The Emerging Role of C-Reactive Protein in Clinical Practice

High-sensitivity CRP (hsCRP) is a simple, relatively inexpensive, and widely available blood test used to detect inflammation, including subclinical inflammation. In case-control and prospective studies, hsCRP levels have been shown to consistently improve risk prediction for cardiovascular disease (CVD) in various populations, even when lipid values are less than the National Heart, Lung, and Blood Institute’s guidelines for optimal lipid control.

Despite the association with CVD, CRP may not play a direct causal role in its pathophysiology. In a recent Mendelian genetics study of the CRP gene locus, CRP gene variants were closely associated with CRP levels but did not predict the development of coronary artery disease. Across the entire population however, CRP levels were closely associated with the development of coronary artery disease.

Currently, measurement of hsCRP is recommended for adults at “intermediate risk” by the Centers for Disease Control and Prevention as well as the American College of Cardiology. By adding hsCRP to traditional risk factors, 30% to 40% of intermediate-risk patients (those with 10% to 20% risk for hard coronary artery disease events in 10 years) can be reclassified as either high or low risk. This reclassification may enable more refined treatment decisions, for example, more judicious use of aspirin and statin therapy. The inclusion of hsCRP as well as family history in global risk assessment has been shown to contribute to prediction of cardiovascular events at least as much as high-density lipoprotein cholesterol and low-density lipoprotein cholesterol.

The role of pharmacotherapy to reduce inflammation is an active area of investigation. Statins lower hsCRP levels as well as low-density lipoprotein cholesterol. The landmark Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study showed that treating patients aged >60 years old with normal low-density lipoprotein cholesterol but hsCRP ≥2 mg/dl can dramatically reduce cardiovascular event rates in men, women, and nearly all ethnic groups (cardiovascular events were defined as myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes).

JUPITER raised many questions about the use of hsCRP. Is lowering hsCRP a key mechanism by which statins decrease cardiovascular events? Are statins simply lowering event rates in patients with elevated metabolic risk as identified by subclinical inflammation? Are there other, simpler ways of identifying patients at risk for subclinical inflammation, such as with routine anthropomorphic measures of obesity and estimates of insulin resistance?

Physiology of Obesity and Inflammation

Obesity is increasingly recognized as an inflammatory disorder. Research from the past decade has elucidated many of the mechanistic associations between obesity, particularly highly metabolically active visceral adiposity, and inflammation. A driving factor in this process is caloric excess, which causes distinct morphologic and metabolic changes in adipose tissue as well as other organ systems, including the pancreas, hypothalamus, skeletal muscle, and liver. These processes lead to an inflammatory infiltration of adipose tissue, aberrant endocrine secretion, and cytokine secretion, all of which promote an increase in systemic inflammation.

At the adipose tissue level, an abundance of triacylglycerol creates large adipocytes that initiate cellular stress responses, leading to the activation of inflammatory signaling pathways. Increased serum levels of free fatty acid and free fatty acid breakdown products trigger proinflammatory cascades, which in turn yield elevated cytokine secretion, promoting an inflammatory milieu. Release of these cytokines (so-called adipokines) promotes the recruitment of monocytes, which are then shunted down the inflammatory pathway to become inflammatory macrophages.

Activated macrophages themselves are essential to the local production of nitric oxide synthase and tumor necrosis factor–α and the expression of interleukin-6, stimulating further expression of CRP. An intriguing finding is that the levels of macrophage invasion of adipose tissue are directly related to the level of obesity and that this process can be reduced with exercise.

It has also been suggested that the association between abdominal obesity and subclinical inflammation may have an anatomic cause. The portal vein drains visceral adipose tissue and terminates at the liver, supplying 80% of its blood supply. It is possible that the direct exposure of cytokines from the adipose tissue to the liver induces greater inflammation. Furthermore, in a nutrient excess state, accumulation of triacylglycerol and free fatty acids overwhelms cellular respiratory machinery in the liver, leading to the accumulation diacylglycerol and ceramide. These molecules are powerful stimulators of the serine kinases IκB kinase and c-Jun-aminoterminal kinase cascades.

Activation of the c-Jun-aminoterminal kinase in liver and adipose tissues leads to increased activated protein 1, whereas increased IκB kinase in liver promotes the activation of nuclear factor κB. These inflammatory cascades, as well as inflammation induced by microhypoxic conditions found in obesity, yield the expression of a broad range of cytokines, including tumor necrosis factor–α, monocyte chemoattractant protein–1, chemokine (C-C motif) ligand 2, interleukin-6, and interleukin-1B, which leads to increased expression of CRP in the liver ( Figure 1 ).

