It is one of a physician's most challenging situations: determining the root cause of seemingly unrelated symptoms, ranging from depression, anxiety, sleep disorders, and anhedonia to weight control issues (anorexia and obesity), fatigue, neurodegeneration, poor focus and memory, and lowered pain threshold. And, unfortunately, "Sickness Syndrome™" (my own trademarked term) has become a more common occurrence. My own research and analysis implicates this syndrome in the diagnosis and treatment of approximately 90% of patients seeking medical care.

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A fairly new phenomenon that is related to stress, Sickness Syndrome is comprised of a set of non-specific symptoms directly caused by peripheral inflammatory cytokines that trigger the local production of inflammatory cytokines in the brain, namely IL-1 and TNF alpha. In fact, the brain actually mirrors the peripheral circulatory system with regard to the inflammatory response. For example, it turns out that the effective and behavioral changes that develop when a patient suffers from influenza infection are actually caused by a transient brain inflammatory response induced by the same pro-inflammatory cytokines as those produced in the patient's bronchial tree.1 I identified this condition, which affects nearly every bodily system, through the results of my own decade-long research into stress-related disorders, as well as from information from numerous seemingly unrelated sources.

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The incidence of Sickness Syndrome was first noted when patients treated with recombinant cytokines as an immunotherapy displayed mood disorders and cognitive disturbances atypical of the symptoms of the sickness being treated.2 Again, these non-specific symptoms are directly caused by peripheral inflammatory cytokines that trigger the local production of inflammatory cytokines in the brain, namely IL-1 and TNF alpha,3 and most often, specifically develop in patients suffering from somatic diseases with an inflammatory component such as cancer, coronary heart disease, rheumatoid arthritis, asthma, cancer, stroke, and various neuropathologies.4-6

Sickness Syndrome can also be triggered by other illnesses and conditions, such as chronic stress, adrenal fatigue, blood sugar imbalance, obesity, infection, and estrogen deficiency, all of which increase the production of peripheral inflammatory cytokines and weaken the body's ability to function at its optimum level.7,9,10,13,17,18

The Stress--Sickness Syndrome Link
Stress, both physical and psychological, is an unfortunate component of daily life and one of the primary causes of Sickness Syndrome. When the body is under stress, the hypothalamus secretes a corticotrophin-releasing hormone, signaling the pituitary gland to begin adding corticotrophin in the blood stream. At this point, the adrenal glands begin secreting glucocorticoids (e.g., cortisol), which serve as the main regulator of the expression and action of pro-inflammatory cytokines in the brain and at the peripheral level.

Although cytokines tend to enhance the production of cortisol, cortisol has a negative feedback mechanism to prevent cytokine production.7 This negative feedback mechanism only works if there is no resistance to cortisol production.8 Chronic stress, however, leads to compromised adrenal function, which, in turn, causes cortisol resistance.

The stress hormone cortisol increases cravings for high-sugar and high-fat foods. Regular and over-consumption of such foods leads to high blood sugar levels, excessive secretion of insulin levels and insulin resistance,9 and increased production of adipocyte tissue (fat cells) and adipose tissue macrophages. (Over 75% of documented cases of obesity involve insulin resistance.)10,11 Insulin secretes inflammatory cytokines, while adipocyte tissue participates in the inflammatory process through the elaboration of cytokines.

Treatment of Sickness Syndrome
While there are currently no nutritional products or pharmaceuticals or standard methods of diagnosing or treating Sickness Syndrome,12 the following represent an introduction to some approaches that I believe will effectively address it.

Enhancing Adrenal Function -- Administering specific herbal, pharmaceutical, and/or nutraceutical compounds regulates cortisol levels, maintains healthy adrenal gland activity, and increases alpha brain wave activity.

The objective is to normalize the hypothalamic-pituitary-adrenal axis, thereby encouraging a healthy physical and psychological response to stress and supporting the health of the adrenal glands, which are responsible for secreting normal levels of cortisol.

Regulating Insulin and Blood Sugar Levels -- Administering specific herbal, pharmaceutical, and/or nutraceutical compounds that normalize blood sugar levels and increase insulin sensitivity, ultimately regulating insulin and blood sugar levels9,13

Controlling Vagus Nerve Responses -- The vagus nerve plays a central role in the pathophysiology of Sickness Syndrome.14,15 Research demonstrates that direct electrical stimulation of the vagus nerve increases expression of inflammatory cytokines in the brain. In fact, undergoing a vagotomy prevents Sickness Syndrome triggered by inflammatory cytokines.3 Another component involved in the treatment of Sickness Syndrome is regulation of vagal output15 through the use of scientifically supported nutraceuticals, herbals, and/or pharmaceutical agents that regulate vagal output, including, but not limited to, those compounds that modulate serotonin levels. Other lifestyle activities (such as yoga exercises) known to regulate vagal output can also be employed as part of a larger treatment protocol.

Reducing Production of Series 2 Prostaglandins -- Since the brain responds to inflammation associated with sickness behavior or Sickness Syndrome, one important process in the management of inflammation in the body is modulation of the inflammatory cascade that leads to the production of Series 1, Series 2, and Series 3 prostaglandins. The Series 2 prostaglandins are pro-inflammatory, while the Series 1 and Series 3 prostaglandins are anti-inflammatory.

