Proteins

Plasma Proteins
Although the proteins in all fluid compartments play a major physiologic
function, the plasma proteins are the most frequently analyzed. More than
500 plasma proteins have been identified. The properties of a few selected
plasma proteins are discussed here.
Prealbumin (Transthyretin)
Prealbumin is decreased in hepatic damage, acute phase inflammatory
response, and tissue necrosis. A low prealbumin level is also a sensitive
marker of poor protein nutritional status. When dietary intake of proteincalories is deficient, hepatic synthesis of proteins is reduced and
catabolism increases. This results in a decrease in the level of the proteins
originating in the liver, including prealbumin, albumin, and globulins
such as transferrin and complement C3. Prealbumin, because of its short
half-life of approximately 2 days, will decrease more rapidly than the other
proteins. Prealbumin is increased in patients receiving steroids, in
alcoholism, and in chronic renal failure.
Albumin
Decreased concentrations of serum albumin may be caused by the
following:
An inadequate source of amino acids, which is seen in malnutrition and
muscle-wasting diseases.
Liver disease, resulting in the inability of hepatocytes to synthesize
albumin. The increase in globulins that occurs in early cirrhosis,
however, will balance the loss in albumin to give a total protein
concentration within acceptable limits. The decline in serum albumin
is insignificant in viral hepatitis.
Gastrointestinal loss as interstitial fluid leaks out in inflammation
and disease of the intestinal mucosa.

Increased serum albumin levels are seen in dehydration. This increase is

a relative increase, because the albumin is contained in a reduced volume
of serum. Administering fluids to treat the dehydration will decrease
serum albumin levels back to normal.

Globulins
1-Antitrypsin.
A deficiency of 1-Antitrypsin is associated with severe, degenerative,
emphysematous pulmonary disease. The lung disease is attributed to the
unchecked proteolytic activity of proteases from leukocytes in the lung
during periods of inflammation. Juvenile hepatic cirrhosis is also a
correlative disease in 1-Antitrypsin deficiency The protein is synthesized
but not released from the hepatocyte.
1-Fetoprotein.
Conditions associated with an elevated AFP level include spina bifida and
neural tube defects, atresia of the gastrointestinal tract, and fetal distress
in general. Its use in determining neural tube defects before term is an
important reason for its assay. It is also increased in ataxia-telangiectasia,
tyrosinosis, and hemolytic disease of the newborn. It is interesting that
maternal serum AFP is also increased in the presence of twins. Low levels of
maternal AFP indicate an increased risk for Down's syndrome and trisomy.
The normal time for screening is between 15 and 20 weeks gestational
age. The maternal AFP increases gradually during this period; therefore,
interpretation requires accurate dating of the pregnancy. Maternal AFP levels
are also affected by maternal weight, which reflects blood volume (inverse
relationship), race (10% higher in African Americans), and diabetes
(lowered value); therefore, test results need to be adjusted for these variables.
It has been found that reporting AFP in multiples of the median (MoM)
leads to good correlation with infant risk. MoM is calculated by dividing
the patient's AFP value by the median reference value for that gestational
age. Most screening programs use 2.0 MoM as the upper limit and 0.5
MoM as the lower limit for maternal serum AFP.
Serum levels of AFP can also be used as a tumor marker. High
concentrations of AFP are found in many cases of hepatocellular carcinoma
(approximately 80%) and certain gonadal tumors in .
1-Acid Glycoprotein (Orosomucoid).
Increased concentration of this protein is the major cause of an increased
glycoprotein level in the serum during inflammation. It is also increased

in cancer, pneumonia, rheumatoid arthritis, and other conditions associated

with cell proliferation.
1-Antichymotrypsin.
Elevations are seen in inflammation, and it appears that the complex
formed between plasma 1-ACT and its target enzymes plays a major role
in signaling acute phase protein synthesis in response to injury
Hereditary deficiency of 1-ACT is associated with asthma and liver
disease.
Inter- 1-trypsin Inhibitor.
Elevations are seen in inflammatory disorders.
Gc-globulin (Group-Specific Component; Vitamin D-Binding
Protein).
Elevations of Gc-globulin are seen in the third trimester of pregnancy and
in patients taking estrogen oral contraceptives. Severe liver disease and
protein-losing syndromes are associated with low levels.
Haptoglobin.
Serum haptoglobin concentration is increased in inflammatory
conditions. It is one of the proteins used to evaluate the rheumatic
diseases. Increases are also seen in conditions such as burns and
nephrotic syndrome when large amounts of fluid and lower-molecularweight proteins have been lost. Determination of a decreased free
haptoglobin level (or haptoglobin-binding capacity) has been used to
evaluate the degree of intravascular hemolysis that has occurred in
transfusion reactions or hemolytic disease of the newborn. Mechanical
breakdown of red cells during athletic trauma may result in a temporary
lowering of haptoglobin levels.
Haptoglobin phenotype has also been reported as an independent risk
factor for cardiovascular disease (CVD) in individuals with type 2 diabetes
mellitus. Haptoglobin 2-2 phenotype is associated with a 5.0 times greater
risk as compared with phenotype 1-1. Haptoglobin phenotype 2-1 is
reported to carry an intermediate risk of developing CVD in the patient with
diabetes.

