INFLAMMATION & DISEASE

Jessica Nagelkirk, ND September 27, 2013 Marquette General Hospital Nutrition and Medicine Conference

Disclosures

Wait, youre an ND not an MD?

Naturopathic physicians are primary care providers who

have graduated from an accredited 4-year medical school after obtaining a bachelor degree that includes premedicine studies.
Complete nearly identical training in the basic sciences,

physical, laboratory, and imaging diagnostics, pharmacology, and minor surgery procedures as conventional medical school.
Pass a national board examination comparable to the

USMLE step 1, 2, and 3 board examination.

Complete a residency program in family medicine.

In addition to conventional training

Naturopathic physicians are experts in the use of
Nutritional IV Therapy
Clinical Nutrition Botanical Medicine Lifestyle Counseling Environmental Medicine Physical Medicine Hydrotherapy Homeopathy

Prasad S, et al. Age-associated chronic disease required age-old medicine: chronic ifnlammation. Prev Med. 2012 May; 54

Inflammation and Disease

Inflammation occurs by both immune and non-immune

mediated mechanisms.
Both pathways lead to the production of reactive oxygen

species (ROS), that alter cell metabolism, genes, and epigenetics.

This sustained inflammatory/oxidative environment leads

to a vicious cycle eventually moving from physiologic dysfunction to true physical pathology.

Immune Mediated Mechanism

Phospholipid/ Non-Immune Mechanisms

Linoleic Acid
From plant based omega-6 fatty acids like nuts, seeds, grains, etc

Arachidonic Acid
From animal based omega-6 fatty acids

Alpha-Linoleinic Acid
From fish and plant based omega-3 fatty acids like flax Delta-6 Desaturase

Delta-6 Desaturase Delta-5 Desaturase

5-lipoxygenase

COX I & II

GLA
Found in borage, black currant, evening primrose, human milk

Leukotrienes

PGE2

EPA

DGLA

DHA

PGE1

Note: Some people are deficient in delta-6 desaturase, an enzyme promoted by vitamin B3, B6, Mn, C, E and inhibited by alcohol and stress.

PGE3

Gastroenterology 2012; 143:550-563 (DOI:10.1053/j.gastro.2012.07.009 )

Inflammation and Alterations

Simone R, et al. Oxidative Stress, inflammation, & Cancer. Free Radical Biology and Medicine 2010

ROS-Linked Pathology
Diseases

Cancer

Acute respiratory distress syndrome Aging Alzheimer Atherosclerosis Cardiovascular disease Diabetes Inflammation Inflammatory joint disease Neurological disease Obesity Parkinson Pulmonary fibrosis Rheumatoid arthritis Vascular disease

Bladder Brain Breast Cervical (secondary to HPV) Gastric Liver Lung Melanoma Multiple myeloma Leukemia Lymphoma Oral Ovarian Pancreatic Prostate sarcoma

Daily Aspirin
Aspirin is the acetylated form of salicylic acid.

It inhibits prostaglandin synthesis decreasing

inflammation but also causes GI bleeding. Data concerning colorectal cancer has become very compelling with regard to aspirins capacity to prevent primary disease. Recent data from multiple trials suggest that long-term daily use of aspirin lowers risk for colorectal cancer. Chronic inflammation has been linked to heart disease, neurological disorders and cancer.

http://archives.focus.hms.harvard.edu/2004/Oct15_2004/anesthesia.html

Aspirin
Aspirin inhibits

cyclooxygenase (COX)-1. It also acetylates COX-2 turning arachidonic acid into the intermediate 15-RHETE which is transformed into the anti-inflammatory ALT by neutrophils.

Aspirin and White Willow Bark (Salix alba)

Salix alba is considered to be the natural form and original

source of the modern aspirin.

Contains phenolic glycosides salicin and salicylic acid

It is the acetylation process of aspirin that allows it to act

on the COX-2 pathway decreasing inflammation.

White Willow Bark and other salicylate-containing herbs

are anti-inflammatory without danger to the stomach, but do not utilize the same COX-2 pathway mechanism, instead it down regulates COX expression.

