What is C-Reactive
protein (CRP) is released by the body in response to acute injury, infection,
or other inflammatory stimuli. C-reactive protein is found in trace amounts in healthy people and is a
leading blood marker of systemic (or body-wide) inflammation: People with
elevated CRP levels are four and one-half times more likely to have a heart
attack, compared with people who have normal levels of the protein.
Furthermore, a variety of serious diseases are associated with high blood
levels of CRP.
The activation of the acute phase response from infection, immune
activation or injury is signaled by interleukin-6, which produces proteins such
as fibrinogen, C-reactive protein (CRP), and serum amyloid A that lead to
inflammatory reactions. Localized
inflammatory responses in the inner (“intimal’) layer of the arterial wall have
been shown to be responsible for many of the aspects of intimal thickening and
plaque disruption, leading to acute cardiovascular events.
CRP levels are elevated in many
different diseases and conditions. The list below is only the beginning as more
is learned about CRP.
What are some of the conditions
associated with an elevated CRP?
of Estradiol with or without Progestagens in Post-Menopausal Women:
Hidden Bacterial Infections?
Heart disease: High CRP levels are a better indicator than either total cholesterol, low
density lipoprotein cholesterol, or homocysteine in predicting the risk of a
heart attack, as well as of death in the first month after coronary-artery
bypass surgery. CRP is present in lesions (commonly, but incorrectly referred
to a cholesterol deposits) that form on blood vessel walls, but not in normal
blood vessel walls. CRP is also strongly associated with the rupture of these
lesions, which can lead to dangerous blood vessel clots.
plaques in diseased arteries typically contain inflammatory cells. Rupture of atheromatous plaque is thought to
be the mechanism for acute myocardial infarction and acute coronary syndrome.
Because the most common site of plaque rupture appears to be where inflammatory
cells are most prominent, the release of acute phase reactants as a response to
inflammation has been proposed as a potential marker of an "unstable"
atheromatous plaque and underlying atherosclerosis.
have shown a positive association between CRP and coronary artery disease. In a
survey of 388 British men aged 50-69, the prevalence of coronary artery disease
increased 1.5 fold for each doubling of CRP level (BMJ.
prospective studies have also demonstrated that baseline CRP is a good marker
of future cardiovascular events (J Investig Med. 1998;46:391-395.)
Consequently, CRP may be a good predictor of cardiovascular risk in addition to
cholesterol and other lipid levels.
Relative risk is the ratio of the chance
of a disease developing among members of a population exposed to a factor
compared to a similar population not exposed to the factor)
RELATIVE RISK FOR:
Future MI (heart attack)
RELATIVE RISK FOR:
FUTURE MI or STROKE
Ref: Ridker, et. Al. Circulation
Ridker, et. al. N. Engl J. Med., 1997; 336:973-979
as CRP is to many as a risk factor in coronary artery disease, Rudolf Virchow,
a German pathologist living from 1821-1902, hypothesized that inflammation was
the causative factor in the atherogenic process. Decades later, scientists
confirmed that increased monocytes (white blood cells critical in early plaque
development) and macrophages (mononuclear phagocytic cells capable of
scavenging and ingesting dead tissue and degenerated cells) are present,
particularly at points of plaque rupture. CRP and several other inflammatory
markers may be elevated many years prior to a coronary event.
a study in the January 25, 2003 edition of the journal Circulation, "The
study provides further conclusive evidence that CRP, until now viewed as an
'innocent bystander' in the formation of heart disease, is in fact a key
culprit that causes inflammation in the arteries, resulting in formation of
clots and plaque that lead to heart attacks and strokes," said Ishwarlal
Jialal, professor of pathology and director of the Laboratory for
Atherosclerosis and Metabolic Research at UC Davis School of Medicine and
study demonstrates that CRP causes cells in the arteries, known as human aortic
endothelial cells, to produce higher levels of an enzyme that inhibits the
breakdown of clots. The enzyme, plasminogen activator inhibitor-1 (PAI-1) is
also a strong risk marker for heart disease, especially in diabetics. The study
used a variety of techniques to convincingly show how CRP activates PAI-1 in
aortic cells, causing lesions in the arteries that ultimately lead to formation
of plaque and blood clots.
study underscores the need to use CRP screening to more accurately assess
at-risk populations. "Based on
these findings, if a patient has normal cholesterol but high levels of CRP, an
aggressive course of treatment is recommended to help the patient reduce the
risk of heart attack, stroke and other heart diseases," said Jialal.