Ceruloplasmin.
Low concentrations of ceruloplasmin at birth gradually increase to adult
levels and slowly continue to rise with age. Adult females have higher
concentrations than males and pregnancy, inflammatory processes,
malignancies, oral estrogen, and contraceptives cause an increased serum
concentration.
Certain diseases or disorders are associated with low serum
concentrations. In Wilson's disease (hepatolenticular degeneration), an
autosomal recessive inherited disease, the levels are typically low (0.1
g/L). Total serum copper is decreased, but the direct reacting fraction is elevated and the urinary excretion of copper is increased. The copper is
deposited in the skin, liver, and brain, resulting in hepatic cirrhosis and
neurologic damage. Copper also deposits in the cornea, producing the
characteristic Kayser-Fleischer rings. Low ceruloplasmin is also seen in
malnutrition; malabsorption; severe liver disease; nephrotic syndrome; and
Menkes syndrome (kinky hair disease), in which a decreased absorption of
copper results in a decrease in ceruloplasmin.
2 Macroglobulin.
In nephrosis, the levels of serum 2-macroglobulin may increase as
much as 10 times because its large size aids in its retention. The protein is
also increased in diabetes and liver disease. Use of contraceptive
medications and pregnancy increase the serum levels by 20%.
Transferrin (Siderophilin).
The most common form of anemia is iron deficiency anemia, a
hypochromic, microcytic anemia. In this type of anemia, transferrin in
serum is normal or increased. A decreased transferrin level generally reflects
an overall decrease in synthesis of protein, such as seen in liver disease or
malnutrition, or it may be seen in protein-losing disorders such as
nephrotic syndrome. Transferrin, a negative acute phase protein, is also
decreased in inflammation. A deficiency of plasma transferrin may result in
the accumulation of iron in apoferritin or in histiocytes or it may precipitate
in tissue as hemosiderin. Patients with hereditary transferrin deficiencies
have been shown to have significant hypochromic anemia. An increase of
iron bound to transferrin is found in a hereditary disorder of iron
metabolism, hemochromatosis, in which excess iron is deposited in the
tissue, especially the liver and the pancreas. This disorder is associated with
bronze skin, cirrhosis, diabetes mellitus, and low plasma transferrin levels.

Hemopexin.
Increased concentrations are also found in diabetes mellitus, Duchennetype muscular dystrophy, and some malignancies, especially melanomas. In
hemolytic disorders, serum hemopexin concentrations decrease. Administration of diphenylhydantoin also results in decreased concentrations.
2-Microglobulin.
Elevated serum levels are the result of impaired clearance by the kidney or
overproduction of the protein that occurs in a number of inflammatory
diseases, such as rheumatoid arthritis and systemic lupus erythematosus.
In patients with human immunodeficiency virus, a high B2M level in the
absence of renal failure indicates a large lymphocyte turnover rate, which
suggests the virus is killing lymphocytes. B 2 M may sometimes be seen
on HRE but, because of its low concentration, it is usually measured by
immunoassay.
Fibrinogen.
Fibrinogen is one of the largest proteins in blood plasma. It is
synthesized in the liver, and it is classified as a glycoprotein because it
has considerable carbohydrate content. On plasma electrophoresis, fibrinogen is seen as a distinct band between the - and gamma globulins.
The function of fibrinogen is to form a fibrin clot when activated by
thrombin; therefore, fibrinogen is virtually all removed in the clotting
process and is not seen in serum.
Fibrinogen customarily has been determined as clottable protein.
Fibrinogen concentration is proportional to the time required to fort a
clot after the addition of thrombin to citrated plasma. Fibrin split products
(degradation products of fibrinogen and fibrin) are determined by
immunoassay methods such as radial immunodiffusion, nephelometry,
and radioimmunoassay
Fibrinogen is one of the acute-phase reactants, a term that refers to
proteins that are significantly increased in plasma during the acute
phase of the inflammatory process. Fibrinogen levels also rise with
pregnancy and the use of birth control pills. Decreased values generally
reflect extensive coagulation, during which the fibrinogen is consumed.

