Entry Level Clinical Nutrition™-Redefining What We Do In A New Age Of Increased Sickness & Increased Scarcity – Part III

The Clinical And Metabolic Foundation: The Acute Phase Response – Definition

“However beautiful the strategy, you should occasionally look at the results”

-Winston Churchill

At the time I first became involved with clinical nutrition, which was 1979 in my dental practice, it was very much in vogue for authors and lecturers in this field to suggest that vitamin and mineral deficiency and/or poor absorption of vitamins and minerals was at the heart of many of the chronic ailments being presented by patients.  In turn, I recommended vitamin/mineral supplements and little else to many patients, expecting to hear many reports of improvements in chief complaints that mirrored the claims of so many authors and lecturers.  Occasionally I did.  But all too often I didn’t.

Nevertheless, I persisted with my enthusiasm with clinical nutrition in relationship to supplemental vitamins and minerals and made it part of my life’s work by selling my practice and gaining full time employment in the professional supplement industry.  Of course, it wasn’t long after joining this industry that authors and lecturers in clinical nutrition who were now company co-workers were proudly and confidently proclaiming that my lack of the above mentioned results were solely due to the fact that I was not recommending the right products made by a company that uses their, exclusive, patented, back to the earth, whole foods, unprocessed, cold processed, raw, low dose, high dose, time tested, brand new, freeze-dried, organic, wild crafted…[Want to play along?  Add your favorite marketing adjective here] method of manufacture that will virtually guarantee resolution of chief complaints with no other interventions.  So with equal pride and confidence I started recommending these products to my customers with the suggestion that these sacred protocols would deliver the almost total improvement in symptoms that were promised.  Occasionally they did.  But all too often they didn’t.  Was I discouraged?  Yes.  For the logic seemed so simple and so profound.  If all chronic illness is a mere manifestation of vitamin and mineral deficiency as so many of my peers in the industry were proclaiming, everyone should get better with a well made multi-nutrient product that uses the exclusive, patented, back to the earth, whole foods, unprocessed, cold processed, raw, low dose…well, I think you get the point.  And occasionally they did. But all too often they didn’t.

Interestingly, in those days my discouragement was compounded by the “experts” in the media and medical journals who, based on exhaustive, peer reviewed, double-blind, placebo-controlled, statistically significant, randomized, prospective, retrospective, epidemiologic, interventive, in vitro, in vivo, human, animal, cell culture, award winning research…[Want to play along?  Add your favorite research parameter here] were smugly proclaiming that vitamin/mineral supplementation was, by comparison, making snake oil seem legitimate.

Nevertheless, while I was discouraged, I was not ready to give up on the idea that vitamin/mineral supplements had value in terms of reducing symptoms and improving quality of life in chronically ill patients.  For, I had a feeling that maybe the issue was not so much one of lack of value of the supplements but one of lack of knowledge about how to use them correctly, which as I suggested in part II of this series, is now being supported by the most current research.  However, back then, this “gut feeling” persisted for quite some time without any real substantiation that it was based on fact until, one day, a fortuitous, somewhat random event occurred in 1994 that not only gave me the substantiation I desired  but changed the course of my life in the world of clinical nutrition.

In the 90s I was very much in a learning mode and, therefore, visited medical libraries whenever possible to find nutritionally oriented research.  One of my visits took me to the hospital where I was born, Blodgett Hospital in Grand Rapids, Michigan.  As I was searching the stacks for interesting nutritional studies, I came upon a somewhat obscure journal entitled New Horizons: The Science and Practice of Acute Medicine, which was a journal devoted to acute care of critically ill patients.  Ordinarily I would not have paid too much attention to such a journal.  However, the subtitle of the May 1994 edition (1) caught my eye:

Frontiers in Critical Care Nutrition

As I leafed through this edition I immediately noticed that, in contrast to many, if not most, medical doctors in the country, the medical doctors who comprised the vast majority of authors of the various papers spoke quite positively about the use of supplemental nutrients, albeit only in the context of critical care.  Which nutrients?  Not obscure nutrients but nutrients we discuss everyday such as antioxidants and magnesium.  Furthermore, they discussed the importance of a nutrient that was just gaining in popularity but was also viewed with great skepticism by the medical community, omega-3 fatty acids.  Even more interestingly, the importance of a supplemental nutrient we hardly ever discussed in those days was emphasized, protein/amino acids.  Then, if this were not exciting enough, I noticed that still more papers were suggesting something about which, as I mentioned, we were receiving a good deal of criticism from the media and medical community – that nutrients have therapeutic value.  In what way?  Two papers suggested nutrients and antioxidants can be used to reduce inflammation.  Another paper discussed nutritional support of gut function.  Still another discussed the relationship between nutrition and wound repair.  Finally, the last paper reviewed a subject that was important to us but one worthy of scorn and ridicule by everyone outside the clinical nutrition community in those days, the role of gut microflora in critical illness.

