Chronic Inflammation

Inflammation is the body’s response to injury. This is true regardless of whether the injury results from a cut, burn, bruise, infection, or even an autoimmune disease such as rheumatoid arthritis. The inflammatory response includes redness, swelling and an increased local supply of white blood cells. These changes are an attempt to ward off infections and to help repair damaged tissue. Even after trauma, however, the inflammatory response may be excessive and result in unnecessary pain. In some conditions, as with rheumatoid arthritis, the inflammation serves no useful purpose and is actually a component of the disease rather than part of the healing process.

 


Signs, symptoms & indicators of Chronic Inflammation

Lab Values - Cells  

High ESR or elevated ESR



 

Microcytic/macrocytic red cells



Symptoms - General  

Minor/major inflammations




Conditions that suggest Chronic Inflammation

Aging  


Inflammation  


 


 

Episcleritis

Episcleritis usually has no apparent cause; however, it is sometimes associated with systemic inflammatory conditions such as arthritis, lupus, and inflammatory bowel disease. Rosacea, herpes simplex, gout, tuberculosis, and other diseases are also occasionally underlying causes.



 


 


Lab Values  

Low Total Cholesterol

What we are beginning to find increasingly is that people who have low cholesterol probably have some kind of low grade or subclinical inflammation. [Journal of the American Geriatrics Society April 1999;47: pp.402-406]



 


Musculo-Skeletal  


 


Nervous System  


Respiratory  


 

Asthma

Asthma is simply a chronic inflammatory condition of the airways rather than some other part of the body, such as the joints. People with asthma have inflamed, hyperreactive airways that produce excessive bronchial mucus.



Tumors, Benign  

Tendency To Develop Polyps

Allergies and infalmmation are associated with polyp development. In a clinical trial that ended in the fall of 1998, it was found that nearly 80% of patients with sporadic colon polyps, the type that can develop into common colon cancer, had their polyps disappear or shrink after taking sulindac, a nonsteroidal anti-inflammatory drug (NSAID), for one year. “This was the first randomized, double-blind project to demonstrate that any drug inhibits premalignant sporadic polyps,” said DiSario, associate professor of gastroenterology at the School of Medicine.




Risk factors for Chronic Inflammation

Circulation  


Habits  

Lack of Sleep

A lack of sleep increases inflammatory cytokines. This helps explain why pain flare-up occurs in response to sleep deprivation in various disorders. Even modest sleep restriction adversely affects inflammatory cytokine levels. In a carefully controlled study, sleep deprivation caused a 40-60% average increase in the inflammatory marker IL-6 in men and women, while men alone showed a 20-30% increase in TNF-a. Both IL-6 and TNF-a are potent pro-inflammatory cytokines that induce systemic inflammation. [Endocrinol Metab Clin North Am. 2002 Mar;31(1): pp.15-36]



Hormones  

Low Adrenal Function / Adrenal Insufficiency

The adrenal glands produce hydrocortisol, the major natural anti-inflammatory steroid in the body. Without enough circulating cortisol there may be a tendency to become easily inflamed.



Lab Values - Chemistries  

(Highly) elevated CRP level



 

(Very) low serum iron



 

Elevated ferritin levels

Less common causes of elevated ferritin levels include the presence of chronic inflammatory disorders, acute hepatitis and Gaucher’s disease.



Counter Indicators
Lab Values - Chemistries  

Normal CRP level



Metabolic  

Problem Caused By Being Overweight

A higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years. These findings suggest a state of low-grade systemic inflammation in overweight and obese persons. [JAMA.1999;282: pp.2131-2135] Fat cells produce inflammatory mediators.



Nutrients  

EFA (Essential Fatty Acid) Requirement

In order to maintain proper balance of the antispasmodic and anti-inflammatory prostaglandins (PGE1 and PGE3) with the pro-spasmodic and pro-inflammatory prostaglandins (PGE2), it is critical to have the proper balance of essential fatty acids.

Without adequate amounts of both Omega-3 and Omega-6 oils in the diet, prostaglandin production will be reduced and problems may result.



