Entry Level Clinical Nutrition™-Redefining What We Do in a New Age of Increased Sickness & Increased Scarcity – Part VIII

Practically Examining the Acute Phase Response in Relation to Chronic Illness More On Sickness Behavior

As I suggested in the last installment of this series, chronic illness, in reality, is much more than just the aches, pains, fatigue, blood sugar imbalances, etc. that tend to first occur to us when we think of our chronically ill patients.  In fact, in the vast majority of chronically ill patients, mood disorders such as depression and anxiety tend to be inextricably linked to the types of somatic issues just mentioned.  Interestingly, this is one area where traditional descriptions of the acute phase response fail us in terms of explaining why our chronically ill patients are ailing and what to do about it.  Why?  I would suspect that a main reason is that patients in critical care situations, for whom the acute phase response was initially applied, tend to be unconscious or heavily sedated.  In turn, I would suspect that the authors of the classic descriptions of the acute phase response in relation to critical care situations felt little need to investigate how the acute phase response might apply to alterations in mood and personality.

Of course, with chronically ill patients and our efforts to improve their quality of life, knowledge of the interrelationship of somatic and mood/personality issues is critical.  Why?  While you can probably suggest many reasons, probably the simplest and most important is that, very often, if we cannot understand and deal with the behavioral aspects of the chronic illness spectrum, somatic concerns will not significantly improve due to lack of patient compliance that is vital to any therapeutic modalities we try to implement.  In turn, we encounter an unfortunate “Catch-22” that frustrates both our patients and you and me; patients need to comply with our recommendations in order to notice improvements in chief complaints revolving around mood and personality yet they cannot comply because their mood and personality issues prevent this compliance from occurring.  In short, while patients often intellectually recognize the need to comply, the neurophysiologic imbalances associated with the behavioral issues that are just as important as the somatic issues keep the patient in a perpetual “not in the mood” mentality.

How can we help our patients break out of this “not in the mood” situation?  First, as I have been suggesting with chronic somatic issues throughout this series, we need a conceptual model that helps us understand the foundational, “big picture” metabolic imbalances that are creating adverse personality changes.  As I hope I have demonstrated, the classic descriptions of the acute phase response and my efforts to adapt it to chronically ill patients via Entry Level Clinical Nutrition™ can easily be applied to somatic chief complaints.  However, because these classic descriptions were not created with behavioral issues in mind, the metabolic foundation that forms the basis of Entry Level Clinical Nutrition™ must be expanded so that we can fully understand and address the behavioral issues that are common to many chronically ill patients but fairly uncommon with the acutely ill.  As I hope I have also demonstrated in the last newsletter and will continue to try to demonstrate in this newsletter, papers that address the phenomenon known as “sickness behavior” do an excellent job of expanding our understanding so that we can now see that metabolic imbalances such as inflammation and insulin resistance not only impact muscle function and blood sugar but neurophysiology and neurochemistry.  In turn, armed with this understanding, we can use Entry Level Clinical Nutrition™ to not only address somatic chief complaints but to interrupt the “Catch-22” compliance vicious circle that keeps the patient from “getting into the mood” to do what we recommend.

Of course, traditional thinking in health care is that breaking up complicated vicious circles is equally complicated.  However, as I hope I demonstrated in the Viljoen and Panzer (1) paper and will try to demonstrate in the papers that follow, the “Salt of the earth” analogy I used in the last issue certainly applies.  First, these papers make it clear that both the somatic and mood/behavioral issues that form the basis of typical chief complaints are not “diseases” per se but are “sickness behaviors” that, in fact, are manifestations of  responses to environmental stressors related to excess or deficiency that have gone on too long.  Second, these papers make it clear that the foundational issues such as inflammation discussed in Entry Level Clinical Nutrition™ can easily be applied to mood and personality issues from both a diagnostic and treatment standpoint.  Therefore, contrary to popular health care thinking, we do not need separate approaches to “mind” and “body” chief complaints presented by patients.  Rather, we need to expand our mindset so that we can truly appreciate and, in turn, help our patients truly appreciate, that whatever we recommend that, at first glance, appears to be solely a “body” treatment, in reality, addresses both “mind” and “body.”  Furthermore, we also need to appreciate and help our patients appreciate the more difficult to accept converse situation that makes it clear that what, at first glance, appears to be solely a “mind” treatment, in reality, addresses both.