Of course, many reading this journal at that time and even now might only see differences; how can the needs of massive burn and trauma patients possibly relate to those of patients with chronic fatigue and rheumatoid arthritis?  However, even though I read of no other nutrition experts who supported my position, I only saw similarities.  Over and over again as I read the papers in this journal I saw that the basic metabolic imbalances seen in critical care were fundamentally the same as the ones we had seen for years in chronically ill patients.  More importantly, though, I immediately came to a major realization.  The authors of these papers were absolutely brilliant clinical nutritionists who had an understanding of nutrition, nutritional biochemistry, and their application far beyond that possessed by me and most people I knew in the clinical nutrition community.  In turn, they were getting better results with the therapeutic use of clinical nutrition than we were using fundamentally the same nutrients because they had much better, more sophisticated knowledge of how to use them.  Rather than giving protocols of primarily micronutrients in cure-all, panacea-like fashion to “cure” disease, they were using micronutrients in a very intricate, precise, and integrated manner along with other nutrients such as protein and fatty acids plus other therapeutic modalities such as drugs and surgery not to “cure” the patient but to fine tune metabolism in order to arrive at the best possible result.

From that time on, even though most of my peers continued to feel that critical care nutrition had little relevance to the needs of chronically ill patients, I continued to maintain my “gut feeling” that critical care nutritionists might be the best instructors in terms of teaching me how to best use clinical nutrition to support the needs of chronically ill patients.  In turn, I started reading every book and paper written by critical care nutritionists that I could obtain.  Of course, even as I read all these papers and books over the years that followed, I still felt quite alone with my “gut feeling” about applicability to chronic illness.  Then, about five years ago, I discovered what I had been searching for, the seminal paper by Bengmark (2) that I discussed in part I of this series, “Acute and ‘chronic’ phase reaction – a mother of disease,” which finally demonstrated that I was not alone in my belief.  In fact, metabolically, there are more similarities between acute and chronically ill patients than there are differences and, therefore, we can use the tremendous and expansive body of excellent published research on critical care nutrition as a guiding model to help us cost and time effectively and in a very practical manner address the complexities of chronic illness.


Some introductory concepts

As I mentioned, I feel that critical care nutritionists are often obtaining better clinical results than we are using clinical nutrition to improve the condition of ailing patients because they approach treatment from a different perspective.  Traditionally, we have used clinical nutrition to treat diseases or a group of signs or symptoms.  In contrast, critical care nutritionists are most often treating the body’s metabolic response to disease or other adverse environmental encounters.  This response, which is actually a collection of responses that involve many different physiologic systems ranging from the endocrine to the gastrointestinal to the immune, is most often given the name “Acute phase response” by most critical care nutritionists.  How important is it to focus on this response when using nutritional supplementation to create evidence-based improvements in health?  In “Overview on metabolic adaptation to stress” by Baracos (3) that can be found in the excellent text Nutrition and Critical Care, the following is stated:

“An understanding of the nature of stress is fundamental to the rational design of nutrient mixtures to feed patients whose homeostasis has been altered by one or more stressors.”

Of course, when most of us consider stress and the stress response we tend to think of adrenal function, adrenal hormones such as cortisol and catecholamines, and the relationship between the adrenals and the hypothalamus and pituitary (HPA axis).  However, the reality is that the stress response is a tightly orchestrated, whole body response that, as I mentioned, includes the HPA axis and a whole lot more and is fundamentally the same qualitatively whether the stressor is a severe burn, a cut finger, or frustration from being caught in traffic.  This orchestrated, whole body response to any stressor is what, as I mentioned, the critical care nutritionists call the acute phase response. 

