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Clinician Home  >  Nutritional Foundation Program  >  Pro-Inflammatory State
THE CHRONIC PRO-INFLAMMATORY STATE

Topics:
1. Acute inflammation versus the chronic pro-inflammatory state
2. Recognizing the chronic pro-inflammatory state in clinical practice
      • Routine blood tests and the pro-inflammatory state
      • Patient history findings and the pro-inflammatory state
      • Physical exam findings and the pro-inflammatory state
      • Medication use for the pro-inflammatory state


1. Acute inflammation versus the chronic pro-inflammatory state

Most clinicians were introduced to the inflammatory process in Guyton’s Physiology. Inflammation was covered within a few pages, wherein we are led to visualize an acute injury or infection that is associated with acute inflammation and subsequent resolution.

The acute view of inflammation is NOT consistent with the chronic pro-inflammatory state. Unlike Guyton’s Physiology, wherein only a few pages are devoted to inflammation, Robbins Contran Pathologic Basis of Disease utilizes three chapters and 100 pages to describe inflammation (28), much of which is not typically measured in clinical practice. For example, in the primary care and most specialty practices, the following three key features of the chronic pro-inflammatory state (28) are not directly measured in laboratory tests:

        1) Reduced ATP synthesis due to compromised mitochondrial function.
2) Oxidative stress, i.e., a net increase in free radical activity.
3) The excess activity/release of numerous diverse inflammatory mediators and signaling molecules, such as nuclear factor kappa-B, adhesion molecules, matrix metalloproteinases, growth factors, kinins, histamine, cytokines, and fatty acid derived mediators such as eicosanoids and platelet activating factor.


A good question: If the chronic pro-inflammatory state is not readily measurable, how then do we know it is present? The answer is straight-forward: Robbins Contran Pathologic Basis of Disease outlined the pro-inflammatory chemistry of most diseases in chapters 1-3, which includes reduced ATP synthesis, oxidative stress, and increase in inflammatory mediators. We are supposed to remember this as we read the remaining 26 chapters, but we tend to forget because our minds are focused on diagnosis and treatment. In short, we need to remember that most of the diseases described in Robbins chapters 4-29 are caused by the pro-inflammatory state described in chapters 1-3.

To help remember, consider for example the metabolic syndrome, which is also called syndrome X and the insulin resistance syndrome. The metabolic syndrome is an excellent example because we know it is a promoter of multiple diseases, such as type 2 diabetes, coronary artery disease, stroke, hypertension, epithelial carcinomas (breast, prostate, colon), obesity, acne, myopia, cutaneous papillomas (skin tags), acanthosis nigricans, polycystic ovary syndrome, male vertex balding, sleep apnea, and rheumatoid arthritis (6,13,20).

The pro-inflammatory state of the metabolic syndrome has been measured and evaluated and is consistent with the three pro-inflammatory factors listed above from Robbins Contran Pathologic Basis of Disease. For the metabolic syndrome, researchers have identified a reduction in mitochondrial mass (low ATP), oxidative stress, and the over-expression of chemical mediators of inflammation (2,10,12,19,36). It is important for clinicians to remember that the pro-inflammatory state of the metabolic syndrome is known to be induced by a pro-inflammatory diet (3,16,17,21,33).


2. Recognizing the chronic pro-inflammatory state in clinical practice:

Multiple aspects of the clinical encounter allow us to consider the presence of the pro-inflammatory state. In many cases, clinicians have learned about these factors as markers for specific diseases. While this can be correct, it should also be understood that in the absence of specific diseases, the presence of these markers should be viewed as indicators for the presence of the chronic pro-inflammatory state. Suspicion and concern should increase as the number of pro-inflammatory factors rises – a disease may be evolving in a subclinical fashion. 

      Routine blood tests and the pro-inflammatory state

The following measurable pro-inflammatory factors are commonly found during a routine blood test. We typically view elevated glycemic factors as markers of diabetes and elevated lipids as markers of cardiovascular disease, however, they are first and foremost a manifestation of a chronic inflammatory state.

        • fasting blood glucose above 100 (upper end of normal for most labs)
• elevated glycosylated hemoglobin
• triglycerides [≥150 mg/dL (49)]
• low HDL cholesterol [<50 mg/dL for females; <40 mg/dL for males] (49)
• elevated LDL cholesterol (>130 is typical for most labs – need to consider presence of other pro-inflammatory factors)
• elevated total cholesterol (variable and dependent on presence of other pro-inflammatory findings – should not be used as sole marker for inflammation or heart disease)
• hsCRP above 1 mg/dl [1-3 mg/dl = moderate risk for CVD; above 3 mg/dl = high risk] (35)
• low serum 25(OH)D [normal = 32-100 ng/ml; ideal above 40-55 ng/ml] (8)


We should view abnormal findings as an indirect method for considering that a patient may suffer with reduced mitochondrial mass, oxidative stress, and increased inflammatory mediators, i.e., the chronic pro-inflammatory state that serves as a promoter of chronic disease.