C-Reactive Protein.
C-Reactive protein (CRP) is synthesized in the liver and appears in the
blood of patients with diverse inflammatory diseases. CRP was so named
because it precipitates with the C substance, a polysaccharide of pneumococci. However, it was found that CRP rises sharply whenever there is
tissue necrosis, whether the damage originates from a pneumococcal
infection or some other source. This led to the discovery that CRP
recognizes and binds to molecular groups found on a wide variety of
bacteria and fungi. CRP bound to bacteria promotes the binding of
complement, which facilitates their uptake by phagocytes. This process of
protein coating to enhance phagocytosis is known as opsonization.
CRP is one of the first acute phase proteins to rise in response to
inflammatory disease. It is significantly elevated in acute rheumatic fever,
bacterial infections, myocardial infarcts, rheumatoid arthritis,
carcinomatosis, gout, and viral infections. CRP has also been recognized
as an independent risk factor in cardiovascular disease based on the
findings that atherothrombosis, in addition to being a disease of lipid
accumulation, also represents a chronic inflammatory process. Using the
hsCRP assay, levels of <1, 1-3, and >3 mg/L correspond to low-,
moderate- and high-risk groups for future cardiovascular events. Elevated
levels of CRP stimulate the production of tissue factor that initiates
coagulation, activates complement, and binds to LDL in the atherosclerotic
plaque; evidence that points to a causal relationship between CRP levels
and cardiovascular disease. Furthermore, interventions such as weight loss,
diet, exercise, and smoking cessation and administration of
pharmacologic agents such as statins all lead to both reduced CRP levels
and reduced vascular risk .

Immunoglobulins (Igs).
When a foreign substance (antigen) is injected into an animal (e.g.,
rabbit or goat), an antibody that will react with that antigen is
synthesized. This reaction is relatively specific; that is, the antibodies will
react specifically and selectively with the antigen used to raise them.
Proteins and polysaccharides are strong antigens. Antibodies can be raised
in rabbits and other animals to the human immunoglobulins as well as the
other serum proteins. These rabbit antihuman immunoglobulin antibodies
are used to detect and to quantitatively assay IgG, IgA, IgM, IgD, and IgE.

A molecule of immunoglobulin derived from the proliferation of one plasma

cell (clone) is called a monoclonal immunoglobulin or paraprotein. A
marked increase in such a monoclonal Ig is found in the serum of patients
who have plasma cell malignancy (myeloma). Monoclonal increases are
seen on electrophoretic patterns as spikes. Although these
immunoglobulins are typically in the or fractions, on occasion, one
may appear in the 2 area.
IgG is increased in liver disease, infections, and collagen disease. A
decrease in IgG is associated with an increased susceptibility to infections
and monoclonal gammopathy of one of the other idiotypes.
IgA is the idiotypic immunoglobulin present in the respiratory and
gastrointestinal mucosa. IgA in fluids other than serum has an
additional secretory peptide, called a J piece. This piece enables the IgA to
appear in secretions. Polyclonal increases in the serum IgA (without the J
piece) are found in liver disease, infections, and autoimmune diseases.
Decreased serum concentrations are found in depressed protein synthesis,
ataxia-telangiectasia, and hereditary immunodeficiency disorders.
IgM is the first antibody that appears in response to antigenic
stimulation. IgM also is the type of antibody that acts as anti-A and antiB antibody to red cell antigens, rheumatoid factors, and heterophile
antibodies. Increased IgM concentration is found in toxoplasmosis, cytomegalovirus, rubella, herpes, syphilis, and various bacterial and fungal
diseases. A monoclonal increase is seen in Waldenstrom's
macroglobulinemia. This increase is seen as a spike in the vicinity of the
late zone of a protein electrophoretic pattern. Decreases are seen in
protein-losing conditions and immunodeficiehcy disorders.
IgD is the immunoglobulin with the fourth highest concentration in
normal serum. Its concentration is increased in infections, liver disease,
and connective-tissue disorders. IgD multiple myeloma also has been
reported with a monoclonal spike in the late zone of the electrophoretic
pattern.
IgE is the idiotypic immunoglobulin associated with allergic and
anaphylactic reactions. Polyclonal increases are seen in allergies,
including asthma and hay fever. Monoclonal increases are seen in IgE
myeloma, a rare disease.