c-reactive protein: what is it? marker of inflammation made in liver 1 acute-phase response ...
TRANSCRIPT
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.