Even more importantly, though, from a clinical nutrition standpoint, this whole body, orchestrated response that includes the adrenal mediated stress response and much more has profound effects on nutrient metabolism.  Baracos (3) states:

“All stresses may be presumed to be associated with characteristic modifications in the metabolism of lipids, carbohydrates, amino acids and micronutrients.”

The author then elaborates on just two of the ways the acute phase response affects nutrient metabolism.  First:

“A number of alterations may take place.  Taking the example of the metabolism of protein and amino acids, multiple modifications of amino acid utilization can occur such that the total and relative amounts of essential amino acids required may change.  In some cases, amino acids normally considered nonessential for humans become conditionally essential in the diet.”

Second, concerning antioxidants:

“Oxidative stress may place a substantial draw on antioxidant nutrients.”

Finally, Baracos (3) makes it clear that a host of other stresses that are secondary to the primary stress that brought the patient to the clinical nutritionist can affect nutritional recommendations:

“Primary stress, as viewed by the attending clinical nutritionist, may be surrounded and complicated by a series of concomitant and previously existing stresses of varying degrees.  The outcome of certain dietary interventions contemplated for the primary stress is inevitably colored by these associated stresses.”

What are these secondary stresses?  As you will see, the author makes it clear that they are those we see everyday in our patients:

  • Fear
  • Anxiety
  • Pain
  • Loss of control
  • Injury
  • Surgery
  • Inflammation
  • Job
  • Money
  • Family
  • Irritable bowel bouts
  • Subclinical nutritional stress

Thus, as I hope you can see, this generalized, whole body response to stress termed the acute phase response is very common in ailing patients and, as I will continue to demonstrate, has a major effect on nutrient metabolism.  Furthermore, as I will demonstrate in future installments of this series, it is this stress response rather than the disease or illness per se that causes many, if not most, of the chief complaints that bring chronically ill patients to our offices.  These signs and symptoms that occur due to the acute phase response have been collectively entitled “sickness behavior” and “sick syndrome,” which will be discussed in detail in a future installment of this series.

A classic example of a common situation where the response rather than the disease causes the chief complaints is the fever associated with influenza.  As most of us know, the fever is the response to the viral infection, not the disease itself.  What you may not know is that the fever is a prototypical example of a classic acute phase response.  In addition, we all know that the fever is a good thing in that it plays a vital role in the body’s plan to rid itself of the virus.  It is only when the fever is prolonged and/or excessive that it becomes bad.  Similarly, the acute phase response is a good thing unless it becomes prolonged and/or excessive.  As has been demonstrated by the critical care nutritionists whose papers I will be reviewing, the aberrations in nutrient metabolism created by a prolonged and/or excessive acute phase response play a major role in creating the signs and symptoms or “sick syndrome” that brings so many chronically ill patients to our offices.  Because critical care nutritionists know this, they have learned from their evidence-based perspective that the best way to use clinical nutrition in terms of improving patient chief complaints and quality of life is not through complicated modalities designed to control or eliminate disease, signs, or symptoms, an approach often used by many in the nutritional community.  Rather, the best way to use clinical nutrition as a tool to improve chief complaints and quality of life is through simple application of basic macro- and micronutrients that eliminate the imbalances created by the response to disease and/or environmental insult collectively called the acute phase response. 

Is primary dietary deficiency and poor absorption, as maintained by so many in the outpatient clinical nutrition community, an issue that needs to be addressed?  Certainly critical care nutritionists regard this as important.  However, in contrast to many outpatient nutritionists who regard it as the sole issue in terms of patient care and improvement of quality of life and thus feel, all to often, we are “home free” once RDA amounts of nutrients are absorbed, critical care nutritionists appear to regard deficiency and absorption as modifying factors in terms of improvements in signs, symptoms, and quality of life.  The central issue is the macro- and micronutrient imbalances created by the acute phase response.  In turn, as I hope to demonstrate, it is their focus on the imbalances caused by the body’s own response to illness rather than on “treating” disease, signs, or symptoms with nutrition, as is often so commonplace with many of our clinical nutrition brethren, which accounts for their superior, research-documented results in terms of patient well being.  Finally, because I now feel so strongly that, in these difficult times, we must now focus only on the best and most practical, research-documented methods of improving patient well-being, I have modeled the seven steps that comprise Entry Level Clinical Nutrition™ after the precepts set by critical care nutritionists that I have briefly highlighted and will explore in detail in the pages that follow.   

