Inflammation and Chronic Disease

Judith Boice, N.D., L.Ac.

You likely are very aware of the symptoms of acute inflammation. After falling on your knee, for example, you may experience pain, swelling, redness and heat in the area where you landed. These acute inflammatory symptoms are designed to protect the immediate area, walling off that region from further damage. Although these reactions are protective in the short term, they slow healing in the long run because they also impede the delivery of nutrients to repair the damaged area.

Chronic inflammation can be more difficult to detect. This low-level of inflammation may not be obvious using most clinical testing methods. Ongoing infection, repeated injuries, chemical exposures, irradiation, bacteria, viruses and fungi all can contribute to chronic inflammation. Another huge contributing factor that we will discuss in more detail below is the quality and quantity of food we eat.

Most physicians monitor severe inflammatory conditions, such as rheumatoid arthritis (RA), with a test called “sedimentation rate,” or “sed rate” for short. This test measures how quickly red blood cells in a test tube clot together and sink to the bottom of the test tube. The more inflammation in the body, the faster the blood cells clot and sink to the bottom of the tube.

When people suffering with Rheumatoid Arthritis go “into remission,” the periods between bouts of acute inflammation, the sed rate may be normal. Chronic, low level inflammation, however, continues to affect the body.

One of the primary tests used to track sub-clinical levels of inflammation (below the level most conventional tests would detect) is C-reactive protein (CRP). This test is an indirect measure of inflammation. Elevated CRP levels indicate increased inflammation in the body.

Over the past decade, conventional medicine has recognized that elevated CRP levels can contribute to a host of chronic conditions, including

• Alzheimer's
• Asthma
• Heart Disease
• Diabesity (a combination of diabetes and obesity)
• Rheumatoid arthritis
• Osteoarthritis
• Inflammatory Bowel Disease (Ulcerative colitis and/or Crohn's Disease)

Alzheimer's Disease

For years researchers assumed age caused changes in brain tissue. Newer thinking points to inflammation as the cause of neurological changes that lead to Alzheimer's.

Dr. Perlmutter first proposed the idea that inflammation, or “fire,” as he colorfully described it, was the primary catalyst for Alzheimer's and other forms of dementia. Research demonstrated that patients who regularly used anti-inflammatory drugs had lower incidence of Alzheimer's disease. Regular ibuprofen users reduced their risk for developing Alzheimer's to only 40% of those who did not take ibuprofen. Aspirin users reduced risk by 26%. Acetaminophen users, however, had a 35% increase in their risk for developing Alzheimer's, possibly because of the toxic metabolites which reduce glutathione.(1, 2, 3, 4)

Perlmutter emphasizes the best treatment is preventative, i.e. minimizing inflammation so that brain changes never begin. Reducing brain inflammation once it has begun is difficult, as cerebral inflammation tends to be self-perpetuating. (5, 6)

Lowering blood sugar levels is an extremely effective way of protecting the brain from age-related damage. A Dutch study revealed that type II diabetics taking insulin had four times the risk of developing dementia. Those who ate fewer calories had fewer free radicals, and therefore less damage. Lower glucose levels also means less glycosylation, i.e. protein damage caused by elevated glucose levels. (7)

Heart Disease

For many years, total cholesterol levels and the ratio of LDL (“bad” cholesterol) to HDL (“good” cholesterol) were considered the best predictors of heart disease. In the early 1990's, however, researchers began to recognize a stronger correlation between elevated homocysteine levels and heart disease than elevated cholesterol and heart disease. (8) High levels of homocysteine, an amino acid, are associated with a range of chronic inflammatory conditions including heart disease, arthritis, and osteoporosis.

Another study, released in 2002, further undermined the conventional medical world's assumptions about heart disease. C-reactive protein, or CRP, was shown to be a better predictor of heart disease than cholesterol levels. In fact, even small, seemingly insignificant cholesterol plaques along blood vessel walls could “blow up” under the influence of CRP.

In a recent study, patients with low cholesterol levels were given Rosuvastatin, a statin drug. Although their cholesterol levels did not change, their CRP levels dropped by 37%! Most physicians have assumed the benefits of statin drugs were related primarily to their cholesterol lowering effects. This new study demonstrates that an even greater benefit may be from the CRP-lowering effects of the statin drugs. (9)

Blood sugar levels also directly impact blood vessel health. When blood sugar levels run high, nitric oxide (NO) levels plummet. Nitric oxide supports blood vessel elasticity and dilation, and therefore helps lower blood pressure levels. Recent research shows L-arginine, an amino acid, can increase NO levels. Save your money, though. Five different enzymes quickly break down L-arginine. You need to dose L-arginine every 4 -5 hours to maintain steady blood levels. Pomegranate juice protects against the break-down of L-arginine, thereby increasing NO levels. You also can increase NO (with no additional supplements!) by reducing calories and steadying blood sugar levels.