Anti-inflammatory Plant Constituents

Cyclooxygenase Inhibitors Flavonoids Phenolic Phenylpropane derivatives Naphthoquinones Akyl amides Tannins 5-Lipoxygenase Inhibitors Phenolic structures Arachidonic acid analogs Long-chain unsaturated fatty acids PAF Inhibitors Ginkgolides Lignans and neolignans

Plants Containing Steroid Precursors

Examples: Glycyrrhiza gabrra (Licorice)
Dioscorea villosa (Wild

Yam)
Most useful for auto-

immune inflammation

Essential Oil-Rich Plants

Examples: Matricaria recutita (Chamomile) Calendula officinalis (Calendula) Hypericum perforatum (St. Johns Wort) Effective for digestive

system inflammation with taken PO. Effective for skin inflammation when used topically.

Histamine Blocking
Examples: Tanacetum parthenium (Feverfew) Scutellaria bailcalensis(Chinese Skullcap) Ginkgo Biloba

Inflammatory Enzyme Modulating

Phosphodiesterase

Inhibitors
Camellia sinensis (tansy) Berberis (Oregon Grape)

Lipoxygenase Inhibitors Quercitin containing herbs like Nettles Cyclooxygenase

Inhibitors
Salicylate containing herbs

like Betula (birch), Populus (Poplar), or Gaultheria (Wintergreen)

Other Types
Many herbs seem to act in anti-inflammatory fashion but

have no known chemical anti-inflammatory component.

Coleus orskholii, Bupleurum, Tanacetum parthenium, Zingiber officinalis, Glycyrrhiza glabra, Scutellaria bicalensis, Panax ginseng, Crataegus oxyacantha, Zizphus, Asarum, nidium, Phellodendron, Copis aponica, Allium cepa, Picrorrhiza kurroa, Tylophora asthmatica, Capsella bursa, Ginkgo biloba, Camellia sinensis, Berberis, Schisandra, Magnolia, Curcuma longa, Ananas comosus, Calendula officinalis, Matricaria spp, Ficus elastica, Hypericum perforatum, Arnica montana, Vaccinium myrtillis, Silybum marianum, Betula, Salix, Populis, Filipendula, Gaultheria, Spirea, Cimicifuga, Linum ussitatissimum, Borago, Ribes, Onethera, Smilax, Yucca, Centella, Hemidesmmus, Ganoderma, Coleus, Eleuthrococcus, Aloe vera, Lentinus, Chlorella, Cinnamomum, Artemesia, Lavendula, Apium graveolens, Carica papaya, Eugenia, Commiphora mukul, Angelica sinensis

Turmeric (Curcuma longa)

Turmeric
Effects Anti-inflammatory Antiplatelet aggregation Antioxidant Antimicrobial Inhibits carcinogenesis Carminative Key Constituents Essential Oil containing sesquiterpene ketones, zingiberene, phellandrene, sabinene, cineole, and borneol Yellow pigments known as diarylheptanoids including curcumin and methoxylated curcumins

Pharmacodynamics of Turmeric
Curcumin appears to undergo rapid biotransformation

during and after gastrointestinal absorption. It has been found that 40-85% of an oral dose of curcumin passes through the gastrointestinal tract unchanged. Due to its low rate of absorption, it is often formulated with bromelain and black pepper for increased absorption as well as enhanced anti-inflammatory effects.

Curcuma longa monograph. Natural Medicines Comprehensive Database

Anti-inflammatory Activity of Turmeric

The anti-inflammatory activity of curcumin was reported as far

back as 1937.
In an extension of this work, it was reported that oral doses of

curcumin possess significant anti-inflammatory action in both acute and chronic models.
MOA: Dual inhibitor of arachidonic acid metabolism via

modulation of COX-2, prostaglandins, leukotrienes, and other cytokine pathways in the pro-inflammatory signaling pathway.
Dual inhibitors of AA are attracting interest as anti-inflammatory

agents since they prevent potentially damaging effects of increased leukotriene production which can result from the use of only COX inhibitors such as aspirin.

Evidence Based Medicine

A search for Curcuma longa and inflammation on PubMed

yielded 162 results.

Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis. Phytother Res. 2013 Aug 7. doi:10.1002/ptr.5045. This meta-analysis found that ingestion of curcuminoids significantly decreased CRP levels. The degree of effect was dependent on bioavailability of curcuminoid compounds used and the duration of use. The highest yield was amongst subject ingestion a bio-availability improved curcuminoid for greater than or equal to 4 weeks.