The impact of abdominal adiposity on inflammation. Abdominal adiposity leads to metabolic abnormalities such as increased levels of free fatty acid (FFA), ceramide, and diacylglycerol (DAG), as well as activation of the serine kinase pathways AP-1 and nuclear factor κB (Nf-kB). These processes lead to cytokine release, promotion of monocyte recruitment, differentiation into the inflammatory monocytes into M1 phenotype macrophages, and release of inflammatory cytokines from adipose tissue. Abdominal adiposity is characterized by decreased adiponectin levels as well as leptin resistance. These endocrine derangements, as well as cytotoxic effects of elevated lipid levels, contribute to impaired glucose handling and the development of the metabolic syndrome. Inflammation derived from adipose tissues, elevated glucose and insulin levels, and dyslipidemia conspire to create a state of systemic inflammation, which promotes atherosclerosis and cardiovascular disease. ER = endoplasmic reticulum; IL-6 = interleukin-6; MCP-1 = monocyte chemoattractant protein–1; TNFa = tumor necrosis factor–α.

Adiponectin levels provide another link between abdominal adiposity and the metabolic syndrome. Adiponectin, produced in adipose tissue, increases in lean individuals and decreases with increasing abdominal adiposity. Adiponectin affects insulin sensitivity by increasing fatty acid oxidation and improving glucose homeostasis. Specifically, adiponectin activates the peroxisome proliferator-activated receptor–α and adenosine monophosphate-activated protein kinase. The activation of peroxisome proliferator-activated receptor–α and monophosphate-activated protein kinase in liver and skeletal muscle yields increased fatty acid oxidation and decreased triglyceride tissue content, which leads to increased insulin sensitivity. Monophosphate-activated protein kinase activity decreases gluconeogenesis in the liver and increases glucose uptake in skeletal muscle, thus improving glucose homeostasis.

Obesity can be assessed by anthropomorphic measures; imaging modalities including computed tomography, magnetic resonance imaging, and dual-energy x-ray absorptiometry; and bioimpedance and skin-fold thickness. Imaging studies offer a direct measure of subcutaneous and visceral adipose tissue, but they are as of yet investigational and not used routinely in clinical practice. Clinical measures of obesity include body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). BMI is calculated by dividing the weight in kilograms by the height in meters squared. BMI does not provide any information about body fat distribution or differentiate between fat and lean mass.

According to National Institutes of Health guidelines, WC is best measured at the top of the right iliac crest using an inelastic tape measuring parallel to the floor at the end of normal expiration, with obesity being defined as >40 inches in men and >35 inches in women. Hip circumference is measured as the widest point over the buttocks and below the iliac crest. The WHR found by dividing the WC by the hip circumference. There is some evidence that WC has a stronger association with visceral adiposity compared to WHR when measured by direct computed tomographic imaging. A large meta-analysis comparing WC and WHR measures to future CVD events found WHR measures to be less reliable in repeated measurements, likely because of technical problems with the need for disrobing and proper positioning of the measuring tape. There are not yet accurate and reliable methods for measuring bioimpedance and skin-fold thickness that have been broadly applied at the clinical level.

Physiology of Obesity and Inflammation

Obesity is increasingly recognized as an inflammatory disorder. Research from the past decade has elucidated many of the mechanistic associations between obesity, particularly highly metabolically active visceral adiposity, and inflammation. A driving factor in this process is caloric excess, which causes distinct morphologic and metabolic changes in adipose tissue as well as other organ systems, including the pancreas, hypothalamus, skeletal muscle, and liver. These processes lead to an inflammatory infiltration of adipose tissue, aberrant endocrine secretion, and cytokine secretion, all of which promote an increase in systemic inflammation.

At the adipose tissue level, an abundance of triacylglycerol creates large adipocytes that initiate cellular stress responses, leading to the activation of inflammatory signaling pathways. Increased serum levels of free fatty acid and free fatty acid breakdown products trigger proinflammatory cascades, which in turn yield elevated cytokine secretion, promoting an inflammatory milieu. Release of these cytokines (so-called adipokines) promotes the recruitment of monocytes, which are then shunted down the inflammatory pathway to become inflammatory macrophages.

