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A Comprehensive Guide to Preventive Blood Testing

May 2004

By Penny Baron

Interleukin-1 beta
IL-1b levels are often high in individuals with systemic inflammatory disease, and synergism with TNF-a has been frequently reported.28 Triggering of the inflammatory cascade by IL-1b and TNF-a can lead to inflammation, tissue destruction, and loss of function. Elevated IL-1b levels have been associated with release of insulin with subsequent B-islet cell death, loss of lean body mass, and insulin resistance.

A study by Lappe et al showed that increased concentration of IL-1b significantly and independently (of CRP) predicted a step-wise increase in the risk of death or myocardial infarction.33

IL-1b is one of the key med-iators of immunobiological responses to physical stress. A study by Brambilla et al showed that IL-1b concentrations were significantly higher in patients with panic disorder both before and after alprazolam (Xanax®) pharmacotherapy, suggesting that IL-1b levels may be a marker of panic disorder that is not related to current levels of symptomology.34

Produced by osteoblasts,35 IL-6 stimulates mature osteoclasts to break down bone (resorption), which may contribute to osteoporosis. Interleukin-6 is over-produced in the aged, which contributes to autoimmune disease, immune dysfunction, osteoporosis, depressions in healing, breast cancer, B-cell lymphoma, and anemia. IL-6 also regulates the growth and differentiation of various types of malignant tumors, including prostate carcinomas; serum levels of IL-6 are elevated in patients with metastatic prostate cancer.36 IL-6 has been identified as an inflammatory cytokine that is likely to play a major role in Alzheimer’s disease. Elevated IL-6 levels are also associated with increased risk for heart attack and stroke, development of type II diabetes, and as a predictor for increased risk of disability and death.

Elevated IL-6 is associated with an increased risk for heart attack and stroke. A 1999 study found that individuals with high levels of both IL-6 and CRP were 2.6 times more likely to die during the nearly five-year study period than those with low levels of both measurements of inflammation.37

Elevated IL-6, along with C-reactive protein, may be predictive of development of type II diabetes.21 Pradhan et al followed 27,628 healthy (free of diagnosed type II diabetes, cardiovascular disease, and cancer) women for four years to determine whether elevated blood levels of IL-6 and CRP were associated with development of type II diabetes. Investigators found that IL-6 was significantly higher among women who subsequently developed diabetes, and that the highest levels of IL-6 increased risk for diabetes 7.5 times (women in the highest CRP ranges were 15.7 times more likely to develop type II diabetes). After adjusting for other risk factors—body mass index, family history, smoking, alcohol, exercise, and hormone replacement therapy—women with the highest levels of IL-6 were 2.3 times more likely to become diabetic (4.2 times for the highest CRP blood levels). Investigators concluded that their data supported a possible role for inflammation in the diabetes.

Elevated IL-6 levels have also been found to predict risk of death from all causes, independent of other mortality risk factors.37 Harris et al followed 1,293 healthy, elderly people for 4.6 years to determine the association between IL-6, CRP, and mortality. The study found that increased levels of IL-6 were associated with a twofold greater risk of death (and, to a lesser extent, CRP), and that risk increased to 2.6 times when levels of both IL-6 and CRP were elevated.

Studies have shown a link between IL-6 and insulin-like growth factor I (IGF-I), which normally declines with age. Cappola et al found that the combination of elevated IL-6 and decreased IGF-I synergistically confers a high risk for progressive disability and death in older women.38 Ferrucci et al found that elderly persons with the highest circulating levels of IL-6 were 1.76 times more likely to develop mobility-disability and 1.62 times more likely to develop mobility plus ADL (activities of daily living)-disability compared with persons with the lowest levels of IL-6.39

Inflammatory Cytokines Reference Interval (Labcorp®)*
TNF-a 0.0–8.1 pg/ml
IL-6 0.0–12.0 pg/ml
IL-1b 0.0–3.73 pg/ml
IL-8 <32 pg/ml
*Note: Labcorp® is one of the world’s largest blood-testing laboratories.

IL-8 is a chemotactic factor attracting neutrophils, basophils, and T-lymphocytes, and is produced by monocytes, neutrophils, and natural killer cells in response to an inflammatory stimulus. IL-8 also activates degranulation of neutrophils. IL-8 may be elevated in some cancer patients, inducing expression of growth factors that further propagate cancer cell growth. Elevated levels have also been seen in patients with hepatitis C, inferring resistance to interferon therapy.

Additional Cardiovascular Tests

Fibrinogen, a protein synthesized in the liver, is an important component in the normal process of blood clotting. As part of the coagulation cascade, fibrinogen is converted to fibrin and, along with platelets, helps to form a stable fibrin clot.

Fibrinogen is also an acute-phase protein reactant, meaning that it increases in response to disease processes involving tissue inflammation or damage. As discussed in the C-reactive protein section, development of atherosclerosis and heart disease are products of inflammatory processes. As such, fibrinogen, which is a measure of inflammation, can help predict risk of heart disease and stroke, and can complement tests for serum cholesterol, cholesterol lipoproteins, lipids, C-reactive protein, and inflammatory cytokines.

