Objectives. Objectives (continued) Upon completion of the learning activity the participant will be able to:

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1 Inflammation: Assessing, Preventing and Treating this Common Denominator in a Variety of Diseases Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner Journal, The Prescribers Letter, American Nurse Today 1 Objectives Upon completion of the learning activity the participant will be able to: Describe the process, contributing factors and clinical consequences of inflammation. Identify select diagnostic testing that can help reveal clinically significant inflammation. 2 Objectives Upon completion of the learning activity the participant will be able to: Discover what measures (including pharmacological) are potentially helpful to minimize inflammatory risk. 3

2 Clinically, we have focused on inflammation as part, not the cause of, acute and chronic illnesses. 4 Inflammation is a complex, highly orchestrated process involving many cell types and molecules, some of which initiate, amplify, or sustain the process, some of which attenuate it, and some of which cause it to resolve. Source- Gabay, C., Kushner, I. Acute-Phase Proteins and Other Systemic Responses to Inflammation, NEJM, Vol. 340: How does inflammation present clinically? 6

Laboratory Identification of Inflammation s Presence Acute-phase protein or acute-phase reactants measurement Defined Protein found in the

inflammatory disorders 7 Conditions that Lead to Changes in Acute-phase Protein Changes Infection Trauma Surgery Immunologically mediated,

3 Laboratory Identification of Inflammation s Presence Acute-phase protein or acute-phase reactants measurement Defined Protein found in the plasma with concentration that increases (positive acute-phase proteins) or decreases (negative acute-phase proteins) by =>25% during inflammatory disorders 7 Conditions that Lead to Changes in Acute-phase Protein Changes Infection Trauma Surgery Immunologically mediated, crystalinduced inflammatory conditions 8 Conditions that Lead to Changes in Acute-phase Protein Changes Malignancy Atherosclerosis Burns Tissue infarction 9

Examples of Acute-phase Proteins ESR Erythrocyte sedimentation rate or sed rate Indirectly measures many proteins associated with inflammation C-reactive protein (CRP) Named D/T its reaction with

4 Examples of Acute-phase Proteins ESR Erythrocyte sedimentation rate or sed rate Indirectly measures many proteins associated with inflammation C-reactive protein (CRP) Named D/T its reaction with pneumococcal C-polysaccharide 10 Acute-phase Proteins after Moderate Inflammatory Stimulus Gabay C and Kushner I. N Engl J Med 1999;340: True or false? Moderate changes in acute-phase proteins can occur after strenuous exercise, childbirth, and exposure to environmental extremes. 12

5 True or false? If a sed rate or CRP is done on a person who is undergoing a significant psychosocial stress, the level is likely to be mildly to moderately elevated. 13 Substances not Usually Measured that Contribute to Inflammatory Cascade Cytokines Intercellular signaling polypeptides produced by activated cells Arise from multiple sources with multiple targets and different function Trigger acute-phase protein production 14 Inflammation-associated Cytokines Largely produced by macrophages and monocytes at inflammatory sites Interleukin-6 (major stimulator) Interleukin-1ß Interleukin-8 Tumor necrosis factor Interferon-Y Transforming growth factor ß 15

6 Atherosclerotic Lesion Hansson GK. N Engl J Med 2005;352: Rheumatoid Arthritis: The Disease Model 17 Cytokine Signaling Pathways Involved in Inflammatory Arthritis Choy E and Panayi G. N Engl J Med 2001;344:

7 If cytokines are the problem, what is the solution in RA? Cytokine inhibitors Cyclosporine, infliximab (Remicade ), etanercept (Enbrel ), corticosteroids IL-1 receptor antagonist Anakinra (Kineret ), others 19 How does inflammation contribute to the development of anemia of chronic disease? 20 Inflammation and Anemia of Chronic Disease Effect of inflammation-associated cytokines Decreased responsiveness of erythrocyte precursors to erythropoietin Decreased erythropoietin production Impaired mobilization of iron from macrophages 21

