| 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
Interleukin-6
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
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 Cardiovascular Tests
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.
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
Selenium
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. |