What is C-Reactive Protein?

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?

§         Heart Disease/Atherosclerosis

§         Strokes

§         Obesity

§         Dental Disease

§         Blood Sugar Disorders

§         Alzheimer’s

§         Arthritis

§         Cancer

§         Viral Diseases

§         Smoking tobacco

§         Use of Estradiol with or without Progestagens in Post-Menopausal Women:

§         Hidden Bacterial Infections?

§         Aging

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.

Atheromatous 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.

Studies 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. 1996;312:1061-5.).

Multiple 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)
MEN	RELATIVE RISK FOR:
CRP (mg/L)	Future MI (heart attack)	Future Stroke
>2.11	2.9	1.9
1.15-2.10	2.6	1.9
0.56-1.14	1.7	1.7
<0.55	1.0	1.0
WOMEN CRP (mg/L)	RELATIVE RISK FOR: FUTURE MI or STROKE
>7.3	5.5
3.8-7.3	3.5
1.5-3.7	2.7
<1.5	1.0
Ref: Ridker, et. Al. Circulation 1998;98:731-733 Ridker, et. al. N. Engl J. Med., 1997; 336:973-979

 

New 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.

In 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 Medical Center.

The 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.

The 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."

The 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.

"In 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."

The 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.

"Interestingly, 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."

Lamarche 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.

Some 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 (November 2001)

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, 1985)

The 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.

Bacteria 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.)

A 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.

Tissue 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 proliferate.

Obesity:  Since 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 (CRP) level.

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 CRP levels.

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 healing. The 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.

“Periodontal 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 Journal of 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.)

Hidden 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?

High 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.

The risk of stroke, according to data reported in the New England Journal of Medicine, 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.

Polyphenolic 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 2001;6(3):248-271)

Certain pro-inflammatory 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.

Because 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.

To 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.”