 

Vitamin D Requirement

Researchers found that vitamin D deficiency is associated with increased inflammation in otherwise healthy people. Increased inflammation in the body can increase the risk of chronic inflammatory conditions, including coronary heart disease (CHD) and diabetes. Further, the researchers found that inflammation was lowered by the use of vitamin D. [

QJM 2002 Dec;95(12):787-96]



 


Supplements and Medications  

History of/occasional/regular COX-2 inhibitor use



Symptoms - Food - Intake  

Vegetable oil consumption

Because prostaglandin E2 is a culprit in inflammation, reducing the consumption of foods that are high in omega-6 fatty acids and increasing the consumption of omega-3 rich foods can be beneficial.



Symptoms - Muscular  

History of tendonitis




Chronic Inflammation suggests the following may be present

Cell Salts  


Circulation  


Nutrients  

Antioxidant Need/Oxidative Stress w/ Supplements

Chronic inflammation, like cigarette smoking, has a strong free radical component in it’s mechanism of action.



 

Antioxidant Need/Oxidative Stress w/o Supplements

Chronic inflammation, like cigarette smoking, has a strong free radical component in it’s mechanism of action.




Chronic Inflammation can lead to

Lab Values  



Recommendations for Chronic Inflammation

Animal-based  

Fish Oil / Krill

In addition to suppressing inflammatory cytokines (please see the link between Chronic Inflammation and DHA), the omega-3 fatty acids found in fish oil help suppress the formation of prostaglandin E2 and to promote synthesis of prostaglandin E3 – thus reducing inflammation.



Botanical  

Thyme

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin biosynthesis, and plays a key role in the inflammatory response. In that essential oils, extracted from plants, have been long used for their aromatherapy, analgesic, and antibacterial properties, Hiroyasu Inoue, from Nara Women’s University (Japan), and colleagues screened a wide range of commercially available essential oils to assess their anti-inflammatory properties. They identified six essential oils, namely — thyme, clove, rose, eucalyptus, fennel and bergamot – that reduced the COX-2 expression in cells by at least 25%. Of these, thyme oil proved the most active, reducing COX-2 levels by almost 75%. Upon further study, the researchers found that carvacrol, a compound present in thyme oil, was the primary active anti-inflammatory agent; when they use pure carvacrol extracts in their tests, COX-2 levels decreased by over 80%. [Mariko Hotta, Rieko Nakata, Michiko Katsukawa, Kazuyuki Hori, Saori Takahashi, Hiroyasu Inoue. “Carvacrol, a component of thyme oil, activates PPAR{alpha} and {gamma} and suppresses COX-2 expression.” J. Lipid Res., Jan 2010; 51: 132 – 139]

This action is similar to the way medications like ibuprofen (a non-steroidal anti-inflammatory drug) effectively treat pain and inflammation.

Warning: do not take thyme oil internally with significant dilution. A preparation will need to be made commercially if there is going to be any successful use of this herb internally for it’s anti-inflammatory action.



 

Turmeric Extract, Curcumin

Curcumin comes from the spice turmeric. The rhizome of this plant has been traditionally used as an anti-inflammatory agent in Ayurvedic medicine. Curcumin appears to reduce proinflammatory leukotriene synthesis and also promotes the breakdown of fibrin. In a double-blinded trial, patients receiving 1,200mg of curcumin per day experienced reductions in stiffness and joint swelling comparable to the effects of phenylbutazone, a potent anti-inflammatory drug. Curcumin has also reduced inflammation in surgical patients.



 


 

Herbal Combinations

Although we try to make generic recommendations and stay away from proprietary products, sometimes a company does provide a quality herbal combination product which we want to mention. ViaViente is such a product. One distributor’s page is located here.



 


 

Green / Oolong / BlackTea (Camellia sinensis)

Researchers at Case Western Reserve University gave arthritis-prone mice either green tea or water. The human equivalent of 4 cups of green tea daily halved the mice’s risk of developing arthritis. Also intriguing: TF-2, the anti-cancer compound in black tea, suppresses the Cox-2 enzyme that triggers inflammation, says research at Rutgers. That’s the same way the drugs Vioxx and Celebrex work.