Stress hormones and high insulin levels inhibit the production of Series 3 and Series 1 anti-inflammatory prostaglandins and favor the production of the pro-inflammatory series 2 prostaglandins. Specifically, stress hormones (including corticosteroids and catecholamines) released during the HPA response inhibit Delta 6 Desaturase activity--an enzyme required for the metabolic conversion of omega-3 fatty acids to the anti-inflammatory Series 3 prostaglandins that help reduce production of pro-inflammatory brain cytokines causing Sickness Syndrome.

Another step, then, in the management of Sickness Syndrome involves reducing the production of Series 2 prostaglandins through the use of herbal, nutraceutical, and/or pharmaceutical compounds that alter signal messaging substances involved in pro-inflammatory series 3 prostaglandin production including, but not limited to, cyclooxegenase inhibitors, lipoxegenase inhibitors, precursors to prostaglandin 1, and prostaglandin 3 production (e.g., eicosapentaenoic acid and omega-3 fatty acids), and inhibitors of arachidonic acid and leukotriene synthesis.

Selectively Inhibiting NF Kappa B activation -- NF Kappa B (NFkB) is a ubiquitous family of transcription factors that initiate inflammation. Inhibiting this family of transcription factors reduces the production of downstream pro-inflammatory prostaglandins and leukotrienes. However, because NFkB is essential to immune function, it is imperative to target only its pathologic manifestations. By precise inhibition of NFkB activation through the use of herbal and/or nutraceutical compounds known to weakly inhibit NFkB activation, inflammation will be reduced without compromising the essential role that NFkB plays in immune system function. (A discussion of specific herbal medicines and nutraceuticals used to address Sickness Syndrome will be included in a follow-up Therapeutic Nutrition column.)

Utilizing Antioxidants and Detoxification Therapies -- Free radicals also stimulate NFkB activation to initiate the inflammatory response. As such, administering appropriate antioxidants that neutralize free radicals is another useful step in the method of addressing Sickness Syndrome. Additionally, reducing toxins diminishes the reactive oxygen species load, which in turn causes pathogenic NFkB activity to selectively diminish. And when toxins translocate across a weakened mucosal barrier into the bloodstream, they stimulate the production of inflammatory cytokines via the HPA axis and increase glutaminase activity, which lowers glutamine and glutathione levels. Glutathione levels contribute significantly to the human liver detoxification system,16 while glutamine is a primary source of fuel for intestinal enterocytes that help maintain the integrity of another important detoxification system, the gastrointestinal tract.

Increasing Levels Of Activated Estrogen Receptors -- Activated estrogen receptors can decrease the production of pro-inflammatory cytokines.17,18 Specifically, activated estrogen receptors reduce levels of tumor necrosis factor alpha (TNF alpha), which bind to receptor sites on most cells in the body and trigger a chain of events that results in the genetic expression of pro-inflammatory cytokines that leads to Sickness Syndrome. In addition, activated estrogen receptors keep NFkB bound to inhibitor Kappa B and prevent it from triggering the production of pro-inflammatory cytokines in the nucleus of the cell.17,18 Individuals deficient in estrogen would benefit from administration of specific levels of herbal, nutraceutical, and/or bio-identical hormone compounds that bind to and activate estrogen receptors, thereby increasing levels of activated estrogen receptors.

Treating Existing Infections -- Sickness Syndrome is considered an adaptive response that permits survival following exposure to a variety of infectious organisms. This is an innate immune response designed to conserve energy and limit the spread of infection to others. However, since infection also leads to the production of inflammatory cytokines, which can increase the symptoms of Sickness Syndrome, a necessary step is to treat infection in the body, when necessary, with the use of select antimicrobial and/or antiviral herbal, nutraceutical, and/or pharmaceutical compounds.

Many herbal and nutraceutical ingredients serve multiple purposes including offering antioxidant activity (e.g., one ingredient, like green tea, is a weak inhibitor of NFkB and an antioxidant; it also increases alpha brain wave activity). As such, some components of nutraceutical formulations for Sickness Syndrome can address multiple steps in the treatment protocol.

Since the non-specific symptoms of Sickness Syndrome represent a facet of the inflammatory process, it becomes imperative to lower the levels of locally produced inflammatory brain cytokines and peripheral pro-inflammatory cytokines that cause the symptoms of sickness behavior. These symptoms are a major source of suffering for patients, often more so than the diseased organ itself.

Treating the symptoms of Sickness Syndrome individually can further weaken the patient's health. By understanding the mechanisms involved in the manifestation of Sickness Syndrome, however, we can apply the diagnostic and treatment modalities available to successfully manage this stress-related condition.

This article serves to provide you with an overall view of some of the key mechanisms involved in Sickness Syndrome™. Future articles by Dr. Nick will provide more detailed information on diagnosing and treating this highly prevalent condition. Dr. Nick is completing a new book on Sickness Syndrome. She will also be presenting new information about the diagnosis and treatment of Sickness Syndrome at the following events:

The Merging Medicine Series I: Stress, Inflammation and Cancer conference November 4 & 5, 2006 at the San Diego Convention Center in San Diego, California. Register at www.calnd.org/events.asp or call 209-245-3521

CAM EXPO West November 11, 2006 at the Hyatt Regency Century Plaza in Los Angeles, California: www.camexpo.com

© COPYRIGHT 2006 Dr. Gina L. Nick

References

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12. Dr. Nick currently maintains patent protection for the treatment of Sickness Syndrome[TM] and has researched and identified appropriate diagnostic and treatment methods to address the condition from a naturopathic perspective. This information will be made available in her upcoming new book on Sickness Syndrome[TM].
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