Sickness behavior and its relationship to suboptimal gut function

In the last installment of this series I discussed the interrelationship between inflammatory mediators and stress hormones in the creation of sickness behaviors that relate to both somatic and behavioral issues.  Now, I would like to present some quotes from several papers that highlight an aspect of Entry Level Clinical Nutrition™ that I have not touched upon to a significant extent so far in this series: suboptimal gut function.  One reason for this, of course, is that most every discipline in the clinical nutrition realm, including functional medicine, has comprehensively addressed this issue for years from both a research and clinical application standpoint.  However, from an Entry Level Clinical Nutrition™ perspective, virtually all of these outstanding disciplines have ignored one important aspect of a very key question – Why does gut dysfunction occur?  Of course, in many ways, this question has been answered quite successfully via many extensive discussions over the years about the relationship between gut function and issues of poor dietary habits, lack of hydrochloric acid, prolonged use of antibiotics, exposure to dysbiotic organisms, etc.  Nevertheless, from an Entry Level Clinical Nutrition™ standpoint and the acute phase response literature upon which it is based, there is one important answer to the question, “Why?” that has not been addressed.  As I have been emphasizing throughout this series, one of the main reasons that clinical signs and symptoms occur is primarily that they are outgrowths of the metabolic changes that occur in response to an adverse set of environmental stressors.  Of course, as I also have been emphasizing, one of the most significant metabolic responses to an adverse environment is a combination of alterations in stress hormones and immune function.  This, in turn, leads to increases in innate immunity and inflammation.  Finally, as I described in the last newsletter, this potent mix expresses itself clinically as mind/body signs and symptoms that make up the phenomenon known as “sickness behavior.”

With this idea in mind that metabolic responses to an adverse environment and subsequent chronic inflammation forms the basis of the chronic “sickness behavior” signs and symptoms we so often see in our patients, I would like to now introduce another, very closely related idea.  Could it be that another metabolic response to an adverse environment that leads to chronic inflammation and sickness behavior involves the gut?  As I hope to demonstrate via quotes from several papers, adverse changes in the gut that occur when the metabolic response to an adverse environment goes on too long are a potent reality.  In turn, even though I have discussed it very little so far, the metabolic responses that involve the gut are just as important to alleviating chief complaints in chronically ill patients as low-grade chronic metabolic acidosis, insulin resistance, loss of muscle mass, and all the other metabolic responses that comprise Entry Level Clinical Nutrition™.

The first paper I would like to present that suggests gut dysfunction in chronically ill patients is actually a response that leads to increased inflammation and subsequent sickness behavior is “Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies” by Loftis et al (2).  In this paper the authors make some interesting observations concerning the impact of exposure to endotoxins/lipopolysaccharides (LPS), which are technical terms for the harmful metabolites produced by gut microflora that can enter the bloodstream due to “leaky gut.”

“In humans, exposure to endotoxins (e.g., lipopolysaccharides) or proinflammatory cytokines induces a number of neuropsychiatric symptoms.  When modeled in animals this constellation of symptoms is often referred to as ‘sickness behavior’.”

Then Loftis et al (2) point out that the “leaky gut” connection with “sickness behavior” has been examined by Maes et al.  In “The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role from gram inflammatory pathophysiology of depression” by Maes et al (3) the authors state the following:

“The results show that intestinal mucosal dysfunction characterized by an increased translocation of gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.  It is suggested that the increased lipopolysaccharide (LPS) translocation may mount an immune response and thus inflammatory response system activation in some patients with major depression and may induce specific ‘sickness behaviour’ symptoms.  It is suggested that patients with major depression should be checked for leaky gut by means of the IgM and IgA panel used in the present study and accordingly should be treated for leaky gut.”