 

Stephania tetrandra

Oral doses of 400-600mg per day have been used to suppress elevated interleukin-6 (IL-6), a proinflammatory cytokine.



 

Noni

“Some of the best results I’ve seen with noni juice were in patients with inflammation problems such as arthritis, tendonitis, bursitis, or carpal tunnel,” states Dr. Steven Hall, M.D. He feels that noni helps the body regulate itself and thereby control the inflammatory process.



Diet  

Therapeutic Fasting

Fasting promotes the resolution of inflammatory processes, as seen, for example, in rheumatoid arthritis.



 

Soy Isoflavones (genistein, daidzein)

An article published online on September 23, 2008 in the European Heart Journal reported the finding of researchers at the University of Hong Kong that consuming a soy isoflavone supplement improves vascular endothelial function and reduces C-reactive protein, a marker of inflammation.

In a randomized, double-blinded trial, 102 patients previously diagnosed with ischemic stroke were given an 80 milligram soy isoflavone supplement or a placebo for 12 weeks. Flow-mediated dilatation of the brachial artery, which assesses endothelial function by measuring the ability of the arteries to dilate following a period of impaired circulation, was evaluated on all participants at the beginning of the study and at the end of the treatment period. Fasting blood samples were analyzed for lipids, high-sensitivity C-reactive protein (CRP), markers of oxidative stress, and other factors.



 

Reduced Calorie Consumption

One of the most dangerous inflammatory cytokines that increases in the aged is interleukin-6 (IL-6). One of the benefits of caloric restriction is a marked reduction in IL-6 levels. Caloric restriction is considered the best-documented method to significantly slow aging, and reduced inflammation contributes to this effect.



 

Increased Fruit/Vegetable Consumption

Fruits and vegetable intake is important for reducing crp levels. It is thought that the fiber content helps to do this, though psyllium failed to do so in a study of overweight individuals without heart disease. [Annals of Family Medicine, March/April 2008]



 

Weight Loss

Obesity has been definitively linked to elevated levels of inflammatory blood markers such as C-reactive protein. Consuming lower-glycemic foods reduces the insulin surge that contributes to chronic inflammatory processes.



 

Raw Food Diet

Eating too much food cooked at high temperatures causes an increase in inflammatory cytokines. Most “junk” foods are cooked at extremely high temperatures, suggesting that these should be avoided.



 

Dairy Products Avoidance

Please see the link between Chronic Inflammation and Increased Protein.



 

Processed Foods Avoidance

Eating too much overcooked food (foods cooked at high temperatures resulting in glycation end products) causes an increase in inflammatory cytokines. Since most “junk” foods are cooked at extremely high temperatures, it makes sense to avoid french fries, hamburgers, potato chips, and other fried foods and snacks that are scorched with hydrogenated fats.

Glycation is the binding of a protein molecule to a glucose molecule, resulting in the formation of damaged protein structures.These destructive glycation reactions render proteins in the body cross-linked and barely functional, which results in age-related disease acceleration. As these degraded proteins accumulate, they cause cells to emit signals that induce the production of inflammatory cytokines (such as IL-6 and TNF-a).



 

High/Increased Protein Diet

It is important to avoid overconsumption of foods high in arachidonic acid such as beef, egg yolk, and dairy products. The enzymes cyclooxgenase-2 (COX-2) and 5-lipooxygenase (5-LOX) degrade arachidonic acid into inflammatory-inducing prostaglandin E2 and leukotriene B4.



Digestion  

Bromelain

Bromelain’s most common application is in the treatment of inflammation and soft tissue injuries. Bromelain’s anti-inflammatory activity appears to be due to a variety of physiological actions. It has been shown to speed healing from bruises and hematomas. Treatment with bromelain following blunt injuries to the musculoskeletal system results in a clear reduction in swelling, pain at rest and during movement, and tenderness. Administration of bromelain pre-surgically can reduce the average number of days for complete disappearance of pain and inflammation. [Fortschr Med 1995;113: pp.303-306]



Drug  

Conventional Drugs / Information

Although they are sometimes necessary, long-term use of the more dangerous antiinflammatory drugs, such as prednisone, can cause diabetes, osteoporosis, or even death.