8 And the clinical outcome 22 Sabrina 29 year-old woman with 6 mo hx Early morning stiffness involving multiple joints Fatigue I can sleep 10 hours and I am still tired. 15 lb (6.8 kg) involuntary weight loss My appetite is not great but I still think I have lost too much weight. 23 Sabrina Hemoglobin=9.8 g/dl (12-16 g/dl) (98 g/l { g/L}) Hematocrit=31% (37-47%) (.31 proportion { proportion}) RBC=3 million ( million) MCV=84 fl (81-99 fl) RDW=12.4% ( %) (.124 proportion { proportion}) 24

9 Sabrina Platelets=620,000 mm 3 (150K- 450K) ESR=45 mm/h (<15 mm/h) Indirectly measures many proteins associated with inflammation 25 Cachexia and Inflammatory Disease Implicated in loss of body mass (skeletal muscle, fat, bone mass) that occurs in severe chronic inflammatory disease Interleukin-1ß Interleukin-6 Tumor necrosis factor Interferon 26 True or false? The anorexia that accompanies an acute febrile illness is likely influenced by cytokine activity. The fatigue and sleepiness that is associated with inflammatory states helps reduce demands for energy. 27

10 Reactive Thrombocytosis Precipitating event present Acute blood loss Infection Inflammatory disease IDA Malignancy Interleukin-6 implicated 28 Implicated in Reactive Thrombocytosis Due to promotion of platelet production Interleukin-6 Interleukin-1 Tumor necrosis factor Source- Chen, J., Afsari, K., Reactive Thrombocytosis Caused by Infection. Infect Med 19(10): , Reactive Thrombocytosis Platelet count>600,000 mm 3 Absent Splenomegaly Typically absent (until=>1 million) Clotting risk 30

11 Reactive Thrombocytosis: True or false? Reactive thrombocytosis quickly resolves when the underlying cause is treated. 31 The Contribution of Inflammation to Other Disease Processes 32 Are adipose cells simply fat storers or metabolically active? Old thought Fixed state where these cells increase and decrease in size but not in number 33

12 Are adipose cells simply fat storers or metabolically active? Newer thought Secrete specialize cytokines (adipokine) including TNF TNF exacerbates insulin resistance by desensitizing insulin receptors 34 Are adipose cells simply fat storers or metabolically active? Adipose tissue also contains numerous macrophages, which provide a rich source of TNF- and interleukin-6, consistent with the view that adiposity is a form of chronic, low-grade inflammation. Source- Charo, I., Ransohoff, R. The Many Roles of Chemokines and Chemokine Receptors in Inflammation. NEJM. Volume 354: February 9, 2006 Number Visceral vs. Subcutaneous Fat 36

Women with PCOS have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1).

13 Inflammation and Cardiovascular Disease: Is Abdominal Obesity the Missing Link? TNF- IL-6 CRP?? Adipose Tissue? Atherogenic, insulin resistant dysmetabolic milieu Risk of acute coronary syndrome Després JP. Int J Obes Relat Metab Disord. 2003;27:S22-S Which came first? Insulin resistance or inflammation? Women with PCOS have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1). 38 Which came first? Insulin resistance or inflammation? It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation. Source- Dhindsa G, Bhatia R, Dhindsa M, Bhatia V. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome. J Postgrad Med 2004;50:

Pathophysiological Characteristics of Polycystic Ovary Syndrome (PCOS) Nestler J. N Engl J Med 2008;358:47-54 40 PCOS Information for Young Women from Children s Hospital, Boston http://www.