Of course, the above quotes, while important clinically, merely suggest that leaky gut can cause sickness behavior.  They do not provide any confirmation for my contention that the leaky gut can occur, as do many of the other as aspects of Entry Level Clinical Nutrition™ such as low-grade chronic metabolic acidosis and insulin resistance, as a consequence of a metabolic response to a stressor that has gone on too long.  Therefore, to provide this confirmation, I would like to again turn to the critical care nutrition literature.  In “Metabolic stress” by Fish and Friedman (4) the authors discuss in detail the “leaky gut” that occurs as part of the metabolic response during stress.  They state:

“Translocation of gut bacteria has been implicated as one of the causal factors in systemic inflammatory response syndrome and multiple organ dysfunction syndrome.  Changes in the gastrointestinal tract during trauma may include stress ulcers, bacterial overgrowth, mucosal atrophy, loss of barrier function, and increased permeability, all of which permit translocation of both endotoxin and bacteria.  A breakdown in the mucosal barrier and impairment in reticuloendothelial system capacity seem to result in systemic endotoxemia, leading to organ dysfunction, further impairment of the mucosal barrier, decreased clotting, and suppressed immune and Kupffer cell function.”

Interestingly, while this quote provides further clarity in terms of what happens during the metabolic response to stress that can contribute to the sickness behavior, it does not suggest why it happens.  As I have pointed out during this entire Entry Level Clinical Nutrition™ series, the various metabolic responses I have been describing do not happen due to random happenings or “bad luck.”  Rather, there is an inherent logic based on the age-old need to mobilize reserves to “escape the saber toothed tiger.”  Unfortunately, the logic of mobilizing reserves to “escape saber toothed tigers” is also based on one critical assumption, that the time frame needed for mobilized reserves is only a short period of time.  In another words, whatever happens, happens quickly (The caveman either escapes or is eaten.  Either way, it happens quickly.).  Unfortunately, what we see in our chronically ill patients is neither.  They neither escape nor get eaten.  Therefore, the stress response, during which time reserves are mobilized, goes on for months or years instead of the minutes for which the response was teleologically designed.  In turn, we see what has been described as chronic illness due to excessive allostatic load, which is a scenario where the mobilization of reserves that has a positive net result in the acute situation yields a negative result in the chronic situation.

With the above in mind, consider one of the primary objectives of the stress response, the need to produce additional glucose that acts as fuel for the key organs required to “escape the saber toothed tiger.”  Where does this sugar come from?  As we all know, much of it comes from the process of gluconeogenesis, which involves converting amino acids to glucose.  Of course, conventionally we have been taught that the source of the amino acids that act as substrates in gluconeogenesis is muscle.  In turn, we often see muscle loss and sarcopenia, a key issue that is addressed in Entry Level Clinical Nutrition™.  However, there is one other, less well known source of amino acids that act as substrates for gluconeogenesis: the gut lining.  In “Overview: Substrate and acute catabolism” by Allison (5) the following is stated:

“An exciting new observation is the finding that, in response to hypoglycemia, amino acids for gluconeogenesis are released from the gut not from muscle.  This finding was discussed and two possible mechanisms were considered.  It seemed most likely that amino acids are derived from the digestion and absorption of cells shed from the tip of the mucosal villus, although the possibility of a labile pool of amino acids within the mucosa was suggested by Dr. Soeters.  It is clear that, whatever the details of the mechanism, the amino acids are derived from the mucosal rather than the smooth-muscle layer of the gut wall.”

Then, Molina and Abumrad in “Hypothalamus, glucopenia, and fuel mobilization” (6) give more detail on this process of using gut derived amino acids for gluconeogenesis:

“The primary site of this proteolytic response is not skeletal muscle but primarily the gastrointestinal tract, resulting in an increased net release of both essential and nonessential amino acids across the extrahepatic splanchnic tissues.  During this process, the majority of amino acids released by the gut are taken up by the liver, but a significant component, specifically that of branched-chain amino acids, is released into the systemic circulation and taken up by other organs, mainly skeletal muscle.”

Finally, Wilmore (7) discusses this unique aspect of gluconeogenesis:

“Additional studies have shown that amino acids are avidly extracted from the bloodstream of the splanchnic bed.  In large part it is represented by extraction of amino acids by the liver for the synthesis of structural, plasma, and acute-phase proteins.”