The acute phase response (APR) – A detailed explanation

Probably the best demonstration of how important it is to understand the APR in order to gain a full understanding of human illness and how to restore health and well being is the fact that so many authors have written some excellent overviews on the subject with little fanfare or readership from most in outpatient clinical care.  The first I would like to discuss is the book chapter “Acute phase response” by Kushner and Rzewnicki that can be found in the excellent text on inflammation, Inflammation: Basic Principles and Clinical Correlates, Third Edition (4).  To begin this excellent book chapter the authors provide a basic definition:

“The term inflammation refers to the complex, localized responses elicited by a variety of noxious stimuli.  In addition to these localized responses, a vast number of distant systemic changes may also occur if the stimulus is severe enough.  These changes are referred to collectively as the acute phase response (APR), because attention was first focused on them by the discovery of C-reactive protein (CRP) in the serum of patients in the acute phase of pneumococcal pneumonia.  Oswald Avery, in whose laboratory this observation was made in 1930, was excited by this discovery, which he regarded as an important lead to understanding what he termed ‘the chemistry of the host’ – the host response to disease.”

Next, the authors point out the following key point that I have been emphasizing in terms of defining Entry Level Clinical Nutrition™:

“An unfortunate consequence of the use of the term acute phase is that many physicians incorrectly believe that acute phase changes are limited to acute inflammatory states and are not found in chronic inflammation.  In fact, the APR persists in many chronic diseases, resulting in what might seem to be an oxymoron, a chronic APR.”

Kushner and Rzewnicki (4) then make the important point that much of the research on human sickness and stress physiology with which we are familiar is actually an examination of a small portion of the APR:

“Many components of the APR have attracted the interest of highly focused biomedical investigators whose interests encompass only limited aspects of the broad APR.  Two such examples are worthy of note.  First, clinicians whose major concerns are the deleterious consequences of the APR have employed the terms systemic inflammatory response syndrome and sepsis to refer to the hemodynamic changes, diffuse alterations in capillary permeability, coagulation defects, and organ failure that may accompany severe infection.  Second, investigators whose major focus is on the neuroendocrine aspects of the APR have employed the term stress response, originated by Hans Selye in the 1940s.  They define stress as a state of disharmony or threatened homeostasis.  Many of these investigators have been particularly interested in the changes that are induced by psychological and emotional stimuli and that are mediated by corticotrophin-releasing hormone (CRH) and the autonomic nervous system.  As indicated later, these types of stimuli may also influence other, nonneuroendocrine components of the APR.”

As I hope you can see, the quote above makes an extremely important, very clinically relevant point.  What we have been learning and discussing for several years about the stress response in relation to cortisol and other stress hormones such as epinephrine and norepinephrine is actually one small facet of the total body stress response known as the APR.  Therefore, we need to realize that our efforts to optimize stress hormones as a way to improve patient health are not an end in and of itself but merely a good initial effort to address a very large phenomenon.

In the next quote the authors discuss the overall significance of the many facets of the APR:

“A large number of changes, distant from inflammatory sites and involving many organ systems, accompany inflammatory states.  New APR phenomena continue to be recognized, year after year.  In general, these represent the substitution of new ‘set points’ for the homeostatic mechanisms that normally maintain a constant internal environment during good health.  These changes can be categorized as affecting plasma protein synthesis, the neuroendocrine and hematologic systems, metabolic processes, intrahepatic constituents, and nonprotein plasma components.”

Next the authors go into more specific detail on the changes that occur during the APR:

Changes in plasma proteins (Often termed acute phase proteins) – According the Kushner and Rzewnicki (4), any plasma protein that changes either in an upward or downward direction 25% from the level seen in a healthy situation is defined as an “acute phase protein.”  The authors elaborate:

“Both increases (positive acute phase proteins) and decreases (negative acute phase proteins) are seen; changes in different proteins occur at different rates and to different degrees.”

What are some of these proteins and how much do they change?  The authors state:

“A few plasma proteins have long been recognized as positive acute phase proteins.  Ceruloplasmin and the complement components C3 and C4 exhibit relatively modest positive acute phase behavior (typically an increase of about 50%).  Concentrations of haptoglobulin, α1-acid glycoprotein (α1-AGP), α1-protease inhibitor, α1-antichymotrypsin, and fibrinogen ordinarily increase about twofold to fivefold.”

