Inflammation

Almost every modern disease today can be linked to chronic inflammation.

If your body is continually exposed to stimuli that triggers an inflammatory response your immune system is always on red alert. Constant inflammation and you’re heading towards illness and premature aging.

Addressing the triggers of inflammation and leading an anti-inflammatory lifestyle can not only increase your lifespan, slowing aging, but also decrease your risk of chronic disease.

Everyone who has had a sore foot, a rash, hives or a cut knows about inflammation. Inflammation is a normal and healthy reaction that we need to survive. It helps our immune system to be mobilized and thereby distinguish friend from foe.

The issue arises when this natural reaction goes rampant and our immune system becomes overactive creating inflammation continually over a long period of time. Many of us are aware of a common reason for chronic inflammatory responses, anyone with allergies can give you a firsthand account of exactly what happens when their immune system overacts to a substance they consume or a substance in their environment. However, inflammation is often not as simple to see, the hidden inflammation that displays no overt symptoms is detrimental to our health.

The aim of holistic anti-inflammatory treatment is not to hinder the body’s ability to have acute inflammation in reaction to trauma but to address the underlying smouldering inflammation.

Anti-inflammatory medications such as steroids, NSAIDs and statins, have the dangerous side effect of stopping the body’s natural immune response (acute inflammation). Hindering this acute reaction not only puts a huge burden on the immune systems and other defenses but is in fact one of the causes of chronic hidden inflammation.

 

Cytokines

Cytokines are  immunomodulating agents, such as interleukins and interferons. They are regulators of host responses to infection, immune responses, inflammation and trauma. Some of them are pro -inflammatory; these are necessary to initiate an inflammatory response necessary to recruit granulocytes, and later on, lymphocytes, to fight disease. However, if they are chronically elevated, they are responsible for many diseases. Other cytokines are anti-inflammatory and serve to reduce inflammation and promote healing once the injury/infection/foreign body has been destroyed.

Anti-inflammatory cytokines are: Il-10 and Il-4. They decrease the production of pro-inflammatory cytokines.

Pro-inflammatory cytokines are: Il-1, Il-6, Il-8, IL-18, TNF-alpha.

Potential genetic variations with cytokines may influence the way our body normally functions. Cytokines can be out of the normal up or down regulated which can lead to a general higher risk of chronic inflammation. In that case additional supplemental and lifestyle support is mandatory.

 

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB is important in the initiation of the inflammatory response and is involved in the underlying promotion of cancer. When cells are exposed to damage signals, such as TNF-alpha or oxidative stress, they activate NF-κB, which turns on the expression of hundreds of genes involved in the inflammatory response. These include other cytokines and pro-inflammatory enzymes, like COX2, which is responsible for synthesizing pro-inflammatory prostaglandins which maintain inflammation and leads to chronic pathological inflammatory states if not resolved.

The NF-kB pathway is the key underlying pathway promoting cancer.

 

To our advantage, although complex in nature, the list of things that causes inflammation is actually rather short:

• Bad diet-refined sugars, white flour, processed food, inflammatory fats like trans fats and saturated fats.
• Lifestyle choices- lack of exercise, high stress and altered emotional states, smoking, lack of sleep
• Hidden infections; such as bacterial infections(i.e. Campylobacter pylori or chronic bacterial infection caused by poor oral hygiene and periodontal disease), viruses (i.e. Lyme disease) and yeast infections (i.e. Candida) or Parasitical infestations
• Allergies such as gluten, lactose, pollen and other sensitivities and intolerances,
• Environmental toxins and chemical irritants such as; mercury, lead, cadmium, pesticides, fungicides, herbicides and molds etc.
• Obesity, and/or chronic over eating

An often forgotten cause for toxins are root canal fillings, which can leave cavities in the jaw bone filled with infectious debris. These can lie hidden for centuries leaching out toxic materials and causing low grade systemic infection.