High fibrinogen levels may indicate a risk of heart disease. Levels are also increased in other inflammatory disorders, in pregnancy, and in women taking oral contraceptives. Decreased levels are seen in patients with hereditary afibrinogenemia, intravascular coagulation, primary and secondary fibrinolysis, and liver disease. An increase in dietary fish oils may result in decreased fibrinogen levels,40 which has important implications for patients at risk for heart disease and stroke.

Factor VIII
Factor VIII, which is also known as antihemophiliac factor (AHF) or fibrin stabilizing factor, is a plasma coagulation protein, and is a critical cofactor in the clotting process.

Data from clinical trials have shown that persons with high levels of factor VIII are at increased risk of cardiovascular disease41 and recurrent venous thromboembolism.42 Furthermore, high levels of factor VIII were determined to be the cause, rather than a consequence, of venous thromboembolism.43

Other recent investigations support the hypothesis that there is a physiological basis to the geriatric syndrome of frailty, which is characterized as a wasting syndrome and physiological state of vulnerability to increased morbidity and mortality. Data show a significant increase in markers of inflammation (factor VIII, fibrinogen, and CRP) in the presence or absence of two prevalent chronic diseases: diabetes and cardiovascular disease. Investigators surmise that these specific physiological abnormalities “may make frail older adults more vulnerable to disease processes, functional decline, and mortality.”44

BNP (brain natriuretic peptide)
BNP is released at continuously low levels by the heart, though the rate of release may be increased by various physiological and neuroendocrine factors that regulate cardiac function. Increased levels of BNP have been associated with hypertension, congestive heart failure (CHF),45 HIV-related cardiomyopathy,46 and atherosclerosis, and is a powerful predictor of left ventricular function and prognosis.47,48

Measurement of BNP involves a relatively simple, inexpensive blood test that is able to diagnose CHF in 15 minutes. CHF is the fourth leading cause of hospitalization in the US, and the leading cause of hospitalization among people over age 65. Its diagnosis is sometimes difficult, with symptoms such as shortness of breath and edema (fluid retention) that are diagnostic of several conditions, and physical examinations prone to error. Although markers such as cytokines and catecholamines (stress hormones) are elevated in CHF, they are hard to measure quickly and often are not elevated until the disease becomes severe.

In a study of 250 patients with shortness of breath who were admitted to urgent care and emergency rooms, BNP measurements of 80 pg/ml were 95% accurate in diagnosing CHF, and lower values were 98% accurate in ruling out the condition. Furthermore, urgent care physicians missed 30 cases of CHF diagnosed by the cardiologists; a BNP test could have brought this figure down to one.49 One of this study’s co-authors remarked that the test has greater diagnostic accuracy than the PSA for prostate cancer, the mammogram for breast cancer, or a PAP smear for cervical cancer. Given that one study estimated that up to 20% of all CHF cases are misdiagnosed, the new test will enable urgent care physicians to provide a more rapid, accurate diagnosis for this group of patients.50

Millions of people worldwide with elevated blood glucose levels/type II diabetes are taking either Avandia® or Actos® (thiazolidinediones) to control hyperglycemia. Patients with type II diabetes are at increased risk of developing or exacerbating CHF, and treatment with thiazolidinediones such as Avandia® or Actos® further increases the risk.51,52

Until very recently, no way existed to identify those most likely to suffer from this devastating side effect. In a recent study, however, data showed that BNP levels were a good marker of left ventricular dysfunction (LVD)/CHF induced by pioglitazone (Actos®). The investigators concluded that type II diabetes patients treated with pioglitazone (Actos®) who had elevated BNP levels prior to the start of treatment should be carefully monitored using regular BNP testing to avoid the adverse effects of CHF.53

Dietary Tests

The selenium test is used to monitor occupational exposure to selenium and detect deficiencies in the serum.

An essential trace mineral, selenium is necessary for normal functioning of the immune system and thyroid gland, and helps protect cells against free radicals that can damage cells, contribute to chronic diseases, and promote cancers. The amount of selenium contained in plant foods is determined by soil content (e.g., high in the Dakotas, very low in some parts of China and Russia). Brazil nuts, walnuts, and bread (in the US) are high in selenium, as is meat from animals that eat grains or plants grown in selenium-rich soils. The current RDA is 55 mcg for men and women, 60 mcg for pregnant women, and 70 mcg for women who are lactating. One ounce of brazil nuts supplies 840 mcg of selenium.

Selenium deficiency, common in areas with selenium-deficient soil, may lead to Keshan disease (enlarged heart and poor heart function). Low levels are also seen in patients on TPN (total parenteral nutrition) and patients with malabsorption problems (severe gastrointestinal disorders). Deficiencies can also affect thyroid function.

Studies indicated that the incidence of death from cancers (lung, colorectal, and prostate) is lower among people with higher blood levels of selenium.54-60 Furthermore, areas of the US with selenium-deficient soils have higher rates of nonmelanoma skin cancer.61

Low levels of selenium may also be associated with an increased risk of heart disease, rheumatoid arthritis, and HIV/AIDS.

Selenium levels should be tested in anyone who suspects occupational exposure (toxic levels) and monitored in those living in areas of selenium-deficient soil, as well as anyone with risk of (or who already has) heart disease, cancer, or arthritis.