Evidence Based Medicine

Immune-stimulatory and anti-inflammatory activities of Curcuma longa extract and its polysaccharide fraction.
Pharmacognosy Res. 2013 Apr;5(2):71-9. doi: 10.4103/0974-8490.110527. Chandrasekaran CV, Sundarajan K, Edwin JR, Gururaja GM, Mundkinajeddu D, Agarwal A.

This study demonstrated that an aqueous solution of

curcuma longa, devoid of curcuminoids, continued to possess anti-inflammatory qualities. This solution appeared to inhibit IL-12 and PGE2 in vitro. This study highlights the complexity of herbal therapeutic action. Even when we identify a therapeutic action, the synergistic action of the whole plant is often more complex.

Evidence Based Medicine

Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol. 2013
Aug;169(8):1672-92. doi: 10.1111/bph.12131. Aggarwal BB, Gupta SC, Sung B.

This meta-analysis examines curcuma longas effects on

TNF and discusses its role as an adjunct or substitute to pharmacologic TNF blockers. This analysis references studies from as early as 1937 demonstrating efficacy of turmeric in treating inflammatory diseases in patients. There are studies documenting curcumins efficacy in treating many inflammatory diseases including rheumatoid arthritis, IBD, many cancers, diabetes, and heart disease.

Evidence Based Medicine

Comparative evaluation of the pain-relieving properties of a lecithinized formulation of curcumin (Meriva()), nimesulide, and acetaminophen. J Pain Res. 2013;6:201-5. doi: 10.2147/JPR.S42184. Epub 2013 Mar 8.
Di Pierro F, Rapacioli G, Di Maio EA, Appendino G, Franceschi F, Togni S.

This pilot study investigated the acute analgesic activity of the curcumin

derivative Meriva. Meriva was compared to nimesulide and acetaminophen and demonstrated an effect comparable to acetaminophen but less than nimesulide. Meriva was more well tolerated than nimesulide and comparable to nimesulide. Meriva was utilized at a larger dose than for chronic inflammation (2 g vs 500 mg) in order to achieve this acute analgesic effect. The effect is thought to stem from COX 2 inhibition and desensitization of receptor potential A1 (a receptor that also mediates the analgesic effects of acetaminophen). Additionally, the authors speculate that the long term attenuation of inflammation from the acute supplementation of Meriva would lead to better control of acute pain.

Mills S, Bone K. Principles & Practice of Phytotherapy

Turmeric in Clinical Practice

Preparations: Dried root may be used as a decoction; liquid extract, or capsules. Dosage: Powdered rhizome provided at a heaped teaspoon (about 4 grams) mixed with water to a slurry and drank 1-2 times daily. A teaspoon of lecithin can be added to improve absorption. 1:1 liquid extract using 45% ethanol or higher recommended at 5-14 ml per day best taken in 4 equal doses throughout the day Encapsulated common sig is 500 mg QID Duration of use & safety: May be taken long term within the recommended dosages. No adverse effects from ingestion of turmeric have been documented at the recommended dosages.

Omega-3 Fatty Acids

Eicosanoids & Inflammation

Eicosanoids are signaling molecules made by

oxygenation of 20-carbon PUFAs Metabolism product of COX and LOX enzymes Modulate:
Cell growth and differentiation

Intensity and duration of inflammatory response

Immunity Platelet Aggregation Angiogenesis

Include: Prostaglandins (PG) Thromboxanes (TX) Leukotrienes (LT)

EPA and DHA

>15,000 studies

published in past 40 years on health benefits of EPA & DHA

EPA and DHA are

natural COX-2 inhibitors

Conversion Pathway of Omega-3 FA

Flax, hemp, canola oils and walnuts

Alpha-Linolenic Acid (ALA) 18:3n-3 Stearidonic Acid 18:4n-3 Eicosatetraenoic Acid 20:4n-3

6-desaturase
Cofactors: B3, B6, Mg, Zn Vit C Inhibited: alcohol, trans fats, diabetes, hyperinsulinemia