"By relying on cholesterol alone, a physician could significantly underestimate
a patient's risk level."
study also closely links CRP and PAI-1 to diabetes and metabolic syndrome, a
disorder characterized by a disproportionate amount of abdominal fat, elevated
blood pressure, blood sugar and triglycerides and low levels of HDL, the
"good" kind of cholesterol.
another important discovery, this study shows that in the presence of high
blood-glucose levels, CRP is especially active in the stimulation of PAI-1. As
a result, the effect of CRP is especially acute for patients with diabetes and
metabolic syndrome," said Sridevi Devaraj, a co-investigator and assistant
professor of pathology at UC Davis. "Given the current pandemic of obesity
which increases one's risk of diabetes, the study's insights about the active
role of CRP and PAI-1 in heart disease are especially valuable."
new study adds to the findings of another landmark study on CRP by Jialal's
team at UC Davis that showed CRP actually damages the blood vessel wall by
blocking a critical "protector" protein and inhibiting nitric oxide.
the new study indicates that activation of PAI-1 was unrelated to the nitric
oxide inhibition identified in the earlier study," said Jialal. "This
indicates that CRP has multiple, independent effects that cause heart disease."
and his colleagues studied 2,037 men aged 45 to 76 with no history of heart
disease in the Quebec Cardiovascular Study. The participants were followed for
five years to see whether there was a relationship between their CRP levels
when they entered the study and their risk of developing heart disease. Over
the course of the period, 105 men developed heart disease. Those cases could have been predicted by the
subjects' baseline CRP levels, analysis showed. "With very subtle changes
in CRP levels, even within the normal range, there's a huge increase in
cardiovascular disease risk," he said.
participants developed the disease late in the study, during years three
through five. Their CRP levels were low at the start, supporting the theory
that there is a short period between elevation of CRP levels and the start of
the disease. "It shows that if you have a high CRP level, something is
going to happen soon," Lamarche said. Archives of Internal Medicine
Zwacka reported in Circulation (2001) that CRP appears able
to bind with LDL cholesterol (a union that increases stickiness and increases
vascular adherence). CRP accomplishes
this by preparing LDL cholesterol for uptake by macrophages and increasing the
formation of foam cells. Macrophages, gorged with fats contained in blood,
become bloated and develop into foam cells. When they have reached their
maximum load, they explode, discharging their fatty contents into the blood
vessel wall at the site of injury. The presence of added fat signals the need
for more macrophages to clean up the mess. They stuff themselves, explode, and
the cycle starts anew. By causing LDL cholesterol to oxidize into a more
reactive, abrasive form, CRP becomes an initiator in this vicious cycle. (Braley,
real question is what is causing the inflammation that leads to the increase in
CRP. In the journal Circulation (2000),
Siscovick at the University of Washington reported that older
people who had the herpes simplex I virus had twice the risk of having a heart
attack or dying from heart disease as those never infected by the virus. The infectious process in heart disease is
mentioned in numerous studies, but the mechanisms are poorly understood. For example, Stefan (2001) and others
completely absolve viruses, i.e., the cytomegalovirus, herpes, and hepatitis B
and C from the infectious process that ends up as arterial disease, believing
only bacterial infections are precursors to heart disease.
appear to gain entry into the heart via immune cells, most likely activated in
the process of clearing infections from the respiratory passages. The bacteria
most suspected of initiating coronary problems are C. pneumoniae, P.
aerogenes, E. endocarditis, S. aureus, E. faecalis, C. albicans, and V. streptococcus. (Some researchers add
H. pylori, a bacteria associated
with duodenal ulcers, peptic ulcers, and chronic gastritis to the list.)
higher white blood cell count, common when the body is fighting off infection,
is associated with an increased coronary risk by diminishing blood flow to the
heart muscle and encouraging blood clot formation. The higher the white blood
cell count, the higher a patient's risk of death from a heart attack or of
developing congestive heart failure.
specimens, from patients who had undergone a carotid endarterectomy, showed
high levels of C. pneumoniae in 11 out of 17 cases. The American Heart Association, also,
reported that C. pneumoniae was found in the infected arteries of autopsied cardiac patients.
