acute inflammation process |
|
Haptoglobin |
Hemolytic anemia, sickle cell anemia, liver disease |
Acute and chronic inflammation disease |
|
Immunoglobulin A (IgA) |
Immune deficiency states, non-IgA myelomas |
Chronic cirrhosis, chronic liver disease, IgA myeloma |
|
Immunoglobulin G (IgG) |
Immune deficiency states, non-IgA myelomas |
Chronic infection, liver disease, IgG myeloma |
|
Immunoglobulin M (IgM) |
Immune deficiency states, non-IgA myelomas |
Chronic infection, liver disease, Waldenstrom’s macroglobulinemia |
|
Prealbumin |
Malnutrition, liver disease, acute inflammation |
Hodgkin’s disease, corticosteroid therapy |
|
RF |
|
Rheumatoid disease |
|
Transferrin |
Inflammation, chronic hepatitis |
Iron deficiency, acute hepatitis, pregnancy |
| Last Reviewed | : | 03 January 2015 |
| Writer | : | Aslinda bt. Tajudin |
| Accreditor | : | Noor Hafizah bt. Yacob |