What is the overall significance of this process metabolically?  As I have noted, it is a response by the body to a stressful situation where the body mobilizes key constituents so that key organs involved with coping with the situation have optimal amounts of energy.  Wilmore (7) states:

“These observations are consistent with other studies of tissue protein synthesis rates following isotropic infusions into ‘stressed’ animals.  Taken together with the human studies these investigations confirms that protein turnover responds to injury and infection in a manner that redistributes body protein to satisfy the body’s needs.  The synthesis rate is decreased in ‘nonessential’ tissues (e.g., limb skeletal muscle or gut) and is maintained or enhanced in tissues where work is increased (respiratory and cardiac muscle, lung, liver, spleen).  Data generally support the hypothesis that serious surgical illness stimulates enhanced protein turnover.”

Therefore, as I hope I have demonstrated, the gut dysfunction that is so common in our chronically ill patients is more than just the result of poor environment and lifestyle choices.  Rather, it occurs as the result of a deliberate effort by the body to cope with a stressful situation that has, very simply, gone on so long that the effort to cope, which is basically a “rob Peter to pay Paul” scenario, has left “Peter” so depleted that dysfunction and the “sickness behavior” that is the theme of this newsletter is the inevitable result.

More evidence that the clinical picture seen with many chronically ill patients is, in fact, sickness behavior induced as a response to inflammation and related metabolic imbalances

An examination of the term “sickness behavior” in Medline reveals very quickly that the major researcher in this area from both a physiological and clinical standpoint is Robert Danzer.  In turn, I would like to present some highlights of a review paper written by this researcher entitled “Cytokine-induced sickness behavior: Mechanisms and implications” (8).

The first quote I would like to present comes from the abstract of the paper and states, very basically, an exact definition of sickness behavior:

“Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection.  At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα).”

The next quote refers to the aspect of sickness behavior that, as I have mentioned repeatedly, is vital to true understanding, the fact that it occurs as a response:

“At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens.”

Next, in the text of the paper, Dantzer (8) expands upon the brief overview and definition presented above to show that what appears to be random signs and symptoms in our patients are actually a visible representation of a coordinated, deliberate set of responses:

“Nonspecific symptoms of infection and inflammation include fever and profound physiological and behavioral changes.  Sick individuals experience weakness, malaise, listlessness, and inability to concentrate.  They become depressed and lethargic, show little interest in their surroundings, and stop eating and drinking.  This constellation of nonspecific symptoms is collectively referred to as ‘sickness behavior’.  Due to their commonality, sickness symptoms are frequently ignored by physicians.  They are considered as uncomfortable, but rather banal, component of the pathogen-induced debilitation.

This view is, however, totally inadequate.  The behavioral symptoms of sickness represent together with the fever response, a highly organized strategy of the organism to fight infection.”

Of course, the classic example where a set of signs and symptoms are, in reality, visible manifestations of a response to an environmental stressor is fever.  In this next quote Dantzer (8) discusses what happens during fever to create the physical manifestations we so often see:

“In physiological terms, fever corresponds to a new homeostatic state that is characterized by a raised set point of body temperature regulation.  A feverish individual feels cold at usual environmental temperatures.  Therefore, the feverish person not only seeks warmer temperatures, but also enhances heat production (increased thermogenesis) and reduces heat loss (decreased thermolysis).  The higher body temperature that is achieved during fever stimulates proliferation of immune cells and is unfavorable for the growth of many bacterial and viral pathogens.  In addition, the reduction of zinc and iron plasma levels that occurs during fever decreases the availability of these vital elements for growth and multiplication of microorganisms.”

Before continuing, please note again the changes that occur with zinc and iron metabolism as a response to an environmental stressor.  An underlying theme of Entry Level Clinical Nutrition™ that I feel deserves continued emphasis is that nutrient deficiency in chronically ill patients is not limited to issues of inadequate intake and/or absorption.  Rather, issues of alteration in metabolism in response to adverse environmental circumstances are just as important.  In turn, as is so often the case, when only issues of intake and absorption are considered when making decisions concerning dietary changes and supplementation, errors in judgment can occur that not only have the potential for decreasing efficacy but for increasing risk of side effects.