Of course, I realize that most of the proteins mentioned above have little meaning to us clinically.  However, there is one other positive acute phase protein that I suspect you will both readily recognize and appreciate its significance: C-reactive protein (CRP).  Kushner and Rzewnicki (4) note:

“The two major human acute phase proteins…are CRP and serum amyloid A (SAA).  Both are normally present in plasma in only trace amounts but can manifest dramatic increases in rate of synthesis and plasma concentration after stimulation, achieving levels more than 1,000 times normal in some severely infected persons.”

What are the negative acute phase proteins?

“The long-recognized negative acute phase reactants in humans are albumin and transferrin.”

Before continuing, I would like to share some thoughts concerning clinical interpretation of these acute phase proteins.  First, the reality of CRP is that it is much more than an indicator of cardiovascular disease (CVD) that came to the popular consciousness about five years ago or so.  In fact, researchers have known for years that when you see elevated CRP, while it certainly can tell you about CVD, it actually tells you so much more.  Primarily, it is telling you that significant systemic inflammation is present that may be affecting the heart but is probably affecting so much more.  In addition, though, it is providing fairly predictable, albeit indirect, information that other aspects of Entry Level Clinical Nutrition™ may be present and need to be ruled out such as metabolic acidosis, insulin resistance, protein deficiency, micronutrient deficiency, etc.  The second thought I would like to share relates the statement I made in the previous sentence about protein deficiency.  You may wonder how a patient can be protein deficient if so many acute phase proteins, including CRP, are elevated?  The answer relates to an extremely important aspect of the acute phase response.  As I have mentioned, a facet of the APR is “hypermetabolism” or increases in metabolic rate.  This increase in metabolic rate means that RDA levels of protein intake are no longer adequate.  In turn, the chronically ill patient that is experiencing one or more aspects of the acute phase response, as most are, will be protein deficient from a metabolic standpoint.  Another important aspect of the acute phase response in this context relates to a reality I have mentioned several times before.  The APR has the effect of sending both macro- and micronutrients in different directions than what is seen in a healthy situation.  This reality is extremely important to note in the case of protein.  As I mentioned above, many acute phase proteins increase in levels during the APR.  Does this mean that less protein is directed towards key entities such as the gut lining, muscles, and ligaments?  Does this mean that less protein is directed towards the production of phase I and II detox enzymes and digestive enzymes?  As you will see, absolutely!!  Why?  Is it because the body now regards detox as unimportant?  Of course not!!  It means that, since the APR is a whole body stress response, it is currently dealing with a threat it regards as more important than detox.  In turn, with this concept in mind, could it be possible that when you give a protein-based detox drink to a chronically ill patient who has not yet gone through an Entry Level Clinical Nutrition™ protocol and is thus acidotic, inflamed, and insulin resistant, that the protein, instead of being directed to the rebuilding of phase I and II detox enzymes, is directed towards the production of more acute phase proteins?  Absolutely!!  Could the fact that the protein you gave is doing more to increase production of pro-inflammatory acute phase proteins than increase levels of detox enzymes explain why your patient is experiencing flu-like “detox reaction” symptomatology?  I feel the answer to this question is obvious.

Changes in neuroendocrine function – Many, including me, have written extensively on the neuroendocrinologic changes that occur during APR.  Nevertheless, I would like to present this quote from the chapter by Kushner and Rzewnicki (4) that provides a brief overview of the issue:

“Among the neuroendocrine changes are fever (literally a resetting of the thermostat), somnolence, anorexia, the ‘sick euthyroid syndrome’, and altered synthesis of many endocrine hormones including CRH, glucagons, insulin, corticotrophin (ACTH), cortisol, adrenal catecholamines, growth hormone, thyroid stimulating hormone, thyroxin, aldosterone, and arginine vasopressin.”

Changes in the hematopoietic system

“Involvement of the hematopoietic system includes leukocytosis, thrombocytosis, and the ‘anemia of chronic disease’ (better designated the ‘anemia of chronic inflammation’), which is seen in most patients with chronic inflammatory states.”