Metformin is a drug used to treat type II diabetes. It functions via different mechanisms to restore youthful metabolic-glucose metabolism. Metformin’s ability to lower elevated blood insulin levels helps explain why it has been shown to significantly lower C-reactive protein levels in human studies, which reduces inflammation.

November 20, 2002 — Preliminary data suggest that the commonly used antibiotic doxycycline (Periostat), which is widely used to treat gum disease, reduces C-reactive protein (CRP) levels by nearly 50% in patients recently hospitalized for an acute coronary syndrome.

The results are drawn from the Metalloproteinase Inhibition with Low-Dose Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) pilot trial.

For the investigation, 50 patients with recent acute coronary syndromes were randomized to low-dose doxycycline (20 mg BID) or placebo. The 20 mg tablet, taken twice daily, provides a sub-antimicrobial dose of the antibiotic.

At enrollment, the two treatment arms had similar demographic and clinical characteristics, including age, sex, and frequency of hypertension, diabetes, smoking, prior cardiac history, extent of coronary disease, presentation with acute myocardial infarction or unstable angina, and need for a percutaneous coronary intervention.

At six-month follow-up, sub-antimicrobial dose doxycyline significantly reduced CRP levels by 45.8 percent compared to baseline values (p<0.05). The drug was also associated with a 33.5 percent reduction in interleukin-6 and a 50 percent reduction in metalloproteinase (MMP)-9 activity (p<0.05).

There was no difference between the low-dose doxycycline and placebo groups in the composite end point of cardiovascular death, myocardial infarction, or troponin-positive unstable angina. Dr. Brown emphasized, however, that the study was too short to permit assessment of a significant difference between the two groups with respect to this end point.

Low-dose doxycycline was safe with no discontinuations due to treatment-related side effects. Two patients in the placebo group discontinued treatment prematurely. Both developed drug rashes that were probably due to another drug they had started at the same time, Dr. Brown said.

“The findings are exciting, since research is now showing that CRP is both a key marker of inflammation leading to future acute coronary events, but also that CRP itself may contribute to the initiation and progression of atherosclerosis,” he noted.



 

Aspirin

Drugs that reduce inflammation are effective, but even the relatively “safe” ones such as aspirin can cause gastritis or even an ulcer.



 

Antibiotics

Please see the link between Inflammation, Chronic and Conventional Drugs about the use of low dose doxycycline (Periostat).



Extract  

Fibrinolytic Enzymes

In Germany and other European countries, serrapeptase is a common treatment for inflammatory and traumatic swellings, and much of the research that exists on this substance is of European origin. One double-blind study was conducted to determine the effect of serrapeptase on post-operative swelling and pain. The patients receiving serrapeptase had reduced swelling and became more rapidly pain-free than the controls. By the tenth postoperative day the pain had disappeared completely in the treated group. [Fortschr Med. 1989;107(4): pp.67-8, 71-2]



Hormone  

DHEA

DHEA has been shown to suppress IL-6, an inflammatory cytokine that often increases as people age. Typical doses of DHEA are 25-50 mg daily, although some people take 100 mg daily.



Miscellaneous  

Reading List

The Maker’s Diet by Jordan Rubin.



Nutrient  

DHA (docosahexaenoic acid)

The DHA (docosahexaenoic acid) portion of fish oil is the probably the best documented supplement to suppress the inflammatory cytokines TNF-a, IL-6, IL-1b, and IL-8. A study of healthy humans and those with rheumatoid disease shows that fish oil suppresses these dangerous cytokines by up to 90%.



 

Essential Fatty Acids

A tendency towards chronic repeated inflammations may be resolved through prostaglandin balancing. The levels of pro-inflammatory and anti-inflammatory prostaglandins are primarily determined by the intake of essential fatty acids. A dietary deficiency of Omega-3 type fatty acids has been associated with a tendency toward chronic inflammation, which regular consumption of these oils can reduce.

