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Tissue necrosis factor-a
TNF-a has a wide range of biological action, and receptors for TNF-a may be found on nearly all cells. Produced primarily by activated macrophages, TNF-a has cytolytic (destructive) and cytostatic (suppressive) effects on tumor cells, and shows chemotactic (responsive) activity towards neutrophils. High levels may be seen in cases of sepsis, autoimmune disease, various infectious diseases, rheumatoid arthritis, inflammatory bowel disease, and transplant rejection.

Elevated levels of TNF-a have also been found in people with high blood pressure,31 and together with IL-6 may be associated with risk of heart disease.32 In a study by Verdeccia et al, levels of TNF-a were measured in persons with or without high blood pressure to ascertain if arterial flow-mediated dilation was affected by hypertension and chronic inflammation. Investigators found that regardless of whether blood pressure was controlled with antihypertensive medication, arterial flow-mediated dilation was significantly impaired in the hypertensive group. This group also showed higher levels of TNF-a, indicating persistent inflammation despite controlling blood pressure. This study showed that even when blood pressure is under control, hypertensives still suffer from continuous damage (endothelial dysfunction) to the inner lining of the arterial wall caused by a chronic inflammatory insult. These findings indicate that hypertensives should have their blood tested for TNF-a to assess how much inner wall (endothelial) arterial damage is occurring. If the level of TNF-a is high, aggressive therapies to suppress the inflammatory cascade should be considered.

Interleukin-1(b)
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 cardio CRP) predicted a step-wise increase in the risk of death or myocardial infarction.33

IL-1b is one of the key mediators 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

Interleukin-6
Produced by osteoblasts,35 IL-6 stimulates mature osteoclasts to break down bone (resorption), which may contribute to osteoporosis. Interleukin-6 is overproduced 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 diabetes Type II, 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 diabetes Type II.21 Pradhan et al followed 27,628 healthy (free of diagnosed diabetes Type II, cardiovascular disease and cancer) women for four years to determine whether elevated blood levels of IL-6 and CRP were associated with development of diabetes Type II. 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 diabetes Type II). 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

Interleukin-8
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 Tests
The tests most often requested by LEF members also include those that may uncover a wide range of conditions over many body functions. A select and important group of these tests is discussed below.

Cardiovascular

Fibrinogen
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.