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Impressum

1.8.8 Inflammation and Blood Proteins

If you have inflammation in a part of your body then extra protein is often released from the site of inflammation which then circulates in the bloodstream. The CRP and ESR blood tests are commonly used to detect this increase in protein and so are considered 'markers' of inflammation - as a rule, the higher the level, the more 'active' the disease. It must however be remembered that ESR and CRP tests are non-specific. That is they cannot identify the cause or disease process behind any inflammation that may be present.

a) Erythrocyte sedimentation rate (ESR or “sed rate”)

First introduced by Westergren in 1921, but known since at least the time of the ancient Greeks, ESR measures the rate of gravitational settling (in 1 hour) of anti-coagulated red blood cells (RBCs) from a fixed point in a calibrated tube of a defined length and diameter held in an upright position. Erythrocytes normally have net negative charges and therefore repel each other. High molecular weight proteins that are positively charged, such as fibrinogen, increase in the acute-phase of (for example) vascular disease, favouring rouleaux formation (the arrangement of red blood cells in uncoagulated blood with their biconcave surfaces in apposition, forming groups that resemble stacks of coins), thereby increasing the ESR.

An ESR that exceeds 100 mm/hour is definitely associated with (predictive value of greater than 95%) infection, malignancy or connective tissue disease (normal levels are <10mm/hr). Rarely does disease remain undiagnosed when the ESR is greatly elevated. However, ESR may not always give a clear indication of disease activity. The ESR value may be affected by a range of factors including: gender, age (of patient and sample), temperature, pregnancy, menstruation, vibrations, certain drugs, smoking, level of plasma proteins, cholesterol, globulins, fibrinogen, and RBC factors such as hematocrit, morphology, and aggregability. Further, inadequate anticoagulation with clotting of the blood sample will consume fibrinogen and may artifactually lower the ESR. Many other factors also lead to a false lowering of ESR and one of the most important to consider in vasculitis conditions is high doses of corticosteroids. However, the presence of an elevated ESR as the only manifestation of a disease process is quite rare and thus an elevated ESR can be highly significant. Alternatively, a low or normal ESR is generally considered to be of little significance. However, some diseases, such as heart failure, polycythaemia, sickle-cell anaemia, and cryoglobulinaemia do lower ESR levels.

Other factors that can increase ESR include: old age, female, pregnancy, anaemia, red blood cell abnormalities (eg; macrycytosis), technical factors (eg; dilutional problems, increased temperature of specimen, or tilted ESR tube), elevated fibrinogen level (infection, inflammation) and malignancy. Factors that can decrease ESR include: extreme leukocytosis, polycythaemia, red blood cell abnormalities (eg; sickle cell anaemia), spherocytosis (eg; acanthocytosis and microcytosis), technical factors (eg; dilutional problems, inadequate mixing, clotting of blood sample, short ESR tube, or vibration during testing) and protein abnormalities (eg; hypofibrinogenaemia, hypogammaglobulinaemia, or dysproteinaemia with hyperviscosity state).

With the development of more specific methods of evaluation, ESR remains a traditional diagnostic factor only in a few conditions including temporal arteritis, polymyalgia rheumatica and, possibly, rheumatoid arthritis. It is useful in monitoring these conditions and may predict relapse in patients with Hodgkin's disease. However, use of the ESR as a screening test to identify patients who have serious disease is not supported by the literature (1).

Erythrocyte sedimentation rate (ESR) may then possibly be used as a non-specific gauge of therapeutic efficacy and as a monitoring tool in several inflammatory conditions, but clinical presentation, comprehensive history, laboratory investigation, and other diagnostic procedures should always be considered when interpreting ESR results, especially where patients are prescribed high doses of corticosteroids, as is so often the case with the vasculitides. Therefore ESR should not be used as the sole rationale for maintaining or increasing corticosteroid therapy if the patient is doing well clinically.