Metabolic changes

Metabolic changes include decreased gluconeogenesis, negative nitrogen balance, and substantial alterations in lipid metabolism.  An extreme consequence of the latter two conditions is the cachexia seen in persons with severe chronic infection or advanced malignancy.  Osteoporosis appears to belong in this category also, as does the reported increase in blood leptin levels in inflammatory states.”

Changes in the liver – While I realize that there are several “two dollar words” in the quotes that follow, it is my hope that they will give you a better understanding of why liver detox efforts can be very unpredictable in chronically ill, chronically inflamed patients when issues that form the basis of Entry Level Clinical Nutrition ™ such as metabolic acidosis, insulin resistance, inflammation, and sarcopenia have not been previously addressed to any meaningful extent:

“A very large number of enzymatic, morphologic, and chemical changes occur in the liver, including increases in metallothionein, inducible nitric oxide synthase (iNOS), heme oxygenase, manganese superoxide dismutase, hepatocyte growth factor activator, and glutathione.”

Furthermore, and even more importantly in relationship to detoxification procedures:

“Decreased expression of many members of the cytochrome P450 family is seen, but several others are induced.”

Changes in plasma nutrient status – I feel the quote that follows is particularly important to note for clinical nutrients since, as I have mentioned repeatedly, metabolic “redirecting” of nutrients during the APR is, as far as I know, hardly ever considered when determining dietary or supplemental recommendations by many if not most clinical nutritionists:

“…changes in nonprotein plasma constituents include hypozincemia, hypoferremia, hypercupremia, increased retinol, and increased glutathione secondary to increased hepatic levels.”

Factors that can induce an acute phase response

As I have mentioned, contrary to the belief of many, the APR is not just a phenomenon that occurs in the intensive care unit in response to severe burns or trauma.  Rather, as the quote below suggests, it is something that accompanies many of the health care situations we encounter everyday in our practices:

“Recognition of an acute phase phenomenon requires in vivo induction by any of a variety of inflammatory stimuli.  In humans, stimuli that commonly give rise to the APR include bacterial and, to a lesser extent, viral infection; surgical or other trauma; neoplasm; burn injury; tissue infarction; various immunologically mediated…inflammatory states; strenuous exercise; heatstroke; and childbirth.  Several psychiatric illnesses and psychological stress are associated with acute phase changes, as is chronic fatigue syndrome…”

Specific inflammatory factors that can affect production of acute phase proteins

Next, Kushner and Rzewnicki (4) discuss the specific cytokines that are involved in the induction of acute phase proteins:

“A number of different cytokines, alone or in a network, may influence acute phase protein synthesis.  These cytokines are elicited during, and participate in, the inflammatory process.  They include IL-6, IL-1, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β).  Some of these cytokines are regarded as proinflammatory, while others are regarded as anti-inflammatory.  Inflammation-associated cytokines may be produced by many different cells, including monocytes, macrophages, fibroblasts, endothelial cells, T lymphocytes, and epithelial cells, but macrophages and monocytes at inflammatory sites clearly play major roles.”

It is also interesting to note that of all the cytokines mentioned above, IL-6 may rank of greatest importance clinically.  Why?  First, it is a major inducer of acute phase protein synthesis.  Second, and more importantly, though, consider the following:

“Psychological stresses may stimulate IL-6 production through release of catecholamines.”

This fact, of course, brings up two important questions.  First, can patients think themselves into a situation where significant amounts of acute phase proteins such as CRP are being produced?  Absolutely!!  Second, in those patients who think themselves into elevations of CRP and other acute phase proteins, can this situation be reversed using dietary changes and supplements alone?  My guess is that you can derive the answer to this question by just “going down memory lane” and thinking about your most difficult patients.

Inducers of acute phase phenomena other than production of acute phase proteins

In this section Kushner and Rzewnicki (4) discuss the various factors, which are primarily cytokines, that induce the various acute phase response changes mentioned above.

Intrahepatic changes – According to the authors:

“Many intracellular hepatic constituents are altered during the APR.  The intracellular heavy metal-binding protein metallothionein is induced by IL-6, but not by IL-1α, with concomitant increase in cellular zinc content and secondary hypozincemia.  IL-6 induces transglutaminase activity.  Cytokines increase synthesis of two physiologically important antioxidants; manganese superoxide dismutase, which is synergistically induced in hepatocytes by IL-6, IL-1, TNF-α, and microsomal heme oxygenase, which is induced by IL-6 in Hep3B cells.”


