Inflammatory debate

While highly regarded in the U.S., British researchers say the value of C-reactive protein is questionable


April 5, 2004

Doctors in Great Britain have called into question the predictive value of a tiny protein that many heart experts in this country say holds titanic implications for public health.

The molecule in the hot seat is called C-reactive protein, a signpost in the blood indicating inflammation anywhere in the body. Doctors say it is critical to detect inflammation because of its role in cardiovascular damage, infection and cancer. A test designed to pinpoint the protein was recommended last year by the American Heart Association and Centers for Disease Control and Prevention. Heart specialists are convinced of a need to screen for more than elevated cholesterol to spot heart attack and stroke risks.

Last week, British researchers shot holes in the notion that C-reactive protein is a valuable marker, saying previous research overstated the magnitude to which people are vulnerable.

So certain, though, are doctors around the world that C-reactive protein red-flags inflammatory damage in arteries that scores of studies involving the protein are under way. Produced by the liver, the protein flares at the first sign of inflammation, resulting from any cause. It remains constant and often rises when arteries are under assault by plaque, doctors say.

Scientists in this country, led by a pioneering cardiovascular researcher at Brigham and Women's Hospital in Boston, say C-reactive protein is the best marker now in hand. Spotting it in elevated levels in a simple blood sample, they say, provides a way to take pre-emptive action in people at high risk.

But reporting last week in the New England Journal of Medicine, British researchers charged that doctors may be wasting their patients' time - if not their own - screening for C-reactive protein.

"C-reactive protein is a relatively moderate predictor of coronary heart disease," said Dr. John Danesh of the University of Cambridge, the study's lead investigator. Danesh added that the science supporting use of tests for the protein is not strong.

"Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be reviewed," Danesh said.

U.S. doctors favor CRP test

The test designed to detect C-reactive protein is so highly regarded in the United States, where doctors increasingly have ordered it, that the CDC last year announced it was one way to identify cardiac patients who otherwise would not be found.

Moreover, U.S. doctors point to the test's convenience. It can be performed in virtually any hospital laboratory at nominal cost - $10 to $15.

Danesh and his research team studied frozen blood samples from people in Iceland, born between 1908 and 1934. From the samples they compared 2,459 who had heart disease to 3,969 without it. Researchers also re-analyzed 22 previous studies of the C protein.

The team found that patients with heart disease indeed had higher C-reactive protein levels. But their risk was calculated to be only 50 percent higher, not 100 percent higher as determined by previous research.

A leading American heart specialist said the British are splitting hairs.

"Dr. Danesh is creating controversy where none existed," said Dr. Paul Ridker of Brigham and Women's Hospital.

"I would never want to be a patient in Great Britain," added Ridker the researcher, widely regarded as the discoverer of C-reactive protein's role in gauging heart disease risks. "I suppose in Great Britain they don't want people to be healthy. What can I say?"

Ridker said he believes in reviewing the scope of a patient's risks from as many approaches as possible. Testing for the dangerous form of cholesterol - LDL - is not enough, he said, because many heart attack and stroke patients have normal LDL readings.

The risk factor

In a journal commentary analyzing Danesh's research, Dr. Alan Tall, a professor of medicine at Columbia University's College of Physicians and Surgeons in Manhattan, said while C-reactive protein is predictive of heart disease, Danesh's study calls into question how well it gauges risk. He thinks Danesh's questions are valid, despite the protests.

"There is a pressing need for research that will lead to the development of better genetic, biochemical or imaging indicators of risk," Tall said. He added that the clinical relevance of measuring C-reactive protein remains largely unproven.

Neither the CDC nor the American Heart Association plans to change its recommendation. The two agencies report an average C-reactive protein reading of 1.5 in healthy people. At levels of 3 or higher, the risk for heart attack and stroke rises dramatically, experts at the CDC say.

The CDC backed the test because estimates have demonstrated that up to 40 percent of U.S. adults are at risk of heart disease, based on age and rates of high cholesterol, diabetes and hypertension.

Indeed, having a test available, experts say, is a way to bring seemingly disparate notions about cardiovascular disorders together.

In the 1950s doctors advanced the cholesterol hypothesis of coronary heart disease. But by the 1970s medical scientists knew there was something more because the body's inflammatory responses were also activated in arterial disease. Although designed by nature to aid the body, the components of inflammation actually created more destruction. That's why researchers such as Ridker say it is important to look for signs of inflammation to gauge risks.

"I want patients to know there is a better way to save their lives," Ridker said. "This is about public health and letting patients and their primary physicians know there is overwhelming evidence that the test works."