A point of emphasis: Something as simple as increased postprandial glycemia should be taken seriously and viewed as a marker of the pro-inflammatory state. Indeed, Barclay et al. (3) concluded that, “our findings support the hypothesis that higher postprandial glycemia is a universal mechanism for disease progression.” 


      Patient history findings and the pro-inflammatory state

The typical history is taken to diagnose the presenting complaint and also for consideration of future disease risk. The history also points to a patient’s inflammatory status. The following findings during the history suggest the presence of a chronic pro-inflammatory state:

        • Regular use of aspirin, OTC NSAIDs, prescription NSAIDS, and acetaminophen. These medications inhibit the conversion of diet linoleic-arachidonic acid into prostaglandin E2, which causes inflammation and pain. [Additional medications are discussed below.]
• Poor dietary choices (4,14-19,21,24,26,32,33,41,48), which will be discussed in detail in the Diet & Inflammation page.
• Overeating (33)
• Skipping meals (44)
• A lack of healthy sun exposure = a lack of vitamin D production (8,23)
• A lack of exercise (30)
• A lack of sleep (46)
• Poor dental hygiene (Quijano)
• Chronic stress caused by the diverse psychological stressors associated with our high-paced modern lifestyle (5).
• Depression (9)
• Poor self-rated health (29)
• Tobacco use (31)
• Alcohol abuse (27)

      Physical exam findings and the pro-inflammatory state

Body mass index (BMI) is sometimes argued as not being an appropriate marker for being overweight or obese. Fit individuals with above average muscle mass usually make this argument because their BMI is commonly at 25 or above, the cut off point for normal weight.

BMI is not useful for fit, well muscled individuals, however, most individuals are not fit and well muscled. When patients are asked about their ideal weight, they typically provide numbers that place their BMI close to or below 25. So for the average over-fat individual, BMI is a useful marker.

It is important to realize that the pro-inflammatory state, such as syndrome x, can exist in people we might typically not consider, such as overweight children, people with a normal BMI (47), up to 20% of people with a BMI of 25-27(47), and athletes, such as college football linemen (7). It is important to appreciate that individuals uniquely express inflammation as their BMI elevates, which is why it is important to look at the multiple factors that augment inflammation.

Typically associated with an elevated BMI, excessive amounts of adipose tissue should not be innocuously viewed as “just some excess weight.” Instead, excess adiposity should be viewed as “excess inflammation.” At some point during the genesis of syndrome X, excess adipose tissue mass begins to function as a pro-inflammatory endocrine organ (2), releasing increased amounts of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). Adipose tissue also modifies the release pattern of its own unique mediators called adipokines; leptin and resistin release increases, while adiponectin release is reduced. Adiponectin is an interesting substance that improves insulin sensitivity and maintains/increases mitochondrial mass in skeletal muscle (2).

The outcome of the pro-inflammatory state created by increased adipose tissue release of TNF, IL-6, leptin, and resistin and reduced adiponectin includes the expression of insulin resistance, endothelial activation (a component of atherosclerosis), depression, sarcopenia of aging, and hypertension (2). An important finding, and one that should be remembered, is that the pro-inflammatory state occurs before these metabolic and symptomatic changes (22).

         • High BMI (18.5-24.9 = normal; 25-29.9 = overweight; over 30 = obese)
• Waist circumference [≥35” for females; ≥40” for males (49)]
• High blood pressure [>130/85 (49)] 
• Increased waist to hip ratio (normal: <0.85 for women; <1.0 for men)

A combination of laboratory tests and physical exam findings have been correlated to the presence of syndrome X. If three of the five following markers are present, the patient is considered to be suffering from syndrome X (49):

          1. Fasting blood sugar over 100
          2. Fasting triglycerides triglycerides ≥150 mg/dL
          3. Low HDL cholesterol (<50 mg/dL for females; <40 mg/dL for males)
          4. Blood pressure >130/85
          5. Waist circumference (≥35” for females; ≥40” for males)

Clinicians should be aware that inflammation expression is diverse, so all the markers discussed in this website section should be considered. In other words, a patient can be chronically inflamed and have less than 3/5 syndrome X factors. 