Obesity: Fat tissue is an endocrine organ, storing and secreting multiple hormones and cytokines affecting metabolism throughout the body. Fat cells produce and secrete TNF-alpha and IL-6, and visceral or abdominal fat also produce these inflammatory cytokines at levels sufficient to induce a strong inflammatory responses. This abdominal fat can produce 3 times the amounts of IL-6 as fat cells elsewhere in the body and overweight individuals may be producing up to 35% of their total IL-6 in their body. Fat cells are also infiltrated by macrophages that produce more cytokines and are proportional to a person’s BMI (Body Mass Index) and appear to be a major cause of low-grade, systemic inflammation in obese people.

Smoking: Cigarette smoke contains inducers of inflammation, particularly reactive oxygen species. Chronic smoking increases the production of several cytokines; TNF-alpha, IL-1beta, IL-6 and IL-8 while simultaneously reducing the production of anti-inflammatory molecules. Smoking will also promote periodontal disease which in and of itself increases systemic inflammation.

Hyperglycemia: Elevated blood sugar levels induce IL-6 from the endothelial cells and macrophages. Meals high in saturated fat and high calorie intact have been associated with increases in inflammatory markers. While over eating we will have an acute inflammatory response, which may become chronic if the overeating is habitual.

Age: Older adults can have consistently elevated levels of several inflammatory molecules, especially IL-6 and TNF-α. These elevations are observed even in healthy older individuals and may reflect cumulative mitochondrial dysfunction and oxidative damage, or may be the result of other risk factors associated with age such as increases in visceral body fat or reductions in sex hormones.

Functional and pathology testing and careful questioning will help you to discover which of the aggressors in the list is the perpetrator.

 

Pathology Testing in serum:

 

CRP

The easiest measure of chronic hidden inflammation in the body is C reactive protein (CRP). A  study showed that of a population of generally healthy elderly people, those with higher levels of CRP are more than 250% more likely to die in the next four years of chronic disease.

CRP is a non-specific acute-phase reactant protein used to indicate an inflammatory illness (rheumatoid arthritis), chronic inflammation and bacterial infectious diseases.

Elevated CRP levels are associated with increased cardiovascular morbidity and mortality in patients with coronary artery disease.

It is also elevated when there is tissue necrosis, malignancies and autoimmune disorders.

CRP tests may also be used postoperatively to detect wound infections. CRP levels increase 4-6 hours after surgery and generally begin to decrease after the third postoperative day. Failure of the levels to fall is an indicator of complications, such as pulmonary infarction.

Optimal levels are: women smaller than 1mg/l; men smaller than 0.5 mg/l

As a general rule, mild inflammatory stimuli, such as viral infections, are associated with CRP levels of 10-40mg/L. More serious conditions, such as bacterial infections or active connective tissue diseases, can be associated with levels of 50-200mg/L.

Levels of greater than 200-300mg/L are typically seen in the setting of severe conditions or injury such as sepsis or burns.

HsCRP

A high-sensitivity C-reactive protein (hs-CRP) test may be used to help evaluate an individual for risk of cardiovascular disease. Hs-CRP is more precise than standard CRP when measuring baseline concentrations and enables a measure of chronic inflammation.

Erythrocyte Sedimentation Rate (ESR)

The ESR is an easy, inexpensive, non-specific test that has been used for many years to help diagnose conditions associated with acute and chronic (that is, short or long duration) inflammation, including infections, cancers and autoimmune diseases. It is a measurement of the rate at which the RBCs settle in saline solution or plasma over a specified time period. ESR is said to be non-specific because increases do not tell exactly where the inflammation is in the body or what is causing it, and also because it can be affected by other conditions besides inflammation. An elevated ESR may be due to events that occurred weeks to months previously and may have resolved at the time of measurement. For this reason, an ESR is typically used in conjunction with other tests.

