Practically Examining the Acute Phase Response in Relation to Chronic Illness Sickness Behavior
“Let’s drink to the salt of the earth
Say a prayer for the common foot soldier
Spare a thought for his back breaking work
Spare a part for his wife and his children
Who burn the fires and who still till the earth”
Salt of the Earth
The Rolling Stones
Up to this point in this series, while my descriptions of the acute phase response (APR) and its relationship to chronic illness have contained several clinical references, most of what I presented involved the biochemistry and physiology of the APR. With this in mind, in this installment I would like to discuss research that focuses more predominantly on the signs and symptoms that are associated with the APR when it goes on too long, as is the case with many (if not most) chronically ill patients. However, before doing so, I would like to discuss a “big picture” issue that has been brought up by many of you in response to my writings and teleconferences on Entry Level Clinical Nutrition™ and will undoubtedly come up again as I discuss research that suggests virtually every one of the most common signs and symptoms that we typically encounter with chronically ill patients have a common cause that involves chronic inflammation and a small selection of other foundational factors. Many of you seem to be very resistant to accept the idea that chronic illnesses that look completely different from patient to patient can actually have more similarities than differences, AND that effective treatment can revolve less around unique, disease specific protocols and more around very basic, low cost, and time efficient supplementation and lifestyle corrections that address foundational metabolic issues such as acid/alkaline balance, protein:carbohydrate ratio, insulin resistance, etc.
Therefore, as suggested by the Rolling Stones, I would like to now present two editorials from The New York Timesthat support my contention that in this age of increasing complexity, the often ignored, under appreciated “common foot soldiers” of health care have, ironically, great power in their simplicity to address the needs of chronically ill patients in terms of resolving chief complaints and improving quality of life. So I would like to take a moment now to hopefully provide proof to you that we do need to honor those simple concepts and therapies that metaphorically “burn the fires and still till the earth” in terms of our patients most fundamental metabolic imbalances. In an age when, all too often, the loudest voices get the most attention no matter what the message, more than ever I feel we need to give credence to the sage advice of the Rolling Stones:
“Let’s drink to the salt of the earth!!”
The first editorial I would like to discuss is entitled “The genome, 10 years later” that appeared in the June 20, 2010 edition of The New York Times. The key question that is addressed is whether the human genome project which, ten years ago, was predicted with great fanfare to rapidly advance the human condition, actually did so over a ten year period of time. The editorial states:
“On June 26, 2000, two scientific teams announced at the White House that they had deciphered virtually the entire human genome, a prodigious feat that involved determining the exact sequence of the chemical units in human genetic material. An enthusiastic President Clinton predicted a revolution in “the diagnosis, prevention and treatment of most, if not all, human diseases.”
Over the last ten years did that bold prediction come to pass? The editorial continues:
“Now 10 years later, a sobering realization has set in. Decoding the genome has led to stunning advances in scientific knowledge and DNA-processing technologies but it has done relatively little to improve medical treatments or human health.
To be fair, many scientists at the time were warning that it would be a long, slow slog to reap clinical benefits.”
Nevertheless, during the last ten years a sobering reality set in that may not have been appreciated with the initial excitement that existed in June of 2000. What was this reality? Complex, chronic illnesses cannot be distilled down to one or two gene variants:
“…the original hope that close study of the genome would identify mutations or variants that cause diseases like cancer, Alzheimer’s and heart ailments – and generate treatments for them – has given way to realization that the causes of most diseases are enormously complex and not easily traced to a simple mutation or two.”
However, does this complexity infer that simple, time-tested diagnostic modalities no longer have value? The editorial states:
“One recent study found that some 100 genetic variants that had been statistically linked to heart disease had no value in predicting who would get the disease among 19,000 women who had been followed for 12 years. The old-fashioned method of taking a family history was a better guide.”
The second editorial I would like to discuss that I feel affirms this point of view appeared in the September 12, 2010 edition of The New York Times and is entitled “Is new better? Not always.” It begins with the following, somewhat sobering statement:
“The Congressional Budget Office estimates that an astonishing half of more of the increased spending for health care in recent decades is due to technological, surgical or clinical advances.
