C-Reactive Protein: What Is It? Marker of inflammation made in liver 1 Acute-phase response Illness or injury 2 Adipocyte release of cytokines.

C-Reactive Protein: What Is It?

Marker of inflammation made in liver1

Acute-phase response Illness or injury2

Adipocyte release of cytokines may trigger release3

Measure of general inflammation = non-specific Further investigation required to

determine actual source2

High-Sensitivity C-Reactive Protein: Difference?

Sensitive measure of chronic inflammation seen in patients with atherosclerosis and other chronic diseases1

hs-CRP assay test that is more sensitive than the standard test4

Stable and easy to measure5

CRP Levels for Risk and Testing

Blood test Low Risk: <1mg/L Average Risk: 2-3mg/L High Risk: >3mg/L Average of 2 measurements taken

At least 2 week apart Normal individual w/o inflammation

or infection: <0.6mg/L2

What is inflammation?

• An attempt for the body to restore homeostasis after an injury. (3)

• Acute inflammation is our bodies initial response to harmful stimuli- it is a positive response that initiates healing (2)

• Chronic inflammation is characterized by the simultaneous healing and destruction of tissue from the inflammatory process

Mechanism of Acute Inflammation(5)

1. Vasodilatation and increased permeability of blood vessels (5)

Mechanism of Acute Inflammation

2. Emigration of phagocytes from the blood into interstitial fluid (5)

Mechanism of Acute Inflammation

Mechanisms of Acute Inflammation

• 3. Repair

CRP Acute Phase ResponseInfections Bacterial,

Systemic/ Severe FungalMycobacterial, viral

Allergic Complications of infection

Rheumatic feverErythema nodosum

Inflammatory Disease Rheumatoid arthritisJuvenile chronic arthritisPsoriatic arthritisCrohn diseaseFamilial Mediterranean fever

Necrosis Myocardial infarctionTumor embolizationAcute pancreatitis

Trauma Sugery, burns, fractures

Malignancy Lymphoma, Carcinoma, Sarcoma

C-Reaction Protein’s Role in Chronic Inflammation

• Strong association between base line CRP and BMI. (3)

• CRP values also associated with many features of insulin resistance, metabolic syndrome, and diabetes. (3)

• Not just a marker for inflammation, but also a participant! (3)

Atherosclerosis (1)

Verma S et al. Circulation 2004;109:1914-1917

Copyright © American Heart Association

Overview of Metabolic Syndrome Pathways

Let’s draw this process step by step!

• What is the role of CRP in this process? Because is a calcium dependent ligand-binding protein, is involved in the acute-phase immune system response. Plasma CRP is produced by hepatocytes in the liver and regulated by pro inflammatory cytokines, especially IL-6 and TNF alpha.

• CRP is a predictor of development of type 2 diabetes.

• Why are we starting this diagram with the picture of lipid droplets?• Because this diagram explains how obesity can lead to several health

problems where many factors including CRP are involved.

Hormones and C-reactive protein

Hormones and C-reactive Protein

NAME ACTION PRODUCED FROM

EFFECT ON CRP

CORTISOL INCREASES GLYCOGENESIS WITHIN LIVER

ADRENAL GLANDS OF THE KIDNEYS

INCREASE CRP WITHIN 24 HOURS- STIMULATES CRP PRODUCTION

DEOXYCORTICOSTERONE

ACTS AS A PRECURSER TO ALDOSTERONE

ADRENAL GLAND

INCREASE CRP WITHIN 24 HOURS

ADRENALIN FIGHT OR FLIGHT RESPONSE – SYMPATHETIC NERVOUS SYSTEM

ADRENAL GLANDS OF KIDNEYS

INCREASE CRP WITHIN 24 HOURS

DEXAMETHASONE ACTS AS AN ANTI-INFLAMMATORY AND IMMUNOSUPRESENT

ELEVATES CRP LEVELS

PROGESTERONE MENSTRUAL HORMONE

OVARIES AS WELL AS THE ADRENAL GLANDS

INCRESES CRP LEVELS DURING MENSTRATION

DEHYDROEPIANDROSTERONE (DHEA)

PRECURSER TO MALE/FEMALE SEX HORMONES

ADRENAL GLAND

FUNCTIONS TO SUPRESS CERTAIN PRO-INFLAMMATORY IMMUNE CYTOKINES THAT CASUE ELEVATED C-REACTIVE PROTEIN

Considering CRP and Estrogen

Many current studies are exploring the connection between hormone replacement therapy and estradiol and the effect it has on increasing CRP levels.

Consider that Fat cells produce estrogen as well as certain cytokines. (if you are obese you thusly have a greater production of these elements)

We know that cytokines trigger an inflammatory response that result in greater levels of blood CRP

Do increased levels of adipocytes produce increased levels of estrogen and therefore result in higher levels of CRP within blood?