“IL-1β, IL-6, and interferons are capable of altering the expression of a number of hepatic P450 cytochromes during inflammatory states.”

As I hope you can see, inflammatory cytokines that are related to the APR have a powerful impact on key liver functions that we focus upon almost daily such as heavy metal elimination, detoxification of chemical toxins, and quenching of free radicals.  In turn, if we are not addressing these cytokine-mediated changes that are part of the APR via procedures advocated in Entry Level Clinical Nutrition™, it should not be a surprise when patient outcomes related to efforts to optimize liver function are somewhat unpredictable.

Fever – The authors state:

“…the final step in the induction of fever requires that IL-6, derived from the endothelium of the hypothalamic circumventricular organs, access the thermoregulatory center in the preoptic region.”

Neuroendocrine changes – According to Kushner and Rzewnicki (4):

“Changes in the neuroendocrine system that occur as a result of both inflammatory stimuli and ‘stress’ unrelated to inflammation reflect complex interactions between inflammation-associated cytokines on the one hand and the hypothalamic-pituitary-adrenal axis and other components of the neuroendocrine system on the other.  IL-6, IL-1, and TNF-α are induced by inflammatory stimuli (or, in noninflammatory states, apparently by catecholamines) and activate the hypothalamic-pituitary-adrenal axis by stimulating the corticotrophin secretagogues CRH and arginine vasopressin, with consequent production of ACTH and cortisol.”

While I realize that the above quote is somewhat complicated, I hope it conveys to you that there is an important and very intimate relationship between stress endocrinology and inflammatory activity.

Next, the authors discuss specific aspects of the neuroendocrine changes that occur during the APR.  First, concerning somnolence and lethargy they state:

“IL-1 and TNF-α are both somnogenic on injection into the lateral cerebral ventricle of rabbits, enhancing non-rapid eye movement (non-REM) sleep while inhibiting REM sleep, and presumably directly affecting the anterior hypothalamic preoptic area.”

Concerning anorexia (loss of appetite), the following is noted:

“Older data suggest that local TNF-α production in the brain may also participate in the development of anorexia.”

As I hope you can see, the above quotes present extremely important clinical information.  First, inflammation associated with the APR can create one of the most common complaints in chronically ill patients, not feeling rested and refreshed after sleeping.  As most of you know, restful sleep, which is the type of sleep most conducive to anabolic reparative activity, is mainly REM sleep.  Since, inflammation associated with the APR stimulates non-REM sleep and inhibits REM sleep, to me it should be clear that reduction of inflammation, a key step in Entry Level Clinical Nutrition™ is absolutely essential to predictably address poor sleep quality, not only a major chief complaint but a major underlying contributing factor to so many other chief complaints.  Second, loss of appetite, or anorexia, is a major problem that occurs very often in the elderly and can certainly have a significant negative impact on compliance with our dietary and supplemental recommendations.  Of course, all too often we have, in the past, addressed this issue as being primarily psychological and motivational in nature.  While these factors certainly need to be addressed with loss of appetite, the knowledge that, unbeknownst to many, inflammation and the APR can also play a crucial role, gives us a much larger array of modalities with which we can address this major roadblock to successful nutritional therapy.

Changes in the hematopoietic system – Given that I have received numerous inquiries over the years about chronically ill patients whose anemia symptoms and signs such as elevated MCV and MCH did not normalize with the usual supplemental program of iron, folate, vitamin B12 etc., I feel knowledge of inflammation and the APR as another major cause of red cell imbalances is extremely important.  On this issue Kushner and Rzewnicki (4) state:

“The mechanisms responsible for the anemia of chronic inflammation, although somewhat poorly understood, include decreased proliferation of red cell progenitors and inadequate erythropoietin production, both caused at least in part by inflammation-associated cytokines.”

Concerning the related finding of low platelets, the authors state:

“Another acute phase phenomenon, thrombocytosis, also appears to be caused by IL-6.”

Then, on the largely ignored issue of low serum iron that is not related to dietary intake or absorption, the following is noted:

Hypoferremia seen during the APR is largely caused by iron sequestration in the reticuloendothelial system.  This sequestration appears to result from increased apoferritin translation in macrophages induced by IL-4 and IL-13, with consequent inhibition of iron release.”