For the most part, such advances are a cause for celebration. But an expensive new drug is not always better than an older, cheaper drug, and sometimes a new technology or treatment that is highly effective for some patients is unnecessary or even dangerous for others.
The system almost seems designed to keep driving up costs.”
What is required to halt this endless progression towards higher cost and lower efficacy? As the editorial makes clear, the first step is recognition that, clearly, the status quo needs to change:
“No one wants to bar patients from getting the treatment they need. But without curtailing the use of unnecessary, overly costly and even dangerous new technologies and surgical procedures, there is little hope of restraining the relentless rise in health care costs.”
Of course, given that this editorial is clearly directed towards the allopathic community, you may wonder why I am bringing this up to you, members of the clinical nutrition community. Is it to “gloat” about how the supplement industry, in contrast, never encourages the use of high priced new products that have no proven record of patient efficacy? Unfortunately no. For me, even a casual perusal of the Internet makes it clear that, while our track record concerning danger is fairly good (The legitimate concerns about folic acid and high doses of vitamin D not withstanding), I do not feel the same concerning efficacy and cost about many of the new generation of products that are promoted with just some of the following teasers:
- Specially processed
- Highly absorbable
- Unique herbal extract
Compared with basic formulations used in a basic manner as is being suggested by Entry Level Clinical Nutrition™, do these new versions of herbal extracts and nutritional substances such as fish oil, coenzyme Q10, etc. have a better performance record in terms of contributing to the resolution of chief complaints in chronically ill patients so as to justify the sometimes significantly higher cost? For the most part, I have not seen definitive evidence that suggests this is, indeed, true. Of course, I do believe the claims made by the manufacturers of this new generation of supplements that they do provide a significant level of clinical efficacy. However, whenever I ask these manufacturers how these new forms of herbs and nutrients compare in terms of patient response to the older, lower cost forms, I rarely, if ever, receive reliable data that assures me that the higher cost is warranted.
The supplement industry is now a multi-billion dollar per year entity. In turn, with the very real, high profile issue of cost containment in health care in mind, we need to ask whether we are part of the solution or part of the problem. To answer this question, though, I feel we need to ask still another question. What percentage of those billions was spent on products that delivered a level of efficacy that was commensurate with the cost? Until that question can be definitively answered, I feel that we need to accept the difficult reality that an editorial entitled “Is new better? Not always” not only provides a justifiable criticism of the current practice of allopathic medicine but may very likely also provide a mirror so that we can better see issues in ourselves that, even though we may not want to see them, we definitely need to look at them.
As someone who derives his income from the sale of supplements, I have long felt that I have an obligation to often look into the reality mirror discussed above. The last time I took a good, hard look was the beginning of the current recession. What I saw was a need to take the long ignored, long under appreciated “common foot soldiers” of clinical nutrition long discussed and researched by critical care nutritionists and put them together in a way that would help our customers use whatever is purchased from us in a way that maximizes patient compliance, time and cost efficiency, and, of course, overall efficacy in relation to what matters most to patients, resolution of chief complaints. Entry Level Clinical Nutrition™ was the result of my desire to fulfill this need. Now, almost one year after I started writing about this approach to clinical nutrition, I take great satisfaction from feedback from so many of you that suggests the successes obtained for years by critical care nutritionists using basic, cost effective tools can be replicated in the outpatient, chronic illness setting. While I realize, as suggested above, that this approach to nutrition-based health care can be difficult to accept due to its radical departure from entrenched systems we have used for years, I hope that those of you who are resistant will keep an open mind to the idea that, even in this age of increased complexity, simplicity is still relevant now, if not more so than ever. So again, as suggested by The New York Times, I propose a toast:
“Let’s drink to the salt of the earth!!”