It is speculated that sex hormones, in conjunction with obesity affect circulating CRP concentrations w/in women

A Closer Look at CRP and Leptin

Leptin is a hormone produced from adipose tissue that signals to the brain when to stop eating. The amount of fat an individual has regulates the amount of leptin produced (weight of the evidence)

current research is trying to determine why when the weight of individual increases their response to leptin decreases

one theory is looking at CRP as the cause based on the similarity of leptin and CRP receptors

-higher fat= greater inflammation = higher production of inflammatory response of CRP from the liver

-greater % fat per body weight= greater % adipose tissue per body weight= greater leptin production. (nature.com)

Lifestyles Impacting CRP Levels:Obesity

Increase in adipose tissue Adipocytes and immune cells that can

secrete cytokines6

One theory: bloated fat cells can leak or break open Macrophages recruited release

cytokines More WBC’s move in = increase in

inflammation More cytokines = more inflammation =

more CRP7

Lifestyles Impacting CRP Levels:Obesity

Fat tissue swells with increased positive energy balance Increases inflammatory activity Spills over into blood stream systemic

chronic, low-grade inflammation Chronic low-grade inflammation

makes brain more resistant to effects of insulin, cortisol, and leptin7

Lifestyles Impacting CRP Levels:Obesity

Metabolic signals sent to hypothalamus “master switch” for inflammation is

chronic overeating Leads to weight gain and insulin

resistance

Weight gain = more adipose tissue = more cytokines = more inflammation = more CRP8

Lifestyles Impacting CRP Levels:Atherogenesis/Atherosclerosis

Atherogenesis: process leading to development of Atherosclerosis

Plaques form when inflammation stimulates WBCs Monocytes become macrophages that

engulf cholesterol foam cells fatty streaks that deposit within smooth muscle9

Lifestyles Impacting CRP Levels:Atherogenesis/Atherosclerosis

Protective fibrin layer forms between arterial lining and fatty deposits (Atheroma) Secretes enzymes that work to enlarge

artery to compensate for narrowing Can rupture forming a Thrombus that

attracts platelets and causes clotting blockage9

CRP found in arterial atheromas Considered risk factor and causal agent

for atherothrombosis10

Verma S et al. Circulation 2004;109:1914-1917

Copyright © American Heart Association

Lifestyles Impacting CRP Levels:Atherogenesis/Atherosclerosis

Atherosclerosis causes angina (chest pain), myocardial infarction, and strokes

CRP has been shown to be elevated (>3mg/L) in these individuals10

CRP and MacronutrientsNutrient CRP Level

Glucose Intake Increases

Fructose Intake Increases

Sucrose Intake Increases

Fiber Intake Decreases

Branched Chain Amino Acid Intake

Decreases

Saturated Fat Intake Increases

Unsaturated Fat Intake Decreases

Trans Fat Intake Increases

CRP and Sugary Sweetened Beverages

• CRP levels were shown to increase after the consumption of sugary sweetened beverages.

• The beverages were sweetened with fructose, glucose and sucrose

• CRP levels increased with each sugar consumption, but rose the most after high fructose consumption1

• CRP increases as fasting and 2 hour postload glucose levels rise.• This indicates that people who are pre-

diabetic, have elevated CRP levels• It is not known whether this is a cause

or an effect2

CRP and Glucose

CRP and Fructose

• As fructose consumption increases, CRP levels increase.

• There is no mechanism that has shown a connection between CRP levels and increased fructose consumption, but it is widely thought that increased fructose consumption increases inflammation through the release of cytokines3.

CRP and Fiber

• As fiber intake increases, CRP levels decrease in individuals with one or more of the following conditions: diabetes, hypertension and CVD.• As fiber intake increases, CRP levels decrease in individuals without any preexisting conditions.• Reduced consumption of fiber showed higher CRP levels regardless of preexisting conditions4.

CRP and Fiber Continued…..

• Increased fiber intake is associated with lower CRP levels in normal weight individuals. Increased fiber intake does not seem to have an effect on CRP levels in obese or overweight individuals5.

CRP and Protein, Fat

• Low levels of branched chain amino acids are correlated with higher levels of CRP and illness in dogs6.

• Trans fat consumption has been shown to increase CRP levels, especially in overweight individuals and those with heart disease7.

1. Aeberli, I., et al (2011). Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial. Am J Clin Nutr, 94, 479-85.

2. Doi, Y., et al (2005). Relationship between c-reactive protein and glucose levels in community-dwelling subject without diabetes. Diabetes Care, 28(5), 1211-3.

3. Pollock, N.K., et al (2012). Greater fructose consumption is associated with cardiometabolic risk markers and visceral adiposity in adolescents. J Nutr, 142, 251-7.

4. King, D.E., Mainous, A.G., Egan, B.M., Woolson, R.F. & Geesey, M.E. (2005). Fiber and c-reactive protein in diabetes, hypertension and obesity. Diabetes Care, 28(6), 1487-9.

5. North, C.J., Venter, C.S. & Jerling, J.C. (2009). The effects of dietary fibre on c-reactive protein, an inflammation marker predicting cardiovascular disease. Euro J Clin Nutr, 63, 921-33.

6. Chan, D.L., Rozanski, E.A. & Freeman, L.M. (2009). Relationship among plasma amino acids, c-reactive protein, illness severity and outcome in critically ill dogs. J Vet Intern Med, 23, 559-63.

7. Mozaffarian, D., Katan, M.B., Ascherio, A., Stampfer, M.J. & Willett, W.C. (2006). Trans fatty acids and cardiovascular disease. N Engl J Med, 354, 1601-13.