In contrast to ESR, CRP is independent of any physical properties and quicker to perform. Usually then an ESR is done in conjunction with CRP. CRP is however a more expensive test.

b) C-Reactive Protein (CRP) analysis (see also 1.8.14 Cardiac Risk Factors)

CRP analysis is used to measure levels of CRP, a type of protein produced in the liver in response to inflammation within the body. CRP is sometimes called an “acute phase protein”. This means that the level of CRP increases when you have certain diseases which cause inflammation (eg; certain infections - mainly bacterial, abscesses, certain types of arthritis, various other muscular and connective tissue disorders, tissue injury and burns, cancers, Crohn's disease, rejection of an organ transplant and vasculitis conditions). Normally CRP should be negative in the bloodstream.

Traditionally CRP has been used to assess inflammation in response to infection, however CRP is also useful in predicting vascular disease, heart attack or stroke. The best treatment for a high C reactive protein level has not yet been defined, however statin drugs, niacin, weight loss, quitting smoking and exercise all appear to improve high C Reactive Protein levels.

Both ESR and CRP are indicative of how much inflammation is involved. However CRP, in contrast to ESR, is independent of any physical properties and quicker to perform. It appears and then disappears sooner than changes in the ESR. This may be important to know when treating a serious infection or a severe flare up of an inflammatory condition. For example, if the CRP level does not fall, it may indicate that the treatment is not working and may prompt a doctor to switch to a different treatment. Alternatively, the CRP level may fall to normal if you have been treated successfully, such as for a flare-up of arthritis or a vasculitis condition, but your ESR may still be abnormal for a while longer. Unfortunately however CRP assessment is a more expensive test.

c) Other proteins

Proteins are made from amino acids and are important constituents of all cells and tissues. There are many different kinds of proteins in the body with many different functions, for example, enzymes, some hormones, haemoglobin (oxygen transport), LDL (cholesterol transport), fibrinogen (blood clotting), collagen (structure of bone and cartilage), and immunoglobulins (antibodies).

Serum proteins are grossly separated into albumin and globulins. In other words, total serum protein = albumin + globulin. Thus albumin and globulin tests measure the amount and type of protein in your blood. They are a general index of overall health and nutrition. The A/G ratio is the albumin (A) laboratory value divided by the globulin (G) value. A low A/G ratio can indicate infection, inflammation, or problems with the liver or kidneys.

Drugs that can affect the measurement of serum proteins include chlorpromazine, corticosteroids, isoniazid, neomycin, phenacemide, salicylates, sulphonamides, and tolbutamide.

i) Albumin is the most prevalent protein in the blood plasma and this test measures the amount of albumin in serum, the clear fluid portion of blood. This helps in determining if a patient has liver disease, kidney disease or if not enough protein is being absorbed by the body.

Albumin transports many small molecules in the blood (for example, bilirubin, calcium, progesterone, and drugs). It is also of prime importance in maintaining the oncotic pressure of the blood (that is, keeping the fluid from leaking out into the tissues). This is because, unlike small molecules such as sodium and chloride, the concentration of albumin in the blood is much greater than it is in the extracellular fluid. If albumin gets very low swelling can occur in the ankles (oedema) and fluid can begin to accumulate in the abdomen (ascites) and in the lungs (pulmonary oedema).

Because albumin is synthesized by the liver, decreased serum albumin may result from liver disease (a diseased liver produces insufficient albumin). It can also result from kidney disease (diseased kidneys sometimes lose large amounts of albumin into the urine faster than the liver can produce it - this is termed nephrotic syndrome). Decreased albumin may also be explained by malnutrition or a low protein diet (in malnutrition or a low protein diet there is not enough protein in the patient's diet for the liver to make new albumin from). People who do not eat meat (in particular red meat) may be prone to low albumin levels (and also low Hgb and Hct levels – see above).

Generally, lower-than-normal levels of albumin may indicate: ascites, burns (extensive), glomerulonephritis, liver disease (for example, hepatitis, cirrhosis, or hepatocellular necrosis "tissue death"), malabsorption syndromes (for example, Crohn's disease, sprue, or Whipple's disease), malnutrition and nephrotic syndrome. Albumin will also be decreased during pregnancy (2).