      Medication use for the pro-inflammatory state

Anti-inflammatory/analgesics
Diet derived arachidonic acid is converted by COX1/2 into painful and inflammatory prostaglandin E2 (PGE2). Prescription or over the counter nonsteroidal anti-inflammatory drugs, such as aspirin, ibuprofen or other traditional NSAIDs, or COX2 inhibitors function to inhibit the conversion of diet-derived arachidonic acid into PGE2. Clearly, chronic use of such medications tells us that a patient is chronically inflamed by a diet-induced chronic inflammatory state. The same conclusion can be made for patients taking corticosteroids.

Tylenol (acetaminophen) is typically viewed as an analgesic, because its central nervous system effects predominate over peripheral effects. However, a mechanism of action for acetaminophen is COX inhibition within the CNS. In other words, acetaminophen also inhibits the conversion of diet-derived arachidonic acid into PGE2. Chronic use of acetaminophen tells us that a patient is chronically inflamed by a diet-induced chronic inflammatory state.

Other medications do not inhibit enzymes that act on dietary fatty acids, so their mechanism of action does not lend to the direct conclusion that use of the medications is generated by diet-derived inflammation. However, the following drugs are used to treat diseases that are promoted by a diet-induced pro-inflammatory state.

Singulair
Singulair is a leukotriene receptor antagonist and it is taken to treat asthma and allergies. The enzyme 5-lipoxygenase converts diet-derived arachidonic acid into leukotrienes A4, B4, C4, D4 and E4. If Singulair is effective in asthma and allergic patients, this is an indication that the patient suffers, in part, from a diet-induced pro-inflammatory state.

TNF inhibitors
Remicade, Enbrel, and Humira are tumor necrosis factor (TNF) inhibitors and used to treat chronic inflammatory conditions such as rheumatoid arthritis. Patients with a high BMI and syndrome X have elevated levels of TNF, suggesting TNF is a nutritionally modifiable inflammatory mediator.

Anti-diabetic medications
Glucophage/metformin, an insulin sensitizer, while the thiazoladinediones, Actos and Avandia, are PPAR-gamma agonists. Each type of drug is used to treat the metabolic syndrome and type II diabetes, which are known to be chronic inflammatory conditions induced by a pro-inflammatory diet and a lack of exercise.

Statins
The family of statin drugs is used to inhibit cholesterol synthesis to treat/prevent cardiovascular disease, which is a chronic pro-inflammatory state that is partly induced by diet. Research has demonstrated that statins have multiple anti-inflammatory benefits. Statins increase anti-inflammatory IL-10 and endothelial nitric oxide, while they have an inhibitory effect on many pro-inflammatory substances such adehesion molecules, IL-1, IL-6, TNF, COX2, TXA2, and matrix metalloproteinases. Statins also reduce thrombosis, platelet aggregation, and recruitment of T-cells and monocytes (25). Regarding cardiovascular disease, it is important to mention that researchers have identified that pro-inflammatory vascular endothelium dysfunction is restored to normal by statins, prior to reductions in cholesterol (25). As statins have an inhibitory effect on cytokines and prostaglandin production, researchers suggest that statins may constitute a novel class of analgesic drugs (40).

VEGF inhibitors
Vascular endothelial growth factor drives angiogenesis, a pro-inflammatory process [when excessive] that is involved in many chronic inflammatory conditions, such as macular degeneration and cancer. VEGF inhibitors such as Lucentis is used to treat macular degeneration, while Avastin is used to treat cancer. VEGF is also involved in osteoarthritis and intervertebral disc herniation, however, VEGF inhibitors are not used as a treatment. The pro-inflammatory nature of cancer is well-known as are dietary connections; however, it is important to know that macular degeneration is also driven by a diet-induced pro-inflammatory state (11,42,43).

Anti-depressants
Depression is not traditionally viewed as a chronic inflammatory state, however, we now know that pro-inflammatory cytokines are involved (9), and we also know that a pro-inflammatory diet is associated with the expression of depression (1,39). Tricyclic antidepressants and SSRIs (Prozac, Lexapro) are used to influence the CNS serotonin and norepinephrine, and we now know that they also have anti-inflammatory benefits (37,38).

Anti-hypertensives
Calcium channel blockers and ACE inhibitors reduce hypertension by their stated names. However, each has an anti-inflammatory effect as well – they improve endothelium-dependent nitric oxide-mediated vasodilation (45). It should be of no surprise that hypertension is driven in part by a pro-inflammatory diet. Hypertension should be viewed as a component of syndrome X.

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