THE TRUE NATURE OF SIGNS, SYMPTOMS, AND ILLNESS: SICKNESS BEHAVIOR
In line with the paradigm of simplicity that I discussed above and, indeed, in this entire series, are what seem to be inherent complexities of signs and symptoms related to illness nothing more than various permutations of a fairly uniform and somewhat simplistic response to the metabolic, biochemical, physiologic, and psychological stressors we encounter everyday? A group of authors using descriptors such as “sickness behavior” and “sick syndrome” are suggesting just that. From a foundational standpoint, Owusu-Apenten discusses illness as a response in the excellent, recently published text Bioactive Peptides: Applications for Improving Nutrition and Health (1). In the chapter entitled “Nutrition and the host response to infection and injury” the author states:
“Illness may be considered a programmed response to infection and injury that is intended to aid recovery in the long term. However, illness can also lead to a set of ‘sickness behaviors’ that include lethargy, sleepiness, loss of appetite (anorexia), reduced grooming, low regard for personal hygiene, and a state of depression. It is thought that sickness behavior is linked with increased levels of cytokines produced in response to invading microbes, injury, or chronic diseases stress. The short-term host response to illness is powered ultimately by muscle loss.”
As I hope you can see from the above quote, many of the most common chief complaints that we encounter from chronically ill patients, such as fatigue and musculoskeletal issues related to muscle loss are actually not isolated illnesses in and of themselves but part of an overall response pattern to often basic environmental stressors. The author then goes on to point out that this response pattern is part of an all-encompassing phenomenon that I have discussed previously in this series, the acute phase response. Furthermore, it is this response that is responsible for metabolic changes we see in patients that we typically associate with patient chief complaints:
“Most organisms demonstrate a programmed response to illness, infection, and injury termed the acute phase response. The host response is responsible for derangements in metabolism and the unwanted loss of lean body mass frequently observed in sick people.”
Of course, as we all well know by now, common chief complaints most often presented by chronically ill patients are no longer limited to physical, somatic issues. Issues of depression and other suboptimal mental states are becoming increasingly more common. Are depression and other associated conditions classically suggested to be independent isolated “diseases” another manifestation of a response to major metabolic stressors such as poor diet, infection, injury, etc.? Many authors are suggesting that this is, indeed, what is happening. In the paper “Non-termination of sickness behavior as a precipitating factor for mental disorders” by Viljoen and Panzer (2), the authors reflect the thoughts of many on this subject, as seen in the first paragraph of their paper that affirms the idea that many of the signs and symptoms we typically see in chronically ill patients are actually aspects of a fairly uniform response:
“Sickness behavior can be defined as a combination of coordinated behavioral and physiological changes that develop in response to infection, inflammatory conditions, physical trauma or even negative emotions that initiate the inflammatory response. The symptoms of sickness behavior can include any combination of the following: fever, fatigue, hyperalgesia, somnolence, anhedonia, loss of appetite, loss of interest in social and sexual interaction, decreased concentration and other cognitive abilities, decreased locomotor and body-care activities, as well as feeling of depression, hopelessness, irritability, anxiety, worthlessness, guilt and the reorganization of perceptions and coping strategies.”
Of course, as I suggested repeatedly in my discussions of the acute phase response, inflammation, which is now considered to be a universal finding with virtually all chronic illnesses, appears to be a primary driver of this collection of signs and symptoms that comprise sickness behavior. In agreement, the authors state:
“The process can be summarized by saying that infectious and inflammatory conditions, as well as most other forms of tissue injury, can stimulate the production of pro-inflammatory cytokines and that these peripherally produced cytokines can upregulate the basal cerebral pro-inflammatory cytokine production and release.”
Furthermore:
“The symptoms of sickness behavior are intended to aid in the recovery from whatever condition initiated the increase in peripheral cytokine production. The adaptational value of neurological, behavioral, metabolic, motor and immunological symptoms of sickness behavior covers a range of physiological and psychological advantages, including prevention of the spread of infections, optimizing the defense of the body against infection, injury and neoplastic growth, as well as reverting energy consumption to the processes of healing and recovery.”
Therefore, as I hope you can see, many (if not most) of the signs and symptoms we typically see in chronically ill patients are manifestations of a process that was intended to restore health. Unfortunately, because these signs and symptoms are chronic in nature, this process has gone on too long, invariably leading to negative sequelae.