Omega-3 fatty acids such as flax oil or fish oil and the digestive aid bromelain make a useful anti-inflammatory combination. Their use can be considered together in trying to resolve any chronic inflammatory condition. While oils should be taken with food because they may cause irritation or indigestion by themselves, bromelain is best taken separately from food. If a person can not tolerate these oils on an empty stomach, then these two products should be rotated; oils with a meal, bromelain between meals. Typical doses are 1T flax oil per day or 3,000-5,000mg fish oil per day along with 125-500mg tid bromelain (3,000 mcu or 2,000 GDU/gm potency).



Vitamins  

Bioflavonoids

Clinical trials have not yet examined the effects of the bioflavonoid quercetin in the treatment of inflammation. However, several inflammation-promoting pathways are known to be inhibited by quercetin.



 

Vitamin K1/K2

[Int J Vitam Nutr Res. 1997;67(5): pp.350-6]



Key

Weak or unproven link
Strong or generally accepted link
Proven definite or direct link
Strongly counter-indicative
May do some good
Likely to help
Highly recommended
May have adverse consequences

Glossary

Bruise

Injury producing a hematoma or diffuse extravasation of blood without breaking the skin.

Autoimmune Disease

One of a large group of diseases in which the immune system turns against the body's own cells, tissues and organs, leading to chronic and often deadly conditions. Examples include multiple sclerosis, rheumatoid arthritis, systemic lupus, Bright's disease and diabetes.

Rheumatoid Arthritis

A long-term, destructive connective tissue disease that results from the body rejecting its own tissue cells (autoimmune reaction).

White Blood Cell

(WBC): A blood cell that does not contain hemoglobin: a blood corpuscle responsible for maintaining the body's immune surveillance system against invasion by foreign substances such as viruses or bacteria. White cells become specifically programmed against foreign invaders and work to inactivate and rid the body of a foreign substance. Also known as a leukocyte.

Arthritis

Inflammation of a joint, usually accompanied by pain, swelling, and stiffness, and resulting from infection, trauma, degenerative changes, metabolic disturbances, or other causes. It occurs in various forms, such as bacterial arthritis, osteoarthritis, or rheumatoid arthritis. Osteoarthritis, the most common form, is characterized by a gradual loss of cartilage and often an overgrowth of bone at the joints.

Herpes Simplex

An infection, often recurrent, caused by herpes virus type 1 and 2. It causes cold sores around the lips and mouth, and also causes painful blisters on the genitals and in the pubic area, thighs, and buttocks.

Gout

A disease characterized by an increased blood uric acid level and sudden onset of episodes of acute arthritis.

Tuberculosis

Also known as TB, Consumption or "The White Plague", tuberculosis is an infectious disease caused by a bacterium called Mycobacterium tuberculosis, usually affecting the lungs but possibly also the brain, kidneys and bones. Patients may at first be symptom-free or experience a flu-like illness. In the secondary stage, there might be a slight fever, night sweats, weight loss, fatigue and various other symptoms, depending on the part of the body affected. Tuberculosis of the lung is usually associated with a dry cough that eventually leads to a productive cough with blood-stained sputum. There might also be chest pain and shortness of breath.

Cholesterol

A waxy, fat-like substance manufactured in the liver and found in all tissues, it facilitates the transport and absorption of fatty acids. In foods, only animal products contain cholesterol. An excess of cholesterol in the bloodstream can contribute to the development of atherosclerosis.

Subclinical

Not manifesting characteristic clinical symptoms. Pertaining to a disease or condition.

Asthma

A lung disorder marked by attacks of breathing difficulty, wheezing, coughing, and thick mucus coming from the lungs. The episodes may be triggered by breathing foreign substances (allergens) or pollutants, infection, vigorous exercise, or emotional stress.

Chronic

Usually Chronic illness: Illness extending over a long period of time.

Allergy

Hypersensitivity caused by exposure to a particular antigen (allergen), resulting in an increased reactivity to that antigen on subsequent exposure, sometimes with harmful immunologic consequences.

Polyp

A usually nonmalignant growth or tumor protruding from the mucous lining of an organ such as the nose, bladder or intestine, often causing obstruction.