14 Pathophysiological Characteristics of Polycystic Ovary Syndrome (PCOS) Nestler J. N Engl J Med 2008;358: PCOS Information for Young Women from Children s Hospital, Boston pcosinfo.html, accessed Morrow, D., Screening for Cardiovascular Risk with C-reactive Protein screening-for-cardiovascular-riskwith-c-reactive-protein#h6, accessed

15 Per Recommendations of UpToDate For patients with intermediate-risk for CVD by Framingham risk score (i.e. 10 to 20 percent risk at 10 years) who do not otherwise qualify for lipid lowering therapy, we suggest a screening measurement of hs-crp. 43 Per Recommendations of UpToDate A value above 10 mg/l should prompt consideration of a source of infection or inflammation, with repeat measurement of hs-crp in two weeks. 44 Per Recommendations of UpToDate A value of 3 to 10 mg/l should prompt a discussion regarding overall CVD risk, life-style modifications, management of risk factors for atherosclerosis, and the possibility of risk reduction therapy using a statin. 45

16 Per Recommendations of UpToDate A value of 1 to 3 mg/l should be repeated in two weeks to determine an average value and prompt a discussion regarding lifestyle modifications and the potential for treatment with a statin if the hs-crp value is 2.0 mg/l or greater. 46 Per Recommendations of UpToDate A value<1 mg/l suggests a lower risk of future CVD events. CV risk calculator incorporating hs-crp Source- Available at accessed Is the inflammation as part of coronary disease a done deal or can select lifestyle changes help minimize this risk? 48

17 Lipoprotein Classes and Inflammation Chylomicrons, VLDL, and their LDL catabolic remnants >30 nm nm Potentially proinflammatory Doi H, et al. Circulation. 2000;102: ; Colome C, et al. Atherosclerosis. 2000;49: ; Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15: HDL 9 15 nm Potentially antiinflammatory 49 hs-crp (mg/l) Effect of Statin Therapy on hs-crp Levels at 6 Weeks *p<0.025 vs. Baseline * * * 0 Baseline Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) Jialal I et al. Circulation 2001;103: The Diabetes Prevention Program Research Group 3,234 adults with impaired glucose tolerance Intensive lifestyle modification Metformin (up to 850 mg BID) Placebo 51

18 The Diabetes Prevention Program Research Group Effects on CRP at 1 y in men -33% in lifestyle group Weight loss most predictive -7% in the metformin group +5% in placebo group 52 The Diabetes Prevention Program Research Group Effects on CRP at 1 y in women -29% in lifestyle group Weight loss most predictive -14% in metformin group 0% in placebo group Source- Diabetes May;54(5): Fat is a problem, but does the way you get rid of it make a difference? Conclusion- Abdominal liposuction does not significantly improve obesity-associated metabolic abnormalities. Decreasing adipose tissue mass alone will not achieve the metabolic benefits of weight loss. Source- Absence of an Effect of Liposuction on Insulin Action and Risk Factors for Coronary Heart Disease, NEJM Vol 350: June 17, 2004 Number

19 Fatty Acids Molecule consisting of chain of 4 to 28 carbon atoms linked to carboxylic acid end (COOH) Short, medium, long-chained fatty acid depending on length of C chain Saturated=No double bonds, solid at room temperature (RT) Unsaturated=Double bonds, liquid at RT 55 Saturated vs. Unsaturated Saturated fatty acids appear to have a negative impact on lipoprotein levels Increasing VLDL, LDL, and reducing HDL Also help build more rigid cell membranes Unsaturated fatty acids appear to have a positive impact on lipoprotein levels Decreasing VLDL, LDL, and raising HDL Also help build more flexible cell membranes 56 Dietary Essential Fatty Acids Ratio of intake important Early humans (hunter gatherers) consumed omega-6: omega-3=1-2:1:1 Modern American diet (omega-6: omega- 3)=Approximately 20-30:1 Too much intake of processed foods high in saturated fats and omega-6 oils Low consumption of omega-3 oils; cold-water fish, and wild meats 57

Metabolic Syndrome. Bill Roberts, M.D., Ph.D. Professor of Pathology University of Utah

Metabolic Syndrome. Bill Roberts, M.D., Ph.D. Professor of Pathology University of Utah Metabolic Syndrome Bill Roberts, M.D., Ph.D. Professor of Pathology University of Utah Objectives Be able to outline the pathophysiology of the metabolic syndrome Be able to list diagnostic criteria for