Viljoen and Panzer (2) then go on to make a thought-provoking suggestion. Could it be that many of the signs and symptoms we typically see in chronically ill patients that we have, for many years, associated purely with stress-induced mental issues that relate solely to disturbances in the hypothalamic-pituitary-adrenal axis (HPA axis) actually have significant involvement with the one factor that is at the heart of the acute phase response, inflammation? The authors state:
“It is intriguing that many of the symptoms of sickness behavior correspond to those seen in a number of mental disorders.”
The authors continue:
“With some exceptions the cytokine-induced changes show a strong resemblance to stress-induced changes and disturbances of these same systems are also found in a variety of mental disorders. Another feature common to sickness behavior, as well as to several mental disorders, is the increase in pro-inflammatory cytokine activity. Mental disorders in which abnormal levels of pro-inflammatory cytokines have been reported include mood disorders, psychotic disorders, delirium, dementia and related cognitive disorders, obsessive-compulsive disorders, and anxiety disorders. There is abundant proof, not only from research on sickness behavior, but also from human cytokine therapy and experimental work that cytokines can cause neurobehavioral disturbances ranging from mild constitutional symptoms (e.g., fatigue, chills, headaches, fever) to serious behavioral problems such as major depressive moods, hallucinations, disorientation, delirium and psychosis.”
With the above in mind, Viljoen and Panzer (2) postulate that a major category of signs and symptoms that is rapidly becoming more prevalent in chronically ill patients, like so many other signs and symptoms I have discussed, is not a mysterious, isolated event that requires new, complicated, high tech, high cost therapies but merely a facet of a generalized response that has gone on too long:
“In view of the similarities between sickness behavior and a number of mental disorders it is hypothesized that continuation of sickness behavior, (i.e., non-termination), after recovery from the initial disease, could form the basis for mental disturbances.”
The authors then elaborate on this hypothesis:
“In view of the cross-sensitization between stressors and the fact that psychological stress can lead to an increase in pro-inflammatory cytokine activity it speaks for itself that psychological stress or a secondary inflammatory or infectious condition, even if subclinical, which coincides with sickness behavior due to another cause, could contribute to the behavioral disturbances and even exacerbate the condition with dire consequences for mental health.”
However, as I mentioned, a major factor that leads to many of the symptoms we see in chronically ill patients, especially those that relate to behavioral issues, is the fact that the response goes on too long:
“For sickness behavior, which constitutes a normal adaptational homeostasis, to progress to a mental disorder, i.e., inappropriate continuation of sickness behavior, there would have to be a failure in the mechanisms involved in the termination once the individual has recovered from the initiating onslaught.”
Are the somatic signs and symptoms we see most often in chronically ill patients part of a bigger response scenario that includes mood disorders?
Viljoen and Panzer (2) make a very strong argument for answering the above question in the affirmative. The authors point out:
“The similarities between the behavioral characteristics of the mood disorders and that of sickness behavior are striking. As previously seen, sickness behavior symptoms may vary with the severity and duration of the condition from flu-like symptoms to anhedonia to severe cognitive disturbances. In considering the symptoms of mood disorders (depressed mood most of the day; nearly every day; markedly diminished interest or pleasure in almost all activities; decreased appetite or weight loss, hypersomnia or insomnia nearly every day; psychomotor retardation or agitation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate and recurrent thoughts of death, suicidal ideation or a suicide attempt-from which at least 5 have to be present to represent a major depressive episode), it is clear that they all fall within the scope of sickness behavior.”
While I would guess many (if not most) of your chronically ill patients are not experiencing major manifestations of severe depression such as thoughts of death and suicide attempts, I would also guess that many (if not most) are experiencing many of the other signs and symptoms described in the above paragraph. Of course, the preceding quote mainly focuses on behavioral disorders. However, in the next quote the authors go on to discuss the idea that, in addition, the somatic signs and symptoms typically associated with specific diseases, most of which we tend to see often in our chronically ill patients, are also actually manifestations of a sickness behavior response:
“Many medical conditions, including almost all chronic and some acute infectious and inflammatory conditions, as well as trauma and surgery-in fact virtually any form of tissue injury, are associated with the typical neuroimmunological profile of sickness behavior, which comprises activation of the inflammatory response accompanied by alterations in the CRH/HPA-axis, CAN/SAM-axis, and central serotonergic activity. Amongst the non-infectious medical conditions where hyperactivation and secretion of cytokines have been reported with the highest incidence are various autoimmune diseases, allergies, multiple sclerosis, rheumatoid arthritis, stroke, trauma, the premenstrual syndrome, post partum depression, several neurodegenerative disorders, sepsis and the systemic inflammatory response syndrome.”
