Download It is synthesized by the liver

Plasma Proteins
Over 300 proteins have been detected in plasma .
The concentration of many of these are affected by
pathological processes; they are therefore measured.
They contain disulphide bonds.
Functions of plasma proteins include:
•Transport
•Maintaining plasma oncotic pressure
•Buffering pH changes
•Humoral immunity
•Enzyme activity
•Clotting
•The acute inflammatory response.
 Metabolism of Plasma Proteins:
 The concentration of plasma proteins (PP) is determined by 3
main factors:
 Rate of synthesis
 Rate of catabolism
 The volume of fluid in which proteins are distributed.
 A) Synthesis:
 Most plasma proteins are synthesized in the liver, although some
of them are produced in other sites e.g. immunoglobulinss by
lymphocytes.
 B) Distribution:
 In health, the total concentration of proteins in plasma is around
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70 g/L in normal adult males
Water passes more freely through capillary walls than proteins
and therefore the concentration of proteins in the vascular space
is affected by fluid distribution.
Application of a tourniquet for extended periods leads to fluid
loss from the occluded veins; increasing apparently plasma
protein concentrations.
C) Catabolism:
PP are degraded throughout the body.
Most proteins are degraded after being taken up by cells within
the body.
 Assessment of PP:
 2 types of techniques are used:
 Quantitative measurement of individual proteins or groups of proteins
 Semiquantitative assessment of the proportions of different proteins
present in plasma or serum.
 A) Quantitative measurement:
 By chemical methods depending on the reaction of peptide bonds with
a chemical reagent. Individual proteins are usually determined by
methods which use either chemical or immunological reactions.
 B) Semiquantitative assessment:
 Proteins are separated from each other on the basis of their
electrical charge.
 In the technique of electrophoresis , serum is applied to a
support medium, usually cellulose acetate or a gel, and an
electrical current applied. After a suitable period the medium is
stained with a dye that visualizes the proteins. In normal
subjects 5 discrete bands of proteins are seen and altered
patterns occur in various diseases.
 The most important abnormalities detected by electrophoresis
are densely staining bands in the 2- region – these are
paraproteins which result from monoclonal proliferations of B
lymphocytes.
 Specific Plasma Proteins
 Prealbumin
 Prealbumin migrates faster than albumin in the classic E/P.
 It can also be separated by high-resolution E/P or
immunoelectrophoresis techniques.
 Prealbumin is the transport protein for thyroid hormones and it
also binds with retinol-binding protein to form a complex that
transports retinol (vitamin A).
 Prealbumin is decreased in liver disease , nephrotic syndrome,
acute phase inflammatory response and malnutrition.
 It has a short half-life of approximately 2 days.
 Albumin
 Albumin is present in higher concentrations than other
plasma proteins ( approximately 40 g/L in normal adults).
Albumin has a molecular weight of approximately 66000
Daltons. Very small amounts cross the glomerular capillary
wall.
 Albumin is synthesized in the liver and has a half-life of
approximately 20 days . Its synthesis is highly dependant
on the supply of AA and therefore the production rate falls
during periods of protein depletion.
 The rate of catabolism of albumin increases as a result of
injury, infection and surgery.
 Functions:
 The main function of albumin is maintenance of plasma oncotic pressure,
transport and buffering pH changes.
 Oncotic pressure: Albumin is responsible for approx. 80% of the plasma
oncotic pressure. This is a major determinant of the distribution of fluids
between intravascular and extravascular compartments. Hypoalbuminemia
leads to edema.
 Buffering.
 Transport: Many substances are transported in the blood bound to albumin e.g.
lipid-soluble substances, hormones e.g. thyroxine, calcium, drugs e.g.
salicylates, nonesterified fatty acids (NEFA) and bilirubin.
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 Reduced serum albumin levels are common in many conditions.
Hyperalbuminemia is rare and is usually caused by dehydration.