In the next quote, Dantzer (8) provides more detail as to what happens physiologically with fever and how the body responds:

“The amount of energy that is required to increase body temperature during the febrile process is quite high since, in human beings, metabolic rate needs to be increased by 13% for a rise of 1oC in body temperature.  Because of the high metabolic cost of fever, there is little room for activities other than those favoring heat production (e.g., shivering) and minimizing thermal losses (e.g., rest, curl-up posture, piloerection.”

In concluding this discussion on fever, Dantzer (8) discusses a fact that we all see clinically every day.  While sickness behavior can be the result of infection and the body’s response to it, sickness behavior/patient signs and symptoms, can also be caused by many other stressors that do not involve the immune system:

“Although sickness behavior is a normal response of the host to pathogens that are recognized by the innate immune system, there is evidence that sickness behavior can be triggered by nonimmune stimuli, in the same way that sickness behavior can alter the organism’s response to environmental stressors.”

The next quote I would like to present from the Dantzer paper (8) emphasizes still again the idea that sickness behavior (The signs and symptoms we typically see in chronically ill patients) is not random expression of disease and physical deterioration.  Rather it is a manifestation of a predictable, logical, and organized response:

“Sickness behavior is usually viewed by physicians as the result of debilitation and physical weakness that inevitably occur in an organism whose resources are engaged in a defensive process against pathogens.  An alternative hypothesis is that sickness behavior is the expression of a highly organized strategy that is critical to the survival of the organism.”

Next, Dantzer (8) focuses on the idea that inflammation, which is a foundational aspect of Entry Level Clinical Nutrition™, is a primary instigator of both the somatic and behavioral aspects of sickness behavior:

“There is already evidence demonstrating that proinflammatory cytokines are responsible for the development of subjective and behavioral symptoms of sickness during infection with a bacterial or viral pathogen.  For instance, patients treated with interferon (IFNα) show fever, anorexia, fatigue, headache, myalgia, and arthralgia.  These symptoms culminate in lethargy and withdrawal from the surroundings.”

In the following section, the author moves from generalities to a discussion of a specific clinical entity that we all see quite often, chronic fatigue syndrome (CFS).  Could CFS, which is often considered to be a random occurrence when a formerly healthy person suddenly, without warning, becomes very tired, actually be a predictable manifestation of the body’s inflammatory response?  Dantzer (8) states:

“There has been much speculation on the possible pathogenic role of cytokines in chronic fatigue syndrome (CFS).  Always feeling tired is a common complaint  of patients afflicted with a viral infection and represents the core symptom of the so-called postviral fatigue syndrome.  CFS patients feel the same, but in the absence of any persistent viral infection.  Their symptoms are real, pervasive, and often incapacitating.  The fact that a substantial proportion of these patients fulfill criteria for major depression and other psychiatric illness does not facilitate the classification of this disorder.  Whatever the case, and in view of the similarities between the  subjective effects of cytokines and the symptoms reported by CFS patients, many researchers have looked for possible overproduction of cytokines in this condition.  Elevated plasma levels of proinflammatory cytokines have been reported in a number of studies of CFS patients…”

To close this discussion on the excellent paper by Dantzer (8) I would like to present a quote that supports a primary contention of Entry Level Clinical Nutrition™ that, contrary to conventional thinking, chronically ill patients are not fundamentally the same as healthy patients except for a few isolated areas of dysfunction that can be addressed with some sort of neutraceutical protocol.  In fact, due to a number of metabolic imbalances including chronic inflammation, these patients are metabolically unique compared to healthy patients from head to toe and must be addressed as such.  The author states:

“A sick individual does not have the same priorities as a well one, and this reorganization of priorities is mediated by the effects of cytokines on a number of peripheral and central targets.”

An example of how an inflammatory response can create sickness behavior and how inflammation and sickness behavior can be lessened with eicosapentaenoic acid (EPA)

Does clinical research exist that shows not only how inflammation can create the sickness behavior that I am suggesting is responsible for many if not most of the major chief complaints seen with chronically ill patients, but how the inflammation and sickness behavior might be lessened?  A fascinating paper by Su (9) entitled “Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a mind-body interface’?” addresses this question in fine fashion.