However, as I have mentioned repeatedly, one of the biggest keys to manifestation of the above is non-termination of the response. What can cause this non-termination? Viljoen and Panzer (2) state:
“The condition of resistance to termination can be exacerbated or prolonged by negative perceptions, feelings of no control or the inability to cope-in fact, by any factor that causes psychological stress.”
With the above in mind, the authors hypothesize that still another common finding, depression, is not an isolated disease per se but a behavioral manifestation of the inflammatory response that, as I have pointed out, is part of a generalized acute phase response:
“In view of the variety of behavioral symptoms, ranging from mild constitutional to psychosis that may be induced by proinflammatory cytokines, one should perhaps rather refer to behavioral disturbances due to a general medical condition, rather than depression due to a general medical condition.”
Could other neurologic disorders beyond depression and mood disorders, instead of being isolated entities, be part of the sickness behavior/response paradigm?
As you will see from the somewhat lengthy quote that follows, the answer to this question, according to the authors, is certainly in the affirmative:
“In addition to being the stimulus for the expression of mood disorders, sickness behavior could very well also serve as the trigger for the development of other mental disorders to which the individual has been predisposed. This statement is based on two facts. The first is that pro-inflammatory cytokines, the initiating factors of the neurobehavioral adaptations of sickness behavior, can lead to a wide spectrum of behavioral problems, including severe chronic fatigue, neurasthenia, asthenia, malaise, lethargy, somnolence, emotional instability, crying spells, agitation, irritability, short temper, overreaction to problems and frustrations, dementia, hallucinations, delirium, delusional ideation, impaired memory and amnesia, aphasia, clouding of consciousness, confusion, disorientation, personality changes, seizures, coma, increased sensitivity to and inability to cope with pain, Parkinson’s like symptoms, anorexia, psychomotor retardation, social withdrawal, depression and gesticulation. The second is the fact that proinflammatory activity has been reported for many mental disturbances. Examples of disturbances where abnormal cytokine activity have been reported include panic disorder, generalized anxiety disorder, post-traumatic stress disorder, anorexia nervosa, obsessive-compulsive disorder, Sydenham’s chorea, Alzheimer’s diseases, mood disorders, schizophrenia, other psychotic disorders and many others.”
Low cortisol and sickness behavior
As many of you may remember, several years ago I wrote an extensive newsletter series that suggested low cortisol and adrenal/HPA disturbances in general were isolated, physiological, functional entities. Based on the information being presented in this series, I now feel that this hypothesis is incorrect. In fact, as theorized by Viljoen and Panzer (2) hypercortisolism is another facet of the general response scenario that is the theme of this series and all of Entry Level Clinical Nutrition™. The authors base this conclusion on the documented relationship between low cortisol and increased cytokine activity, which, as I have mentioned, is a foundational aspect of the acute phase response:
“In addition to hyperactivation, early life experiences may also predispose to hypoactivity of the CRH/HPA-axis. A fact that, at first glance, would appear to directly predispose to inappropriate continuation of the inflammatory response-even in the absence of cortisol resistance. In fact, low cortisol levels may even stimulate the secretion of proinflammatory cytokines.”
Viljoen and Panzer (2) go on to state:
“Hypocortisolemia, often accompanied by baseline sympathetic nervous system hypofunction and low serum serotonin and L-tryptophan levels, is reported for subsets of patients with PTSD, fibromyalgia, chronic fatigue syndrome, chemical intolerance and other stress related somatic disorders.”
Other disorders typically considered to be isolated entities but, in fact, may be manifestations of low cortisol, hyperinflammatory sickness behavior are the following:
“Low cortisol levels have been reported in various types of idiopathic pain and with gastrointestinal disorders for which no organic cause could be found. Typical examples of hypocortisolism in association with idiopathic pain include recurrent headaches, idiopathic chronic pelvic pain in women, recurrent abdominal pain in children and idiopathic pain in combination with functional gastrointestinal disorders.”