 Causes of Hypoalbuminemia:
 Artefacual : diluted specimens
 Physiological:
 Pregnancy
 Recumbency
 Pathological:
 Decreased production:
 Reduced availability of AA
 Manlnutrition
 Malabsorption
 Defective synthesis:
 Analbuminemia
 Chronic liver diseases
Increased volume of distribution:
Increased plasma water: overhydration
Redistribution of Albumin:
Liver cirrhosis due to ascites
Increased Loss:
From the Kidney: Nephrotic syndrome
From GIT: Protein losing enterpathies
Incresed Catabolismm:
Surgery
Trauma
Infection
 1-Antitrypsin:
 It is synthesized by the liver and macrophages
 It inhibits proteases
 Proteases arise from several sources including endogenous
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production, leukocytes and bacteria.
Digestive enzymes such as trypsin and chymotrypsin are
released into the circulation in small amounts and other
endogenous proteases include elastase and thrombin.
Infection leads to protease release from bacteria and from
leucocytes
Deficiency of 1-Antitrypsin occurs as an inherited
condition.
It may be detected by noting the absence of an 1 band on
protein E/P or by measuring the protein specifically.
 Genetic Polymorphisms of 1-Antitrypsin
 Several variants of 1-Antitrypsin occur, the phenotypes
being designed by the prefix Pi (Protease inhibitor) and
over 30 alleles have been described, these being designed
by a letter. The most common type is M.
 Deficiency of 1-Antitrypsin is most commonly found in
the PiZZ phenotype.
 Synthesis of the defective 1-Antitrypsin occurs in the liver
but there is a failure to secrete the protein , So it
accumulates in hepatocytes and is deficient in plasma.
 Clinical Consequences of 1-Antitrypsin
deficiency:
 Neonatal hepatitis with evidence of cholestasis, childhood cirrhosis and
emphysema in young adults result from 1-Antitrypsin deficiency.
 1-Fetoprotein: (AFT)
 Is synthesized in the developing embryo and fetus and then by the
parenchymal cells of the liver . AFT levels decreases gradually after birth,
reaching adult levels by 8-12 months. However , AFT has no known function in
normal adults.
 The physiological function of AFT has not been completely identified but it has
been proposed that the AFT protects the fetus from immunologic attack by the
mother.
 Conditions associated with an elevated maternal AFT
levels include:
 Neural tube defects
 Spina bifida
 Anencephaly
 Low levels of maternal AFT indicates an increased risk for Down
syndrome.
 AFT is a tumor marker for hepatoma.
 1-acid glycoprotein (Orosomucoid):
 This protein is produced by the liver and is an acute phase reactant.
 It is suggested that 1-Acid glycoprotein regulates immune responses.
 Ceruloplasmin:
 Synthesized in the liver
 Its function is not clear.
 Contains over 90% of serum copper – the metal is tightly bound and
does not exchange readily.
 It is an oxidoreductase and this property is important in acute phase
response as it is able to inactivate reactive O2 species (ROS) that
produce tissue damage. It is important for iron absorption from the
intestine.
 Plasma levels are usually low in Wilson’s disease in which copper is
accumulated in the liver leading to cirrhosis , and in the basal ganglia
of the brain leading to choreoathetosis.
 Plasma level of ceruloplasmin are very sensitive to the effects of
estrogens and rise during pregnancy and in response to oral estrogens
 Haptoglobin:
 It is synthesized by the liver
 It binds free hemoglobin to form complexes that
are metabolized in the RES, this has the effect of
limiting Iron losses which may occur as Hb is small
enough to be filtered by the glomerulus.
 Its plasma level decreases during hemolysis and
increases in acute inflammatory conditions (acute
phase reactant).
2-Macroglobulin:
 Synthesized in the liver & macrophages
 It is a protease inhibitor for trypsin, thrombin and plasmin
 It is a carrier for cytokines.