Colon

The part of the large intestine that extends to the rectum. The colon takes the contents of the small intestine, moving them to the rectum by contracting.

Cancer

Refers to the various types of malignant neoplasms that contain cells growing out of control and invading adjacent tissues, which may metastasize to distant tissues.

Anti-inflammatory

Reducing inflammation by acting on body mechanisms, without directly acting on the cause of inflammation, e.g., glucocorticoids, aspirin.

NSAID

Non-steroidal anti-inflammatory drug.

Cytokines

Cytokines are chemical messengers that control immune responses. They are secreted by white blood cells, T cells, epithelial cells and some other body cells. There are at least 17 different kinds of interleuken and 3 classes of interferon called alpha, beta and gamma and various subsets. Interleukens and interferons are called “cytokines” and there are two general groupings, Th1 and Th2. Th1 (T-cell Helper type 1) promote cell-mediated immunity (CMI) while Th2 (T-cell Helper type 2) induce humoral immunity (antibodies).

IL-6

Interleukin-6. IL-6 is a pro-inflammatory and immunosuppressive cytokine. Elevations in serum IL-6 correlate with adverse disease features and shortened survival in chronic lymphocytic leukemia.

Steroid

Any of a large number of hormonal substances with a similar basic chemical structure containing a 17-carbon 14-ring system and including the sterols and various hormones and glycosides.

Acute

An illness or symptom of sudden onset, which generally has a short duration.

Hepatitis

Inflammation of the liver usually resulting in jaundice (yellowing of the skin), loss of appetite, stomach discomfort, abnormal liver function, clay-colored stools, and dark urine. May be caused by a bacterial or viral infection, parasitic infestation, alcohol, drugs, toxins or transfusion of incompatible blood. Can be life-threatening. Severe hepatitis may lead to cirrhosis and chronic liver dysfunction.

CRP

C-reactive protein. A sensitive measure of inflammation in the body.

Antispasmodic

Preventing spasms.

Prostaglandin

Any of a class of physiologically active substances present in many tissues, with effects such as vasodilation, vasoconstriction, stimulation of the smooth muscles of the bronchus or intestine, uterine stimulation; also involved in pain, inflammation, fever, allergic diarrhea, and dysmenorrhea. A potent hormone -- similar in structure to an unsaturated fatty acid -- that acts in extremely low concentrations on local target organs; first isolated from the prostate.

Essential Fatty Acid

(EFA): A substance that the human body cannot manufacture and therefore must be supplied in the diet.

Vitamin D

A fat-soluble vitamin essential to one's health. Regulates the amount of calcium and phosphorus in the blood by improving their absorption and utilization. Necessary for normal growth and formation of bones and teeth. For Vitamin D only, 1mcg translates to 40 IU.

Diabetes Mellitus

A disease with increased blood glucose levels due to lack or ineffectiveness of insulin. Diabetes is found in two forms; insulin-dependent diabetes (juvenile-onset) and non-insulin-dependent (adult-onset). Symptoms include increased thirst; increased urination; weight loss in spite of increased appetite; fatigue; nausea; vomiting; frequent infections including bladder, vaginal, and skin; blurred vision; impotence in men; bad breath; cessation of menses; diminished skin fullness. Other symptoms include bleeding gums; ear noise/buzzing; diarrhea; depression; confusion.

Fatty Acids

Chemical chains of carbon, hydrogen, and oxygen atoms that are part of a fat (lipid) and are the major component of triglycerides. Depending on the number and arrangement of these atoms, fatty acids are classified as either saturated, polyunsaturated, or monounsaturated. They are nutritional substances found in nature which include cholesterol, prostaglandins, and stearic, palmitic, linoleic, linolenic, eicosapentanoic (EPA), and decohexanoic acids. Important nutritional lipids include lecithin, choline, gamma-linoleic acid, and inositol.

Free Radical

A free radical is an atom or group of atoms that has at least one unpaired electron. Because another element can easily pick up this free electron and cause a chemical reaction, these free radicals can effect dramatic and destructive changes in the body. Free radicals are activated in heated and rancid oils and by radiation in the atmosphere, among other things.

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