The bottom line: although cholesterol levels can dramatically affect blood vessel health, homocysteine and CRP levels are better predictors for heart disease.

Remember we can reduce CRP and homocysteine levels with nutrients and lifestyle choices, NOT just drugs.

Asthma

Usually allergic reactions trigger asthma, e.g. an allergy to pollen or dust. Exercise and cold exposure also can stimulate an asthma attack. Recent research shows roughly half of the asthma sufferers in the U.S. whose symptoms begin in adulthood have no allergic tendencies, but they do have significantly elevated CRP levels. I've worked with several patients who fall into this category. Some are diagnosed with “asthma” and other with “reactive airway disease,” or RAD.

Obesity + Diabetes = Diabesity

For years we have known that carrying too many pounds can increase insulin resistance. Newer evidence suggests that the cell receptors resist insulin because of inflammation triggered by fat cells. Fat cells release inflammatory cytokines which in turn trigger an inflammatory cascade in the body that inhibits cell response to insulin. (10, 11, 12)

Reduced response to insulin may continue for many years before someone is diagnosed with diabetes. This period of impaired blood sugar control has many names, including metabolic syndrome, insulin resistance, syndrome x, and borderline diabetes. People struggling with blood sugar regulation often have high triglyceride levels, reduced HDL (the “good” cholesterol), increased inflammation, three times the risk for heart attack, higher risk for stroke and diabetes.

Insulin is a vital hormone that “unlocks” cell walls so that blood sugar can enter. Imagine a long corridor in a hotel, with rooms on either side of the hallway. Each room represents a separate cell. Insulin “unlocks” the door so that blood sugar can enter the cell. Without insulin, blood sugar would continue to mill around in the hallway, waiting for a “door” to open.

Someone may produce enough insulin, but the insulin may fail to “unlock” the cell door. The cell “locks” are resistant to insulin's effect, and blood sugar continues to circulate in the hallway while the cells are empty. In essence the cells are “starving in a sea of plenty.”

Inflammatory bowel disease

The primary inflammatory marker associated with Inflammatory Bowel Disease is tumor necrosis factor-alpha (TNF-alpha). This tumor marker, produced by macrophages in the immune system, destroys and suppresses tumor cells. Researchers have discovered TNF-alpha is elevated with sepsis (systemic infection), autoimmune diseases (included rheumatoid arthritis), psoriasis, and inflammatory bowel disease.

Stress increases systemic inflammation

Recent research demonstrates that increased stress causes spikes in cortisol, which in turn increase inflammation in the body. Increased stress can contribute to Alzheimer's disease, heart disease, blood sugar dysregulation and diabetes.

Inflammatory and anti-inflammatory pathways in the body

Most of the inflammatory reactions in our body are mediated by a group of fatty acids called prostaglandins. Our bodies have three prostaglandin pathways that either increase or reduce inflammation in the body:

PGE1 (prostaglandin 1)

• Reduces inflammation
• Decreases blood pressure
• Reduces allergic reaction
• Increases mucous production in the stomach
• Increases immune response
• Promotes nerve function

Food sources of PGE1: the body uses linoleic acid, an essential fatty acid, to make PGE1 in the body. “Essential” fatty acids must be consumed in our diets. We cannot produce them internally; hence, they are essential to include in our diet. Food sources of linoleic acid include safflower oil, sesame oil and seeds, evening primrose oil, black currant seed oil, borage oil, soy oil, corn oil, gamma linolenic acid (GLA), and breast milk.

PGE2

• Increases inflammation
• Suppresses immune function
• Promotes allergy response
• Increases platelet aggregation (how easily platelets in the blood stick togther, forming micro-clots along blood vessel walls)
• Increases smooth muscle contraction/spasticity

Food sources of PGE2: meats, dairy products including human breast milk.