The ESR is helpful in diagnosing two specific inflammatory diseases, temporal arteritis and polymyalgia rheumatica. A high ESR is one of the main test results used to confirm the diagnosis. It is also used to monitor disease activity and response to therapy in both of these diseases.

Men 0-22 mm/hr and women 0-29 mm/hr. The upper threshold may vary from one medical practice to another.

Marked elevation of ESR (greater than 100mm/hr), on the other hand, is almost always significant. In patients with an ESR greater than 100mm/hr, a significant diagnosis will be made in over 90% of cases.

Cytokine Inflammation Marker Test

Interleukin 6 (IL-6) is a molecule that is produced by a range of cells and plays a central role in the immune system, especially by inducing inflammatory responses to injury and infection. IL-6 is also known as a "cytokine", which is a signaling protein that is secreted by the cells in the nervous system and other systems and functions in intracellular communication. IL-6 can be secreted by many different cells including fibroblasts, monoctyes, macrophages, T-cells and some tumour cells.

IL-6 testing is used to aid in the diagnosis of various autoimmune or inflammatory diseases, in the diagnosis of organ transplant rejection, and in the diagnosis of bacterial meningitis or systemic lupus erythematosus.

TNF-α: Chronic inflammation modulated by cytokines such as tumor necrosis factor-ɑ (TNF-ɑ) is the common denominator of all age-related disease. A blood test can be used to  identify elevated levels of tumor necrosis factor-ɑ (TNF-ɑ). TNF-ɑ can be elevated in chronic infections, certain cancers, and hepatitis C. TNF-ɑ is also a growth factor for immune cells and osteoclasts (cells that break down bone).

Homocysteine

Homocysteine is a chemical in the blood that is produced when an amino acid (a building block of protein) called methionine is broken down in the body. We all have some homocysteine in our blood. Elevated homocysteine levels (also called hyperhomocysteinemia) may cause irritation of the blood vessels. Elevated levels of homocysteine show an increased risk for hardening of the arteries (atherosclerosis), which could eventually result in a heart attack and/or stroke, and blood clots in the veins (venous thrombosis).

Because elevated homocysteine levels are associated with vitamin B12 or folate deficiency, this is a reasonable test to use for the detection and surveillance of malnutrition as well as genetic impairment of MTHFR, MTR genes.

It is metabolised by two major pathways: remethylation and trans-sulfuration.

Increased levels
Some people have elevated homocysteine levels caused by a deficiency of B vitamins and folate in their diets. High homocysteine levels are also seen in people with cardiovascular disease, cerebrovascular disease, peripheral vascular disease, cystinuria, vitamin B6 or B12 deficiency, folate deficiency and malnutrition, low levels of thyroid hormones, psoriasis, and with certain medications (such as antiepileptic drugs and methotrexate). It has been recognised that some people have a common genetic variant (called methylenetetrahydrofolate reductase, abbreviated MTHFR) that impairs their ability to process folate. This defective gene leads to elevated levels of homocysteine in some people who inherit MTHFR variants from both parents.

Decreased levels
Down syndrome and hyperthyroidism.

The optimal range for homocysteine is 5-8 mmol/l and not 5-15 mmol/l as often indicated on pathology reports.

Under 4 mmol/l is considered over methylation which can happen with CBS polymorphism or high doses of 5-THF.

Over 9 mmol/l is a sign of under methylation which can happen with MTHFR polymorphism, deficiencies of 5-THF, inflammation.

Triglycerides

High triglyceride levels are a sign of inflammation and high carbohydrate diet. Healthy range: 40 to 160 mg/dL

Ratio of neutrophil to lymphocyte counts

One routinely available marker of the systemic inflammatory response is the neutrophil- lymphocyte ratio (NLR), which is derived from the absolute neutrophil and absolute lymphocyte counts of a full blood count. It is calculated by dividing the number of neutrophils by number of lymphocytes.