To address the relationship between inflammation and common behavioral and somatic symptoms, the author considered depression, a very prevalent form of chronic illness.  As Su (9) points out, the signs and symptoms we often see in our chronically ill patients are also often seen with depressed patients:

“Depressive disorders with predominately somatic presentation are the most common forms of depression.  In a clinical study, somatic symptoms, particularly somatic anxiety and fatigue were documented in up to 80% of a sample of major depression.  Two of the three most common symptoms (low mood: 76%, fatigue: 73%, sleep disturbances: 63%) reported during a current depressive episode were somatic…Somatic symptoms were the main reason for the initial visit to the primary care physician.  In a US study, two thirds (69%) of depressed patients complained of general aches and pains, implying the close relationship between painful somatic symptoms and depression.”

Su (9) then points out what I have been suggesting concerning the similarity between the somatic symptoms we typically see in our chronically ill patients and sickness behavior:

“Somatic symptoms are similar to typical symptoms of sickness, including general weakness, malaise, fatigue, muscle and joint aches, loss of interest in the surroundings, loss of appetite, and inability to concentrate.”

Next, the author mentions the relationship between inflammation and sickness behavior that is the theme of this newsletter:

“The idea of sickness behaviour sprang from a series of observed symptoms related to infection and cytokine/prostaglandin administration in humans and animals.”

Then, Su (9) goes beyond the generalities that I have been presenting and gives an actual clinical example proving that inflammation can cause sickness behavior, and by extension, many if not most of the chief complaints we see in chronically ill patients:

“…in patients receiving interferon-α (IFN-α) therapy for chronic hepatitis C virus (HCV) infection or cancers, almost all patients experience an acute cytokine-induced sickness behaviour.”

The table below (please see PDF version to view table), which comes from the paper by Su (9) shows, in very graphic fashion, the similarities between symptoms typically seen in chronically ill patients, in this case patients categorized as suffering from major depression disorder (MDD), and symptoms that are induced by an inflammatory cytokine, in this case IFN-α.  In turn, I feel that a very strong argument can be made that the chief complaints typically encountered with chronically ill patients are, as I have been suggesting, a manifestation of a response to a stressful situation, which, in this case, is inflammation, but can also include all of the complementary and interrelated metabolic imbalances that make up the Entry Level Clinical Nutrition™ spectrum.

Interestingly, one factor that makes the Su (9) paper special compared to the others I have reviewed is that it does not stop with just a discussion of the problem.  Rather, it shows how a supplement we use everyday has an impact on sickness behavior far beyond what we may have expected.  Concerning eicosapentaenoic acid (EPA) and sickness behavior the author states the following:

“According to the evidence on the effects of EPA on antagonizing sickness behavior in animals, we hypothesized that EPA might be specifically deficient in patients with cytokine-induced sickness behaviour.  As mentioned previously, IFN-α can induce sickness behaviour and depression in a significant proportion of patients receiving this treatment; hence, this can provide an excellent model to study somatic symptoms in depression.  By using this model, we have found that patients with HCV who had lower EPA levels at the early stage of IFN-α therapy developed more IFN-α sickness behaviour.”

Of course, as we all know, even though the quote above refers only to depression, the relationship between chronic inflammation and chronic illness can be extrapolated to virtually every other major chronic illness.  Su (9) states:

“Chronic low-grade systemic inflammation is a feature of chronic diseases such as metabolic syndrome, type 2 diabetes, cardiovascular disease, coronary artery disease, cancers, and dementia…”

Therefore, with all the above in mind, I feel strongly that the following can be concluded:

  • Major chief complaints and symptoms seen with most chronic illnesses are manifestations of the body’s response to illness, which to a great extent, involves chronic inflammation but also includes other related metabolic imbalances such as insulin resistance, nutrient deficiencies such as vitamin D, gut dysfunction, and loss of muscle mass (sarcopenia) caused by a protein deficient diet and prolonged catabolic physiology. 
  • Reducing inflammation using agents such as fish oil and herbals such as curcumin that impact both on cytokine and prostaglandin activity can have a profound impact on patient well-being way beyond resolution of signs and symptoms classically related to inflammation. 