(Vink et al., 2001) Dr. Tatu Juvonen, from Oulu University Hospital in Finland, explains that C. pneumoniae is a specific
microbial antigen that causes inflammation and atherosclerotic cells to
human fat cells, particularly those that form around the abdomen (belly), release the pro-inflammatory
cytokine interleukin 6, and interleukin 6 induces low-grade systemic
inflammation, it has been proposed that persons with excess body fat are likely
to have higher levels of CRP. Marjolein
Visser, et al in The Third National Health and Nutrition Examination
Survey (1988 to 1994) studied the blood levels of CRP in 16,616 adult men and
nonpregnant women to determine if being overweight and obesity are associated
with low-grade systemic inflammation as measured by serum C-reactive protein
Elevated CRP levels were present in 27.6% of the
population. Both overweight and obese
persons were more likely to have elevated CRP levels than their normal-weight
counterparts. Waist-to-hip ratio was
positively associated with both elevated and clinically raised CRP levels,
independent of body size. Restricting the analyses to young adults (aged 17-39
years) and excluding smokers, persons with inflammatory disease, cardiovascular
disease, or diabetes mellitus and estrogen users did not change the main
findings. These findings suggest a state
of low-grade systemic inflammation in overweight and obese persons. (JAMA. 1999;282:2131-5).
The implications are that being fat
is partly an inflammatory disorder, and body fat promotes inflammation. This
may be part of the reason why being overweight increases the risk of diabetes,
heart disease, and other disorders. CRP levels are generally elevated in
overweight children as well as adults.
Blood sugar disorders. Insulin resistance, Syndrome X, and diabetes are all associated with
increased levels of CRP. This is significant because each of these conditions
increases the risk of coronary artery disease. High CRP levels have also been
found in patients with Alzheimer's
disease, which is increasingly being viewed as an inflammatory brain
disorder. Not surprisingly, people with arthritis
and cancer also tend to have high
Dental disease. People with periodontal disease also have elevated CRP levels. This
elevation may be the result of chronic infection or inflammation of the gums.
It may also reflect inadequate levels of antioxidants, which would promote
Journal of Periodontology reported that inflammatory effects from periodontal
disease, a chronic bacterial infection of the gums, cause oral bacterial
byproducts to enter the bloodstream and trigger the liver to make proteins such
as CRP that inflame arteries and promote blood clot formation.
disease needs to be considered as a major contributor to increased levels of
CRP by the medical community,” said Dr. Steven Offenbacher, member of the American Academy of Periodontology.
Viral Infections: Zhu and other researchers hypothesized in the
the American College of Cardiology (1999) that the cytomegalovirus (CMV), a
member of the herpes virus family, may stimulate an inflammatory response,
reflected by elevated CRP levels. Patients
with influenza A, a flu virus, tend to have much higher levels of CRP.
Smoking. Tobacco smoke raises CRP levels, and some researchers have found that
they remain elevated in ex-smokers.
Use of Estradiol with or without Progestagens in
Post-Menopausal Women: CRP levels increased significantly during 12 weeks in both
the Estradiol 2mg alone and the Estradiol 2mg with a synthetic progestagen
compared to placebo. The median change
from baseline in both treatment groups together was +87% at 4 weeks and +114%
at 12 weeks compared to the placebo group. These observations raise the possibility that
the increased risk of cardiovascular events seen with hormone therapy is
related to an initial increase in CRP levels after starting hormone replacement
therapy. (Thromb Haemost 1999 Jun;81(6):925-8.)
Bacterial Infections? To assess the utility of
serum C-reactive protein (CRP) as a screen for hidden bacterial infection in children, Daniel J. Isaacman, MD and Bonnie L. Burke,
MS studied 256 children ages 3 to 36 months who visited an urban
children's hospital emergency department for a fever and received a complete
blood cell count and blood culture as part of their evaluation. Twenty-nine (11.3%) cases of a serious “hidden”
bacterial infection were identified. The use of achieved a sensitivity of 63%
and a specificity of 81% for detection of occult bacterial infections in this
population. Performing a CRP in this
setting added little diagnostic utility. (Arch Pediatr Adolesc Med.