PGE3

• Reduces inflammation
• Inhibits the release of PGE2
• Increases HDL, the “good” cholesterol
• Decreases triglycerides
• Decreases platelet aggregation

Food sources of PGE3: the body uses alpha-linolenic acid to make PGE3 in the body. Foods rich in alpha-linolenic acid include EPA (fish oil), DHA (fish oil), flaxseed oil (the richest natural source of omega-3 fatty acids), walnuts, pumpkin seeds, soybeans, and hemp seeds and oil.

What's the correct ratio of Omega-6 and Omega-3 essential fatty acids?

Ideally we would eat four parts Omego-6 essential fatty acids to one part Omega-3. Most Americans, however, eat far too much of the Omega-6 fatty acids, often twenty times as much as the Omega-3's.

You can help rectify this imbalance in two ways:

1. Reduce overall fat consumption. Most Americans eat 4 – 50% of their calories from fat. In contrast, most traditional Asian diets rely on fat for 10 – 20% of their calorie intake!
2. Increase foods rich in Omega-3 fatty acids: fish and fish oil; freshly ground flax seeds and flax oil; pumpkin seeds; freshly ground hemp seeds and hemp oil.
3. For more information visit fats and oils, the extended article about fats and oils.

What are NSAIDs doing in my body?

Pharmaceutical drugs prescribed for pain and inflammation disrupt different parts of the prostaglandin pathways. As we walk through those pathways, you will see that the drugs intentionally block some pathways while inadvertently interrupting others.

Phospholipase A2 (PLA2) is an enzyme that catalyzes the release of arachadonic acid from the membrane of the cell walls. Arachadonic acid is the first building block in the cascade of reactions that fuel inflammation in the body.

Cyclooxygenase, another enzyme, triggers the conversion of arachadonic acid to PGE2, thromboxanes and prostacyclins – three different types of inflammatory substances in the body.

Cyclooxegenase-1 pathway promotes the formation of the stomach lining, while the cyclooxygenase-2 pathway promotes inflammation. Pharmaceutical anti-inflammatory drugs inhibit both cyclooxygenase pathways. In other words, they reduce inflammation and they block the formation of the stomach lining, thereby damaging the stomach lining over time.

In addition, NSAIDS block all three prostaglandin pathways, thereby reducing both inflammatory and anti-inflammatory pathways.

Lipoxygenase, yet another enzyme, catalyzes the conversion of arachadonic acid into other inflammatory prostaglandins.

Most of us have been trained to address pain and inflammation by taking steroids (prednisone and other steroid drugs) and non-steroidal anti-inflammatories (NSAIDS). These drugs do reduce inflammation, but at great cost to the body

Steriod anti-inflammatories

Steroid drugs reduce immune function and, with long term use, damage connective tissue (e.g. bones, skin, internal organs). Steroids also increase blood sugar levels and encourage fluid retention.

NSAIDS

Non-steroidal anti-inflammatories block all three prostaglandin pathways, thereby inhibiting both inflammatory and anti-inflammatory activity in the body. NSAIDs block cyclooxygenase activity, inhibiting the production of PGE2 inflammatory prostaglandins, but also blocking the production of a healthy stomach lining.

Long term use of NSAIDS can damage both kidney and liver tissue. Liver damage is directly correlated with the dose. In other words, the higher the over-dose of an NSAID someone takes, the greater the liver damage. Kidney damage is related to changes in prostaglandins that normally cause the afferent arterioles of the glomeruli in the kidneys to dilate. Relaxing and opening these arterioles helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. NSAID use, particularly for someone with kidney disease, causes blood vessel constriction, which inhibits blood circulation within the kidneys. Over time, the NSAIDS can cause actual kidney damage.

What other options do I have for reducing inflammation?

Dietary

• Reduce meat, dairy and eggs in your diet. These foods contain arachadonic acid, which runs the PGE2 inflammatory pathways in the body.
• Reduce simple carbohydrates such as sugar, white flour and white rice. These foods increase acidity in the body. The more acidic the body, the more inflamed it becomes.
• Steady blood sugar levels. The more blood sugar spikes you have, the more acidic the body becomes. See (Jason, insert here) for more information about steadying blood sugar levels.
• Eliminate food intolerances. Unknowingly eating food intolerances also increases overall inflammation in the body. Even “healthy” foods may not be healthy for a particular person. Pears usually are listed on hypo-allergenic diets, for example, ye they are a severe intolerance for me, triggering severe inflammation in my body! A “healthy” diet is an individualized diet, one that suits your particular body.
• Increase fruits, vegetables, and other “alkaline-forming” foods. The more alkaline your body, the less inflammation.
• Add GLA, omego-3 and fish oil to your diet. These oils help run the PGE1 and PGE3 pathways, both of which support anti-inflammatory responses in the body.
• Add green tea to your diet (as long as this is NOT a food intolerance for you!). Research shows that theaflavin, a constituent in black and green tea, blocks the gene expression of cytokine interleukin-8 (IL-8).(13) Elevated IL-8 levels are associated with asthma, gum disease, inflammatory bowel disease, cancer, and cardiovascular disease. Both British and Japanese studies also demonstrated black tea reduces platelet aggregation, the beginning of the clotting cascade.(14, 15)
• Lose weight if you are overweight. Remember that fat cells release cytkines, which trigger inflammatory reactions in the body.