Sickness Syndrome and the writings by Gina L. Nick, PhD, ND

Of course, I am not the only writer who has surmised that inflammation-induced sickness behavior that has been traditionally linked only with mood disorders in the literature is actually a phenomenon seen with virtually every chronic illness and every chronically ill patient.  In the excellent the paper “Sickness syndrome: Introduction to a new condition – Part I, Nick (10) states:

“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.”

In the next quote, Nick (10) discusses the involvement of inflammatory mediators with Sickness Syndrome and how, even though it was initially described only in relation to mood disorders, can, in actuality, be linked with virtually every chronic illness:

“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.  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, and most often, specifically develop in patients suffering from somatic diseases with an inflammatory component such as cancer, coronary heart disease, rheumatoid arthritis, asthma, stroke, and various neuropathologies.

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.”


As suggested by Nick (10) in the above quotes, it seems, more and more, that the patients we encounter in today’s world involve such a high degree of complexity, both in terms of diagnosis and treatment, that the best we can hope accomplish is some semblance of superficial, palliative relief of symptoms and optimizing of laboratory test values.  However, as I have been suggesting throughout this series on the acute phase response and its clinical implications, this complexity may, in reality, not be inherent in nature, but merely a function of a lack of understanding of the true nature of chronic illness.

I believe we need to truly internalize the very difficult to accept reality that much of what we traditionally learned about chronic illness and the signs and symptoms associated with it, in terms of being random occurrences of bad genes, bad luck, and a bad environment that can only be addressed with panacea-like medical procedures, pharmaceuticals, or neutraceuticals, is fundamentally flawed.  Instead, we need to realize that chronic illness is much like a symphony made up of individual notes and individual instruments that only seems complex because we have not taken the opportunity to learn how to read the music and play the instruments.

The critical care nutritionists, in my opinion, truly understand the “notes” that comprise the “symphony” of illness and have learned how to play the nutritional “instruments” required for its performance.  Granted, like a symphony that has been adapted to another musical genre such as jazz, for example, some alterations need to be made so that the precepts set by the critical care nutritionists can be applied to chronic illness.  Nevertheless, as the symphony that has been adapted to a jazz format is still fundamentally the same, so too are the foundations of critical care nutrition fundamentally the same when applied to chronic illness.  Hopefully, through the Entry Level Clinical Nutrition™ paradigm, I have been successful in adapting the symphony critical care nutritionists have written for acute illness to the very similar metabolic world of the chronically ill patient.  I look forward to your feedback.

In part IX of this series I will begin a detailed exploration of the research relating to each of the components of Entry Level Clinical Nutrition™, starting with low-grade chronic metabolic acidosis and its relationship to fluid/electrolyte imbalances.  While I provided an introduction to this literature in the product newsletters, this exploration will be much more in depth and detailed. 

Moss Nutrition Report #236 – 12/01/2010 – PDF Version


  1. Viljoen M & Panzer A. Non-termination of sickness behavior as precipitating factor for mental disorders. Med Hypotheses. 2005;65:316-329.
  2. Loftis JM et al. Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies. Neurobiology of Disease. 2010;37:519-533.
  3. Maes M et al. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocriol Lett. 2008;29(1):117-24.
  4. Fish JA & Friedman JM. Metabolic stress. In: Matarese LE & Gottschlich MM, ed. Contemporary Nutrition Support Practice: A Clinical Guide. Philadelphia: W.B. Saunders Co; 1998:539-546.
  5. Allison SP. Overview: Substrate and acute catabolism. In: Kinney JM & Tucker HN, ed. Organ Metabolism and Nutrition: Ideas for Future Critical Care. New York: Raven Press; 1994.
  6. Molina PE & Abumrad NN. Hypothalamus, glucopenia, and fuel mobilization. Organ Metabolism and Nutrition: Ideas for Future Critical Care. New York: Raven Press; 1994:69-90.
  7. Wilmore DW. Metabolic response to severe surgical illness: Overview. World J Surg. 2000;24:705-711.
  8. Dantzer R. Cytokine-induced sickness behavior: Mechanisms and implications. Annals NY Acad Sci. 2006;933:222-234.
  9. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a ‘mind body interface’? Neurosignals. 2009;17:144-152.
  10. Nick GL. Sickness syndrome: Introduction to a new condition – Part I. Townsend Letter for Doctors and Patients. 2006(October):58-61.