2002;156:905-9). This implies that bacterial infections may
not induce significant increases in the CRP and that inflammation that induces
CRP may not be due to bacteria.
Aging. Plasma CRP values in general adult populations from Augsburg, Germany (2291 males and 2203 females; ages, 25-74 years) and Glasgow, Scotland (604 males and 650 females; ages, 25-64 years) were
very similar. The median CRP approximately doubled with age, from approximately
1 mg/L in the youngest decade to approximately 2 mg/L in the oldest, and tended
to be higher in females. This extensive
data set, tells us that CRP is not necessarily related to nationality but more
likely related to age and other factors. (Clin Chem 2000 Jul;46(7):934-8)
What are some of the
methods to lower CRP?
intake of vitamin E reduces CRP levels especially among type II diabetic
patients (Free Radic Biol Med. 2000 Oct
15;29(8):790-2.). It should be noted
that there are several forms of vitamin E and that synthetic forms of vitamin E
do not have the same biological activity or potency as natural forms of vitamin
E. In addition, there are at least eight
forms of vitamin E, the most common form available is alpha-tocopherol, which
is not necessarily the most effective.
Use of high quality whole food derived vitamin E has been a priority in
my practice unless allergies do not permit.
A 5 year study showed that
treatment with an HMG-CoA Reductase Inhibitor, pravastatin, which is used
primarily to lower cholesterol, appears to significantly reduce the level of
CRP (Circulation. 1999;100:230-5.) In a study done on blood samples from the
Cholesterol and Recurrent Events (CARE) trial. The CARE trial was a secondary
prevention trial of cardiovascular disease in 4159 patients with a history of
myocardial infarction who had total cholesterol <240 mg/dL and LDL
cholesterol between 115 and 175 mg/dL.
risk of stroke, according to data reported in the New England Journal of
decreased among those using statin drugs to 3.7% compared to 4.5% in the
placebo group. (White et al., 2000) The Cholesterol and Recurrent Events trial
concluded that pravastatin (administered long-term) appears to be doing more
than reduce cholesterol, perhaps acting as an anti-inflammatory. The NEJM reported that
Pravastatin reduced C-reactive protein levels after both 12 and 24 weeks
administration, independent of LDL cholesterol. It appears statin therapy may
prevent coronary events among individuals with relatively low lipid levels but
with elevated levels of CRP. (Ridker et al., 2001) Conversely, some drugs
including hormone replacement therapy, actually increase CRP levels and the
inflammatory response. JAMA
reported that large LDL cholesterol, an independent predictor of coronary
events in a typical population with myocardial infarction, was not present
among patients who were treated with pravastatin. (Campos, 2001)
The ability of
HMG-CoA Reductase inhibitors to lower C-reactive protein levels has recently
brought into question the mechanisms of action of the statin drugs. Because
these medications lower incidences of acute cardiovascular events as well as
decreasing morbidity and mortality well before the effects of lowered LDL
cholesterol can be expected to occur, questions have been asked about whether
they may work independently of LDL-lowering mechanisms. Red yeast rice contains a naturally-occurring statin (lovastatin)
as well as other cholesterol-lowering compounds, some with antioxidant effects.
compounds present in virgin olive oil
also have anti-inflammatory and antioxidative effects in cardiovascular
disease. The phenolic compounds in virgin olive oil may explain some of the
protective effects found in epidemiological studies. (Altern Med Rev
immune cytokines cause elevated C-reactive protein. These cytokines may be
suppressed by taking supplements such as the DHA, the hormone DHEA, vitamin K, and nettle leaf extract. As
research continues, it may be found that many other nutrients and herbals known
for their anti-inflammatory properties are equally valuable in maintaining
healthy CRP levels.
CRP appears to cause depletion of vitamins A, C, and E, as well as carotenoids,
zinc, and selenium, Individuals with elevations in CRP may wish to emphasize
these nutrients for their contribution to cardiac health.
Weight loss, esepcially with resulting loss of
abdominal fat, would be expected to lower the CRP. Eating fewer refined carbohydrates and
high-glycemic foods engaging in moderate physical activity, and losing weight
should take priority over pharmaceutical approaches.
reduce levels of CRP, and presumably the risk of cardiovascular disease, not
only would it be important to lose weight if you are overweight, but it would
also be important to get your gums treated.”