A high neutrophil-to-lymphocyte ratio (NLR) has been reported to be a poor prognostic indicator in several malignancies.
Neutrophilia (higher than normal count of Neutrophils) as an inflammatory response inhibits the immune system by suppressing the cytolytic activity of immune cells such as lymphocytes, activated T cells, and natural killer cells.The importance of lymphocytes has been highlighted in several studies in which increasing infiltration of tumors with lymphocytes has been associated with better response to cytotoxic treatment and prognosis in cancer patients. Inflammatory cytokines and chemokines can be produced by both the tumor and associated host cells such as leukocytes and contribute to malignant progression.

Over 60 studies (>37,000 patients) have examined NLR to predict patient outcomes in a variety of cancers.

It should be noted that although the NLR is easy to measure, its utility as a marker of systemic inflammation may be affected by many conditions, including coronary disease, metabolic syndrome, inflammatory diseases and any medication related to inflammatory conditions, significant stress, infections and chemotherapy.

With regard to the threshold defining an elevated NLR, it ranged between >3 and >5 in most studies.

In summary, a high NLR is associated with adverse survival in many solid tumors.

 

Examples for Functional Testing:

Comprehensive Stool Analysis: Lactoferrin is a marker of acute inflammation. It helps differentiate IBD from IBS. A comprehensive stool analysis is able to evaluate inadequate physical and immune barrier functions and inadequate digestive and absorptive function. Both of them can indicate inflammatory processes.

The Intestinal Permeability (IP) test, also referred to as a “leaky gut” test, is a precise and non-invasive method for assessing gastrointestinal mucosal integrity. Leaky gut leads to systemic inflammation.

Immunoglobulin tests: Immunoglobulins may be ordered when a person has signs of chronic inflammation or chronic infection, autoimmune disease, allergy, food intolerances and when excess or abnormal immunoglobulin production is suspected.

Infection tests: Latent infections such as Epstein Barr Virus, Lyme Disease, Clamydia, Hepatitis C Virus, Toxoplasmosis, Human Cytomegalovirus  can cause chronic inflammation.

If the body is in a high state of chronic underlying inflammation, removal of the root cause from the list above it is the primary goal. Once the primary aggressor is removed or changed, your CRP, IL-6 and homocysteine should lower quite dramatically. Once this is complete it is important to begin an anti-inflammatory lifestyle.

Anti-inflammatory foods:

• Turmeric
• Ginger
• Garlic
• Onions
• Omega 3
• Gamma linolenic acid

Foods to avoid:

• Gluten
• Dairy
• Sugar (especially fructose)
• Sodas
• Carbonated drinks
• Processed food
• Allergenic/sensitivity foods.

Inflammation is an immune response, therefore immune modulation is also very important.

Having a powerful immune system is all about having a balanced system. Therefore, a healthy plant based diet, rich in fiber and leafy green vegetables with the occasional organic, grass fed red meat is optimal for lowering inflammation and reducing the risk of chronic disease.

Supplements which reduce inflammation:

• Omega 3 cod liver oil
• Sulforaphane (Sulforaphane activates PPARgamma which binds to NFKappaB and inhibits transcription of  IL-6, up-regulates Vitamin D Receptor, ensuring Vitamin D can effectively impact on IL-6 gene expression
• Vitamin D (inhibits Cox pathways, decreases Il-6 expression)
• Zinc (IL-6 is thought to be influenced by zinc status)
• Curcumin
• Pine Bark (inhibits Cox1and Cox2 enzymes)
• Probiotics
• Wobenzym
• Boswellia serrata

Have a look at this inflammation graph. It shows clearly the influence and causes of inflammation / lowered immune system.

 

Further reading recommended: 

Article: Chronic inflammation :The Cause of all Disease

https://www.trulyheal.com/chronic-inflammation-the-cause-of-all-disease/

Further reading but not required:

Book: Chronic Inflammation: Mechanism and Regulation by Masayuki Miyasaka MD