Activated macrophages themselves are essential to the local production of nitric oxide synthase and tumor necrosis factor–α and the expression of interleukin-6, stimulating further expression of CRP. An intriguing finding is that the levels of macrophage invasion of adipose tissue are directly related to the level of obesity and that this process can be reduced with exercise.

It has also been suggested that the association between abdominal obesity and subclinical inflammation may have an anatomic cause. The portal vein drains visceral adipose tissue and terminates at the liver, supplying 80% of its blood supply. It is possible that the direct exposure of cytokines from the adipose tissue to the liver induces greater inflammation. Furthermore, in a nutrient excess state, accumulation of triacylglycerol and free fatty acids overwhelms cellular respiratory machinery in the liver, leading to the accumulation diacylglycerol and ceramide. These molecules are powerful stimulators of the serine kinases IκB kinase and c-Jun-aminoterminal kinase cascades.

Activation of the c-Jun-aminoterminal kinase in liver and adipose tissues leads to increased activated protein 1, whereas increased IκB kinase in liver promotes the activation of nuclear factor κB. These inflammatory cascades, as well as inflammation induced by microhypoxic conditions found in obesity, yield the expression of a broad range of cytokines, including tumor necrosis factor–α, monocyte chemoattractant protein–1, chemokine (C-C motif) ligand 2, interleukin-6, and interleukin-1B, which leads to increased expression of CRP in the liver ( Figure 1 ).

The impact of abdominal adiposity on inflammation. Abdominal adiposity leads to metabolic abnormalities such as increased levels of free fatty acid (FFA), ceramide, and diacylglycerol (DAG), as well as activation of the serine kinase pathways AP-1 and nuclear factor κB (Nf-kB). These processes lead to cytokine release, promotion of monocyte recruitment, differentiation into the inflammatory monocytes into M1 phenotype macrophages, and release of inflammatory cytokines from adipose tissue. Abdominal adiposity is characterized by decreased adiponectin levels as well as leptin resistance. These endocrine derangements, as well as cytotoxic effects of elevated lipid levels, contribute to impaired glucose handling and the development of the metabolic syndrome. Inflammation derived from adipose tissues, elevated glucose and insulin levels, and dyslipidemia conspire to create a state of systemic inflammation, which promotes atherosclerosis and cardiovascular disease. ER = endoplasmic reticulum; IL-6 = interleukin-6; MCP-1 = monocyte chemoattractant protein–1; TNFa = tumor necrosis factor–α.

Adiponectin levels provide another link between abdominal adiposity and the metabolic syndrome. Adiponectin, produced in adipose tissue, increases in lean individuals and decreases with increasing abdominal adiposity. Adiponectin affects insulin sensitivity by increasing fatty acid oxidation and improving glucose homeostasis. Specifically, adiponectin activates the peroxisome proliferator-activated receptor–α and adenosine monophosphate-activated protein kinase. The activation of peroxisome proliferator-activated receptor–α and monophosphate-activated protein kinase in liver and skeletal muscle yields increased fatty acid oxidation and decreased triglyceride tissue content, which leads to increased insulin sensitivity. Monophosphate-activated protein kinase activity decreases gluconeogenesis in the liver and increases glucose uptake in skeletal muscle, thus improving glucose homeostasis.

Obesity can be assessed by anthropomorphic measures; imaging modalities including computed tomography, magnetic resonance imaging, and dual-energy x-ray absorptiometry; and bioimpedance and skin-fold thickness. Imaging studies offer a direct measure of subcutaneous and visceral adipose tissue, but they are as of yet investigational and not used routinely in clinical practice. Clinical measures of obesity include body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). BMI is calculated by dividing the weight in kilograms by the height in meters squared. BMI does not provide any information about body fat distribution or differentiate between fat and lean mass.

According to National Institutes of Health guidelines, WC is best measured at the top of the right iliac crest using an inelastic tape measuring parallel to the floor at the end of normal expiration, with obesity being defined as >40 inches in men and >35 inches in women. Hip circumference is measured as the widest point over the buttocks and below the iliac crest. The WHR found by dividing the WC by the hip circumference. There is some evidence that WC has a stronger association with visceral adiposity compared to WHR when measured by direct computed tomographic imaging. A large meta-analysis comparing WC and WHR measures to future CVD events found WHR measures to be less reliable in repeated measurements, likely because of technical problems with the need for disrobing and proper positioning of the measuring tape. There are not yet accurate and reliable methods for measuring bioimpedance and skin-fold thickness that have been broadly applied at the clinical level.