Metabolic changes – As we know, the metabolic changes such as cachexia and osteoporosis are incredibly important clinically.  What role does inflammation and the APR play in these issues?  Kushner and Rzewnicki (4) first state the following about cachexia and muscle loss:

“Cachexia, the loss of body mass that accompanies chronic inflammatory states and cancer, results from decreases in skeletal muscle, fat tissue, and bone mass.  There is considerable evidence that IL-1, IL-6, TNF-α, and IFN-γ all contribute to these processes.  Loss of skeletal muscle is caused by the combination of decreased protein synthesis and increased proteolysis.”

Specifically concerning the loss of bone mass, the authors state the following:

Osteoporosis is also a consequence of chronic inflammation.  Several inflammation-associated cytokines stimulate bone resorption and suppress osteocalcin expression.”

Before continuing, please note again the statement about osteocalcin, which is now getting more attention due to the fact that its activity is dependent upon vitamin K.  As I hope you can see, the benefits of the increasingly popular practice of supplementing with vitamin K to maintain or improve bone mass can potentially be negated if inflammation and the APR are not also addressed.

Next, the authors address the APR and lipid metabolism.  Hopefully, the incredible clinical importance of the following quote is self evident and needs no further elaboration:

Lipid metabolism is markedly altered during the APR.  Loss of fat tissue results, at least in part, from inhibition of lipoprotein lipase production by cytokines.  Increases in serum triglycerides, very-low-density lipoproteins, and low-density lipoproteins are seen.  Effects on high-density lipoproteins (HDLs) are particularly striking.  HDL levels fall during inflammatory states, and serum amyloid A may largely displace apolipoprotein I (apo A-I) in HDL.”

As many of you know, apo A-I is considered to be a major HDL constituent that confers protection from cardiovascular disease.

Finally, in the section on metabolic changes, the authors discuss the relationship between the APR and postsurgical immunosuppression and thyroid dysfunction:

“IL-10, regarded as an anti-inflammatory cytokine, has been implicated in the pathogenesis of postoperative immunosuppression, which is probably also an acute phase phenomenon.  Inflammation-associated cytokines play a major role in the pathogenesis of septic shock and are believed to play a role in the ‘sick euthyroid syndrome.'”


I hope you can see from the above quotes that much of what we have traditionally treated as isolated diseases, syndromes, and conditions is actually part of a coordinated response by the body to a harmful or threatening situation.  In turn, I hope you can also see that when these issues are considered as part of a whole instead of isolated entities, potential exists to greatly simplify both diagnosis and treatment.  In particular, as has been emphasized, this simplification revolves around one key goal, reduction of inflammation, which is now considered by many experts in the health care community to be ubiquitous in chronically ill patients no matter what the clinical presentation.  In turn, I hope it is now obvious why reduction of chronic inflammation is one of the most crucial aspects of Entry Level Clinical Nutrition™.  Finally, I hope it is obvious why simple and cost effective efforts to reduce inflammation such as ruling out food sensitivities, improving gut function, and supplementing with anti-inflammatory herbs and enzymes can have such a major impact on patient outcome and resolution of chief complaints no matter what the clinical presentation in chronically ill patients.

In the next installment of this series I will continue this discussion on the APR, starting with a presentation of the conclusion to the book chapter by Kushner and Rzewnicki (4).  In this conclusion, which may be the most interesting portion of the chapter, the authors discuss why the APR exists, since, on the surface, it appears to be a primarily harmful phenomenon.

Moss Nutrition Report #231 – 02/01/2010 – PDF Version


  1. Zaloga GP. New Horizons: The Science and Practice of Acute Medicine: Frontiers in Critical Care Nutrition. Vol. 2; 1994.
  2. Bengmark S. Acute and “chronic” phase reaction – a mother of disease. Clin Nutr. 2004;23:1256-1266.
  3. Baracos VE. Overview on metabolic adaptation to stress. In: Cynober L & Moore FA, ed. Nutrition and Critical Care. Vol. 8. Vevey, Switzerland: Karger; 2003:1-13.
  4. Kushner I & Rzewnicki. Acute phase response. In: Gallin JI & Snyderman R, ed. Inflammation: Basic Principles and Clinical Correlations, 3rd Edition. Philadephia: Lippincott Williams & Wilkins; 1999:317-329.