 The plasma level of 2-macroglobulin increases in
nephritic syndrome because its large size aids in its
retention and also due to increased hepatic synthesis
Transferrin:
• The major iron-tansporting protein in the plasma binding up to
2 atoms of iron per molecule of protein
• Normally , 30% saturated with iron.
• Its function is to transport iron from the intestine and between
sites of synthesis and degradation of hemoglobin and other
iron-containing proteins.
• Concentrations are reduced in malnutrition, liver disease,
inflammatory conditions and malignancy.
• Iron deficiency results in increased hepatic synthesis.
• It is a negative acute phase protein
 2 – Microglobulin:
 It is a component of human leukocyte Antigen (HLA).
 Found on the surface of most nucleated cells and present in high
concentration on lymphocytes.
 Because of its small size, it is filtered by the renal glomeruli but most
(>99%) is reabsorbed and catabolized in the proximal tubules.
 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
erythrematosus (SLE).
 It may be used as a tumor marker for leukemia, lymphomas and
multiple myeloma.
 C-Reactive Protein:
 It is so named as it binds to the C polysaccharide of pneumococcal cell walls.
 It is synthesized by liver
 It is important for phagocytosis
 Very large increases in plasma C-reactive protein occur in many inflammatory
conditions and is measured to detect and monitor diseases e.g. rheumatoid
arthritis.
 It is an acute-phase protein
 Fibrinogen:
 Is one of the largest proteins in the plasma.
 Synthesized in the liver.
 On plasma E/P, fibrinogen is seen as a distinct band between the  and
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 globulins.
Its function 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.
It is one of the acute phase reactants.
Its level rises with pregnancy and the use of oral contraceptives.
Decreased values generally reflects extensive coagulation during which
the fibrinogen is consumed.
 Immunoglobulins: (Igs)
 Igs which are antibodies are a heterogeneous group of
plasma proteins produced by B lymphocytes.
 Most are found in the  region on E/P although some occur
in the  & 2 regions.
 Five classes of Igs are recognized (M, A, G, E & D)
 Hypergammaglobulinemia;
 Increases Ig levels may result from stimulation of many clones of
B cells (Polyclonal hypergammaglobulinemia) or monoclonal
proliferation (Paraproteinemia).
 Polyclonal Hypergammaglobulinemia:
 Stimulation of many clones of B cells produce a wide range of
antibodies that appear as diffuse increase in -globulin on E/P.
 Acute and chronic infections , autoimmune diseases and
chronic liver diseases produce this type of response
 Monoclonal
Hypergammaglobulinemia:
 Proliferation of a single B-cell clone produces a single Ig which
appears as a discrete densely stained band (Paraprotein or M
band) on E/P.
 Paraproteins are characteristic of malignant B-cell proliferation.
 Multiple myeloma is the commonest cause of paraproteinemia
 Paraproteinemia is rare in chronic lymphayic leukemia and
lymphomas.
 Acute phase reactants:
 Stresses increases plasma protein as MI, inflammation , malignancy, trauma or
major surgery.
 These proteins are termed acute phase reactants and their synthesis is a part of
body’s response to injury.
 They include;
 1-Antitypsin (1-acid glycoprotein)
 Haptoglobin
 Ceruloplasmin
 Fibrinogen
 C-reactive protein,
 These acute phase reactants are increased within
24 h of injury in response to humoral mediators
(Cytokines – IL-1, IL-6, tumor necrosis factors 
and  , the interferons, and platelet activating
factors) which are produced by tissue
macrophages, monocytes and endothelial cells.
 Functions:
 Binding to polysaccharides in bacterial walls
 Activating complement
 Stimulating phagocytosis
 Humoral effects of IL-1 and IL-6 include increased
production of ACTH and hence cortisol and
inhibition of hepatic synthesis of proteins such as
albumin, prealbumin and transferrin (negative
acute phase proteins)
 The protease inhibitors probably inactivate
enzymes released from lysosomes and minimize
damage that these may cause.