Of course, in line with the theme of this series, low cortisol is also a response to adverse circumstances. The authors state:
“In most of these patients, where low cortisol levels were found, there were also histories of poor coping abilities, multiple major stressful life events, and in women with chronic pelvic pain, high rates of physical and sexual abuse. In fact it would appear that most individuals with serious multiple inexplicable health complaints have previously suffered from clusters of severe infectious complications, physical or emotional trauma – factors…seen to have the ability to predispose to hypofunction of the CRH/HPA-axis and to stimulate the production of proinflammatory cytokines.”
With all of the above in mind, Viljoen and Panzer (2) present the following overview statement that sums up their hypothesis that low cortisol and excessive pro-inflammatory activity, two metabolic issues that over the years many (including me) have concluded are isolated entities, are, in fact, two facets of the same response mechanism that creates sickness behavior, which consists of the most commonly seen signs and symptoms in our chronically ill patients:
“To accept that sickness behavior can develop into syndromes marked by multiple subjective health complaints, such as with fibromyalgia, chronic fatigue syndrome or Gulf War Syndrome one would expect to find indications of pro-inflammatory activity. There are reasons to expect that an inflammatory process may be present in those subsets of individuals characterized by hypoactivity of the HPA-axis.”
Furthermore:
“…there are reasons, such as the similarity in symptoms, the apparent history of factors such as infectious or traumatic events, and the suppressed negative feedback on inflammatory cytokine production as a result of low cortisol, to suspect that sickness behavior may render the individual vulnerable to the development of somatoform and related multi-symptom or subjective health complaint disturbances.”
CONCLUDING REMARKS
Hopefully, my review of this excellent paper makes it clear that the biochemistry, endocrinology, and physiology of the acute phase response (APR) which includes, among many factors, increased cytokine levels and aberrant cortisol activity, can specifically create virtually all of the physical and mental/emotional symptoms we typically see in our chronically ill patients. However, before closing, I would like to comment on the quote above that points out that hypocortisolemia is often accompanied by low L-tryptophan. As you may recall, a key aspect of Entry Level Clinical Nutrition™ is that, due to a poor quality, low protein diet and long term catabolic physiology, low levels of protein and amino acids, along with many other factors such as chronic inflammation, are common causational factors in creating the most prevalent signs and symptoms seen in chronically ill patients. Therefore, for me, the fact that Viljoen and Panzer {Viljoen M & Panzer A, 2005 #1111} link low L-tryptophan with hypocortisolemia in creating sickness behavior provides even more proof that, as I have been maintaining with Entry Level Clinical Nutrition™ and advocates of functional medicine have been maintaining for years, signs and symptoms seen with chronic illnesses and their metabolic foundations are not isolated physiologic/metabolic entities but are all manifestations of a response to an adverse environment that has, very simply, gone on too long.
In conclusion, could the above review be accused, given my theme of simplicity, of being overly complicated just to prove a fundamental point? Perhaps. In turn, let me end by, one more time, saluting the idea that, just maybe, chronic illness signs and symptoms and the keys to their resolution are simpler than we ever dared to hope or realize.
“Let’s drink to the salt of the earth!!”
To, hopefully, bring further understanding of the points made by Viljoen and Panzer (2), please see the diagram from their paper that comes after the references in this newsletter.
In the next installment of this series I will present more published literature on this sickness behavior concept that I feel strongly confirms the contention made by Entry Level Clinical Nutrition™ and functional medicine, of which Entry Level Clinical Nutrition™ is an extension, that seemingly isolated chronic illness signs and symptoms are, in reality, part of a common set of metabolic imbalances.
Moss Nutrition Report #235 – 10/01/2010 – PDF Version
REFERENCES
- Owusu-Apenten R. Bioactive Peptides: Applications for Improving Nutrition and Health Boca Raton: CRC Press; 2010.
- Viljoen M & Panzer A. Non-termination of sickness behavior as precipitating factor for mental disorders. Med Hypotheses. 2005;65:316-329.
Moss Nutrition Library 