Hemp, modified vegetable oils, fish

Fish, Fish Oil

Eicosapentaenoic Acid (EPA) 20:5n-3 Docosapentaenoic Acid (DPA) 22:5n-3 Docosahexaenoic Acid (DHA) 22:6n-3 Anti-Inflammatory Resolvins & Protectins

Fish, Fish Oil, Algae

Dong-Soon IM. Omega-3 fatty acids in anti-inflammation on GPCRs. Progress in Lipid Research. July 2012. 51(3):232-237

Resolvins & Protectins

Anti-inflammatory actions that lead to the resolution of

the inflammatory cycle

Experimental evidence indicates that resolvins and

protectins reduce cellular inflammation by stopping excessive neutrophil infiltration and clearing apoptotic PMN leukocytes from sites of inflammation
They are synthesized from either eicosapentaenoic acid

(EPA) or docosahexaenoic acid (DHA)

Both series of resolvins (E and D) increase with use of

low dose aspirin or supplementation with EPA/DHA

Evidence Based Medicine

N-3 polyunsatruated fatty acids: relationship to inflammation in healthy adults and adults exhibiting features of metabolic syndrome.
Robinson LE, Mazurak VC. Lipids. 2014 Apr;48(4)319-32.

This review article supports the recommendation that a diet rich in omega-3 fatty acids plays a role in the prevention and reduction of inflammation.

Evidence Based Medicine

Omega-3 fatty acids and inflammatory processes.
Calder PC. Nutrients. 2010 Mar;2(3);355-74

This review article evaluated the mechanisms in which EPA and DHA modulate inflammation in which they concluded a variety of mechanisms were involved. Anti-inflammatory actions of marine n-3 PUFAs were specifically identified to be useful in inflammatory conditions including RA and atherosclerosis, however the authors speculate n-3 PUFAs would be useful in nearly all inflammatory conditions due to the known MOA.

Williams CM, Burdge G. Long-chain n-3 PUFA: Plant v. marine sources. Proc Nutr Soc. 2006 Feb; 65(1):42-50

Is Conversion of ALA to LCPUFA Efficient?

ALA 18:3n-3 An intake of 2 grams of ALA would yield approximately 160 mg EPA at a conversion rate of 8% and approximately 10 mg DHA at a conversion rate of 0.5%. EPA 20:5n-3 DPA 22:5n-3 0.2-8% Conversion

0.13-6% Conversion

DHA 22:6n-3

Trace- 0.5% Conversion

Omega-3 as Inflammatory Modulator in Clinical Practice

Ratio 1:2 EPA:DHA Dose 3 grams EPA+DHA po qd Reference Health Canada Warning: Make sure to have your patients purchase

products that undergo third party testing for purity and content.

Giugliano D, et al. The effects of diet on inflammation. Journal of Amer Col Card. 2006. 48(4)

Anti-Inflammatory Diet
Low consumption of fruit and vegetables, together with physical inactivity, are now among the top 10 causes of mortality in developed countries.

What is an anti-inflammatory diet?

It depends who you ask.

Several different versions, that all have the same basic

guidelines:
Increase omega-3 fatty acids Increase anti-oxidants

Decrease processed foods

Decrease alcohol and caffeine Eliminate known allergens Eliminate sugar

Some guidelines go further and eliminate: Nightshade vegetables (potato, tomato, eggplant, bell peppers etc.) Common allergens like soy, peanuts, gluten, dairy, & eggs

Sears B, Ricordi C. Anti-inflammatory nutrition as a pharmacological approach to treat obesity. J Obes. 2011

MOA of Diet and Inflammation

Dietary intake of arachidonic acid up-regulates

prostaglandin synthesis. Increased prostaglandin and inflammation leads to insulin resistance and lipid oxidation. This leads to increases in silent inflammation and obesity. Greater intake of antioxidant containing foods reduces inflammatory cytokines and mitigates this process.

Inflammation and Disease

Inflammation has been implicated in many chronic

diseases. There are many ways to decrease inflammation through diet and lifestyle. Herbs and fish oil are a helpful adjunct to these interventions. By addressing inflammation as a preventive measure, we can work towards increasing quality of life and decreasing morbidity and mortality in our patients.

Contact Information

Jnagelkirk@ncnm.edu
503-552-1874