Some drugs affect albumin levels and your health care provider will advise you, if necessary, to discontinue drugs that may affect the test. Drugs that can increase albumin measurements include anabolic steroids, androgens, growth hormone and insulin. Further, if you are receiving large amounts of intravenous fluids, the results of this test may be inaccurate. Albumin levels are also extremely sensitive to the state of hydration of the body. A person that is dehydrated will have an artificially high albumin level.

ii) Globulin is the "antibody" protein, important for fighting disease. Globulins are roughly divided into alpha- beta- and gamma-globulins. These can be separated and quantified in the laboratory by electrophoresis and densitometry (alpha-globulins display the most rapid migration under electrophoresis and gamma-globulins the slowest). At one time, gamma-globulins came to be used as a synonym for immunoglobulins since most immunoglobulins are gamma-globulins. But since the discovery that some immunoglobulins exhibit an alpha- or beta-electrophoretic mobility, that usage is in decline.

The gamma-globulin fraction includes the various types of antibodies (i.e., IgA, IgD, IgE, IgG and IgM). Increased gamma-globulin proteins may indicate: multiple myeloma, chronic inflammatory disease (for example, rheumatoid arthritis and SLE), hyperimmunisation, acute infection and Waldenstrom's macroglobulinemia.

Injections of gamma-globulin are used to create a rapid but temporary immunity (up to 3 months) in patients who have been exposed to certain diseases. Children who have been exposed to, but are not immunized against (for example) hepatitis, measles, rabies, tetanus or varicella, receive some protection from gamma-globulin when it is administered during the incubation period of the infection. The gamma-globulin used for such purposes is extracted from blood plasma from a large, diverse adult population; the resulting admixture is thus likely to contain antibodies from individuals who had been exposed to the appropriate infections (3). It is important to note that this procedure does not replace normal immunisation techniques. Indeed, because gamma-globulin may interfere with development of good protection after measles, mumps, rubella or varicella vaccination, people who have received gamma-globulin should not receive these vaccines for the next three months (4).

Alpha-globulin is a type of globulin in blood plasma that exhibits great colloidal mobility in electrically charged neutral or alkaline solutions. This subgroup of globulins is divided into faster and slower alpha(1)- and alpha(2)-globulins. There are a number of types of alpha-globulin including: alpha 1-Antichymotrypsin, alpha 1-Antitrypsin, alpha-Macroglobulins, Antiplasmin, Antithrombin III, Ceruloplasmin, Haptoglobins, Heparin Cofactor II, Orosomucoid, Progesterone-Binding Globulin, Retinol Binding Proteins and Transcortin.

Beta-globulins include: beta-2 Microglobulin, beta-Thromboglobulin, Haemopexin, Plasminogen, Properdin, Sex Hormone-Binding Globulin, Transferrin and complement factor H.

iii) Other serum proteins include fibronectins, macro-globulins (alpha-Macroglobulins) and transcobalamins (Acyl Carrier Protein, Calcium-Binding Proteins, Calmodulin-Binding Proteins, Ceruloplasmin, Neurophysins, Periplasmic Binding Proteins, Retinol Binding Proteins, Sex Hormone-Binding Globulin, Thyroxine-Binding Proteins, Transcobalamins, Transcortin, Vitamin D-Binding Protein, Follistatin, Transferrin-Binding Proteins, Insulin-Like Growth-Factor-Binding Proteins, RNA-Binding Proteins, Androgen Binding Protein, GTP-Binding Proteins, Membrane Transport Proteins, Phosphate-Binding Proteins, Iron-Binding Proteins, Follistatin-Related Proteins, F-Box Proteins, S-Phase Kinase-Associated Proteins and Light-Harvesting Protein Complexes) (5).

It is beyond the scope of this article to define (outside the glossary) the effects of high or low titres of each of the proteins mentioned above. However the RPNVC does have the eventual goal to provide descriptions of as many of the above as we can. Visitors are advised to check back regularly for updates.

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1.8.9