Reduce stress

• 10 deep breaths, 3 – 4 times a day. Deep breathing is one of the fastest, most effective ways of shifting the body from stress to relaxation.
• Meditation, at least 20 minutes once a day. Studies in the 1980's demonstrated that regular meditators have higher DHEA levels, which in turn reduce PGE2 (inflammatory) activity. More time spent in meditation (and deep relaxation) increases DHEA and reduces inflammation in the body. (16)
• Guided deep relaxation – during the day and/or at bedtime

Exercise

• “Uses up” cortisol and other stress-related hormones. Recent research comparing fit and unfit women found that women who exercised regularly released less cortisol in response to stressful events. (17) Remember that increased cortisol levels can contribute to Alzheimer's disease, cardiovascular disease, diabesity, and a host of other chronic, inflammatory conditions.
• Reduces muscle tension
• Strengthens bones
• Improves sleep

Increase sleep

• A study published in the February 15, 2011 issue of the Journal of Cancer demonstrated that people sleeping six or less hours per night had a 50% increase in the risk of developing colorectal adenomas. Adenomas are growths in the colon that can become malignant, e.g. turn into colon cancer.
• Improves immune function
• Improves short term memory and concentration

ENDNOTES

1. Alafuzoff I, et al. 2000. Lower counts of astroglia and activated microglia in patients with Alzheimer's disease with regular use of non-steroidal anti-inflammatory drugs. J Alzheimer's Dis 2:37-46.
2. Anthony JC, et al. 2000. Reduced prevalence of Alzheimer's disease in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 54(11):2066-71.
3. Lim GP, et al. 2000. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. Journal of Neuroscience 20:5709-14.
4. MacKenzie IR, et al. 1998. Nonsteroidal anti-inflammatory drug use an Alzheimer-type pathology in aging. Neurol 50:986-90.
5. Teismann P, et al. Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. PNAS 2003; 100 (9):5473-5478.
6. Pompl PN, et al. A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003; 10.1096/fj.02- 0876fje
7. Ott A, Stolk RP, van HF, et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999 Dec 10;53(9):1937-42.
8. Lambert J. et al. Familial hyperhomocysteinaemia and endothelium-dependent vasodilatation and arterial distensibility of large arteries. Cardiovasc Res. 1999 Jun;42(3):743-51.
9. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein. N Engl J Med. 2008 Nov 9.
10. Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003 Sep;41(9):1120-30.
11. Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008 Jul;149(7):3549-58.
12. Leiter EH, Reifsnyder PC, Xiao Q, Mistry J. Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice. Obesity (Silver Spring). 2007 Aug;15(8):1961-8.
13. Aneja R, Odoms K, Denenberg AG, Wong HR. Theaflavin, a black tea extract, is a novel anti-inflammatory compound. Crit Care Med. 2004 Oct;32(10):2097-103.
14. Steptoe A, Gibson EL, Vuononvirta R, et al. The effects of chronic tea intake on platelet activation and inflammation: a double-blind placebo controlled trial. Atherosclerosis. 2007 Aug;193(2):277-82.
15. Sugatani J, Fukazawa N, Ujihara K, et al. Tea polyphenols inhibit acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and platelet-activating factor-induced platelet aggregation. Int Arch Allergy Immunol. 2004 May;134(1):17-28.
16. MacLean CR, Walton KG, Wenneberg SR, et al. Effects of the Transcendental Meditation program on adaptive mechanisms: changes in hormone levels and responses to stress after 4 months of practice. Psychoneuroendocrinology. 1997 May;22(4):277-95.
17. Traustadottir T, Bosch PR, Matt KS. The HPA axis response to stress in women: effects of aging and fitness. Psychoneuroendocrinology. 2005 May;30(4):392-402.